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Lymphocyte, monocyte data can predict treatment response in follicular lymphoma
Absolute lymphocyte cell (ALC) and absolute monocyte cell (AMC) counts, as well as their ratio (LMR) proved to be prognostic factors for treatment results, as shown by a database analysis of follicular lymphoma (FL) patients.
Progressive disease and stable disease after first-line therapy, as well as the mortality rate, were significantly associated with lower ALC, higher AMC, and higher LMR, according to the report published online.
Researchers analyzed the data of 100 FL variant patients admitted and treated between January 2009 and June 2018 at a single center.
Area under the curve analysis for discriminating between survival times showed 0.57 x 109 cells/L was the most discriminative ALC cutoff value, 1.24 x 109/L was the most discriminative AMC cutoff value, and 1.63 x 109/L was the most discriminative LMR cutoff value.
Shorter overall survival (OS) was significantly associated with lower ALC, compared with those having higher ALC. Shorter OS and progression-free survival (PFS) were significantly associated with higher AMC, compared with those having lower AMC. Shorter OS and PFS were also significantly associated with lower LMR, compared with those having higher LMR.
Overall, a high-risk score in the Follicular Lymphoma International Prognostic Index (FLIPI) and having a low LMR were considered risk factors for prediction of OS in all the studied FL patients in univariate analysis and multivariate analysis, according to the researchers.
“Our results prove the effect of lymphocyte and monocyte in the tumor immune response, which gives opportunity to several therapeutic strategies that target myeloid-derived suppressor cells (MDSCs), including monocytes and their progeny and improves the T-cell function in eradication strategies,” the researchers concluded.
No study funding or disclosure details were provided.
SOURCE: Mohsen A et al. Clin Lymphoma Myeloma Leuk. 2020 Mar 20. doi: 10.1016/j.clml.2020.03.007.
Absolute lymphocyte cell (ALC) and absolute monocyte cell (AMC) counts, as well as their ratio (LMR) proved to be prognostic factors for treatment results, as shown by a database analysis of follicular lymphoma (FL) patients.
Progressive disease and stable disease after first-line therapy, as well as the mortality rate, were significantly associated with lower ALC, higher AMC, and higher LMR, according to the report published online.
Researchers analyzed the data of 100 FL variant patients admitted and treated between January 2009 and June 2018 at a single center.
Area under the curve analysis for discriminating between survival times showed 0.57 x 109 cells/L was the most discriminative ALC cutoff value, 1.24 x 109/L was the most discriminative AMC cutoff value, and 1.63 x 109/L was the most discriminative LMR cutoff value.
Shorter overall survival (OS) was significantly associated with lower ALC, compared with those having higher ALC. Shorter OS and progression-free survival (PFS) were significantly associated with higher AMC, compared with those having lower AMC. Shorter OS and PFS were also significantly associated with lower LMR, compared with those having higher LMR.
Overall, a high-risk score in the Follicular Lymphoma International Prognostic Index (FLIPI) and having a low LMR were considered risk factors for prediction of OS in all the studied FL patients in univariate analysis and multivariate analysis, according to the researchers.
“Our results prove the effect of lymphocyte and monocyte in the tumor immune response, which gives opportunity to several therapeutic strategies that target myeloid-derived suppressor cells (MDSCs), including monocytes and their progeny and improves the T-cell function in eradication strategies,” the researchers concluded.
No study funding or disclosure details were provided.
SOURCE: Mohsen A et al. Clin Lymphoma Myeloma Leuk. 2020 Mar 20. doi: 10.1016/j.clml.2020.03.007.
Absolute lymphocyte cell (ALC) and absolute monocyte cell (AMC) counts, as well as their ratio (LMR) proved to be prognostic factors for treatment results, as shown by a database analysis of follicular lymphoma (FL) patients.
Progressive disease and stable disease after first-line therapy, as well as the mortality rate, were significantly associated with lower ALC, higher AMC, and higher LMR, according to the report published online.
Researchers analyzed the data of 100 FL variant patients admitted and treated between January 2009 and June 2018 at a single center.
Area under the curve analysis for discriminating between survival times showed 0.57 x 109 cells/L was the most discriminative ALC cutoff value, 1.24 x 109/L was the most discriminative AMC cutoff value, and 1.63 x 109/L was the most discriminative LMR cutoff value.
Shorter overall survival (OS) was significantly associated with lower ALC, compared with those having higher ALC. Shorter OS and progression-free survival (PFS) were significantly associated with higher AMC, compared with those having lower AMC. Shorter OS and PFS were also significantly associated with lower LMR, compared with those having higher LMR.
Overall, a high-risk score in the Follicular Lymphoma International Prognostic Index (FLIPI) and having a low LMR were considered risk factors for prediction of OS in all the studied FL patients in univariate analysis and multivariate analysis, according to the researchers.
“Our results prove the effect of lymphocyte and monocyte in the tumor immune response, which gives opportunity to several therapeutic strategies that target myeloid-derived suppressor cells (MDSCs), including monocytes and their progeny and improves the T-cell function in eradication strategies,” the researchers concluded.
No study funding or disclosure details were provided.
SOURCE: Mohsen A et al. Clin Lymphoma Myeloma Leuk. 2020 Mar 20. doi: 10.1016/j.clml.2020.03.007.
FROM CLINICAL LYMPHOMA, MYELOMA AND LEUKEMIA
Stage I mycosis fungoides is the general dermatologist’s bailiwick
LAHAINA, HAWAII – without bringing in a medical oncologist, Trilokraj Tejasvi, MBBS, said at the Hawaii Dermatology Seminar provided by Global Academy for Medical Education/Skin Disease Education Foundation.
This approach is in the best interest of patients with stage I mycosis fungoides, the skin-limited, patch/plaque form of the disease that generally responds well to skin-directed therapies without needing to resort to the medical oncologist’s arsenal of toxic treatments.
“For many medical oncologists, a lymphoma is a lymphoma. The first thing they give is CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone), and all the variants of CHOP,” cautioned Dr. Tejasvi, a dermatologist who is director of the cutaneous lymphoma program at the University of Michigan, Ann Arbor, and chief of the dermatology service at the Ann Arbor Veteran Affairs Hospital.
Stage IA mycosis fungoides is defined under the TNMB (tumor, node, metastasis, blood) classification as patches and/or plaques covering less than 10% of body surface area along with negative nodes, no metastases, and no or low burden of disease in the blood. Stage IB differs only in that it features 10% or greater body surface area involvement. The extent of body surface area involvement can be estimated by hands-on measurement in which the area of one of the patient’s hands – palm plus fingers – is considered equivalent to 1% of that individual’s total body surface area.
The first question patients newly diagnosed with a cutaneous T-cell lymphoma ask concerns their prognosis. For those with stage IA or IB mycosis fungoides, the news is very good, as highlighted in a retrospective study of nearly 1,400 patients with mycosis fungoides, 71% of whom presented with patch/plaque stage disease (J Clin Oncol. 2010 Nov 1;28[31]:4730-9).
The median overall survival was 35.5 years in patients with stage IA disease and 21.5 years in those with stage IB disease.
“I tell patients with stage IA disease that whether we treat it or not will not change the course of their life,” Dr. Tejasvri said.
His message to patients with stage IB disease is that, because of their 38% risk of disease progression, he wants to see them in follow-up annually for the rest of their life.
Stage IIA disease – that is, patches and/or plaques with lymph node involvement with no effacement – is a tipping point at which serious consideration should be given to possible referral to a specialized multidisciplinary lymphoma center, in his view. That’s because the 10-year overall survival rate is only 52%.
Topical therapies
Topical corticosteroids remain the time-honored first-line skin-directed treatment. The mechanism of benefit involves induction of apoptosis and inhibition of lymphocyte binding. In one prospective study, clobetasol propionate achieved a 94% overall response rate in patients with stage IA or B disease, with minimal toxicity.
Alternatives include topical 5% imiquimod (Aldara), with an overall response rate of 80% and complete response rate of 45% in a 20-patient study. A newer formulation of mechlorethamine gel (Valchlor), is reported to have a 59% overall response rate and a sustained response in 86% of initial responders. For refractory skin lesions, 1% bexarotene gel (Targretin) is an option, with overall response rates of 44%-63% reported in prospective trials.
“I like it if the patient’s insurance covers it. Otherwise, it’s like buying a Prius: it’s $30,000 for a 45-g tube, which is insane,” Dr. Tejasvi commented.
Narrow-band UVB phototherapy is an effective modality for thin plaques and patches, as is PUVA for thicker ones. Dr. Tejasvi typically treats with topical steroids and/or phototherapy for at least 3 months before tapering.
When to suspect mycosis fungoides
“Mycosis fungoides is a great masquerader,” the dermatologist observed. For that reason, it deserves to be included in the differential diagnosis of an atypical psoriasiform or eczematoid rash, any new-onset rash in an elderly patient, or a rash with fever, night sweats, and unintended weight loss in a patient of any age. Generalized erythema with severe itching is another red flag.
“This pruritus is so severe that the only other condition which in my clinical practice would match it is Norwegian scabies,” according to Dr. Tejasvi.
Polychromatic patches or plaques in skin of color warrant further investigation as possible mycosis fungoides, he added.
Dr. Tejasvi reported having no financial conflicts of interest regarding his presentation.
SDEF/Global Academy for Medical Education and this news organization are owned by the same parent company.
LAHAINA, HAWAII – without bringing in a medical oncologist, Trilokraj Tejasvi, MBBS, said at the Hawaii Dermatology Seminar provided by Global Academy for Medical Education/Skin Disease Education Foundation.
This approach is in the best interest of patients with stage I mycosis fungoides, the skin-limited, patch/plaque form of the disease that generally responds well to skin-directed therapies without needing to resort to the medical oncologist’s arsenal of toxic treatments.
“For many medical oncologists, a lymphoma is a lymphoma. The first thing they give is CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone), and all the variants of CHOP,” cautioned Dr. Tejasvi, a dermatologist who is director of the cutaneous lymphoma program at the University of Michigan, Ann Arbor, and chief of the dermatology service at the Ann Arbor Veteran Affairs Hospital.
Stage IA mycosis fungoides is defined under the TNMB (tumor, node, metastasis, blood) classification as patches and/or plaques covering less than 10% of body surface area along with negative nodes, no metastases, and no or low burden of disease in the blood. Stage IB differs only in that it features 10% or greater body surface area involvement. The extent of body surface area involvement can be estimated by hands-on measurement in which the area of one of the patient’s hands – palm plus fingers – is considered equivalent to 1% of that individual’s total body surface area.
The first question patients newly diagnosed with a cutaneous T-cell lymphoma ask concerns their prognosis. For those with stage IA or IB mycosis fungoides, the news is very good, as highlighted in a retrospective study of nearly 1,400 patients with mycosis fungoides, 71% of whom presented with patch/plaque stage disease (J Clin Oncol. 2010 Nov 1;28[31]:4730-9).
The median overall survival was 35.5 years in patients with stage IA disease and 21.5 years in those with stage IB disease.
“I tell patients with stage IA disease that whether we treat it or not will not change the course of their life,” Dr. Tejasvri said.
His message to patients with stage IB disease is that, because of their 38% risk of disease progression, he wants to see them in follow-up annually for the rest of their life.
Stage IIA disease – that is, patches and/or plaques with lymph node involvement with no effacement – is a tipping point at which serious consideration should be given to possible referral to a specialized multidisciplinary lymphoma center, in his view. That’s because the 10-year overall survival rate is only 52%.
Topical therapies
Topical corticosteroids remain the time-honored first-line skin-directed treatment. The mechanism of benefit involves induction of apoptosis and inhibition of lymphocyte binding. In one prospective study, clobetasol propionate achieved a 94% overall response rate in patients with stage IA or B disease, with minimal toxicity.
Alternatives include topical 5% imiquimod (Aldara), with an overall response rate of 80% and complete response rate of 45% in a 20-patient study. A newer formulation of mechlorethamine gel (Valchlor), is reported to have a 59% overall response rate and a sustained response in 86% of initial responders. For refractory skin lesions, 1% bexarotene gel (Targretin) is an option, with overall response rates of 44%-63% reported in prospective trials.
“I like it if the patient’s insurance covers it. Otherwise, it’s like buying a Prius: it’s $30,000 for a 45-g tube, which is insane,” Dr. Tejasvi commented.
Narrow-band UVB phototherapy is an effective modality for thin plaques and patches, as is PUVA for thicker ones. Dr. Tejasvi typically treats with topical steroids and/or phototherapy for at least 3 months before tapering.
When to suspect mycosis fungoides
“Mycosis fungoides is a great masquerader,” the dermatologist observed. For that reason, it deserves to be included in the differential diagnosis of an atypical psoriasiform or eczematoid rash, any new-onset rash in an elderly patient, or a rash with fever, night sweats, and unintended weight loss in a patient of any age. Generalized erythema with severe itching is another red flag.
“This pruritus is so severe that the only other condition which in my clinical practice would match it is Norwegian scabies,” according to Dr. Tejasvi.
Polychromatic patches or plaques in skin of color warrant further investigation as possible mycosis fungoides, he added.
Dr. Tejasvi reported having no financial conflicts of interest regarding his presentation.
