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Development of Debilitating Neuropathy After Two Cycles of Pembrolizumab
Case Report
73-year-old white male presented with large right shoulder soft tissue mass (17x5 cm) near the scapula, and was subsequently sent for surgical resection by his primary care. Pathology showed nodular melanoma with positive margin, lymphovascular invasion and neurotropism present with high mitosis. PET-CT scan showed positive uptake in axillary and supraclavicular lymph nodes as well as uptake in the left proximal tibia. Biopsy of the bone was also positive for melanoma. Molecular study showed BRAF mutation at L597, high tumor mutation burden (24 mutations/Mb), and PD-L1 positive in 60% of tumor cells and PD-1 was positive in immune cells, but not in tumor cells. One other distinct feature of this clinical presentation was the abundance of macrophages (CD68+) in the tumor microenvironment. Patient was initiated therapy with pembrolizumab. However, three weeks after his second cycle, he was admitted to hospital due to severe weakness in both upper extremities and pain at night. He also experienced a new onset of polyarthralgia in both hands, unable to play musical instruments. He was started on steroid treatment and showed significant improvement. Once steroid was tapered off, the sensation of pain substantially decreased but persisted. EMG showed right median motor neuropathy and left median sensory neuropathy. Blood test detected ANA positive, and as TSH was high, levothyroxine was initiated.
Outcome
His PET-CT scan showed improvement after only two cycles of treatment and has remained stable for over ten months without any treatment (patient elected to stop pembrolizumab treatment due to frequent traveling). We have performed a more detailed study of the macrophages in his tumor sample and interestingly, the majority of macrophages were type-1 (CD 80+), with some, type-2 macrophages (CD163+). It is known that type-1 macrophages are pro-inflammatory and have antitumor effect, while type-2 macrophages have opposite effect and often promote tumor growth and metastasis. This could explain the side effect and long duration of response despite only two cycles of pembrolizumab treatment. Characteristics of macrophages in melanoma tumor samples may be an important parameter to predict side effect and tumor response beyond PD1 or PD-L1 expression.
Case Report
73-year-old white male presented with large right shoulder soft tissue mass (17x5 cm) near the scapula, and was subsequently sent for surgical resection by his primary care. Pathology showed nodular melanoma with positive margin, lymphovascular invasion and neurotropism present with high mitosis. PET-CT scan showed positive uptake in axillary and supraclavicular lymph nodes as well as uptake in the left proximal tibia. Biopsy of the bone was also positive for melanoma. Molecular study showed BRAF mutation at L597, high tumor mutation burden (24 mutations/Mb), and PD-L1 positive in 60% of tumor cells and PD-1 was positive in immune cells, but not in tumor cells. One other distinct feature of this clinical presentation was the abundance of macrophages (CD68+) in the tumor microenvironment. Patient was initiated therapy with pembrolizumab. However, three weeks after his second cycle, he was admitted to hospital due to severe weakness in both upper extremities and pain at night. He also experienced a new onset of polyarthralgia in both hands, unable to play musical instruments. He was started on steroid treatment and showed significant improvement. Once steroid was tapered off, the sensation of pain substantially decreased but persisted. EMG showed right median motor neuropathy and left median sensory neuropathy. Blood test detected ANA positive, and as TSH was high, levothyroxine was initiated.
Outcome
His PET-CT scan showed improvement after only two cycles of treatment and has remained stable for over ten months without any treatment (patient elected to stop pembrolizumab treatment due to frequent traveling). We have performed a more detailed study of the macrophages in his tumor sample and interestingly, the majority of macrophages were type-1 (CD 80+), with some, type-2 macrophages (CD163+). It is known that type-1 macrophages are pro-inflammatory and have antitumor effect, while type-2 macrophages have opposite effect and often promote tumor growth and metastasis. This could explain the side effect and long duration of response despite only two cycles of pembrolizumab treatment. Characteristics of macrophages in melanoma tumor samples may be an important parameter to predict side effect and tumor response beyond PD1 or PD-L1 expression.
Case Report
73-year-old white male presented with large right shoulder soft tissue mass (17x5 cm) near the scapula, and was subsequently sent for surgical resection by his primary care. Pathology showed nodular melanoma with positive margin, lymphovascular invasion and neurotropism present with high mitosis. PET-CT scan showed positive uptake in axillary and supraclavicular lymph nodes as well as uptake in the left proximal tibia. Biopsy of the bone was also positive for melanoma. Molecular study showed BRAF mutation at L597, high tumor mutation burden (24 mutations/Mb), and PD-L1 positive in 60% of tumor cells and PD-1 was positive in immune cells, but not in tumor cells. One other distinct feature of this clinical presentation was the abundance of macrophages (CD68+) in the tumor microenvironment. Patient was initiated therapy with pembrolizumab. However, three weeks after his second cycle, he was admitted to hospital due to severe weakness in both upper extremities and pain at night. He also experienced a new onset of polyarthralgia in both hands, unable to play musical instruments. He was started on steroid treatment and showed significant improvement. Once steroid was tapered off, the sensation of pain substantially decreased but persisted. EMG showed right median motor neuropathy and left median sensory neuropathy. Blood test detected ANA positive, and as TSH was high, levothyroxine was initiated.
Outcome
His PET-CT scan showed improvement after only two cycles of treatment and has remained stable for over ten months without any treatment (patient elected to stop pembrolizumab treatment due to frequent traveling). We have performed a more detailed study of the macrophages in his tumor sample and interestingly, the majority of macrophages were type-1 (CD 80+), with some, type-2 macrophages (CD163+). It is known that type-1 macrophages are pro-inflammatory and have antitumor effect, while type-2 macrophages have opposite effect and often promote tumor growth and metastasis. This could explain the side effect and long duration of response despite only two cycles of pembrolizumab treatment. Characteristics of macrophages in melanoma tumor samples may be an important parameter to predict side effect and tumor response beyond PD1 or PD-L1 expression.
Double Hit: Epstein-Barr Virus Causing Infectious Mononucleosis Followed by Hemolytic Uremic Syndrome
Introduction
Epstein-Barr virus (EBV) is a herpes virus that commonly causes infectious mononucleosis (IM) and linked to different hematological conditions. Here we present a case of EBV-triggered Hemolytic Uremic Syndrome (HUS) with pulmonary involvement.
Case Presentation
A 20-year-old male presented with fever, thrombocytopenia, and splenomegaly. Acute EBV serology was positive. Creatinine and hemoglobin were normal. He was diagnosed with IM. platelet count improved within 3 weeks. 4 weeks later, he returned with severe hemoptysis. Hgb 6.8g/dL, platelet 133,000/uL, lactate dehydrogenase 969u/L, creatinine 21mg/dL, and schistocytes on peripheral smear. Chest computed tomography showed bilateral opacities consistent with diffuse alveolar hemorrhage (DAH). Emergent hemodialysis and plasmapheresis were started. Infectious work up was negative. Autoimmune work up was also negative (anti-neutrophil cytoplasmic, anti-basement membrane antibodies, ANA). Aadamts13 activity was 62% (normal ~66%) ruling out thrombotic thrombocytopenic purpura (TTP). Kidney biopsy revealed thrombotic microangiopathic process. The patient was eventually diagnosed with HUS and treated with Eculizumab. 4 months later his renal function has partially recovered and no longer needs hemodialysis.
Discussion
HUS is a rare entity that is known to be triggered by different underlying pathologies. However, its link to EBV remains unclear. Literature review has revealed only two cases of EBV-triggered HUS, even though almost 90-95% of adults are EBV-seropositive. What unique about our case is the patient initially presented with documented IM, and HUS happened a month later. This raises the theory that HUS could be a sequela of the infection, rather than an effect of acute viral phase and this is the first case to report such correlation. The other unique thing is pulmonary involvement in HUS. With consultation with pulmonary service, we believe our patient had DAH based on clinical and radiographic findings. To our knowledge this is the first case to show this association.
Conclusion
EBV is a common virus with high seropositivity among world’s population. Its link to HUS remains unclear and needs more investigation. Providers should recognize HUS as a complication of EBV infection, either in the acute phase or as a sequela. Adolescents are at higher risk for such complication since IM is common in this population.
Introduction
Epstein-Barr virus (EBV) is a herpes virus that commonly causes infectious mononucleosis (IM) and linked to different hematological conditions. Here we present a case of EBV-triggered Hemolytic Uremic Syndrome (HUS) with pulmonary involvement.
Case Presentation
A 20-year-old male presented with fever, thrombocytopenia, and splenomegaly. Acute EBV serology was positive. Creatinine and hemoglobin were normal. He was diagnosed with IM. platelet count improved within 3 weeks. 4 weeks later, he returned with severe hemoptysis. Hgb 6.8g/dL, platelet 133,000/uL, lactate dehydrogenase 969u/L, creatinine 21mg/dL, and schistocytes on peripheral smear. Chest computed tomography showed bilateral opacities consistent with diffuse alveolar hemorrhage (DAH). Emergent hemodialysis and plasmapheresis were started. Infectious work up was negative. Autoimmune work up was also negative (anti-neutrophil cytoplasmic, anti-basement membrane antibodies, ANA). Aadamts13 activity was 62% (normal ~66%) ruling out thrombotic thrombocytopenic purpura (TTP). Kidney biopsy revealed thrombotic microangiopathic process. The patient was eventually diagnosed with HUS and treated with Eculizumab. 4 months later his renal function has partially recovered and no longer needs hemodialysis.
Discussion
HUS is a rare entity that is known to be triggered by different underlying pathologies. However, its link to EBV remains unclear. Literature review has revealed only two cases of EBV-triggered HUS, even though almost 90-95% of adults are EBV-seropositive. What unique about our case is the patient initially presented with documented IM, and HUS happened a month later. This raises the theory that HUS could be a sequela of the infection, rather than an effect of acute viral phase and this is the first case to report such correlation. The other unique thing is pulmonary involvement in HUS. With consultation with pulmonary service, we believe our patient had DAH based on clinical and radiographic findings. To our knowledge this is the first case to show this association.
Conclusion
EBV is a common virus with high seropositivity among world’s population. Its link to HUS remains unclear and needs more investigation. Providers should recognize HUS as a complication of EBV infection, either in the acute phase or as a sequela. Adolescents are at higher risk for such complication since IM is common in this population.
Introduction
Epstein-Barr virus (EBV) is a herpes virus that commonly causes infectious mononucleosis (IM) and linked to different hematological conditions. Here we present a case of EBV-triggered Hemolytic Uremic Syndrome (HUS) with pulmonary involvement.
Case Presentation
A 20-year-old male presented with fever, thrombocytopenia, and splenomegaly. Acute EBV serology was positive. Creatinine and hemoglobin were normal. He was diagnosed with IM. platelet count improved within 3 weeks. 4 weeks later, he returned with severe hemoptysis. Hgb 6.8g/dL, platelet 133,000/uL, lactate dehydrogenase 969u/L, creatinine 21mg/dL, and schistocytes on peripheral smear. Chest computed tomography showed bilateral opacities consistent with diffuse alveolar hemorrhage (DAH). Emergent hemodialysis and plasmapheresis were started. Infectious work up was negative. Autoimmune work up was also negative (anti-neutrophil cytoplasmic, anti-basement membrane antibodies, ANA). Aadamts13 activity was 62% (normal ~66%) ruling out thrombotic thrombocytopenic purpura (TTP). Kidney biopsy revealed thrombotic microangiopathic process. The patient was eventually diagnosed with HUS and treated with Eculizumab. 4 months later his renal function has partially recovered and no longer needs hemodialysis.
Discussion
HUS is a rare entity that is known to be triggered by different underlying pathologies. However, its link to EBV remains unclear. Literature review has revealed only two cases of EBV-triggered HUS, even though almost 90-95% of adults are EBV-seropositive. What unique about our case is the patient initially presented with documented IM, and HUS happened a month later. This raises the theory that HUS could be a sequela of the infection, rather than an effect of acute viral phase and this is the first case to report such correlation. The other unique thing is pulmonary involvement in HUS. With consultation with pulmonary service, we believe our patient had DAH based on clinical and radiographic findings. To our knowledge this is the first case to show this association.
Conclusion
EBV is a common virus with high seropositivity among world’s population. Its link to HUS remains unclear and needs more investigation. Providers should recognize HUS as a complication of EBV infection, either in the acute phase or as a sequela. Adolescents are at higher risk for such complication since IM is common in this population.
Methods of Identifying Real World mCRPC Patients from the Veterans Health Administration System
Purpose
Prostate cancer is the fifth leading cause of death in the United States. Genomic testing is essential to guide treatment decisions in patients with metastatic castration resistant prostate cancer (mCRPC), the most advanced stage of prostate cancer. However, identifying mCRPC patients from administrative data is challenging and hinders researchers’ ability to assess testing among these patients. This study aims to develop algorithms using structured data and unstructured data with Natural language processing (NLP) methods to identify veterans by disease stage and hormone sensitivity, and to assess patient characteristics as well as receipt of tumor NGS testing.
Methods
We used biopsy, pathology, and diagnosis codes, to identify veterans with newly diagnosed PC within the Veterans Health Administration (VA) from January 1, 2017 to December 31, 2020. We developed and deployed: 1. A structured algorithm that used medication and Prostate-Specific Antigen (PSA) data to assess hormone sensitivity. 2. NLP tools to extract disease stage and hormone sensitivity from clinical notes. We report descriptive statistics on patient demographics, clinical characteristics, disease status, androgen deprivation therapy (ADT), and receipt of tumor NGS testing.
Results
There were 42,485 veterans with newly diagnosed prostate cancer between 2017-2020. This represented ~0.18% of veterans served in the VA and consisted of Whites (57%), Blacks (33%), and others (10%). During the study period, 3,113 (7.3%) patients had documentation of assessment for intraductal carcinoma, 5,160 (12.1%) had ADT treatment, 1,481 (3.5%) had CRPC, and 3,246 (7.6%) had metastatic disease. Among the 42,485 veterans, 422 received tumor NGS testing within VA, and 300 of them had metastatic disease. NLP tool and structured data algorithm collectively showed that 38% of the 422 tumor NGS testing recipients had mCRPC. Among all newly diagnosed PC patients, White patients had highest rates of tumor-based testing (2.3%), then Native Hawaiians (1.7%), Asians and Blacks (1.2% each), compared to Native Americans (0.4%).
