User login
An unusual case of primary cardiac prosthetic valve-associated lymphoma
Primary cardiac tumors are extremely rare neoplasms with an incidence of less than 0.4%.1-3 Primary cardiac lymphoma (PCL), the majority of which is non-Hodgkin lymphoma, accounts for around 2% of cardiac tumors and less than 0.5% of extranodal lymphomas.1,4-6 Primary lymphoma involving cardiac valves has been described in few case reports and small case series owing to its rarity.7-10 Most cases of PCL present with manifestations of congestive heart failure or cardiac arrhythmias,11 whereas primary valve-associated lymphoma (PV-AL) is usually diagnosed incidentally during valve repair or replacement. The pathophysiology remains unclear, but a few cases have been associated with Epstein Barr virus (EBV).7 Cases previously described in the literature carried an overall poor prognosis and to date there is no standardized treatment approach. We provide here an unusual case of primary prosthetic valve-associated cardiac large B-cell lymphoma, which was successfully treated with adjuvant chemotherapy after valve repair and which resulted in an excellent long-term outcome.
Case presentation and summary
The patient presented in 2012 as a 65-year-old man with a history of ascending aortic aneurysm with secondary aortic insufficiency who in 2004 had undergone composite valve replacement of the aortic valve (AV) root and ascending aorta with a St Jude Toronto root. In June 2011, he was found to have a right parietal intraparenchymal hemorrhage that was thought to be a thromboembolic hemorrhagic ischemic stroke. In March 2012, he had routine follow-up brain magnetic resonance imaging that incidentally showed a left frontal ischemic stroke with hemorrhagic conversion. In June 2012, he was found to have first degree atrioventricular block with episodic runs of supraventricular tachycardia.
In September 2012, transthoracic echocardiography was done for further evaluation of possible recurrent cryptogenic strokes. The results showed a hypo-echogenic mass within the proximal ascending aortic root, but this was not confirmed on transesophageal echocardiography. A chest computed-tomography (CT) scan was therefore performed, and it showed aneurysmal dilatation of the aortic root with an irregular marginal filling defect just above the AV suggestive of intraluminal thrombus. The patient was placed on full anticoagulation with warfarin and referred for cardiothoracic surgery to consider graft and valve replacement. However, 3 weeks later and before the surgery, the patient developed a third thromboembolic ischemic event (transient ischemic attack). The recurrent strokes were attributed to thromboembolic events secondary to prosthetic AV thrombosis.
A repeat transthoracic echocardiography was significant for an abnormal AV bioprosthesis with associated thrombus extending to the ascending aorta. Surgical excision and replacement of the AV conduit explant were performed in November 2012. The final pathology was consistent with EBV-associated large B-cell lymphoma (Figure). The initial staging evaluation, including a CT and positron-emission tomography scan and bone marrow biopsy, was negative for any systemic disease. The patient received 4 cycles of R-CHOP-21 (rituximab 375 mg/m2, cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2 , vincristine 2 mg, and prednisone 100 mg) every 3 weeks in an “adjuvant” setting (because patient had no evidence of disease when given the systemic chemotherapy). The patient tolerated chemotherapy well without significant complications, and he is now over 36 months post-treatment without evidence of recurrent disease.
Discussion
Cardiac lymphoma limited only to prosthetic valves is rare, but it has been reported increasingly over the past few years. Until 2010, only six cases of PV-AL had been reported in the literature.7 Including our case, we identified four additional PubMed-indexed cases (using a PubMed search through February 2015). The patient characteristics and treatments received for all identified cases are described in the accompanying Table. The pathology from all of the cases revealed non-Hodgkin lymphoma of large B-cell subtype. PV-AL predominated among men (60%) and older patients with a median age of 62.5 years at diagnosis (range, 48-80 years). Patients had a median duration of 8 years (range, 4-24 years) from date of prosthesis placement to date of lymphoma diagnosis. The three most common presenting manifestations were valvular dysfunction, stroke, and congestive heart failure. All of the patients had surgical intervention on initial presentation. However, management after surgery was not uniform, with only 3 patients reported to have received systemic chemotherapy (Table). None of the patients received adjuvant radiation therapy. Calculated from date of diagnosis, survival duration ranged from less than a month7 to more than 36 months (as reported in our case).
The pathophysiology of PV-AL is not well understood given the rarity of the condition. Similar to other prosthetic-related neoplasms (metallic implants, breast implants),12-14 it has been hypothesized that chronic inflammation and EBV infection may play an essential role in the pathogenesis of this entity. Further, it has been suggested that Dacron, which is used in composite cardiac valve replacements, is carcinogenic and may play a role in some cases.7,15 PV-AL should be highly considered in the differential diagnosis of a suspicious prosthetic valve mass. Various imaging modalities, including echocardiography, CT, and magnetic resonance imaging have been described to have a role in the preoperative evaluation of cardiac tumors by assessing the cardiac function and defining the location and extent of the cardiac tumors.16-19
Given the rarity of this disease entity, there is no standardized approach for treatment. Surgical resection along with repair or replacement of primary involved prosthetic valve is essential for initial treatment. However, there is no consensus about the best approach for subsequent therapy. We cannot be conclusive about the optimum treatment, because of the limited number of published cases, but based on our reading of those cases, it would seem that early surgical intervention and “adjuvant” systemic therapy may have influenced prognosis. We speculate that poor outcomes in the first 6 months were most likely related to primary cardiopulmonary deterioration, whereas later poor outcomes were more likely to be attributable to recurrent lymphoma, particularly for patients who received suboptimal systemic chemotherapy treatment after surgery. All 3 patients who received chemotherapy had no evidence of recurrent disease at last follow-up. Of the 4 patients who received no chemotherapy and survived longer than 6 months (all except 1 died; Table), 2 had recurrent valve lymphoma, 1 had secondary systemic lymphoma, and 1 died of metastatic breast cancer. Those outcomes are in contrast to the 2 out of 3 patients who received adjuvant chemotherapy and who were reported to be alive at 16 and 36 months after diagnosis.
In conclusion, cardiac PV-AL is an increasingly recognized entity that warrants greater awareness among health care providers for early diagnosis and timely surgical intervention. Most of the cases are large B-cell lymphoma. Similar to patients with limited-stage DLBCL, fit patients should be highly considered for “adjuvant” systemic chemotherapy to optimize long-term outcomes. Reporting of similar cases is highly encouraged to better define this rare iatrogenic malignancy.
1. Hudzik B, Miszalski-Jamka K, Glowacki J, et al. Malignant tumors of the heart. Cancer epidemiol. 2015;39(5):665-672.
2. Travis WD, Brambilla E, Müller-Hermelink HK, Harris CC, eds. Pathology and genetics of tumours of the lung, pleura, thymus and heart. Lyon, France: IARC Press; 2004.
3. Reynen K. Frequency of primary tumors of the heart. Am J Cardiol. 1996;77(1):107.
4. Neragi-Miandoab S, Kim J, Vlahakes GJ. Malignant tumours of the heart: a review of tumour type, diagnosis and therapy. Clin Oncol. 2007;19(10):748-756.
5. Butany J, Nair V, Naseemuddin A, Nair GM, Catton C, Yau T. Cardiac tumours: diagnosis and management. Lancet Oncol. 2005;6(4):219-228.
6. Burke A, Virmani R. Tumors of the heart and great vessels. In: Atlas of tumor pathology, 3rd Series, Fascicle 16. Washington, DC: Armed Forces Institute of Pathology, 1996.
7. Miller DV, Firchau DJ, McClure RF, Kurtin PJ, Feldman AL. Epstein-Barr virus-associated diffuse large B-cell lymphoma arising on cardiac prostheses. Am J Surg Pathol. 2010;34(3):377-384.
8. Albat B, Messner-Pellenc P, Thevenet A. Surgical treatment for primary lymphoma of the heart simulating prosthetic mitral valve thrombosis. J Thoracic Cardiovasc Surg. 1994;108(1):188-189.
9. Bagwan IN, Desai S, Wotherspoon A, Sheppard MN. Unusual presentation of primary cardiac lymphoma. Interact Cardiovasc Thorac Surg. 2009;9(1):127-129.
10. Durrleman NM, El-Hamamsy I, Demaria RG, Carrier M, Perrault LP, Albat B. Cardiac lymphoma following mitral valve replacement. Ann Thorac Surg. 2005;79(3):1040-1042.
11. Petrich A, Cho SI, Billett H. Primary cardiac lymphoma: an analysis of presentation, treatment, and outcome patterns. Cancer. 2011;117(3):581-589.
12. Cheuk W, Chan AC, Chan JK, Lau GT, Chan VN, Yiu HH. Metallic implant-associated lymphoma: a distinct subgroup of large B-cell lymphoma related to pyothorax-associated lymphoma? Am J Surg Pathol. 2005;29(6):832-836.
13. Roden AC, Macon WR, Keeney GL, Myers JL, Feldman AL, Dogan A. Seroma-associated primary anaplastic large-cell lymphoma adjacent to breast implants: an indolent T-cell lymphoproliferative disorder. Mod Pathol. 2008;21(4):455-463.
14. de Jong D, Vasmel WL, de Boer JP, et al. Anaplastic large-cell lymphoma in women with breast implants. JAMA. 2008;300(17):2030-2035.
15. Durrleman N, El Hamamsy I, Demaria R, Carrier M, Perrault LP, Albat B. Is Dacron carcinogenic? Apropos of a case and review of the literature [In French]. Arch Mal Coeur Vaiss. 2004 Mar;97(3):267-270.16. Peters PJ, Reinhardt S. The echocardiographic evaluation of intracardiac masses: a review. J Am Soc Echocard. 2006;19(2):230-240.
17. Gulati G, Sharma S, Kothari SS, Juneja R, Saxena A, Talwar KK. Comparison of echo and MRI in the imaging evaluation of intracardiac masses. Cardiovasc Intervent Radiol. 2004;27(5):459-469.
18. Krombach GA, Spuentrup E, Buecker A, et al. Heart tumors: magnetic resonance imaging and multislice spiral CT [In German]. RoFo. 2005;177(9):1205-1218.
19. Hoey ET, Mankad K, Puppala S, Gopalan D, Sivananthan MU. MRI and CT appearances of cardiac tumours in adults. Clin Radiol. 2009;64(12):1214-1230.
20. Bonnichsen CR, Dearani JA, Maleszewski JJ, Colgan JP, Williamson EE, Ammash NM. Recurrent Epstein-Barr virus-associated diffuse large B-cell lymphoma in an ascending aorta graft. Circulation. 2013;128(13):1481-1483.
21. Berrio G, Suryadevara A, Singh NK, Wesly OH. Diffuse large B-cell lymphoma in an aortic valve allograft. Tex Heart Inst J. 2010;37(4):492-493.
22. Gruver AM, Huba MA, Dogan A, Hsi ED. Fibrin-associated large B-cell lymphoma: part of the spectrum of cardiac lymphomas. Am J Surg Pathol. 2012;36(10):1527-1537.
23. Farah FJ, Chiles CD. Recurrent primary cardiac lymphoma on aortic valve allograft: implications for therapy. Tex Heart Inst J. 2014;41(5):543-546.
Primary cardiac tumors are extremely rare neoplasms with an incidence of less than 0.4%.1-3 Primary cardiac lymphoma (PCL), the majority of which is non-Hodgkin lymphoma, accounts for around 2% of cardiac tumors and less than 0.5% of extranodal lymphomas.1,4-6 Primary lymphoma involving cardiac valves has been described in few case reports and small case series owing to its rarity.7-10 Most cases of PCL present with manifestations of congestive heart failure or cardiac arrhythmias,11 whereas primary valve-associated lymphoma (PV-AL) is usually diagnosed incidentally during valve repair or replacement. The pathophysiology remains unclear, but a few cases have been associated with Epstein Barr virus (EBV).7 Cases previously described in the literature carried an overall poor prognosis and to date there is no standardized treatment approach. We provide here an unusual case of primary prosthetic valve-associated cardiac large B-cell lymphoma, which was successfully treated with adjuvant chemotherapy after valve repair and which resulted in an excellent long-term outcome.
Case presentation and summary
The patient presented in 2012 as a 65-year-old man with a history of ascending aortic aneurysm with secondary aortic insufficiency who in 2004 had undergone composite valve replacement of the aortic valve (AV) root and ascending aorta with a St Jude Toronto root. In June 2011, he was found to have a right parietal intraparenchymal hemorrhage that was thought to be a thromboembolic hemorrhagic ischemic stroke. In March 2012, he had routine follow-up brain magnetic resonance imaging that incidentally showed a left frontal ischemic stroke with hemorrhagic conversion. In June 2012, he was found to have first degree atrioventricular block with episodic runs of supraventricular tachycardia.
In September 2012, transthoracic echocardiography was done for further evaluation of possible recurrent cryptogenic strokes. The results showed a hypo-echogenic mass within the proximal ascending aortic root, but this was not confirmed on transesophageal echocardiography. A chest computed-tomography (CT) scan was therefore performed, and it showed aneurysmal dilatation of the aortic root with an irregular marginal filling defect just above the AV suggestive of intraluminal thrombus. The patient was placed on full anticoagulation with warfarin and referred for cardiothoracic surgery to consider graft and valve replacement. However, 3 weeks later and before the surgery, the patient developed a third thromboembolic ischemic event (transient ischemic attack). The recurrent strokes were attributed to thromboembolic events secondary to prosthetic AV thrombosis.
A repeat transthoracic echocardiography was significant for an abnormal AV bioprosthesis with associated thrombus extending to the ascending aorta. Surgical excision and replacement of the AV conduit explant were performed in November 2012. The final pathology was consistent with EBV-associated large B-cell lymphoma (Figure). The initial staging evaluation, including a CT and positron-emission tomography scan and bone marrow biopsy, was negative for any systemic disease. The patient received 4 cycles of R-CHOP-21 (rituximab 375 mg/m2, cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2 , vincristine 2 mg, and prednisone 100 mg) every 3 weeks in an “adjuvant” setting (because patient had no evidence of disease when given the systemic chemotherapy). The patient tolerated chemotherapy well without significant complications, and he is now over 36 months post-treatment without evidence of recurrent disease.
Discussion
Cardiac lymphoma limited only to prosthetic valves is rare, but it has been reported increasingly over the past few years. Until 2010, only six cases of PV-AL had been reported in the literature.7 Including our case, we identified four additional PubMed-indexed cases (using a PubMed search through February 2015). The patient characteristics and treatments received for all identified cases are described in the accompanying Table. The pathology from all of the cases revealed non-Hodgkin lymphoma of large B-cell subtype. PV-AL predominated among men (60%) and older patients with a median age of 62.5 years at diagnosis (range, 48-80 years). Patients had a median duration of 8 years (range, 4-24 years) from date of prosthesis placement to date of lymphoma diagnosis. The three most common presenting manifestations were valvular dysfunction, stroke, and congestive heart failure. All of the patients had surgical intervention on initial presentation. However, management after surgery was not uniform, with only 3 patients reported to have received systemic chemotherapy (Table). None of the patients received adjuvant radiation therapy. Calculated from date of diagnosis, survival duration ranged from less than a month7 to more than 36 months (as reported in our case).
The pathophysiology of PV-AL is not well understood given the rarity of the condition. Similar to other prosthetic-related neoplasms (metallic implants, breast implants),12-14 it has been hypothesized that chronic inflammation and EBV infection may play an essential role in the pathogenesis of this entity. Further, it has been suggested that Dacron, which is used in composite cardiac valve replacements, is carcinogenic and may play a role in some cases.7,15 PV-AL should be highly considered in the differential diagnosis of a suspicious prosthetic valve mass. Various imaging modalities, including echocardiography, CT, and magnetic resonance imaging have been described to have a role in the preoperative evaluation of cardiac tumors by assessing the cardiac function and defining the location and extent of the cardiac tumors.16-19
Given the rarity of this disease entity, there is no standardized approach for treatment. Surgical resection along with repair or replacement of primary involved prosthetic valve is essential for initial treatment. However, there is no consensus about the best approach for subsequent therapy. We cannot be conclusive about the optimum treatment, because of the limited number of published cases, but based on our reading of those cases, it would seem that early surgical intervention and “adjuvant” systemic therapy may have influenced prognosis. We speculate that poor outcomes in the first 6 months were most likely related to primary cardiopulmonary deterioration, whereas later poor outcomes were more likely to be attributable to recurrent lymphoma, particularly for patients who received suboptimal systemic chemotherapy treatment after surgery. All 3 patients who received chemotherapy had no evidence of recurrent disease at last follow-up. Of the 4 patients who received no chemotherapy and survived longer than 6 months (all except 1 died; Table), 2 had recurrent valve lymphoma, 1 had secondary systemic lymphoma, and 1 died of metastatic breast cancer. Those outcomes are in contrast to the 2 out of 3 patients who received adjuvant chemotherapy and who were reported to be alive at 16 and 36 months after diagnosis.
In conclusion, cardiac PV-AL is an increasingly recognized entity that warrants greater awareness among health care providers for early diagnosis and timely surgical intervention. Most of the cases are large B-cell lymphoma. Similar to patients with limited-stage DLBCL, fit patients should be highly considered for “adjuvant” systemic chemotherapy to optimize long-term outcomes. Reporting of similar cases is highly encouraged to better define this rare iatrogenic malignancy.
Primary cardiac tumors are extremely rare neoplasms with an incidence of less than 0.4%.1-3 Primary cardiac lymphoma (PCL), the majority of which is non-Hodgkin lymphoma, accounts for around 2% of cardiac tumors and less than 0.5% of extranodal lymphomas.1,4-6 Primary lymphoma involving cardiac valves has been described in few case reports and small case series owing to its rarity.7-10 Most cases of PCL present with manifestations of congestive heart failure or cardiac arrhythmias,11 whereas primary valve-associated lymphoma (PV-AL) is usually diagnosed incidentally during valve repair or replacement. The pathophysiology remains unclear, but a few cases have been associated with Epstein Barr virus (EBV).7 Cases previously described in the literature carried an overall poor prognosis and to date there is no standardized treatment approach. We provide here an unusual case of primary prosthetic valve-associated cardiac large B-cell lymphoma, which was successfully treated with adjuvant chemotherapy after valve repair and which resulted in an excellent long-term outcome.
Case presentation and summary
The patient presented in 2012 as a 65-year-old man with a history of ascending aortic aneurysm with secondary aortic insufficiency who in 2004 had undergone composite valve replacement of the aortic valve (AV) root and ascending aorta with a St Jude Toronto root. In June 2011, he was found to have a right parietal intraparenchymal hemorrhage that was thought to be a thromboembolic hemorrhagic ischemic stroke. In March 2012, he had routine follow-up brain magnetic resonance imaging that incidentally showed a left frontal ischemic stroke with hemorrhagic conversion. In June 2012, he was found to have first degree atrioventricular block with episodic runs of supraventricular tachycardia.
In September 2012, transthoracic echocardiography was done for further evaluation of possible recurrent cryptogenic strokes. The results showed a hypo-echogenic mass within the proximal ascending aortic root, but this was not confirmed on transesophageal echocardiography. A chest computed-tomography (CT) scan was therefore performed, and it showed aneurysmal dilatation of the aortic root with an irregular marginal filling defect just above the AV suggestive of intraluminal thrombus. The patient was placed on full anticoagulation with warfarin and referred for cardiothoracic surgery to consider graft and valve replacement. However, 3 weeks later and before the surgery, the patient developed a third thromboembolic ischemic event (transient ischemic attack). The recurrent strokes were attributed to thromboembolic events secondary to prosthetic AV thrombosis.
A repeat transthoracic echocardiography was significant for an abnormal AV bioprosthesis with associated thrombus extending to the ascending aorta. Surgical excision and replacement of the AV conduit explant were performed in November 2012. The final pathology was consistent with EBV-associated large B-cell lymphoma (Figure). The initial staging evaluation, including a CT and positron-emission tomography scan and bone marrow biopsy, was negative for any systemic disease. The patient received 4 cycles of R-CHOP-21 (rituximab 375 mg/m2, cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2 , vincristine 2 mg, and prednisone 100 mg) every 3 weeks in an “adjuvant” setting (because patient had no evidence of disease when given the systemic chemotherapy). The patient tolerated chemotherapy well without significant complications, and he is now over 36 months post-treatment without evidence of recurrent disease.
Discussion
Cardiac lymphoma limited only to prosthetic valves is rare, but it has been reported increasingly over the past few years. Until 2010, only six cases of PV-AL had been reported in the literature.7 Including our case, we identified four additional PubMed-indexed cases (using a PubMed search through February 2015). The patient characteristics and treatments received for all identified cases are described in the accompanying Table. The pathology from all of the cases revealed non-Hodgkin lymphoma of large B-cell subtype. PV-AL predominated among men (60%) and older patients with a median age of 62.5 years at diagnosis (range, 48-80 years). Patients had a median duration of 8 years (range, 4-24 years) from date of prosthesis placement to date of lymphoma diagnosis. The three most common presenting manifestations were valvular dysfunction, stroke, and congestive heart failure. All of the patients had surgical intervention on initial presentation. However, management after surgery was not uniform, with only 3 patients reported to have received systemic chemotherapy (Table). None of the patients received adjuvant radiation therapy. Calculated from date of diagnosis, survival duration ranged from less than a month7 to more than 36 months (as reported in our case).
The pathophysiology of PV-AL is not well understood given the rarity of the condition. Similar to other prosthetic-related neoplasms (metallic implants, breast implants),12-14 it has been hypothesized that chronic inflammation and EBV infection may play an essential role in the pathogenesis of this entity. Further, it has been suggested that Dacron, which is used in composite cardiac valve replacements, is carcinogenic and may play a role in some cases.7,15 PV-AL should be highly considered in the differential diagnosis of a suspicious prosthetic valve mass. Various imaging modalities, including echocardiography, CT, and magnetic resonance imaging have been described to have a role in the preoperative evaluation of cardiac tumors by assessing the cardiac function and defining the location and extent of the cardiac tumors.16-19
Given the rarity of this disease entity, there is no standardized approach for treatment. Surgical resection along with repair or replacement of primary involved prosthetic valve is essential for initial treatment. However, there is no consensus about the best approach for subsequent therapy. We cannot be conclusive about the optimum treatment, because of the limited number of published cases, but based on our reading of those cases, it would seem that early surgical intervention and “adjuvant” systemic therapy may have influenced prognosis. We speculate that poor outcomes in the first 6 months were most likely related to primary cardiopulmonary deterioration, whereas later poor outcomes were more likely to be attributable to recurrent lymphoma, particularly for patients who received suboptimal systemic chemotherapy treatment after surgery. All 3 patients who received chemotherapy had no evidence of recurrent disease at last follow-up. Of the 4 patients who received no chemotherapy and survived longer than 6 months (all except 1 died; Table), 2 had recurrent valve lymphoma, 1 had secondary systemic lymphoma, and 1 died of metastatic breast cancer. Those outcomes are in contrast to the 2 out of 3 patients who received adjuvant chemotherapy and who were reported to be alive at 16 and 36 months after diagnosis.
In conclusion, cardiac PV-AL is an increasingly recognized entity that warrants greater awareness among health care providers for early diagnosis and timely surgical intervention. Most of the cases are large B-cell lymphoma. Similar to patients with limited-stage DLBCL, fit patients should be highly considered for “adjuvant” systemic chemotherapy to optimize long-term outcomes. Reporting of similar cases is highly encouraged to better define this rare iatrogenic malignancy.
1. Hudzik B, Miszalski-Jamka K, Glowacki J, et al. Malignant tumors of the heart. Cancer epidemiol. 2015;39(5):665-672.
2. Travis WD, Brambilla E, Müller-Hermelink HK, Harris CC, eds. Pathology and genetics of tumours of the lung, pleura, thymus and heart. Lyon, France: IARC Press; 2004.
3. Reynen K. Frequency of primary tumors of the heart. Am J Cardiol. 1996;77(1):107.
4. Neragi-Miandoab S, Kim J, Vlahakes GJ. Malignant tumours of the heart: a review of tumour type, diagnosis and therapy. Clin Oncol. 2007;19(10):748-756.
5. Butany J, Nair V, Naseemuddin A, Nair GM, Catton C, Yau T. Cardiac tumours: diagnosis and management. Lancet Oncol. 2005;6(4):219-228.
6. Burke A, Virmani R. Tumors of the heart and great vessels. In: Atlas of tumor pathology, 3rd Series, Fascicle 16. Washington, DC: Armed Forces Institute of Pathology, 1996.
7. Miller DV, Firchau DJ, McClure RF, Kurtin PJ, Feldman AL. Epstein-Barr virus-associated diffuse large B-cell lymphoma arising on cardiac prostheses. Am J Surg Pathol. 2010;34(3):377-384.
8. Albat B, Messner-Pellenc P, Thevenet A. Surgical treatment for primary lymphoma of the heart simulating prosthetic mitral valve thrombosis. J Thoracic Cardiovasc Surg. 1994;108(1):188-189.
9. Bagwan IN, Desai S, Wotherspoon A, Sheppard MN. Unusual presentation of primary cardiac lymphoma. Interact Cardiovasc Thorac Surg. 2009;9(1):127-129.
10. Durrleman NM, El-Hamamsy I, Demaria RG, Carrier M, Perrault LP, Albat B. Cardiac lymphoma following mitral valve replacement. Ann Thorac Surg. 2005;79(3):1040-1042.
11. Petrich A, Cho SI, Billett H. Primary cardiac lymphoma: an analysis of presentation, treatment, and outcome patterns. Cancer. 2011;117(3):581-589.
12. Cheuk W, Chan AC, Chan JK, Lau GT, Chan VN, Yiu HH. Metallic implant-associated lymphoma: a distinct subgroup of large B-cell lymphoma related to pyothorax-associated lymphoma? Am J Surg Pathol. 2005;29(6):832-836.