SDEF/Global Academy for Medical Education and this news organization are owned by the same parent company.
LAHAINA, HAWAII – without bringing in a medical oncologist, Trilokraj Tejasvi, MBBS, said at the Hawaii Dermatology Seminar provided by Global Academy for Medical Education/Skin Disease Education Foundation.
This approach is in the best interest of patients with stage I mycosis fungoides, the skin-limited, patch/plaque form of the disease that generally responds well to skin-directed therapies without needing to resort to the medical oncologist’s arsenal of toxic treatments.
“For many medical oncologists, a lymphoma is a lymphoma. The first thing they give is CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone), and all the variants of CHOP,” cautioned Dr. Tejasvi, a dermatologist who is director of the cutaneous lymphoma program at the University of Michigan, Ann Arbor, and chief of the dermatology service at the Ann Arbor Veteran Affairs Hospital.
Stage IA mycosis fungoides is defined under the TNMB (tumor, node, metastasis, blood) classification as patches and/or plaques covering less than 10% of body surface area along with negative nodes, no metastases, and no or low burden of disease in the blood. Stage IB differs only in that it features 10% or greater body surface area involvement. The extent of body surface area involvement can be estimated by hands-on measurement in which the area of one of the patient’s hands – palm plus fingers – is considered equivalent to 1% of that individual’s total body surface area.
The first question patients newly diagnosed with a cutaneous T-cell lymphoma ask concerns their prognosis. For those with stage IA or IB mycosis fungoides, the news is very good, as highlighted in a retrospective study of nearly 1,400 patients with mycosis fungoides, 71% of whom presented with patch/plaque stage disease (J Clin Oncol. 2010 Nov 1;28[31]:4730-9).
The median overall survival was 35.5 years in patients with stage IA disease and 21.5 years in those with stage IB disease.
“I tell patients with stage IA disease that whether we treat it or not will not change the course of their life,” Dr. Tejasvri said.
His message to patients with stage IB disease is that, because of their 38% risk of disease progression, he wants to see them in follow-up annually for the rest of their life.
Stage IIA disease – that is, patches and/or plaques with lymph node involvement with no effacement – is a tipping point at which serious consideration should be given to possible referral to a specialized multidisciplinary lymphoma center, in his view. That’s because the 10-year overall survival rate is only 52%.
Topical therapies
Topical corticosteroids remain the time-honored first-line skin-directed treatment. The mechanism of benefit involves induction of apoptosis and inhibition of lymphocyte binding. In one prospective study, clobetasol propionate achieved a 94% overall response rate in patients with stage IA or B disease, with minimal toxicity.
Alternatives include topical 5% imiquimod (Aldara), with an overall response rate of 80% and complete response rate of 45% in a 20-patient study. A newer formulation of mechlorethamine gel (Valchlor), is reported to have a 59% overall response rate and a sustained response in 86% of initial responders. For refractory skin lesions, 1% bexarotene gel (Targretin) is an option, with overall response rates of 44%-63% reported in prospective trials.
“I like it if the patient’s insurance covers it. Otherwise, it’s like buying a Prius: it’s $30,000 for a 45-g tube, which is insane,” Dr. Tejasvi commented.
Narrow-band UVB phototherapy is an effective modality for thin plaques and patches, as is PUVA for thicker ones. Dr. Tejasvi typically treats with topical steroids and/or phototherapy for at least 3 months before tapering.
When to suspect mycosis fungoides
“Mycosis fungoides is a great masquerader,” the dermatologist observed. For that reason, it deserves to be included in the differential diagnosis of an atypical psoriasiform or eczematoid rash, any new-onset rash in an elderly patient, or a rash with fever, night sweats, and unintended weight loss in a patient of any age. Generalized erythema with severe itching is another red flag.
“This pruritus is so severe that the only other condition which in my clinical practice would match it is Norwegian scabies,” according to Dr. Tejasvi.
Polychromatic patches or plaques in skin of color warrant further investigation as possible mycosis fungoides, he added.
Dr. Tejasvi reported having no financial conflicts of interest regarding his presentation.
SDEF/Global Academy for Medical Education and this news organization are owned by the same parent company.
REPORTING FROM SDEF HAWAII DERMATOLOGY SEMINAR
CAR T cells produce complete responses in T-cell malignancies
ORLANDO – Anti-CD5 chimeric antigen receptor (CAR) T cells can produce complete responses (CRs) in patients with relapsed or refractory T-cell malignancies, according to findings from a phase 1 trial.
Three of 11 patients achieved a CR after CAR T-cell therapy, and one patient achieved a mixed response that deepened to a CR after transplant. Three responders, all of whom had T-cell lymphoma, were still alive and in CR at last follow-up.
There were no cases of severe cytokine release syndrome (CRS) or severe neurotoxicity, no serious infectious complications, and no nonhematologic grade 4 adverse events in this trial.
LaQuisa C. Hill, MD, of Baylor College of Medicine, Houston, presented these results at the annual meeting of the American Society of Hematology.
“While CD19 CAR T cells have revolutionized the treatment of relapsed/refractory B-cell malignancies, development of CAR T-cell platforms targeting T-cell-driven malignancies have been hindered by three main factors: CAR T-cell fratricide due to shared expression of target antigens leading to impaired expansion, ablation of normal T cells continuing to cause profound immunodeficiency, and the potential of transduced tumor cells providing a means of tumor escape,” Dr. Hill said.
Researchers have theorized that anti-CD5 CAR T cells can overcome these obstacles. In preclinical studies, anti-CD5 CAR T cells eliminated malignant blasts in vitro and in vivo and resulted in “limited and transient” fratricide (Blood. 2015 Aug 20;126[8]:983-92).
With this in mind, Dr. Hill and her colleagues tested CD5.28z CAR T cells in a phase 1 trial (NCT03081910). Eleven patients have been treated thus far – five with T-cell acute lymphoblastic leukemia (T-ALL), three with peripheral T-cell lymphoma (PTCL), two with angioimmunoblastic T-cell lymphoma (AITL), and one with Sézary syndrome.
The patients’ median age at baseline was 62 years (range, 21-71 years), and 63% were men. They had received a median of 5 prior therapies (range, 3-18). Two patients had relapsed after allogeneic hematopoietic stem cell transplant (HSCT), three had relapsed after autologous HSCT, and five were primary refractory.
Patients underwent lymphodepletion with fludarabine and cyclophosphamide, then received CAR T cells at doses of 1 x 107 or 5 x 107.
Response
Three lymphoma patients – two with AITL and one with PTCL – were still alive and in CR at last follow-up. The PTCL patient achieved a CR after CAR T-cell therapy and declined a subsequent HSCT. The patient has not received additional therapy and has retained the CR for 7 months.
One AITL patient achieved a CR and declined transplant as well. He relapsed after 7 months but received subsequent therapy and achieved another CR. The other AITL patient had a mixed response to CAR T-cell therapy but proceeded to allogeneic HSCT and achieved a CR that has lasted 9 months.
The remaining three lymphoma patients – two with PTCL and one with Sézary syndrome – progressed and died.
One T-ALL patient achieved a CR lasting 6 weeks, but the patient died while undergoing transplant workup. Two T-ALL patients did not respond to treatment and died. The remaining two patients progressed, and one of them died. The other patient who progressed is still alive and in CR after receiving subsequent therapy.
Factors associated with response
Dr. Hill said a shortened manufacturing process may be associated with enhanced response, as all responders received CAR T cells produced via a shorter manufacturing process. The shortened process involves freezing cells on day 4-5 post transduction, as opposed to day 7.
“While the numbers are too small to make any definitive conclusions, this seems to correlate with less terminal differentiation, which might improve potency,” Dr. Hill said. “However, additional analyses are ongoing.”
Dr. Hill also pointed out that CAR T-cell expansion was observed in all patients, with higher peak levels observed at the higher dose. In addition, CAR T-cell persistence was durable at both dose levels.
“We have been able to detect the CAR transgene at all follow-up time points, out to 9 months for some patients,” Dr. Hill said. “While limited persistence may play a role in nonresponders, it does not appear to be the only factor.”
Safety
“Surprisingly, no selective ablation of normal T cells has been observed,” Dr. Hill said. “As CAR T cells dwindled [after infusion], we were able to see recovery of normal T cells, all of which expressed normal levels of CD5. This was observed in all patients on study, except for one patient who had prolonged pancytopenia.”
Cytopenias were the most common grade 3/4 adverse events, including neutropenia (n = 8), anemia (n = 7), and thrombocytopenia (n = 5). Other grade 3/4 events included elevated aspartate aminotransferase (n = 2), hypoalbuminemia (n = 1), hyponatremia (n = 1), hypophosphatemia (n = 1), and elevated alanine aminotransferase (n = 1). There were no grade 5 adverse events.
Two patients developed grade 1 CRS, and two had grade 2 CRS. Both patients with grade 2 CRS were treated with tocilizumab, and their symptoms resolved.
One patient developed grade 2 immune effector cell-associated neurotoxicity syndrome, but this resolved with supportive care.
One patient had a central line–associated bloodstream infection (coagulase-negative staphylococci), and one had cytomegalovirus and BK virus reactivation. There were no fungal infections.
“We have demonstrated that CD5 CAR T cells can be manufactured from heavily pretreated patients with T-cell malignancies, and therapy is well tolerated,” Dr. Hill said. “We have seen strong and promising activity in T-cell lymphoma, which we hope to be able to translate to T-ALL as well.”
Dr. Hill said she and her colleagues hope to improve upon these results with a higher dose level of CD5 CAR T cells (1 x 108), which the team plans to start testing soon. The researchers may also investigate other target antigens, such as CD7, as well as the use of donor-derived CAR T cells for patients who have relapsed after allogeneic HSCT.
Dr. Hill said she has no relevant disclosures. Baylor College of Medicine is sponsoring this trial.
SOURCE: Hill L et al. ASH 2019. Abstract 199.
ORLANDO – Anti-CD5 chimeric antigen receptor (CAR) T cells can produce complete responses (CRs) in patients with relapsed or refractory T-cell malignancies, according to findings from a phase 1 trial.
Three of 11 patients achieved a CR after CAR T-cell therapy, and one patient achieved a mixed response that deepened to a CR after transplant. Three responders, all of whom had T-cell lymphoma, were still alive and in CR at last follow-up.
There were no cases of severe cytokine release syndrome (CRS) or severe neurotoxicity, no serious infectious complications, and no nonhematologic grade 4 adverse events in this trial.
LaQuisa C. Hill, MD, of Baylor College of Medicine, Houston, presented these results at the annual meeting of the American Society of Hematology.
“While CD19 CAR T cells have revolutionized the treatment of relapsed/refractory B-cell malignancies, development of CAR T-cell platforms targeting T-cell-driven malignancies have been hindered by three main factors: CAR T-cell fratricide due to shared expression of target antigens leading to impaired expansion, ablation of normal T cells continuing to cause profound immunodeficiency, and the potential of transduced tumor cells providing a means of tumor escape,” Dr. Hill said.
Researchers have theorized that anti-CD5 CAR T cells can overcome these obstacles. In preclinical studies, anti-CD5 CAR T cells eliminated malignant blasts in vitro and in vivo and resulted in “limited and transient” fratricide (Blood. 2015 Aug 20;126[8]:983-92).
With this in mind, Dr. Hill and her colleagues tested CD5.28z CAR T cells in a phase 1 trial (NCT03081910). Eleven patients have been treated thus far – five with T-cell acute lymphoblastic leukemia (T-ALL), three with peripheral T-cell lymphoma (PTCL), two with angioimmunoblastic T-cell lymphoma (AITL), and one with Sézary syndrome.
The patients’ median age at baseline was 62 years (range, 21-71 years), and 63% were men. They had received a median of 5 prior therapies (range, 3-18). Two patients had relapsed after allogeneic hematopoietic stem cell transplant (HSCT), three had relapsed after autologous HSCT, and five were primary refractory.
Patients underwent lymphodepletion with fludarabine and cyclophosphamide, then received CAR T cells at doses of 1 x 107 or 5 x 107.
Response
Three lymphoma patients – two with AITL and one with PTCL – were still alive and in CR at last follow-up. The PTCL patient achieved a CR after CAR T-cell therapy and declined a subsequent HSCT. The patient has not received additional therapy and has retained the CR for 7 months.
One AITL patient achieved a CR and declined transplant as well. He relapsed after 7 months but received subsequent therapy and achieved another CR. The other AITL patient had a mixed response to CAR T-cell therapy but proceeded to allogeneic HSCT and achieved a CR that has lasted 9 months.
The remaining three lymphoma patients – two with PTCL and one with Sézary syndrome – progressed and died.
One T-ALL patient achieved a CR lasting 6 weeks, but the patient died while undergoing transplant workup. Two T-ALL patients did not respond to treatment and died. The remaining two patients progressed, and one of them died. The other patient who progressed is still alive and in CR after receiving subsequent therapy.
Factors associated with response
Dr. Hill said a shortened manufacturing process may be associated with enhanced response, as all responders received CAR T cells produced via a shorter manufacturing process. The shortened process involves freezing cells on day 4-5 post transduction, as opposed to day 7.
“While the numbers are too small to make any definitive conclusions, this seems to correlate with less terminal differentiation, which might improve potency,” Dr. Hill said. “However, additional analyses are ongoing.”