Implications
NLP tools alongside structured data algorithms successfully identified variables required to measure access to tumor NGS testing. Efforts to validate and apply this method is ongoing to assess receipt of precision prostate cancer care in VA.
Purpose
Prostate cancer is the fifth leading cause of death in the United States. Genomic testing is essential to guide treatment decisions in patients with metastatic castration resistant prostate cancer (mCRPC), the most advanced stage of prostate cancer. However, identifying mCRPC patients from administrative data is challenging and hinders researchers’ ability to assess testing among these patients. This study aims to develop algorithms using structured data and unstructured data with Natural language processing (NLP) methods to identify veterans by disease stage and hormone sensitivity, and to assess patient characteristics as well as receipt of tumor NGS testing.
Methods
We used biopsy, pathology, and diagnosis codes, to identify veterans with newly diagnosed PC within the Veterans Health Administration (VA) from January 1, 2017 to December 31, 2020. We developed and deployed: 1. A structured algorithm that used medication and Prostate-Specific Antigen (PSA) data to assess hormone sensitivity. 2. NLP tools to extract disease stage and hormone sensitivity from clinical notes. We report descriptive statistics on patient demographics, clinical characteristics, disease status, androgen deprivation therapy (ADT), and receipt of tumor NGS testing.
Results
There were 42,485 veterans with newly diagnosed prostate cancer between 2017-2020. This represented ~0.18% of veterans served in the VA and consisted of Whites (57%), Blacks (33%), and others (10%). During the study period, 3,113 (7.3%) patients had documentation of assessment for intraductal carcinoma, 5,160 (12.1%) had ADT treatment, 1,481 (3.5%) had CRPC, and 3,246 (7.6%) had metastatic disease. Among the 42,485 veterans, 422 received tumor NGS testing within VA, and 300 of them had metastatic disease. NLP tool and structured data algorithm collectively showed that 38% of the 422 tumor NGS testing recipients had mCRPC. Among all newly diagnosed PC patients, White patients had highest rates of tumor-based testing (2.3%), then Native Hawaiians (1.7%), Asians and Blacks (1.2% each), compared to Native Americans (0.4%).
Implications
NLP tools alongside structured data algorithms successfully identified variables required to measure access to tumor NGS testing. Efforts to validate and apply this method is ongoing to assess receipt of precision prostate cancer care in VA.
Purpose
Prostate cancer is the fifth leading cause of death in the United States. Genomic testing is essential to guide treatment decisions in patients with metastatic castration resistant prostate cancer (mCRPC), the most advanced stage of prostate cancer. However, identifying mCRPC patients from administrative data is challenging and hinders researchers’ ability to assess testing among these patients. This study aims to develop algorithms using structured data and unstructured data with Natural language processing (NLP) methods to identify veterans by disease stage and hormone sensitivity, and to assess patient characteristics as well as receipt of tumor NGS testing.
Methods
We used biopsy, pathology, and diagnosis codes, to identify veterans with newly diagnosed PC within the Veterans Health Administration (VA) from January 1, 2017 to December 31, 2020. We developed and deployed: 1. A structured algorithm that used medication and Prostate-Specific Antigen (PSA) data to assess hormone sensitivity. 2. NLP tools to extract disease stage and hormone sensitivity from clinical notes. We report descriptive statistics on patient demographics, clinical characteristics, disease status, androgen deprivation therapy (ADT), and receipt of tumor NGS testing.
Results
There were 42,485 veterans with newly diagnosed prostate cancer between 2017-2020. This represented ~0.18% of veterans served in the VA and consisted of Whites (57%), Blacks (33%), and others (10%). During the study period, 3,113 (7.3%) patients had documentation of assessment for intraductal carcinoma, 5,160 (12.1%) had ADT treatment, 1,481 (3.5%) had CRPC, and 3,246 (7.6%) had metastatic disease. Among the 42,485 veterans, 422 received tumor NGS testing within VA, and 300 of them had metastatic disease. NLP tool and structured data algorithm collectively showed that 38% of the 422 tumor NGS testing recipients had mCRPC. Among all newly diagnosed PC patients, White patients had highest rates of tumor-based testing (2.3%), then Native Hawaiians (1.7%), Asians and Blacks (1.2% each), compared to Native Americans (0.4%).
Implications
NLP tools alongside structured data algorithms successfully identified variables required to measure access to tumor NGS testing. Efforts to validate and apply this method is ongoing to assess receipt of precision prostate cancer care in VA.
Diagnosis of Prostate Cancer and Prostate-specific Antigen Level on Initial Prostate Biopsy: Does Race Matter?
Objective
To determine whether Black Veterans are at higher risk for prostate cancer diagnosis on their first prostate biopsy compared to non-Hispanic White (White) Veterans.
Background
Prostate-specific antigen (PSA) testing is widely used to screen for prostate cancer. Although men of African ancestry display an increased incidence of prostate cancer and more aggressive disease, specific PSA thresholds for biopsy referral have yet to be proposed for this population.
Methods
We used the VHA’s electronic medical record data to collect Veterans’ demographic and clinical characteristics including self-identified race/ethnicity, age, date of first prostate biopsy, PSA results, and prostate cancer diagnosis. Veterans’ ZIP code of residence was used to determine urban/rural status, income, and education. We estimated multivariable logistic regression models to predict the likelihood of prostate cancer diagnosis on the first biopsy using race, baseline PSA, age at first PSA test, age at initial biopsy, smoking status, use of statins, and socioeconomic factors as predictors. We calculated adjusted predicted probabilities of cancer detection on the first prostate biopsy from the logistic models at different PSA levels.
Results
We identified 246,056 White and 71,653 Black Veterans who underwent their first prostate biopsy through February 28, 2020 and who had no previous prostate cancer diagnosis or treatment prior to that biopsy. Black Veterans appeared to receive their first PSA test four years earlier and undergo their first prostate biopsy two years earlier than their White counterparts (median age of 57 vs. 61 and 63 vs. 65, respectively). After controlling for selected covariates, we found that Black Veterans were 52% more likely to be diagnosed with prostate cancer on their first prostate biopsy compared to White Veterans (OR 1.52, 95% CI 1.49-1.55). Our model indicated that a Black Veteran with a PSA of 4.0 ng/ml has an equivalent risk of prostate cancer detection as a White Veteran with a PSA of 9.7 ng/ml.
Implications
Our findings suggested that developing a risk-based PSA threshold for referral to prostate biopsy may lead to earlier diagnosis of clinically significant prostate cancer in a population of Veterans known to have an increased incidence and risk of aggressive disease.
Objective
To determine whether Black Veterans are at higher risk for prostate cancer diagnosis on their first prostate biopsy compared to non-Hispanic White (White) Veterans.
Background
Prostate-specific antigen (PSA) testing is widely used to screen for prostate cancer. Although men of African ancestry display an increased incidence of prostate cancer and more aggressive disease, specific PSA thresholds for biopsy referral have yet to be proposed for this population.
Methods
We used the VHA’s electronic medical record data to collect Veterans’ demographic and clinical characteristics including self-identified race/ethnicity, age, date of first prostate biopsy, PSA results, and prostate cancer diagnosis. Veterans’ ZIP code of residence was used to determine urban/rural status, income, and education. We estimated multivariable logistic regression models to predict the likelihood of prostate cancer diagnosis on the first biopsy using race, baseline PSA, age at first PSA test, age at initial biopsy, smoking status, use of statins, and socioeconomic factors as predictors. We calculated adjusted predicted probabilities of cancer detection on the first prostate biopsy from the logistic models at different PSA levels.
Results
We identified 246,056 White and 71,653 Black Veterans who underwent their first prostate biopsy through February 28, 2020 and who had no previous prostate cancer diagnosis or treatment prior to that biopsy. Black Veterans appeared to receive their first PSA test four years earlier and undergo their first prostate biopsy two years earlier than their White counterparts (median age of 57 vs. 61 and 63 vs. 65, respectively). After controlling for selected covariates, we found that Black Veterans were 52% more likely to be diagnosed with prostate cancer on their first prostate biopsy compared to White Veterans (OR 1.52, 95% CI 1.49-1.55). Our model indicated that a Black Veteran with a PSA of 4.0 ng/ml has an equivalent risk of prostate cancer detection as a White Veteran with a PSA of 9.7 ng/ml.
Implications
Our findings suggested that developing a risk-based PSA threshold for referral to prostate biopsy may lead to earlier diagnosis of clinically significant prostate cancer in a population of Veterans known to have an increased incidence and risk of aggressive disease.
Objective
To determine whether Black Veterans are at higher risk for prostate cancer diagnosis on their first prostate biopsy compared to non-Hispanic White (White) Veterans.
Background
Prostate-specific antigen (PSA) testing is widely used to screen for prostate cancer. Although men of African ancestry display an increased incidence of prostate cancer and more aggressive disease, specific PSA thresholds for biopsy referral have yet to be proposed for this population.
Methods
We used the VHA’s electronic medical record data to collect Veterans’ demographic and clinical characteristics including self-identified race/ethnicity, age, date of first prostate biopsy, PSA results, and prostate cancer diagnosis. Veterans’ ZIP code of residence was used to determine urban/rural status, income, and education. We estimated multivariable logistic regression models to predict the likelihood of prostate cancer diagnosis on the first biopsy using race, baseline PSA, age at first PSA test, age at initial biopsy, smoking status, use of statins, and socioeconomic factors as predictors. We calculated adjusted predicted probabilities of cancer detection on the first prostate biopsy from the logistic models at different PSA levels.
Results
We identified 246,056 White and 71,653 Black Veterans who underwent their first prostate biopsy through February 28, 2020 and who had no previous prostate cancer diagnosis or treatment prior to that biopsy. Black Veterans appeared to receive their first PSA test four years earlier and undergo their first prostate biopsy two years earlier than their White counterparts (median age of 57 vs. 61 and 63 vs. 65, respectively). After controlling for selected covariates, we found that Black Veterans were 52% more likely to be diagnosed with prostate cancer on their first prostate biopsy compared to White Veterans (OR 1.52, 95% CI 1.49-1.55). Our model indicated that a Black Veteran with a PSA of 4.0 ng/ml has an equivalent risk of prostate cancer detection as a White Veteran with a PSA of 9.7 ng/ml.
Implications
Our findings suggested that developing a risk-based PSA threshold for referral to prostate biopsy may lead to earlier diagnosis of clinically significant prostate cancer in a population of Veterans known to have an increased incidence and risk of aggressive disease.
Racial Disparities in Treatment and Survival for Early-Stage Non-Small Cell Lung Cancer: Is Equal Access Health Care System the Answer?
Background
Survival for early-stage non-small cell lung cancer (NSCLC) has dramatically improved with advancement in surgical and radiation techniques over last two decades but there exists a disparity for African Americans (AA) having worse overall survival (OS) in recent studies on the general US population. We studied this racial disparity in Veteran population.
Methods
Data for 2589 AA and 14184 Caucasian Veterans diagnosed with early-stage (I, II) NSCLC between 2011-2017 was obtained from the Cancer Cube Registry (VACCR). IRB approval was obtained.
Results
The distribution of newly diagnosed cases of Stage I (73.92% AA vs 74.71% Caucasians) and Stage II (26.07% vs 25.29%) between the two races was comparable (p = .41). More Caucasians were diagnosed above the age of 60 compared to AA (92.22% vs 84.51%, p < .05). More AA were diagnosed with adenocarcinoma at diagnosis (56.01% vs 45.88% Caucasians, p < .05) for both Stage I and II disease. For the limited number of Veterans with reported performance status (PS), similar proportion of patients had a good PS defined as ECOG 0-2 among the two races (93.70% AA vs 93.97% Caucasians, p = .73). There was no statistically significant difference between 5-year OS for AA and Caucasians (69.81% vs 70.78%, p = .33) for both Stage I and II NSCLC. Both groups had similar rate of receipt of surgery as first line treatment or in combination with other treatments (58.90% AA vs 59.07% Caucasians, p = .90). Similarly, the rate of receiving radiation therapy was comparable between AA and Caucasians (42.4% vs 42.3%, p = .96). Although both races showed improved 5-year OS after surgery, there was no statistical difference in survival benefit between AA and Caucasians (69.8% vs 70.8%, p = .33).
Conclusion
In contrast to the studies assessing general US population trends, there was no racial disparity for 5-year OS in early-stage NSCLC for the Veteran population. This points to the inequities in access to treatment and preventive healthcare services as a possible contributing cause to the increased mortality in AA in general US population and a more equitable healthcare delivery within the VHA system.
Background
Survival for early-stage non-small cell lung cancer (NSCLC) has dramatically improved with advancement in surgical and radiation techniques over last two decades but there exists a disparity for African Americans (AA) having worse overall survival (OS) in recent studies on the general US population. We studied this racial disparity in Veteran population.
Methods
Data for 2589 AA and 14184 Caucasian Veterans diagnosed with early-stage (I, II) NSCLC between 2011-2017 was obtained from the Cancer Cube Registry (VACCR). IRB approval was obtained.
Results
The distribution of newly diagnosed cases of Stage I (73.92% AA vs 74.71% Caucasians) and Stage II (26.07% vs 25.29%) between the two races was comparable (p = .41). More Caucasians were diagnosed above the age of 60 compared to AA (92.22% vs 84.51%, p < .05). More AA were diagnosed with adenocarcinoma at diagnosis (56.01% vs 45.88% Caucasians, p < .05) for both Stage I and II disease. For the limited number of Veterans with reported performance status (PS), similar proportion of patients had a good PS defined as ECOG 0-2 among the two races (93.70% AA vs 93.97% Caucasians, p = .73). There was no statistically significant difference between 5-year OS for AA and Caucasians (69.81% vs 70.78%, p = .33) for both Stage I and II NSCLC. Both groups had similar rate of receipt of surgery as first line treatment or in combination with other treatments (58.90% AA vs 59.07% Caucasians, p = .90). Similarly, the rate of receiving radiation therapy was comparable between AA and Caucasians (42.4% vs 42.3%, p = .96). Although both races showed improved 5-year OS after surgery, there was no statistical difference in survival benefit between AA and Caucasians (69.8% vs 70.8%, p = .33).
