B Cell Lymphoma

Photo courtesy of ASH

SAN DIEGO—A recurrent mutation in BCL2, the therapeutic target of venetoclax, appears to be a major contributor to drug resistance in patients with chronic lymphocytic leukemia (CLL), investigators reported.

The mutation has been detected in some patients with CLL up to 2 years before resistance to venetoclax actually develops, according to Piers Blombery, MBBS, of the Peter MacCallum Cancer Center in Melbourne, Victoria, Australia.

“We have identified the first acquired BCL2 mutation developed in patients clinically treated with venetoclax,” he said during the late-breaking abstracts session at the 2018 ASH Annual Meeting.

The mutation, which the investigators have labeled BCL2 Gly101Val, “is a recurrent and frequent mediator of resistance and may be detected years before clinical relapse occurs,” Dr. Blombery added.

A paper on the mutation was published in Cancer Discovery to coincide with the presentation at ASH (abstract LBA-7).

Despite the demonstrated efficacy of venetoclax as continuous therapy in patients with relapsed or refractory CLL, the majority of patients experience disease progression, prompting the investigators to explore molecular mechanisms of secondary resistance.

To do this, they analyzed paired samples from 15 patients with CLL, enrolled in clinical trials of venetoclax, collected both before the start of venetoclax therapy and at the time of disease progression.

In seven patients, the investigators identified a novel mutation that showed up at the time of progression but was absent from the pre-venetoclax samples.

The mutation first became detectable from about 19 to 42 months after the start of therapy and preceded clinical progression by as much as 25 months, the investigators found.

They pinned the mutation down to the BH3-binding groove on BCL2, the same molecular site targeted by venetoclax. They found the mutation was not present in samples from 96 patients with venetoclax-naive CLL nor in any other B-cell malignancies.

Searches for references to the mutation in both a cancer database (COSMIC) and a population database (gnomAD) came up empty.

In other experiments, the investigators determined that cell lines overexpressing BCL2 Gly101Val are resistant to venetoclax, and, in the presence of venetoclax in vitro, BCL2 Gly101Val-expressing cells have a growth advantage compared with wild-type cells.

Additionally, they showed that the mutation results in impaired venetoclax binding in vitro.

“BCL2 Gly101Val is observed subclonally, implicating multiple mechanisms of venetoclax resistance in the same patient,” Dr. Blombery said.

He added that the identification of the resistance mutation is a strong rationale for using combination therapy to treat patients with relapsed or refractory CLL to help prevent or attenuate selection pressures that lead to resistance.

Dr. Blombery reported having no relevant disclosures. The investigators were supported by the Wilson Center for Lymphoma Genomics, Snowdome Foundation, National Health Medical Research Council, Leukemia and Lymphoma Society, Leukemia Foundation, Cancer Council of Victoria, and Australian Cancer Research Foundation.

Photo courtesy of ASH

SAN DIEGO—A recurrent mutation in BCL2, the therapeutic target of venetoclax, appears to be a major contributor to drug resistance in patients with chronic lymphocytic leukemia (CLL), investigators reported.

The mutation has been detected in some patients with CLL up to 2 years before resistance to venetoclax actually develops, according to Piers Blombery, MBBS, of the Peter MacCallum Cancer Center in Melbourne, Victoria, Australia.

“We have identified the first acquired BCL2 mutation developed in patients clinically treated with venetoclax,” he said during the late-breaking abstracts session at the 2018 ASH Annual Meeting.

The mutation, which the investigators have labeled BCL2 Gly101Val, “is a recurrent and frequent mediator of resistance and may be detected years before clinical relapse occurs,” Dr. Blombery added.

A paper on the mutation was published in Cancer Discovery to coincide with the presentation at ASH (abstract LBA-7).

Despite the demonstrated efficacy of venetoclax as continuous therapy in patients with relapsed or refractory CLL, the majority of patients experience disease progression, prompting the investigators to explore molecular mechanisms of secondary resistance.

To do this, they analyzed paired samples from 15 patients with CLL, enrolled in clinical trials of venetoclax, collected both before the start of venetoclax therapy and at the time of disease progression.

In seven patients, the investigators identified a novel mutation that showed up at the time of progression but was absent from the pre-venetoclax samples.

The mutation first became detectable from about 19 to 42 months after the start of therapy and preceded clinical progression by as much as 25 months, the investigators found.

They pinned the mutation down to the BH3-binding groove on BCL2, the same molecular site targeted by venetoclax. They found the mutation was not present in samples from 96 patients with venetoclax-naive CLL nor in any other B-cell malignancies.

Searches for references to the mutation in both a cancer database (COSMIC) and a population database (gnomAD) came up empty.

In other experiments, the investigators determined that cell lines overexpressing BCL2 Gly101Val are resistant to venetoclax, and, in the presence of venetoclax in vitro, BCL2 Gly101Val-expressing cells have a growth advantage compared with wild-type cells.

Additionally, they showed that the mutation results in impaired venetoclax binding in vitro.

“BCL2 Gly101Val is observed subclonally, implicating multiple mechanisms of venetoclax resistance in the same patient,” Dr. Blombery said.

He added that the identification of the resistance mutation is a strong rationale for using combination therapy to treat patients with relapsed or refractory CLL to help prevent or attenuate selection pressures that lead to resistance.

Dr. Blombery reported having no relevant disclosures. The investigators were supported by the Wilson Center for Lymphoma Genomics, Snowdome Foundation, National Health Medical Research Council, Leukemia and Lymphoma Society, Leukemia Foundation, Cancer Council of Victoria, and Australian Cancer Research Foundation.

Photo courtesy of ASH

SAN DIEGO—A recurrent mutation in BCL2, the therapeutic target of venetoclax, appears to be a major contributor to drug resistance in patients with chronic lymphocytic leukemia (CLL), investigators reported.

The mutation has been detected in some patients with CLL up to 2 years before resistance to venetoclax actually develops, according to Piers Blombery, MBBS, of the Peter MacCallum Cancer Center in Melbourne, Victoria, Australia.

“We have identified the first acquired BCL2 mutation developed in patients clinically treated with venetoclax,” he said during the late-breaking abstracts session at the 2018 ASH Annual Meeting.

The mutation, which the investigators have labeled BCL2 Gly101Val, “is a recurrent and frequent mediator of resistance and may be detected years before clinical relapse occurs,” Dr. Blombery added.

A paper on the mutation was published in Cancer Discovery to coincide with the presentation at ASH (abstract LBA-7).

Despite the demonstrated efficacy of venetoclax as continuous therapy in patients with relapsed or refractory CLL, the majority of patients experience disease progression, prompting the investigators to explore molecular mechanisms of secondary resistance.

To do this, they analyzed paired samples from 15 patients with CLL, enrolled in clinical trials of venetoclax, collected both before the start of venetoclax therapy and at the time of disease progression.

In seven patients, the investigators identified a novel mutation that showed up at the time of progression but was absent from the pre-venetoclax samples.

The mutation first became detectable from about 19 to 42 months after the start of therapy and preceded clinical progression by as much as 25 months, the investigators found.

They pinned the mutation down to the BH3-binding groove on BCL2, the same molecular site targeted by venetoclax. They found the mutation was not present in samples from 96 patients with venetoclax-naive CLL nor in any other B-cell malignancies.

Searches for references to the mutation in both a cancer database (COSMIC) and a population database (gnomAD) came up empty.

In other experiments, the investigators determined that cell lines overexpressing BCL2 Gly101Val are resistant to venetoclax, and, in the presence of venetoclax in vitro, BCL2 Gly101Val-expressing cells have a growth advantage compared with wild-type cells.

Additionally, they showed that the mutation results in impaired venetoclax binding in vitro.

“BCL2 Gly101Val is observed subclonally, implicating multiple mechanisms of venetoclax resistance in the same patient,” Dr. Blombery said.

He added that the identification of the resistance mutation is a strong rationale for using combination therapy to treat patients with relapsed or refractory CLL to help prevent or attenuate selection pressures that lead to resistance.

Dr. Blombery reported having no relevant disclosures. The investigators were supported by the Wilson Center for Lymphoma Genomics, Snowdome Foundation, National Health Medical Research Council, Leukemia and Lymphoma Society, Leukemia Foundation, Cancer Council of Victoria, and Australian Cancer Research Foundation.

Intravascular large B-cell lymphoma (IVBCL) is an aggressive and systemically disseminated disease that affects the elderly, with a median age of diagnosis around 70 years and no gender predilection. It is a rare subtype of extranodal diffuse large B-cell lymphoma (DLBCL) characterized by selective growth of neoplastic cells within blood vessel lumen without any obvious extravascular tumor mass. Hence, an absence of marked lymphadenopathy and heterogeneous clinical presentation make it difficult to diagnose accurately and timely, with roughly half of the cases found postmortem in previous case reports.^1,2 The exact incidence of this disease is not known, but more recently, the accuracy of diagnosis of this type of lymphoma has improved with random skin and bone marrow biopsy.^1,2 We present here a clinical case of this disease with an atypical presentation followed by a detailed review of its clinical aspects.