Dr. Hill also pointed out that CAR T-cell expansion was observed in all patients, with higher peak levels observed at the higher dose. In addition, CAR T-cell persistence was durable at both dose levels.
“We have been able to detect the CAR transgene at all follow-up time points, out to 9 months for some patients,” Dr. Hill said. “While limited persistence may play a role in nonresponders, it does not appear to be the only factor.”
Safety
“Surprisingly, no selective ablation of normal T cells has been observed,” Dr. Hill said. “As CAR T cells dwindled [after infusion], we were able to see recovery of normal T cells, all of which expressed normal levels of CD5. This was observed in all patients on study, except for one patient who had prolonged pancytopenia.”
Cytopenias were the most common grade 3/4 adverse events, including neutropenia (n = 8), anemia (n = 7), and thrombocytopenia (n = 5). Other grade 3/4 events included elevated aspartate aminotransferase (n = 2), hypoalbuminemia (n = 1), hyponatremia (n = 1), hypophosphatemia (n = 1), and elevated alanine aminotransferase (n = 1). There were no grade 5 adverse events.
Two patients developed grade 1 CRS, and two had grade 2 CRS. Both patients with grade 2 CRS were treated with tocilizumab, and their symptoms resolved.
One patient developed grade 2 immune effector cell-associated neurotoxicity syndrome, but this resolved with supportive care.
One patient had a central line–associated bloodstream infection (coagulase-negative staphylococci), and one had cytomegalovirus and BK virus reactivation. There were no fungal infections.
“We have demonstrated that CD5 CAR T cells can be manufactured from heavily pretreated patients with T-cell malignancies, and therapy is well tolerated,” Dr. Hill said. “We have seen strong and promising activity in T-cell lymphoma, which we hope to be able to translate to T-ALL as well.”
Dr. Hill said she and her colleagues hope to improve upon these results with a higher dose level of CD5 CAR T cells (1 x 108), which the team plans to start testing soon. The researchers may also investigate other target antigens, such as CD7, as well as the use of donor-derived CAR T cells for patients who have relapsed after allogeneic HSCT.
Dr. Hill said she has no relevant disclosures. Baylor College of Medicine is sponsoring this trial.
SOURCE: Hill L et al. ASH 2019. Abstract 199.
ORLANDO – Anti-CD5 chimeric antigen receptor (CAR) T cells can produce complete responses (CRs) in patients with relapsed or refractory T-cell malignancies, according to findings from a phase 1 trial.
Three of 11 patients achieved a CR after CAR T-cell therapy, and one patient achieved a mixed response that deepened to a CR after transplant. Three responders, all of whom had T-cell lymphoma, were still alive and in CR at last follow-up.
There were no cases of severe cytokine release syndrome (CRS) or severe neurotoxicity, no serious infectious complications, and no nonhematologic grade 4 adverse events in this trial.
LaQuisa C. Hill, MD, of Baylor College of Medicine, Houston, presented these results at the annual meeting of the American Society of Hematology.
“While CD19 CAR T cells have revolutionized the treatment of relapsed/refractory B-cell malignancies, development of CAR T-cell platforms targeting T-cell-driven malignancies have been hindered by three main factors: CAR T-cell fratricide due to shared expression of target antigens leading to impaired expansion, ablation of normal T cells continuing to cause profound immunodeficiency, and the potential of transduced tumor cells providing a means of tumor escape,” Dr. Hill said.
Researchers have theorized that anti-CD5 CAR T cells can overcome these obstacles. In preclinical studies, anti-CD5 CAR T cells eliminated malignant blasts in vitro and in vivo and resulted in “limited and transient” fratricide (Blood. 2015 Aug 20;126[8]:983-92).
With this in mind, Dr. Hill and her colleagues tested CD5.28z CAR T cells in a phase 1 trial (NCT03081910). Eleven patients have been treated thus far – five with T-cell acute lymphoblastic leukemia (T-ALL), three with peripheral T-cell lymphoma (PTCL), two with angioimmunoblastic T-cell lymphoma (AITL), and one with Sézary syndrome.
The patients’ median age at baseline was 62 years (range, 21-71 years), and 63% were men. They had received a median of 5 prior therapies (range, 3-18). Two patients had relapsed after allogeneic hematopoietic stem cell transplant (HSCT), three had relapsed after autologous HSCT, and five were primary refractory.
Patients underwent lymphodepletion with fludarabine and cyclophosphamide, then received CAR T cells at doses of 1 x 107 or 5 x 107.
Response
Three lymphoma patients – two with AITL and one with PTCL – were still alive and in CR at last follow-up. The PTCL patient achieved a CR after CAR T-cell therapy and declined a subsequent HSCT. The patient has not received additional therapy and has retained the CR for 7 months.
One AITL patient achieved a CR and declined transplant as well. He relapsed after 7 months but received subsequent therapy and achieved another CR. The other AITL patient had a mixed response to CAR T-cell therapy but proceeded to allogeneic HSCT and achieved a CR that has lasted 9 months.
The remaining three lymphoma patients – two with PTCL and one with Sézary syndrome – progressed and died.
One T-ALL patient achieved a CR lasting 6 weeks, but the patient died while undergoing transplant workup. Two T-ALL patients did not respond to treatment and died. The remaining two patients progressed, and one of them died. The other patient who progressed is still alive and in CR after receiving subsequent therapy.
Factors associated with response
Dr. Hill said a shortened manufacturing process may be associated with enhanced response, as all responders received CAR T cells produced via a shorter manufacturing process. The shortened process involves freezing cells on day 4-5 post transduction, as opposed to day 7.
“While the numbers are too small to make any definitive conclusions, this seems to correlate with less terminal differentiation, which might improve potency,” Dr. Hill said. “However, additional analyses are ongoing.”
Dr. Hill also pointed out that CAR T-cell expansion was observed in all patients, with higher peak levels observed at the higher dose. In addition, CAR T-cell persistence was durable at both dose levels.
“We have been able to detect the CAR transgene at all follow-up time points, out to 9 months for some patients,” Dr. Hill said. “While limited persistence may play a role in nonresponders, it does not appear to be the only factor.”
Safety
“Surprisingly, no selective ablation of normal T cells has been observed,” Dr. Hill said. “As CAR T cells dwindled [after infusion], we were able to see recovery of normal T cells, all of which expressed normal levels of CD5. This was observed in all patients on study, except for one patient who had prolonged pancytopenia.”
Cytopenias were the most common grade 3/4 adverse events, including neutropenia (n = 8), anemia (n = 7), and thrombocytopenia (n = 5). Other grade 3/4 events included elevated aspartate aminotransferase (n = 2), hypoalbuminemia (n = 1), hyponatremia (n = 1), hypophosphatemia (n = 1), and elevated alanine aminotransferase (n = 1). There were no grade 5 adverse events.
Two patients developed grade 1 CRS, and two had grade 2 CRS. Both patients with grade 2 CRS were treated with tocilizumab, and their symptoms resolved.
One patient developed grade 2 immune effector cell-associated neurotoxicity syndrome, but this resolved with supportive care.
One patient had a central line–associated bloodstream infection (coagulase-negative staphylococci), and one had cytomegalovirus and BK virus reactivation. There were no fungal infections.
“We have demonstrated that CD5 CAR T cells can be manufactured from heavily pretreated patients with T-cell malignancies, and therapy is well tolerated,” Dr. Hill said. “We have seen strong and promising activity in T-cell lymphoma, which we hope to be able to translate to T-ALL as well.”
Dr. Hill said she and her colleagues hope to improve upon these results with a higher dose level of CD5 CAR T cells (1 x 108), which the team plans to start testing soon. The researchers may also investigate other target antigens, such as CD7, as well as the use of donor-derived CAR T cells for patients who have relapsed after allogeneic HSCT.
Dr. Hill said she has no relevant disclosures. Baylor College of Medicine is sponsoring this trial.
SOURCE: Hill L et al. ASH 2019. Abstract 199.
REPORTING FROM ASH 2019
Study halted; ‘hyperprogression’ seen with nivolumab for R/R PTCL
ORLANDO – There is an urgent need for new therapies to treat relapsed or refractory peripheral T-cell lymphoma, but results of a phase 2 study suggest that monotherapy with the immune checkpoint inhibitor nivolumab (Opdivo) is not the hoped-for salvage treatment.
An interim analysis of data on 12 patients with peripheral T-cell lymphoma (PTCL) treated with nivolumab monotherapy showed an overall response rate of 33%, consisting of 2 complete responses and 2 partial responses. But the responses were short lived, and one patient had hyperprogressive disease – dramatic progression within one cycle of treatment – while two more had progression within two cycles, leading to a trial halt, reported N. Nora Bennani, MD, from the Mayo Clinic in Rochester, Minn.
“These findings likely reflect the distinct biology of PTCL and should be considered when designing future studies using checkpoint inhibitors in these diseases,” she said at the annual meeting of the American Society of Hematology.
The rationale for using an immune checkpoint inhibitor directed against the programmed death–1 protein and its ligands (PD and PD-L1/2) is that malignant cells in PTCL induce a profoundly immunosuppressive tumor microenvironment. Checkpoint inhibitors have shown strong activity against relapsed Hodgkin lymphoma, and the Mayo Clinic researchers speculated that an anti-PD-1 agent could have a similar effect in PTCL.
They had originally planned to enroll 29 patients into a phase 2 trial with nivolumab delivered 240 mg every 2 weeks for eight cycles, followed by a dose of 480 mg given every 4 weeks until disease progression or intolerable toxicities.
Patients were eligible if they had biopsy-confirmed relapsed or refractory PTCL, measurable disease on cross-sectional imaging of at least 1.5 cm, and prior systemic chemoimmunotherapy and/or autologous stem cell transplantation.
The interim analysis included 12 patients who received at least one dose of nivolumab. Of the 12 patients, 6 had angioimmunoblastic T-cell lymphoma (AITL), 3 had PTCL not otherwise specified, and 1 each had ALK-negative anaplastic large cell lymphoma (ALK-ALCL), enteropathy-associated T-cell lymphoma (EATL), or hepatosplenic gamma/delta T-cell lymphoma.
All patients had Ann Arbor stage III/IV disease, and 11 had extranodal involvement.
As noted, there were 4 responses among the 12 patients, consisting of 1 complete response in the patient with ALK-ALCL and 1 in a patient with AITL, and 2 partial responses – 1 in a patient with PTCL-NOS, and 1 in the patient with EATL.
The median progression-free survival for all 12 patients was short at 2.7 months, and the median overall survival was estimated at 6.7 months.
“It was staggering to see this: The duration of response was significantly short, less than 2 months,” Dr. Bennani said.
Nonhematologic toxicities were seen in 5 of the 12 patients (42%), and hematologic adverse events occurred in 3 (25%). All patients are now off treatment, 10 because of disease progression, 1 because of acute pancreatitis, and the aforementioned patient with hyperprogressive disease.
The patient with hyperprogressive disease had significant progression in tonsillar and cervical lymphadenopathy within 7-10 days of nivolumab infusion, with biopsy-proven AITL in the involved nodes.
“I believe that, in this patient population, combination therapies will be key. I think checkpoint blockers alone are not going to be sufficient to see meaningful outcomes in these patients,” Dr. Bennani said in an interview.
“An overall response rate of 33% is significant, because most other agents that were FDA approved in this patient population have response rates around 30%,” she said, adding that it’s possible that the patients with rapid progression had disease too advanced to be effectively treated with a checkpoint inhibitor.
“Ideally however, if we want to move forward, it will need to be with combinations of checkpoint inhibitors with HDAC [histone deacetylase] inhibitors, hypomethylating agents, or even PI3 kinase inhibitors,” she said.
The study was supported by Bristol-Myers Squibb. Dr. Bennani reported research funding and advisory board activities for Bristol-Myers Squibb and others.
SOURCE: Bennani NN et al. ASH 2019, Abstract 467.
ORLANDO – There is an urgent need for new therapies to treat relapsed or refractory peripheral T-cell lymphoma, but results of a phase 2 study suggest that monotherapy with the immune checkpoint inhibitor nivolumab (Opdivo) is not the hoped-for salvage treatment.
An interim analysis of data on 12 patients with peripheral T-cell lymphoma (PTCL) treated with nivolumab monotherapy showed an overall response rate of 33%, consisting of 2 complete responses and 2 partial responses. But the responses were short lived, and one patient had hyperprogressive disease – dramatic progression within one cycle of treatment – while two more had progression within two cycles, leading to a trial halt, reported N. Nora Bennani, MD, from the Mayo Clinic in Rochester, Minn.
“These findings likely reflect the distinct biology of PTCL and should be considered when designing future studies using checkpoint inhibitors in these diseases,” she said at the annual meeting of the American Society of Hematology.
The rationale for using an immune checkpoint inhibitor directed against the programmed death–1 protein and its ligands (PD and PD-L1/2) is that malignant cells in PTCL induce a profoundly immunosuppressive tumor microenvironment. Checkpoint inhibitors have shown strong activity against relapsed Hodgkin lymphoma, and the Mayo Clinic researchers speculated that an anti-PD-1 agent could have a similar effect in PTCL.