13. Roden AC, Macon WR, Keeney GL, Myers JL, Feldman AL, Dogan A. Seroma-associated primary anaplastic large-cell lymphoma adjacent to breast implants: an indolent T-cell lymphoproliferative disorder. Mod Pathol. 2008;21(4):455-463.
14. de Jong D, Vasmel WL, de Boer JP, et al. Anaplastic large-cell lymphoma in women with breast implants. JAMA. 2008;300(17):2030-2035.
15. Durrleman N, El Hamamsy I, Demaria R, Carrier M, Perrault LP, Albat B. Is Dacron carcinogenic? Apropos of a case and review of the literature [In French]. Arch Mal Coeur Vaiss. 2004 Mar;97(3):267-270.16. Peters PJ, Reinhardt S. The echocardiographic evaluation of intracardiac masses: a review. J Am Soc Echocard. 2006;19(2):230-240.
17. Gulati G, Sharma S, Kothari SS, Juneja R, Saxena A, Talwar KK. Comparison of echo and MRI in the imaging evaluation of intracardiac masses. Cardiovasc Intervent Radiol. 2004;27(5):459-469.
18. Krombach GA, Spuentrup E, Buecker A, et al. Heart tumors: magnetic resonance imaging and multislice spiral CT [In German]. RoFo. 2005;177(9):1205-1218.
19. Hoey ET, Mankad K, Puppala S, Gopalan D, Sivananthan MU. MRI and CT appearances of cardiac tumours in adults. Clin Radiol. 2009;64(12):1214-1230.
20. Bonnichsen CR, Dearani JA, Maleszewski JJ, Colgan JP, Williamson EE, Ammash NM. Recurrent Epstein-Barr virus-associated diffuse large B-cell lymphoma in an ascending aorta graft. Circulation. 2013;128(13):1481-1483.
21. Berrio G, Suryadevara A, Singh NK, Wesly OH. Diffuse large B-cell lymphoma in an aortic valve allograft. Tex Heart Inst J. 2010;37(4):492-493.
22. Gruver AM, Huba MA, Dogan A, Hsi ED. Fibrin-associated large B-cell lymphoma: part of the spectrum of cardiac lymphomas. Am J Surg Pathol. 2012;36(10):1527-1537.
23. Farah FJ, Chiles CD. Recurrent primary cardiac lymphoma on aortic valve allograft: implications for therapy. Tex Heart Inst J. 2014;41(5):543-546.
1. Hudzik B, Miszalski-Jamka K, Glowacki J, et al. Malignant tumors of the heart. Cancer epidemiol. 2015;39(5):665-672.
2. Travis WD, Brambilla E, Müller-Hermelink HK, Harris CC, eds. Pathology and genetics of tumours of the lung, pleura, thymus and heart. Lyon, France: IARC Press; 2004.
3. Reynen K. Frequency of primary tumors of the heart. Am J Cardiol. 1996;77(1):107.
4. Neragi-Miandoab S, Kim J, Vlahakes GJ. Malignant tumours of the heart: a review of tumour type, diagnosis and therapy. Clin Oncol. 2007;19(10):748-756.
5. Butany J, Nair V, Naseemuddin A, Nair GM, Catton C, Yau T. Cardiac tumours: diagnosis and management. Lancet Oncol. 2005;6(4):219-228.
6. Burke A, Virmani R. Tumors of the heart and great vessels. In: Atlas of tumor pathology, 3rd Series, Fascicle 16. Washington, DC: Armed Forces Institute of Pathology, 1996.
7. Miller DV, Firchau DJ, McClure RF, Kurtin PJ, Feldman AL. Epstein-Barr virus-associated diffuse large B-cell lymphoma arising on cardiac prostheses. Am J Surg Pathol. 2010;34(3):377-384.
8. Albat B, Messner-Pellenc P, Thevenet A. Surgical treatment for primary lymphoma of the heart simulating prosthetic mitral valve thrombosis. J Thoracic Cardiovasc Surg. 1994;108(1):188-189.
9. Bagwan IN, Desai S, Wotherspoon A, Sheppard MN. Unusual presentation of primary cardiac lymphoma. Interact Cardiovasc Thorac Surg. 2009;9(1):127-129.
10. Durrleman NM, El-Hamamsy I, Demaria RG, Carrier M, Perrault LP, Albat B. Cardiac lymphoma following mitral valve replacement. Ann Thorac Surg. 2005;79(3):1040-1042.
11. Petrich A, Cho SI, Billett H. Primary cardiac lymphoma: an analysis of presentation, treatment, and outcome patterns. Cancer. 2011;117(3):581-589.
12. Cheuk W, Chan AC, Chan JK, Lau GT, Chan VN, Yiu HH. Metallic implant-associated lymphoma: a distinct subgroup of large B-cell lymphoma related to pyothorax-associated lymphoma? Am J Surg Pathol. 2005;29(6):832-836.
13. Roden AC, Macon WR, Keeney GL, Myers JL, Feldman AL, Dogan A. Seroma-associated primary anaplastic large-cell lymphoma adjacent to breast implants: an indolent T-cell lymphoproliferative disorder. Mod Pathol. 2008;21(4):455-463.
14. de Jong D, Vasmel WL, de Boer JP, et al. Anaplastic large-cell lymphoma in women with breast implants. JAMA. 2008;300(17):2030-2035.
15. Durrleman N, El Hamamsy I, Demaria R, Carrier M, Perrault LP, Albat B. Is Dacron carcinogenic? Apropos of a case and review of the literature [In French]. Arch Mal Coeur Vaiss. 2004 Mar;97(3):267-270.16. Peters PJ, Reinhardt S. The echocardiographic evaluation of intracardiac masses: a review. J Am Soc Echocard. 2006;19(2):230-240.
17. Gulati G, Sharma S, Kothari SS, Juneja R, Saxena A, Talwar KK. Comparison of echo and MRI in the imaging evaluation of intracardiac masses. Cardiovasc Intervent Radiol. 2004;27(5):459-469.
18. Krombach GA, Spuentrup E, Buecker A, et al. Heart tumors: magnetic resonance imaging and multislice spiral CT [In German]. RoFo. 2005;177(9):1205-1218.
19. Hoey ET, Mankad K, Puppala S, Gopalan D, Sivananthan MU. MRI and CT appearances of cardiac tumours in adults. Clin Radiol. 2009;64(12):1214-1230.
20. Bonnichsen CR, Dearani JA, Maleszewski JJ, Colgan JP, Williamson EE, Ammash NM. Recurrent Epstein-Barr virus-associated diffuse large B-cell lymphoma in an ascending aorta graft. Circulation. 2013;128(13):1481-1483.
21. Berrio G, Suryadevara A, Singh NK, Wesly OH. Diffuse large B-cell lymphoma in an aortic valve allograft. Tex Heart Inst J. 2010;37(4):492-493.
22. Gruver AM, Huba MA, Dogan A, Hsi ED. Fibrin-associated large B-cell lymphoma: part of the spectrum of cardiac lymphomas. Am J Surg Pathol. 2012;36(10):1527-1537.
23. Farah FJ, Chiles CD. Recurrent primary cardiac lymphoma on aortic valve allograft: implications for therapy. Tex Heart Inst J. 2014;41(5):543-546.
Durable response to pralatrexate for aggressive PTCL subtypes
Peripheral T-cell lymphoma (PTCL) is a heterogeneous group of mature T- and natural killer-cell neoplasms that comprise about 10%-15% of all non-Hodgkin lymphomas in the United States.1,2 The development of effective therapies for PTCL has been challenging because of the rare nature and heterogeneity of these lymphomas. Most therapies are a derivative of aggressive B-cell lymphoma therapies, including CHOP (cyclophosphamide, hydroxydaunorubicin, vinicristine, prednisone) and CHOEP (cyclophosphamide, hydroxydaunorubicin, vinicristine, etoposide, prednisone).1 Many centers use autologous or allogeneic stem cell transplant in this setting,1 but outcomes remain poor and progress in developing effective treatments has been slow.
Pralatrexate is the first drug to have been approved by the US Food and Drug Administration specifically for treating patients with relapsed or refractory PTCL.3 As a folate analog metabolic inhibitor, pralatrexate competitively inhibits dihydrofolate reductase and reduces cellular levels of thymidine monophosphate, which prevents the cell from synthesizing genetic material and triggers it to undergo apoptosis.4 The agency’s approval of pralatrexate was based on results from the PROPEL study, which is possibly the largest prospective study conducted in patients with relapsed or refractory PTCL (109 evaluable patients).2 Findings from the study showed an overall response rate (ORR) of 29%, and a median duration of response (DoR) of 10 months.2
Pralatrexate is administered intravenously at 30 mg/m2 once weekly for 6 weeks of a 7-week treatment cycle. It is generally continued until disease progression or an unacceptable level of toxicity.2 Alternative dosing schedules have been described, including 15 mg/m2 once weekly for 3 weeks of a 4-week treatment cycle for cutaneous T-cell lymphomas.5
In this case series, we examine the outcomes of 2 patients with particularly aggressive subtypes of PTCL who were treated with pralatrexate. The significance of this report is in describing the long duration of response and reporting on a PTCL subtype – subcutaneous panniculitis-like T-cell lymphoma, alpha/beta type – that was underrepresented in the PROPEL study and is underreported in the literature.
Case presentations and summaries
Case 1
A 23-year-old Asian American man with a medical history of osteogenesis imperfecta presented to Emergency Department at the Hospital of University of Pennsylvania with bilateral lower extremity edema, low-grade fevers, a weight loss of 25 lb, and flat hyperpigmented scaly skin patches across his torso. Symptoms had started manifesting around five months prior to the visit. A punch biopsy of a skin lesion revealed skin tissue with focal infiltrate of small- to medium-sized, atypical lymphocytes infiltrating subcutaneous adipose tissue (panniculitis-like) and adnexa. Immunohistochemical stains showed that the abnormal lymphocytes were positive for CD3, CD8, perforin, granzyme B, TIA-1 (minor subset), and TCR beta; and negative for CD4, CD56, and CD30. Proliferation index (Ki67) was 70%. The findings were consistent with primary subcutaneous panniculitis-like T-cell lymphoma, alpha/beta type (Figure 1). A staging positron-emission tomography–computed tomography (PET–CT) scan demonstrated stage IVB lymphoma with subcutaneous involvement without nodal disease.
He was initially treated with aggressive combination regimens including EPOCH (etoposide, prednisolone, vincristine, cyclophosphamide, hydroxydaunorubicin) and ICE (ifosfamide, carboplatin, etoposide), but he had no response and his disease was primary refractory. Because of his osteogenesis imperfecta, he was not a candidate for allogenic stem cell transplant.
He responded to hyperCVAD B combination therapy (methotrexate and cytarabine), but the course was complicated by cytarabine-induced ataxia and dysarthia. He was then treated with 3 months of intravenous alemtuzumab without response. Intravenous methotrexate (2,000 mg/m2) was then used for 3 cycles, but this exacerbated his previous cytarabine-induced neurological symptoms and resulted in only partial response with persistent fluorine-18-deoxyglucose (FDG) avid lesions on a subsequent PET–CT scan.
At that point, the patient was started on pralatrexate at 15 mg/m2 weekly for 3 weeks on a 4-week cycle schedule. This was his fifth line of therapy and at 16 months from his initial diagnosis. This dosage was continued for 6 months, and he tolerated the therapy well. He reported no exacerbations of his dysarthia, and by the second month, he had achieved clinical and radiographic remission with complete resolution of B symptoms (fevers, night sweats, and weight loss). The dosing was modified to 15 mg/m2 every 2 weeks for 3 months. A whole body PET–CT scan showed resolution of previously FDG avid lesions.
The patient was then continued on 15 mg/m2 pralatrexate every 3 weeks for 1 year and he has been maintained on once-a-month dosing for a second and now third year of therapy. He continues to tolerate the therapy and remains disease free at nearly 2 years since starting pralatrexate.
Case 2
A 64-year-old white man with a medical history of myasthenia gravis (in remission) and invasive thymoma (after thymectomy) presented with diffuse bulky lymphadenopathy and lung lesions to outpatient clinic at the Abramson Cancer Center at the University of Pennsylvania. His LDH was elevated (278 U/L, reference range 98-192 U/L). Excisional biopsy of a left inguinal lymph node revealed sheets of mitotically active large cells with oval to irregular nuclei, clumped chromatin, conspicuous and sometimes multiple nucleoli, and ample eosinophilic cytoplasm. Immunohistochemical staining showed that the neoplastic cells were positive for CD3, CD4, CD30, BCL2 (variable), and MUM1; and negative for ALK 1, CD5, CD8, CD15, CD43, and CD56. Proliferation index (Ki67) was 90% (Figure 2). PET-CT scan showed widespread hypermetabolic lymphoma in the chest, neck, abdomen, and pelvis with pulmonary metastases. Imaging also demonstrated FDG-avid lesions in the gastric and sinus area. The findings were consistent with ALK-negative, anaplastic large cell lymphoma. He was stage IVA; had gastric, lung, and sinus involvement; and disease above and below the diaphragm.
The patient was initially treated with 6 cycles of CHOP and intrathecal methotrexate injections. His post-treatment PET–CT scan showed persistent FDG-avid disease and his LDH level remained elevated. He underwent 1 cycle of ICE and then BCV (busulfan, cyclophosphamide, etoposide) autologous stem cell transplant. Post-transplant PET–CT scan showed improvement from previous 2 scans but still showed several hypermetabolic lymph nodes consistent with persistent disease.
The patient was started on a pralatrexate regimen of 30 mg/m2 once weekly for 6 weeks of a 7-week treatment cycle. After 5 doses, he developed thrombocytopenia and mucositis, which were deemed pralatrexate related. The dosage was reduced to 20 mg/m2 once weekly with variable frequency depending on tolerability. His response assessment with PET–CT scan demonstrated radiographic complete response with resolution of hypermetabolic lesions (Figure 3B).
He then proceeded with pralatrexate for 4 more doses. PET-CT imaging 2 months after the last dose of pralatrexate was consistent with metabolic complete response, and he opted to hold further therapy. His last imaging at 4 years after completion of therapy showed continued remission. At press time, he had been clinically disease free for more than 6 years after his last dose of pralatrexate.
Discussion
PTCL is a rare and heterogeneous lymphoma with poor prognosis. Only 3 agents – pralatrexate, belinostat, and romidespin – have been approved specifically for the treatment of PTCL and all of them have an ORR of less than 30%, based on findings from phase 2 studies.2,6,7 In the PROPEL study, pralatrexate showed an ORR of 29% and a median DoR of 10 months.2 Those results could be considered discouraging, but some PTCL patients may have durable response to pralatrexate monotherapy.
In this case series, each of the patients presented with a particularly aggressive subtype of PTCL, and 1 suffered from a notably rare subtype for which there was scant clinical data to guide treatment. Both patients went through several lines of aggressive treatment that were ineffective and resulted in minimal response. However, both were able to achieve complete resolution of their disease and maintained remission for a significant duration of time after treatment with pralatrexate. In addition, each patient has maintained his remission – one for 6 years after the last dose. These are noteworthy results, and give both patients and clinicians hope that this therapy can be highly effective in some settings.
A better understanding at the molecular level of the oncogenic mechanisms in PTCL patients will be necessary to guide our therapy choices. In these 2 cases, it is likely that the tumor demonstrated superior sensitivity to dihydrofolate reductase inhibition by pralatrexate. In the future, we hope that analysis of the tumor tissue from PTCL patients will allow us to better categorize the tumor sensitivities to particular therapeutic agents. We believe that individualized treatment will lead to better overall outcomes in this challenging group of lymphomas.
1. d'Amore F, Relander T, Lauritzsen GF, et al. Up-front autologous stem-cell transplantation in peripheral T-cell lymphoma: NLG-T-01. J Clin Oncol. 2012;30(25):3093-3099.
2. O'Connor OA, Pro B, Pinter-Brown L, et al. Pralatrexate in patients with relapsed or refractory peripheral T-cell lymphoma: results from the pivotal PROPEL study. J Clin Oncol. 2011;29(9):1182-1189.
3. Dondi A, Bari A, Pozzi S, Ferri P, Sacchi S. The potential of pralatrexate as a treatment of peripheral T-cell lymphoma. Expert Opin Investig Drugs. 2014;23(5):711-718.
4. Hui J, Przespo E, Elefante A. Pralatrexate: a novel synthetic antifolate for relapsed or refractory peripheral T-cell lymphoma and other potential uses. J Oncol Pharm Pract. 2012;18(2):275-283.
5. Horwitz SM, Kim YH, Foss F, et al. Identification of an active, well-tolerated dose of pralatrexate in patients with relapsed or refractory cutaneous T-cell lymphoma. Blood. 2012;119(18):4115-4122.
6. O'Connor OA, Horwitz S, Masszi T, et al. Belinostat in patients with relapsed or refractory peripheral T-cell lymphoma: Results of the pivotal phase II BELIEF (CLN-19) study. J Clin Oncol. 2015;33(23):2492-2499.
7. Coiffier B, Pro B, Prince HM, et al. Results from a pivotal, open-label, phase II study of romidepsin in relapsed or refractory peripheral T-cell lymphoma after prior systemic therapy. J Clin Oncol. 2012;30(6):631-636.
Peripheral T-cell lymphoma (PTCL) is a heterogeneous group of mature T- and natural killer-cell neoplasms that comprise about 10%-15% of all non-Hodgkin lymphomas in the United States.1,2 The development of effective therapies for PTCL has been challenging because of the rare nature and heterogeneity of these lymphomas. Most therapies are a derivative of aggressive B-cell lymphoma therapies, including CHOP (cyclophosphamide, hydroxydaunorubicin, vinicristine, prednisone) and CHOEP (cyclophosphamide, hydroxydaunorubicin, vinicristine, etoposide, prednisone).1 Many centers use autologous or allogeneic stem cell transplant in this setting,1 but outcomes remain poor and progress in developing effective treatments has been slow.
Pralatrexate is the first drug to have been approved by the US Food and Drug Administration specifically for treating patients with relapsed or refractory PTCL.3 As a folate analog metabolic inhibitor, pralatrexate competitively inhibits dihydrofolate reductase and reduces cellular levels of thymidine monophosphate, which prevents the cell from synthesizing genetic material and triggers it to undergo apoptosis.4 The agency’s approval of pralatrexate was based on results from the PROPEL study, which is possibly the largest prospective study conducted in patients with relapsed or refractory PTCL (109 evaluable patients).2 Findings from the study showed an overall response rate (ORR) of 29%, and a median duration of response (DoR) of 10 months.2
Pralatrexate is administered intravenously at 30 mg/m2 once weekly for 6 weeks of a 7-week treatment cycle. It is generally continued until disease progression or an unacceptable level of toxicity.2 Alternative dosing schedules have been described, including 15 mg/m2 once weekly for 3 weeks of a 4-week treatment cycle for cutaneous T-cell lymphomas.5
In this case series, we examine the outcomes of 2 patients with particularly aggressive subtypes of PTCL who were treated with pralatrexate. The significance of this report is in describing the long duration of response and reporting on a PTCL subtype – subcutaneous panniculitis-like T-cell lymphoma, alpha/beta type – that was underrepresented in the PROPEL study and is underreported in the literature.
Case presentations and summaries
Case 1
A 23-year-old Asian American man with a medical history of osteogenesis imperfecta presented to Emergency Department at the Hospital of University of Pennsylvania with bilateral lower extremity edema, low-grade fevers, a weight loss of 25 lb, and flat hyperpigmented scaly skin patches across his torso. Symptoms had started manifesting around five months prior to the visit. A punch biopsy of a skin lesion revealed skin tissue with focal infiltrate of small- to medium-sized, atypical lymphocytes infiltrating subcutaneous adipose tissue (panniculitis-like) and adnexa. Immunohistochemical stains showed that the abnormal lymphocytes were positive for CD3, CD8, perforin, granzyme B, TIA-1 (minor subset), and TCR beta; and negative for CD4, CD56, and CD30. Proliferation index (Ki67) was 70%. The findings were consistent with primary subcutaneous panniculitis-like T-cell lymphoma, alpha/beta type (Figure 1). A staging positron-emission tomography–computed tomography (PET–CT) scan demonstrated stage IVB lymphoma with subcutaneous involvement without nodal disease.
He was initially treated with aggressive combination regimens including EPOCH (etoposide, prednisolone, vincristine, cyclophosphamide, hydroxydaunorubicin) and ICE (ifosfamide, carboplatin, etoposide), but he had no response and his disease was primary refractory. Because of his osteogenesis imperfecta, he was not a candidate for allogenic stem cell transplant.
He responded to hyperCVAD B combination therapy (methotrexate and cytarabine), but the course was complicated by cytarabine-induced ataxia and dysarthia. He was then treated with 3 months of intravenous alemtuzumab without response. Intravenous methotrexate (2,000 mg/m2) was then used for 3 cycles, but this exacerbated his previous cytarabine-induced neurological symptoms and resulted in only partial response with persistent fluorine-18-deoxyglucose (FDG) avid lesions on a subsequent PET–CT scan.
At that point, the patient was started on pralatrexate at 15 mg/m2 weekly for 3 weeks on a 4-week cycle schedule. This was his fifth line of therapy and at 16 months from his initial diagnosis. This dosage was continued for 6 months, and he tolerated the therapy well. He reported no exacerbations of his dysarthia, and by the second month, he had achieved clinical and radiographic remission with complete resolution of B symptoms (fevers, night sweats, and weight loss). The dosing was modified to 15 mg/m2 every 2 weeks for 3 months. A whole body PET–CT scan showed resolution of previously FDG avid lesions.
The patient was then continued on 15 mg/m2 pralatrexate every 3 weeks for 1 year and he has been maintained on once-a-month dosing for a second and now third year of therapy. He continues to tolerate the therapy and remains disease free at nearly 2 years since starting pralatrexate.
Case 2
A 64-year-old white man with a medical history of myasthenia gravis (in remission) and invasive thymoma (after thymectomy) presented with diffuse bulky lymphadenopathy and lung lesions to outpatient clinic at the Abramson Cancer Center at the University of Pennsylvania. His LDH was elevated (278 U/L, reference range 98-192 U/L). Excisional biopsy of a left inguinal lymph node revealed sheets of mitotically active large cells with oval to irregular nuclei, clumped chromatin, conspicuous and sometimes multiple nucleoli, and ample eosinophilic cytoplasm. Immunohistochemical staining showed that the neoplastic cells were positive for CD3, CD4, CD30, BCL2 (variable), and MUM1; and negative for ALK 1, CD5, CD8, CD15, CD43, and CD56. Proliferation index (Ki67) was 90% (Figure 2). PET-CT scan showed widespread hypermetabolic lymphoma in the chest, neck, abdomen, and pelvis with pulmonary metastases. Imaging also demonstrated FDG-avid lesions in the gastric and sinus area. The findings were consistent with ALK-negative, anaplastic large cell lymphoma. He was stage IVA; had gastric, lung, and sinus involvement; and disease above and below the diaphragm.
The patient was initially treated with 6 cycles of CHOP and intrathecal methotrexate injections. His post-treatment PET–CT scan showed persistent FDG-avid disease and his LDH level remained elevated. He underwent 1 cycle of ICE and then BCV (busulfan, cyclophosphamide, etoposide) autologous stem cell transplant. Post-transplant PET–CT scan showed improvement from previous 2 scans but still showed several hypermetabolic lymph nodes consistent with persistent disease.
The patient was started on a pralatrexate regimen of 30 mg/m2 once weekly for 6 weeks of a 7-week treatment cycle. After 5 doses, he developed thrombocytopenia and mucositis, which were deemed pralatrexate related. The dosage was reduced to 20 mg/m2 once weekly with variable frequency depending on tolerability. His response assessment with PET–CT scan demonstrated radiographic complete response with resolution of hypermetabolic lesions (Figure 3B).
He then proceeded with pralatrexate for 4 more doses. PET-CT imaging 2 months after the last dose of pralatrexate was consistent with metabolic complete response, and he opted to hold further therapy. His last imaging at 4 years after completion of therapy showed continued remission. At press time, he had been clinically disease free for more than 6 years after his last dose of pralatrexate.
Discussion
PTCL is a rare and heterogeneous lymphoma with poor prognosis. Only 3 agents – pralatrexate, belinostat, and romidespin – have been approved specifically for the treatment of PTCL and all of them have an ORR of less than 30%, based on findings from phase 2 studies.2,6,7 In the PROPEL study, pralatrexate showed an ORR of 29% and a median DoR of 10 months.2 Those results could be considered discouraging, but some PTCL patients may have durable response to pralatrexate monotherapy.
In this case series, each of the patients presented with a particularly aggressive subtype of PTCL, and 1 suffered from a notably rare subtype for which there was scant clinical data to guide treatment. Both patients went through several lines of aggressive treatment that were ineffective and resulted in minimal response. However, both were able to achieve complete resolution of their disease and maintained remission for a significant duration of time after treatment with pralatrexate. In addition, each patient has maintained his remission – one for 6 years after the last dose. These are noteworthy results, and give both patients and clinicians hope that this therapy can be highly effective in some settings.
A better understanding at the molecular level of the oncogenic mechanisms in PTCL patients will be necessary to guide our therapy choices. In these 2 cases, it is likely that the tumor demonstrated superior sensitivity to dihydrofolate reductase inhibition by pralatrexate. In the future, we hope that analysis of the tumor tissue from PTCL patients will allow us to better categorize the tumor sensitivities to particular therapeutic agents. We believe that individualized treatment will lead to better overall outcomes in this challenging group of lymphomas.