Case presentation and summary

A 43-year-old white woman with a history of hypothyroidism and recurrent ovarian cysts presented to clinic with 3 months of loss of appetite, abdominal distension, pelvic pain, and progressive lower-extremity swelling. A physical examination was notable for marked abdominal distension, diffuse lower abdominal tenderness, and pitting lower-extremity edema. No skin rash or any other cutaneous abnormality was noted on exam. Laboratory test results revealed a lactate dehydrogenase (LDH) level of 1652 U/L and a CA-125 level of 50 U/mL (reference range, 0-35 U/mL). No significant beta-human chorionic gonadotropin and alpha-fetoprotein levels were detected. Computed-tomographic (CT) imaging revealed small bilateral pleural effusions and gallbladder wall thickening with abdominal wall edema, but it was otherwise unrevealing. An echocardiogram showed normal cardiac structure and function, with a left ventricular ejection fraction of 60%. No protein was detected in the patient’s urine, and thyroid function tests were unrevealing. Doppler ultrasound studies of her lower extremities and abdomen revealed no thrombosis. Given the patient’s continued pelvic pain, history of ovarian cysts, and elevation in CA-125, she underwent a laparoscopic total abdominal hysterectomy and bilateral salpingoopherectomy.

Histologic examination revealed neoplastic cells involving only the vascular lumina of the cervix, endomyometrium, bilateral fallopian tubes, and bilateral ovaries (Figure 1). Immunohistochemistry stains were positive for CD5, CD20, PAX-5, CD45, BCL-2, and BCL-6 and focally positive for CD10. Peripheral smear showed pseudo-Pelger–Huet cells with 5% atypical lymphoma cells (Figure 2). Complete staging with positron-emission and CT (PET–CT) imaging revealed no metabolic activity, and a bone marrow biopsy showed trilineage hematopoiesis with adequate maturation and less than 5% of the marrow involved with large B-cell lymphoma cells. A diagnosis of IVBCL was made.

Discussion

Clinical presentation

The clinical manifestation of this disease is highly variable, and virtually any organ can be involved. Besides causing constitutional symptoms, including fatigue, B symptoms, and decline in performance status, heterogeneity of the clinical presentation depends on the organ system involved. One of the exceptional features of this disease is the difference in clinical presentation based on the geographical origin of the patient.^2-4

Western-variant IVBCL has a higher frequency of CNS and skin involvement, whereas Asian-variant IVBCL shows preferential involvement of bone marrow with hemophagocytosis, hepatosplenomegaly, and thrombocytopenia. However, these 2 clinical variants have no difference in clinical outcome, except with the cutaneous-variant kind.²⁴ A retrospective case series of 38 Western-variant IVBCL cases showed that 55% of patients had B symptoms with poor performance status.³ Brain and skin were the organs that were most frequently involved, with 68% of patients having involvement of at least 1 of those organs. Ten patients in this case series had disease that was exclusively limited to the skin and described as a “cutaneous variant” of IVBCL.³

Similarly, a retrospective case series of 96 cases of Asian-variant IVBCL showed B symptoms in 76% of patients, with predominant bone marrow involvement in 75% of patients, accompanied by hemophagocytosis in 66% and hepatosplenomegaly and anemia/thrombocytopenia in 77% and 84% of the patients, respectively.⁴ This difference in clinical presentation might have existed as a result of ethnic difference associated with production of inflammatory cytokines, including interferon gamma, tumor necrosis factor-alpha, interlukin-1 beta, and soluble interlukin-2 receptor, with levels of soluble interlukin-2 receptor found to be significantly higher in Asian patients than non-Asian patients.²
 

Diagnosis

Involved organ biopsy is mandatory for establishing the diagnosis of IVBCL. Laboratory findings are nonspecific, with the most common abnormality being increased serum LDH and beta-2 microglobulin levels observed in 80% to 90% or more of patients. Despite its intravascular growth pattern, IVBCL was associated with peripheral blood involvement in only 5% to 9% of patients.¹

Staging

Clinical staging work-up suggested for IVBCL patients by International Extranodal lymphoma study group in 2005 included physical examination (with emphasis on nervous system and skin), routine blood studies, peripheral blood smear, total body CT scan with contrast or PET–CT scan, MRI brain with contrast, CSF cytology, and bone marrow or organ biopsy.¹ The role of fluorodeoxyglucose-PET scan is controversial but can be helpful to detect unexpected locations for biopsy and to assess treatment response.^5,6

Morphology and immunophenotyping

In general, IVBCL histopathology shows large neoplastic lymphoid cells with large nuclei along with one or more nucleoli and scant cytoplasm within blood vessel lumen. Immunophenotypically, IVBCL cells mostly express nongerminal B-cell–associated markers with CD79a (100%), CD20 (96%), MUM-IRF4 (95%), CD5 (38%), and CD10 (12%) expressions. IVBCL cells have been demonstrated to lack cell surface protein CD29 and CD54 critical to transvascular migration. Similarly, aberrant expression of proteins such as CD11a and CXCR3 allows lymphoma cells to be attracted to endothelial cells, which might explain their intravascular confinement.⁷
 

Genetics

No pathognomic cytogenetic abnormalities have been reported in IVBCL to date, and the genetic features of this disease are not yet completely understood.^2,7
 

Management

IVBCL is considered a stage IV disseminated disease with an International Prognostic Index score of high-intermediate to high in most cases. Half of the patients with IVBCL who were treated with anthracycline-based chemotherapy relapsed and died within 18 months of diagnosis. One third of the relapses involved the CNS, thereby highlighting the importance of prophylactic CNS-directed Intrathecal therapy in an induction treatment regimen.^2-4 Ferreri and colleagues reported in their case series response rates of about 60%, with an overall survival (OS) of 3 years of 30% in patients who were treated with anthracycline-based chemotherapy. A multivariate analysis of the entire series showed cutaneous variant of the disease to be an independent favorable prognostic factor for OS.³

In the Murase and colleagues case series, the authors reported 67% response rates and a median OS of 13 months with CHOP (cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, prednisone) or CHOP-like regimens. Multivariate analysis showed older age, thrombocytopenia, and absence of anthracycline-based chemotherapy to be an independent negative prognostic factor for OS.⁴ Another retrospective analysis by Shimada and colleagues of 106 patients with IVBCL showed improved outcome with the addition of rituximab to CHOP-based chemotherapy (R-CHOP). Complete response rate (CR), 2-year progression-free survival, and OS were significantly higher for patients in rituximab-chemotherapy group than for those in the chemotherapy-alone group (CR, 82% vs 51%, respectively, P = .001; PFS, 56% vs 27%; OS, 66% vs 46%, P = .001), thereby establishing rituximab with CHOP-based therapy as induction therapy for IVBCL patients.⁸

The role of high-dose chemotherapy followed by ASCT could also be used as consolidation therapy to improve clinical outcomes as reported in 7 patients, showing durable remission after transplant in these 2 case series.^3,4 Another retrospective analysis of 6 patients with IVBCL who were treated with 6 cycles of R-CHOP as induction therapy and consolidated with ASCT reported all patients to be alive and in complete remission after a median follow-up of 56 months.⁹ Based on the retrospective case series data by Kato and colleagues and considering that more than 80% of the patients with IVBCL were in the high-risk International Prognostic Index group, ASCT in first remission might be a useful treatment option for durable remission; however, because the median age for the diagnosis of IVBCL is about 70 years, ASCT may not be a realistic option for all patients.
 

Conclusions

IVBCL is a rare, aggressive, and distinct type of DLBCL with complex constellations of symptoms requiring strong clinical suspicion to establish this challenging diagnosis. Rituximab with anthracycline-based therapy along with prophylactic CNS-directed therapy followed by consolidative ASCT may lead to long-term remission. More research is needed into the genetic features of this disease to better understand its pathogenesis and potential targets for treatment.

Intravascular large B-cell lymphoma (IVBCL) is an aggressive and systemically disseminated disease that affects the elderly, with a median age of diagnosis around 70 years and no gender predilection. It is a rare subtype of extranodal diffuse large B-cell lymphoma (DLBCL) characterized by selective growth of neoplastic cells within blood vessel lumen without any obvious extravascular tumor mass. Hence, an absence of marked lymphadenopathy and heterogeneous clinical presentation make it difficult to diagnose accurately and timely, with roughly half of the cases found postmortem in previous case reports.^1,2 The exact incidence of this disease is not known, but more recently, the accuracy of diagnosis of this type of lymphoma has improved with random skin and bone marrow biopsy.^1,2 We present here a clinical case of this disease with an atypical presentation followed by a detailed review of its clinical aspects.

Case presentation and summary

A 43-year-old white woman with a history of hypothyroidism and recurrent ovarian cysts presented to clinic with 3 months of loss of appetite, abdominal distension, pelvic pain, and progressive lower-extremity swelling. A physical examination was notable for marked abdominal distension, diffuse lower abdominal tenderness, and pitting lower-extremity edema. No skin rash or any other cutaneous abnormality was noted on exam. Laboratory test results revealed a lactate dehydrogenase (LDH) level of 1652 U/L and a CA-125 level of 50 U/mL (reference range, 0-35 U/mL). No significant beta-human chorionic gonadotropin and alpha-fetoprotein levels were detected. Computed-tomographic (CT) imaging revealed small bilateral pleural effusions and gallbladder wall thickening with abdominal wall edema, but it was otherwise unrevealing. An echocardiogram showed normal cardiac structure and function, with a left ventricular ejection fraction of 60%. No protein was detected in the patient’s urine, and thyroid function tests were unrevealing. Doppler ultrasound studies of her lower extremities and abdomen revealed no thrombosis. Given the patient’s continued pelvic pain, history of ovarian cysts, and elevation in CA-125, she underwent a laparoscopic total abdominal hysterectomy and bilateral salpingoopherectomy.