They had originally planned to enroll 29 patients into a phase 2 trial with nivolumab delivered 240 mg every 2 weeks for eight cycles, followed by a dose of 480 mg given every 4 weeks until disease progression or intolerable toxicities.
Patients were eligible if they had biopsy-confirmed relapsed or refractory PTCL, measurable disease on cross-sectional imaging of at least 1.5 cm, and prior systemic chemoimmunotherapy and/or autologous stem cell transplantation.
The interim analysis included 12 patients who received at least one dose of nivolumab. Of the 12 patients, 6 had angioimmunoblastic T-cell lymphoma (AITL), 3 had PTCL not otherwise specified, and 1 each had ALK-negative anaplastic large cell lymphoma (ALK-ALCL), enteropathy-associated T-cell lymphoma (EATL), or hepatosplenic gamma/delta T-cell lymphoma.
All patients had Ann Arbor stage III/IV disease, and 11 had extranodal involvement.
As noted, there were 4 responses among the 12 patients, consisting of 1 complete response in the patient with ALK-ALCL and 1 in a patient with AITL, and 2 partial responses – 1 in a patient with PTCL-NOS, and 1 in the patient with EATL.
The median progression-free survival for all 12 patients was short at 2.7 months, and the median overall survival was estimated at 6.7 months.
“It was staggering to see this: The duration of response was significantly short, less than 2 months,” Dr. Bennani said.
Nonhematologic toxicities were seen in 5 of the 12 patients (42%), and hematologic adverse events occurred in 3 (25%). All patients are now off treatment, 10 because of disease progression, 1 because of acute pancreatitis, and the aforementioned patient with hyperprogressive disease.
The patient with hyperprogressive disease had significant progression in tonsillar and cervical lymphadenopathy within 7-10 days of nivolumab infusion, with biopsy-proven AITL in the involved nodes.
“I believe that, in this patient population, combination therapies will be key. I think checkpoint blockers alone are not going to be sufficient to see meaningful outcomes in these patients,” Dr. Bennani said in an interview.
“An overall response rate of 33% is significant, because most other agents that were FDA approved in this patient population have response rates around 30%,” she said, adding that it’s possible that the patients with rapid progression had disease too advanced to be effectively treated with a checkpoint inhibitor.
“Ideally however, if we want to move forward, it will need to be with combinations of checkpoint inhibitors with HDAC [histone deacetylase] inhibitors, hypomethylating agents, or even PI3 kinase inhibitors,” she said.
The study was supported by Bristol-Myers Squibb. Dr. Bennani reported research funding and advisory board activities for Bristol-Myers Squibb and others.
SOURCE: Bennani NN et al. ASH 2019, Abstract 467.
ORLANDO – There is an urgent need for new therapies to treat relapsed or refractory peripheral T-cell lymphoma, but results of a phase 2 study suggest that monotherapy with the immune checkpoint inhibitor nivolumab (Opdivo) is not the hoped-for salvage treatment.
An interim analysis of data on 12 patients with peripheral T-cell lymphoma (PTCL) treated with nivolumab monotherapy showed an overall response rate of 33%, consisting of 2 complete responses and 2 partial responses. But the responses were short lived, and one patient had hyperprogressive disease – dramatic progression within one cycle of treatment – while two more had progression within two cycles, leading to a trial halt, reported N. Nora Bennani, MD, from the Mayo Clinic in Rochester, Minn.
“These findings likely reflect the distinct biology of PTCL and should be considered when designing future studies using checkpoint inhibitors in these diseases,” she said at the annual meeting of the American Society of Hematology.
The rationale for using an immune checkpoint inhibitor directed against the programmed death–1 protein and its ligands (PD and PD-L1/2) is that malignant cells in PTCL induce a profoundly immunosuppressive tumor microenvironment. Checkpoint inhibitors have shown strong activity against relapsed Hodgkin lymphoma, and the Mayo Clinic researchers speculated that an anti-PD-1 agent could have a similar effect in PTCL.
They had originally planned to enroll 29 patients into a phase 2 trial with nivolumab delivered 240 mg every 2 weeks for eight cycles, followed by a dose of 480 mg given every 4 weeks until disease progression or intolerable toxicities.
Patients were eligible if they had biopsy-confirmed relapsed or refractory PTCL, measurable disease on cross-sectional imaging of at least 1.5 cm, and prior systemic chemoimmunotherapy and/or autologous stem cell transplantation.
The interim analysis included 12 patients who received at least one dose of nivolumab. Of the 12 patients, 6 had angioimmunoblastic T-cell lymphoma (AITL), 3 had PTCL not otherwise specified, and 1 each had ALK-negative anaplastic large cell lymphoma (ALK-ALCL), enteropathy-associated T-cell lymphoma (EATL), or hepatosplenic gamma/delta T-cell lymphoma.
All patients had Ann Arbor stage III/IV disease, and 11 had extranodal involvement.
As noted, there were 4 responses among the 12 patients, consisting of 1 complete response in the patient with ALK-ALCL and 1 in a patient with AITL, and 2 partial responses – 1 in a patient with PTCL-NOS, and 1 in the patient with EATL.
The median progression-free survival for all 12 patients was short at 2.7 months, and the median overall survival was estimated at 6.7 months.
“It was staggering to see this: The duration of response was significantly short, less than 2 months,” Dr. Bennani said.
Nonhematologic toxicities were seen in 5 of the 12 patients (42%), and hematologic adverse events occurred in 3 (25%). All patients are now off treatment, 10 because of disease progression, 1 because of acute pancreatitis, and the aforementioned patient with hyperprogressive disease.
The patient with hyperprogressive disease had significant progression in tonsillar and cervical lymphadenopathy within 7-10 days of nivolumab infusion, with biopsy-proven AITL in the involved nodes.
“I believe that, in this patient population, combination therapies will be key. I think checkpoint blockers alone are not going to be sufficient to see meaningful outcomes in these patients,” Dr. Bennani said in an interview.
“An overall response rate of 33% is significant, because most other agents that were FDA approved in this patient population have response rates around 30%,” she said, adding that it’s possible that the patients with rapid progression had disease too advanced to be effectively treated with a checkpoint inhibitor.
“Ideally however, if we want to move forward, it will need to be with combinations of checkpoint inhibitors with HDAC [histone deacetylase] inhibitors, hypomethylating agents, or even PI3 kinase inhibitors,” she said.
The study was supported by Bristol-Myers Squibb. Dr. Bennani reported research funding and advisory board activities for Bristol-Myers Squibb and others.
SOURCE: Bennani NN et al. ASH 2019, Abstract 467.
REPORTING FROM ASH 2019
HDAC/HMA combo shows ‘remarkable’ activity in PTCL
LUGANO, SWITZERLAND – A combination of 5-azacytidine and romidepsin showed promising activity in patients with peripheral T cell lymphomas, particularly angioimmunoblastic T-cell lymphoma (AITL) and primary cutaneous follicular helper T-cell lymphoma (PTCL-TFH), results of a phase 2 study showed.
Of 16 patients with AITL or PTCL-TFH, 11 (69%) had a clinical response to the 5-azacytidine (AZA)/romidepsin combination, including 8 (50%) with complete responses (CRs), and 3 with partial responses (PRs), reported Lorenzo Falchi, MD, of Columbia University Medical Center and New York Presbyterian Hospital, New York, and colleagues.
“We show that the combination of oral AZA/romidepsin is remarkably active in patients with T-cell lymphomas. Clearly more patients with other subtypes are needed to better evaluate this combination,” Dr. Falchi said at the International Conference on Malignant Lymphoma.
The combination is intended to target epigenetic changes in PTCLs, which often bear mutations in TET2, DNMT3A, and IDH2. These mutations create global hypermethylation and cause transcriptional silencing of tumor suppressor genes, Dr. Falchi said.
Both histone deacetylase inhibitors such as romidepsin, and hypomethylating agents such as AZA have been shown to have single-agent activity against PTCL, and as previously reported at the 2018 T-cell Lymphoma Forum, the combination produced a higher overall response rate (ORR) and prolonged progression-free survival (PFS) in patients with T-cell lymphomas.
Dr. Falchi presented the phase 2 results at 15-ICML. A total of 25 patients with newly diagnosed or relapsed/refractory PTCL were treated with AZA 300 mg daily on days 1-14 and romidepsin 14 mg/m2 on days 8, 15, and 22, every 35 days.
A total of 24 patients were evaluable for response. The ORR – the primary endpoint – was achieved in 14 patients (58%), and included 10 CRs and 4 PRs. Three additional patients had stable disease, and six patients experienced disease progression (response data for one patient was not complete at the time of the presentation).
In total, 11 of 16 patients with AITL/PTCL-TFH had responses, compared with 3 of 8 patients with other histologies.
A secondary analysis of 16 patients with information on mutational status showed that 10 of 12 patients with TET2 mutations (83%) had responses, including 8 CRs and 2 PRs. Two additional patients with TET2 mutations had disease progression. In contrast, among four patients without TET2 mutations, one had a CR, one a PR, and two had disease progression.
Of the 10 patients overall with CRs, 5 patients were receiving the combination in the first line, and 5 patients were receiving it for relapsed/refractory disease.
Median PFS among all patients was 8.7 months. The median overall survival has not been reached. Among patients with the AITL or PTCL-TFH subtypes, median PFS was 8.7 months, compared with 2.3 months for patients with other histologies.
The most frequent hematologic grade 3 or 4 adverse events were thrombocytopenia and neutropenia. The most frequent nonhematologic grade 3 or 4 events included lung infection and febrile neutropenia. Common grade 1 or 2 toxicities included anemia, diarrhea, fatigue, nausea, and vomiting. No patients discontinued therapy because of adverse events.
Dr. Falchi noted that a phase 1 trial evaluating the immune checkpoint inhibitor durvalumab (Imfinzi) with AZA or romidepsin alone or in combination, or pralatrexate and romidepsin, is currently recruiting.
Dr. Falchi reported having no financial disclosures. Other investigators reported funding from Celgene, which supported the study.
SOURCE: Falchi L et al. 15-ICML, Abstract 129.
LUGANO, SWITZERLAND – A combination of 5-azacytidine and romidepsin showed promising activity in patients with peripheral T cell lymphomas, particularly angioimmunoblastic T-cell lymphoma (AITL) and primary cutaneous follicular helper T-cell lymphoma (PTCL-TFH), results of a phase 2 study showed.
Of 16 patients with AITL or PTCL-TFH, 11 (69%) had a clinical response to the 5-azacytidine (AZA)/romidepsin combination, including 8 (50%) with complete responses (CRs), and 3 with partial responses (PRs), reported Lorenzo Falchi, MD, of Columbia University Medical Center and New York Presbyterian Hospital, New York, and colleagues.
“We show that the combination of oral AZA/romidepsin is remarkably active in patients with T-cell lymphomas. Clearly more patients with other subtypes are needed to better evaluate this combination,” Dr. Falchi said at the International Conference on Malignant Lymphoma.
The combination is intended to target epigenetic changes in PTCLs, which often bear mutations in TET2, DNMT3A, and IDH2. These mutations create global hypermethylation and cause transcriptional silencing of tumor suppressor genes, Dr. Falchi said.
Both histone deacetylase inhibitors such as romidepsin, and hypomethylating agents such as AZA have been shown to have single-agent activity against PTCL, and as previously reported at the 2018 T-cell Lymphoma Forum, the combination produced a higher overall response rate (ORR) and prolonged progression-free survival (PFS) in patients with T-cell lymphomas.
Dr. Falchi presented the phase 2 results at 15-ICML. A total of 25 patients with newly diagnosed or relapsed/refractory PTCL were treated with AZA 300 mg daily on days 1-14 and romidepsin 14 mg/m2 on days 8, 15, and 22, every 35 days.
A total of 24 patients were evaluable for response. The ORR – the primary endpoint – was achieved in 14 patients (58%), and included 10 CRs and 4 PRs. Three additional patients had stable disease, and six patients experienced disease progression (response data for one patient was not complete at the time of the presentation).
In total, 11 of 16 patients with AITL/PTCL-TFH had responses, compared with 3 of 8 patients with other histologies.
A secondary analysis of 16 patients with information on mutational status showed that 10 of 12 patients with TET2 mutations (83%) had responses, including 8 CRs and 2 PRs. Two additional patients with TET2 mutations had disease progression. In contrast, among four patients without TET2 mutations, one had a CR, one a PR, and two had disease progression.
Of the 10 patients overall with CRs, 5 patients were receiving the combination in the first line, and 5 patients were receiving it for relapsed/refractory disease.
Median PFS among all patients was 8.7 months. The median overall survival has not been reached. Among patients with the AITL or PTCL-TFH subtypes, median PFS was 8.7 months, compared with 2.3 months for patients with other histologies.
The most frequent hematologic grade 3 or 4 adverse events were thrombocytopenia and neutropenia. The most frequent nonhematologic grade 3 or 4 events included lung infection and febrile neutropenia. Common grade 1 or 2 toxicities included anemia, diarrhea, fatigue, nausea, and vomiting. No patients discontinued therapy because of adverse events.
Dr. Falchi noted that a phase 1 trial evaluating the immune checkpoint inhibitor durvalumab (Imfinzi) with AZA or romidepsin alone or in combination, or pralatrexate and romidepsin, is currently recruiting.