Conclusion
In contrast to the studies assessing general US population trends, there was no racial disparity for 5-year OS in early-stage NSCLC for the Veteran population. This points to the inequities in access to treatment and preventive healthcare services as a possible contributing cause to the increased mortality in AA in general US population and a more equitable healthcare delivery within the VHA system.
Background
Survival for early-stage non-small cell lung cancer (NSCLC) has dramatically improved with advancement in surgical and radiation techniques over last two decades but there exists a disparity for African Americans (AA) having worse overall survival (OS) in recent studies on the general US population. We studied this racial disparity in Veteran population.
Methods
Data for 2589 AA and 14184 Caucasian Veterans diagnosed with early-stage (I, II) NSCLC between 2011-2017 was obtained from the Cancer Cube Registry (VACCR). IRB approval was obtained.
Results
The distribution of newly diagnosed cases of Stage I (73.92% AA vs 74.71% Caucasians) and Stage II (26.07% vs 25.29%) between the two races was comparable (p = .41). More Caucasians were diagnosed above the age of 60 compared to AA (92.22% vs 84.51%, p < .05). More AA were diagnosed with adenocarcinoma at diagnosis (56.01% vs 45.88% Caucasians, p < .05) for both Stage I and II disease. For the limited number of Veterans with reported performance status (PS), similar proportion of patients had a good PS defined as ECOG 0-2 among the two races (93.70% AA vs 93.97% Caucasians, p = .73). There was no statistically significant difference between 5-year OS for AA and Caucasians (69.81% vs 70.78%, p = .33) for both Stage I and II NSCLC. Both groups had similar rate of receipt of surgery as first line treatment or in combination with other treatments (58.90% AA vs 59.07% Caucasians, p = .90). Similarly, the rate of receiving radiation therapy was comparable between AA and Caucasians (42.4% vs 42.3%, p = .96). Although both races showed improved 5-year OS after surgery, there was no statistical difference in survival benefit between AA and Caucasians (69.8% vs 70.8%, p = .33).
Conclusion
In contrast to the studies assessing general US population trends, there was no racial disparity for 5-year OS in early-stage NSCLC for the Veteran population. This points to the inequities in access to treatment and preventive healthcare services as a possible contributing cause to the increased mortality in AA in general US population and a more equitable healthcare delivery within the VHA system.
Survival Analysis of Untreated Early-Stage Non-Small Cell Lung Cancer (NSCLC) in a Veteran Population
Introduction
Veterans with early-stage NSCLC who do not receive any form of treatment have been shown to have a worse overall survival compared to those who receive treatment. Factors that may influence the decision to administer treatment including age, performance status (PS), comorbidities, and racial disparity have not been assessed on a national level in recent years.
Methods
Data for 31,966 veterans diagnosed with early-stage (0, I) NSCLC between 2003-2017 was obtained from the Cancer cube registry (VACCR). IRB approval was obtained.
Results
Patients were divided into treatment (26,833/31,966, 83.16%) and no-treatment group (3096/31966, 9.68%). Of the no-treatment group, 3004 patients were stage I and 92 were stage 0 whereas in the treatment group, the distribution was 26,584 and 249 respectively. Gender, race, and histology distribution were comparable between the two. Patients with poor PS (defined as ECOG III and IV) received less treatment with any modality compared to those with good PS (ECOG I and II) (15.07% in no treatment group vs 4.03% in treatment group, p<0.05). The treatment group had a better 5-year overall survival (OS) as compared to no-treatment group (43.1% vs 14.7%, p<0.05). Regardless of treatment, patients above the age of 60 (41% vs 13.4%, p<0.05) and those with poor PS (19.6% vs 5.8%, p<0.05) had worse 5-year survival, with the effect being greater in the treatment group. Adenocarcinoma had a better 5-year survival compared to squamous cell carcinoma (SCC) in both groups (49.56% vs 39.1% p<0.05). There was no clinically significant OS difference in terms of race (Caucasian or African American) or tumor location (upper, middle, or lower lobe) in between the two groups. Our study was limited by lack of patient- level data including smoking status or reason why no treatment was given.
Conclusion
Patients with early-stage NSCLC who receive no treatment based on poor PS have a worse overall survival compared to the patients that receive treatment. Further investigation is required to assess what other criteria are used to decide treatment eligibility and whether these patients would be candidates for immunotherapy or targeted therapy in the future.
Introduction
Veterans with early-stage NSCLC who do not receive any form of treatment have been shown to have a worse overall survival compared to those who receive treatment. Factors that may influence the decision to administer treatment including age, performance status (PS), comorbidities, and racial disparity have not been assessed on a national level in recent years.
Methods
Data for 31,966 veterans diagnosed with early-stage (0, I) NSCLC between 2003-2017 was obtained from the Cancer cube registry (VACCR). IRB approval was obtained.
Results
Patients were divided into treatment (26,833/31,966, 83.16%) and no-treatment group (3096/31966, 9.68%). Of the no-treatment group, 3004 patients were stage I and 92 were stage 0 whereas in the treatment group, the distribution was 26,584 and 249 respectively. Gender, race, and histology distribution were comparable between the two. Patients with poor PS (defined as ECOG III and IV) received less treatment with any modality compared to those with good PS (ECOG I and II) (15.07% in no treatment group vs 4.03% in treatment group, p<0.05). The treatment group had a better 5-year overall survival (OS) as compared to no-treatment group (43.1% vs 14.7%, p<0.05). Regardless of treatment, patients above the age of 60 (41% vs 13.4%, p<0.05) and those with poor PS (19.6% vs 5.8%, p<0.05) had worse 5-year survival, with the effect being greater in the treatment group. Adenocarcinoma had a better 5-year survival compared to squamous cell carcinoma (SCC) in both groups (49.56% vs 39.1% p<0.05). There was no clinically significant OS difference in terms of race (Caucasian or African American) or tumor location (upper, middle, or lower lobe) in between the two groups. Our study was limited by lack of patient- level data including smoking status or reason why no treatment was given.
Conclusion
Patients with early-stage NSCLC who receive no treatment based on poor PS have a worse overall survival compared to the patients that receive treatment. Further investigation is required to assess what other criteria are used to decide treatment eligibility and whether these patients would be candidates for immunotherapy or targeted therapy in the future.
Introduction
Veterans with early-stage NSCLC who do not receive any form of treatment have been shown to have a worse overall survival compared to those who receive treatment. Factors that may influence the decision to administer treatment including age, performance status (PS), comorbidities, and racial disparity have not been assessed on a national level in recent years.
Methods
Data for 31,966 veterans diagnosed with early-stage (0, I) NSCLC between 2003-2017 was obtained from the Cancer cube registry (VACCR). IRB approval was obtained.
Results
Patients were divided into treatment (26,833/31,966, 83.16%) and no-treatment group (3096/31966, 9.68%). Of the no-treatment group, 3004 patients were stage I and 92 were stage 0 whereas in the treatment group, the distribution was 26,584 and 249 respectively. Gender, race, and histology distribution were comparable between the two. Patients with poor PS (defined as ECOG III and IV) received less treatment with any modality compared to those with good PS (ECOG I and II) (15.07% in no treatment group vs 4.03% in treatment group, p<0.05). The treatment group had a better 5-year overall survival (OS) as compared to no-treatment group (43.1% vs 14.7%, p<0.05). Regardless of treatment, patients above the age of 60 (41% vs 13.4%, p<0.05) and those with poor PS (19.6% vs 5.8%, p<0.05) had worse 5-year survival, with the effect being greater in the treatment group. Adenocarcinoma had a better 5-year survival compared to squamous cell carcinoma (SCC) in both groups (49.56% vs 39.1% p<0.05). There was no clinically significant OS difference in terms of race (Caucasian or African American) or tumor location (upper, middle, or lower lobe) in between the two groups. Our study was limited by lack of patient- level data including smoking status or reason why no treatment was given.
Conclusion
Patients with early-stage NSCLC who receive no treatment based on poor PS have a worse overall survival compared to the patients that receive treatment. Further investigation is required to assess what other criteria are used to decide treatment eligibility and whether these patients would be candidates for immunotherapy or targeted therapy in the future.
Hemophagocytic Lymphohistiocytosis: Early Treatment Leading to an Excellent Outcome
HLH is a rare and deadly disease increasingly more present in adults, but following treatment protocol may yield favorable results.
Hemophagocytic lymphohistiocytosis (HLH) is a rare and deadly disease in which unregulated proliferation of histiocytes and T-cell infiltration takes place. It is known as a pediatric disease in which gene defects result in impaired cytotoxic NK- and T-cell function. It has been associated with autosomal recessive inheritance pattern. Without therapy, survival for these patients with active familial HLH is approximately 2 months.
Recognition of the disease has increased over the years, and as a result the diagnosis of HLH in adults also has increased. An acquired form can be triggered by viruses like Epstein-Barr virus, influenza, HIV, lymphoid malignancies, rheumatologic disorders, or immunodeficiency disorders. Survival rates for untreated HLH have been reported at < 5%.1 Despite early recognition and adequate treatment, HLH carries an overall mortality of 50% in the initial presentation, 90% die in the first 8 weeks of treatment due to uncontrolled disease.2
Case Presentation
A 56-year-old man with no active medical issues except for a remote history of non-Hodgkin lymphoma treated with chemotherapy and splenectomy in 1990 presented to the Veterans Affairs Caribbean Healthcare System in San Juan, Puerto Rico. He was admitted to the medicine ward due to community acquired pneumonia. Three days into admission his clinical status deteriorated, and the patient was transferred to the intensive care unit (ICU) due to acute respiratory failure and sepsis secondary to worsening pneumonia. Chest imaging demonstrated rapidly progressing diffuse bilateral infiltrates. Due to the severity of the chest imaging, a diagnostic bronchoscopy was performed.
The patient’s antibiotics regimen was empirically escalated to vancomycin 1500 mg IV every 12 hours and meropenem 2 g IV every 8 hours. Despite optimization of therapy, the patient did not show clinical signs of improvement. Febrile episodes persisted, pulmonary infiltrates and hypoxemia worsened, and the patient required a neuromuscular blockade. Since the bronchoscopy was nondiagnostic and deterioration persistent, the differential diagnosis was broadened. This led to the ordering of inflammatory markers. Laboratory testing showed ferritin levels > 16,000 ng/mL, pointing to HLH as a possible diagnosis. Further workup was remarkable for triglycerides of 1234 mg/dL and a fibrinogen of 0.77 g/L. In the setting of bicytopenia and persistent fever, HLH-94 regimen was started with dexamethasone 40 mg daily and etoposide 100 mg/m2. CD25 levels of 154,701 pg/mL were demonstrated as well as a decreased immunoglobulin (Ig) G levels with absent IgM and IgA. Bone marrow biopsy was consistent with hemophagocytosis. The patient eventually was extubated and sent to the oncology ward to continue chemotherapy.
Discussion
A high clinical suspicion is warranted for rapid diagnosis and treatment as HLH evolves in most cases to multiorgan failure and death. The diagnostic criteria for HLH was developed by the Histiocyte Society in 1991 and then restructured in 2004.3,4 In the first diagnostic tool developed in 1991, diagnosis was based on 5 criteria (fever, splenomegaly, bicytopenia, hypertriglyceridemia and/or hypofibrinogenemia, and hemophagocytosis). Three additional laboratory findings were also described as part of HLH diagnosis since 2004: low or absent NK-cell-activity, hyperferritinemia of > 500 ng/dL, and high-soluble interleukin-2-receptor levels (CD25) > 2400 U/mL. Overall, 5 of 8 criteria are needed for the HLH diagnosis.
Despite the common use of these diagnostic criteria, they were developed for the pediatric population but have not been validated for adult patients.5 For adult patients, the HScore was developed in 2014. It has 9 variables: 3 are based on clinical findings (known underlying immunosuppression, high temperature, and organomegaly; 5 are based on laboratory values (ferritin, serum glutamic oxaloacetic transaminase, cytopenia, triglycerides, and fibrinogen levels); the last variable uses cytologic findings in the bone marrow. In the initial study, probability of having HLH ranged from < 1% with an HScore of ≤ 90% to > 99% with an HScore of ≥ 250 in noncritically ill adults.5 A recently published retrospective study demonstrated the diagnostic reliability of both the HLH-2004 criteria and HScore in critically ill adult patients. This study concluded that the best prediction accuracy of HLH diagnosis for a cutoff of 4 fulfilled HLH-2004 criteria had a 95.0% sensitivity and 93.6% specificity and HScore cutoff of 168 reached a 100% sensitivity and 94.1% specificity.6
The early negative bronchoscopy lowered the possibility of an infection as the etiology of the clinical presentation and narrowed the hyperferritinemia differential diagnosis. Hyperferritinemia has a sensitivity and specificity of > 90% for diagnosis when above 10,000 ng/dL in the pediatric population.7 This is not the case in adults. Hyperferritinemia is a marker of different inflammatory responses, such as histoplasmosis infection, malignancy, or iron overload rather than an isolated diagnostic tool for HLH.8 It has been reported that CD25 levels less than the diagnostic threshold of 2400 U/mL have a 100% sensitivity for the diagnosis and therefore can rule out the diagnosis. When this is taken into consideration, it can be concluded that CD25 level is a better diagnostic tool when compared with ferritin, but its main limitation is its lack of widespread availability.9 Still, there is a limited number of pathologies that are associated with marked hyperferritinemia, specifically using thresholds of more than 6000 ng/dL.10 Taking into consideration the high mortality of untreated HLH, isolated hyperferritinemia still warrants HLH workup to aggressively pursue the diagnosis and improve outcomes.