Peripheral T-cell lymphoma (PTCL) is a heterogeneous group of mature T- and natural killer-cell neoplasms that comprise about 10%-15% of all non-Hodgkin lymphomas in the United States.1,2 The development of effective therapies for PTCL has been challenging because of the rare nature and heterogeneity of these lymphomas. Most therapies are a derivative of aggressive B-cell lymphoma therapies, including CHOP (cyclophosphamide, hydroxydaunorubicin, vinicristine, prednisone) and CHOEP (cyclophosphamide, hydroxydaunorubicin, vinicristine, etoposide, prednisone).1 Many centers use autologous or allogeneic stem cell transplant in this setting,1 but outcomes remain poor and progress in developing effective treatments has been slow.
Pralatrexate is the first drug to have been approved by the US Food and Drug Administration specifically for treating patients with relapsed or refractory PTCL.3 As a folate analog metabolic inhibitor, pralatrexate competitively inhibits dihydrofolate reductase and reduces cellular levels of thymidine monophosphate, which prevents the cell from synthesizing genetic material and triggers it to undergo apoptosis.4 The agency’s approval of pralatrexate was based on results from the PROPEL study, which is possibly the largest prospective study conducted in patients with relapsed or refractory PTCL (109 evaluable patients).2 Findings from the study showed an overall response rate (ORR) of 29%, and a median duration of response (DoR) of 10 months.2
Pralatrexate is administered intravenously at 30 mg/m2 once weekly for 6 weeks of a 7-week treatment cycle. It is generally continued until disease progression or an unacceptable level of toxicity.2 Alternative dosing schedules have been described, including 15 mg/m2 once weekly for 3 weeks of a 4-week treatment cycle for cutaneous T-cell lymphomas.5
In this case series, we examine the outcomes of 2 patients with particularly aggressive subtypes of PTCL who were treated with pralatrexate. The significance of this report is in describing the long duration of response and reporting on a PTCL subtype – subcutaneous panniculitis-like T-cell lymphoma, alpha/beta type – that was underrepresented in the PROPEL study and is underreported in the literature.
Case presentations and summaries
Case 1
A 23-year-old Asian American man with a medical history of osteogenesis imperfecta presented to Emergency Department at the Hospital of University of Pennsylvania with bilateral lower extremity edema, low-grade fevers, a weight loss of 25 lb, and flat hyperpigmented scaly skin patches across his torso. Symptoms had started manifesting around five months prior to the visit. A punch biopsy of a skin lesion revealed skin tissue with focal infiltrate of small- to medium-sized, atypical lymphocytes infiltrating subcutaneous adipose tissue (panniculitis-like) and adnexa. Immunohistochemical stains showed that the abnormal lymphocytes were positive for CD3, CD8, perforin, granzyme B, TIA-1 (minor subset), and TCR beta; and negative for CD4, CD56, and CD30. Proliferation index (Ki67) was 70%. The findings were consistent with primary subcutaneous panniculitis-like T-cell lymphoma, alpha/beta type (Figure 1). A staging positron-emission tomography–computed tomography (PET–CT) scan demonstrated stage IVB lymphoma with subcutaneous involvement without nodal disease.
He was initially treated with aggressive combination regimens including EPOCH (etoposide, prednisolone, vincristine, cyclophosphamide, hydroxydaunorubicin) and ICE (ifosfamide, carboplatin, etoposide), but he had no response and his disease was primary refractory. Because of his osteogenesis imperfecta, he was not a candidate for allogenic stem cell transplant.
He responded to hyperCVAD B combination therapy (methotrexate and cytarabine), but the course was complicated by cytarabine-induced ataxia and dysarthia. He was then treated with 3 months of intravenous alemtuzumab without response. Intravenous methotrexate (2,000 mg/m2) was then used for 3 cycles, but this exacerbated his previous cytarabine-induced neurological symptoms and resulted in only partial response with persistent fluorine-18-deoxyglucose (FDG) avid lesions on a subsequent PET–CT scan.
At that point, the patient was started on pralatrexate at 15 mg/m2 weekly for 3 weeks on a 4-week cycle schedule. This was his fifth line of therapy and at 16 months from his initial diagnosis. This dosage was continued for 6 months, and he tolerated the therapy well. He reported no exacerbations of his dysarthia, and by the second month, he had achieved clinical and radiographic remission with complete resolution of B symptoms (fevers, night sweats, and weight loss). The dosing was modified to 15 mg/m2 every 2 weeks for 3 months. A whole body PET–CT scan showed resolution of previously FDG avid lesions.
The patient was then continued on 15 mg/m2 pralatrexate every 3 weeks for 1 year and he has been maintained on once-a-month dosing for a second and now third year of therapy. He continues to tolerate the therapy and remains disease free at nearly 2 years since starting pralatrexate.
Case 2
A 64-year-old white man with a medical history of myasthenia gravis (in remission) and invasive thymoma (after thymectomy) presented with diffuse bulky lymphadenopathy and lung lesions to outpatient clinic at the Abramson Cancer Center at the University of Pennsylvania. His LDH was elevated (278 U/L, reference range 98-192 U/L). Excisional biopsy of a left inguinal lymph node revealed sheets of mitotically active large cells with oval to irregular nuclei, clumped chromatin, conspicuous and sometimes multiple nucleoli, and ample eosinophilic cytoplasm. Immunohistochemical staining showed that the neoplastic cells were positive for CD3, CD4, CD30, BCL2 (variable), and MUM1; and negative for ALK 1, CD5, CD8, CD15, CD43, and CD56. Proliferation index (Ki67) was 90% (Figure 2). PET-CT scan showed widespread hypermetabolic lymphoma in the chest, neck, abdomen, and pelvis with pulmonary metastases. Imaging also demonstrated FDG-avid lesions in the gastric and sinus area. The findings were consistent with ALK-negative, anaplastic large cell lymphoma. He was stage IVA; had gastric, lung, and sinus involvement; and disease above and below the diaphragm.
The patient was initially treated with 6 cycles of CHOP and intrathecal methotrexate injections. His post-treatment PET–CT scan showed persistent FDG-avid disease and his LDH level remained elevated. He underwent 1 cycle of ICE and then BCV (busulfan, cyclophosphamide, etoposide) autologous stem cell transplant. Post-transplant PET–CT scan showed improvement from previous 2 scans but still showed several hypermetabolic lymph nodes consistent with persistent disease.
The patient was started on a pralatrexate regimen of 30 mg/m2 once weekly for 6 weeks of a 7-week treatment cycle. After 5 doses, he developed thrombocytopenia and mucositis, which were deemed pralatrexate related. The dosage was reduced to 20 mg/m2 once weekly with variable frequency depending on tolerability. His response assessment with PET–CT scan demonstrated radiographic complete response with resolution of hypermetabolic lesions (Figure 3B).
He then proceeded with pralatrexate for 4 more doses. PET-CT imaging 2 months after the last dose of pralatrexate was consistent with metabolic complete response, and he opted to hold further therapy. His last imaging at 4 years after completion of therapy showed continued remission. At press time, he had been clinically disease free for more than 6 years after his last dose of pralatrexate.
Discussion
PTCL is a rare and heterogeneous lymphoma with poor prognosis. Only 3 agents – pralatrexate, belinostat, and romidespin – have been approved specifically for the treatment of PTCL and all of them have an ORR of less than 30%, based on findings from phase 2 studies.2,6,7 In the PROPEL study, pralatrexate showed an ORR of 29% and a median DoR of 10 months.2 Those results could be considered discouraging, but some PTCL patients may have durable response to pralatrexate monotherapy.
In this case series, each of the patients presented with a particularly aggressive subtype of PTCL, and 1 suffered from a notably rare subtype for which there was scant clinical data to guide treatment. Both patients went through several lines of aggressive treatment that were ineffective and resulted in minimal response. However, both were able to achieve complete resolution of their disease and maintained remission for a significant duration of time after treatment with pralatrexate. In addition, each patient has maintained his remission – one for 6 years after the last dose. These are noteworthy results, and give both patients and clinicians hope that this therapy can be highly effective in some settings.
A better understanding at the molecular level of the oncogenic mechanisms in PTCL patients will be necessary to guide our therapy choices. In these 2 cases, it is likely that the tumor demonstrated superior sensitivity to dihydrofolate reductase inhibition by pralatrexate. In the future, we hope that analysis of the tumor tissue from PTCL patients will allow us to better categorize the tumor sensitivities to particular therapeutic agents. We believe that individualized treatment will lead to better overall outcomes in this challenging group of lymphomas.
1. d'Amore F, Relander T, Lauritzsen GF, et al. Up-front autologous stem-cell transplantation in peripheral T-cell lymphoma: NLG-T-01. J Clin Oncol. 2012;30(25):3093-3099.
2. O'Connor OA, Pro B, Pinter-Brown L, et al. Pralatrexate in patients with relapsed or refractory peripheral T-cell lymphoma: results from the pivotal PROPEL study. J Clin Oncol. 2011;29(9):1182-1189.
3. Dondi A, Bari A, Pozzi S, Ferri P, Sacchi S. The potential of pralatrexate as a treatment of peripheral T-cell lymphoma. Expert Opin Investig Drugs. 2014;23(5):711-718.
4. Hui J, Przespo E, Elefante A. Pralatrexate: a novel synthetic antifolate for relapsed or refractory peripheral T-cell lymphoma and other potential uses. J Oncol Pharm Pract. 2012;18(2):275-283.
5. Horwitz SM, Kim YH, Foss F, et al. Identification of an active, well-tolerated dose of pralatrexate in patients with relapsed or refractory cutaneous T-cell lymphoma. Blood. 2012;119(18):4115-4122.
6. O'Connor OA, Horwitz S, Masszi T, et al. Belinostat in patients with relapsed or refractory peripheral T-cell lymphoma: Results of the pivotal phase II BELIEF (CLN-19) study. J Clin Oncol. 2015;33(23):2492-2499.
7. Coiffier B, Pro B, Prince HM, et al. Results from a pivotal, open-label, phase II study of romidepsin in relapsed or refractory peripheral T-cell lymphoma after prior systemic therapy. J Clin Oncol. 2012;30(6):631-636.
1. d'Amore F, Relander T, Lauritzsen GF, et al. Up-front autologous stem-cell transplantation in peripheral T-cell lymphoma: NLG-T-01. J Clin Oncol. 2012;30(25):3093-3099.
2. O'Connor OA, Pro B, Pinter-Brown L, et al. Pralatrexate in patients with relapsed or refractory peripheral T-cell lymphoma: results from the pivotal PROPEL study. J Clin Oncol. 2011;29(9):1182-1189.
3. Dondi A, Bari A, Pozzi S, Ferri P, Sacchi S. The potential of pralatrexate as a treatment of peripheral T-cell lymphoma. Expert Opin Investig Drugs. 2014;23(5):711-718.
4. Hui J, Przespo E, Elefante A. Pralatrexate: a novel synthetic antifolate for relapsed or refractory peripheral T-cell lymphoma and other potential uses. J Oncol Pharm Pract. 2012;18(2):275-283.
5. Horwitz SM, Kim YH, Foss F, et al. Identification of an active, well-tolerated dose of pralatrexate in patients with relapsed or refractory cutaneous T-cell lymphoma. Blood. 2012;119(18):4115-4122.
6. O'Connor OA, Horwitz S, Masszi T, et al. Belinostat in patients with relapsed or refractory peripheral T-cell lymphoma: Results of the pivotal phase II BELIEF (CLN-19) study. J Clin Oncol. 2015;33(23):2492-2499.
7. Coiffier B, Pro B, Prince HM, et al. Results from a pivotal, open-label, phase II study of romidepsin in relapsed or refractory peripheral T-cell lymphoma after prior systemic therapy. J Clin Oncol. 2012;30(6):631-636.
Innovations Lead to More Targeted Prostate Cancer Treatments (FULL)
The main treatment for prostate cancer—the third leading cause of cancer death in American men—often is “watchful waiting.” But what happens before, during, and after that waiting period has changed tremendously in recent years. Innovative and improved methods and drugs allow for a more precise diagnosis, better risk stratification, targeted treatment options, and longer survival.
Innovations in diagnosis include a revised histologic grading system, which was incorporated into the 2016 World Health Organization classification of tumors. The new grading system ranks prostate cancer on a 1-to-5 scale, making it more discriminating, as validated in a study of more than 25,000 men.
The use of new prognostic biomarkers has advanced risk stratification. According to a recent review, biopsy guided by ultrasound misses between 21% and 28% of prostate cancers and undergrades between 14% and 17%.1 But new serum-, tissue-, and image-based biomarkers may help identify potential false negatives. The prostate cancer antigen 3 test, for example, has an 88% negative predictive value for subsequent biopsy. Molecular biomarkers also can predict clinical progression, risk of adverse pathology, and metastatic risk.
Fortunately, biopsy guided by ultrasound is getting more precise. Advances in magnetic resonance imaging (MRI) now allow for “targeted biopsies.” The enhanced MRI has 89% sensitivity and 73% specificity for identifying prostate cancer. According to one study of 1,003 men, targeted prostate biopsy using MRI-ultrasound fusion identified 30% more cases of Gleason score ≥ 4 + 3 than did systematic prostate biopsy.1 Updates in positron emission tomography are garnering interest for improved staging because this technology allows for better detection of local recurrence, regional lymph node metastases, and distant metastases.
Once a prostate cancer diagnosis has been confirmed, the decision of what to do next may be watchful waiting (treating symptoms palliatively), but recent research suggests that active surveillance that includes regular prostate-specific antigen testing, physical examinations, and prostate biopsies may be a better choice, particularly for men with less aggressive cancer. One study of 1,298 men with mostly very low-risk disease followed for up to 60 months found metastasis in only 5; only 2 died. The Prostate Testing for Cancer and Treatment (ProtecT) trial found that the number of deaths in the active monitoring group did not differ significantly from those in the surgery or radiation groups.
What should be the contemporary standard of care? Androgen deprivation therapy (ADT) is still the go-to treatment for men with metastatic prostate cancer. Although ADT has been associated with toxicity, a meta-analysis found continuous ADT was better than intermittent in terms of disease progression and survival.1
Other research has focused on which types of prostate cancer respond best to specific therapies. Molecular subtyping (already available in bladder and breast cancer) is gaining popularity. Prostate cancer was thought to derive from glandular luminal cells, but recent evidence supports the idea that basal cells play a role as well. Researchers who analyzed nearly 4,000 samples suggest that luminal B tumors respond better to postoperative ADT than do nonluminal B cancers. These findings suggest that “personalized” ADT treatment may be possible.2
Several drugs have been shown to improve survival: Among them, docetaxel, abiraterone acetate, enzalutamide, and cabazitaxel. In the STAMPEDE trial, men with locally advanced or metastatic prostate cancer who received ADT plus abiraterone and prednisolone had significantly higher rates of overall and failure-free survival.3
Docetaxel, which can extend survival by 10 to 13 months compared with standard ADT, is taking on a bigger role for its ability to delay progression and recurrence while being well tolerated. Options for men whose cancer does not respond to ADT include abiraterone and enzalutamide. Both act on the androgen axis to slow progression and improve survival.
More than 30% of patients treated with radical prostatectomy will have recurrent cancer as will 50% of those treated with salvage radiation therapy. Bicalutamide has shown extremely promising action against recurrent cancer. In one study, the cumulative incidence of metastatic prostate cancer at 12 years was 14.5% in the bicalutamide group, compared with 23.0% in the placebo group.4
But while that study was going on, it was superseded by injectable gonadotropin-releasing hormone agonists as first-choice hormonal therapy with radiation. However, the researchers say that does not
Multimodal therapy and precision medicine are becoming bywords in prostate cancer treatment. Drugs on the horizon likely will be tailored to tumor molecular biology, with genetic information used to specifically guide diagnosis and treatment. Prostate cancer may still be a slow killer, but immunotherapies (like sipuleucel-T, the first FDA-approved cancer vaccine), hormonal therapies, and bone-targeting agents enable men with prostate cancer to not only live longer but also with a better quality of life.
Click here to read the digital edition.
1. Litwin MS, Tan HJ. The diagnosis and treatment of prostate cancer: a review. JAMA. 2017;317(24):2532-2542.
2. Zhao SG, Chang SL, Erho N, et al. Associations of luminal and basal subtyping of prostate cancer with prognosis and response to androgen deprivation therapy. JAMA Oncol. 2017. [Epub ahead of print.]
3. James ND, de Bono JS, Spears MR, et al; for the STAMPEDE Investigators. Abiraterone for prostate cancer not previously treated with hormone therapy. N Engl J Med. 2017. [Epub ahead of print.]
4. Shipley WU, Seiferheld W, Lukka HR, et al; NRG Oncology RTOG. Radiation with or without antiandrogen therapy in recurrent prostate cancer. N Engl J Med. 2017;376(5):417-428.
The main treatment for prostate cancer—the third leading cause of cancer death in American men—often is “watchful waiting.” But what happens before, during, and after that waiting period has changed tremendously in recent years. Innovative and improved methods and drugs allow for a more precise diagnosis, better risk stratification, targeted treatment options, and longer survival.
Innovations in diagnosis include a revised histologic grading system, which was incorporated into the 2016 World Health Organization classification of tumors. The new grading system ranks prostate cancer on a 1-to-5 scale, making it more discriminating, as validated in a study of more than 25,000 men.
The use of new prognostic biomarkers has advanced risk stratification. According to a recent review, biopsy guided by ultrasound misses between 21% and 28% of prostate cancers and undergrades between 14% and 17%.1 But new serum-, tissue-, and image-based biomarkers may help identify potential false negatives. The prostate cancer antigen 3 test, for example, has an 88% negative predictive value for subsequent biopsy. Molecular biomarkers also can predict clinical progression, risk of adverse pathology, and metastatic risk.
Fortunately, biopsy guided by ultrasound is getting more precise. Advances in magnetic resonance imaging (MRI) now allow for “targeted biopsies.” The enhanced MRI has 89% sensitivity and 73% specificity for identifying prostate cancer. According to one study of 1,003 men, targeted prostate biopsy using MRI-ultrasound fusion identified 30% more cases of Gleason score ≥ 4 + 3 than did systematic prostate biopsy.1 Updates in positron emission tomography are garnering interest for improved staging because this technology allows for better detection of local recurrence, regional lymph node metastases, and distant metastases.
Once a prostate cancer diagnosis has been confirmed, the decision of what to do next may be watchful waiting (treating symptoms palliatively), but recent research suggests that active surveillance that includes regular prostate-specific antigen testing, physical examinations, and prostate biopsies may be a better choice, particularly for men with less aggressive cancer. One study of 1,298 men with mostly very low-risk disease followed for up to 60 months found metastasis in only 5; only 2 died. The Prostate Testing for Cancer and Treatment (ProtecT) trial found that the number of deaths in the active monitoring group did not differ significantly from those in the surgery or radiation groups.
What should be the contemporary standard of care? Androgen deprivation therapy (ADT) is still the go-to treatment for men with metastatic prostate cancer. Although ADT has been associated with toxicity, a meta-analysis found continuous ADT was better than intermittent in terms of disease progression and survival.1
Other research has focused on which types of prostate cancer respond best to specific therapies. Molecular subtyping (already available in bladder and breast cancer) is gaining popularity. Prostate cancer was thought to derive from glandular luminal cells, but recent evidence supports the idea that basal cells play a role as well. Researchers who analyzed nearly 4,000 samples suggest that luminal B tumors respond better to postoperative ADT than do nonluminal B cancers. These findings suggest that “personalized” ADT treatment may be possible.2
Several drugs have been shown to improve survival: Among them, docetaxel, abiraterone acetate, enzalutamide, and cabazitaxel. In the STAMPEDE trial, men with locally advanced or metastatic prostate cancer who received ADT plus abiraterone and prednisolone had significantly higher rates of overall and failure-free survival.3
Docetaxel, which can extend survival by 10 to 13 months compared with standard ADT, is taking on a bigger role for its ability to delay progression and recurrence while being well tolerated. Options for men whose cancer does not respond to ADT include abiraterone and enzalutamide. Both act on the androgen axis to slow progression and improve survival.
More than 30% of patients treated with radical prostatectomy will have recurrent cancer as will 50% of those treated with salvage radiation therapy. Bicalutamide has shown extremely promising action against recurrent cancer. In one study, the cumulative incidence of metastatic prostate cancer at 12 years was 14.5% in the bicalutamide group, compared with 23.0% in the placebo group.4
But while that study was going on, it was superseded by injectable gonadotropin-releasing hormone agonists as first-choice hormonal therapy with radiation. However, the researchers say that does not
Multimodal therapy and precision medicine are becoming bywords in prostate cancer treatment. Drugs on the horizon likely will be tailored to tumor molecular biology, with genetic information used to specifically guide diagnosis and treatment. Prostate cancer may still be a slow killer, but immunotherapies (like sipuleucel-T, the first FDA-approved cancer vaccine), hormonal therapies, and bone-targeting agents enable men with prostate cancer to not only live longer but also with a better quality of life.
Click here to read the digital edition.
The main treatment for prostate cancer—the third leading cause of cancer death in American men—often is “watchful waiting.” But what happens before, during, and after that waiting period has changed tremendously in recent years. Innovative and improved methods and drugs allow for a more precise diagnosis, better risk stratification, targeted treatment options, and longer survival.
Innovations in diagnosis include a revised histologic grading system, which was incorporated into the 2016 World Health Organization classification of tumors. The new grading system ranks prostate cancer on a 1-to-5 scale, making it more discriminating, as validated in a study of more than 25,000 men.
The use of new prognostic biomarkers has advanced risk stratification. According to a recent review, biopsy guided by ultrasound misses between 21% and 28% of prostate cancers and undergrades between 14% and 17%.1 But new serum-, tissue-, and image-based biomarkers may help identify potential false negatives. The prostate cancer antigen 3 test, for example, has an 88% negative predictive value for subsequent biopsy. Molecular biomarkers also can predict clinical progression, risk of adverse pathology, and metastatic risk.
Fortunately, biopsy guided by ultrasound is getting more precise. Advances in magnetic resonance imaging (MRI) now allow for “targeted biopsies.” The enhanced MRI has 89% sensitivity and 73% specificity for identifying prostate cancer. According to one study of 1,003 men, targeted prostate biopsy using MRI-ultrasound fusion identified 30% more cases of Gleason score ≥ 4 + 3 than did systematic prostate biopsy.1 Updates in positron emission tomography are garnering interest for improved staging because this technology allows for better detection of local recurrence, regional lymph node metastases, and distant metastases.
Once a prostate cancer diagnosis has been confirmed, the decision of what to do next may be watchful waiting (treating symptoms palliatively), but recent research suggests that active surveillance that includes regular prostate-specific antigen testing, physical examinations, and prostate biopsies may be a better choice, particularly for men with less aggressive cancer. One study of 1,298 men with mostly very low-risk disease followed for up to 60 months found metastasis in only 5; only 2 died. The Prostate Testing for Cancer and Treatment (ProtecT) trial found that the number of deaths in the active monitoring group did not differ significantly from those in the surgery or radiation groups.
What should be the contemporary standard of care? Androgen deprivation therapy (ADT) is still the go-to treatment for men with metastatic prostate cancer. Although ADT has been associated with toxicity, a meta-analysis found continuous ADT was better than intermittent in terms of disease progression and survival.1
Other research has focused on which types of prostate cancer respond best to specific therapies. Molecular subtyping (already available in bladder and breast cancer) is gaining popularity. Prostate cancer was thought to derive from glandular luminal cells, but recent evidence supports the idea that basal cells play a role as well. Researchers who analyzed nearly 4,000 samples suggest that luminal B tumors respond better to postoperative ADT than do nonluminal B cancers. These findings suggest that “personalized” ADT treatment may be possible.2
Several drugs have been shown to improve survival: Among them, docetaxel, abiraterone acetate, enzalutamide, and cabazitaxel. In the STAMPEDE trial, men with locally advanced or metastatic prostate cancer who received ADT plus abiraterone and prednisolone had significantly higher rates of overall and failure-free survival.3
Docetaxel, which can extend survival by 10 to 13 months compared with standard ADT, is taking on a bigger role for its ability to delay progression and recurrence while being well tolerated. Options for men whose cancer does not respond to ADT include abiraterone and enzalutamide. Both act on the androgen axis to slow progression and improve survival.
More than 30% of patients treated with radical prostatectomy will have recurrent cancer as will 50% of those treated with salvage radiation therapy. Bicalutamide has shown extremely promising action against recurrent cancer. In one study, the cumulative incidence of metastatic prostate cancer at 12 years was 14.5% in the bicalutamide group, compared with 23.0% in the placebo group.4
But while that study was going on, it was superseded by injectable gonadotropin-releasing hormone agonists as first-choice hormonal therapy with radiation. However, the researchers say that does not
Multimodal therapy and precision medicine are becoming bywords in prostate cancer treatment. Drugs on the horizon likely will be tailored to tumor molecular biology, with genetic information used to specifically guide diagnosis and treatment. Prostate cancer may still be a slow killer, but immunotherapies (like sipuleucel-T, the first FDA-approved cancer vaccine), hormonal therapies, and bone-targeting agents enable men with prostate cancer to not only live longer but also with a better quality of life.
Click here to read the digital edition.
1. Litwin MS, Tan HJ. The diagnosis and treatment of prostate cancer: a review. JAMA. 2017;317(24):2532-2542.
2. Zhao SG, Chang SL, Erho N, et al. Associations of luminal and basal subtyping of prostate cancer with prognosis and response to androgen deprivation therapy. JAMA Oncol. 2017. [Epub ahead of print.]
3. James ND, de Bono JS, Spears MR, et al; for the STAMPEDE Investigators. Abiraterone for prostate cancer not previously treated with hormone therapy. N Engl J Med. 2017. [Epub ahead of print.]
4. Shipley WU, Seiferheld W, Lukka HR, et al; NRG Oncology RTOG. Radiation with or without antiandrogen therapy in recurrent prostate cancer. N Engl J Med. 2017;376(5):417-428.