Dr. Falchi reported having no financial disclosures. Other investigators reported funding from Celgene, which supported the study.
SOURCE: Falchi L et al. 15-ICML, Abstract 129.
LUGANO, SWITZERLAND – A combination of 5-azacytidine and romidepsin showed promising activity in patients with peripheral T cell lymphomas, particularly angioimmunoblastic T-cell lymphoma (AITL) and primary cutaneous follicular helper T-cell lymphoma (PTCL-TFH), results of a phase 2 study showed.
Of 16 patients with AITL or PTCL-TFH, 11 (69%) had a clinical response to the 5-azacytidine (AZA)/romidepsin combination, including 8 (50%) with complete responses (CRs), and 3 with partial responses (PRs), reported Lorenzo Falchi, MD, of Columbia University Medical Center and New York Presbyterian Hospital, New York, and colleagues.
“We show that the combination of oral AZA/romidepsin is remarkably active in patients with T-cell lymphomas. Clearly more patients with other subtypes are needed to better evaluate this combination,” Dr. Falchi said at the International Conference on Malignant Lymphoma.
The combination is intended to target epigenetic changes in PTCLs, which often bear mutations in TET2, DNMT3A, and IDH2. These mutations create global hypermethylation and cause transcriptional silencing of tumor suppressor genes, Dr. Falchi said.
Both histone deacetylase inhibitors such as romidepsin, and hypomethylating agents such as AZA have been shown to have single-agent activity against PTCL, and as previously reported at the 2018 T-cell Lymphoma Forum, the combination produced a higher overall response rate (ORR) and prolonged progression-free survival (PFS) in patients with T-cell lymphomas.
Dr. Falchi presented the phase 2 results at 15-ICML. A total of 25 patients with newly diagnosed or relapsed/refractory PTCL were treated with AZA 300 mg daily on days 1-14 and romidepsin 14 mg/m2 on days 8, 15, and 22, every 35 days.
A total of 24 patients were evaluable for response. The ORR – the primary endpoint – was achieved in 14 patients (58%), and included 10 CRs and 4 PRs. Three additional patients had stable disease, and six patients experienced disease progression (response data for one patient was not complete at the time of the presentation).
In total, 11 of 16 patients with AITL/PTCL-TFH had responses, compared with 3 of 8 patients with other histologies.
A secondary analysis of 16 patients with information on mutational status showed that 10 of 12 patients with TET2 mutations (83%) had responses, including 8 CRs and 2 PRs. Two additional patients with TET2 mutations had disease progression. In contrast, among four patients without TET2 mutations, one had a CR, one a PR, and two had disease progression.
Of the 10 patients overall with CRs, 5 patients were receiving the combination in the first line, and 5 patients were receiving it for relapsed/refractory disease.
Median PFS among all patients was 8.7 months. The median overall survival has not been reached. Among patients with the AITL or PTCL-TFH subtypes, median PFS was 8.7 months, compared with 2.3 months for patients with other histologies.
The most frequent hematologic grade 3 or 4 adverse events were thrombocytopenia and neutropenia. The most frequent nonhematologic grade 3 or 4 events included lung infection and febrile neutropenia. Common grade 1 or 2 toxicities included anemia, diarrhea, fatigue, nausea, and vomiting. No patients discontinued therapy because of adverse events.
Dr. Falchi noted that a phase 1 trial evaluating the immune checkpoint inhibitor durvalumab (Imfinzi) with AZA or romidepsin alone or in combination, or pralatrexate and romidepsin, is currently recruiting.
Dr. Falchi reported having no financial disclosures. Other investigators reported funding from Celgene, which supported the study.
SOURCE: Falchi L et al. 15-ICML, Abstract 129.
REPORTING FROM 15-ICML
Lymphoma risk prompts FDA recall of Allergan’s textured breast implants
The Food and Drug Administration requested on July 24 that Allergan pull six brands of textured breast implants and breast expanders from the U.S. market, an action the agency took because of new data that substantially increased the number of women who developed a rare cancer – anaplastic large-cell lymphoma – in association with receiving these textured breast devices.
This is the first product recall the FDA has made to address the issue of breast implant–associated anaplastic large-cell lymphoma (BIA-ALCL), a complication that first came to national attention with a 2011 FDA report that had tallied 60 identified BIA-ALCL cases worldwide. By the end of September 2018, the number of reported worldwide BIA-ALCL cases had jumped to 457 cases reported to the agency via medical device reporting. In July 2019, the FDA cited a total of 573 unique, global case reports for BIA-ALCL sent to the agency through July 6, including 33 episodes that led to death.
It was inclusion of these additional 116 cases since September 2018 and 24 additional deaths that led FDA researchers to conclude that “the risk of BIA-ALCL with Allergan BIOCELL textured implants is approximately six-times the risk of BIA-ALCL with textured implants from other manufacturers marketing in the U.S.,” according to a statement from the agency.
The FDA is not recommending that patients who received one of the six products covered by the recall have the material removed if symptoms have not appeared because of the potential risk from explantation.
The agency also stressed that its investigation of the risk posed by placement of other brands of textured breast implants is ongoing and that overall less than 5% of all breast implants performed in current U.S. practice involve the macrotextured implants of the type specified in the Allergan recall.
This U.S. recall follows similar actions taken in France (and the rest of the European Union), Canada, and Australia, and it contrasts with the agency’s prior decision in May 2019 not to start a recall or ban of textured implants following a advisory committee meeting that discussed BIA-ALCL.
The six products that Allergan agreed to recall from marketing at the FDA’s request are four textured breast implants (Natrelle Saline-Filled Breast Implants, Natrelle Silicone-Filled Breast Implants, Natrelle Inspira Silicone-Filled breast Implants, and Natrelle 410 Highly Cohesive Anatomically Shaped Silicone-Filled Breast Implants) and two tissue expanders used prior to a breast implant (Natrelle 133 Plus Tissue Expander and the Natrelle 133 Tissue Expander with Suture Tabs).
FDA officials said they are considering recommendations for changes to the labeling of breast implant products, including a possible boxed warning and beefed up patient information.
“The recall of these textured implants is a big deal in protecting women from the potential risks of developing, and dying from, this rare type of aggressive lymphoma,” Joshua Brody, MD, a medical oncologist and director of the lymphoma immunotherapy program at Mount Sinai Medical Center in New York said in a statement. “While case reports have suggested a potential link between some types of breast implants and this disease – anaplastic lymphoma – for over 20 years, it has taken time to gain sufficient evidence to suggest, and understand, the causality. Some types of implants induce inflammation, which can both increase the chance of developing cancer, and also help to ‘hide’ developing cancers from the immune system. By preventing further use of these implants, the FDA is helping women to protect themselves from the medically serious and emotionally exhausting effects of these risks.”
Dr. Brody reported having no relevant disclosures.
The Food and Drug Administration requested on July 24 that Allergan pull six brands of textured breast implants and breast expanders from the U.S. market, an action the agency took because of new data that substantially increased the number of women who developed a rare cancer – anaplastic large-cell lymphoma – in association with receiving these textured breast devices.
This is the first product recall the FDA has made to address the issue of breast implant–associated anaplastic large-cell lymphoma (BIA-ALCL), a complication that first came to national attention with a 2011 FDA report that had tallied 60 identified BIA-ALCL cases worldwide. By the end of September 2018, the number of reported worldwide BIA-ALCL cases had jumped to 457 cases reported to the agency via medical device reporting. In July 2019, the FDA cited a total of 573 unique, global case reports for BIA-ALCL sent to the agency through July 6, including 33 episodes that led to death.
It was inclusion of these additional 116 cases since September 2018 and 24 additional deaths that led FDA researchers to conclude that “the risk of BIA-ALCL with Allergan BIOCELL textured implants is approximately six-times the risk of BIA-ALCL with textured implants from other manufacturers marketing in the U.S.,” according to a statement from the agency.
The FDA is not recommending that patients who received one of the six products covered by the recall have the material removed if symptoms have not appeared because of the potential risk from explantation.
The agency also stressed that its investigation of the risk posed by placement of other brands of textured breast implants is ongoing and that overall less than 5% of all breast implants performed in current U.S. practice involve the macrotextured implants of the type specified in the Allergan recall.
This U.S. recall follows similar actions taken in France (and the rest of the European Union), Canada, and Australia, and it contrasts with the agency’s prior decision in May 2019 not to start a recall or ban of textured implants following a advisory committee meeting that discussed BIA-ALCL.
The six products that Allergan agreed to recall from marketing at the FDA’s request are four textured breast implants (Natrelle Saline-Filled Breast Implants, Natrelle Silicone-Filled Breast Implants, Natrelle Inspira Silicone-Filled breast Implants, and Natrelle 410 Highly Cohesive Anatomically Shaped Silicone-Filled Breast Implants) and two tissue expanders used prior to a breast implant (Natrelle 133 Plus Tissue Expander and the Natrelle 133 Tissue Expander with Suture Tabs).
FDA officials said they are considering recommendations for changes to the labeling of breast implant products, including a possible boxed warning and beefed up patient information.
“The recall of these textured implants is a big deal in protecting women from the potential risks of developing, and dying from, this rare type of aggressive lymphoma,” Joshua Brody, MD, a medical oncologist and director of the lymphoma immunotherapy program at Mount Sinai Medical Center in New York said in a statement. “While case reports have suggested a potential link between some types of breast implants and this disease – anaplastic lymphoma – for over 20 years, it has taken time to gain sufficient evidence to suggest, and understand, the causality. Some types of implants induce inflammation, which can both increase the chance of developing cancer, and also help to ‘hide’ developing cancers from the immune system. By preventing further use of these implants, the FDA is helping women to protect themselves from the medically serious and emotionally exhausting effects of these risks.”
Dr. Brody reported having no relevant disclosures.
The Food and Drug Administration requested on July 24 that Allergan pull six brands of textured breast implants and breast expanders from the U.S. market, an action the agency took because of new data that substantially increased the number of women who developed a rare cancer – anaplastic large-cell lymphoma – in association with receiving these textured breast devices.
This is the first product recall the FDA has made to address the issue of breast implant–associated anaplastic large-cell lymphoma (BIA-ALCL), a complication that first came to national attention with a 2011 FDA report that had tallied 60 identified BIA-ALCL cases worldwide. By the end of September 2018, the number of reported worldwide BIA-ALCL cases had jumped to 457 cases reported to the agency via medical device reporting. In July 2019, the FDA cited a total of 573 unique, global case reports for BIA-ALCL sent to the agency through July 6, including 33 episodes that led to death.
It was inclusion of these additional 116 cases since September 2018 and 24 additional deaths that led FDA researchers to conclude that “the risk of BIA-ALCL with Allergan BIOCELL textured implants is approximately six-times the risk of BIA-ALCL with textured implants from other manufacturers marketing in the U.S.,” according to a statement from the agency.
The FDA is not recommending that patients who received one of the six products covered by the recall have the material removed if symptoms have not appeared because of the potential risk from explantation.
The agency also stressed that its investigation of the risk posed by placement of other brands of textured breast implants is ongoing and that overall less than 5% of all breast implants performed in current U.S. practice involve the macrotextured implants of the type specified in the Allergan recall.
This U.S. recall follows similar actions taken in France (and the rest of the European Union), Canada, and Australia, and it contrasts with the agency’s prior decision in May 2019 not to start a recall or ban of textured implants following a advisory committee meeting that discussed BIA-ALCL.
The six products that Allergan agreed to recall from marketing at the FDA’s request are four textured breast implants (Natrelle Saline-Filled Breast Implants, Natrelle Silicone-Filled Breast Implants, Natrelle Inspira Silicone-Filled breast Implants, and Natrelle 410 Highly Cohesive Anatomically Shaped Silicone-Filled Breast Implants) and two tissue expanders used prior to a breast implant (Natrelle 133 Plus Tissue Expander and the Natrelle 133 Tissue Expander with Suture Tabs).
FDA officials said they are considering recommendations for changes to the labeling of breast implant products, including a possible boxed warning and beefed up patient information.
“The recall of these textured implants is a big deal in protecting women from the potential risks of developing, and dying from, this rare type of aggressive lymphoma,” Joshua Brody, MD, a medical oncologist and director of the lymphoma immunotherapy program at Mount Sinai Medical Center in New York said in a statement. “While case reports have suggested a potential link between some types of breast implants and this disease – anaplastic lymphoma – for over 20 years, it has taken time to gain sufficient evidence to suggest, and understand, the causality. Some types of implants induce inflammation, which can both increase the chance of developing cancer, and also help to ‘hide’ developing cancers from the immune system. By preventing further use of these implants, the FDA is helping women to protect themselves from the medically serious and emotionally exhausting effects of these risks.”
Dr. Brody reported having no relevant disclosures.
Creating CAR T-cell therapies for T-cell malignancies
NEWPORT BEACH, CALIF. – Preclinical research has revealed workarounds that may make chimeric antigen receptor (CAR) T-cell therapy feasible for patients with T-cell malignancies.
Researchers have found that using allogeneic cells for CAR T-cell therapy can eliminate contamination by malignant T cells, and editing those allogeneic T cells to delete the target antigen and the T-cell receptor alpha chain (TRAC) can prevent fratricide and graft-versus-host disease (GVHD).