The goal of therapy in HLH is prompt inactivation of the dysregulated inflammation with aggressive immunosuppression. In our deteriorating patient, the treatment was started with only 4 of the 8 HLH-2004 diagnostic criteria being met. As per the 2018 Histiocyte Society consensus statement, the decision to start the HLH-94 treatment relies on not only the HLH-2004 diagnostic criteria, but also the patient’s clinical evolution.11 In 1994 the Histiocyte Society also published a treatment protocol termed HLH-94. A Korean retrospective study demonstrated that this protocol led to a 5-year survival rate of 60 to 80% depending on the HLH trigger and response to initial treatment.12 The protocol consists of etoposide at 150 mg/m2, 2 weekly doses in the first 2 weeks and then 1 dose weekly for the next 6 weeks. Dexamethasone is the steroid of choice as it readily crosses the blood-brain barrier. Its dosage consists of 10 mg/m2 for the first 2 weeks and then it is halved every 2 weeks until the eighth week of treatment. A slow taper follows to avoid adrenal insufficiency. Once 8 weeks of treatment have been completed, cyclosporine is added to a goal trough of 200 mcg/dL. If there is central nervous system (CNS) involvement, early aggressive treatment with intrathecal methotrexate is indicated if no improvement is noted during initial therapy.11
In 2004 the Histiocyte Society restructured the HLH-94 treatment protocol with the aim of presenting a more aggressive treatment strategy. The protocol added cyclosporine to the initial induction therapy, rather than later in the ninth week as HLH-94. Neither the use of cyclosporine nor the HLH-2004 have been demonstrated to be superior to the use of etoposide and dexamethasone alone or in the HLH-94 protocol, respectively.13 Cyclosporine is associated with adverse effects (AEs) and may have many contraindications in the acute phase of the disease. Therefore, the HLH-94 protocol is still the recommended regimen.11
To assess adequate clinical response, several clinical and laboratory parameters are followed. Clinically, resolution of fever, improvement in hepatosplenomegaly, lymphadenopathy, and mental status can be useful. Laboratories can be used to assess improvement from organ specific damage such as hepatic involvement or cytopenia. The limitation of these diagnostic studies is that they could falsely suggest an inadequate response to treatment due to concomitant infection or medication AEs. Other markers such as ferritin levels, CD25, and NK cell activity levels are more specific to HLH. Out of them, a decreasing ferritin level has the needed specificity and widespread availability for repeated assessment. On the other hand, both CD25 and NK cell activity are readily available only in specialized centers. An initial high ferritin level is a marker for a poor prognosis, and the rate of decline correlates with mortality. Studies have demonstrated that persistently elevated ferritin levels after treatment initiation are associated with worse outcomes.14,15
Several salvage treatments have been identified in recalcitrant or relapsing disease. In general, chemotherapy needs to be intensified, either by returning to the initial high dosage if recurrence occurs in the weaning phase of treatment or adding other agents if no response was initially achieved. Emapalumab, an interferon γ antibody, was approved by the US Food and Drug Administration for the treatment of intractable HLH after it demonstrated that when added to dexamethasone, it lead to treatment response in 17 out of 27 pediatric patients, with a relatively safe AE profile.16 The goal of intensifying chemotherapy is to have the patient tolerate allogenic stem cell transplant, which is clinically indicated in familial HLH, malignancy induced HLH, and recalcitrant cases. In patients who undergo hematopoietic cell transplantation (HCT) there is a tendency to increase survival to 66% at 5 years.12
Conclusions
HLH is a rare and deadly disease increasingly more present in adults. Our patient who initially presented with a sepsis diagnosis was suspected of having a hematologic etiology for his clinical findings due to markedly elevated ferritin levels. In our patient, the HLH-94 treatment protocol was used, yielding favorable results. Given the lack of specific scientific data backing updated protocols such as HLH-2004 and a comparatively favorable safety profile, current guidelines still recommend using the HLH-94 treatment protocol. Decreasing ferritin levels may be used in conjunction with clinical improvement to demonstrate therapeutic response. Persistence of disease despite standard treatment may warrant novel therapies, such as emapalumab or HCT. Physicians need to be wary of an HLH diagnosis as early identification and treatment may improve its otherwise grim prognosis.
1. Chen TY, Hsu MH, Kuo HC, Sheen JM, Cheng MC, Lin YJ. Outcome analysis of pediatric hemophagocytic lymphohistiocytosis. J Formos Med Assoc. 2021;120(1, pt 1):172-179. doi:10.1016/j.jfma.2020.03.025
2. Henter JI, Samuelsson-Horne A, Aricò M, et al. Treatment of hemophagocytic lymphohistiocytosis with HLH-94 immunochemotherapy and bone marrow transplantation. Blood. 2002;100(7):2367-2373. doi:10.1182/blood-2002-01-0172
3. Henter JI, Elinder G, Ost A. Diagnostic guidelines for hemophagocytic lymphohistiocytosis. The FHL Study Group of the Histiocyte Society. Semin Oncol. 1991;18(1):29-33.
4. Henter JI, Horne A, Aricó M, et al. HLH-2004: Diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer. 2007;48(2):124-131. doi:10.1002/pbc.21039
5. Knaak C, Nyvlt P, Schuster FS, et al. Hemophagocytic lymphohistiocytosis in critically ill patients: diagnostic reliability of HLH-2004 criteria and HScore. Crit Care. 2020;24(1):244. Published 2020 May 24. doi:10.1186/s13054-020-02941-3
6. Fardet L, Galicier L, Lambotte O, et al. Development and validation of the HScore, a score for the diagnosis of reactive hemophagocytic syndrome. Arthritis Rheumatol. 2014;66(9):2613-2620. doi:10.1002/art.38690
7. La Rosée P, Horne A, Hines M, et al. Recommendations for the management of hemophagocytic lymphohistiocytosis in adults. Blood. 2019;133(23):2465-2477. doi:10.1182/blood.2018894618
8. Schaffner M, Rosenstein L, Ballas Z, Suneja M. Significance of Hyperferritinemia in Hospitalized Adults. Am J Med Sci. 2017;354(2):152-158. doi:10.1016/j.amjms.2017.04.016
9. Hayden A, Lin M, Park S, et al. Soluble interleukin-2 receptor is a sensitive diagnostic test in adult HLH. Blood Adv. 2017;1(26):2529-2534. Published 2017 Dec 6. doi:10.1182/bloodadvances.2017012310
10. Belfeki N, Strazzulla A, Picque M, Diamantis S. Extreme hyperferritinemia: etiological spectrum and impact on prognosis. Reumatismo. 2020;71(4):199-202. Published 2020 Jan 28. doi:10.4081/reumatismo.2019.1221
11. Ehl S, Astigarraga I, von Bahr Greenwood T, et al. Recommendations for the use of etoposide-based therapy and bone marrow transplantation for the treatment of HLH: consensus statements by the HLH Steering Committee of the Histiocyte Society. J Allergy Clin Immunol Pract. 2018;6(5):1508-1517. doi:10.1016/j.jaip.2018.05.031
12. Yoon JH, Park SS, Jeon YW, et al. Treatment outcomes and prognostic factors in adult patients with secondary hemophagocytic lymphohistiocytosis not associated with malignancy. Haematologica. 2019;104(2):269-276. doi:10.3324/haematol.2018.198655
13. Bergsten E, Horne A, Aricó M, et al. Confirmed efficacy of etoposide and dexamethasone in HLH treatment: long-term results of the cooperative HLH-2004 study. Blood. 2017;130(25):2728-2738. doi:10.1182/blood-2017-06-788349
14. Lin TF, Ferlic-Stark LL, Allen CE, Kozinetz CA, McClain KL. Rate of decline of ferritin in patients with hemophagocytic lymphohistiocytosis as a prognostic variable for mortality. Pediatr Blood Cancer. 2011;56(1):154-155. doi:10.1002/pbc.22774
15. Zhou J, Zhou J, Shen DT, Goyal H, Wu ZQ, Xu HG. Development and validation of the prognostic value of ferritin in adult patients with Hemophagocytic Lymphohistiocytosis. Orphanet J Rare Dis. 2020;15(1):71. Published 2020 Mar 12. doi:10.1186/s13023-020-1336-616. Locatelli F, Jordan MB, Allen CE, et al. Safety and efficacy of emapalumab in pediatric patients with primary hemophagocytic lymphohistiocytosis. Presented at: American Society of Hematology Annual Meeting, November 29, 2018. Blood. 2018;132(suppl 1):LBA-6. doi:10.1182/blood-2018-120810
HLH is a rare and deadly disease increasingly more present in adults, but following treatment protocol may yield favorable results.
HLH is a rare and deadly disease increasingly more present in adults, but following treatment protocol may yield favorable results.
Hemophagocytic lymphohistiocytosis (HLH) is a rare and deadly disease in which unregulated proliferation of histiocytes and T-cell infiltration takes place. It is known as a pediatric disease in which gene defects result in impaired cytotoxic NK- and T-cell function. It has been associated with autosomal recessive inheritance pattern. Without therapy, survival for these patients with active familial HLH is approximately 2 months.
Recognition of the disease has increased over the years, and as a result the diagnosis of HLH in adults also has increased. An acquired form can be triggered by viruses like Epstein-Barr virus, influenza, HIV, lymphoid malignancies, rheumatologic disorders, or immunodeficiency disorders. Survival rates for untreated HLH have been reported at < 5%.1 Despite early recognition and adequate treatment, HLH carries an overall mortality of 50% in the initial presentation, 90% die in the first 8 weeks of treatment due to uncontrolled disease.2
Case Presentation
A 56-year-old man with no active medical issues except for a remote history of non-Hodgkin lymphoma treated with chemotherapy and splenectomy in 1990 presented to the Veterans Affairs Caribbean Healthcare System in San Juan, Puerto Rico. He was admitted to the medicine ward due to community acquired pneumonia. Three days into admission his clinical status deteriorated, and the patient was transferred to the intensive care unit (ICU) due to acute respiratory failure and sepsis secondary to worsening pneumonia. Chest imaging demonstrated rapidly progressing diffuse bilateral infiltrates. Due to the severity of the chest imaging, a diagnostic bronchoscopy was performed.
The patient’s antibiotics regimen was empirically escalated to vancomycin 1500 mg IV every 12 hours and meropenem 2 g IV every 8 hours. Despite optimization of therapy, the patient did not show clinical signs of improvement. Febrile episodes persisted, pulmonary infiltrates and hypoxemia worsened, and the patient required a neuromuscular blockade. Since the bronchoscopy was nondiagnostic and deterioration persistent, the differential diagnosis was broadened. This led to the ordering of inflammatory markers. Laboratory testing showed ferritin levels > 16,000 ng/mL, pointing to HLH as a possible diagnosis. Further workup was remarkable for triglycerides of 1234 mg/dL and a fibrinogen of 0.77 g/L. In the setting of bicytopenia and persistent fever, HLH-94 regimen was started with dexamethasone 40 mg daily and etoposide 100 mg/m2. CD25 levels of 154,701 pg/mL were demonstrated as well as a decreased immunoglobulin (Ig) G levels with absent IgM and IgA. Bone marrow biopsy was consistent with hemophagocytosis. The patient eventually was extubated and sent to the oncology ward to continue chemotherapy.
Discussion
A high clinical suspicion is warranted for rapid diagnosis and treatment as HLH evolves in most cases to multiorgan failure and death. The diagnostic criteria for HLH was developed by the Histiocyte Society in 1991 and then restructured in 2004.3,4 In the first diagnostic tool developed in 1991, diagnosis was based on 5 criteria (fever, splenomegaly, bicytopenia, hypertriglyceridemia and/or hypofibrinogenemia, and hemophagocytosis). Three additional laboratory findings were also described as part of HLH diagnosis since 2004: low or absent NK-cell-activity, hyperferritinemia of > 500 ng/dL, and high-soluble interleukin-2-receptor levels (CD25) > 2400 U/mL. Overall, 5 of 8 criteria are needed for the HLH diagnosis.
Despite the common use of these diagnostic criteria, they were developed for the pediatric population but have not been validated for adult patients.5 For adult patients, the HScore was developed in 2014. It has 9 variables: 3 are based on clinical findings (known underlying immunosuppression, high temperature, and organomegaly; 5 are based on laboratory values (ferritin, serum glutamic oxaloacetic transaminase, cytopenia, triglycerides, and fibrinogen levels); the last variable uses cytologic findings in the bone marrow. In the initial study, probability of having HLH ranged from < 1% with an HScore of ≤ 90% to > 99% with an HScore of ≥ 250 in noncritically ill adults.5 A recently published retrospective study demonstrated the diagnostic reliability of both the HLH-2004 criteria and HScore in critically ill adult patients. This study concluded that the best prediction accuracy of HLH diagnosis for a cutoff of 4 fulfilled HLH-2004 criteria had a 95.0% sensitivity and 93.6% specificity and HScore cutoff of 168 reached a 100% sensitivity and 94.1% specificity.6
The early negative bronchoscopy lowered the possibility of an infection as the etiology of the clinical presentation and narrowed the hyperferritinemia differential diagnosis. Hyperferritinemia has a sensitivity and specificity of > 90% for diagnosis when above 10,000 ng/dL in the pediatric population.7 This is not the case in adults. Hyperferritinemia is a marker of different inflammatory responses, such as histoplasmosis infection, malignancy, or iron overload rather than an isolated diagnostic tool for HLH.8 It has been reported that CD25 levels less than the diagnostic threshold of 2400 U/mL have a 100% sensitivity for the diagnosis and therefore can rule out the diagnosis. When this is taken into consideration, it can be concluded that CD25 level is a better diagnostic tool when compared with ferritin, but its main limitation is its lack of widespread availability.9 Still, there is a limited number of pathologies that are associated with marked hyperferritinemia, specifically using thresholds of more than 6000 ng/dL.10 Taking into consideration the high mortality of untreated HLH, isolated hyperferritinemia still warrants HLH workup to aggressively pursue the diagnosis and improve outcomes.