1. Litwin MS, Tan HJ. The diagnosis and treatment of prostate cancer: a review. JAMA. 2017;317(24):2532-2542.
2. Zhao SG, Chang SL, Erho N, et al. Associations of luminal and basal subtyping of prostate cancer with prognosis and response to androgen deprivation therapy. JAMA Oncol. 2017. [Epub ahead of print.]
3. James ND, de Bono JS, Spears MR, et al; for the STAMPEDE Investigators. Abiraterone for prostate cancer not previously treated with hormone therapy. N Engl J Med. 2017. [Epub ahead of print.]
4. Shipley WU, Seiferheld W, Lukka HR, et al; NRG Oncology RTOG. Radiation with or without antiandrogen therapy in recurrent prostate cancer. N Engl J Med. 2017;376(5):417-428.
Immunotherapies shape the treatment landscape for hematologic malignancies
The treatment landscape for hematologic malignancies is evolving faster than ever before, with a range of available therapeutic options that is now almost as diverse as this group of tumors. Immunotherapy in particular is front and center in the battle to control these diseases. Here, we describe the latest promising developments.
Exploiting T cells
The treatment landscape for hematologic malignancies is diverse, but one particular type of therapy has led the charge in improving patient outcomes. Several features of hematologic malignancies may make them particularly amenable to immunotherapy, including the fact that they are derived from corrupt immune cells and come into constant contact with other immune cells within the hematopoietic environment in which they reside. One of the oldest forms of immunotherapy, hematopoietic stem-cell transplantation (HSCT), remains the only curative option for many patients with hematologic malignancies.1,2
Given the central role of T lymphocytes in antitumor immunity, research efforts have focused on harnessing their activity for cancer treatment. One example of this is adoptive cellular therapy (ACT), in which T cells are collected from a patient, grown outside the body to increase their number and then reinfused back to the patient. Allogeneic HSCT, in which the stem cells are collected from a matching donor and transplanted into the patient, is a crude example of ACT. The graft-versus-tumor effect is driven by donor cells present in the transplant, but is limited by the development of graft-versus-host disease (GvHD), whereby the donor T cells attack healthy host tissue.
Other types of ACT have been developed in an effort to capitalize on the anti-tumor effects of the patients own T cells and thus avoid the potentially fatal complication of GvHD. Tumor-infiltrating lymphocyte (TIL) therapy was developed to exploit the presence of tumor-specific T cells in the tumor microenvironment. To date, the efficacy of TIL therapy has been predominantly limited to melanoma.1,3,4
Most recently, there has been a substantial buzz around the idea of genetically engineering T cells before they are reintroduced into the patient, to increase their anti-tumor efficacy and minimize damage to healthy tissue. This is achieved either by manipulating the antigen binding portion of the T-cell receptor to alter its specificity (TCR T cells) or by generating artificial fusion receptors known as chimeric antigen receptors (CAR T cells; Figure 1). The former is limited by the need for the TCR to be genetically matched to the patient’s immune type, whereas the latter is more flexible in this regard and has proved most successful.
CARs are formed by fusing part of the single-chain variable fragment of a monoclonal antibody to part of the TCR and one or more costimulatory molecules. In this way, the T cell is guided to the tumor through antibody recognition of a particular tumor-associated antigen, whereupon its effector functions are activated by engagement of the TCR and costimulatory signal.5
Headlining advancements with CAR T cells
CAR T cells directed against the CD19 antigen, found on the surface of many hematologic malignancies, are the most clinically advanced in this rapidly evolving field (Table 1). Durable remissions have been demonstrated in patients with relapsed and refractory hematologic malignancies, including non-Hodgkin lymphoma (NHL), chronic lymphocytic leukemia (CLL), and acute lymphoblastic lymphoma (ALL), with efficacy in both the pre- and posttransplant setting and in patients with chemotherapy-refractory disease.4,5
CTL019, a CD19-targeted CAR-T cell therapy, also known as tisagenlecleucel-T, has received breakthrough therapy designation from the US Food and Drug Administration (FDA) for the treatment of pediatric and adult patients with relapsed/refractory B-cell ALL and, more recently, for the treatment of adult patients with relapsed/refractory diffuse large B cell lymphoma.6
It is edging closer to FDA approval for the ALL indication, having been granted priority review in March on the basis of the phase 2 ELIANA trial, in which 50 patients received a single infusion of CTL019. Data presented at the American Society of Hematology annual meeting in December 2016 showed that 82% of patients achieved either complete remission (CR) or CR with incomplete blood count recovery (CRi) 3 months after treatment.7
Meanwhile, Kite Pharma has a rolling submission with the FDA for KTE-C19 (axicabtagene ciloleucel) for the treatment of patients with relapsed/refractory B-cell NHL who are ineligible for HSCT. In the ZUMA-1 trial, this therapy demonstrated an overall response rate (ORR) of 71%.8 Juno Therapeutics is developing several CAR T-cell therapies, including JCAR017, which elicited CR in 60% of patients with relapsed/refractory NHL.9
Target antigens other than CD19 are being explored, but these are mostly in the early stages of clinical development. While the focus has predominantly been on the treatment of lymphoma and leukemia, a presentation at the American Society for Clinical Oncology annual meeting in June reported the efficacy of a CAR-T cell therapy targeting the B-cell maturation antigen in patients with multiple myeloma. Results from 19 patients enrolled in an ongoing phase 1 trial in China showed that 14 had achieved stringent CR, 1 partial remission (PR) and 4 very good partial remission (VGPR).10
Antibodies evolve
Another type of immunotherapy that has revolutionized the treatment of hematologic malignancies is monoclonal antibodies (mAbs), targeting antigens on the surface of malignant B and T cells, in particular CD20. The approval of CD20-targeting mAb rituximab in 1997 was the first coup for the development of immunotherapy for the treatment of hematologic malignancies. It has become part of the standard treatment regimen for B-cell malignancies, including NHL and CLL, in combination with various types of chemotherapy.
Several other CD20-targeting antibodies have been developed (Table 2), some of which work in the same way as rituximab (eg, ofatumumab) and some that have a slightly different mechanism of action (eg, obinutuzumab).11 Both types of antibody have proved highly effective; ofatumumab is FDA approved for the treatment of advanced CLL and is being evaluated in phase 3 trials in other hematologic malignancies, while obinutuzumab has received regulatory approval for the first-line treatment of CLL, replacing the standard rituximab-containing regimen.12
The use of ofatumumab as maintenance therapy is supported by the results of the phase 3 PROLONG study in which 474 patients were randomly assigned to ofatumumab maintenance for 2 years or observation. Over a median follow-up of close to 20 months, ofatumumab-treated patients experienced improved progression-free survival (PFS; median PFS: 29.4 months vs 15.2 months; hazard ratio [HR], 0.50; P < .0001).13 Obinutuzumab’s new indication is based on data from the phase 3 GADOLIN trial, in which the obinutuzumab arm showed improved 3-year PFS compared with rituximab.14Until recently, multiple myeloma had proven relatively resistant to mAb therapy, but two new drug targets have dramatically altered the treatment landscape for this type of hematologic malignancy. CD2 subset 1 (CS1), also known as signaling lymphocytic activation molecule 7 (SLAMF7), and CD38 are glycoproteins expressed highly and nearly uniformly on the surface of multiple myeloma cells and only at low levels on other lymphoid and myeloid cells.15
Several antibodies directed at these targets are in clinical development, but daratumumab and elotuzumab, targeting CD38 and CS1, respectively, are both newly approved by the FDA for relapsed/refractory disease, daratumumab as monotherapy and elotuzumab in combination with lenalidomide and dexamethasone.
The indication for daratumumab was subsequently expanded to include its use in combination with lenalidomide plus dexamethasone or bortezomib plus dexamethasone. Support for this new indication came from 2 pivotal phase 3 trials. In the CASTOR trial, the combination of daratumumab with bortezomib–dexamethasone reduced the risk of disease progression or death by 61%, compared with bortezomib–dexamethasone alone, whereas daratumumab with lenalidomide–dexamethasone reduced the risk of disease progression or death by 63% in the POLLUX trial.16,17
Numerous clinical trials for both drugs are ongoing, including in the front-line setting in multiple myeloma, as well as trials in other types of B-cell malignancy, and several other CD38-targeting mAbs are also in development, including isatuximab, which has reached the phase 3 stage (NCT02990338).
Innovative design
Newer drug designs, which have sought to take mAb therapy to the next level, have also shown significant efficacy in hematologic malignancies. Antibody-drug conjugates (ADCs) combine the cytotoxic efficacy of chemotherapeutic agents with the specificity of a mAb targeting a tumor-specific antigen. This essentially creates a targeted payload that improves upon the efficacy of mAb monotherapy but mitigates some of the side effects of chemotherapy related to their indiscriminate killing of both cancerous and healthy cells.
The development of ADCs has been somewhat of a rollercoaster ride, with the approval and subsequent withdrawal of the first-in-class drug gemtuzumab ozogamicin in 2010, but the field was reinvigorated with the successful development of brentuximab vedotin, which targets the CD30 antigen and is approved for the treatment of multiple different hematologic malignancies, including, most recently, for posttransplant consolidation therapy in patients with Hodgkin lymphoma at high risk of relapse or progression.18
Brentuximab vedotin may soon be joined by another FDA-approved ADC, this one targeting CD22. Inotuzumab ozogamicin was recently granted priority review for the treatment of relapsed/refractory ALL. The FDA is reviewing data from the phase 3 INO-VATE study in which inotuzumab ozogamicin reduced the risk of disease progression or death by 55% compared with standard therapy, and a decision is expected by August.19 Other ADC targets being investigated in clinical trials include CD138, CD19, and CD33 (Table 3). Meanwhile, a meta-analysis of randomized trials suggested that the withdrawal of gemtuzumab ozogamicin may have been premature, indicating that it does improve long-term overall survival (OS) and reduces the risk of relapse.20
Bispecific antibodies that link natural killer (NK) cells to tumor cells, by targeting the NK-cell receptor CD16, known as BiKEs, are also in development in an attempt to harness the power of the innate immune response.
B-cell signaling a ripe target
Beyond immunotherapy, molecularly targeted drugs directed against key drivers of hematologic malignancies are also showing great promise. In particular, the B-cell receptor (BCR) signaling pathway, a central regulator of B-cell function, and its constituent kinases that are frequently dysregulated in B cell malignancies, has emerged as an exciting therapeutic avenue.
A variety of small molecule inhibitors targeting different nodes of the BCR pathway have been developed (Table 4), but the greatest success to date has been achieved with drugs targeting Bruton’s tyrosine kinase (BTK). Their clinical development culminated in the approval of ibrutinib for the treatment of patients with mantle cell lymphoma in 2013 and subsequently for patients with CLL, Waldenström macroglobulinemia, and most recently for patients with marginal zone lymphoma.
More than 100 clinical trials of ibrutinib are ongoing in an effort to further clarify its role in a variety of different disease settings. Furthermore, in an effort to address some of the toxicity concerns with ibrutinib, more specific BTK inhibitors are also being developed.
Other kinases that orchestrate the BCR pathway, including phosphatidylinositol-3-kinase (PI3K) and SYK, are also being targeted. The delta isoform of PI3K is expressed exclusively in hematopoietic cells and a number of PI3K delta inhibitors have been developed. Idelalisib received regulatory approval for the treatment of patients with CLL in combination with rituximab, and for patients with follicular lymphoma and small lymphocytic leukemia.
As with ibrutinib, a plethora of clinical trials are ongoing, however a major setback was suffered in the frontline setting when Gilead Sciences halted 6 clinical trials due to reports of increased rates of adverse events, including deaths.26 Meanwhile, SYK inhibitors have lagged behind somewhat in their development, but one such offering, entospletinib, is showing promise in patients with AML.27
Finally, there has been some success in targeting one of the downstream targets of the BCR signaling pathway, the Bcl2 protein that is involved in the regulation of apoptosis. Venetoclax was approved last year for the treatment of patients with relapsed/refractory CLL in patients who have a chromosome 17p deletion, based on the demonstration of impressive, durable responses.28
1. Bachireddy P, Burkhardt UE, Rajasagi M, Wu CJ. Haemato- logical malignancies: at the forefront of immunotherapeutic innovation. Nat Rev Cancer. 2015;15(4):201-215.
2. Im A, Pavletic SZ. Immunotherapy in hematologic malignancies: past, present, and future. J Hematol Oncol. 2017;10(1):94.
3. Gill S. Planes, trains, and automobiles: perspectives on CAR T cells and other cellular therapies for hematologic malignancies. Curr Hematol Malig Rep. 2016;11(4):318-325.
4. Ye B, Stary CM, Gao Q, et al. Genetically modified T-cell-based adoptive immunotherapy in hematological malignancies. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5237740/. Published January 2, 2017. Accessed July 22, 2017.
5. Sharpe M, Mount N. Genetically modified T cells in cancer therapy: opportunities and challenges. Dis Model Mech. 2015;8(4):337-350.
6. Novartis. Novartis personalized cell therapy CTL019 receives FDA breakthrough therapy designation. https://www.novartis.com/news/media-releases/novartis-personalized-cell-therapy-ctl019-receivesfda-breakthrough-therapy. Published July 7, 2014. Accessed June 19,
2017.
7. Novartis. Novartis presents results from first global registration trial of CTL019 in pediatric and young adult patients with r/r B-ALL. https://www.novartis.com/news/media-releases/novartis-presentsresults-first-global-registration-trial-ctl019-pediatric-and. Published December 4, 2016. Accessed June 19, 2017.
8. Locke FL, Neelapu SS, Bartlett NL, et al. Phase 1 Results of ZUMA1: a multicenter study of KTE-C19 Anti-CD19 CAR T cell therapy in refractory aggressive lymphoma. Mol Ther. 2017;25(1):285-295.
9. Abramson JS, Palomba L, Gordon L. Transcend NHL 001: immunotherapy with the CD19-Directd CAR T-cell product JCAR017 results in high complete response rates in relapsed or refractory B-cell non-Hodgkin lymphoma. Paper presented at 58th American Society of Hematology Annual Meeting; December 3-6, 2016; San Diego, CA.
10. Fan F, Zhao W, Liu J, et al. Durable remissions with BCMA-specific chimeric antigen receptor (CAR)-modified T cells in patients with refractory/relapsed multiple myeloma. J Clin Oncol. 2017;35(suppl;):Abstr LBA3001.
11. Okroj M, Osterborg A, Blom AM. Effector mechanisms of anti-CD20 monoclonal antibodies in B cell malignancies. Cancer Treat Rev. 2013;39(6):632-639.
12. Safdari Y, Ahmadzadeh V, Farajnia S. CD20-targeting in B-cell malignancies: novel prospects for antibodies and combination therapies. Invest New Drugs. 2016;34(4):497-512.
13. van Oers MH, Kuliczkowski K, Smolej L, et al. Ofatumumab maintenance versus observation in relapsed chronic lymphocytic leukaemia (PROLONG): an open-label, multicentre, randomised phase 3 study. Lancet Oncol. 2015;16(13):1370-1379.
14. Sehn LH, Chua N, Mayer J, et al. Obinutuzumab plus bendamustine versus bendamustine monotherapy in patients with rituximab-refractory indolent non-Hodgkin lymphoma (GADOLIN): a randomised, controlled, open-label, multicentre, phase 3 trial. Lancet Oncol. 2016;17(8):1081-1093.
15. Touzeau C, Moreau P, Dumontet C. Monoclonal antibody therapy in multiple myeloma. Leukemia. 2017;31(5):1039-1047.
16. Palumbo A, Chanan-Khan A, Weisel K, et al. Daratumumab, bortezomib, and dexamethasone for multiple myeloma. N Engl J Med. 2016;375(8):754-766.
17. Dimopoulos MA, Oriol A, Nahi H, et al. Daratumumab, lenalidomide, and dexamethasone for multiple myeloma. N Engl J Med. 2016;375(14):1319-1331.
18. Beck A, Goetsch L, Dumontet C, Corvaia N. Strategies and challenges for the next generation of antibody-drug conjugates. Nat Rev Drug Discov. 2017;16(5):315-337.
19. Kantarjian HM, DeAngelo DJ, Stelljes M, et al. Inotuzumab ozogamicin versus standard therapy for acute lymphoblastic leukemia. N Engl J Med. 2016;375(8):740-753.
20. Hills RK, Castaigne S, Appelbaum FR, et al. Addition of gemtuzumab ozogamicin to induction chemotherapy in adult patients with acute myeloid leukaemia: a meta-analysis of individual patient data from randomised controlled trials. Lancet Oncol. 2014;15(9):986-996.
21. Huehls AM, Coupet TA, Sentman CL. Bispecific T-cell engagers for cancer immunotherapy. Immunol Cell Biol. 2015;93(3):290-296.
22. Kantarjian H, Stein A, Gokbuget N, et al. Blinatumomab versus chemotherapy for advanced acute lymphoblastic leukemia. N Engl J Med. 2017;376(9):836-847.
23. Koehrer S, Burger JA. B-cell receptor signaling in chronic lymphocytic leukemia and other B-cell malignancies. Clin Adv Hematol Oncol. 2016;14(1):55-65.
24. Seda V, Mraz M. B-cell receptor signalling and its crosstalk with other pathways in normal and malignant cells. Eur J Haematol. 2015;94(3):193-205.
25. Bojarczuk K, Bobrowicz M, Dwojak M, et al. B-cell receptor signaling in the pathogenesis of lymphoid malignancies. Blood Cells Mol Dis. 2015;55(3):255-265.
26. Medscape Medical News. Gilead stops six trials adding idelalisib to other drugs. http://www.medscape.com/viewarticle/860372. Published March 14, 2016. Accessed June 19, 2017.
27. Sharman J, Di Paolo J. Targeting B-cell receptor signaling kinases in chronic lymphocytic leukemia: the promise of entospletinib. Ther Adv Hematol. 2016;7(3):157-170.
28. Food and Drug Administration. FDA approves new drug for chronic lymphocytic leukemia in patients with a specific chromosomal abnormality. https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm495253.htm. Released April 11, 2016. Accessed June 19, 2017.
The treatment landscape for hematologic malignancies is evolving faster than ever before, with a range of available therapeutic options that is now almost as diverse as this group of tumors. Immunotherapy in particular is front and center in the battle to control these diseases. Here, we describe the latest promising developments.
Exploiting T cells
The treatment landscape for hematologic malignancies is diverse, but one particular type of therapy has led the charge in improving patient outcomes. Several features of hematologic malignancies may make them particularly amenable to immunotherapy, including the fact that they are derived from corrupt immune cells and come into constant contact with other immune cells within the hematopoietic environment in which they reside. One of the oldest forms of immunotherapy, hematopoietic stem-cell transplantation (HSCT), remains the only curative option for many patients with hematologic malignancies.1,2
Given the central role of T lymphocytes in antitumor immunity, research efforts have focused on harnessing their activity for cancer treatment. One example of this is adoptive cellular therapy (ACT), in which T cells are collected from a patient, grown outside the body to increase their number and then reinfused back to the patient. Allogeneic HSCT, in which the stem cells are collected from a matching donor and transplanted into the patient, is a crude example of ACT. The graft-versus-tumor effect is driven by donor cells present in the transplant, but is limited by the development of graft-versus-host disease (GvHD), whereby the donor T cells attack healthy host tissue.
Other types of ACT have been developed in an effort to capitalize on the anti-tumor effects of the patients own T cells and thus avoid the potentially fatal complication of GvHD. Tumor-infiltrating lymphocyte (TIL) therapy was developed to exploit the presence of tumor-specific T cells in the tumor microenvironment. To date, the efficacy of TIL therapy has been predominantly limited to melanoma.1,3,4
Most recently, there has been a substantial buzz around the idea of genetically engineering T cells before they are reintroduced into the patient, to increase their anti-tumor efficacy and minimize damage to healthy tissue. This is achieved either by manipulating the antigen binding portion of the T-cell receptor to alter its specificity (TCR T cells) or by generating artificial fusion receptors known as chimeric antigen receptors (CAR T cells; Figure 1). The former is limited by the need for the TCR to be genetically matched to the patient’s immune type, whereas the latter is more flexible in this regard and has proved most successful.
CARs are formed by fusing part of the single-chain variable fragment of a monoclonal antibody to part of the TCR and one or more costimulatory molecules. In this way, the T cell is guided to the tumor through antibody recognition of a particular tumor-associated antigen, whereupon its effector functions are activated by engagement of the TCR and costimulatory signal.5
Headlining advancements with CAR T cells
CAR T cells directed against the CD19 antigen, found on the surface of many hematologic malignancies, are the most clinically advanced in this rapidly evolving field (Table 1). Durable remissions have been demonstrated in patients with relapsed and refractory hematologic malignancies, including non-Hodgkin lymphoma (NHL), chronic lymphocytic leukemia (CLL), and acute lymphoblastic lymphoma (ALL), with efficacy in both the pre- and posttransplant setting and in patients with chemotherapy-refractory disease.4,5
CTL019, a CD19-targeted CAR-T cell therapy, also known as tisagenlecleucel-T, has received breakthrough therapy designation from the US Food and Drug Administration (FDA) for the treatment of pediatric and adult patients with relapsed/refractory B-cell ALL and, more recently, for the treatment of adult patients with relapsed/refractory diffuse large B cell lymphoma.6
It is edging closer to FDA approval for the ALL indication, having been granted priority review in March on the basis of the phase 2 ELIANA trial, in which 50 patients received a single infusion of CTL019. Data presented at the American Society of Hematology annual meeting in December 2016 showed that 82% of patients achieved either complete remission (CR) or CR with incomplete blood count recovery (CRi) 3 months after treatment.7
Meanwhile, Kite Pharma has a rolling submission with the FDA for KTE-C19 (axicabtagene ciloleucel) for the treatment of patients with relapsed/refractory B-cell NHL who are ineligible for HSCT. In the ZUMA-1 trial, this therapy demonstrated an overall response rate (ORR) of 71%.8 Juno Therapeutics is developing several CAR T-cell therapies, including JCAR017, which elicited CR in 60% of patients with relapsed/refractory NHL.9
Target antigens other than CD19 are being explored, but these are mostly in the early stages of clinical development. While the focus has predominantly been on the treatment of lymphoma and leukemia, a presentation at the American Society for Clinical Oncology annual meeting in June reported the efficacy of a CAR-T cell therapy targeting the B-cell maturation antigen in patients with multiple myeloma. Results from 19 patients enrolled in an ongoing phase 1 trial in China showed that 14 had achieved stringent CR, 1 partial remission (PR) and 4 very good partial remission (VGPR).10
Antibodies evolve
Another type of immunotherapy that has revolutionized the treatment of hematologic malignancies is monoclonal antibodies (mAbs), targeting antigens on the surface of malignant B and T cells, in particular CD20. The approval of CD20-targeting mAb rituximab in 1997 was the first coup for the development of immunotherapy for the treatment of hematologic malignancies. It has become part of the standard treatment regimen for B-cell malignancies, including NHL and CLL, in combination with various types of chemotherapy.
Several other CD20-targeting antibodies have been developed (Table 2), some of which work in the same way as rituximab (eg, ofatumumab) and some that have a slightly different mechanism of action (eg, obinutuzumab).11 Both types of antibody have proved highly effective; ofatumumab is FDA approved for the treatment of advanced CLL and is being evaluated in phase 3 trials in other hematologic malignancies, while obinutuzumab has received regulatory approval for the first-line treatment of CLL, replacing the standard rituximab-containing regimen.12
The use of ofatumumab as maintenance therapy is supported by the results of the phase 3 PROLONG study in which 474 patients were randomly assigned to ofatumumab maintenance for 2 years or observation. Over a median follow-up of close to 20 months, ofatumumab-treated patients experienced improved progression-free survival (PFS; median PFS: 29.4 months vs 15.2 months; hazard ratio [HR], 0.50; P < .0001).13 Obinutuzumab’s new indication is based on data from the phase 3 GADOLIN trial, in which the obinutuzumab arm showed improved 3-year PFS compared with rituximab.14Until recently, multiple myeloma had proven relatively resistant to mAb therapy, but two new drug targets have dramatically altered the treatment landscape for this type of hematologic malignancy. CD2 subset 1 (CS1), also known as signaling lymphocytic activation molecule 7 (SLAMF7), and CD38 are glycoproteins expressed highly and nearly uniformly on the surface of multiple myeloma cells and only at low levels on other lymphoid and myeloid cells.15
Several antibodies directed at these targets are in clinical development, but daratumumab and elotuzumab, targeting CD38 and CS1, respectively, are both newly approved by the FDA for relapsed/refractory disease, daratumumab as monotherapy and elotuzumab in combination with lenalidomide and dexamethasone.
The indication for daratumumab was subsequently expanded to include its use in combination with lenalidomide plus dexamethasone or bortezomib plus dexamethasone. Support for this new indication came from 2 pivotal phase 3 trials. In the CASTOR trial, the combination of daratumumab with bortezomib–dexamethasone reduced the risk of disease progression or death by 61%, compared with bortezomib–dexamethasone alone, whereas daratumumab with lenalidomide–dexamethasone reduced the risk of disease progression or death by 63% in the POLLUX trial.16,17
Numerous clinical trials for both drugs are ongoing, including in the front-line setting in multiple myeloma, as well as trials in other types of B-cell malignancy, and several other CD38-targeting mAbs are also in development, including isatuximab, which has reached the phase 3 stage (NCT02990338).
Innovative design
Newer drug designs, which have sought to take mAb therapy to the next level, have also shown significant efficacy in hematologic malignancies. Antibody-drug conjugates (ADCs) combine the cytotoxic efficacy of chemotherapeutic agents with the specificity of a mAb targeting a tumor-specific antigen. This essentially creates a targeted payload that improves upon the efficacy of mAb monotherapy but mitigates some of the side effects of chemotherapy related to their indiscriminate killing of both cancerous and healthy cells.