Additionally, an interleukin-7 molecule called NT-I7 has been shown to enhance CAR T-cell proliferation, differentiation, and tumor killing in a mouse model of a T-cell malignancy.
John F. DiPersio, MD, PhD, of Washington University in St. Louis, described this work in a presentation at the Acute Leukemia Forum of Hemedicus.
Obstacles to development
“The primary obstacle for targeting T-cell malignancies with a T cell is that all of the targets that are on the [malignant] T cells are also expressed on the normal T cells,” Dr. DiPersio said. “So when you put a CAR into a normal T cell, it just kills itself. It’s called fratricide.”
A second issue that has limited development is that the phenotype of the malignant T cell in the blood is similar to a normal T cell, so they can’t be separated, he explained.
“So if you were to do anything to a normal T cell, you would also be doing it, in theory, to the malignant T cell – in theory, making it resistant to therapy,” he said.
A third obstacle, which has been seen in patients with B-cell malignancies as well, is the inability to harvest enough T cells to generate effective CAR T-cell therapy.
And a fourth obstacle is that T cells from patients with malignancies may not function normally because they have been exposed to prior therapies.
Dr. DiPersio and his colleagues believe these obstacles can be overcome by creating CAR T-cell therapies using T cells derived from healthy donors or cord blood, using gene editing to remove the target antigen and TRAC, and using NT-I7 to enhance the efficacy of these universal, “off-the-shelf” CAR T cells.
The researchers have tested these theories, and achieved successes, in preclinical models. The team is now planning a clinical trial in patients at Washington University. Dr. DiPersio and his colleagues also created a company called WUGEN that will develop the universal CAR T-cell therapies if the initial proof-of-principle trial proves successful.
UCART7
One of the universal CAR T-cell therapies Dr. DiPersio and his colleagues have tested is UCART7, which targets CD7. Dr. DiPersio noted that CD7 is expressed on 98% of T-cell acute lymphoblastic leukemias (T-ALLs), 24% of acute myeloid leukemias, natural killer (NK) cells, and T cells.
The researchers created UCART7 by using CRISPR/Cas9 to delete CD7 and TRAC from allogeneic T cells and following this with lentiviral transduction with a third-generation CD7-CAR. The team found a way to delete both TRAC and CD7 in a single day with 95% efficiency, Dr. DiPersio noted.
“Knocking out CD7 doesn’t seem to have any impact on the expansion or trafficking of these T cells in vivo,” Dr. DiPersio said. “So we think that deleting that target in a normal T cell will not affect its overall ability to kill a target when we put a CAR into those T cells.”
In fact, the researchers’ experiments showed that UCART7 can kill T-ALL cells in vitro and target primary T-ALL in vivo without inducing GVHD (Leukemia. 2018 Sep;32[9]:1970-83.)
UCART2 and NT-I7
Dr. DiPersio and his colleagues have also tested UCART2, an allogeneic CAR T-cell therapy in which CD2 and TRAC are deleted. The therapy targets CD2 because this antigen is expressed on T-ALL and other T-cell and NK-cell malignancies. Experiments showed that UCART2 targets T-cell malignancies, including T-ALL and cutaneous T-cell lymphoma, in vitro.
The researchers also tested UCART2 in a mouse model of Sézary syndrome. In these experiments, UCART2 was combined with NT-I7.
NT-I7 enhanced the proliferation, persistence, and tumor killing ability of UCART2. Sézary mice that received UCART2 and NT-I7 had “virtually no tumor burden,” according to researchers, and survived longer than mice treated with UCART2 alone (Blood. 2018;132:340).
Dr. DiPersio noted that there was no cytokine release syndrome because these were immunodeficient mice. However, cytokine release syndrome may be a side effect of NT-I7 in patients as NT-I7 induces rapid expansion of CAR T cells.
Dr. DiPersio reported ownership and investment in WUGEN and Magenta Therapeutics. He also has relationships with Cellworks Group, Tioma Therapeutics, RiverVest Venture Partners, Bioline, Asterias Biotherapeutics, Amphivena Therapeutics, Bluebird Bio, Celgene, Incyte, NeoImuneTech, and MacroGenics.
The Acute Leukemia Forum is organized by Hemedicus, which is owned by the same company as this news organization.
NEWPORT BEACH, CALIF. – Preclinical research has revealed workarounds that may make chimeric antigen receptor (CAR) T-cell therapy feasible for patients with T-cell malignancies.
Researchers have found that using allogeneic cells for CAR T-cell therapy can eliminate contamination by malignant T cells, and editing those allogeneic T cells to delete the target antigen and the T-cell receptor alpha chain (TRAC) can prevent fratricide and graft-versus-host disease (GVHD).
Additionally, an interleukin-7 molecule called NT-I7 has been shown to enhance CAR T-cell proliferation, differentiation, and tumor killing in a mouse model of a T-cell malignancy.
John F. DiPersio, MD, PhD, of Washington University in St. Louis, described this work in a presentation at the Acute Leukemia Forum of Hemedicus.
Obstacles to development
“The primary obstacle for targeting T-cell malignancies with a T cell is that all of the targets that are on the [malignant] T cells are also expressed on the normal T cells,” Dr. DiPersio said. “So when you put a CAR into a normal T cell, it just kills itself. It’s called fratricide.”
A second issue that has limited development is that the phenotype of the malignant T cell in the blood is similar to a normal T cell, so they can’t be separated, he explained.
“So if you were to do anything to a normal T cell, you would also be doing it, in theory, to the malignant T cell – in theory, making it resistant to therapy,” he said.
A third obstacle, which has been seen in patients with B-cell malignancies as well, is the inability to harvest enough T cells to generate effective CAR T-cell therapy.
And a fourth obstacle is that T cells from patients with malignancies may not function normally because they have been exposed to prior therapies.
Dr. DiPersio and his colleagues believe these obstacles can be overcome by creating CAR T-cell therapies using T cells derived from healthy donors or cord blood, using gene editing to remove the target antigen and TRAC, and using NT-I7 to enhance the efficacy of these universal, “off-the-shelf” CAR T cells.
The researchers have tested these theories, and achieved successes, in preclinical models. The team is now planning a clinical trial in patients at Washington University. Dr. DiPersio and his colleagues also created a company called WUGEN that will develop the universal CAR T-cell therapies if the initial proof-of-principle trial proves successful.
UCART7
One of the universal CAR T-cell therapies Dr. DiPersio and his colleagues have tested is UCART7, which targets CD7. Dr. DiPersio noted that CD7 is expressed on 98% of T-cell acute lymphoblastic leukemias (T-ALLs), 24% of acute myeloid leukemias, natural killer (NK) cells, and T cells.
The researchers created UCART7 by using CRISPR/Cas9 to delete CD7 and TRAC from allogeneic T cells and following this with lentiviral transduction with a third-generation CD7-CAR. The team found a way to delete both TRAC and CD7 in a single day with 95% efficiency, Dr. DiPersio noted.
“Knocking out CD7 doesn’t seem to have any impact on the expansion or trafficking of these T cells in vivo,” Dr. DiPersio said. “So we think that deleting that target in a normal T cell will not affect its overall ability to kill a target when we put a CAR into those T cells.”
In fact, the researchers’ experiments showed that UCART7 can kill T-ALL cells in vitro and target primary T-ALL in vivo without inducing GVHD (Leukemia. 2018 Sep;32[9]:1970-83.)
UCART2 and NT-I7
Dr. DiPersio and his colleagues have also tested UCART2, an allogeneic CAR T-cell therapy in which CD2 and TRAC are deleted. The therapy targets CD2 because this antigen is expressed on T-ALL and other T-cell and NK-cell malignancies. Experiments showed that UCART2 targets T-cell malignancies, including T-ALL and cutaneous T-cell lymphoma, in vitro.
The researchers also tested UCART2 in a mouse model of Sézary syndrome. In these experiments, UCART2 was combined with NT-I7.
NT-I7 enhanced the proliferation, persistence, and tumor killing ability of UCART2. Sézary mice that received UCART2 and NT-I7 had “virtually no tumor burden,” according to researchers, and survived longer than mice treated with UCART2 alone (Blood. 2018;132:340).
Dr. DiPersio noted that there was no cytokine release syndrome because these were immunodeficient mice. However, cytokine release syndrome may be a side effect of NT-I7 in patients as NT-I7 induces rapid expansion of CAR T cells.
Dr. DiPersio reported ownership and investment in WUGEN and Magenta Therapeutics. He also has relationships with Cellworks Group, Tioma Therapeutics, RiverVest Venture Partners, Bioline, Asterias Biotherapeutics, Amphivena Therapeutics, Bluebird Bio, Celgene, Incyte, NeoImuneTech, and MacroGenics.
The Acute Leukemia Forum is organized by Hemedicus, which is owned by the same company as this news organization.
NEWPORT BEACH, CALIF. – Preclinical research has revealed workarounds that may make chimeric antigen receptor (CAR) T-cell therapy feasible for patients with T-cell malignancies.
Researchers have found that using allogeneic cells for CAR T-cell therapy can eliminate contamination by malignant T cells, and editing those allogeneic T cells to delete the target antigen and the T-cell receptor alpha chain (TRAC) can prevent fratricide and graft-versus-host disease (GVHD).
Additionally, an interleukin-7 molecule called NT-I7 has been shown to enhance CAR T-cell proliferation, differentiation, and tumor killing in a mouse model of a T-cell malignancy.
John F. DiPersio, MD, PhD, of Washington University in St. Louis, described this work in a presentation at the Acute Leukemia Forum of Hemedicus.
Obstacles to development
“The primary obstacle for targeting T-cell malignancies with a T cell is that all of the targets that are on the [malignant] T cells are also expressed on the normal T cells,” Dr. DiPersio said. “So when you put a CAR into a normal T cell, it just kills itself. It’s called fratricide.”
A second issue that has limited development is that the phenotype of the malignant T cell in the blood is similar to a normal T cell, so they can’t be separated, he explained.
“So if you were to do anything to a normal T cell, you would also be doing it, in theory, to the malignant T cell – in theory, making it resistant to therapy,” he said.
A third obstacle, which has been seen in patients with B-cell malignancies as well, is the inability to harvest enough T cells to generate effective CAR T-cell therapy.
And a fourth obstacle is that T cells from patients with malignancies may not function normally because they have been exposed to prior therapies.
Dr. DiPersio and his colleagues believe these obstacles can be overcome by creating CAR T-cell therapies using T cells derived from healthy donors or cord blood, using gene editing to remove the target antigen and TRAC, and using NT-I7 to enhance the efficacy of these universal, “off-the-shelf” CAR T cells.
The researchers have tested these theories, and achieved successes, in preclinical models. The team is now planning a clinical trial in patients at Washington University. Dr. DiPersio and his colleagues also created a company called WUGEN that will develop the universal CAR T-cell therapies if the initial proof-of-principle trial proves successful.
UCART7
One of the universal CAR T-cell therapies Dr. DiPersio and his colleagues have tested is UCART7, which targets CD7. Dr. DiPersio noted that CD7 is expressed on 98% of T-cell acute lymphoblastic leukemias (T-ALLs), 24% of acute myeloid leukemias, natural killer (NK) cells, and T cells.
The researchers created UCART7 by using CRISPR/Cas9 to delete CD7 and TRAC from allogeneic T cells and following this with lentiviral transduction with a third-generation CD7-CAR. The team found a way to delete both TRAC and CD7 in a single day with 95% efficiency, Dr. DiPersio noted.
“Knocking out CD7 doesn’t seem to have any impact on the expansion or trafficking of these T cells in vivo,” Dr. DiPersio said. “So we think that deleting that target in a normal T cell will not affect its overall ability to kill a target when we put a CAR into those T cells.”
In fact, the researchers’ experiments showed that UCART7 can kill T-ALL cells in vitro and target primary T-ALL in vivo without inducing GVHD (Leukemia. 2018 Sep;32[9]:1970-83.)
UCART2 and NT-I7
Dr. DiPersio and his colleagues have also tested UCART2, an allogeneic CAR T-cell therapy in which CD2 and TRAC are deleted. The therapy targets CD2 because this antigen is expressed on T-ALL and other T-cell and NK-cell malignancies. Experiments showed that UCART2 targets T-cell malignancies, including T-ALL and cutaneous T-cell lymphoma, in vitro.
The researchers also tested UCART2 in a mouse model of Sézary syndrome. In these experiments, UCART2 was combined with NT-I7.
NT-I7 enhanced the proliferation, persistence, and tumor killing ability of UCART2. Sézary mice that received UCART2 and NT-I7 had “virtually no tumor burden,” according to researchers, and survived longer than mice treated with UCART2 alone (Blood. 2018;132:340).
Dr. DiPersio noted that there was no cytokine release syndrome because these were immunodeficient mice. However, cytokine release syndrome may be a side effect of NT-I7 in patients as NT-I7 induces rapid expansion of CAR T cells.
Dr. DiPersio reported ownership and investment in WUGEN and Magenta Therapeutics. He also has relationships with Cellworks Group, Tioma Therapeutics, RiverVest Venture Partners, Bioline, Asterias Biotherapeutics, Amphivena Therapeutics, Bluebird Bio, Celgene, Incyte, NeoImuneTech, and MacroGenics.