Histologic examination revealed neoplastic cells involving only the vascular lumina of the cervix, endomyometrium, bilateral fallopian tubes, and bilateral ovaries (Figure 1). Immunohistochemistry stains were positive for CD5, CD20, PAX-5, CD45, BCL-2, and BCL-6 and focally positive for CD10. Peripheral smear showed pseudo-Pelger–Huet cells with 5% atypical lymphoma cells (Figure 2). Complete staging with positron-emission and CT (PET–CT) imaging revealed no metabolic activity, and a bone marrow biopsy showed trilineage hematopoiesis with adequate maturation and less than 5% of the marrow involved with large B-cell lymphoma cells. A diagnosis of IVBCL was made.

Discussion

Clinical presentation

The clinical manifestation of this disease is highly variable, and virtually any organ can be involved. Besides causing constitutional symptoms, including fatigue, B symptoms, and decline in performance status, heterogeneity of the clinical presentation depends on the organ system involved. One of the exceptional features of this disease is the difference in clinical presentation based on the geographical origin of the patient.^2-4

Western-variant IVBCL has a higher frequency of CNS and skin involvement, whereas Asian-variant IVBCL shows preferential involvement of bone marrow with hemophagocytosis, hepatosplenomegaly, and thrombocytopenia. However, these 2 clinical variants have no difference in clinical outcome, except with the cutaneous-variant kind.²⁴ A retrospective case series of 38 Western-variant IVBCL cases showed that 55% of patients had B symptoms with poor performance status.³ Brain and skin were the organs that were most frequently involved, with 68% of patients having involvement of at least 1 of those organs. Ten patients in this case series had disease that was exclusively limited to the skin and described as a “cutaneous variant” of IVBCL.³

Similarly, a retrospective case series of 96 cases of Asian-variant IVBCL showed B symptoms in 76% of patients, with predominant bone marrow involvement in 75% of patients, accompanied by hemophagocytosis in 66% and hepatosplenomegaly and anemia/thrombocytopenia in 77% and 84% of the patients, respectively.⁴ This difference in clinical presentation might have existed as a result of ethnic difference associated with production of inflammatory cytokines, including interferon gamma, tumor necrosis factor-alpha, interlukin-1 beta, and soluble interlukin-2 receptor, with levels of soluble interlukin-2 receptor found to be significantly higher in Asian patients than non-Asian patients.²
 

Diagnosis

Involved organ biopsy is mandatory for establishing the diagnosis of IVBCL. Laboratory findings are nonspecific, with the most common abnormality being increased serum LDH and beta-2 microglobulin levels observed in 80% to 90% or more of patients. Despite its intravascular growth pattern, IVBCL was associated with peripheral blood involvement in only 5% to 9% of patients.¹

Staging

Clinical staging work-up suggested for IVBCL patients by International Extranodal lymphoma study group in 2005 included physical examination (with emphasis on nervous system and skin), routine blood studies, peripheral blood smear, total body CT scan with contrast or PET–CT scan, MRI brain with contrast, CSF cytology, and bone marrow or organ biopsy.¹ The role of fluorodeoxyglucose-PET scan is controversial but can be helpful to detect unexpected locations for biopsy and to assess treatment response.^5,6

Morphology and immunophenotyping

In general, IVBCL histopathology shows large neoplastic lymphoid cells with large nuclei along with one or more nucleoli and scant cytoplasm within blood vessel lumen. Immunophenotypically, IVBCL cells mostly express nongerminal B-cell–associated markers with CD79a (100%), CD20 (96%), MUM-IRF4 (95%), CD5 (38%), and CD10 (12%) expressions. IVBCL cells have been demonstrated to lack cell surface protein CD29 and CD54 critical to transvascular migration. Similarly, aberrant expression of proteins such as CD11a and CXCR3 allows lymphoma cells to be attracted to endothelial cells, which might explain their intravascular confinement.⁷
 

Genetics

No pathognomic cytogenetic abnormalities have been reported in IVBCL to date, and the genetic features of this disease are not yet completely understood.^2,7
 

Management

IVBCL is considered a stage IV disseminated disease with an International Prognostic Index score of high-intermediate to high in most cases. Half of the patients with IVBCL who were treated with anthracycline-based chemotherapy relapsed and died within 18 months of diagnosis. One third of the relapses involved the CNS, thereby highlighting the importance of prophylactic CNS-directed Intrathecal therapy in an induction treatment regimen.^2-4 Ferreri and colleagues reported in their case series response rates of about 60%, with an overall survival (OS) of 3 years of 30% in patients who were treated with anthracycline-based chemotherapy. A multivariate analysis of the entire series showed cutaneous variant of the disease to be an independent favorable prognostic factor for OS.³

In the Murase and colleagues case series, the authors reported 67% response rates and a median OS of 13 months with CHOP (cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, prednisone) or CHOP-like regimens. Multivariate analysis showed older age, thrombocytopenia, and absence of anthracycline-based chemotherapy to be an independent negative prognostic factor for OS.⁴ Another retrospective analysis by Shimada and colleagues of 106 patients with IVBCL showed improved outcome with the addition of rituximab to CHOP-based chemotherapy (R-CHOP). Complete response rate (CR), 2-year progression-free survival, and OS were significantly higher for patients in rituximab-chemotherapy group than for those in the chemotherapy-alone group (CR, 82% vs 51%, respectively, P = .001; PFS, 56% vs 27%; OS, 66% vs 46%, P = .001), thereby establishing rituximab with CHOP-based therapy as induction therapy for IVBCL patients.⁸

The role of high-dose chemotherapy followed by ASCT could also be used as consolidation therapy to improve clinical outcomes as reported in 7 patients, showing durable remission after transplant in these 2 case series.^3,4 Another retrospective analysis of 6 patients with IVBCL who were treated with 6 cycles of R-CHOP as induction therapy and consolidated with ASCT reported all patients to be alive and in complete remission after a median follow-up of 56 months.⁹ Based on the retrospective case series data by Kato and colleagues and considering that more than 80% of the patients with IVBCL were in the high-risk International Prognostic Index group, ASCT in first remission might be a useful treatment option for durable remission; however, because the median age for the diagnosis of IVBCL is about 70 years, ASCT may not be a realistic option for all patients.
 

Conclusions

IVBCL is a rare, aggressive, and distinct type of DLBCL with complex constellations of symptoms requiring strong clinical suspicion to establish this challenging diagnosis. Rituximab with anthracycline-based therapy along with prophylactic CNS-directed therapy followed by consolidative ASCT may lead to long-term remission. More research is needed into the genetic features of this disease to better understand its pathogenesis and potential targets for treatment.

Intravascular large B-cell lymphoma (IVBCL) is an aggressive and systemically disseminated disease that affects the elderly, with a median age of diagnosis around 70 years and no gender predilection. It is a rare subtype of extranodal diffuse large B-cell lymphoma (DLBCL) characterized by selective growth of neoplastic cells within blood vessel lumen without any obvious extravascular tumor mass. Hence, an absence of marked lymphadenopathy and heterogeneous clinical presentation make it difficult to diagnose accurately and timely, with roughly half of the cases found postmortem in previous case reports.^1,2 The exact incidence of this disease is not known, but more recently, the accuracy of diagnosis of this type of lymphoma has improved with random skin and bone marrow biopsy.^1,2 We present here a clinical case of this disease with an atypical presentation followed by a detailed review of its clinical aspects.

Case presentation and summary

A 43-year-old white woman with a history of hypothyroidism and recurrent ovarian cysts presented to clinic with 3 months of loss of appetite, abdominal distension, pelvic pain, and progressive lower-extremity swelling. A physical examination was notable for marked abdominal distension, diffuse lower abdominal tenderness, and pitting lower-extremity edema. No skin rash or any other cutaneous abnormality was noted on exam. Laboratory test results revealed a lactate dehydrogenase (LDH) level of 1652 U/L and a CA-125 level of 50 U/mL (reference range, 0-35 U/mL). No significant beta-human chorionic gonadotropin and alpha-fetoprotein levels were detected. Computed-tomographic (CT) imaging revealed small bilateral pleural effusions and gallbladder wall thickening with abdominal wall edema, but it was otherwise unrevealing. An echocardiogram showed normal cardiac structure and function, with a left ventricular ejection fraction of 60%. No protein was detected in the patient’s urine, and thyroid function tests were unrevealing. Doppler ultrasound studies of her lower extremities and abdomen revealed no thrombosis. Given the patient’s continued pelvic pain, history of ovarian cysts, and elevation in CA-125, she underwent a laparoscopic total abdominal hysterectomy and bilateral salpingoopherectomy.