The development of ADCs has been somewhat of a rollercoaster ride, with the approval and subsequent withdrawal of the first-in-class drug gemtuzumab ozogamicin in 2010, but the field was reinvigorated with the successful development of brentuximab vedotin, which targets the CD30 antigen and is approved for the treatment of multiple different hematologic malignancies, including, most recently, for posttransplant consolidation therapy in patients with Hodgkin lymphoma at high risk of relapse or progression.18
Brentuximab vedotin may soon be joined by another FDA-approved ADC, this one targeting CD22. Inotuzumab ozogamicin was recently granted priority review for the treatment of relapsed/refractory ALL. The FDA is reviewing data from the phase 3 INO-VATE study in which inotuzumab ozogamicin reduced the risk of disease progression or death by 55% compared with standard therapy, and a decision is expected by August.19 Other ADC targets being investigated in clinical trials include CD138, CD19, and CD33 (Table 3). Meanwhile, a meta-analysis of randomized trials suggested that the withdrawal of gemtuzumab ozogamicin may have been premature, indicating that it does improve long-term overall survival (OS) and reduces the risk of relapse.20
Bispecific antibodies that link natural killer (NK) cells to tumor cells, by targeting the NK-cell receptor CD16, known as BiKEs, are also in development in an attempt to harness the power of the innate immune response.
B-cell signaling a ripe target
Beyond immunotherapy, molecularly targeted drugs directed against key drivers of hematologic malignancies are also showing great promise. In particular, the B-cell receptor (BCR) signaling pathway, a central regulator of B-cell function, and its constituent kinases that are frequently dysregulated in B cell malignancies, has emerged as an exciting therapeutic avenue.
A variety of small molecule inhibitors targeting different nodes of the BCR pathway have been developed (Table 4), but the greatest success to date has been achieved with drugs targeting Bruton’s tyrosine kinase (BTK). Their clinical development culminated in the approval of ibrutinib for the treatment of patients with mantle cell lymphoma in 2013 and subsequently for patients with CLL, Waldenström macroglobulinemia, and most recently for patients with marginal zone lymphoma.
More than 100 clinical trials of ibrutinib are ongoing in an effort to further clarify its role in a variety of different disease settings. Furthermore, in an effort to address some of the toxicity concerns with ibrutinib, more specific BTK inhibitors are also being developed.
Other kinases that orchestrate the BCR pathway, including phosphatidylinositol-3-kinase (PI3K) and SYK, are also being targeted. The delta isoform of PI3K is expressed exclusively in hematopoietic cells and a number of PI3K delta inhibitors have been developed. Idelalisib received regulatory approval for the treatment of patients with CLL in combination with rituximab, and for patients with follicular lymphoma and small lymphocytic leukemia.
As with ibrutinib, a plethora of clinical trials are ongoing, however a major setback was suffered in the frontline setting when Gilead Sciences halted 6 clinical trials due to reports of increased rates of adverse events, including deaths.26 Meanwhile, SYK inhibitors have lagged behind somewhat in their development, but one such offering, entospletinib, is showing promise in patients with AML.27
Finally, there has been some success in targeting one of the downstream targets of the BCR signaling pathway, the Bcl2 protein that is involved in the regulation of apoptosis. Venetoclax was approved last year for the treatment of patients with relapsed/refractory CLL in patients who have a chromosome 17p deletion, based on the demonstration of impressive, durable responses.28
The treatment landscape for hematologic malignancies is evolving faster than ever before, with a range of available therapeutic options that is now almost as diverse as this group of tumors. Immunotherapy in particular is front and center in the battle to control these diseases. Here, we describe the latest promising developments.
Exploiting T cells
The treatment landscape for hematologic malignancies is diverse, but one particular type of therapy has led the charge in improving patient outcomes. Several features of hematologic malignancies may make them particularly amenable to immunotherapy, including the fact that they are derived from corrupt immune cells and come into constant contact with other immune cells within the hematopoietic environment in which they reside. One of the oldest forms of immunotherapy, hematopoietic stem-cell transplantation (HSCT), remains the only curative option for many patients with hematologic malignancies.1,2
Given the central role of T lymphocytes in antitumor immunity, research efforts have focused on harnessing their activity for cancer treatment. One example of this is adoptive cellular therapy (ACT), in which T cells are collected from a patient, grown outside the body to increase their number and then reinfused back to the patient. Allogeneic HSCT, in which the stem cells are collected from a matching donor and transplanted into the patient, is a crude example of ACT. The graft-versus-tumor effect is driven by donor cells present in the transplant, but is limited by the development of graft-versus-host disease (GvHD), whereby the donor T cells attack healthy host tissue.
Other types of ACT have been developed in an effort to capitalize on the anti-tumor effects of the patients own T cells and thus avoid the potentially fatal complication of GvHD. Tumor-infiltrating lymphocyte (TIL) therapy was developed to exploit the presence of tumor-specific T cells in the tumor microenvironment. To date, the efficacy of TIL therapy has been predominantly limited to melanoma.1,3,4
Most recently, there has been a substantial buzz around the idea of genetically engineering T cells before they are reintroduced into the patient, to increase their anti-tumor efficacy and minimize damage to healthy tissue. This is achieved either by manipulating the antigen binding portion of the T-cell receptor to alter its specificity (TCR T cells) or by generating artificial fusion receptors known as chimeric antigen receptors (CAR T cells; Figure 1). The former is limited by the need for the TCR to be genetically matched to the patient’s immune type, whereas the latter is more flexible in this regard and has proved most successful.
CARs are formed by fusing part of the single-chain variable fragment of a monoclonal antibody to part of the TCR and one or more costimulatory molecules. In this way, the T cell is guided to the tumor through antibody recognition of a particular tumor-associated antigen, whereupon its effector functions are activated by engagement of the TCR and costimulatory signal.5
Headlining advancements with CAR T cells
CAR T cells directed against the CD19 antigen, found on the surface of many hematologic malignancies, are the most clinically advanced in this rapidly evolving field (Table 1). Durable remissions have been demonstrated in patients with relapsed and refractory hematologic malignancies, including non-Hodgkin lymphoma (NHL), chronic lymphocytic leukemia (CLL), and acute lymphoblastic lymphoma (ALL), with efficacy in both the pre- and posttransplant setting and in patients with chemotherapy-refractory disease.4,5
CTL019, a CD19-targeted CAR-T cell therapy, also known as tisagenlecleucel-T, has received breakthrough therapy designation from the US Food and Drug Administration (FDA) for the treatment of pediatric and adult patients with relapsed/refractory B-cell ALL and, more recently, for the treatment of adult patients with relapsed/refractory diffuse large B cell lymphoma.6
It is edging closer to FDA approval for the ALL indication, having been granted priority review in March on the basis of the phase 2 ELIANA trial, in which 50 patients received a single infusion of CTL019. Data presented at the American Society of Hematology annual meeting in December 2016 showed that 82% of patients achieved either complete remission (CR) or CR with incomplete blood count recovery (CRi) 3 months after treatment.7
Meanwhile, Kite Pharma has a rolling submission with the FDA for KTE-C19 (axicabtagene ciloleucel) for the treatment of patients with relapsed/refractory B-cell NHL who are ineligible for HSCT. In the ZUMA-1 trial, this therapy demonstrated an overall response rate (ORR) of 71%.8 Juno Therapeutics is developing several CAR T-cell therapies, including JCAR017, which elicited CR in 60% of patients with relapsed/refractory NHL.9
Target antigens other than CD19 are being explored, but these are mostly in the early stages of clinical development. While the focus has predominantly been on the treatment of lymphoma and leukemia, a presentation at the American Society for Clinical Oncology annual meeting in June reported the efficacy of a CAR-T cell therapy targeting the B-cell maturation antigen in patients with multiple myeloma. Results from 19 patients enrolled in an ongoing phase 1 trial in China showed that 14 had achieved stringent CR, 1 partial remission (PR) and 4 very good partial remission (VGPR).10
Antibodies evolve
Another type of immunotherapy that has revolutionized the treatment of hematologic malignancies is monoclonal antibodies (mAbs), targeting antigens on the surface of malignant B and T cells, in particular CD20. The approval of CD20-targeting mAb rituximab in 1997 was the first coup for the development of immunotherapy for the treatment of hematologic malignancies. It has become part of the standard treatment regimen for B-cell malignancies, including NHL and CLL, in combination with various types of chemotherapy.
Several other CD20-targeting antibodies have been developed (Table 2), some of which work in the same way as rituximab (eg, ofatumumab) and some that have a slightly different mechanism of action (eg, obinutuzumab).11 Both types of antibody have proved highly effective; ofatumumab is FDA approved for the treatment of advanced CLL and is being evaluated in phase 3 trials in other hematologic malignancies, while obinutuzumab has received regulatory approval for the first-line treatment of CLL, replacing the standard rituximab-containing regimen.12
The use of ofatumumab as maintenance therapy is supported by the results of the phase 3 PROLONG study in which 474 patients were randomly assigned to ofatumumab maintenance for 2 years or observation. Over a median follow-up of close to 20 months, ofatumumab-treated patients experienced improved progression-free survival (PFS; median PFS: 29.4 months vs 15.2 months; hazard ratio [HR], 0.50; P < .0001).13 Obinutuzumab’s new indication is based on data from the phase 3 GADOLIN trial, in which the obinutuzumab arm showed improved 3-year PFS compared with rituximab.14Until recently, multiple myeloma had proven relatively resistant to mAb therapy, but two new drug targets have dramatically altered the treatment landscape for this type of hematologic malignancy. CD2 subset 1 (CS1), also known as signaling lymphocytic activation molecule 7 (SLAMF7), and CD38 are glycoproteins expressed highly and nearly uniformly on the surface of multiple myeloma cells and only at low levels on other lymphoid and myeloid cells.15
Several antibodies directed at these targets are in clinical development, but daratumumab and elotuzumab, targeting CD38 and CS1, respectively, are both newly approved by the FDA for relapsed/refractory disease, daratumumab as monotherapy and elotuzumab in combination with lenalidomide and dexamethasone.
The indication for daratumumab was subsequently expanded to include its use in combination with lenalidomide plus dexamethasone or bortezomib plus dexamethasone. Support for this new indication came from 2 pivotal phase 3 trials. In the CASTOR trial, the combination of daratumumab with bortezomib–dexamethasone reduced the risk of disease progression or death by 61%, compared with bortezomib–dexamethasone alone, whereas daratumumab with lenalidomide–dexamethasone reduced the risk of disease progression or death by 63% in the POLLUX trial.16,17
Numerous clinical trials for both drugs are ongoing, including in the front-line setting in multiple myeloma, as well as trials in other types of B-cell malignancy, and several other CD38-targeting mAbs are also in development, including isatuximab, which has reached the phase 3 stage (NCT02990338).
Innovative design
Newer drug designs, which have sought to take mAb therapy to the next level, have also shown significant efficacy in hematologic malignancies. Antibody-drug conjugates (ADCs) combine the cytotoxic efficacy of chemotherapeutic agents with the specificity of a mAb targeting a tumor-specific antigen. This essentially creates a targeted payload that improves upon the efficacy of mAb monotherapy but mitigates some of the side effects of chemotherapy related to their indiscriminate killing of both cancerous and healthy cells.
The development of ADCs has been somewhat of a rollercoaster ride, with the approval and subsequent withdrawal of the first-in-class drug gemtuzumab ozogamicin in 2010, but the field was reinvigorated with the successful development of brentuximab vedotin, which targets the CD30 antigen and is approved for the treatment of multiple different hematologic malignancies, including, most recently, for posttransplant consolidation therapy in patients with Hodgkin lymphoma at high risk of relapse or progression.18
Brentuximab vedotin may soon be joined by another FDA-approved ADC, this one targeting CD22. Inotuzumab ozogamicin was recently granted priority review for the treatment of relapsed/refractory ALL. The FDA is reviewing data from the phase 3 INO-VATE study in which inotuzumab ozogamicin reduced the risk of disease progression or death by 55% compared with standard therapy, and a decision is expected by August.19 Other ADC targets being investigated in clinical trials include CD138, CD19, and CD33 (Table 3). Meanwhile, a meta-analysis of randomized trials suggested that the withdrawal of gemtuzumab ozogamicin may have been premature, indicating that it does improve long-term overall survival (OS) and reduces the risk of relapse.20
Bispecific antibodies that link natural killer (NK) cells to tumor cells, by targeting the NK-cell receptor CD16, known as BiKEs, are also in development in an attempt to harness the power of the innate immune response.
B-cell signaling a ripe target
Beyond immunotherapy, molecularly targeted drugs directed against key drivers of hematologic malignancies are also showing great promise. In particular, the B-cell receptor (BCR) signaling pathway, a central regulator of B-cell function, and its constituent kinases that are frequently dysregulated in B cell malignancies, has emerged as an exciting therapeutic avenue.
A variety of small molecule inhibitors targeting different nodes of the BCR pathway have been developed (Table 4), but the greatest success to date has been achieved with drugs targeting Bruton’s tyrosine kinase (BTK). Their clinical development culminated in the approval of ibrutinib for the treatment of patients with mantle cell lymphoma in 2013 and subsequently for patients with CLL, Waldenström macroglobulinemia, and most recently for patients with marginal zone lymphoma.
More than 100 clinical trials of ibrutinib are ongoing in an effort to further clarify its role in a variety of different disease settings. Furthermore, in an effort to address some of the toxicity concerns with ibrutinib, more specific BTK inhibitors are also being developed.
Other kinases that orchestrate the BCR pathway, including phosphatidylinositol-3-kinase (PI3K) and SYK, are also being targeted. The delta isoform of PI3K is expressed exclusively in hematopoietic cells and a number of PI3K delta inhibitors have been developed. Idelalisib received regulatory approval for the treatment of patients with CLL in combination with rituximab, and for patients with follicular lymphoma and small lymphocytic leukemia.
As with ibrutinib, a plethora of clinical trials are ongoing, however a major setback was suffered in the frontline setting when Gilead Sciences halted 6 clinical trials due to reports of increased rates of adverse events, including deaths.26 Meanwhile, SYK inhibitors have lagged behind somewhat in their development, but one such offering, entospletinib, is showing promise in patients with AML.27
Finally, there has been some success in targeting one of the downstream targets of the BCR signaling pathway, the Bcl2 protein that is involved in the regulation of apoptosis. Venetoclax was approved last year for the treatment of patients with relapsed/refractory CLL in patients who have a chromosome 17p deletion, based on the demonstration of impressive, durable responses.28
1. Bachireddy P, Burkhardt UE, Rajasagi M, Wu CJ. Haemato- logical malignancies: at the forefront of immunotherapeutic innovation. Nat Rev Cancer. 2015;15(4):201-215.
2. Im A, Pavletic SZ. Immunotherapy in hematologic malignancies: past, present, and future. J Hematol Oncol. 2017;10(1):94.
3. Gill S. Planes, trains, and automobiles: perspectives on CAR T cells and other cellular therapies for hematologic malignancies. Curr Hematol Malig Rep. 2016;11(4):318-325.
4. Ye B, Stary CM, Gao Q, et al. Genetically modified T-cell-based adoptive immunotherapy in hematological malignancies. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5237740/. Published January 2, 2017. Accessed July 22, 2017.
5. Sharpe M, Mount N. Genetically modified T cells in cancer therapy: opportunities and challenges. Dis Model Mech. 2015;8(4):337-350.
6. Novartis. Novartis personalized cell therapy CTL019 receives FDA breakthrough therapy designation. https://www.novartis.com/news/media-releases/novartis-personalized-cell-therapy-ctl019-receivesfda-breakthrough-therapy. Published July 7, 2014. Accessed June 19,
2017.
7. Novartis. Novartis presents results from first global registration trial of CTL019 in pediatric and young adult patients with r/r B-ALL. https://www.novartis.com/news/media-releases/novartis-presentsresults-first-global-registration-trial-ctl019-pediatric-and. Published December 4, 2016. Accessed June 19, 2017.
8. Locke FL, Neelapu SS, Bartlett NL, et al. Phase 1 Results of ZUMA1: a multicenter study of KTE-C19 Anti-CD19 CAR T cell therapy in refractory aggressive lymphoma. Mol Ther. 2017;25(1):285-295.
9. Abramson JS, Palomba L, Gordon L. Transcend NHL 001: immunotherapy with the CD19-Directd CAR T-cell product JCAR017 results in high complete response rates in relapsed or refractory B-cell non-Hodgkin lymphoma. Paper presented at 58th American Society of Hematology Annual Meeting; December 3-6, 2016; San Diego, CA.
10. Fan F, Zhao W, Liu J, et al. Durable remissions with BCMA-specific chimeric antigen receptor (CAR)-modified T cells in patients with refractory/relapsed multiple myeloma. J Clin Oncol. 2017;35(suppl;):Abstr LBA3001.
11. Okroj M, Osterborg A, Blom AM. Effector mechanisms of anti-CD20 monoclonal antibodies in B cell malignancies. Cancer Treat Rev. 2013;39(6):632-639.
12. Safdari Y, Ahmadzadeh V, Farajnia S. CD20-targeting in B-cell malignancies: novel prospects for antibodies and combination therapies. Invest New Drugs. 2016;34(4):497-512.
13. van Oers MH, Kuliczkowski K, Smolej L, et al. Ofatumumab maintenance versus observation in relapsed chronic lymphocytic leukaemia (PROLONG): an open-label, multicentre, randomised phase 3 study. Lancet Oncol. 2015;16(13):1370-1379.
14. Sehn LH, Chua N, Mayer J, et al. Obinutuzumab plus bendamustine versus bendamustine monotherapy in patients with rituximab-refractory indolent non-Hodgkin lymphoma (GADOLIN): a randomised, controlled, open-label, multicentre, phase 3 trial. Lancet Oncol. 2016;17(8):1081-1093.
15. Touzeau C, Moreau P, Dumontet C. Monoclonal antibody therapy in multiple myeloma. Leukemia. 2017;31(5):1039-1047.
16. Palumbo A, Chanan-Khan A, Weisel K, et al. Daratumumab, bortezomib, and dexamethasone for multiple myeloma. N Engl J Med. 2016;375(8):754-766.
17. Dimopoulos MA, Oriol A, Nahi H, et al. Daratumumab, lenalidomide, and dexamethasone for multiple myeloma. N Engl J Med. 2016;375(14):1319-1331.
18. Beck A, Goetsch L, Dumontet C, Corvaia N. Strategies and challenges for the next generation of antibody-drug conjugates. Nat Rev Drug Discov. 2017;16(5):315-337.
19. Kantarjian HM, DeAngelo DJ, Stelljes M, et al. Inotuzumab ozogamicin versus standard therapy for acute lymphoblastic leukemia. N Engl J Med. 2016;375(8):740-753.
20. Hills RK, Castaigne S, Appelbaum FR, et al. Addition of gemtuzumab ozogamicin to induction chemotherapy in adult patients with acute myeloid leukaemia: a meta-analysis of individual patient data from randomised controlled trials. Lancet Oncol. 2014;15(9):986-996.
21. Huehls AM, Coupet TA, Sentman CL. Bispecific T-cell engagers for cancer immunotherapy. Immunol Cell Biol. 2015;93(3):290-296.
22. Kantarjian H, Stein A, Gokbuget N, et al. Blinatumomab versus chemotherapy for advanced acute lymphoblastic leukemia. N Engl J Med. 2017;376(9):836-847.
23. Koehrer S, Burger JA. B-cell receptor signaling in chronic lymphocytic leukemia and other B-cell malignancies. Clin Adv Hematol Oncol. 2016;14(1):55-65.
24. Seda V, Mraz M. B-cell receptor signalling and its crosstalk with other pathways in normal and malignant cells. Eur J Haematol. 2015;94(3):193-205.
25. Bojarczuk K, Bobrowicz M, Dwojak M, et al. B-cell receptor signaling in the pathogenesis of lymphoid malignancies. Blood Cells Mol Dis. 2015;55(3):255-265.
26. Medscape Medical News. Gilead stops six trials adding idelalisib to other drugs. http://www.medscape.com/viewarticle/860372. Published March 14, 2016. Accessed June 19, 2017.
27. Sharman J, Di Paolo J. Targeting B-cell receptor signaling kinases in chronic lymphocytic leukemia: the promise of entospletinib. Ther Adv Hematol. 2016;7(3):157-170.
28. Food and Drug Administration. FDA approves new drug for chronic lymphocytic leukemia in patients with a specific chromosomal abnormality. https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm495253.htm. Released April 11, 2016. Accessed June 19, 2017.
1. Bachireddy P, Burkhardt UE, Rajasagi M, Wu CJ. Haemato- logical malignancies: at the forefront of immunotherapeutic innovation. Nat Rev Cancer. 2015;15(4):201-215.
2. Im A, Pavletic SZ. Immunotherapy in hematologic malignancies: past, present, and future. J Hematol Oncol. 2017;10(1):94.
3. Gill S. Planes, trains, and automobiles: perspectives on CAR T cells and other cellular therapies for hematologic malignancies. Curr Hematol Malig Rep. 2016;11(4):318-325.
4. Ye B, Stary CM, Gao Q, et al. Genetically modified T-cell-based adoptive immunotherapy in hematological malignancies. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5237740/. Published January 2, 2017. Accessed July 22, 2017.
5. Sharpe M, Mount N. Genetically modified T cells in cancer therapy: opportunities and challenges. Dis Model Mech. 2015;8(4):337-350.
6. Novartis. Novartis personalized cell therapy CTL019 receives FDA breakthrough therapy designation. https://www.novartis.com/news/media-releases/novartis-personalized-cell-therapy-ctl019-receivesfda-breakthrough-therapy. Published July 7, 2014. Accessed June 19,
2017.
7. Novartis. Novartis presents results from first global registration trial of CTL019 in pediatric and young adult patients with r/r B-ALL. https://www.novartis.com/news/media-releases/novartis-presentsresults-first-global-registration-trial-ctl019-pediatric-and. Published December 4, 2016. Accessed June 19, 2017.
8. Locke FL, Neelapu SS, Bartlett NL, et al. Phase 1 Results of ZUMA1: a multicenter study of KTE-C19 Anti-CD19 CAR T cell therapy in refractory aggressive lymphoma. Mol Ther. 2017;25(1):285-295.
9. Abramson JS, Palomba L, Gordon L. Transcend NHL 001: immunotherapy with the CD19-Directd CAR T-cell product JCAR017 results in high complete response rates in relapsed or refractory B-cell non-Hodgkin lymphoma. Paper presented at 58th American Society of Hematology Annual Meeting; December 3-6, 2016; San Diego, CA.
10. Fan F, Zhao W, Liu J, et al. Durable remissions with BCMA-specific chimeric antigen receptor (CAR)-modified T cells in patients with refractory/relapsed multiple myeloma. J Clin Oncol. 2017;35(suppl;):Abstr LBA3001.
11. Okroj M, Osterborg A, Blom AM. Effector mechanisms of anti-CD20 monoclonal antibodies in B cell malignancies. Cancer Treat Rev. 2013;39(6):632-639.
12. Safdari Y, Ahmadzadeh V, Farajnia S. CD20-targeting in B-cell malignancies: novel prospects for antibodies and combination therapies. Invest New Drugs. 2016;34(4):497-512.
13. van Oers MH, Kuliczkowski K, Smolej L, et al. Ofatumumab maintenance versus observation in relapsed chronic lymphocytic leukaemia (PROLONG): an open-label, multicentre, randomised phase 3 study. Lancet Oncol. 2015;16(13):1370-1379.
14. Sehn LH, Chua N, Mayer J, et al. Obinutuzumab plus bendamustine versus bendamustine monotherapy in patients with rituximab-refractory indolent non-Hodgkin lymphoma (GADOLIN): a randomised, controlled, open-label, multicentre, phase 3 trial. Lancet Oncol. 2016;17(8):1081-1093.
15. Touzeau C, Moreau P, Dumontet C. Monoclonal antibody therapy in multiple myeloma. Leukemia. 2017;31(5):1039-1047.
16. Palumbo A, Chanan-Khan A, Weisel K, et al. Daratumumab, bortezomib, and dexamethasone for multiple myeloma. N Engl J Med. 2016;375(8):754-766.
17. Dimopoulos MA, Oriol A, Nahi H, et al. Daratumumab, lenalidomide, and dexamethasone for multiple myeloma. N Engl J Med. 2016;375(14):1319-1331.
18. Beck A, Goetsch L, Dumontet C, Corvaia N. Strategies and challenges for the next generation of antibody-drug conjugates. Nat Rev Drug Discov. 2017;16(5):315-337.
19. Kantarjian HM, DeAngelo DJ, Stelljes M, et al. Inotuzumab ozogamicin versus standard therapy for acute lymphoblastic leukemia. N Engl J Med. 2016;375(8):740-753.
20. Hills RK, Castaigne S, Appelbaum FR, et al. Addition of gemtuzumab ozogamicin to induction chemotherapy in adult patients with acute myeloid leukaemia: a meta-analysis of individual patient data from randomised controlled trials. Lancet Oncol. 2014;15(9):986-996.
21. Huehls AM, Coupet TA, Sentman CL. Bispecific T-cell engagers for cancer immunotherapy. Immunol Cell Biol. 2015;93(3):290-296.
22. Kantarjian H, Stein A, Gokbuget N, et al. Blinatumomab versus chemotherapy for advanced acute lymphoblastic leukemia. N Engl J Med. 2017;376(9):836-847.
23. Koehrer S, Burger JA. B-cell receptor signaling in chronic lymphocytic leukemia and other B-cell malignancies. Clin Adv Hematol Oncol. 2016;14(1):55-65.
24. Seda V, Mraz M. B-cell receptor signalling and its crosstalk with other pathways in normal and malignant cells. Eur J Haematol. 2015;94(3):193-205.
25. Bojarczuk K, Bobrowicz M, Dwojak M, et al. B-cell receptor signaling in the pathogenesis of lymphoid malignancies. Blood Cells Mol Dis. 2015;55(3):255-265.