The goal of therapy in HLH is prompt inactivation of the dysregulated inflammation with aggressive immunosuppression. In our deteriorating patient, the treatment was started with only 4 of the 8 HLH-2004 diagnostic criteria being met. As per the 2018 Histiocyte Society consensus statement, the decision to start the HLH-94 treatment relies on not only the HLH-2004 diagnostic criteria, but also the patient’s clinical evolution.11 In 1994 the Histiocyte Society also published a treatment protocol termed HLH-94. A Korean retrospective study demonstrated that this protocol led to a 5-year survival rate of 60 to 80% depending on the HLH trigger and response to initial treatment.12 The protocol consists of etoposide at 150 mg/m2, 2 weekly doses in the first 2 weeks and then 1 dose weekly for the next 6 weeks. Dexamethasone is the steroid of choice as it readily crosses the blood-brain barrier. Its dosage consists of 10 mg/m2 for the first 2 weeks and then it is halved every 2 weeks until the eighth week of treatment. A slow taper follows to avoid adrenal insufficiency. Once 8 weeks of treatment have been completed, cyclosporine is added to a goal trough of 200 mcg/dL. If there is central nervous system (CNS) involvement, early aggressive treatment with intrathecal methotrexate is indicated if no improvement is noted during initial therapy.11
In 2004 the Histiocyte Society restructured the HLH-94 treatment protocol with the aim of presenting a more aggressive treatment strategy. The protocol added cyclosporine to the initial induction therapy, rather than later in the ninth week as HLH-94. Neither the use of cyclosporine nor the HLH-2004 have been demonstrated to be superior to the use of etoposide and dexamethasone alone or in the HLH-94 protocol, respectively.13 Cyclosporine is associated with adverse effects (AEs) and may have many contraindications in the acute phase of the disease. Therefore, the HLH-94 protocol is still the recommended regimen.11
To assess adequate clinical response, several clinical and laboratory parameters are followed. Clinically, resolution of fever, improvement in hepatosplenomegaly, lymphadenopathy, and mental status can be useful. Laboratories can be used to assess improvement from organ specific damage such as hepatic involvement or cytopenia. The limitation of these diagnostic studies is that they could falsely suggest an inadequate response to treatment due to concomitant infection or medication AEs. Other markers such as ferritin levels, CD25, and NK cell activity levels are more specific to HLH. Out of them, a decreasing ferritin level has the needed specificity and widespread availability for repeated assessment. On the other hand, both CD25 and NK cell activity are readily available only in specialized centers. An initial high ferritin level is a marker for a poor prognosis, and the rate of decline correlates with mortality. Studies have demonstrated that persistently elevated ferritin levels after treatment initiation are associated with worse outcomes.14,15
Several salvage treatments have been identified in recalcitrant or relapsing disease. In general, chemotherapy needs to be intensified, either by returning to the initial high dosage if recurrence occurs in the weaning phase of treatment or adding other agents if no response was initially achieved. Emapalumab, an interferon γ antibody, was approved by the US Food and Drug Administration for the treatment of intractable HLH after it demonstrated that when added to dexamethasone, it lead to treatment response in 17 out of 27 pediatric patients, with a relatively safe AE profile.16 The goal of intensifying chemotherapy is to have the patient tolerate allogenic stem cell transplant, which is clinically indicated in familial HLH, malignancy induced HLH, and recalcitrant cases. In patients who undergo hematopoietic cell transplantation (HCT) there is a tendency to increase survival to 66% at 5 years.12
Conclusions
HLH is a rare and deadly disease increasingly more present in adults. Our patient who initially presented with a sepsis diagnosis was suspected of having a hematologic etiology for his clinical findings due to markedly elevated ferritin levels. In our patient, the HLH-94 treatment protocol was used, yielding favorable results. Given the lack of specific scientific data backing updated protocols such as HLH-2004 and a comparatively favorable safety profile, current guidelines still recommend using the HLH-94 treatment protocol. Decreasing ferritin levels may be used in conjunction with clinical improvement to demonstrate therapeutic response. Persistence of disease despite standard treatment may warrant novel therapies, such as emapalumab or HCT. Physicians need to be wary of an HLH diagnosis as early identification and treatment may improve its otherwise grim prognosis.
Hemophagocytic lymphohistiocytosis (HLH) is a rare and deadly disease in which unregulated proliferation of histiocytes and T-cell infiltration takes place. It is known as a pediatric disease in which gene defects result in impaired cytotoxic NK- and T-cell function. It has been associated with autosomal recessive inheritance pattern. Without therapy, survival for these patients with active familial HLH is approximately 2 months.
Recognition of the disease has increased over the years, and as a result the diagnosis of HLH in adults also has increased. An acquired form can be triggered by viruses like Epstein-Barr virus, influenza, HIV, lymphoid malignancies, rheumatologic disorders, or immunodeficiency disorders. Survival rates for untreated HLH have been reported at < 5%.1 Despite early recognition and adequate treatment, HLH carries an overall mortality of 50% in the initial presentation, 90% die in the first 8 weeks of treatment due to uncontrolled disease.2
Case Presentation
A 56-year-old man with no active medical issues except for a remote history of non-Hodgkin lymphoma treated with chemotherapy and splenectomy in 1990 presented to the Veterans Affairs Caribbean Healthcare System in San Juan, Puerto Rico. He was admitted to the medicine ward due to community acquired pneumonia. Three days into admission his clinical status deteriorated, and the patient was transferred to the intensive care unit (ICU) due to acute respiratory failure and sepsis secondary to worsening pneumonia. Chest imaging demonstrated rapidly progressing diffuse bilateral infiltrates. Due to the severity of the chest imaging, a diagnostic bronchoscopy was performed.
The patient’s antibiotics regimen was empirically escalated to vancomycin 1500 mg IV every 12 hours and meropenem 2 g IV every 8 hours. Despite optimization of therapy, the patient did not show clinical signs of improvement. Febrile episodes persisted, pulmonary infiltrates and hypoxemia worsened, and the patient required a neuromuscular blockade. Since the bronchoscopy was nondiagnostic and deterioration persistent, the differential diagnosis was broadened. This led to the ordering of inflammatory markers. Laboratory testing showed ferritin levels > 16,000 ng/mL, pointing to HLH as a possible diagnosis. Further workup was remarkable for triglycerides of 1234 mg/dL and a fibrinogen of 0.77 g/L. In the setting of bicytopenia and persistent fever, HLH-94 regimen was started with dexamethasone 40 mg daily and etoposide 100 mg/m2. CD25 levels of 154,701 pg/mL were demonstrated as well as a decreased immunoglobulin (Ig) G levels with absent IgM and IgA. Bone marrow biopsy was consistent with hemophagocytosis. The patient eventually was extubated and sent to the oncology ward to continue chemotherapy.
Discussion
A high clinical suspicion is warranted for rapid diagnosis and treatment as HLH evolves in most cases to multiorgan failure and death. The diagnostic criteria for HLH was developed by the Histiocyte Society in 1991 and then restructured in 2004.3,4 In the first diagnostic tool developed in 1991, diagnosis was based on 5 criteria (fever, splenomegaly, bicytopenia, hypertriglyceridemia and/or hypofibrinogenemia, and hemophagocytosis). Three additional laboratory findings were also described as part of HLH diagnosis since 2004: low or absent NK-cell-activity, hyperferritinemia of > 500 ng/dL, and high-soluble interleukin-2-receptor levels (CD25) > 2400 U/mL. Overall, 5 of 8 criteria are needed for the HLH diagnosis.
Despite the common use of these diagnostic criteria, they were developed for the pediatric population but have not been validated for adult patients.5 For adult patients, the HScore was developed in 2014. It has 9 variables: 3 are based on clinical findings (known underlying immunosuppression, high temperature, and organomegaly; 5 are based on laboratory values (ferritin, serum glutamic oxaloacetic transaminase, cytopenia, triglycerides, and fibrinogen levels); the last variable uses cytologic findings in the bone marrow. In the initial study, probability of having HLH ranged from < 1% with an HScore of ≤ 90% to > 99% with an HScore of ≥ 250 in noncritically ill adults.5 A recently published retrospective study demonstrated the diagnostic reliability of both the HLH-2004 criteria and HScore in critically ill adult patients. This study concluded that the best prediction accuracy of HLH diagnosis for a cutoff of 4 fulfilled HLH-2004 criteria had a 95.0% sensitivity and 93.6% specificity and HScore cutoff of 168 reached a 100% sensitivity and 94.1% specificity.6
The early negative bronchoscopy lowered the possibility of an infection as the etiology of the clinical presentation and narrowed the hyperferritinemia differential diagnosis. Hyperferritinemia has a sensitivity and specificity of > 90% for diagnosis when above 10,000 ng/dL in the pediatric population.7 This is not the case in adults. Hyperferritinemia is a marker of different inflammatory responses, such as histoplasmosis infection, malignancy, or iron overload rather than an isolated diagnostic tool for HLH.8 It has been reported that CD25 levels less than the diagnostic threshold of 2400 U/mL have a 100% sensitivity for the diagnosis and therefore can rule out the diagnosis. When this is taken into consideration, it can be concluded that CD25 level is a better diagnostic tool when compared with ferritin, but its main limitation is its lack of widespread availability.9 Still, there is a limited number of pathologies that are associated with marked hyperferritinemia, specifically using thresholds of more than 6000 ng/dL.10 Taking into consideration the high mortality of untreated HLH, isolated hyperferritinemia still warrants HLH workup to aggressively pursue the diagnosis and improve outcomes.
The goal of therapy in HLH is prompt inactivation of the dysregulated inflammation with aggressive immunosuppression. In our deteriorating patient, the treatment was started with only 4 of the 8 HLH-2004 diagnostic criteria being met. As per the 2018 Histiocyte Society consensus statement, the decision to start the HLH-94 treatment relies on not only the HLH-2004 diagnostic criteria, but also the patient’s clinical evolution.11 In 1994 the Histiocyte Society also published a treatment protocol termed HLH-94. A Korean retrospective study demonstrated that this protocol led to a 5-year survival rate of 60 to 80% depending on the HLH trigger and response to initial treatment.12 The protocol consists of etoposide at 150 mg/m2, 2 weekly doses in the first 2 weeks and then 1 dose weekly for the next 6 weeks. Dexamethasone is the steroid of choice as it readily crosses the blood-brain barrier. Its dosage consists of 10 mg/m2 for the first 2 weeks and then it is halved every 2 weeks until the eighth week of treatment. A slow taper follows to avoid adrenal insufficiency. Once 8 weeks of treatment have been completed, cyclosporine is added to a goal trough of 200 mcg/dL. If there is central nervous system (CNS) involvement, early aggressive treatment with intrathecal methotrexate is indicated if no improvement is noted during initial therapy.11
In 2004 the Histiocyte Society restructured the HLH-94 treatment protocol with the aim of presenting a more aggressive treatment strategy. The protocol added cyclosporine to the initial induction therapy, rather than later in the ninth week as HLH-94. Neither the use of cyclosporine nor the HLH-2004 have been demonstrated to be superior to the use of etoposide and dexamethasone alone or in the HLH-94 protocol, respectively.13 Cyclosporine is associated with adverse effects (AEs) and may have many contraindications in the acute phase of the disease. Therefore, the HLH-94 protocol is still the recommended regimen.11
To assess adequate clinical response, several clinical and laboratory parameters are followed. Clinically, resolution of fever, improvement in hepatosplenomegaly, lymphadenopathy, and mental status can be useful. Laboratories can be used to assess improvement from organ specific damage such as hepatic involvement or cytopenia. The limitation of these diagnostic studies is that they could falsely suggest an inadequate response to treatment due to concomitant infection or medication AEs. Other markers such as ferritin levels, CD25, and NK cell activity levels are more specific to HLH. Out of them, a decreasing ferritin level has the needed specificity and widespread availability for repeated assessment. On the other hand, both CD25 and NK cell activity are readily available only in specialized centers. An initial high ferritin level is a marker for a poor prognosis, and the rate of decline correlates with mortality. Studies have demonstrated that persistently elevated ferritin levels after treatment initiation are associated with worse outcomes.14,15
Several salvage treatments have been identified in recalcitrant or relapsing disease. In general, chemotherapy needs to be intensified, either by returning to the initial high dosage if recurrence occurs in the weaning phase of treatment or adding other agents if no response was initially achieved. Emapalumab, an interferon γ antibody, was approved by the US Food and Drug Administration for the treatment of intractable HLH after it demonstrated that when added to dexamethasone, it lead to treatment response in 17 out of 27 pediatric patients, with a relatively safe AE profile.16 The goal of intensifying chemotherapy is to have the patient tolerate allogenic stem cell transplant, which is clinically indicated in familial HLH, malignancy induced HLH, and recalcitrant cases. In patients who undergo hematopoietic cell transplantation (HCT) there is a tendency to increase survival to 66% at 5 years.12
Conclusions
HLH is a rare and deadly disease increasingly more present in adults. Our patient who initially presented with a sepsis diagnosis was suspected of having a hematologic etiology for his clinical findings due to markedly elevated ferritin levels. In our patient, the HLH-94 treatment protocol was used, yielding favorable results. Given the lack of specific scientific data backing updated protocols such as HLH-2004 and a comparatively favorable safety profile, current guidelines still recommend using the HLH-94 treatment protocol. Decreasing ferritin levels may be used in conjunction with clinical improvement to demonstrate therapeutic response. Persistence of disease despite standard treatment may warrant novel therapies, such as emapalumab or HCT. Physicians need to be wary of an HLH diagnosis as early identification and treatment may improve its otherwise grim prognosis.
1. Chen TY, Hsu MH, Kuo HC, Sheen JM, Cheng MC, Lin YJ. Outcome analysis of pediatric hemophagocytic lymphohistiocytosis. J Formos Med Assoc. 2021;120(1, pt 1):172-179. doi:10.1016/j.jfma.2020.03.025
2. Henter JI, Samuelsson-Horne A, Aricò M, et al. Treatment of hemophagocytic lymphohistiocytosis with HLH-94 immunochemotherapy and bone marrow transplantation. Blood. 2002;100(7):2367-2373. doi:10.1182/blood-2002-01-0172
3. Henter JI, Elinder G, Ost A. Diagnostic guidelines for hemophagocytic lymphohistiocytosis. The FHL Study Group of the Histiocyte Society. Semin Oncol. 1991;18(1):29-33.