Histologic examination revealed neoplastic cells involving only the vascular lumina of the cervix, endomyometrium, bilateral fallopian tubes, and bilateral ovaries (Figure 1). Immunohistochemistry stains were positive for CD5, CD20, PAX-5, CD45, BCL-2, and BCL-6 and focally positive for CD10. Peripheral smear showed pseudo-Pelger–Huet cells with 5% atypical lymphoma cells (Figure 2). Complete staging with positron-emission and CT (PET–CT) imaging revealed no metabolic activity, and a bone marrow biopsy showed trilineage hematopoiesis with adequate maturation and less than 5% of the marrow involved with large B-cell lymphoma cells. A diagnosis of IVBCL was made.

Discussion

Clinical presentation

The clinical manifestation of this disease is highly variable, and virtually any organ can be involved. Besides causing constitutional symptoms, including fatigue, B symptoms, and decline in performance status, heterogeneity of the clinical presentation depends on the organ system involved. One of the exceptional features of this disease is the difference in clinical presentation based on the geographical origin of the patient.^2-4

Western-variant IVBCL has a higher frequency of CNS and skin involvement, whereas Asian-variant IVBCL shows preferential involvement of bone marrow with hemophagocytosis, hepatosplenomegaly, and thrombocytopenia. However, these 2 clinical variants have no difference in clinical outcome, except with the cutaneous-variant kind.²⁴ A retrospective case series of 38 Western-variant IVBCL cases showed that 55% of patients had B symptoms with poor performance status.³ Brain and skin were the organs that were most frequently involved, with 68% of patients having involvement of at least 1 of those organs. Ten patients in this case series had disease that was exclusively limited to the skin and described as a “cutaneous variant” of IVBCL.³

Similarly, a retrospective case series of 96 cases of Asian-variant IVBCL showed B symptoms in 76% of patients, with predominant bone marrow involvement in 75% of patients, accompanied by hemophagocytosis in 66% and hepatosplenomegaly and anemia/thrombocytopenia in 77% and 84% of the patients, respectively.⁴ This difference in clinical presentation might have existed as a result of ethnic difference associated with production of inflammatory cytokines, including interferon gamma, tumor necrosis factor-alpha, interlukin-1 beta, and soluble interlukin-2 receptor, with levels of soluble interlukin-2 receptor found to be significantly higher in Asian patients than non-Asian patients.²
 

Diagnosis

Involved organ biopsy is mandatory for establishing the diagnosis of IVBCL. Laboratory findings are nonspecific, with the most common abnormality being increased serum LDH and beta-2 microglobulin levels observed in 80% to 90% or more of patients. Despite its intravascular growth pattern, IVBCL was associated with peripheral blood involvement in only 5% to 9% of patients.¹

Staging

Clinical staging work-up suggested for IVBCL patients by International Extranodal lymphoma study group in 2005 included physical examination (with emphasis on nervous system and skin), routine blood studies, peripheral blood smear, total body CT scan with contrast or PET–CT scan, MRI brain with contrast, CSF cytology, and bone marrow or organ biopsy.¹ The role of fluorodeoxyglucose-PET scan is controversial but can be helpful to detect unexpected locations for biopsy and to assess treatment response.^5,6

Morphology and immunophenotyping

In general, IVBCL histopathology shows large neoplastic lymphoid cells with large nuclei along with one or more nucleoli and scant cytoplasm within blood vessel lumen. Immunophenotypically, IVBCL cells mostly express nongerminal B-cell–associated markers with CD79a (100%), CD20 (96%), MUM-IRF4 (95%), CD5 (38%), and CD10 (12%) expressions. IVBCL cells have been demonstrated to lack cell surface protein CD29 and CD54 critical to transvascular migration. Similarly, aberrant expression of proteins such as CD11a and CXCR3 allows lymphoma cells to be attracted to endothelial cells, which might explain their intravascular confinement.⁷
 

Genetics

No pathognomic cytogenetic abnormalities have been reported in IVBCL to date, and the genetic features of this disease are not yet completely understood.^2,7
 

Management

IVBCL is considered a stage IV disseminated disease with an International Prognostic Index score of high-intermediate to high in most cases. Half of the patients with IVBCL who were treated with anthracycline-based chemotherapy relapsed and died within 18 months of diagnosis. One third of the relapses involved the CNS, thereby highlighting the importance of prophylactic CNS-directed Intrathecal therapy in an induction treatment regimen.^2-4 Ferreri and colleagues reported in their case series response rates of about 60%, with an overall survival (OS) of 3 years of 30% in patients who were treated with anthracycline-based chemotherapy. A multivariate analysis of the entire series showed cutaneous variant of the disease to be an independent favorable prognostic factor for OS.³

In the Murase and colleagues case series, the authors reported 67% response rates and a median OS of 13 months with CHOP (cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, prednisone) or CHOP-like regimens. Multivariate analysis showed older age, thrombocytopenia, and absence of anthracycline-based chemotherapy to be an independent negative prognostic factor for OS.⁴ Another retrospective analysis by Shimada and colleagues of 106 patients with IVBCL showed improved outcome with the addition of rituximab to CHOP-based chemotherapy (R-CHOP). Complete response rate (CR), 2-year progression-free survival, and OS were significantly higher for patients in rituximab-chemotherapy group than for those in the chemotherapy-alone group (CR, 82% vs 51%, respectively, P = .001; PFS, 56% vs 27%; OS, 66% vs 46%, P = .001), thereby establishing rituximab with CHOP-based therapy as induction therapy for IVBCL patients.⁸

The role of high-dose chemotherapy followed by ASCT could also be used as consolidation therapy to improve clinical outcomes as reported in 7 patients, showing durable remission after transplant in these 2 case series.^3,4 Another retrospective analysis of 6 patients with IVBCL who were treated with 6 cycles of R-CHOP as induction therapy and consolidated with ASCT reported all patients to be alive and in complete remission after a median follow-up of 56 months.⁹ Based on the retrospective case series data by Kato and colleagues and considering that more than 80% of the patients with IVBCL were in the high-risk International Prognostic Index group, ASCT in first remission might be a useful treatment option for durable remission; however, because the median age for the diagnosis of IVBCL is about 70 years, ASCT may not be a realistic option for all patients.
 

Conclusions

IVBCL is a rare, aggressive, and distinct type of DLBCL with complex constellations of symptoms requiring strong clinical suspicion to establish this challenging diagnosis. Rituximab with anthracycline-based therapy along with prophylactic CNS-directed therapy followed by consolidative ASCT may lead to long-term remission. More research is needed into the genetic features of this disease to better understand its pathogenesis and potential targets for treatment.

SAN DIEGO – The potential rituximab biosimilar drug PF-05280586 showed efficacy, safety, immunogenicity, pharmacokinetics, and pharmacodynamics similar to those of rituximab at up to 26 weeks in a randomized phase 3 study of treatment-naive patients with CD20-positive low tumor burden follicular lymphoma (LTB-FL).

Sharon Worcester/MDedge News

The primary endpoint of overall response rate at 26 weeks was 75.5% in 196 patients randomized to receive PF-05280586, and 70.7% in 198 patients who received a rituximab reference product sourced from the European Union (MabThera; rituximab‑EU), Jeff Sharman, MD, reported at the annual meeting of the American Society of Hematology.

“This resulted in a difference between the two arms of 4.66%,” said Dr. Sharman of Willamette Valley Cancer Institute and Research Center, Springfield, Ore.

The 95% confidence interval for this difference ... was entirely contained within the prespecified equivalence margin, he said.

“Depth of response was a key secondary endpoint, and rates of complete response were 29.3% and 30.4%, respectively,” he said, noting that rates of partial response, stable response, and progressive disease were also similar between the two study arms.

Estimated 1-year progression-free survival (PFS) rates were also highly similar at 76.4% and 81.2% in the PF-05280586 and rituximab-EU arms.


Rapid depletion in CD19-positive B-cell counts was observed in both groups after initial dosing, with recovery by week 39 and a sustained increase until the end of week 52.

Treatment-emergent adverse events (TEAEs) occurred in 78.6% vs. 72.1% of patients in the PF‑05280586 vs. rituximab‑EU arms, respectively, and the rates of serious adverse events and grade 3 events were similar in the groups, as were rates of infusion interruptions or infusion-related reactions (IRRs), Dr. Sharman said.

IRRs occurred in about 25% of patients in each arm, and most were grade 1 or 2. Grade 3 IRRs occurred in 2.6% vs. 0.5% of patients in the groups, respectively, and no grade 4 IRRs occurred.

Rates of anti-drug antibodies were also similar in the two groups, as were serum drug concentrations – regardless of anti-drug antibody status, he noted.

Study subjects were adults with a mean age of 60 years and histologically confirmed CD20-positive grade 1-3a follicular lymphoma with no prior rituximab or system therapy for B-cell non-Hodgkin lymphoma (NHL). They had Ann Arbor disease stages II (26.9%), III (44.2%) or IV (28.9%), ECOG performance status of 0-1, and at least 1 measurable disease lesion identifiable on imaging.