The Acute Leukemia Forum is organized by Hemedicus, which is owned by the same company as this news organization.
EXPERT ANALYSIS FROM ALF 2019
Case report may link gluteal implants to lymphoma
Patients with textured silicone gluteal implants could be at risk of anaplastic large cell lymphoma, based on a possible case of ALCL in a patient diagnosed 1 year after implant placement.
The 49-year-old woman was initially diagnosed with anaplastic lymphoma kinase–negative ALCL via a lung mass and pleural fluid before bilateral gluteal ulceration occurred 1 month later, reported Orr Shauly of the University of Southern California in Los Angeles, and his colleagues.
Soft-tissue disease and fluid accumulation around the gluteal implants suggested that the lung mass had metastasized from primary neoplasia in the gluteal region. If ALCL did originate at the site of the gluteal implants, it would represent a first for silicone implant–associated ALCL, which has historically been associated exclusively with breast implants.
“As many as 200 cases of [breast implant-associated ALCL] have been described worldwide, with a majority in the context of cosmetic primary breast augmentation or cancer-related breast reconstruction with the use of a textured implant (57% of all cases),” the investigators wrote in Aesthetic Surgery Journal. “Recently however, it has been hypothesized that the relationship of ALCL with the placement of textured silicone implants may not [be] limited to the breast due to its multifactorial nature and association with texturization of the implant surface.”
During the initial work-up, a CT showed fluid collection and enhancement around the gluteal implants. Following ALCL diagnosis via lung mass biopsy and histopathology, the patient was transferred to a different facility for chemotherapy. When the patient presented 1 month later to the original facility with gluteal ulceration, the oncology team suspected infection; however, all cultures from fluid around the implants were negative.
Because of the possibility of false-negative tests, the patient was started on a regimen of acyclovir, vancomycin, metronidazole, and isavuconazole. Explantation was planned, but before this could occur, the patient deteriorated rapidly and died of respiratory and renal failure.
ALCL was not confirmed via cytology or histopathology in the gluteal region, and the patient’s family did not consent to autopsy, so a definitive diagnosis of gluteal implant–associated ALCL remained elusive.
“In this instance, it can only be concluded that the patient’s condition may have been associated with placement of textured silicone gluteal implants, but [we] still lack evidence of causation,” the investigators wrote. “It should also be noted that ALCL does not typically present with skin ulceration, and this may be a unique disease process in this patient or as a result of her bedridden state given the late stage of her disease. Furthermore, this presentation was uniquely aggressive and presented extremely quickly after placement of the gluteal implants. In most patients, ALCL develops and presents approximately 10 years after implantation.”
The investigators cautioned that “care should be taken to avoid sensationalizing all implant-associated ALCL.”
The authors reported having no conflicts of interest and the study did not receive funding.
SOURCE: Shauly O et al. Aesthet Surg J. 2019 Feb 15. doi: 10.1093/asj/sjz044.
Patients with textured silicone gluteal implants could be at risk of anaplastic large cell lymphoma, based on a possible case of ALCL in a patient diagnosed 1 year after implant placement.
The 49-year-old woman was initially diagnosed with anaplastic lymphoma kinase–negative ALCL via a lung mass and pleural fluid before bilateral gluteal ulceration occurred 1 month later, reported Orr Shauly of the University of Southern California in Los Angeles, and his colleagues.
Soft-tissue disease and fluid accumulation around the gluteal implants suggested that the lung mass had metastasized from primary neoplasia in the gluteal region. If ALCL did originate at the site of the gluteal implants, it would represent a first for silicone implant–associated ALCL, which has historically been associated exclusively with breast implants.
“As many as 200 cases of [breast implant-associated ALCL] have been described worldwide, with a majority in the context of cosmetic primary breast augmentation or cancer-related breast reconstruction with the use of a textured implant (57% of all cases),” the investigators wrote in Aesthetic Surgery Journal. “Recently however, it has been hypothesized that the relationship of ALCL with the placement of textured silicone implants may not [be] limited to the breast due to its multifactorial nature and association with texturization of the implant surface.”
During the initial work-up, a CT showed fluid collection and enhancement around the gluteal implants. Following ALCL diagnosis via lung mass biopsy and histopathology, the patient was transferred to a different facility for chemotherapy. When the patient presented 1 month later to the original facility with gluteal ulceration, the oncology team suspected infection; however, all cultures from fluid around the implants were negative.
Because of the possibility of false-negative tests, the patient was started on a regimen of acyclovir, vancomycin, metronidazole, and isavuconazole. Explantation was planned, but before this could occur, the patient deteriorated rapidly and died of respiratory and renal failure.
ALCL was not confirmed via cytology or histopathology in the gluteal region, and the patient’s family did not consent to autopsy, so a definitive diagnosis of gluteal implant–associated ALCL remained elusive.
“In this instance, it can only be concluded that the patient’s condition may have been associated with placement of textured silicone gluteal implants, but [we] still lack evidence of causation,” the investigators wrote. “It should also be noted that ALCL does not typically present with skin ulceration, and this may be a unique disease process in this patient or as a result of her bedridden state given the late stage of her disease. Furthermore, this presentation was uniquely aggressive and presented extremely quickly after placement of the gluteal implants. In most patients, ALCL develops and presents approximately 10 years after implantation.”
The investigators cautioned that “care should be taken to avoid sensationalizing all implant-associated ALCL.”
The authors reported having no conflicts of interest and the study did not receive funding.
SOURCE: Shauly O et al. Aesthet Surg J. 2019 Feb 15. doi: 10.1093/asj/sjz044.
Patients with textured silicone gluteal implants could be at risk of anaplastic large cell lymphoma, based on a possible case of ALCL in a patient diagnosed 1 year after implant placement.
The 49-year-old woman was initially diagnosed with anaplastic lymphoma kinase–negative ALCL via a lung mass and pleural fluid before bilateral gluteal ulceration occurred 1 month later, reported Orr Shauly of the University of Southern California in Los Angeles, and his colleagues.
Soft-tissue disease and fluid accumulation around the gluteal implants suggested that the lung mass had metastasized from primary neoplasia in the gluteal region. If ALCL did originate at the site of the gluteal implants, it would represent a first for silicone implant–associated ALCL, which has historically been associated exclusively with breast implants.
“As many as 200 cases of [breast implant-associated ALCL] have been described worldwide, with a majority in the context of cosmetic primary breast augmentation or cancer-related breast reconstruction with the use of a textured implant (57% of all cases),” the investigators wrote in Aesthetic Surgery Journal. “Recently however, it has been hypothesized that the relationship of ALCL with the placement of textured silicone implants may not [be] limited to the breast due to its multifactorial nature and association with texturization of the implant surface.”
During the initial work-up, a CT showed fluid collection and enhancement around the gluteal implants. Following ALCL diagnosis via lung mass biopsy and histopathology, the patient was transferred to a different facility for chemotherapy. When the patient presented 1 month later to the original facility with gluteal ulceration, the oncology team suspected infection; however, all cultures from fluid around the implants were negative.
Because of the possibility of false-negative tests, the patient was started on a regimen of acyclovir, vancomycin, metronidazole, and isavuconazole. Explantation was planned, but before this could occur, the patient deteriorated rapidly and died of respiratory and renal failure.
ALCL was not confirmed via cytology or histopathology in the gluteal region, and the patient’s family did not consent to autopsy, so a definitive diagnosis of gluteal implant–associated ALCL remained elusive.
“In this instance, it can only be concluded that the patient’s condition may have been associated with placement of textured silicone gluteal implants, but [we] still lack evidence of causation,” the investigators wrote. “It should also be noted that ALCL does not typically present with skin ulceration, and this may be a unique disease process in this patient or as a result of her bedridden state given the late stage of her disease. Furthermore, this presentation was uniquely aggressive and presented extremely quickly after placement of the gluteal implants. In most patients, ALCL develops and presents approximately 10 years after implantation.”
The investigators cautioned that “care should be taken to avoid sensationalizing all implant-associated ALCL.”
The authors reported having no conflicts of interest and the study did not receive funding.
SOURCE: Shauly O et al. Aesthet Surg J. 2019 Feb 15. doi: 10.1093/asj/sjz044.
FROM AESTHETIC SURGERY JOURNAL
Alisertib response rate in PTCL patients was 33%
An open-label randomized phase 3 trial of oral alisertib for relapsed/refractory peripheral T-cell lymphoma (rrPTCL) was terminated in 2015 after it became clear that it was not going to prove significantly superior to options already on the market.
A new report explains what happened. Oral Alisertib was compared to two agents approved for rrPTCL: intravenous pralatrexate (Folotyn) and romidepsin (Istodax), as well as a common off-label option, intravenous gemcitabine (Gemzar). In all, 138 adults were randomized to alisertib 50 mg two times per day on days 1-7, with a median of four 21-day cycles; 133 were randomized to a comparator, the majority to gemcitabine, and again with repeated cycles as tolerated (J Clin Oncol. 2019 Feb 1. doi: 10.1200/JCO.18.00899).
Overall response rate (ORR) was 33% for alisertib versus 45% for the comparator arm (odds ratio, 0.60; 95% confidence interval, 0.33-1.08). Median progression-free survival was 115 days for alisertib versus 104 days for the comparators, a non–statistically significant difference (hazard ratio, 0.87; 95% CI, 0.637-1.178). Median overall survival was 415 days in the alisertib arm versus 367 days in the comparator arm, also not statistically significant (HR, 0.98; 95% CI, 0.707-1.369).
In patients with rrPTCL, alisertib “did not demonstrate superior efficacy over comparators,” concluded investigators led by oncologist Owen A. O’Connor, MD, PhD, of the Columbia University Medical Center, New York.
Another downside to this drug is that it was associated with adverse events in more than half of patients who took it. While 53% of alisertib patients developed anemia and 47% became neutropenic, in the comparator arm, only 34% and 31% developed anemia and neutropenia, respectively. Further, three deaths in the trial were judged to have be related to alisertib. An additional two deaths occurred in this trial; those were judged to have been related to the rival treatments.
Despite alisertib’s less than great results, the story of this drug’s use for rrPTCL may not be over.
There were hints of benefits for rrPCLT, which might play out in a more focused trial, maybe “in a subgroup of patients with PTCL who responded poorly to comparator agents,” perhaps as a last ditch option. There’s also “potential for treatment combinations of alisertib with novel agents,” the investigators said.
The ORR differences were driven mostly by better performance with the approved agents: ORR was 61% with romidepsin and 43% with pralatrexate; however, alisertib’s ORR (33%) was similar to that for gemcitabine (35%) with “the potential benefits of ... oral administration,” the researchers said.
Also, the number of patients who discontinued treatment because of adverse events was higher in the comparator arm (14%) than in the alisertib group (9%), and more comparator patients required dose reductions (33% versus 28%) because of drug side effects.
Alisertib binds to and inhibits Aurora A kinase (AAK), which is essential for mitosis; studies have demonstrated overexpression in PTCL, which supports AAK inhibition as a novel therapeutic strategy. Research on alisertib for other cancer indications continues, including breast and lung cancer and leukemia.
Most of the subjects in both study arms were white, and about two-thirds were men; the median age was 63 years in both arms.
The work was funded by alisertib maker Millennium Pharmaceuticals, a subsidiary of Takeda. Dr. O’Connor and other investigators reported various ties to Millennium and Takeda, including research funding, honoraria, and consulting work. The study included employees of the companies.
SOURCE: O’Connor OA et al. J Clin Oncol. 2019 Feb 1. doi: 10.1200/JCO.18.00899.
An open-label randomized phase 3 trial of oral alisertib for relapsed/refractory peripheral T-cell lymphoma (rrPTCL) was terminated in 2015 after it became clear that it was not going to prove significantly superior to options already on the market.
A new report explains what happened. Oral Alisertib was compared to two agents approved for rrPTCL: intravenous pralatrexate (Folotyn) and romidepsin (Istodax), as well as a common off-label option, intravenous gemcitabine (Gemzar). In all, 138 adults were randomized to alisertib 50 mg two times per day on days 1-7, with a median of four 21-day cycles; 133 were randomized to a comparator, the majority to gemcitabine, and again with repeated cycles as tolerated (J Clin Oncol. 2019 Feb 1. doi: 10.1200/JCO.18.00899).
Overall response rate (ORR) was 33% for alisertib versus 45% for the comparator arm (odds ratio, 0.60; 95% confidence interval, 0.33-1.08). Median progression-free survival was 115 days for alisertib versus 104 days for the comparators, a non–statistically significant difference (hazard ratio, 0.87; 95% CI, 0.637-1.178). Median overall survival was 415 days in the alisertib arm versus 367 days in the comparator arm, also not statistically significant (HR, 0.98; 95% CI, 0.707-1.369).
In patients with rrPTCL, alisertib “did not demonstrate superior efficacy over comparators,” concluded investigators led by oncologist Owen A. O’Connor, MD, PhD, of the Columbia University Medical Center, New York.
Another downside to this drug is that it was associated with adverse events in more than half of patients who took it. While 53% of alisertib patients developed anemia and 47% became neutropenic, in the comparator arm, only 34% and 31% developed anemia and neutropenia, respectively. Further, three deaths in the trial were judged to have be related to alisertib. An additional two deaths occurred in this trial; those were judged to have been related to the rival treatments.