4. Henter JI, Horne A, Aricó M, et al. HLH-2004: Diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer. 2007;48(2):124-131. doi:10.1002/pbc.21039
5. Knaak C, Nyvlt P, Schuster FS, et al. Hemophagocytic lymphohistiocytosis in critically ill patients: diagnostic reliability of HLH-2004 criteria and HScore. Crit Care. 2020;24(1):244. Published 2020 May 24. doi:10.1186/s13054-020-02941-3
6. Fardet L, Galicier L, Lambotte O, et al. Development and validation of the HScore, a score for the diagnosis of reactive hemophagocytic syndrome. Arthritis Rheumatol. 2014;66(9):2613-2620. doi:10.1002/art.38690
7. La Rosée P, Horne A, Hines M, et al. Recommendations for the management of hemophagocytic lymphohistiocytosis in adults. Blood. 2019;133(23):2465-2477. doi:10.1182/blood.2018894618
8. Schaffner M, Rosenstein L, Ballas Z, Suneja M. Significance of Hyperferritinemia in Hospitalized Adults. Am J Med Sci. 2017;354(2):152-158. doi:10.1016/j.amjms.2017.04.016
9. Hayden A, Lin M, Park S, et al. Soluble interleukin-2 receptor is a sensitive diagnostic test in adult HLH. Blood Adv. 2017;1(26):2529-2534. Published 2017 Dec 6. doi:10.1182/bloodadvances.2017012310
10. Belfeki N, Strazzulla A, Picque M, Diamantis S. Extreme hyperferritinemia: etiological spectrum and impact on prognosis. Reumatismo. 2020;71(4):199-202. Published 2020 Jan 28. doi:10.4081/reumatismo.2019.1221
11. Ehl S, Astigarraga I, von Bahr Greenwood T, et al. Recommendations for the use of etoposide-based therapy and bone marrow transplantation for the treatment of HLH: consensus statements by the HLH Steering Committee of the Histiocyte Society. J Allergy Clin Immunol Pract. 2018;6(5):1508-1517. doi:10.1016/j.jaip.2018.05.031
12. Yoon JH, Park SS, Jeon YW, et al. Treatment outcomes and prognostic factors in adult patients with secondary hemophagocytic lymphohistiocytosis not associated with malignancy. Haematologica. 2019;104(2):269-276. doi:10.3324/haematol.2018.198655
13. Bergsten E, Horne A, Aricó M, et al. Confirmed efficacy of etoposide and dexamethasone in HLH treatment: long-term results of the cooperative HLH-2004 study. Blood. 2017;130(25):2728-2738. doi:10.1182/blood-2017-06-788349
14. Lin TF, Ferlic-Stark LL, Allen CE, Kozinetz CA, McClain KL. Rate of decline of ferritin in patients with hemophagocytic lymphohistiocytosis as a prognostic variable for mortality. Pediatr Blood Cancer. 2011;56(1):154-155. doi:10.1002/pbc.22774
15. Zhou J, Zhou J, Shen DT, Goyal H, Wu ZQ, Xu HG. Development and validation of the prognostic value of ferritin in adult patients with Hemophagocytic Lymphohistiocytosis. Orphanet J Rare Dis. 2020;15(1):71. Published 2020 Mar 12. doi:10.1186/s13023-020-1336-616. Locatelli F, Jordan MB, Allen CE, et al. Safety and efficacy of emapalumab in pediatric patients with primary hemophagocytic lymphohistiocytosis. Presented at: American Society of Hematology Annual Meeting, November 29, 2018. Blood. 2018;132(suppl 1):LBA-6. doi:10.1182/blood-2018-120810
1. Chen TY, Hsu MH, Kuo HC, Sheen JM, Cheng MC, Lin YJ. Outcome analysis of pediatric hemophagocytic lymphohistiocytosis. J Formos Med Assoc. 2021;120(1, pt 1):172-179. doi:10.1016/j.jfma.2020.03.025
2. Henter JI, Samuelsson-Horne A, Aricò M, et al. Treatment of hemophagocytic lymphohistiocytosis with HLH-94 immunochemotherapy and bone marrow transplantation. Blood. 2002;100(7):2367-2373. doi:10.1182/blood-2002-01-0172
3. Henter JI, Elinder G, Ost A. Diagnostic guidelines for hemophagocytic lymphohistiocytosis. The FHL Study Group of the Histiocyte Society. Semin Oncol. 1991;18(1):29-33.
4. Henter JI, Horne A, Aricó M, et al. HLH-2004: Diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer. 2007;48(2):124-131. doi:10.1002/pbc.21039
5. Knaak C, Nyvlt P, Schuster FS, et al. Hemophagocytic lymphohistiocytosis in critically ill patients: diagnostic reliability of HLH-2004 criteria and HScore. Crit Care. 2020;24(1):244. Published 2020 May 24. doi:10.1186/s13054-020-02941-3
6. Fardet L, Galicier L, Lambotte O, et al. Development and validation of the HScore, a score for the diagnosis of reactive hemophagocytic syndrome. Arthritis Rheumatol. 2014;66(9):2613-2620. doi:10.1002/art.38690
7. La Rosée P, Horne A, Hines M, et al. Recommendations for the management of hemophagocytic lymphohistiocytosis in adults. Blood. 2019;133(23):2465-2477. doi:10.1182/blood.2018894618
8. Schaffner M, Rosenstein L, Ballas Z, Suneja M. Significance of Hyperferritinemia in Hospitalized Adults. Am J Med Sci. 2017;354(2):152-158. doi:10.1016/j.amjms.2017.04.016
9. Hayden A, Lin M, Park S, et al. Soluble interleukin-2 receptor is a sensitive diagnostic test in adult HLH. Blood Adv. 2017;1(26):2529-2534. Published 2017 Dec 6. doi:10.1182/bloodadvances.2017012310
10. Belfeki N, Strazzulla A, Picque M, Diamantis S. Extreme hyperferritinemia: etiological spectrum and impact on prognosis. Reumatismo. 2020;71(4):199-202. Published 2020 Jan 28. doi:10.4081/reumatismo.2019.1221
11. Ehl S, Astigarraga I, von Bahr Greenwood T, et al. Recommendations for the use of etoposide-based therapy and bone marrow transplantation for the treatment of HLH: consensus statements by the HLH Steering Committee of the Histiocyte Society. J Allergy Clin Immunol Pract. 2018;6(5):1508-1517. doi:10.1016/j.jaip.2018.05.031
12. Yoon JH, Park SS, Jeon YW, et al. Treatment outcomes and prognostic factors in adult patients with secondary hemophagocytic lymphohistiocytosis not associated with malignancy. Haematologica. 2019;104(2):269-276. doi:10.3324/haematol.2018.198655
13. Bergsten E, Horne A, Aricó M, et al. Confirmed efficacy of etoposide and dexamethasone in HLH treatment: long-term results of the cooperative HLH-2004 study. Blood. 2017;130(25):2728-2738. doi:10.1182/blood-2017-06-788349
14. Lin TF, Ferlic-Stark LL, Allen CE, Kozinetz CA, McClain KL. Rate of decline of ferritin in patients with hemophagocytic lymphohistiocytosis as a prognostic variable for mortality. Pediatr Blood Cancer. 2011;56(1):154-155. doi:10.1002/pbc.22774
15. Zhou J, Zhou J, Shen DT, Goyal H, Wu ZQ, Xu HG. Development and validation of the prognostic value of ferritin in adult patients with Hemophagocytic Lymphohistiocytosis. Orphanet J Rare Dis. 2020;15(1):71. Published 2020 Mar 12. doi:10.1186/s13023-020-1336-616. Locatelli F, Jordan MB, Allen CE, et al. Safety and efficacy of emapalumab in pediatric patients with primary hemophagocytic lymphohistiocytosis. Presented at: American Society of Hematology Annual Meeting, November 29, 2018. Blood. 2018;132(suppl 1):LBA-6. doi:10.1182/blood-2018-120810
A Rapidly Progressive Thoracic Tumor
Introduction
SMARCA4-deficient thoracic sarcomas are a rare entity, first described in 2015 in a study of 19 patients with a median age of 41 years who presented with large compressive masses with frequent infiltration into surrounding tissues [1]. This malignancy is more frequent in younger males (median 41-59 years) with an extensive smoking history and has an aggressive course with a median overall survival of 4-7 months [1-3]. There is currently no established treatment, but case reports show promise for immunotherapy and immuno- chemotherapy [4-8].
Case Report
We present the case of a 62 year old male with a 44 pack year smoking history who first presented to the emergency department (ED) with left shoulder pain in December 2020. He was initially treated with muscle relaxers but returned to the ED ten days later with hemoptysis and rapid weight loss. X-ray showed a 14.2 X 11.7 cm mass with rightward deviation of the trachea. PET scan showed extensive central necrosis with a surrounding pleural effusion and local pleural and nodal metastasis but no distant disease. He underwent thoracentesis which was negative for malignant cells. He underwent CT-guided biopsy in 1/2021, which showed predominantly discohesive small blue cells with pleomorphic cell contour and slightly plasmacytoid features. Extensive pathology review led to a diagnosis of SMARCA4 deficient thoracic sarcoma. On presentation to oncology clinic in 2/2021 his functional status had markedly deteriorated. He was started on ipilimumab/ nivolumab (ipi/nivo) and 1 week after his first cycle was admitted for severe left arm swelling and pain. Imaging showed significant progression of disease and new adrenal metastasis. He received cycle two of ipi/ nivo and was able to be discharged home on oxygen. By his follow-up appointment for cycle three of ipi/nivo in 3/2021, the patient was wheelchair bound with severe dyspnea. X-ray showed the mass now occupied the majority of the left hemi-thorax with worsening tracheal deviation. After discussion, the patient went home on hospice and died 8 days later. As demonstrated by this case, SMARCA4-deficient sarcoma requires high clinical suspicion with prompt diagnosis and treatment given its remarkably rapid progression and poor outcomes.
Introduction
SMARCA4-deficient thoracic sarcomas are a rare entity, first described in 2015 in a study of 19 patients with a median age of 41 years who presented with large compressive masses with frequent infiltration into surrounding tissues [1]. This malignancy is more frequent in younger males (median 41-59 years) with an extensive smoking history and has an aggressive course with a median overall survival of 4-7 months [1-3]. There is currently no established treatment, but case reports show promise for immunotherapy and immuno- chemotherapy [4-8].
Case Report
We present the case of a 62 year old male with a 44 pack year smoking history who first presented to the emergency department (ED) with left shoulder pain in December 2020. He was initially treated with muscle relaxers but returned to the ED ten days later with hemoptysis and rapid weight loss. X-ray showed a 14.2 X 11.7 cm mass with rightward deviation of the trachea. PET scan showed extensive central necrosis with a surrounding pleural effusion and local pleural and nodal metastasis but no distant disease. He underwent thoracentesis which was negative for malignant cells. He underwent CT-guided biopsy in 1/2021, which showed predominantly discohesive small blue cells with pleomorphic cell contour and slightly plasmacytoid features. Extensive pathology review led to a diagnosis of SMARCA4 deficient thoracic sarcoma. On presentation to oncology clinic in 2/2021 his functional status had markedly deteriorated. He was started on ipilimumab/ nivolumab (ipi/nivo) and 1 week after his first cycle was admitted for severe left arm swelling and pain. Imaging showed significant progression of disease and new adrenal metastasis. He received cycle two of ipi/ nivo and was able to be discharged home on oxygen. By his follow-up appointment for cycle three of ipi/nivo in 3/2021, the patient was wheelchair bound with severe dyspnea. X-ray showed the mass now occupied the majority of the left hemi-thorax with worsening tracheal deviation. After discussion, the patient went home on hospice and died 8 days later. As demonstrated by this case, SMARCA4-deficient sarcoma requires high clinical suspicion with prompt diagnosis and treatment given its remarkably rapid progression and poor outcomes.
Introduction
SMARCA4-deficient thoracic sarcomas are a rare entity, first described in 2015 in a study of 19 patients with a median age of 41 years who presented with large compressive masses with frequent infiltration into surrounding tissues [1]. This malignancy is more frequent in younger males (median 41-59 years) with an extensive smoking history and has an aggressive course with a median overall survival of 4-7 months [1-3]. There is currently no established treatment, but case reports show promise for immunotherapy and immuno- chemotherapy [4-8].
Case Report
We present the case of a 62 year old male with a 44 pack year smoking history who first presented to the emergency department (ED) with left shoulder pain in December 2020. He was initially treated with muscle relaxers but returned to the ED ten days later with hemoptysis and rapid weight loss. X-ray showed a 14.2 X 11.7 cm mass with rightward deviation of the trachea. PET scan showed extensive central necrosis with a surrounding pleural effusion and local pleural and nodal metastasis but no distant disease. He underwent thoracentesis which was negative for malignant cells. He underwent CT-guided biopsy in 1/2021, which showed predominantly discohesive small blue cells with pleomorphic cell contour and slightly plasmacytoid features. Extensive pathology review led to a diagnosis of SMARCA4 deficient thoracic sarcoma. On presentation to oncology clinic in 2/2021 his functional status had markedly deteriorated. He was started on ipilimumab/ nivolumab (ipi/nivo) and 1 week after his first cycle was admitted for severe left arm swelling and pain. Imaging showed significant progression of disease and new adrenal metastasis. He received cycle two of ipi/ nivo and was able to be discharged home on oxygen. By his follow-up appointment for cycle three of ipi/nivo in 3/2021, the patient was wheelchair bound with severe dyspnea. X-ray showed the mass now occupied the majority of the left hemi-thorax with worsening tracheal deviation. After discussion, the patient went home on hospice and died 8 days later. As demonstrated by this case, SMARCA4-deficient sarcoma requires high clinical suspicion with prompt diagnosis and treatment given its remarkably rapid progression and poor outcomes.
Old saying about prostate cancer not true when it’s metastatic
.
The findings fill an information gap because, remarkably, “data are lacking” on causes of death among men whose prostate cancer has spread to other sites, say lead author Ahmed Elmehrath, MD, of Cairo University, Egypt, and colleagues.
“It was an important realization by our team that prostate cancer was the cause of death in 78% of patients,” said senior author Omar Alhalabi, MD, of University of Texas MD Anderson Cancer Center, Houston, in an email.
“Most patients with metastatic prostate cancer die from it, rather than other possible causes of death,” confirm Samuel Merriel, MSc, Tanimola Martins, PhD, and Sarah Bailey, PhD, University of Exeter, United Kingdom, in an accompanying editorial. The study was published last month in JAMA Network Open.
The findings represent the near opposite of a commonly held – and comforting – belief about early-stage disease: “You die with prostate cancer, not from it.”
That old saying is articulated in various ways, such as this from the Prostate Cancer Foundation: “We can confirm that there are those prostate cancers a man may die with and not of, while others are very aggressive.” The American Cancer Society says this: “Prostate cancer can be a serious disease, but most men diagnosed with prostate cancer do not die from it.”