Risk level as assessed by the Follicular Lymphoma International Prognostic Index–2 was low in 28.4%, medium in 66%, and high in 5.6% of patients.

Treatment with each agent was given at intravenous doses of 375 mg/m² weekly for 4 weeks at days 1, 8, 15, and 22.

PF-05280586 is being developed by Pfizer, and in this 52-week double-blind study – the largest study to date of the early use of the potential rituximab biosimilar in patients with previously untreated CD20-positive LTB-FL – the primary endpoint was met, demonstrating its therapeutic equivalence with rituximab-EU for overall response rate at week 26, Dr. Sharman said.

“These results therefore confirm the biosimilarity of PF-05280586 with rituximab-EU,” he concluded.

Of note, the reporting of these findings comes on the heels of the first Food and Drug Administration approval of a biosimilar rituximab product for the treatment of NHL; Celltrion’s product Truxima (formerly CT-P10), a biosimilar of Genentech’s Rituxan (rituximab), was approved Nov. 28 to treat adults with CD20-positive, B-cell NHL, either as a single agent or in combination with chemotherapy.

The PF-0528056 study was sponsored by Pfizer. Dr. Sharman has been a consultant for, and/or received research funding and honoraria from Acerta, Pharmacyclics (an AbbVie Company), Pfizer, TG Therapeutics, Abbvie, and Genentech.

SOURCE: Sharman J et al. ASH 2018: Abstract 394.

SAN DIEGO – The potential rituximab biosimilar drug PF-05280586 showed efficacy, safety, immunogenicity, pharmacokinetics, and pharmacodynamics similar to those of rituximab at up to 26 weeks in a randomized phase 3 study of treatment-naive patients with CD20-positive low tumor burden follicular lymphoma (LTB-FL).

Sharon Worcester/MDedge News

The primary endpoint of overall response rate at 26 weeks was 75.5% in 196 patients randomized to receive PF-05280586, and 70.7% in 198 patients who received a rituximab reference product sourced from the European Union (MabThera; rituximab‑EU), Jeff Sharman, MD, reported at the annual meeting of the American Society of Hematology.

“This resulted in a difference between the two arms of 4.66%,” said Dr. Sharman of Willamette Valley Cancer Institute and Research Center, Springfield, Ore.

The 95% confidence interval for this difference ... was entirely contained within the prespecified equivalence margin, he said.

“Depth of response was a key secondary endpoint, and rates of complete response were 29.3% and 30.4%, respectively,” he said, noting that rates of partial response, stable response, and progressive disease were also similar between the two study arms.

Estimated 1-year progression-free survival (PFS) rates were also highly similar at 76.4% and 81.2% in the PF-05280586 and rituximab-EU arms.


Rapid depletion in CD19-positive B-cell counts was observed in both groups after initial dosing, with recovery by week 39 and a sustained increase until the end of week 52.

Treatment-emergent adverse events (TEAEs) occurred in 78.6% vs. 72.1% of patients in the PF‑05280586 vs. rituximab‑EU arms, respectively, and the rates of serious adverse events and grade 3 events were similar in the groups, as were rates of infusion interruptions or infusion-related reactions (IRRs), Dr. Sharman said.

IRRs occurred in about 25% of patients in each arm, and most were grade 1 or 2. Grade 3 IRRs occurred in 2.6% vs. 0.5% of patients in the groups, respectively, and no grade 4 IRRs occurred.

Rates of anti-drug antibodies were also similar in the two groups, as were serum drug concentrations – regardless of anti-drug antibody status, he noted.

Study subjects were adults with a mean age of 60 years and histologically confirmed CD20-positive grade 1-3a follicular lymphoma with no prior rituximab or system therapy for B-cell non-Hodgkin lymphoma (NHL). They had Ann Arbor disease stages II (26.9%), III (44.2%) or IV (28.9%), ECOG performance status of 0-1, and at least 1 measurable disease lesion identifiable on imaging.

Risk level as assessed by the Follicular Lymphoma International Prognostic Index–2 was low in 28.4%, medium in 66%, and high in 5.6% of patients.

Treatment with each agent was given at intravenous doses of 375 mg/m² weekly for 4 weeks at days 1, 8, 15, and 22.

PF-05280586 is being developed by Pfizer, and in this 52-week double-blind study – the largest study to date of the early use of the potential rituximab biosimilar in patients with previously untreated CD20-positive LTB-FL – the primary endpoint was met, demonstrating its therapeutic equivalence with rituximab-EU for overall response rate at week 26, Dr. Sharman said.

“These results therefore confirm the biosimilarity of PF-05280586 with rituximab-EU,” he concluded.

Of note, the reporting of these findings comes on the heels of the first Food and Drug Administration approval of a biosimilar rituximab product for the treatment of NHL; Celltrion’s product Truxima (formerly CT-P10), a biosimilar of Genentech’s Rituxan (rituximab), was approved Nov. 28 to treat adults with CD20-positive, B-cell NHL, either as a single agent or in combination with chemotherapy.

The PF-0528056 study was sponsored by Pfizer. Dr. Sharman has been a consultant for, and/or received research funding and honoraria from Acerta, Pharmacyclics (an AbbVie Company), Pfizer, TG Therapeutics, Abbvie, and Genentech.

SOURCE: Sharman J et al. ASH 2018: Abstract 394.

SAN DIEGO – The potential rituximab biosimilar drug PF-05280586 showed efficacy, safety, immunogenicity, pharmacokinetics, and pharmacodynamics similar to those of rituximab at up to 26 weeks in a randomized phase 3 study of treatment-naive patients with CD20-positive low tumor burden follicular lymphoma (LTB-FL).

Sharon Worcester/MDedge News

The primary endpoint of overall response rate at 26 weeks was 75.5% in 196 patients randomized to receive PF-05280586, and 70.7% in 198 patients who received a rituximab reference product sourced from the European Union (MabThera; rituximab‑EU), Jeff Sharman, MD, reported at the annual meeting of the American Society of Hematology.

“This resulted in a difference between the two arms of 4.66%,” said Dr. Sharman of Willamette Valley Cancer Institute and Research Center, Springfield, Ore.

The 95% confidence interval for this difference ... was entirely contained within the prespecified equivalence margin, he said.

“Depth of response was a key secondary endpoint, and rates of complete response were 29.3% and 30.4%, respectively,” he said, noting that rates of partial response, stable response, and progressive disease were also similar between the two study arms.

Estimated 1-year progression-free survival (PFS) rates were also highly similar at 76.4% and 81.2% in the PF-05280586 and rituximab-EU arms.


Rapid depletion in CD19-positive B-cell counts was observed in both groups after initial dosing, with recovery by week 39 and a sustained increase until the end of week 52.

Treatment-emergent adverse events (TEAEs) occurred in 78.6% vs. 72.1% of patients in the PF‑05280586 vs. rituximab‑EU arms, respectively, and the rates of serious adverse events and grade 3 events were similar in the groups, as were rates of infusion interruptions or infusion-related reactions (IRRs), Dr. Sharman said.

IRRs occurred in about 25% of patients in each arm, and most were grade 1 or 2. Grade 3 IRRs occurred in 2.6% vs. 0.5% of patients in the groups, respectively, and no grade 4 IRRs occurred.

Rates of anti-drug antibodies were also similar in the two groups, as were serum drug concentrations – regardless of anti-drug antibody status, he noted.

Study subjects were adults with a mean age of 60 years and histologically confirmed CD20-positive grade 1-3a follicular lymphoma with no prior rituximab or system therapy for B-cell non-Hodgkin lymphoma (NHL). They had Ann Arbor disease stages II (26.9%), III (44.2%) or IV (28.9%), ECOG performance status of 0-1, and at least 1 measurable disease lesion identifiable on imaging.

Risk level as assessed by the Follicular Lymphoma International Prognostic Index–2 was low in 28.4%, medium in 66%, and high in 5.6% of patients.

Treatment with each agent was given at intravenous doses of 375 mg/m² weekly for 4 weeks at days 1, 8, 15, and 22.

PF-05280586 is being developed by Pfizer, and in this 52-week double-blind study – the largest study to date of the early use of the potential rituximab biosimilar in patients with previously untreated CD20-positive LTB-FL – the primary endpoint was met, demonstrating its therapeutic equivalence with rituximab-EU for overall response rate at week 26, Dr. Sharman said.

“These results therefore confirm the biosimilarity of PF-05280586 with rituximab-EU,” he concluded.

Of note, the reporting of these findings comes on the heels of the first Food and Drug Administration approval of a biosimilar rituximab product for the treatment of NHL; Celltrion’s product Truxima (formerly CT-P10), a biosimilar of Genentech’s Rituxan (rituximab), was approved Nov. 28 to treat adults with CD20-positive, B-cell NHL, either as a single agent or in combination with chemotherapy.

The PF-0528056 study was sponsored by Pfizer. Dr. Sharman has been a consultant for, and/or received research funding and honoraria from Acerta, Pharmacyclics (an AbbVie Company), Pfizer, TG Therapeutics, Abbvie, and Genentech.

SOURCE: Sharman J et al. ASH 2018: Abstract 394.

SAN DIEGO – A recurrent mutation in BCL2, the therapeutic target of venetoclax (Venclexta), appears to be a major contributor to drug resistance in patients with chronic lymphocytic leukemia (CLL), investigators reported.