26. Medscape Medical News. Gilead stops six trials adding idelalisib to other drugs. http://www.medscape.com/viewarticle/860372. Published March 14, 2016. Accessed June 19, 2017.
27. Sharman J, Di Paolo J. Targeting B-cell receptor signaling kinases in chronic lymphocytic leukemia: the promise of entospletinib. Ther Adv Hematol. 2016;7(3):157-170.
28. Food and Drug Administration. FDA approves new drug for chronic lymphocytic leukemia in patients with a specific chromosomal abnormality. https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm495253.htm. Released April 11, 2016. Accessed June 19, 2017.
Caution urged over real-world bleeding risk with ibrutinib
The Bruton tyrosine kinase inhibitor ibrutinib has been linked to an almost 20-fold increased risk of major bleeding in blood cancer patients taking concomitant antiplatelet and anticoagulation therapy in a clinical setting.
Caution should be used when weighing the risks and benefits of ibrutinib for patients already taking antiplatelet or anticoagulation therapy, or both, wrote Paul R. Kunk, MD, of University of Virginia, Charlottesville, and his colleagues. Their report is in Clinical Lymphoma, Myeloma & Leukemia.
Ibrutinib had been associated with an increased risk of bleeding, albeit low, in the clinical trial setting but the authors suggested that this rate could be higher in everyday clinical practice.
“Much of the information [from clinical trials] on the bleeding risk with ibrutinib, included pooled analyses, was from patients exclusively treated in clinical trials with specific exclusion criteria. These criteria have generally excluded patients with significant comorbidities. However, these patients are seen in clinical practice,” the researchers wrote.
They conducted a review of patients attending their center and associated regional clinics between January 2012 and May 2016. They identified 70 patients, average age 72, who were taking ibrutinib for chronic lymphocytic leukemia (64%) and mantle cell lymphoma (27%), diffuse large B-cell lymphoma (4%), lymphoblastic lymphoma (3%), and Waldenström macroglobulinemia (1%).
The analysis showed that bleeding of any grade occurred in 56% of patients, mostly grade 1-2 bruising and epistaxis. However, major bleeding, defined as grade 3, occurred in 13 patients (19%), a figure that the authors noted was greater than the rate of around 7% reported by clinical trials.
Of these patients, seven were taking combined antiplatelet and anticoagulant therapy, four were taking antiplatelets alone, one was taking an anticoagulant agent alone, and one was taking only ibrutinib.
Univariate analysis showed that the factors associated with an increased risk of major bleeding included antiplatelet or anticoagulant medication, the combination of the two medications or interacting medications, anemia (hemoglobin less than 12 g/dL) and an elevated international normalized ratio (greater than 1.5).
However, in a multivariate analysis, only combined antiplatelet and anticoagulant use (hazard ratio, 20.0; 95% confidence interval, 2.1-200.0; P less than .01) and an elevated INR (HR, 4.6; 95% CI, 1.1-19.6; P less than .01) remained statistically significant.
The researchers said the risk of major bleeding in patients taking both antiplatelet and anticoagulant therapy was “unacceptably high” and “medications other than ibrutinib should be considered” in this patient population.
Overall, they said their findings confirmed “the increasingly recognized risk of major bleeding complications with ibrutinib compared with what was originally reported in the clinical trial setting.
“As ibrutinib increases in use, it is paramount to increase awareness of the known adverse events. This is especially important given the association of ibrutinib use with atrial fibrillation,” they wrote.
They noted that their trial was limited by the relatively small population size. Their finding that platelet count was not associated with bleeding risk was also “counterintuitive,” they noted.
SOURCE: Kunk PR et al. Clin Lymphoma Myeloma Leuk. 2018 Jul 15. doi: 10.1016/j.clml.2018.07.287.
The Bruton tyrosine kinase inhibitor ibrutinib has been linked to an almost 20-fold increased risk of major bleeding in blood cancer patients taking concomitant antiplatelet and anticoagulation therapy in a clinical setting.
Caution should be used when weighing the risks and benefits of ibrutinib for patients already taking antiplatelet or anticoagulation therapy, or both, wrote Paul R. Kunk, MD, of University of Virginia, Charlottesville, and his colleagues. Their report is in Clinical Lymphoma, Myeloma & Leukemia.
Ibrutinib had been associated with an increased risk of bleeding, albeit low, in the clinical trial setting but the authors suggested that this rate could be higher in everyday clinical practice.
“Much of the information [from clinical trials] on the bleeding risk with ibrutinib, included pooled analyses, was from patients exclusively treated in clinical trials with specific exclusion criteria. These criteria have generally excluded patients with significant comorbidities. However, these patients are seen in clinical practice,” the researchers wrote.
They conducted a review of patients attending their center and associated regional clinics between January 2012 and May 2016. They identified 70 patients, average age 72, who were taking ibrutinib for chronic lymphocytic leukemia (64%) and mantle cell lymphoma (27%), diffuse large B-cell lymphoma (4%), lymphoblastic lymphoma (3%), and Waldenström macroglobulinemia (1%).
The analysis showed that bleeding of any grade occurred in 56% of patients, mostly grade 1-2 bruising and epistaxis. However, major bleeding, defined as grade 3, occurred in 13 patients (19%), a figure that the authors noted was greater than the rate of around 7% reported by clinical trials.
Of these patients, seven were taking combined antiplatelet and anticoagulant therapy, four were taking antiplatelets alone, one was taking an anticoagulant agent alone, and one was taking only ibrutinib.
Univariate analysis showed that the factors associated with an increased risk of major bleeding included antiplatelet or anticoagulant medication, the combination of the two medications or interacting medications, anemia (hemoglobin less than 12 g/dL) and an elevated international normalized ratio (greater than 1.5).
However, in a multivariate analysis, only combined antiplatelet and anticoagulant use (hazard ratio, 20.0; 95% confidence interval, 2.1-200.0; P less than .01) and an elevated INR (HR, 4.6; 95% CI, 1.1-19.6; P less than .01) remained statistically significant.
The researchers said the risk of major bleeding in patients taking both antiplatelet and anticoagulant therapy was “unacceptably high” and “medications other than ibrutinib should be considered” in this patient population.
Overall, they said their findings confirmed “the increasingly recognized risk of major bleeding complications with ibrutinib compared with what was originally reported in the clinical trial setting.
“As ibrutinib increases in use, it is paramount to increase awareness of the known adverse events. This is especially important given the association of ibrutinib use with atrial fibrillation,” they wrote.
They noted that their trial was limited by the relatively small population size. Their finding that platelet count was not associated with bleeding risk was also “counterintuitive,” they noted.
SOURCE: Kunk PR et al. Clin Lymphoma Myeloma Leuk. 2018 Jul 15. doi: 10.1016/j.clml.2018.07.287.
The Bruton tyrosine kinase inhibitor ibrutinib has been linked to an almost 20-fold increased risk of major bleeding in blood cancer patients taking concomitant antiplatelet and anticoagulation therapy in a clinical setting.
Caution should be used when weighing the risks and benefits of ibrutinib for patients already taking antiplatelet or anticoagulation therapy, or both, wrote Paul R. Kunk, MD, of University of Virginia, Charlottesville, and his colleagues. Their report is in Clinical Lymphoma, Myeloma & Leukemia.
Ibrutinib had been associated with an increased risk of bleeding, albeit low, in the clinical trial setting but the authors suggested that this rate could be higher in everyday clinical practice.
“Much of the information [from clinical trials] on the bleeding risk with ibrutinib, included pooled analyses, was from patients exclusively treated in clinical trials with specific exclusion criteria. These criteria have generally excluded patients with significant comorbidities. However, these patients are seen in clinical practice,” the researchers wrote.
They conducted a review of patients attending their center and associated regional clinics between January 2012 and May 2016. They identified 70 patients, average age 72, who were taking ibrutinib for chronic lymphocytic leukemia (64%) and mantle cell lymphoma (27%), diffuse large B-cell lymphoma (4%), lymphoblastic lymphoma (3%), and Waldenström macroglobulinemia (1%).
The analysis showed that bleeding of any grade occurred in 56% of patients, mostly grade 1-2 bruising and epistaxis. However, major bleeding, defined as grade 3, occurred in 13 patients (19%), a figure that the authors noted was greater than the rate of around 7% reported by clinical trials.
Of these patients, seven were taking combined antiplatelet and anticoagulant therapy, four were taking antiplatelets alone, one was taking an anticoagulant agent alone, and one was taking only ibrutinib.
Univariate analysis showed that the factors associated with an increased risk of major bleeding included antiplatelet or anticoagulant medication, the combination of the two medications or interacting medications, anemia (hemoglobin less than 12 g/dL) and an elevated international normalized ratio (greater than 1.5).
However, in a multivariate analysis, only combined antiplatelet and anticoagulant use (hazard ratio, 20.0; 95% confidence interval, 2.1-200.0; P less than .01) and an elevated INR (HR, 4.6; 95% CI, 1.1-19.6; P less than .01) remained statistically significant.
The researchers said the risk of major bleeding in patients taking both antiplatelet and anticoagulant therapy was “unacceptably high” and “medications other than ibrutinib should be considered” in this patient population.
Overall, they said their findings confirmed “the increasingly recognized risk of major bleeding complications with ibrutinib compared with what was originally reported in the clinical trial setting.
“As ibrutinib increases in use, it is paramount to increase awareness of the known adverse events. This is especially important given the association of ibrutinib use with atrial fibrillation,” they wrote.
They noted that their trial was limited by the relatively small population size. Their finding that platelet count was not associated with bleeding risk was also “counterintuitive,” they noted.
SOURCE: Kunk PR et al. Clin Lymphoma Myeloma Leuk. 2018 Jul 15. doi: 10.1016/j.clml.2018.07.287.
FROM CLINICAL LYMPHOMA, MYELOMA & LEUKEMIA
Key clinical point: Clinicians should exercise caution when prescribing antiplatelet and anticoagulant medications in people taking the Bruton tyrosine kinase inhibitor ibrutinib.
Major finding: The use of both antiplatelet and anticoagulant therapy significantly increased the risk of a major bleed event (HR, 19.2; 95% CI, 2.3-166.7; P less than .01) in patients also taking ibrutinib.
Study details: A retrospective analysis of prescription data from 70 patients seen at a single U.S. cancer center and its regional clinics between January 2012 and May 2016.
Disclosures: Two of the authors reported receiving clinical trial support from Acerta and Abbvie.
Source: Kunk PR et al. Clin Lymphoma Myeloma Leuk. 2018 Jul 15. doi: 10.1016/j.clml.2018.07.287.
Make The Diagnosis - September 2018
Some have postulated an infectious agent as the cause. Atopic dermatitis may confer an increased risk because of the chronic stimulation of T cells. Males are more commonly affected than females by a 2:1 ratio. A worse prognosis is associated with advanced age. Children and adolescents may be affected as well.
With mycosis fungoides, there are three main types of skin lesions: patch, plaque, and tumor. Patients will progress from patch to plaque to tumor stage in classic MF. Often, lesions begin as scaly, erythematous patches that resemble eczema. Because of the nonspecific nature of early lesions, the median duration from the onset of skin lesions to the diagnosis of MF is 4-6 years. Patch stage lesions may be pruritic or asymptomatic. Commonly, they present in non–sun-exposed areas, such as the buttocks. Annular, infiltrated, red-brown or violaceous plaques can develop, which represent malignant T-cell infiltration. Many patients never progress past the plaque stage. Tumor stage MF is more aggressive, with nodules that may undergo necrosis and ulceration.
The leukemic form of MF is Sézary syndrome. Patients present with pruritic erythroderma and lymphadenopathy. Nail dystrophy, scaling of palms and soles, and alopecia may be present. A peripheral blood smear reveals Sézary cells, which are large, hyperconvoluted lymphocytes. The count of Sézary cells is usually greater than 1000 cells/mm3.
Histology of early lesions may not be diagnostic for CTCL. Often, biopsies will be read as eczematous or psoriasiform for years before the diagnosis of MF is made. Classically, epidermotropism (single-cell exocytosis of lymphocytes into the epidermis) is present. Advanced stages may show a dense infiltrate of lymphocytes in the dermis. Groups of lymphocytes in the epidermis form Pautrier’s microabscesses. Mycosis cells may exhibit cerebriform nuclei. Neoplastic cells in MF are CD3+, CD4+, CD45RO+, CD8–. Tissue can be sent for T-cell gene rearrangement polymerase chain reaction. The presence of monoclonal T-cell gene receptor rearrangements can aid in the diagnosis of MF.
Treatment includes topical steroids, mechlorethamine (nitrogen mustard) or bexarotene gel, PUVA therapy, and narrow-band UVB light for limited and/or patch disease. Localized radiotherapy can be used for more resistant lesions. Topical therapies are preferred in the early stages in MF. Systemic treatments for patients who do not respond to local therapy, or in more advanced disease include methotrexate, interferon-alpha, oral bexarotene, denileukin diftitox, and combination chemotherapy. Photopheresis is reserved for erythrodermic disease.
This case and photo were submitted by Dr. Bilu Martin.
Dr. Bilu Martin is a board-certified dermatologist in private practice in Aventura, Fla. More diagnostic cases are available at edermatologynews.com. To submit a case for possible publication, send an email to [email protected].
Some have postulated an infectious agent as the cause. Atopic dermatitis may confer an increased risk because of the chronic stimulation of T cells. Males are more commonly affected than females by a 2:1 ratio. A worse prognosis is associated with advanced age. Children and adolescents may be affected as well.
With mycosis fungoides, there are three main types of skin lesions: patch, plaque, and tumor. Patients will progress from patch to plaque to tumor stage in classic MF. Often, lesions begin as scaly, erythematous patches that resemble eczema. Because of the nonspecific nature of early lesions, the median duration from the onset of skin lesions to the diagnosis of MF is 4-6 years. Patch stage lesions may be pruritic or asymptomatic. Commonly, they present in non–sun-exposed areas, such as the buttocks. Annular, infiltrated, red-brown or violaceous plaques can develop, which represent malignant T-cell infiltration. Many patients never progress past the plaque stage. Tumor stage MF is more aggressive, with nodules that may undergo necrosis and ulceration.
The leukemic form of MF is Sézary syndrome. Patients present with pruritic erythroderma and lymphadenopathy. Nail dystrophy, scaling of palms and soles, and alopecia may be present. A peripheral blood smear reveals Sézary cells, which are large, hyperconvoluted lymphocytes. The count of Sézary cells is usually greater than 1000 cells/mm3.
Histology of early lesions may not be diagnostic for CTCL. Often, biopsies will be read as eczematous or psoriasiform for years before the diagnosis of MF is made. Classically, epidermotropism (single-cell exocytosis of lymphocytes into the epidermis) is present. Advanced stages may show a dense infiltrate of lymphocytes in the dermis. Groups of lymphocytes in the epidermis form Pautrier’s microabscesses. Mycosis cells may exhibit cerebriform nuclei. Neoplastic cells in MF are CD3+, CD4+, CD45RO+, CD8–. Tissue can be sent for T-cell gene rearrangement polymerase chain reaction. The presence of monoclonal T-cell gene receptor rearrangements can aid in the diagnosis of MF.
Treatment includes topical steroids, mechlorethamine (nitrogen mustard) or bexarotene gel, PUVA therapy, and narrow-band UVB light for limited and/or patch disease. Localized radiotherapy can be used for more resistant lesions. Topical therapies are preferred in the early stages in MF. Systemic treatments for patients who do not respond to local therapy, or in more advanced disease include methotrexate, interferon-alpha, oral bexarotene, denileukin diftitox, and combination chemotherapy. Photopheresis is reserved for erythrodermic disease.
This case and photo were submitted by Dr. Bilu Martin.
Dr. Bilu Martin is a board-certified dermatologist in private practice in Aventura, Fla. More diagnostic cases are available at edermatologynews.com. To submit a case for possible publication, send an email to [email protected].
Some have postulated an infectious agent as the cause. Atopic dermatitis may confer an increased risk because of the chronic stimulation of T cells. Males are more commonly affected than females by a 2:1 ratio. A worse prognosis is associated with advanced age. Children and adolescents may be affected as well.
With mycosis fungoides, there are three main types of skin lesions: patch, plaque, and tumor. Patients will progress from patch to plaque to tumor stage in classic MF. Often, lesions begin as scaly, erythematous patches that resemble eczema. Because of the nonspecific nature of early lesions, the median duration from the onset of skin lesions to the diagnosis of MF is 4-6 years. Patch stage lesions may be pruritic or asymptomatic. Commonly, they present in non–sun-exposed areas, such as the buttocks. Annular, infiltrated, red-brown or violaceous plaques can develop, which represent malignant T-cell infiltration. Many patients never progress past the plaque stage. Tumor stage MF is more aggressive, with nodules that may undergo necrosis and ulceration.
The leukemic form of MF is Sézary syndrome. Patients present with pruritic erythroderma and lymphadenopathy. Nail dystrophy, scaling of palms and soles, and alopecia may be present. A peripheral blood smear reveals Sézary cells, which are large, hyperconvoluted lymphocytes. The count of Sézary cells is usually greater than 1000 cells/mm3.
Histology of early lesions may not be diagnostic for CTCL. Often, biopsies will be read as eczematous or psoriasiform for years before the diagnosis of MF is made. Classically, epidermotropism (single-cell exocytosis of lymphocytes into the epidermis) is present. Advanced stages may show a dense infiltrate of lymphocytes in the dermis. Groups of lymphocytes in the epidermis form Pautrier’s microabscesses. Mycosis cells may exhibit cerebriform nuclei. Neoplastic cells in MF are CD3+, CD4+, CD45RO+, CD8–. Tissue can be sent for T-cell gene rearrangement polymerase chain reaction. The presence of monoclonal T-cell gene receptor rearrangements can aid in the diagnosis of MF.
Treatment includes topical steroids, mechlorethamine (nitrogen mustard) or bexarotene gel, PUVA therapy, and narrow-band UVB light for limited and/or patch disease. Localized radiotherapy can be used for more resistant lesions. Topical therapies are preferred in the early stages in MF. Systemic treatments for patients who do not respond to local therapy, or in more advanced disease include methotrexate, interferon-alpha, oral bexarotene, denileukin diftitox, and combination chemotherapy. Photopheresis is reserved for erythrodermic disease.
This case and photo were submitted by Dr. Bilu Martin.
Dr. Bilu Martin is a board-certified dermatologist in private practice in Aventura, Fla. More diagnostic cases are available at edermatologynews.com. To submit a case for possible publication, send an email to [email protected].
Mogamulizumab prolongs PFS in CTCL
Mogamulizumab is an effective treatment option for relapsed/refractory cutaneous T-cell lymphoma (CTCL), according to researchers.
In the phase 3 MAVORIC trial, mogamulizumab prolonged progression-free survival (PFS) and produced better overall response rates (ORRs) than vorinostat in patients with relapsed/refractory CTCL.
The most common adverse events (AEs) in patients treated with mogamulizumab were infusion-related reactions, diarrhea, fatigue, and drug eruptions.
Youn Kim MD, of the Stanford Cancer Institute in Palo Alto, California, and her colleagues reported these results in The Lancet Oncology.
The results supported the recent approval of mogamulizumab by the US Food and Drug Administration.
The study was sponsored by Kyowa Hakko Kirin Co., Ltd., the company developing/marketing mogamulizumab.
Treatment
For MAVORIC, researchers compared mogamulizumab and vorinostat in adults with mycosis fungoides (MF) or Sézary syndrome (SS) who had received at least 1 prior systemic therapy.
The trial included 372 patients who were randomized to receive mogamulizumab at 1.0 mg/kg (weekly for the first cycle and then every 2 weeks) or vorinostat at 400 mg daily for 28-day cycles.
Patients were treated until disease progression or unacceptable toxicity. Patients on vorinostat who progressed or experienced intolerable toxicity after 2 cycles, despite dose reduction and appropriate management of AEs, could cross over to treatment with mogamulizumab.
There were 184 patients in the mogamulizumab arm and 186 in the vorinostat arm who received treatment.
The median duration of follow-up was 17.0 months.
Most patients (n=157) ultimately discontinued mogamulizumab. Reasons included:
- Disease progression (n=76 by CTCL criteria and 22 by clinical criteria)
- AEs (n=28)
- Withdrawn consent (n=13)
- Investigator decision (n=9)
- Patient decision (n=6)
- Death (n=2)
- Noncompliance (n=1).
Most patients (n=136) in the vorinostat arm crossed over to the mogamulizumab arm, 109 due to disease progression and 27 due to treatment intolerance.
Of the 40 patients who did not cross over to mogamulizumab, reasons for stopping vorinostat included:
- Progressive disease (n=10 by CTCL criteria and 8 by clinical criteria)
- Patient decision (n=9)
- Withdrawn consent (n=5)
- AEs (n=5)
- Death (n=2)
- Lost to follow-up (n=1).
At the data cutoff, there were 27 patients assigned to mogamulizumab and 10 assigned to vorinostat who remained on treatment. There were 31 patients still on treatment who had crossed over from vorinostat to mogamulizumab.
Patient characteristics
Baseline characteristics were similar between the treatment arms.
| Mogamulizumab (n=186) | Vorinostat (n=186) | |
| Median age | 64 (range, 54-73) | 65 (range, 56-72) |
| Male | 109 (59%) | 107 (58%) |
| Female | 77 (41%) | 79 (42%) |
| MF | 105 (56%) | 99 (53%) |
| SS | 81 (44%) | 87 (47%) |
| Time from diagnosis, months | 41.0 (range, 17.4-78.8) | 35.4 (range, 16.2-68.2) |
| Median number of previous systemic regimens | 3 (range, 2-5) | 3 (range, 2-5) |
PFS and ORR
Mogamulizumab provided a significant improvement in PFS, the study’s primary endpoint.
According to investigators, the median PFS was 7.7 months with mogamulizumab and 3.1 months with vorinostat (hazard ratio=0.53, P<0.0001).
According to independent review, the median PFS was 6.7 months and 3.8 months, respectively (hazard ratio=0.64, P<0.0007).
There was a significant improvement in ORR with mogamulizumab.
According to independent review, the global ORR was 23% (43/186) in the mogamulizumab arm and 4% (7/186) in the vorinostat arm (risk ratio=19.4, P<0.0001).
According to investigators, the global ORR was 28% (52/186) and 5% (9/186), respectively (risk ratio=23.1, P<0.0001).
For patients with MF, the investigator-assessed ORR was 21% (22/105) with mogamulizumab and 7% (7/99) with vorinostat.
For SS patients, the investigator-assessed ORR was 37% (30/81) and 2% (2/87), respectively.
Responses by disease compartment were superior with mogamulizumab as well.
The investigator-assessed blood ORR was 68% (83/122) with mogamulizumab and 19% (23/123) with vorinostat. The skin ORR was 42% (78/186) and 16% (29/186), respectively.
The lymph node ORR was 17% (21/124) and 4% (5/122), respectively. The viscera ORR was 0% in both arms.
Crossover
Among patients who crossed over from vorinostat to mogamulizumab, the ORR was 31% (41/133). In these patients, the median PFS was 8.9 months.
In the 319 patients who were assigned to mogamulizumab or crossed over to that arm, the median PFS was 8.4 months.
Safety
The most common treatment-emergent, grade 1-2 AEs, occurring in at least 20% of patients in either arm (mogamulizumab and vorinostat, respectively), were:
- Thrombocytopenia (14% vs 34%)
- Diarrhea (23% vs 57%)
- Nausea (15% vs 41%)
- Fatigue (22% vs 32%)
- Increased blood creatinine (3% vs 28%)
- Decreased appetite (7% vs 24%)
- Dysgeusia (3% vs 28%)
- Drug eruptions (20% vs 1%)
- Infusion-related reactions (32% vs 1%).
Grade 3 AEs in the mogamulizumab arm included drug eruptions (n=8), hypertension (n=8), pneumonia (n=6), fatigue (n=3), cellulitis (n=3), infusion-related reactions (n=3), sepsis (n=2), decreased appetite (n=2), AST increase (n=2), weight decrease (n=1), pyrexia (n=1), constipation (n=1), nausea (n=1), and diarrhea (n=1).
Grade 4 AEs with mogamulizumab were cellulitis (n=1) and pneumonia (n=1). Grade 5 AEs included pneumonia (n=1) and sepsis (n=1).
Mogamulizumab is an effective treatment option for relapsed/refractory cutaneous T-cell lymphoma (CTCL), according to researchers.
In the phase 3 MAVORIC trial, mogamulizumab prolonged progression-free survival (PFS) and produced better overall response rates (ORRs) than vorinostat in patients with relapsed/refractory CTCL.
The most common adverse events (AEs) in patients treated with mogamulizumab were infusion-related reactions, diarrhea, fatigue, and drug eruptions.
Youn Kim MD, of the Stanford Cancer Institute in Palo Alto, California, and her colleagues reported these results in The Lancet Oncology.
The results supported the recent approval of mogamulizumab by the US Food and Drug Administration.
The study was sponsored by Kyowa Hakko Kirin Co., Ltd., the company developing/marketing mogamulizumab.
Treatment
For MAVORIC, researchers compared mogamulizumab and vorinostat in adults with mycosis fungoides (MF) or Sézary syndrome (SS) who had received at least 1 prior systemic therapy.
The trial included 372 patients who were randomized to receive mogamulizumab at 1.0 mg/kg (weekly for the first cycle and then every 2 weeks) or vorinostat at 400 mg daily for 28-day cycles.
Patients were treated until disease progression or unacceptable toxicity. Patients on vorinostat who progressed or experienced intolerable toxicity after 2 cycles, despite dose reduction and appropriate management of AEs, could cross over to treatment with mogamulizumab.
There were 184 patients in the mogamulizumab arm and 186 in the vorinostat arm who received treatment.