Despite alisertib’s less than great results, the story of this drug’s use for rrPTCL may not be over.
There were hints of benefits for rrPCLT, which might play out in a more focused trial, maybe “in a subgroup of patients with PTCL who responded poorly to comparator agents,” perhaps as a last ditch option. There’s also “potential for treatment combinations of alisertib with novel agents,” the investigators said.
The ORR differences were driven mostly by better performance with the approved agents: ORR was 61% with romidepsin and 43% with pralatrexate; however, alisertib’s ORR (33%) was similar to that for gemcitabine (35%) with “the potential benefits of ... oral administration,” the researchers said.
Also, the number of patients who discontinued treatment because of adverse events was higher in the comparator arm (14%) than in the alisertib group (9%), and more comparator patients required dose reductions (33% versus 28%) because of drug side effects.
Alisertib binds to and inhibits Aurora A kinase (AAK), which is essential for mitosis; studies have demonstrated overexpression in PTCL, which supports AAK inhibition as a novel therapeutic strategy. Research on alisertib for other cancer indications continues, including breast and lung cancer and leukemia.
Most of the subjects in both study arms were white, and about two-thirds were men; the median age was 63 years in both arms.
The work was funded by alisertib maker Millennium Pharmaceuticals, a subsidiary of Takeda. Dr. O’Connor and other investigators reported various ties to Millennium and Takeda, including research funding, honoraria, and consulting work. The study included employees of the companies.
SOURCE: O’Connor OA et al. J Clin Oncol. 2019 Feb 1. doi: 10.1200/JCO.18.00899.
An open-label randomized phase 3 trial of oral alisertib for relapsed/refractory peripheral T-cell lymphoma (rrPTCL) was terminated in 2015 after it became clear that it was not going to prove significantly superior to options already on the market.
A new report explains what happened. Oral Alisertib was compared to two agents approved for rrPTCL: intravenous pralatrexate (Folotyn) and romidepsin (Istodax), as well as a common off-label option, intravenous gemcitabine (Gemzar). In all, 138 adults were randomized to alisertib 50 mg two times per day on days 1-7, with a median of four 21-day cycles; 133 were randomized to a comparator, the majority to gemcitabine, and again with repeated cycles as tolerated (J Clin Oncol. 2019 Feb 1. doi: 10.1200/JCO.18.00899).
Overall response rate (ORR) was 33% for alisertib versus 45% for the comparator arm (odds ratio, 0.60; 95% confidence interval, 0.33-1.08). Median progression-free survival was 115 days for alisertib versus 104 days for the comparators, a non–statistically significant difference (hazard ratio, 0.87; 95% CI, 0.637-1.178). Median overall survival was 415 days in the alisertib arm versus 367 days in the comparator arm, also not statistically significant (HR, 0.98; 95% CI, 0.707-1.369).
In patients with rrPTCL, alisertib “did not demonstrate superior efficacy over comparators,” concluded investigators led by oncologist Owen A. O’Connor, MD, PhD, of the Columbia University Medical Center, New York.
Another downside to this drug is that it was associated with adverse events in more than half of patients who took it. While 53% of alisertib patients developed anemia and 47% became neutropenic, in the comparator arm, only 34% and 31% developed anemia and neutropenia, respectively. Further, three deaths in the trial were judged to have be related to alisertib. An additional two deaths occurred in this trial; those were judged to have been related to the rival treatments.
Despite alisertib’s less than great results, the story of this drug’s use for rrPTCL may not be over.
There were hints of benefits for rrPCLT, which might play out in a more focused trial, maybe “in a subgroup of patients with PTCL who responded poorly to comparator agents,” perhaps as a last ditch option. There’s also “potential for treatment combinations of alisertib with novel agents,” the investigators said.
The ORR differences were driven mostly by better performance with the approved agents: ORR was 61% with romidepsin and 43% with pralatrexate; however, alisertib’s ORR (33%) was similar to that for gemcitabine (35%) with “the potential benefits of ... oral administration,” the researchers said.
Also, the number of patients who discontinued treatment because of adverse events was higher in the comparator arm (14%) than in the alisertib group (9%), and more comparator patients required dose reductions (33% versus 28%) because of drug side effects.
Alisertib binds to and inhibits Aurora A kinase (AAK), which is essential for mitosis; studies have demonstrated overexpression in PTCL, which supports AAK inhibition as a novel therapeutic strategy. Research on alisertib for other cancer indications continues, including breast and lung cancer and leukemia.
Most of the subjects in both study arms were white, and about two-thirds were men; the median age was 63 years in both arms.
The work was funded by alisertib maker Millennium Pharmaceuticals, a subsidiary of Takeda. Dr. O’Connor and other investigators reported various ties to Millennium and Takeda, including research funding, honoraria, and consulting work. The study included employees of the companies.
SOURCE: O’Connor OA et al. J Clin Oncol. 2019 Feb 1. doi: 10.1200/JCO.18.00899.
FROM THE JOURNAL OF CLINICAL ONCOLOGY
Hidradenitis suppurativa linked to increased lymphoma risk
Lymphomas appear to be up to four times more likely in patients with hidradenitis suppurativa than among the general population, Rachel Tannenbaum and her colleagues reported in a Research Letter in JAMA Dermatology.
The risks of Hodgkin (HL), non-Hodgkin (NHL), and cutaneous T-cell lymphoma (CTCL) all were significantly higher among patients with HS, wrote Ms. Tannenbaum, Andrew Strunk, and Amit Garg, MD. Males and older patients carried higher risks than females and younger patients, they found.
The team members, of Hofstra University, Hempstead, N.Y., conducted a health care database study comprising 55 million patients included in 27 integrated U.S. health care systems. All the subjects were at least 18 years old; records indicated active HS during the study period of 2013-2018. A regression analysis controlled for age and sex.
The database contained 62,690 patients with HS. The majority (74%) were female and were aged 44 years or younger (57%).
All three lymphomas were more common among HS patients than patients without HS, including non-Hodgkin lymphoma (0.40% vs. 0.35%,) Hodgkin lymphoma (0.17% vs. 0.09%), and cutaneous T-cell lymphoma (0.06% vs. 0.02%).
The multivariate analysis determined that HS patients were twice as likely to develop both non-Hodgkin and Hodgkin lymphoma (odds ratio, 2.0 and 2.21, respectively). They were four times more likely to develop cutaneous T-cell lymphoma (OR, 4.31).
All three lymphomas were more common among males than females: NHL, 0.62% vs. 0.32%; HL, 0.28% vs. 0.13%; and CTCL, 0.09% vs. 0.04%. This translated into significantly increased HS-associated risks, Ms. Tannenbaum and her coauthors noted. “For example, the [odds ratios] for the association between HS and HL were higher in males (OR, 2.97; 95% confidence interval, 2.22-3.99) than in females (OR, 1.86; 95% CI, 1.44-2.39) (P = .02),” they wrote.
Lymphomas were more common among HS patients in every age group. Patients with HS aged 45-64 years were 38% more likely to develop NHL, and those older than 65, about twice as likely (OR, 1.99).
“To our knowledge, this is the first investigation to systematically evaluate this association in a U.S. population of patients with HS,” the research team concluded.
The study was supported by a grant from AbbVie. Ms. Tannenbaum and Mr. Strunk reported no disclosures. Dr. Garg reported financial relationships with AbbVie and several other pharmaceutical companies.
SOURCE: Tannenbaum R et al. JAMA Dermatol. 2019 Jan 30. doi: 10.1001/jamadermatol.2018.5230.
Lymphomas appear to be up to four times more likely in patients with hidradenitis suppurativa than among the general population, Rachel Tannenbaum and her colleagues reported in a Research Letter in JAMA Dermatology.
The risks of Hodgkin (HL), non-Hodgkin (NHL), and cutaneous T-cell lymphoma (CTCL) all were significantly higher among patients with HS, wrote Ms. Tannenbaum, Andrew Strunk, and Amit Garg, MD. Males and older patients carried higher risks than females and younger patients, they found.
The team members, of Hofstra University, Hempstead, N.Y., conducted a health care database study comprising 55 million patients included in 27 integrated U.S. health care systems. All the subjects were at least 18 years old; records indicated active HS during the study period of 2013-2018. A regression analysis controlled for age and sex.
The database contained 62,690 patients with HS. The majority (74%) were female and were aged 44 years or younger (57%).
All three lymphomas were more common among HS patients than patients without HS, including non-Hodgkin lymphoma (0.40% vs. 0.35%,) Hodgkin lymphoma (0.17% vs. 0.09%), and cutaneous T-cell lymphoma (0.06% vs. 0.02%).
The multivariate analysis determined that HS patients were twice as likely to develop both non-Hodgkin and Hodgkin lymphoma (odds ratio, 2.0 and 2.21, respectively). They were four times more likely to develop cutaneous T-cell lymphoma (OR, 4.31).
All three lymphomas were more common among males than females: NHL, 0.62% vs. 0.32%; HL, 0.28% vs. 0.13%; and CTCL, 0.09% vs. 0.04%. This translated into significantly increased HS-associated risks, Ms. Tannenbaum and her coauthors noted. “For example, the [odds ratios] for the association between HS and HL were higher in males (OR, 2.97; 95% confidence interval, 2.22-3.99) than in females (OR, 1.86; 95% CI, 1.44-2.39) (P = .02),” they wrote.
Lymphomas were more common among HS patients in every age group. Patients with HS aged 45-64 years were 38% more likely to develop NHL, and those older than 65, about twice as likely (OR, 1.99).
“To our knowledge, this is the first investigation to systematically evaluate this association in a U.S. population of patients with HS,” the research team concluded.
The study was supported by a grant from AbbVie. Ms. Tannenbaum and Mr. Strunk reported no disclosures. Dr. Garg reported financial relationships with AbbVie and several other pharmaceutical companies.
SOURCE: Tannenbaum R et al. JAMA Dermatol. 2019 Jan 30. doi: 10.1001/jamadermatol.2018.5230.
Lymphomas appear to be up to four times more likely in patients with hidradenitis suppurativa than among the general population, Rachel Tannenbaum and her colleagues reported in a Research Letter in JAMA Dermatology.
The risks of Hodgkin (HL), non-Hodgkin (NHL), and cutaneous T-cell lymphoma (CTCL) all were significantly higher among patients with HS, wrote Ms. Tannenbaum, Andrew Strunk, and Amit Garg, MD. Males and older patients carried higher risks than females and younger patients, they found.
The team members, of Hofstra University, Hempstead, N.Y., conducted a health care database study comprising 55 million patients included in 27 integrated U.S. health care systems. All the subjects were at least 18 years old; records indicated active HS during the study period of 2013-2018. A regression analysis controlled for age and sex.
The database contained 62,690 patients with HS. The majority (74%) were female and were aged 44 years or younger (57%).
All three lymphomas were more common among HS patients than patients without HS, including non-Hodgkin lymphoma (0.40% vs. 0.35%,) Hodgkin lymphoma (0.17% vs. 0.09%), and cutaneous T-cell lymphoma (0.06% vs. 0.02%).
The multivariate analysis determined that HS patients were twice as likely to develop both non-Hodgkin and Hodgkin lymphoma (odds ratio, 2.0 and 2.21, respectively). They were four times more likely to develop cutaneous T-cell lymphoma (OR, 4.31).
All three lymphomas were more common among males than females: NHL, 0.62% vs. 0.32%; HL, 0.28% vs. 0.13%; and CTCL, 0.09% vs. 0.04%. This translated into significantly increased HS-associated risks, Ms. Tannenbaum and her coauthors noted. “For example, the [odds ratios] for the association between HS and HL were higher in males (OR, 2.97; 95% confidence interval, 2.22-3.99) than in females (OR, 1.86; 95% CI, 1.44-2.39) (P = .02),” they wrote.
Lymphomas were more common among HS patients in every age group. Patients with HS aged 45-64 years were 38% more likely to develop NHL, and those older than 65, about twice as likely (OR, 1.99).
“To our knowledge, this is the first investigation to systematically evaluate this association in a U.S. population of patients with HS,” the research team concluded.
The study was supported by a grant from AbbVie. Ms. Tannenbaum and Mr. Strunk reported no disclosures. Dr. Garg reported financial relationships with AbbVie and several other pharmaceutical companies.
SOURCE: Tannenbaum R et al. JAMA Dermatol. 2019 Jan 30. doi: 10.1001/jamadermatol.2018.5230.
FROM JAMA DERMATOLOGY
Key clinical point: Hidradenitis suppurativa appears to increase the risk of cutaneous T-cell lymphoma, Hodgkin, and non-Hodgkin lymphomas.
Major finding: Lymphomas are up to four times more common among patients with hidradenitis suppurativa than those without the chronic inflammatory disorder.
Study details: The database review comprised more than 55 million patients in 27 linked health care systems.
Disclosures: This study was supported by a grant from AbbVie. Ms. Tannenbaum and Mr. Strunk reported no disclosures. Dr. Garg reported financial relationships with AbbVie and several other pharmaceutical companies.
Source: Tannenbaum R et al. JAMA Dermatol. 2019 Jan 30. doi: 10.1001/jamadermatol.2018.5230.