The mutation has been detected in some patients with CLL up to 2 years before resistance to venetoclax actually develops, said lead author Piers Blombery, MBBS, from the Peter MacCallum Cancer Center in Melbourne.

“We have identified the first acquired BCL2 mutation developed in patients clinically treated with venetoclax,” he said in a late-breaking oral abstract session at the annual meeting of the American Society of Hematology.

The mutation, which the investigators have labeled BCL2 Gly101Val, “is a recurrent and frequent mediator of resistance and may be detected years before clinical relapse occurs,” he added.

The paper was published online in Cancer Discovery (2018 Dec 4. doi: 10.1158/2159-8290.CD-18-1119) to coincide with the presentation at ASH.

Despite the demonstrated efficacy of venetoclax as continuous therapy in patients with relapsed or refractory CLL, the majority of patients experience disease progression, prompting the investigators to explore molecular mechanisms of secondary resistance.

To do this, they analyzed paired samples from 15 patients with CLL, enrolled in clinical trials of venetoclax, collected both before the start of venetoclax therapy and at the time of disease progression.

In seven of the patients, they identified a novel mutation that showed up at the time of progression, but was absent from the pre-venetoclax samples. The mutation first became detectable from about 19 to 42 months after the start of therapy and preceded clinical progression by as much as 25 months, the investigators found.

They pinned the mutation down to the BH3-binding groove on BCL2, the same molecular site targeted by venetoclax. They found that the mutation was not present in samples from 96 patients with venetoclax-naive CLL nor in any other B-cell malignancies. Searches for references to the mutation in both a cancer database (COSMIC) and a population database (gnomAD) came up empty.

In other experiments, they determined that cell lines overexpressing BCL2 Gly101Val are resistant to venetoclax, and that in the presence of venetoclax in vitro, BCL2 Gly101Val-expressing cells have a growth advantage, compared with wild type cells.

Additionally, they showed that the mutation results in impaired venetoclax binding in vitro.

“BCL2 Gly101Val is observed subclonally, implicating multiple mechanisms of venetoclax resistance in the same patient,” Dr. Blombery said.

In an interview, Dr. Blombery said that the identification of the resistance mutation is a strong rationale for using combination therapy to treat patients with relapsed or refractory CLL to help prevent or attenuate selection pressures that lead to resistance.

The investigators were supported by the Wilson Center for Lymphoma Genomics, Snowdome Foundation, National Health Medical Research Council, Leukemia and Lymphoma Society, Leukemia Foundation, Cancer Council of Victoria, and Australian Cancer Research Foundation. Dr. Blombery reported having no relevant disclosures.

SOURCE: Blombery P et al. ASH 2018, Abstract LBA-7.

SAN DIEGO – A recurrent mutation in BCL2, the therapeutic target of venetoclax (Venclexta), appears to be a major contributor to drug resistance in patients with chronic lymphocytic leukemia (CLL), investigators reported.

The mutation has been detected in some patients with CLL up to 2 years before resistance to venetoclax actually develops, said lead author Piers Blombery, MBBS, from the Peter MacCallum Cancer Center in Melbourne.

“We have identified the first acquired BCL2 mutation developed in patients clinically treated with venetoclax,” he said in a late-breaking oral abstract session at the annual meeting of the American Society of Hematology.

The mutation, which the investigators have labeled BCL2 Gly101Val, “is a recurrent and frequent mediator of resistance and may be detected years before clinical relapse occurs,” he added.

The paper was published online in Cancer Discovery (2018 Dec 4. doi: 10.1158/2159-8290.CD-18-1119) to coincide with the presentation at ASH.

Despite the demonstrated efficacy of venetoclax as continuous therapy in patients with relapsed or refractory CLL, the majority of patients experience disease progression, prompting the investigators to explore molecular mechanisms of secondary resistance.

To do this, they analyzed paired samples from 15 patients with CLL, enrolled in clinical trials of venetoclax, collected both before the start of venetoclax therapy and at the time of disease progression.

In seven of the patients, they identified a novel mutation that showed up at the time of progression, but was absent from the pre-venetoclax samples. The mutation first became detectable from about 19 to 42 months after the start of therapy and preceded clinical progression by as much as 25 months, the investigators found.

They pinned the mutation down to the BH3-binding groove on BCL2, the same molecular site targeted by venetoclax. They found that the mutation was not present in samples from 96 patients with venetoclax-naive CLL nor in any other B-cell malignancies. Searches for references to the mutation in both a cancer database (COSMIC) and a population database (gnomAD) came up empty.

In other experiments, they determined that cell lines overexpressing BCL2 Gly101Val are resistant to venetoclax, and that in the presence of venetoclax in vitro, BCL2 Gly101Val-expressing cells have a growth advantage, compared with wild type cells.

Additionally, they showed that the mutation results in impaired venetoclax binding in vitro.

“BCL2 Gly101Val is observed subclonally, implicating multiple mechanisms of venetoclax resistance in the same patient,” Dr. Blombery said.

In an interview, Dr. Blombery said that the identification of the resistance mutation is a strong rationale for using combination therapy to treat patients with relapsed or refractory CLL to help prevent or attenuate selection pressures that lead to resistance.

The investigators were supported by the Wilson Center for Lymphoma Genomics, Snowdome Foundation, National Health Medical Research Council, Leukemia and Lymphoma Society, Leukemia Foundation, Cancer Council of Victoria, and Australian Cancer Research Foundation. Dr. Blombery reported having no relevant disclosures.

SOURCE: Blombery P et al. ASH 2018, Abstract LBA-7.

SAN DIEGO – A recurrent mutation in BCL2, the therapeutic target of venetoclax (Venclexta), appears to be a major contributor to drug resistance in patients with chronic lymphocytic leukemia (CLL), investigators reported.

The mutation has been detected in some patients with CLL up to 2 years before resistance to venetoclax actually develops, said lead author Piers Blombery, MBBS, from the Peter MacCallum Cancer Center in Melbourne.

“We have identified the first acquired BCL2 mutation developed in patients clinically treated with venetoclax,” he said in a late-breaking oral abstract session at the annual meeting of the American Society of Hematology.

The mutation, which the investigators have labeled BCL2 Gly101Val, “is a recurrent and frequent mediator of resistance and may be detected years before clinical relapse occurs,” he added.

The paper was published online in Cancer Discovery (2018 Dec 4. doi: 10.1158/2159-8290.CD-18-1119) to coincide with the presentation at ASH.

Despite the demonstrated efficacy of venetoclax as continuous therapy in patients with relapsed or refractory CLL, the majority of patients experience disease progression, prompting the investigators to explore molecular mechanisms of secondary resistance.

To do this, they analyzed paired samples from 15 patients with CLL, enrolled in clinical trials of venetoclax, collected both before the start of venetoclax therapy and at the time of disease progression.

In seven of the patients, they identified a novel mutation that showed up at the time of progression, but was absent from the pre-venetoclax samples. The mutation first became detectable from about 19 to 42 months after the start of therapy and preceded clinical progression by as much as 25 months, the investigators found.

They pinned the mutation down to the BH3-binding groove on BCL2, the same molecular site targeted by venetoclax. They found that the mutation was not present in samples from 96 patients with venetoclax-naive CLL nor in any other B-cell malignancies. Searches for references to the mutation in both a cancer database (COSMIC) and a population database (gnomAD) came up empty.

In other experiments, they determined that cell lines overexpressing BCL2 Gly101Val are resistant to venetoclax, and that in the presence of venetoclax in vitro, BCL2 Gly101Val-expressing cells have a growth advantage, compared with wild type cells.

Additionally, they showed that the mutation results in impaired venetoclax binding in vitro.

“BCL2 Gly101Val is observed subclonally, implicating multiple mechanisms of venetoclax resistance in the same patient,” Dr. Blombery said.

In an interview, Dr. Blombery said that the identification of the resistance mutation is a strong rationale for using combination therapy to treat patients with relapsed or refractory CLL to help prevent or attenuate selection pressures that lead to resistance.

The investigators were supported by the Wilson Center for Lymphoma Genomics, Snowdome Foundation, National Health Medical Research Council, Leukemia and Lymphoma Society, Leukemia Foundation, Cancer Council of Victoria, and Australian Cancer Research Foundation. Dr. Blombery reported having no relevant disclosures.

SOURCE: Blombery P et al. ASH 2018, Abstract LBA-7.

©ASH/Scott Morgan 2018

SAN DIEGO—A shortened regimen of four cycles of rituximab (R) plus cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapy was noninferior in efficacy to the standard six cycles of R-CHOP in younger patients with favorable-risk diffuse large B-cell lymphoma (DLBCL), according to investigators of the FLYER trial.

In addition, the truncated regimen was associated with about a one-third reduction in non-hematologic adverse events.

Viola Poeschel, MD, of Saarland University Medical School in Homburg/Saar, Germany, reported results of this study on behalf of the German High-Grade Non-Hodgkin’s Lymphoma Study Group/German Lymphoma Alliance at the 2018 ASH Annual Meeting (abstract 781).