However, these commonplace comments do not cover metastatic disease, which is what the authors of the new study decided to focus on.
The team used data from the Surveillance, Epidemiology, and End Results Program (SEER) database to gather a sample of 26,168 U.S. men who received a diagnosis of metastatic prostate cancer from January 2000 to December 2016. They then analyzed the data in 2020 and found that 16,732 men (64%) had died during the follow-up period.
The majority of these deaths (77.8%) were from prostate cancer, 5.5% were from other cancers, and 16.7% were from noncancer causes, including cardiovascular diseases, chronic obstructive pulmonary disease, and cerebrovascular diseases.
Senior author Dr. Alhalabi acknowledged a limitation in these findings – that the SEER database relies on causes of death extracted from death certificates. “Death certificates have limited granularity in terms of the details they can contain about the cause of death and also have reporting bias,” he said.
Most of the prostate cancer deaths (59%) occurred within 2 years. The 5-year overall survival rate in the study group was 26%.
The deadliness of metastatic disease “reinforces the need for innovations to promote early-stage diagnosis,” comment the editorialists. Striking a hopeful note, they also say that “new tests for prostate cancer detection may reduce the proportion of patients who receive a diagnosis at a late stage.”
Death from other causes
The mean age at metastatic prostate cancer diagnosis in the study was roughly 71 years. Most of the cohort was White (74.5%) and had a diagnosis of stage M1b metastatic prostate cancer (72.7%), which means the cancer had spread to the bones.
Among men in the cohort, the rates of death from septicemia, suicide, accidents, COPD, and cerebrovascular diseases were significantly increased compared with the general U.S. male population, the team observes.
Thus, the study authors were concerned with not only with death from metastatic prostate cancer but death from other causes.
That concern is rooted in the established fact that there is now improved survival among patients with prostate cancer in the U.S., including among men with advanced disease. “Patients tend to live long enough after a prostate cancer diagnosis for non–cancer-related comorbidities to be associated with their overall survival,” they write.
The editorialists agree: Prostate cancer “has a high long-term survival rate compared with almost all other cancer types and signals the need for greater holistic care for patients.”
As noted above, cardiovascular diseases were the most common cause of nonprostate cancer–related deaths in the new study.
As in the management of other cancers, there is concern among clinicians and researchers about the cardiotoxic effects of prostate cancer treatments.
The study authors point to a 2017 analysis that showed that men with prostate cancer and no prior cardiac disease had greater risk of heart failure after taking androgen deprivation therapy (ADT), a common treatment used when the disease recurs after definitive treatment. Another study suggested an association between cardiotoxic effects of ADT and myocardial infarction regardless of medical history in general.
The authors of the current study say that such findings highlight “the importance of multidisciplinary care for such patients and the role of primary care physicians in optimizing cardiovascular risk prevention and providing early referrals to cardiologists.”
Further, the team says that tailoring “ADT to each patient’s needs may be associated with improved survival, especially for patients with factors associated with cardiovascular disease.”
Who should lead the way in multidisciplinary care? “The answer probably is case-by-case,” said Dr. Alhalabi, adding that it might depend on the presence of underlying morbidities such as cardiovascular disease and COPD.
“It is also important for the oncologist (‘the gatekeeper’) to try to mitigate the potential metabolic effects of hormonal deprivation therapy such as weight gain, decreased muscle mass, hyperlipidemia, etc.,” he added.
The study had no specific funding. The study authors and editorialists have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
.
The findings fill an information gap because, remarkably, “data are lacking” on causes of death among men whose prostate cancer has spread to other sites, say lead author Ahmed Elmehrath, MD, of Cairo University, Egypt, and colleagues.
“It was an important realization by our team that prostate cancer was the cause of death in 78% of patients,” said senior author Omar Alhalabi, MD, of University of Texas MD Anderson Cancer Center, Houston, in an email.
“Most patients with metastatic prostate cancer die from it, rather than other possible causes of death,” confirm Samuel Merriel, MSc, Tanimola Martins, PhD, and Sarah Bailey, PhD, University of Exeter, United Kingdom, in an accompanying editorial. The study was published last month in JAMA Network Open.
The findings represent the near opposite of a commonly held – and comforting – belief about early-stage disease: “You die with prostate cancer, not from it.”
That old saying is articulated in various ways, such as this from the Prostate Cancer Foundation: “We can confirm that there are those prostate cancers a man may die with and not of, while others are very aggressive.” The American Cancer Society says this: “Prostate cancer can be a serious disease, but most men diagnosed with prostate cancer do not die from it.”
However, these commonplace comments do not cover metastatic disease, which is what the authors of the new study decided to focus on.
The team used data from the Surveillance, Epidemiology, and End Results Program (SEER) database to gather a sample of 26,168 U.S. men who received a diagnosis of metastatic prostate cancer from January 2000 to December 2016. They then analyzed the data in 2020 and found that 16,732 men (64%) had died during the follow-up period.
The majority of these deaths (77.8%) were from prostate cancer, 5.5% were from other cancers, and 16.7% were from noncancer causes, including cardiovascular diseases, chronic obstructive pulmonary disease, and cerebrovascular diseases.
Senior author Dr. Alhalabi acknowledged a limitation in these findings – that the SEER database relies on causes of death extracted from death certificates. “Death certificates have limited granularity in terms of the details they can contain about the cause of death and also have reporting bias,” he said.
Most of the prostate cancer deaths (59%) occurred within 2 years. The 5-year overall survival rate in the study group was 26%.
The deadliness of metastatic disease “reinforces the need for innovations to promote early-stage diagnosis,” comment the editorialists. Striking a hopeful note, they also say that “new tests for prostate cancer detection may reduce the proportion of patients who receive a diagnosis at a late stage.”
Death from other causes
The mean age at metastatic prostate cancer diagnosis in the study was roughly 71 years. Most of the cohort was White (74.5%) and had a diagnosis of stage M1b metastatic prostate cancer (72.7%), which means the cancer had spread to the bones.
Among men in the cohort, the rates of death from septicemia, suicide, accidents, COPD, and cerebrovascular diseases were significantly increased compared with the general U.S. male population, the team observes.
Thus, the study authors were concerned with not only with death from metastatic prostate cancer but death from other causes.
That concern is rooted in the established fact that there is now improved survival among patients with prostate cancer in the U.S., including among men with advanced disease. “Patients tend to live long enough after a prostate cancer diagnosis for non–cancer-related comorbidities to be associated with their overall survival,” they write.
The editorialists agree: Prostate cancer “has a high long-term survival rate compared with almost all other cancer types and signals the need for greater holistic care for patients.”
As noted above, cardiovascular diseases were the most common cause of nonprostate cancer–related deaths in the new study.
As in the management of other cancers, there is concern among clinicians and researchers about the cardiotoxic effects of prostate cancer treatments.
The study authors point to a 2017 analysis that showed that men with prostate cancer and no prior cardiac disease had greater risk of heart failure after taking androgen deprivation therapy (ADT), a common treatment used when the disease recurs after definitive treatment. Another study suggested an association between cardiotoxic effects of ADT and myocardial infarction regardless of medical history in general.
The authors of the current study say that such findings highlight “the importance of multidisciplinary care for such patients and the role of primary care physicians in optimizing cardiovascular risk prevention and providing early referrals to cardiologists.”
Further, the team says that tailoring “ADT to each patient’s needs may be associated with improved survival, especially for patients with factors associated with cardiovascular disease.”
Who should lead the way in multidisciplinary care? “The answer probably is case-by-case,” said Dr. Alhalabi, adding that it might depend on the presence of underlying morbidities such as cardiovascular disease and COPD.
“It is also important for the oncologist (‘the gatekeeper’) to try to mitigate the potential metabolic effects of hormonal deprivation therapy such as weight gain, decreased muscle mass, hyperlipidemia, etc.,” he added.
The study had no specific funding. The study authors and editorialists have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
.
The findings fill an information gap because, remarkably, “data are lacking” on causes of death among men whose prostate cancer has spread to other sites, say lead author Ahmed Elmehrath, MD, of Cairo University, Egypt, and colleagues.
“It was an important realization by our team that prostate cancer was the cause of death in 78% of patients,” said senior author Omar Alhalabi, MD, of University of Texas MD Anderson Cancer Center, Houston, in an email.
“Most patients with metastatic prostate cancer die from it, rather than other possible causes of death,” confirm Samuel Merriel, MSc, Tanimola Martins, PhD, and Sarah Bailey, PhD, University of Exeter, United Kingdom, in an accompanying editorial. The study was published last month in JAMA Network Open.
The findings represent the near opposite of a commonly held – and comforting – belief about early-stage disease: “You die with prostate cancer, not from it.”
That old saying is articulated in various ways, such as this from the Prostate Cancer Foundation: “We can confirm that there are those prostate cancers a man may die with and not of, while others are very aggressive.” The American Cancer Society says this: “Prostate cancer can be a serious disease, but most men diagnosed with prostate cancer do not die from it.”
However, these commonplace comments do not cover metastatic disease, which is what the authors of the new study decided to focus on.
The team used data from the Surveillance, Epidemiology, and End Results Program (SEER) database to gather a sample of 26,168 U.S. men who received a diagnosis of metastatic prostate cancer from January 2000 to December 2016. They then analyzed the data in 2020 and found that 16,732 men (64%) had died during the follow-up period.
The majority of these deaths (77.8%) were from prostate cancer, 5.5% were from other cancers, and 16.7% were from noncancer causes, including cardiovascular diseases, chronic obstructive pulmonary disease, and cerebrovascular diseases.
Senior author Dr. Alhalabi acknowledged a limitation in these findings – that the SEER database relies on causes of death extracted from death certificates. “Death certificates have limited granularity in terms of the details they can contain about the cause of death and also have reporting bias,” he said.
Most of the prostate cancer deaths (59%) occurred within 2 years. The 5-year overall survival rate in the study group was 26%.
The deadliness of metastatic disease “reinforces the need for innovations to promote early-stage diagnosis,” comment the editorialists. Striking a hopeful note, they also say that “new tests for prostate cancer detection may reduce the proportion of patients who receive a diagnosis at a late stage.”
Death from other causes
The mean age at metastatic prostate cancer diagnosis in the study was roughly 71 years. Most of the cohort was White (74.5%) and had a diagnosis of stage M1b metastatic prostate cancer (72.7%), which means the cancer had spread to the bones.
Among men in the cohort, the rates of death from septicemia, suicide, accidents, COPD, and cerebrovascular diseases were significantly increased compared with the general U.S. male population, the team observes.
Thus, the study authors were concerned with not only with death from metastatic prostate cancer but death from other causes.
That concern is rooted in the established fact that there is now improved survival among patients with prostate cancer in the U.S., including among men with advanced disease. “Patients tend to live long enough after a prostate cancer diagnosis for non–cancer-related comorbidities to be associated with their overall survival,” they write.
The editorialists agree: Prostate cancer “has a high long-term survival rate compared with almost all other cancer types and signals the need for greater holistic care for patients.”
As noted above, cardiovascular diseases were the most common cause of nonprostate cancer–related deaths in the new study.
As in the management of other cancers, there is concern among clinicians and researchers about the cardiotoxic effects of prostate cancer treatments.
The study authors point to a 2017 analysis that showed that men with prostate cancer and no prior cardiac disease had greater risk of heart failure after taking androgen deprivation therapy (ADT), a common treatment used when the disease recurs after definitive treatment. Another study suggested an association between cardiotoxic effects of ADT and myocardial infarction regardless of medical history in general.
The authors of the current study say that such findings highlight “the importance of multidisciplinary care for such patients and the role of primary care physicians in optimizing cardiovascular risk prevention and providing early referrals to cardiologists.”
Further, the team says that tailoring “ADT to each patient’s needs may be associated with improved survival, especially for patients with factors associated with cardiovascular disease.”
Who should lead the way in multidisciplinary care? “The answer probably is case-by-case,” said Dr. Alhalabi, adding that it might depend on the presence of underlying morbidities such as cardiovascular disease and COPD.
“It is also important for the oncologist (‘the gatekeeper’) to try to mitigate the potential metabolic effects of hormonal deprivation therapy such as weight gain, decreased muscle mass, hyperlipidemia, etc.,” he added.
The study had no specific funding. The study authors and editorialists have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
‘Dawn of a new era’ in the treatment of renal cell carcinoma
according to expert opinion.
The high hopes have been generated by results from the randomized, phase 3 KEYNOTE-564 trial, showing that monotherapy with pembrolizumab (Keytruda, Merck) was associated with significantly longer disease-free survival (DFS) after nephrectomy than placebo (77.3% vs. 68.1%, respectively). Median follow-up was 24 months.
The results come from the trial’s first interim analysis of data from 994 patients with clear-cell renal cell carcinoma (RCC) at high risk of recurrence.
For the pembrolizumab group, the estimated percentage alive at 24 months was 96.6%, compared with 93.5% in the placebo group (hazard ratio for death, 0.54), said Toni Choueiri, MD, of the Dana-Farber Cancer Institute, Boston, and colleagues.
However, grade 3 or higher adverse events (any cause) occurred at almost twice the rate in the pembrolizumab versus the placebo group (32.4% vs. 17.7%). The new study was published online Aug. 18, 2021, in the New England Journal of Medicine.
The study results were first presented at the 2021 American Society of Clinical Oncology annual meeting and described as likely to be practice changing in this setting, as reported by this news organization.
Currently, this patient population has “no options for adjuvant therapy to reduce the risk of recurrence that have high levels of supporting evidence,” observed the authors.
That’s about to change, as the trial results “herald the dawn of a new era in the treatment of renal cell carcinoma,” Rana McKay, MD, University of California San Diego Health, wrote in an accompanying editorial.
Multiple studies have investigated potential adjuvant therapies in RCC since the 1980s, she observed.
“For the first time, we now have an effective adjuvant immunotherapy option for patients with resected renal cell carcinoma at high risk of recurrence,” Dr. McKay said in an interview.
To date, the lack of clinically beneficial adjuvant therapy options in RCC has been “humbling,” Dr. Choueiri said in an interview. “We hope we can push the envelope further and get more patients with RCC some good options that make them live longer and better.”