The median duration of follow-up was 17.0 months.
Most patients (n=157) ultimately discontinued mogamulizumab. Reasons included:
- Disease progression (n=76 by CTCL criteria and 22 by clinical criteria)
- AEs (n=28)
- Withdrawn consent (n=13)
- Investigator decision (n=9)
- Patient decision (n=6)
- Death (n=2)
- Noncompliance (n=1).
Most patients (n=136) in the vorinostat arm crossed over to the mogamulizumab arm, 109 due to disease progression and 27 due to treatment intolerance.
Of the 40 patients who did not cross over to mogamulizumab, reasons for stopping vorinostat included:
- Progressive disease (n=10 by CTCL criteria and 8 by clinical criteria)
- Patient decision (n=9)
- Withdrawn consent (n=5)
- AEs (n=5)
- Death (n=2)
- Lost to follow-up (n=1).
At the data cutoff, there were 27 patients assigned to mogamulizumab and 10 assigned to vorinostat who remained on treatment. There were 31 patients still on treatment who had crossed over from vorinostat to mogamulizumab.
Patient characteristics
Baseline characteristics were similar between the treatment arms.
| Mogamulizumab (n=186) | Vorinostat (n=186) | |
| Median age | 64 (range, 54-73) | 65 (range, 56-72) |
| Male | 109 (59%) | 107 (58%) |
| Female | 77 (41%) | 79 (42%) |
| MF | 105 (56%) | 99 (53%) |
| SS | 81 (44%) | 87 (47%) |
| Time from diagnosis, months | 41.0 (range, 17.4-78.8) | 35.4 (range, 16.2-68.2) |
| Median number of previous systemic regimens | 3 (range, 2-5) | 3 (range, 2-5) |
PFS and ORR
Mogamulizumab provided a significant improvement in PFS, the study’s primary endpoint.
According to investigators, the median PFS was 7.7 months with mogamulizumab and 3.1 months with vorinostat (hazard ratio=0.53, P<0.0001).
According to independent review, the median PFS was 6.7 months and 3.8 months, respectively (hazard ratio=0.64, P<0.0007).
There was a significant improvement in ORR with mogamulizumab.
According to independent review, the global ORR was 23% (43/186) in the mogamulizumab arm and 4% (7/186) in the vorinostat arm (risk ratio=19.4, P<0.0001).
According to investigators, the global ORR was 28% (52/186) and 5% (9/186), respectively (risk ratio=23.1, P<0.0001).
For patients with MF, the investigator-assessed ORR was 21% (22/105) with mogamulizumab and 7% (7/99) with vorinostat.
For SS patients, the investigator-assessed ORR was 37% (30/81) and 2% (2/87), respectively.
Responses by disease compartment were superior with mogamulizumab as well.
The investigator-assessed blood ORR was 68% (83/122) with mogamulizumab and 19% (23/123) with vorinostat. The skin ORR was 42% (78/186) and 16% (29/186), respectively.
The lymph node ORR was 17% (21/124) and 4% (5/122), respectively. The viscera ORR was 0% in both arms.
Crossover
Among patients who crossed over from vorinostat to mogamulizumab, the ORR was 31% (41/133). In these patients, the median PFS was 8.9 months.
In the 319 patients who were assigned to mogamulizumab or crossed over to that arm, the median PFS was 8.4 months.
Safety
The most common treatment-emergent, grade 1-2 AEs, occurring in at least 20% of patients in either arm (mogamulizumab and vorinostat, respectively), were:
- Thrombocytopenia (14% vs 34%)
- Diarrhea (23% vs 57%)
- Nausea (15% vs 41%)
- Fatigue (22% vs 32%)
- Increased blood creatinine (3% vs 28%)
- Decreased appetite (7% vs 24%)
- Dysgeusia (3% vs 28%)
- Drug eruptions (20% vs 1%)
- Infusion-related reactions (32% vs 1%).
Grade 3 AEs in the mogamulizumab arm included drug eruptions (n=8), hypertension (n=8), pneumonia (n=6), fatigue (n=3), cellulitis (n=3), infusion-related reactions (n=3), sepsis (n=2), decreased appetite (n=2), AST increase (n=2), weight decrease (n=1), pyrexia (n=1), constipation (n=1), nausea (n=1), and diarrhea (n=1).
Grade 4 AEs with mogamulizumab were cellulitis (n=1) and pneumonia (n=1). Grade 5 AEs included pneumonia (n=1) and sepsis (n=1).
Mogamulizumab is an effective treatment option for relapsed/refractory cutaneous T-cell lymphoma (CTCL), according to researchers.
In the phase 3 MAVORIC trial, mogamulizumab prolonged progression-free survival (PFS) and produced better overall response rates (ORRs) than vorinostat in patients with relapsed/refractory CTCL.
The most common adverse events (AEs) in patients treated with mogamulizumab were infusion-related reactions, diarrhea, fatigue, and drug eruptions.
Youn Kim MD, of the Stanford Cancer Institute in Palo Alto, California, and her colleagues reported these results in The Lancet Oncology.
The results supported the recent approval of mogamulizumab by the US Food and Drug Administration.
The study was sponsored by Kyowa Hakko Kirin Co., Ltd., the company developing/marketing mogamulizumab.
Treatment
For MAVORIC, researchers compared mogamulizumab and vorinostat in adults with mycosis fungoides (MF) or Sézary syndrome (SS) who had received at least 1 prior systemic therapy.
The trial included 372 patients who were randomized to receive mogamulizumab at 1.0 mg/kg (weekly for the first cycle and then every 2 weeks) or vorinostat at 400 mg daily for 28-day cycles.
Patients were treated until disease progression or unacceptable toxicity. Patients on vorinostat who progressed or experienced intolerable toxicity after 2 cycles, despite dose reduction and appropriate management of AEs, could cross over to treatment with mogamulizumab.
There were 184 patients in the mogamulizumab arm and 186 in the vorinostat arm who received treatment.
The median duration of follow-up was 17.0 months.
Most patients (n=157) ultimately discontinued mogamulizumab. Reasons included:
- Disease progression (n=76 by CTCL criteria and 22 by clinical criteria)
- AEs (n=28)
- Withdrawn consent (n=13)
- Investigator decision (n=9)
- Patient decision (n=6)
- Death (n=2)
- Noncompliance (n=1).
Most patients (n=136) in the vorinostat arm crossed over to the mogamulizumab arm, 109 due to disease progression and 27 due to treatment intolerance.
Of the 40 patients who did not cross over to mogamulizumab, reasons for stopping vorinostat included:
- Progressive disease (n=10 by CTCL criteria and 8 by clinical criteria)
- Patient decision (n=9)
- Withdrawn consent (n=5)
- AEs (n=5)
- Death (n=2)
- Lost to follow-up (n=1).
At the data cutoff, there were 27 patients assigned to mogamulizumab and 10 assigned to vorinostat who remained on treatment. There were 31 patients still on treatment who had crossed over from vorinostat to mogamulizumab.
Patient characteristics
Baseline characteristics were similar between the treatment arms.
| Mogamulizumab (n=186) | Vorinostat (n=186) | |
| Median age | 64 (range, 54-73) | 65 (range, 56-72) |
| Male | 109 (59%) | 107 (58%) |
| Female | 77 (41%) | 79 (42%) |
| MF | 105 (56%) | 99 (53%) |
| SS | 81 (44%) | 87 (47%) |
| Time from diagnosis, months | 41.0 (range, 17.4-78.8) | 35.4 (range, 16.2-68.2) |
| Median number of previous systemic regimens | 3 (range, 2-5) | 3 (range, 2-5) |
PFS and ORR
Mogamulizumab provided a significant improvement in PFS, the study’s primary endpoint.
According to investigators, the median PFS was 7.7 months with mogamulizumab and 3.1 months with vorinostat (hazard ratio=0.53, P<0.0001).
According to independent review, the median PFS was 6.7 months and 3.8 months, respectively (hazard ratio=0.64, P<0.0007).
There was a significant improvement in ORR with mogamulizumab.
According to independent review, the global ORR was 23% (43/186) in the mogamulizumab arm and 4% (7/186) in the vorinostat arm (risk ratio=19.4, P<0.0001).
According to investigators, the global ORR was 28% (52/186) and 5% (9/186), respectively (risk ratio=23.1, P<0.0001).
For patients with MF, the investigator-assessed ORR was 21% (22/105) with mogamulizumab and 7% (7/99) with vorinostat.
For SS patients, the investigator-assessed ORR was 37% (30/81) and 2% (2/87), respectively.
Responses by disease compartment were superior with mogamulizumab as well.
The investigator-assessed blood ORR was 68% (83/122) with mogamulizumab and 19% (23/123) with vorinostat. The skin ORR was 42% (78/186) and 16% (29/186), respectively.
The lymph node ORR was 17% (21/124) and 4% (5/122), respectively. The viscera ORR was 0% in both arms.
Crossover
Among patients who crossed over from vorinostat to mogamulizumab, the ORR was 31% (41/133). In these patients, the median PFS was 8.9 months.
In the 319 patients who were assigned to mogamulizumab or crossed over to that arm, the median PFS was 8.4 months.
Safety
The most common treatment-emergent, grade 1-2 AEs, occurring in at least 20% of patients in either arm (mogamulizumab and vorinostat, respectively), were:
- Thrombocytopenia (14% vs 34%)
- Diarrhea (23% vs 57%)
- Nausea (15% vs 41%)
- Fatigue (22% vs 32%)
- Increased blood creatinine (3% vs 28%)
- Decreased appetite (7% vs 24%)
- Dysgeusia (3% vs 28%)
- Drug eruptions (20% vs 1%)
- Infusion-related reactions (32% vs 1%).
Grade 3 AEs in the mogamulizumab arm included drug eruptions (n=8), hypertension (n=8), pneumonia (n=6), fatigue (n=3), cellulitis (n=3), infusion-related reactions (n=3), sepsis (n=2), decreased appetite (n=2), AST increase (n=2), weight decrease (n=1), pyrexia (n=1), constipation (n=1), nausea (n=1), and diarrhea (n=1).
Grade 4 AEs with mogamulizumab were cellulitis (n=1) and pneumonia (n=1). Grade 5 AEs included pneumonia (n=1) and sepsis (n=1).
Insurance status linked to survival in FL patients
Having health insurance can mean the difference between life and death for US patients with follicular lymphoma (FL), according to research published in Blood.
The study showed that patients with private health insurance had nearly 2-fold better survival outcomes than patients without insurance or those who were covered by Medicare or Medicaid.
A review of records on more than 43,000 FL patients showed that, compared with patients under age 65 with private insurance, the hazard ratios (HR) for death among patients in the same age bracket were 1.96 for those with no insurance, 1.83 for those with Medicaid, and 1.96 for those with Medicare (P<0.0001 for each comparison).
“Our study finds that insurance status contributes to survival disparities in FL,” Christopher R. Flowers, MD, of Emory University in Atlanta, Georgia, and his colleagues wrote in Blood.
“Future studies on outcomes in FL should include insurance status as an important predictor. Further research on prognosis for FL should examine the impact of public policy, such as the passage of the [Affordable Care Act], on FL outcomes, as well as examine other factors that influence access to care, such as individual-level socioeconomic status, regular primary care visits, access to prescription medications, and care affordability.”
Earlier research showed that patients with Medicaid or no insurance were more likely than privately insured patients to be diagnosed with cancers at advanced stages, and some patients with aggressive non-Hodgkin lymphomas have been shown to have insurance-related disparities in treatments and outcomes.
To see whether the same could be true for patients with indolent-histology lymphomas such as FL, Dr Flowers and his colleagues extracted data from the National Cancer Database, a nationwide hospital-based cancer registry sponsored jointly by the American College of Surgeons and the American Cancer Society.
The investigators identified 43,648 patients, age 18 and older, who were diagnosed with FL from 2004 through 2014. The team looked at patients ages 18 to 64 as well as patients age 65 and older to account for changes in insurance with Medicare eligibility.
Overall survival among patients younger than 65 was significantly worse for patients with public insurance (Medicaid or Medicare) or no insurance in Cox proportional hazard models controlling for available data on sociodemographic factors and prognostic indicators.
However, compared with patients age 65 and older with private insurance, only patients with Medicare as their sole source of insurance had significantly worse overall survival (HR, 1.28; P<0.0001).
Patients who were uninsured or had Medicaid were more likely than others to have lower socioeconomic status, present with advanced-stage disease, have systemic symptoms, and have multiple comorbidities that persisted after controlling for known sociodemographic and prognostic factors.
The investigators found that, among patients under age 65, those with a comorbidity score of 1 had an HR for death of 1.71, compared with patients with no comorbidities, and patients with a score of 2 or greater had an HR of 3.1 (P<0.0001 for each comparison).
“The findings of the study indicate that improving access to affordable, quality healthcare may reduce disparities in survival for those currently lacking coverage,” the investigators wrote.
The study was supported by Emory University, the National Institutes of Health, and the National Center for Advancing Translational Sciences. Dr Flowers reported financial relationships with AbbVie, Spectrum, Celgene, and several other companies. The other authors reported having nothing to disclose.
Having health insurance can mean the difference between life and death for US patients with follicular lymphoma (FL), according to research published in Blood.
The study showed that patients with private health insurance had nearly 2-fold better survival outcomes than patients without insurance or those who were covered by Medicare or Medicaid.
A review of records on more than 43,000 FL patients showed that, compared with patients under age 65 with private insurance, the hazard ratios (HR) for death among patients in the same age bracket were 1.96 for those with no insurance, 1.83 for those with Medicaid, and 1.96 for those with Medicare (P<0.0001 for each comparison).
“Our study finds that insurance status contributes to survival disparities in FL,” Christopher R. Flowers, MD, of Emory University in Atlanta, Georgia, and his colleagues wrote in Blood.
“Future studies on outcomes in FL should include insurance status as an important predictor. Further research on prognosis for FL should examine the impact of public policy, such as the passage of the [Affordable Care Act], on FL outcomes, as well as examine other factors that influence access to care, such as individual-level socioeconomic status, regular primary care visits, access to prescription medications, and care affordability.”
Earlier research showed that patients with Medicaid or no insurance were more likely than privately insured patients to be diagnosed with cancers at advanced stages, and some patients with aggressive non-Hodgkin lymphomas have been shown to have insurance-related disparities in treatments and outcomes.
To see whether the same could be true for patients with indolent-histology lymphomas such as FL, Dr Flowers and his colleagues extracted data from the National Cancer Database, a nationwide hospital-based cancer registry sponsored jointly by the American College of Surgeons and the American Cancer Society.
The investigators identified 43,648 patients, age 18 and older, who were diagnosed with FL from 2004 through 2014. The team looked at patients ages 18 to 64 as well as patients age 65 and older to account for changes in insurance with Medicare eligibility.
Overall survival among patients younger than 65 was significantly worse for patients with public insurance (Medicaid or Medicare) or no insurance in Cox proportional hazard models controlling for available data on sociodemographic factors and prognostic indicators.
However, compared with patients age 65 and older with private insurance, only patients with Medicare as their sole source of insurance had significantly worse overall survival (HR, 1.28; P<0.0001).
Patients who were uninsured or had Medicaid were more likely than others to have lower socioeconomic status, present with advanced-stage disease, have systemic symptoms, and have multiple comorbidities that persisted after controlling for known sociodemographic and prognostic factors.
The investigators found that, among patients under age 65, those with a comorbidity score of 1 had an HR for death of 1.71, compared with patients with no comorbidities, and patients with a score of 2 or greater had an HR of 3.1 (P<0.0001 for each comparison).
“The findings of the study indicate that improving access to affordable, quality healthcare may reduce disparities in survival for those currently lacking coverage,” the investigators wrote.
The study was supported by Emory University, the National Institutes of Health, and the National Center for Advancing Translational Sciences. Dr Flowers reported financial relationships with AbbVie, Spectrum, Celgene, and several other companies. The other authors reported having nothing to disclose.
Having health insurance can mean the difference between life and death for US patients with follicular lymphoma (FL), according to research published in Blood.
The study showed that patients with private health insurance had nearly 2-fold better survival outcomes than patients without insurance or those who were covered by Medicare or Medicaid.
A review of records on more than 43,000 FL patients showed that, compared with patients under age 65 with private insurance, the hazard ratios (HR) for death among patients in the same age bracket were 1.96 for those with no insurance, 1.83 for those with Medicaid, and 1.96 for those with Medicare (P<0.0001 for each comparison).
“Our study finds that insurance status contributes to survival disparities in FL,” Christopher R. Flowers, MD, of Emory University in Atlanta, Georgia, and his colleagues wrote in Blood.
“Future studies on outcomes in FL should include insurance status as an important predictor. Further research on prognosis for FL should examine the impact of public policy, such as the passage of the [Affordable Care Act], on FL outcomes, as well as examine other factors that influence access to care, such as individual-level socioeconomic status, regular primary care visits, access to prescription medications, and care affordability.”
Earlier research showed that patients with Medicaid or no insurance were more likely than privately insured patients to be diagnosed with cancers at advanced stages, and some patients with aggressive non-Hodgkin lymphomas have been shown to have insurance-related disparities in treatments and outcomes.
To see whether the same could be true for patients with indolent-histology lymphomas such as FL, Dr Flowers and his colleagues extracted data from the National Cancer Database, a nationwide hospital-based cancer registry sponsored jointly by the American College of Surgeons and the American Cancer Society.
The investigators identified 43,648 patients, age 18 and older, who were diagnosed with FL from 2004 through 2014. The team looked at patients ages 18 to 64 as well as patients age 65 and older to account for changes in insurance with Medicare eligibility.
Overall survival among patients younger than 65 was significantly worse for patients with public insurance (Medicaid or Medicare) or no insurance in Cox proportional hazard models controlling for available data on sociodemographic factors and prognostic indicators.
However, compared with patients age 65 and older with private insurance, only patients with Medicare as their sole source of insurance had significantly worse overall survival (HR, 1.28; P<0.0001).
Patients who were uninsured or had Medicaid were more likely than others to have lower socioeconomic status, present with advanced-stage disease, have systemic symptoms, and have multiple comorbidities that persisted after controlling for known sociodemographic and prognostic factors.
The investigators found that, among patients under age 65, those with a comorbidity score of 1 had an HR for death of 1.71, compared with patients with no comorbidities, and patients with a score of 2 or greater had an HR of 3.1 (P<0.0001 for each comparison).
“The findings of the study indicate that improving access to affordable, quality healthcare may reduce disparities in survival for those currently lacking coverage,” the investigators wrote.
The study was supported by Emory University, the National Institutes of Health, and the National Center for Advancing Translational Sciences. Dr Flowers reported financial relationships with AbbVie, Spectrum, Celgene, and several other companies. The other authors reported having nothing to disclose.
Groups release guidelines for CAR T treatment in children
emphasize the need for a flexible approach to detect early signs of serious complications for younger patients treated with this emerging class of medicines.
Researchers at the University of Texas MD Anderson Cancer Center, Houston, and the Pediatric Acute Lung Injury and Sepsis Investigators Network (PALISI) developed the guidelines, which were published in Nature Reviews Clinical Oncology. The recommendations build on the guidelines for more general use of these medicines from MD Anderson’s CARTOX Program, which Nature Reviews Clinical Oncology published in 2017.
Among the chief concerns with this new class of medicines are cytokine-release syndrome (CRS) and CAR T cell-related encephalopathy syndrome (CRES), according to Kris Michael Mahadeo, MD MPH, of the MD Anderson Cancer Center and his coauthors of the new paper.
Some of the tools used for older patients in screening for complications with CAR T drugs don’t work as well with younger ones, Dr. Mahadeo said in an interview. For instance, at MD Anderson, a handwriting sample is used to monitor patients for CAR T cell-related encephalopathy syndrome, which has symptoms of confusion and delirium. Patients provide a baseline handwriting sample of a single sentence that’s scanned into the medical record, and then they are asked to write this again during their time in the hospital, he said. But this tool may not work for children too young to write well.
The new guidelines suggest using the Cornell Assessment of Pediatric Delirium (CAPD) or to evaluate a child’s mental state, asking questions about eye contact, and level of awareness and mood, Dr. Mahadeo said. An alternative for patients aged 12 years and older with greater cognitive ability is the CARTOX-10 grading system.
“The nurses who spent most of the day with these patients will observe them over their shift and kind of get an idea of what was normal and answer a series of questions” through the CAPD tool, which is already used in ICUs, Dr. Mahadeo said. “It takes into consideration both the nurses’ perception and the parents, or whoever is at the bedside with the child. So that if they have a concern, it gives them a point that actually escalates things upward.”
The newly published recommendations also remind physicians and others caring for young patients to pay attention to these reports.
“Parent and/or caregiver concerns should be addressed because early signs or symptoms of CRS can be subtle and best recognized by those who know the child best,” Dr. Mahadeo and his colleagues wrote in a summary of key recommendations in the paper.
The recommendations also noted a need for close monitoring for complications such as hypotension, hypocalcemia, and catheter-related pain in young patients who require a leukapheresis catheter for cell collection. Infant and younger children “might not verbalize these symptoms,” according to the researchers.
Other recommendations include:
- Obtaining the child’s assent when appropriate, with psychological services often aiding in this goal. Dr. Mahadeo and his colleagues recommend considering “age-appropriate advance directives.”
- Maintaining high vigilance for sinus tachycardia as an early sign of CRS, using age-specific normal range or baseline values.
- Giving pediatric dosing of tocilizumab, with patients weighing less than 30 kg receiving 12 mg/kg, and those weighing 30 kg or greater receiving 8 mg/kg.
- Considering participation with a prospective collaboration with intensive-care registries that could allow accurate data entry of cell-therapy variables into the Center for International Blood and Marrow Transplant Research registry by cell-therapy programs.
The Food and Drug Administration approved the first two CAR T-cell therapies in the United States in 2017: Novartis’ tisagenlecleucel (Kymriah) for children and young adults with B-cell precursor acute lymphoblastic leukemia and later for adults with large B-cell lymphoma; and axicabtagene ciloleucel (Yescarta), sold by Gilead, for adults with large B-cell lymphoma. The therapies involve reengineering a patient’s T cells such that they recognize the threat of cancer, and then introducing them back into the body. The European Medicines Agency’s Committee for Medicinal Products for Human Use in June recommended granting marketing authorization to these drugs.
In the new pediatric guidelines, Dr. Mahadeo and his colleagues noted the use of CAR T-cell therapies for treatment of solid tumors and other malignancies in children already “is being explored.” “Moreover, consideration of earlier or upfront use of CAR T-cell therapy might spare patients the acute and long-term toxicities associated with traditional chemotherapy and/or radiation regimens,” they wrote.
There’s been great interest in learning how to most safely use the CAR T cell therapies, said Helen Heslop, MD, of Baylor College of Medicine.
She pointed to a 2014 publication in the journal Blood from Daniel W. Lee and his colleagues as an earlier example of this research. By now, cancer centers will have worked out their own procedures for pediatric use of CAR T therapies, hewing to standards set by the Foundation for the Accreditation of Cellular Therapy (FACT), Dr. Heslop said.
Dr. Heslop also stressed the role of the FDA in requiring risk evaluation and management strategy programs for these drugs. All of this, including the new guidelines from Dr. Mahadeo and his colleagues, is part of a growing body of research into safe use of CAR T therapies, Dr. Heslop said.
“It’s an active area of research,” she said. “Most centers will look at all of it and then develop what works best in their own individual center for providing the best care for the patients.”
The newly published guidelines could prove an “important contribution” to managing the risk of CAR T therapies, Phyllis I. Warkentin, MD, chief medical officer for FACT, said in an interview, while stressing that they were not more or less important than other similar efforts. Physicians learning how to use the CAR T therapies may welcome new input, as most of what’s been published has been about adults, she said.
“You don’t have the luxury of a lot of time to be learning on the job, so to speak,” with CAR T therapies, she said. “Many of the toxicities are fairly severe and fairly sudden.”
Dr. Heslop has been on advisory board for Gilead and Novartis. Dr. Warkentin and Dr. Mahadeo each reported having no financial disclosures. Other authors of the guidelines paper reported a patent with applications in the field of gene-modified T cell therapy for cancer, as well as financial ties to Cellectis, NexImmune, Torque Pharma, Kite Pharma (a Gilead company), Poseida Therapeutics, Celgene, Novartis, and Unum Therapeutics.
SOURCE: Mahadeo KM et al. Nat Rev Clin Oncol. 2018 Aug 6. doi: 10.1038/s41571-018-0075-2.
emphasize the need for a flexible approach to detect early signs of serious complications for younger patients treated with this emerging class of medicines.
Researchers at the University of Texas MD Anderson Cancer Center, Houston, and the Pediatric Acute Lung Injury and Sepsis Investigators Network (PALISI) developed the guidelines, which were published in Nature Reviews Clinical Oncology. The recommendations build on the guidelines for more general use of these medicines from MD Anderson’s CARTOX Program, which Nature Reviews Clinical Oncology published in 2017.
Among the chief concerns with this new class of medicines are cytokine-release syndrome (CRS) and CAR T cell-related encephalopathy syndrome (CRES), according to Kris Michael Mahadeo, MD MPH, of the MD Anderson Cancer Center and his coauthors of the new paper.
Some of the tools used for older patients in screening for complications with CAR T drugs don’t work as well with younger ones, Dr. Mahadeo said in an interview. For instance, at MD Anderson, a handwriting sample is used to monitor patients for CAR T cell-related encephalopathy syndrome, which has symptoms of confusion and delirium. Patients provide a baseline handwriting sample of a single sentence that’s scanned into the medical record, and then they are asked to write this again during their time in the hospital, he said. But this tool may not work for children too young to write well.
The new guidelines suggest using the Cornell Assessment of Pediatric Delirium (CAPD) or to evaluate a child’s mental state, asking questions about eye contact, and level of awareness and mood, Dr. Mahadeo said. An alternative for patients aged 12 years and older with greater cognitive ability is the CARTOX-10 grading system.