Among 588 evaluable patients younger than 60 with favorable-prognosis DLBCL, there were no significant differences in progression-free survival (PFS), event-free survival (EFS), or overall survival (OS) between patients who received four cycles of R-CHOP and those who received six cycles, Dr. Poeschel reported.

“Six cycles of R-CHOP led to a higher toxicity with respect to leukocytopenia and anemia, both of any grade and also of grades 3 to 4, compared to four cycles of R-CHOP,” she said.

The findings suggest that, for younger patients with favorable-prognosis DLBCL—defined as an age-adjusted International Prognostic Index score of 0 and low tumor burden (less than 7.5 cm)—four cycles of R-CHOP can be a new standard of care, Dr. Poeschel said.

The investigators were prompted to look at the question of a shorter R-CHOP regimen by results of the MInT trial, in which a subpopulation of favorable-prognosis DLBCL patients had a 3-year PFS rate of 89%.

The FLYER trial (NCT00278421) was designed as a non-inferiority study to see whether, in a similar group of patients, reducing the number of R-CHOP cycles could maintain efficacy while reducing toxicity.

At a median follow-up of 66 months, the PFS rate, the primary endpoint, was 94% in the six-cycle group and 96% for the four-cycle group.

“As the lower limit of the 95% confidence interval of our experimental arm was 94%, it is shown that it is definitely non-inferior to the standard arm, six cycles of R-CHOP,” Dr. Poeschel said.

Similarly, the rate of 3-year OS was 98% in the six-cycle group, compared with 99% in the four-cycle group, and the survival curves were virtually superimposable out to more than 10 years of follow-up.

Treatment with six cycles was associated with more frequent hematologic adverse events than four cycles. Leukopenia of any grade occurred in 237 and 171 patients, respectively. Grade 3-4 leukopenia occurred in 110 and 80 patients, respectively.

Any-grade anemia occurred in 172 patients assigned to six cycles and 107 assigned to four cycles. Rates of grade 3-4 anemia were similar between the groups, as were rates of thrombocytopenia of any grade or grade 3-4.

Non-hematologic adverse events of any grade or grade 3-4 that were more frequent with six cycles included parasthesia, nausea, infection, vomiting, and mucositis.

The total number of non-hematologic adverse events was reduced by about one-third.

“We are certainly always looking for ways to make treatments easier for our patients to reduce adverse effects, and, certainly, for this subgroup of patients, it appears that we can make their treatment shorter and have less burden but equivalent efficacy,” said David Steensma, MD, of the Dana-Farber Cancer Institute/Harvard Cancer Center in Boston, Massachusetts.

Drs. Steensma and Poeschel both cautioned that the results of this study pertain only to those patients with DLBCL who are younger and have favorable-prognosis disease.

“We can’t extend it to other subtypes of large-cell lymphoma, but that’s always a laudable goal, so I think this will immediately influence clinical practice,” Dr. Steensma said.

The study was supported by Deutsche Krebshilfe. Dr. Poeschel disclosed travel grants from Roche and Amgen. Dr. Steensma had no disclosures relevant to the study. 

©ASH/Scott Morgan 2018

SAN DIEGO—A shortened regimen of four cycles of rituximab (R) plus cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapy was noninferior in efficacy to the standard six cycles of R-CHOP in younger patients with favorable-risk diffuse large B-cell lymphoma (DLBCL), according to investigators of the FLYER trial.

In addition, the truncated regimen was associated with about a one-third reduction in non-hematologic adverse events.

Viola Poeschel, MD, of Saarland University Medical School in Homburg/Saar, Germany, reported results of this study on behalf of the German High-Grade Non-Hodgkin’s Lymphoma Study Group/German Lymphoma Alliance at the 2018 ASH Annual Meeting (abstract 781).

Among 588 evaluable patients younger than 60 with favorable-prognosis DLBCL, there were no significant differences in progression-free survival (PFS), event-free survival (EFS), or overall survival (OS) between patients who received four cycles of R-CHOP and those who received six cycles, Dr. Poeschel reported.

“Six cycles of R-CHOP led to a higher toxicity with respect to leukocytopenia and anemia, both of any grade and also of grades 3 to 4, compared to four cycles of R-CHOP,” she said.

The findings suggest that, for younger patients with favorable-prognosis DLBCL—defined as an age-adjusted International Prognostic Index score of 0 and low tumor burden (less than 7.5 cm)—four cycles of R-CHOP can be a new standard of care, Dr. Poeschel said.

The investigators were prompted to look at the question of a shorter R-CHOP regimen by results of the MInT trial, in which a subpopulation of favorable-prognosis DLBCL patients had a 3-year PFS rate of 89%.

The FLYER trial (NCT00278421) was designed as a non-inferiority study to see whether, in a similar group of patients, reducing the number of R-CHOP cycles could maintain efficacy while reducing toxicity.

At a median follow-up of 66 months, the PFS rate, the primary endpoint, was 94% in the six-cycle group and 96% for the four-cycle group.

“As the lower limit of the 95% confidence interval of our experimental arm was 94%, it is shown that it is definitely non-inferior to the standard arm, six cycles of R-CHOP,” Dr. Poeschel said.

Similarly, the rate of 3-year OS was 98% in the six-cycle group, compared with 99% in the four-cycle group, and the survival curves were virtually superimposable out to more than 10 years of follow-up.

Treatment with six cycles was associated with more frequent hematologic adverse events than four cycles. Leukopenia of any grade occurred in 237 and 171 patients, respectively. Grade 3-4 leukopenia occurred in 110 and 80 patients, respectively.

Any-grade anemia occurred in 172 patients assigned to six cycles and 107 assigned to four cycles. Rates of grade 3-4 anemia were similar between the groups, as were rates of thrombocytopenia of any grade or grade 3-4.

Non-hematologic adverse events of any grade or grade 3-4 that were more frequent with six cycles included parasthesia, nausea, infection, vomiting, and mucositis.

The total number of non-hematologic adverse events was reduced by about one-third.

“We are certainly always looking for ways to make treatments easier for our patients to reduce adverse effects, and, certainly, for this subgroup of patients, it appears that we can make their treatment shorter and have less burden but equivalent efficacy,” said David Steensma, MD, of the Dana-Farber Cancer Institute/Harvard Cancer Center in Boston, Massachusetts.

Drs. Steensma and Poeschel both cautioned that the results of this study pertain only to those patients with DLBCL who are younger and have favorable-prognosis disease.

“We can’t extend it to other subtypes of large-cell lymphoma, but that’s always a laudable goal, so I think this will immediately influence clinical practice,” Dr. Steensma said.

The study was supported by Deutsche Krebshilfe. Dr. Poeschel disclosed travel grants from Roche and Amgen. Dr. Steensma had no disclosures relevant to the study. 

©ASH/Scott Morgan 2018

SAN DIEGO—A shortened regimen of four cycles of rituximab (R) plus cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapy was noninferior in efficacy to the standard six cycles of R-CHOP in younger patients with favorable-risk diffuse large B-cell lymphoma (DLBCL), according to investigators of the FLYER trial.

In addition, the truncated regimen was associated with about a one-third reduction in non-hematologic adverse events.

Viola Poeschel, MD, of Saarland University Medical School in Homburg/Saar, Germany, reported results of this study on behalf of the German High-Grade Non-Hodgkin’s Lymphoma Study Group/German Lymphoma Alliance at the 2018 ASH Annual Meeting (abstract 781).

Among 588 evaluable patients younger than 60 with favorable-prognosis DLBCL, there were no significant differences in progression-free survival (PFS), event-free survival (EFS), or overall survival (OS) between patients who received four cycles of R-CHOP and those who received six cycles, Dr. Poeschel reported.

“Six cycles of R-CHOP led to a higher toxicity with respect to leukocytopenia and anemia, both of any grade and also of grades 3 to 4, compared to four cycles of R-CHOP,” she said.

The findings suggest that, for younger patients with favorable-prognosis DLBCL—defined as an age-adjusted International Prognostic Index score of 0 and low tumor burden (less than 7.5 cm)—four cycles of R-CHOP can be a new standard of care, Dr. Poeschel said.

The investigators were prompted to look at the question of a shorter R-CHOP regimen by results of the MInT trial, in which a subpopulation of favorable-prognosis DLBCL patients had a 3-year PFS rate of 89%.

The FLYER trial (NCT00278421) was designed as a non-inferiority study to see whether, in a similar group of patients, reducing the number of R-CHOP cycles could maintain efficacy while reducing toxicity.

At a median follow-up of 66 months, the PFS rate, the primary endpoint, was 94% in the six-cycle group and 96% for the four-cycle group.

“As the lower limit of the 95% confidence interval of our experimental arm was 94%, it is shown that it is definitely non-inferior to the standard arm, six cycles of R-CHOP,” Dr. Poeschel said.

Similarly, the rate of 3-year OS was 98% in the six-cycle group, compared with 99% in the four-cycle group, and the survival curves were virtually superimposable out to more than 10 years of follow-up.

Treatment with six cycles was associated with more frequent hematologic adverse events than four cycles. Leukopenia of any grade occurred in 237 and 171 patients, respectively. Grade 3-4 leukopenia occurred in 110 and 80 patients, respectively.