Although the standard of care for patients diagnosed with locoregional RCC is partial or total nephrectomy, nearly half of patients eventually experience disease recurrence following surgery, Dr. Choueiri noted.
“No standard, globally approved adjuvant therapy options are currently available for this population,” he said. Clinical guidelines recommend patients at high risk of disease recurrence after surgery be entered into a clinical trial or undergo active surveillance.
Researchers will continue to follow the results for overall survival, a secondary endpoint. “The very early look suggests encouraging results [in overall survival] with an HR of 0.54,” Dr. Choueiri noted.
In the meantime, the prolongation of DFS represents a clear clinical benefit, said Dr. McKay, “given the magnitude of the increase” and “the limited incidence of toxic effects.”
KEYNOTE-564 will alter the adjuvant treatment landscape for RCC as a positive phase 3 trial of adjuvant immunotherapy for the disease, she added.
A number of earlier studies have investigated the use of adjuvant vascular endothelial growth factor–targeting agents in RCC. Only the 2016 Sunitinib Treatment of Renal Adjuvant Cancer (S-TRAC) trial showed improved DFS with sunitinib, compared with placebo (6.8 vs. 5.6 years). Subsequently, sunitinib was approved for adjuvant use in the United States. However, the S-TRAC trial also showed that sunitinib therapy was associated with an increased incidence of toxic effects and lower quality of life scores, and researchers did not observe any benefit in overall survival.
“Despite regulatory approval in the U.S., sunitinib is not approved for adjuvant use by the European Medicines Agency and has limited utilization in clinical practice given the low benefit-risk ratio,” Dr. McKay pointed out.
Study details
KEYNOTE-564 involved 996 patients with clear-cell RCC at high risk for recurrence after nephrectomy, with or without metastasectomy. They were randomly assigned in a 1:1 ratio to receive a 200-mg dose of adjuvant pembrolizumab or placebo given intravenously once every 3 weeks for up to 17 cycles for approximately 1 year.
The vast majority of patients enrolled in the study had localized disease with no evidence of metastases (M0) and intermediate to high or high risk of disease recurrence after partial or complete nephrectomy. However, 5.8% of patients in both the pembrolizumab and placebo groups had M1 NED (metastatic stage 1, no evidence of disease) status after nephrectomy and resection of metastatic lesions. These patients were also at intermediate to high or high risk of recurrence.
The benefit of pembrolizumab, compared with placebo, was maintained in this subgroup, said the investigators. “At this point, we continue to look at the data, but we know that there was a benefit for DFS in the population we included,” said Dr. Choueiri. “When we looked at several subgroups such as PD-L1 status, geography, gender, performance status, M0/M1, all HRs were less than 1 suggesting benefit from pembrolizumab over placebo.”
“Subset analyses by stage are going to be important to determine which group of patients will derive the most benefit,” asserted Dr. McKay. “While those with M1 NED appear to derive benefit with HR for DFS of 0.29, those with M1 NED comprise a small percentage of patient enrolled in the trial.”
Studies exploring tissue- and blood-based biomarkers, including circulating tumor DNA, will be key to identify patients at highest risk for recurrence or adjuvant treatment, Dr. McKay emphasized. “The adoption of adjuvant immune checkpoint inhibitors brings along new questions regarding patient selection, therapeutic use in patients with non–clear-cell renal cell carcinoma, and systemic treatment after recurrence during or after the receipt of adjuvant therapy.”
KEYNOTE-564 was funded by Merck. Multiple study authors including Dr. Choueiri have financial ties to the pharmaceutical industry, including Merck.
A version of this article first appeared on Medscape.com.
according to expert opinion.
The high hopes have been generated by results from the randomized, phase 3 KEYNOTE-564 trial, showing that monotherapy with pembrolizumab (Keytruda, Merck) was associated with significantly longer disease-free survival (DFS) after nephrectomy than placebo (77.3% vs. 68.1%, respectively). Median follow-up was 24 months.
The results come from the trial’s first interim analysis of data from 994 patients with clear-cell renal cell carcinoma (RCC) at high risk of recurrence.
For the pembrolizumab group, the estimated percentage alive at 24 months was 96.6%, compared with 93.5% in the placebo group (hazard ratio for death, 0.54), said Toni Choueiri, MD, of the Dana-Farber Cancer Institute, Boston, and colleagues.
However, grade 3 or higher adverse events (any cause) occurred at almost twice the rate in the pembrolizumab versus the placebo group (32.4% vs. 17.7%). The new study was published online Aug. 18, 2021, in the New England Journal of Medicine.
The study results were first presented at the 2021 American Society of Clinical Oncology annual meeting and described as likely to be practice changing in this setting, as reported by this news organization.
Currently, this patient population has “no options for adjuvant therapy to reduce the risk of recurrence that have high levels of supporting evidence,” observed the authors.
That’s about to change, as the trial results “herald the dawn of a new era in the treatment of renal cell carcinoma,” Rana McKay, MD, University of California San Diego Health, wrote in an accompanying editorial.
Multiple studies have investigated potential adjuvant therapies in RCC since the 1980s, she observed.
“For the first time, we now have an effective adjuvant immunotherapy option for patients with resected renal cell carcinoma at high risk of recurrence,” Dr. McKay said in an interview.
To date, the lack of clinically beneficial adjuvant therapy options in RCC has been “humbling,” Dr. Choueiri said in an interview. “We hope we can push the envelope further and get more patients with RCC some good options that make them live longer and better.”
Although the standard of care for patients diagnosed with locoregional RCC is partial or total nephrectomy, nearly half of patients eventually experience disease recurrence following surgery, Dr. Choueiri noted.
“No standard, globally approved adjuvant therapy options are currently available for this population,” he said. Clinical guidelines recommend patients at high risk of disease recurrence after surgery be entered into a clinical trial or undergo active surveillance.
Researchers will continue to follow the results for overall survival, a secondary endpoint. “The very early look suggests encouraging results [in overall survival] with an HR of 0.54,” Dr. Choueiri noted.
In the meantime, the prolongation of DFS represents a clear clinical benefit, said Dr. McKay, “given the magnitude of the increase” and “the limited incidence of toxic effects.”
KEYNOTE-564 will alter the adjuvant treatment landscape for RCC as a positive phase 3 trial of adjuvant immunotherapy for the disease, she added.
A number of earlier studies have investigated the use of adjuvant vascular endothelial growth factor–targeting agents in RCC. Only the 2016 Sunitinib Treatment of Renal Adjuvant Cancer (S-TRAC) trial showed improved DFS with sunitinib, compared with placebo (6.8 vs. 5.6 years). Subsequently, sunitinib was approved for adjuvant use in the United States. However, the S-TRAC trial also showed that sunitinib therapy was associated with an increased incidence of toxic effects and lower quality of life scores, and researchers did not observe any benefit in overall survival.
“Despite regulatory approval in the U.S., sunitinib is not approved for adjuvant use by the European Medicines Agency and has limited utilization in clinical practice given the low benefit-risk ratio,” Dr. McKay pointed out.
Study details
KEYNOTE-564 involved 996 patients with clear-cell RCC at high risk for recurrence after nephrectomy, with or without metastasectomy. They were randomly assigned in a 1:1 ratio to receive a 200-mg dose of adjuvant pembrolizumab or placebo given intravenously once every 3 weeks for up to 17 cycles for approximately 1 year.
The vast majority of patients enrolled in the study had localized disease with no evidence of metastases (M0) and intermediate to high or high risk of disease recurrence after partial or complete nephrectomy. However, 5.8% of patients in both the pembrolizumab and placebo groups had M1 NED (metastatic stage 1, no evidence of disease) status after nephrectomy and resection of metastatic lesions. These patients were also at intermediate to high or high risk of recurrence.
The benefit of pembrolizumab, compared with placebo, was maintained in this subgroup, said the investigators. “At this point, we continue to look at the data, but we know that there was a benefit for DFS in the population we included,” said Dr. Choueiri. “When we looked at several subgroups such as PD-L1 status, geography, gender, performance status, M0/M1, all HRs were less than 1 suggesting benefit from pembrolizumab over placebo.”
“Subset analyses by stage are going to be important to determine which group of patients will derive the most benefit,” asserted Dr. McKay. “While those with M1 NED appear to derive benefit with HR for DFS of 0.29, those with M1 NED comprise a small percentage of patient enrolled in the trial.”
Studies exploring tissue- and blood-based biomarkers, including circulating tumor DNA, will be key to identify patients at highest risk for recurrence or adjuvant treatment, Dr. McKay emphasized. “The adoption of adjuvant immune checkpoint inhibitors brings along new questions regarding patient selection, therapeutic use in patients with non–clear-cell renal cell carcinoma, and systemic treatment after recurrence during or after the receipt of adjuvant therapy.”
KEYNOTE-564 was funded by Merck. Multiple study authors including Dr. Choueiri have financial ties to the pharmaceutical industry, including Merck.
A version of this article first appeared on Medscape.com.
according to expert opinion.
The high hopes have been generated by results from the randomized, phase 3 KEYNOTE-564 trial, showing that monotherapy with pembrolizumab (Keytruda, Merck) was associated with significantly longer disease-free survival (DFS) after nephrectomy than placebo (77.3% vs. 68.1%, respectively). Median follow-up was 24 months.
The results come from the trial’s first interim analysis of data from 994 patients with clear-cell renal cell carcinoma (RCC) at high risk of recurrence.
For the pembrolizumab group, the estimated percentage alive at 24 months was 96.6%, compared with 93.5% in the placebo group (hazard ratio for death, 0.54), said Toni Choueiri, MD, of the Dana-Farber Cancer Institute, Boston, and colleagues.
However, grade 3 or higher adverse events (any cause) occurred at almost twice the rate in the pembrolizumab versus the placebo group (32.4% vs. 17.7%). The new study was published online Aug. 18, 2021, in the New England Journal of Medicine.
The study results were first presented at the 2021 American Society of Clinical Oncology annual meeting and described as likely to be practice changing in this setting, as reported by this news organization.
Currently, this patient population has “no options for adjuvant therapy to reduce the risk of recurrence that have high levels of supporting evidence,” observed the authors.
That’s about to change, as the trial results “herald the dawn of a new era in the treatment of renal cell carcinoma,” Rana McKay, MD, University of California San Diego Health, wrote in an accompanying editorial.
Multiple studies have investigated potential adjuvant therapies in RCC since the 1980s, she observed.
“For the first time, we now have an effective adjuvant immunotherapy option for patients with resected renal cell carcinoma at high risk of recurrence,” Dr. McKay said in an interview.
To date, the lack of clinically beneficial adjuvant therapy options in RCC has been “humbling,” Dr. Choueiri said in an interview. “We hope we can push the envelope further and get more patients with RCC some good options that make them live longer and better.”
Although the standard of care for patients diagnosed with locoregional RCC is partial or total nephrectomy, nearly half of patients eventually experience disease recurrence following surgery, Dr. Choueiri noted.
“No standard, globally approved adjuvant therapy options are currently available for this population,” he said. Clinical guidelines recommend patients at high risk of disease recurrence after surgery be entered into a clinical trial or undergo active surveillance.
Researchers will continue to follow the results for overall survival, a secondary endpoint. “The very early look suggests encouraging results [in overall survival] with an HR of 0.54,” Dr. Choueiri noted.
In the meantime, the prolongation of DFS represents a clear clinical benefit, said Dr. McKay, “given the magnitude of the increase” and “the limited incidence of toxic effects.”
KEYNOTE-564 will alter the adjuvant treatment landscape for RCC as a positive phase 3 trial of adjuvant immunotherapy for the disease, she added.
A number of earlier studies have investigated the use of adjuvant vascular endothelial growth factor–targeting agents in RCC. Only the 2016 Sunitinib Treatment of Renal Adjuvant Cancer (S-TRAC) trial showed improved DFS with sunitinib, compared with placebo (6.8 vs. 5.6 years). Subsequently, sunitinib was approved for adjuvant use in the United States. However, the S-TRAC trial also showed that sunitinib therapy was associated with an increased incidence of toxic effects and lower quality of life scores, and researchers did not observe any benefit in overall survival.
“Despite regulatory approval in the U.S., sunitinib is not approved for adjuvant use by the European Medicines Agency and has limited utilization in clinical practice given the low benefit-risk ratio,” Dr. McKay pointed out.
Study details
KEYNOTE-564 involved 996 patients with clear-cell RCC at high risk for recurrence after nephrectomy, with or without metastasectomy. They were randomly assigned in a 1:1 ratio to receive a 200-mg dose of adjuvant pembrolizumab or placebo given intravenously once every 3 weeks for up to 17 cycles for approximately 1 year.
The vast majority of patients enrolled in the study had localized disease with no evidence of metastases (M0) and intermediate to high or high risk of disease recurrence after partial or complete nephrectomy. However, 5.8% of patients in both the pembrolizumab and placebo groups had M1 NED (metastatic stage 1, no evidence of disease) status after nephrectomy and resection of metastatic lesions. These patients were also at intermediate to high or high risk of recurrence.
The benefit of pembrolizumab, compared with placebo, was maintained in this subgroup, said the investigators. “At this point, we continue to look at the data, but we know that there was a benefit for DFS in the population we included,” said Dr. Choueiri. “When we looked at several subgroups such as PD-L1 status, geography, gender, performance status, M0/M1, all HRs were less than 1 suggesting benefit from pembrolizumab over placebo.”
“Subset analyses by stage are going to be important to determine which group of patients will derive the most benefit,” asserted Dr. McKay. “While those with M1 NED appear to derive benefit with HR for DFS of 0.29, those with M1 NED comprise a small percentage of patient enrolled in the trial.”
Studies exploring tissue- and blood-based biomarkers, including circulating tumor DNA, will be key to identify patients at highest risk for recurrence or adjuvant treatment, Dr. McKay emphasized. “The adoption of adjuvant immune checkpoint inhibitors brings along new questions regarding patient selection, therapeutic use in patients with non–clear-cell renal cell carcinoma, and systemic treatment after recurrence during or after the receipt of adjuvant therapy.”
KEYNOTE-564 was funded by Merck. Multiple study authors including Dr. Choueiri have financial ties to the pharmaceutical industry, including Merck.
A version of this article first appeared on Medscape.com.