“The nurses who spent most of the day with these patients will observe them over their shift and kind of get an idea of what was normal and answer a series of questions” through the CAPD tool, which is already used in ICUs, Dr. Mahadeo said. “It takes into consideration both the nurses’ perception and the parents, or whoever is at the bedside with the child. So that if they have a concern, it gives them a point that actually escalates things upward.”
The newly published recommendations also remind physicians and others caring for young patients to pay attention to these reports.
“Parent and/or caregiver concerns should be addressed because early signs or symptoms of CRS can be subtle and best recognized by those who know the child best,” Dr. Mahadeo and his colleagues wrote in a summary of key recommendations in the paper.
The recommendations also noted a need for close monitoring for complications such as hypotension, hypocalcemia, and catheter-related pain in young patients who require a leukapheresis catheter for cell collection. Infant and younger children “might not verbalize these symptoms,” according to the researchers.
Other recommendations include:
- Obtaining the child’s assent when appropriate, with psychological services often aiding in this goal. Dr. Mahadeo and his colleagues recommend considering “age-appropriate advance directives.”
- Maintaining high vigilance for sinus tachycardia as an early sign of CRS, using age-specific normal range or baseline values.
- Giving pediatric dosing of tocilizumab, with patients weighing less than 30 kg receiving 12 mg/kg, and those weighing 30 kg or greater receiving 8 mg/kg.
- Considering participation with a prospective collaboration with intensive-care registries that could allow accurate data entry of cell-therapy variables into the Center for International Blood and Marrow Transplant Research registry by cell-therapy programs.
The Food and Drug Administration approved the first two CAR T-cell therapies in the United States in 2017: Novartis’ tisagenlecleucel (Kymriah) for children and young adults with B-cell precursor acute lymphoblastic leukemia and later for adults with large B-cell lymphoma; and axicabtagene ciloleucel (Yescarta), sold by Gilead, for adults with large B-cell lymphoma. The therapies involve reengineering a patient’s T cells such that they recognize the threat of cancer, and then introducing them back into the body. The European Medicines Agency’s Committee for Medicinal Products for Human Use in June recommended granting marketing authorization to these drugs.
In the new pediatric guidelines, Dr. Mahadeo and his colleagues noted the use of CAR T-cell therapies for treatment of solid tumors and other malignancies in children already “is being explored.” “Moreover, consideration of earlier or upfront use of CAR T-cell therapy might spare patients the acute and long-term toxicities associated with traditional chemotherapy and/or radiation regimens,” they wrote.
There’s been great interest in learning how to most safely use the CAR T cell therapies, said Helen Heslop, MD, of Baylor College of Medicine.
She pointed to a 2014 publication in the journal Blood from Daniel W. Lee and his colleagues as an earlier example of this research. By now, cancer centers will have worked out their own procedures for pediatric use of CAR T therapies, hewing to standards set by the Foundation for the Accreditation of Cellular Therapy (FACT), Dr. Heslop said.
Dr. Heslop also stressed the role of the FDA in requiring risk evaluation and management strategy programs for these drugs. All of this, including the new guidelines from Dr. Mahadeo and his colleagues, is part of a growing body of research into safe use of CAR T therapies, Dr. Heslop said.
“It’s an active area of research,” she said. “Most centers will look at all of it and then develop what works best in their own individual center for providing the best care for the patients.”
The newly published guidelines could prove an “important contribution” to managing the risk of CAR T therapies, Phyllis I. Warkentin, MD, chief medical officer for FACT, said in an interview, while stressing that they were not more or less important than other similar efforts. Physicians learning how to use the CAR T therapies may welcome new input, as most of what’s been published has been about adults, she said.
“You don’t have the luxury of a lot of time to be learning on the job, so to speak,” with CAR T therapies, she said. “Many of the toxicities are fairly severe and fairly sudden.”
Dr. Heslop has been on advisory board for Gilead and Novartis. Dr. Warkentin and Dr. Mahadeo each reported having no financial disclosures. Other authors of the guidelines paper reported a patent with applications in the field of gene-modified T cell therapy for cancer, as well as financial ties to Cellectis, NexImmune, Torque Pharma, Kite Pharma (a Gilead company), Poseida Therapeutics, Celgene, Novartis, and Unum Therapeutics.
SOURCE: Mahadeo KM et al. Nat Rev Clin Oncol. 2018 Aug 6. doi: 10.1038/s41571-018-0075-2.
emphasize the need for a flexible approach to detect early signs of serious complications for younger patients treated with this emerging class of medicines.
Researchers at the University of Texas MD Anderson Cancer Center, Houston, and the Pediatric Acute Lung Injury and Sepsis Investigators Network (PALISI) developed the guidelines, which were published in Nature Reviews Clinical Oncology. The recommendations build on the guidelines for more general use of these medicines from MD Anderson’s CARTOX Program, which Nature Reviews Clinical Oncology published in 2017.
Among the chief concerns with this new class of medicines are cytokine-release syndrome (CRS) and CAR T cell-related encephalopathy syndrome (CRES), according to Kris Michael Mahadeo, MD MPH, of the MD Anderson Cancer Center and his coauthors of the new paper.
Some of the tools used for older patients in screening for complications with CAR T drugs don’t work as well with younger ones, Dr. Mahadeo said in an interview. For instance, at MD Anderson, a handwriting sample is used to monitor patients for CAR T cell-related encephalopathy syndrome, which has symptoms of confusion and delirium. Patients provide a baseline handwriting sample of a single sentence that’s scanned into the medical record, and then they are asked to write this again during their time in the hospital, he said. But this tool may not work for children too young to write well.
The new guidelines suggest using the Cornell Assessment of Pediatric Delirium (CAPD) or to evaluate a child’s mental state, asking questions about eye contact, and level of awareness and mood, Dr. Mahadeo said. An alternative for patients aged 12 years and older with greater cognitive ability is the CARTOX-10 grading system.
“The nurses who spent most of the day with these patients will observe them over their shift and kind of get an idea of what was normal and answer a series of questions” through the CAPD tool, which is already used in ICUs, Dr. Mahadeo said. “It takes into consideration both the nurses’ perception and the parents, or whoever is at the bedside with the child. So that if they have a concern, it gives them a point that actually escalates things upward.”
The newly published recommendations also remind physicians and others caring for young patients to pay attention to these reports.
“Parent and/or caregiver concerns should be addressed because early signs or symptoms of CRS can be subtle and best recognized by those who know the child best,” Dr. Mahadeo and his colleagues wrote in a summary of key recommendations in the paper.
The recommendations also noted a need for close monitoring for complications such as hypotension, hypocalcemia, and catheter-related pain in young patients who require a leukapheresis catheter for cell collection. Infant and younger children “might not verbalize these symptoms,” according to the researchers.
Other recommendations include:
- Obtaining the child’s assent when appropriate, with psychological services often aiding in this goal. Dr. Mahadeo and his colleagues recommend considering “age-appropriate advance directives.”
- Maintaining high vigilance for sinus tachycardia as an early sign of CRS, using age-specific normal range or baseline values.
- Giving pediatric dosing of tocilizumab, with patients weighing less than 30 kg receiving 12 mg/kg, and those weighing 30 kg or greater receiving 8 mg/kg.
- Considering participation with a prospective collaboration with intensive-care registries that could allow accurate data entry of cell-therapy variables into the Center for International Blood and Marrow Transplant Research registry by cell-therapy programs.
The Food and Drug Administration approved the first two CAR T-cell therapies in the United States in 2017: Novartis’ tisagenlecleucel (Kymriah) for children and young adults with B-cell precursor acute lymphoblastic leukemia and later for adults with large B-cell lymphoma; and axicabtagene ciloleucel (Yescarta), sold by Gilead, for adults with large B-cell lymphoma. The therapies involve reengineering a patient’s T cells such that they recognize the threat of cancer, and then introducing them back into the body. The European Medicines Agency’s Committee for Medicinal Products for Human Use in June recommended granting marketing authorization to these drugs.
In the new pediatric guidelines, Dr. Mahadeo and his colleagues noted the use of CAR T-cell therapies for treatment of solid tumors and other malignancies in children already “is being explored.” “Moreover, consideration of earlier or upfront use of CAR T-cell therapy might spare patients the acute and long-term toxicities associated with traditional chemotherapy and/or radiation regimens,” they wrote.
There’s been great interest in learning how to most safely use the CAR T cell therapies, said Helen Heslop, MD, of Baylor College of Medicine.
She pointed to a 2014 publication in the journal Blood from Daniel W. Lee and his colleagues as an earlier example of this research. By now, cancer centers will have worked out their own procedures for pediatric use of CAR T therapies, hewing to standards set by the Foundation for the Accreditation of Cellular Therapy (FACT), Dr. Heslop said.
Dr. Heslop also stressed the role of the FDA in requiring risk evaluation and management strategy programs for these drugs. All of this, including the new guidelines from Dr. Mahadeo and his colleagues, is part of a growing body of research into safe use of CAR T therapies, Dr. Heslop said.
“It’s an active area of research,” she said. “Most centers will look at all of it and then develop what works best in their own individual center for providing the best care for the patients.”
The newly published guidelines could prove an “important contribution” to managing the risk of CAR T therapies, Phyllis I. Warkentin, MD, chief medical officer for FACT, said in an interview, while stressing that they were not more or less important than other similar efforts. Physicians learning how to use the CAR T therapies may welcome new input, as most of what’s been published has been about adults, she said.
“You don’t have the luxury of a lot of time to be learning on the job, so to speak,” with CAR T therapies, she said. “Many of the toxicities are fairly severe and fairly sudden.”
Dr. Heslop has been on advisory board for Gilead and Novartis. Dr. Warkentin and Dr. Mahadeo each reported having no financial disclosures. Other authors of the guidelines paper reported a patent with applications in the field of gene-modified T cell therapy for cancer, as well as financial ties to Cellectis, NexImmune, Torque Pharma, Kite Pharma (a Gilead company), Poseida Therapeutics, Celgene, Novartis, and Unum Therapeutics.
SOURCE: Mahadeo KM et al. Nat Rev Clin Oncol. 2018 Aug 6. doi: 10.1038/s41571-018-0075-2.
FROM NATURE REVIEWS CLINICAL ONCOLOGY
Key clinical point: Multidisciplinary approach aids in managing CAR T-cell therapy’s severe potential toxicities in children.
Major finding: The guideline calls for pediatric dosing of tocilizumab, with patients weighing less than 30 kg receiving 12 mg/kg, and those weighing 30 kg or greater receiving 8 mg/kg.
Study details: Consensus guidelines on the care of children receiving CAR T-cell therapy from the Pediatric Acute Lung Injury and Sepsis Investigators and the MD Anderson Cancer Center CARTOX program.
Disclosures: Dr. Mahadeo reported having no financial disclosures. Other coauthors reported a patent with applications in the field of gene-modified T cell therapy for cancer, as well as financial ties to Cellectis, NexImmune, Torque Pharma, Kite Pharma (a Gilead company), Poseida Therapeutics, Celgene, Novartis, and Unum Therapeutics.
Source: Mahadeo KM et al. Nat Rev Clin Oncol. 2018 Aug 6. doi: 10.1038/s41571-018-0075-2.
Acute Leukemia of Ambiguous Lineage in Elderly Patients: A SEER-Medicare Database Analysis (FULL)
About Research in Context
In this article, the authors of recent scholarship have been asked to discuss the implications of their research on federal health care providers and specifically the veteran and active-duty service member patient populations. Because the article does not include new research and cannot be blinded, it has undergone an abbreviated peer review process. The original article can be found at Guru Murthy GS, Dhakal I, Lee JY, Mehta P. Acute leukemia of ambiguous lineage in elderly patients - analysis of survival using surveillance epidemiology and end results-Medicare database. Clin Lymphoma Myeloma Leuk. 2017;17(2):100-107.
Acute leukemia of ambiguous lineage (ALAL) is a rare disorder in adults, constituting about 3% to 5% of acute leukemia cases. Unlike acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL), ALAL cannot be clearly differentiated into a single subtype based on immunophenotyping. The diagnostic criteria for accurately identifying ALAL has evolved over time. There is paucity of information regarding the outcomes and management of this rare leukemia especially in elderly patients, and it is unclear whether treatment improves survival in these patients.
We performed a retrospective analysis of the Surveillance, Epidemiology, and End Results (SEER)-Medicare linked database to describe the outcomes of ALAL in the elderly population in U.S.1 Patients included in the analysis were aged > 65 years, with a pathologically confirmed diagnosis of ALAL, diagnosed between 1992-2010, and on active follow-up. Information on patient demographics, treatment, chemotherapeutic agents used in treatment, and survival was obtained and analyzed using appropriate statistical methods. A total of 705 patients with a median age of 80 years were included. There was a higher proportion of males than females and a higher proportion of white patients compared with African Americans and other races. We found that the overall survival (OS) declined significantly with increasing age, and treatment with chemotherapy improved the survival. However, factors such as gender, race, or type of chemotherapy received (ALL based, AML based, or other regimens) did not significantly influence the survival.
Even in the current era, the optimal therapy for ALAL is not well established. Although options such as AML-based or ALL-based chemotherapy are available, the best chemotherapy regimen and its sequence is unknown as prior studies have demonstrated varying results.2-5 Among elderly patients, numerous factors such as performance status, comorbidities, and ability to tolerate therapy influence the treatment decision. In light of the poor prognosis in elderly patients, a question often arises in the clinician’s mind about whether chemotherapy would provide any benefit for the patient.
Our study results showed that chemotherapy likely improves survival in these patients. However, due to the smaller number of patients, caution is needed in interpreting the result that there was no significant difference between AML-directed or ALL-directed chemotherapy. Another factor highlighted in the study was that only about 21.5% of patients had been treated with chemotherapy. Due to the inherent nature of the database, we could not identify the factors that may have influenced treatment decisions in these patients. Additionally, patients with stem cell transplantation-related claims could not be included in the analysis due to noncontinuous Medicare coverage during the study period. Hence, the role of stem cell transplantation in these patients could not be determined.
Implications Among Veterans
Actual incidence of ALAL among veterans is not known. Whether the incidence of ALAL relates to exposures to chemicals or toxins during military training and service also is unknown. However, ALAL is likely to be at least as prevalent as it is in the nonveteran population and perhaps more so because of exposures and stresses during military training and service.
It is unclear whether veterans attending VA hospitals receive less or different treatment given the higher comorbidities. Finally, it also is not known whether the outcomes for veterans would be different with or without treatment.
Our findings suggest that treatment should be seriously considered in all patients (veterans or not) who are healthy enough to receive chemotherapy regardless of their age. More research is needed to determine the disease incidence and prevalence among veterans and to evaluate whether there are specific etiologic correlations between ALAL and military exposures, whether the natural history is similar to other populations, and to delineate responsiveness to treatment.
Conclusion
This study suggests a poor survival for elderly patients with ALAL in the U.S. Although treatment is associated with an improvement in survival, only 21.5% of patients have received therapy. The optimal choice of chemotherapy for this disease is still not known and warrants prospective studies.
Click here to read the digital edition.
1. Guru Murthy GS, Dhakal I, Lee JY, Mehta P. Acute leukemia of ambiguous lineage in elderly patients—analysis of survival using surveillance epidemiology and end results—Medicare database. Clin Lymphoma Myeloma Leuk. 2017;17(2):100-107.
2. Rubnitz JE, Onciu M, Pounds S, et al. Acute mixed lineage leukemia in children: the experience of St Jude Children’s Research Hospital. Blood. 2009;113(21):5083-5089.
3. Matutes E, Pickl WF, Van’t Veer M, et al. Mixed phenotype acute leukemia: clinical and laboratory features and out-come in 100 patients defined according to the WHO classification. Blood. 2011;117(11):3163-3171.
4. Wolach O, Stone RM. How I treat mixed-phenotype acute leukemia. Blood. 2015;125(16):2477-2485.
5. Lee JH, Min YH, Chung CW, et al; Korean Society of Hematology AML/MDS Working Party. Prognostic implications of the immunophenotype in biphenotypic acute leukemia. Leuk Lymphoma. 2008;49(4):700-709.
About Research in Context
In this article, the authors of recent scholarship have been asked to discuss the implications of their research on federal health care providers and specifically the veteran and active-duty service member patient populations. Because the article does not include new research and cannot be blinded, it has undergone an abbreviated peer review process. The original article can be found at Guru Murthy GS, Dhakal I, Lee JY, Mehta P. Acute leukemia of ambiguous lineage in elderly patients - analysis of survival using surveillance epidemiology and end results-Medicare database. Clin Lymphoma Myeloma Leuk. 2017;17(2):100-107.
Acute leukemia of ambiguous lineage (ALAL) is a rare disorder in adults, constituting about 3% to 5% of acute leukemia cases. Unlike acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL), ALAL cannot be clearly differentiated into a single subtype based on immunophenotyping. The diagnostic criteria for accurately identifying ALAL has evolved over time. There is paucity of information regarding the outcomes and management of this rare leukemia especially in elderly patients, and it is unclear whether treatment improves survival in these patients.
We performed a retrospective analysis of the Surveillance, Epidemiology, and End Results (SEER)-Medicare linked database to describe the outcomes of ALAL in the elderly population in U.S.1 Patients included in the analysis were aged > 65 years, with a pathologically confirmed diagnosis of ALAL, diagnosed between 1992-2010, and on active follow-up. Information on patient demographics, treatment, chemotherapeutic agents used in treatment, and survival was obtained and analyzed using appropriate statistical methods. A total of 705 patients with a median age of 80 years were included. There was a higher proportion of males than females and a higher proportion of white patients compared with African Americans and other races. We found that the overall survival (OS) declined significantly with increasing age, and treatment with chemotherapy improved the survival. However, factors such as gender, race, or type of chemotherapy received (ALL based, AML based, or other regimens) did not significantly influence the survival.
Even in the current era, the optimal therapy for ALAL is not well established. Although options such as AML-based or ALL-based chemotherapy are available, the best chemotherapy regimen and its sequence is unknown as prior studies have demonstrated varying results.2-5 Among elderly patients, numerous factors such as performance status, comorbidities, and ability to tolerate therapy influence the treatment decision. In light of the poor prognosis in elderly patients, a question often arises in the clinician’s mind about whether chemotherapy would provide any benefit for the patient.
Our study results showed that chemotherapy likely improves survival in these patients. However, due to the smaller number of patients, caution is needed in interpreting the result that there was no significant difference between AML-directed or ALL-directed chemotherapy. Another factor highlighted in the study was that only about 21.5% of patients had been treated with chemotherapy. Due to the inherent nature of the database, we could not identify the factors that may have influenced treatment decisions in these patients. Additionally, patients with stem cell transplantation-related claims could not be included in the analysis due to noncontinuous Medicare coverage during the study period. Hence, the role of stem cell transplantation in these patients could not be determined.
Implications Among Veterans
Actual incidence of ALAL among veterans is not known. Whether the incidence of ALAL relates to exposures to chemicals or toxins during military training and service also is unknown. However, ALAL is likely to be at least as prevalent as it is in the nonveteran population and perhaps more so because of exposures and stresses during military training and service.
It is unclear whether veterans attending VA hospitals receive less or different treatment given the higher comorbidities. Finally, it also is not known whether the outcomes for veterans would be different with or without treatment.
Our findings suggest that treatment should be seriously considered in all patients (veterans or not) who are healthy enough to receive chemotherapy regardless of their age. More research is needed to determine the disease incidence and prevalence among veterans and to evaluate whether there are specific etiologic correlations between ALAL and military exposures, whether the natural history is similar to other populations, and to delineate responsiveness to treatment.
Conclusion
This study suggests a poor survival for elderly patients with ALAL in the U.S. Although treatment is associated with an improvement in survival, only 21.5% of patients have received therapy. The optimal choice of chemotherapy for this disease is still not known and warrants prospective studies.
Click here to read the digital edition.
About Research in Context
In this article, the authors of recent scholarship have been asked to discuss the implications of their research on federal health care providers and specifically the veteran and active-duty service member patient populations. Because the article does not include new research and cannot be blinded, it has undergone an abbreviated peer review process. The original article can be found at Guru Murthy GS, Dhakal I, Lee JY, Mehta P. Acute leukemia of ambiguous lineage in elderly patients - analysis of survival using surveillance epidemiology and end results-Medicare database. Clin Lymphoma Myeloma Leuk. 2017;17(2):100-107.
Acute leukemia of ambiguous lineage (ALAL) is a rare disorder in adults, constituting about 3% to 5% of acute leukemia cases. Unlike acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL), ALAL cannot be clearly differentiated into a single subtype based on immunophenotyping. The diagnostic criteria for accurately identifying ALAL has evolved over time. There is paucity of information regarding the outcomes and management of this rare leukemia especially in elderly patients, and it is unclear whether treatment improves survival in these patients.
We performed a retrospective analysis of the Surveillance, Epidemiology, and End Results (SEER)-Medicare linked database to describe the outcomes of ALAL in the elderly population in U.S.1 Patients included in the analysis were aged > 65 years, with a pathologically confirmed diagnosis of ALAL, diagnosed between 1992-2010, and on active follow-up. Information on patient demographics, treatment, chemotherapeutic agents used in treatment, and survival was obtained and analyzed using appropriate statistical methods. A total of 705 patients with a median age of 80 years were included. There was a higher proportion of males than females and a higher proportion of white patients compared with African Americans and other races. We found that the overall survival (OS) declined significantly with increasing age, and treatment with chemotherapy improved the survival. However, factors such as gender, race, or type of chemotherapy received (ALL based, AML based, or other regimens) did not significantly influence the survival.
Even in the current era, the optimal therapy for ALAL is not well established. Although options such as AML-based or ALL-based chemotherapy are available, the best chemotherapy regimen and its sequence is unknown as prior studies have demonstrated varying results.2-5 Among elderly patients, numerous factors such as performance status, comorbidities, and ability to tolerate therapy influence the treatment decision. In light of the poor prognosis in elderly patients, a question often arises in the clinician’s mind about whether chemotherapy would provide any benefit for the patient.
Our study results showed that chemotherapy likely improves survival in these patients. However, due to the smaller number of patients, caution is needed in interpreting the result that there was no significant difference between AML-directed or ALL-directed chemotherapy. Another factor highlighted in the study was that only about 21.5% of patients had been treated with chemotherapy. Due to the inherent nature of the database, we could not identify the factors that may have influenced treatment decisions in these patients. Additionally, patients with stem cell transplantation-related claims could not be included in the analysis due to noncontinuous Medicare coverage during the study period. Hence, the role of stem cell transplantation in these patients could not be determined.
Implications Among Veterans
Actual incidence of ALAL among veterans is not known. Whether the incidence of ALAL relates to exposures to chemicals or toxins during military training and service also is unknown. However, ALAL is likely to be at least as prevalent as it is in the nonveteran population and perhaps more so because of exposures and stresses during military training and service.
It is unclear whether veterans attending VA hospitals receive less or different treatment given the higher comorbidities. Finally, it also is not known whether the outcomes for veterans would be different with or without treatment.
Our findings suggest that treatment should be seriously considered in all patients (veterans or not) who are healthy enough to receive chemotherapy regardless of their age. More research is needed to determine the disease incidence and prevalence among veterans and to evaluate whether there are specific etiologic correlations between ALAL and military exposures, whether the natural history is similar to other populations, and to delineate responsiveness to treatment.
Conclusion
This study suggests a poor survival for elderly patients with ALAL in the U.S. Although treatment is associated with an improvement in survival, only 21.5% of patients have received therapy. The optimal choice of chemotherapy for this disease is still not known and warrants prospective studies.
Click here to read the digital edition.
1. Guru Murthy GS, Dhakal I, Lee JY, Mehta P. Acute leukemia of ambiguous lineage in elderly patients—analysis of survival using surveillance epidemiology and end results—Medicare database. Clin Lymphoma Myeloma Leuk. 2017;17(2):100-107.
2. Rubnitz JE, Onciu M, Pounds S, et al. Acute mixed lineage leukemia in children: the experience of St Jude Children’s Research Hospital. Blood. 2009;113(21):5083-5089.
3. Matutes E, Pickl WF, Van’t Veer M, et al. Mixed phenotype acute leukemia: clinical and laboratory features and out-come in 100 patients defined according to the WHO classification. Blood. 2011;117(11):3163-3171.
4. Wolach O, Stone RM. How I treat mixed-phenotype acute leukemia. Blood. 2015;125(16):2477-2485.
5. Lee JH, Min YH, Chung CW, et al; Korean Society of Hematology AML/MDS Working Party. Prognostic implications of the immunophenotype in biphenotypic acute leukemia. Leuk Lymphoma. 2008;49(4):700-709.
1. Guru Murthy GS, Dhakal I, Lee JY, Mehta P. Acute leukemia of ambiguous lineage in elderly patients—analysis of survival using surveillance epidemiology and end results—Medicare database. Clin Lymphoma Myeloma Leuk. 2017;17(2):100-107.
2. Rubnitz JE, Onciu M, Pounds S, et al. Acute mixed lineage leukemia in children: the experience of St Jude Children’s Research Hospital. Blood. 2009;113(21):5083-5089.
3. Matutes E, Pickl WF, Van’t Veer M, et al. Mixed phenotype acute leukemia: clinical and laboratory features and out-come in 100 patients defined according to the WHO classification. Blood. 2011;117(11):3163-3171.
4. Wolach O, Stone RM. How I treat mixed-phenotype acute leukemia. Blood. 2015;125(16):2477-2485.
5. Lee JH, Min YH, Chung CW, et al; Korean Society of Hematology AML/MDS Working Party. Prognostic implications of the immunophenotype in biphenotypic acute leukemia. Leuk Lymphoma. 2008;49(4):700-709.