Any-grade anemia occurred in 172 patients assigned to six cycles and 107 assigned to four cycles. Rates of grade 3-4 anemia were similar between the groups, as were rates of thrombocytopenia of any grade or grade 3-4.

Non-hematologic adverse events of any grade or grade 3-4 that were more frequent with six cycles included parasthesia, nausea, infection, vomiting, and mucositis.

The total number of non-hematologic adverse events was reduced by about one-third.

“We are certainly always looking for ways to make treatments easier for our patients to reduce adverse effects, and, certainly, for this subgroup of patients, it appears that we can make their treatment shorter and have less burden but equivalent efficacy,” said David Steensma, MD, of the Dana-Farber Cancer Institute/Harvard Cancer Center in Boston, Massachusetts.

Drs. Steensma and Poeschel both cautioned that the results of this study pertain only to those patients with DLBCL who are younger and have favorable-prognosis disease.

“We can’t extend it to other subtypes of large-cell lymphoma, but that’s always a laudable goal, so I think this will immediately influence clinical practice,” Dr. Steensma said.

The study was supported by Deutsche Krebshilfe. Dr. Poeschel disclosed travel grants from Roche and Amgen. Dr. Steensma had no disclosures relevant to the study. 

Photo courtesy of ASH

SAN DIEGO—A newly approved treatment regimen provides a survival benefit over standard therapy for patients with CD30-positive peripheral T-cell lymphomas (PTCLs), according to a presentation at the 2018 ASH Annual Meeting.

In the ECHELON-2 trial, patients who received brentuximab vedotin (BV) plus cyclophosphamide, doxorubicin, and prednisone (CHP) had superior progression-free survival (PFS) and overall survival (OS) compared to patients who received standard treatment with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP).

These results supported the recent U.S. approval of BV in combination with CHP for adults with previously untreated, systemic anaplastic large-cell lymphoma or other CD30-expressing PTCLs, including angioimmunoblastic T-cell lymphoma and PTCL not otherwise specified.

“ECHELON-2 is the first prospective trial in peripheral T-cell lymphoma to show an overall survival benefit over CHOP,” said Steven M. Horwitz, MD, of Memorial Sloan Kettering Cancer Center in Basking Ridge, New Jersey.

Dr. Horwitz presented results from this trial at ASH as abstract 997. Results were simultaneously published in The Lancet.

Patients and treatment

ECHELON-2 (NCT01777152) enrolled 452 patients with previously untreated, CD30-positive PTCL. Subtypes included ALK-positive (n=98) or -negative (n=218) systemic anaplastic large-cell lymphoma, PTCL not otherwise specified (n=72), angioimmunoblastic T-cell lymphoma (n=54), enteropathy-associated T-cell lymphoma (n=7), and adult T-cell leukemia/lymphoma (n=3).

Patients were randomized to receive BV-CHP plus placebo (n=226) or CHOP plus placebo (n=226) every 3 weeks for six to eight cycles.

At baseline, the median age was 58 in both the BV-CHP arm (range, 18-85) and the CHOP arm (range, 18-83). The majority of patients were male—59% in the BV-CHP arm and 67% in the CHOP arm—and most patients had stage III/IV disease—81% and 80%, respectively.

Eighty-nine percent of patients in the BV-CHP arm and 81% in the CHOP arm completed six or more cycles of their assigned treatment.

Twenty-seven percent of patients in the BV-CHP arm and 19% in the CHOP arm received consolidation consisting of radiotherapy (6% and 3%, respectively) and/or stem cell transplant (22% and 17%).

Twenty-six percent of patients in the BV-CHP arm and 42% in the CHOP arm received systemic therapy for residual or progressive disease, and 4% of patients in each arm received palliative radiation.

Efficacy

The overall response rate was 83% in the BV-CHP arm and 72% in the CHOP arm (P=0.0032). The complete response rates were 68% and 56%, respectively (P=0.0066).

At a median follow-up of 36.2 months, the median PFS was 48.2 months in the BV-CHP arm and 20.8 months in the CHOP arm. The rate of death or progression was 42% in the BV-CHP arm and 55% in the CHOP arm (hazard ratio=0.71, P=0.011).

At a median follow-up of 42.1 months, the median OS was not reached in either treatment arm. The rate of death was 23% in the BV-CHP arm and 32% in the CHOP arm (hazard ratio=0.66, P=0.0244).

Dr. Horwitz noted that this study was not powered to determine differences in OS or PFS according to PTCL subtypes.

Safety

BV-CHP had a comparable safety profile to CHOP, Dr. Horwitz said.

The rate of adverse events (AEs) was 99% in the BV-CHP arm and 98% in the CHOP arm. Grade 3 or higher AEs occurred in 66% and 65% of patients, respectively. Serious AEs occurred in 39% and 38%, respectively.

Three percent of patients in the BV-CHP arm and 4% of those in the CHOP arm had fatal AEs.

The most common AEs of any grade occurring in at least 20% of patients (in the BV-CHP and CHOP arms, respectively) were:

• Nausea (46% and 38%)
• Peripheral sensory neuropathy (45% and 41%)
• Neutropenia (38% for both)
• Diarrhea (38% and 20%)
• Constipation (29% and 30%)
• Alopecia (26% and 25%)
• Pyrexia (26% and 19%)
• Vomiting (26% and 17%)
• Fatigue (24% and 20%)
• Anemia (21% and 16%).

This research was funded by Seattle Genetics Inc. and Millennium Pharmaceuticals Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited.

Dr. Horwitz disclosed relationships with Seattle Genetics, Aileron Therapeutics, Innate Pharma, Millennium/Takeda, Forty Seven, Corvus, Mundipharma, ADC Therapeutics, Trillium, Celgene, Portola, Infinity/Verastem, Spectrum, and Kyowa-Hakka-Kirin.

Photo courtesy of ASH

SAN DIEGO—A newly approved treatment regimen provides a survival benefit over standard therapy for patients with CD30-positive peripheral T-cell lymphomas (PTCLs), according to a presentation at the 2018 ASH Annual Meeting.

In the ECHELON-2 trial, patients who received brentuximab vedotin (BV) plus cyclophosphamide, doxorubicin, and prednisone (CHP) had superior progression-free survival (PFS) and overall survival (OS) compared to patients who received standard treatment with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP).

These results supported the recent U.S. approval of BV in combination with CHP for adults with previously untreated, systemic anaplastic large-cell lymphoma or other CD30-expressing PTCLs, including angioimmunoblastic T-cell lymphoma and PTCL not otherwise specified.

“ECHELON-2 is the first prospective trial in peripheral T-cell lymphoma to show an overall survival benefit over CHOP,” said Steven M. Horwitz, MD, of Memorial Sloan Kettering Cancer Center in Basking Ridge, New Jersey.

Dr. Horwitz presented results from this trial at ASH as abstract 997. Results were simultaneously published in The Lancet.

Patients and treatment

ECHELON-2 (NCT01777152) enrolled 452 patients with previously untreated, CD30-positive PTCL. Subtypes included ALK-positive (n=98) or -negative (n=218) systemic anaplastic large-cell lymphoma, PTCL not otherwise specified (n=72), angioimmunoblastic T-cell lymphoma (n=54), enteropathy-associated T-cell lymphoma (n=7), and adult T-cell leukemia/lymphoma (n=3).

Patients were randomized to receive BV-CHP plus placebo (n=226) or CHOP plus placebo (n=226) every 3 weeks for six to eight cycles.

At baseline, the median age was 58 in both the BV-CHP arm (range, 18-85) and the CHOP arm (range, 18-83). The majority of patients were male—59% in the BV-CHP arm and 67% in the CHOP arm—and most patients had stage III/IV disease—81% and 80%, respectively.

Eighty-nine percent of patients in the BV-CHP arm and 81% in the CHOP arm completed six or more cycles of their assigned treatment.

Twenty-seven percent of patients in the BV-CHP arm and 19% in the CHOP arm received consolidation consisting of radiotherapy (6% and 3%, respectively) and/or stem cell transplant (22% and 17%).

Twenty-six percent of patients in the BV-CHP arm and 42% in the CHOP arm received systemic therapy for residual or progressive disease, and 4% of patients in each arm received palliative radiation.

Efficacy

The overall response rate was 83% in the BV-CHP arm and 72% in the CHOP arm (P=0.0032). The complete response rates were 68% and 56%, respectively (P=0.0066).

At a median follow-up of 36.2 months, the median PFS was 48.2 months in the BV-CHP arm and 20.8 months in the CHOP arm. The rate of death or progression was 42% in the BV-CHP arm and 55% in the CHOP arm (hazard ratio=0.71, P=0.011).

At a median follow-up of 42.1 months, the median OS was not reached in either treatment arm. The rate of death was 23% in the BV-CHP arm and 32% in the CHOP arm (hazard ratio=0.66, P=0.0244).

Dr. Horwitz noted that this study was not powered to determine differences in OS or PFS according to PTCL subtypes.

Safety

BV-CHP had a comparable safety profile to CHOP, Dr. Horwitz said.

The rate of adverse events (AEs) was 99% in the BV-CHP arm and 98% in the CHOP arm. Grade 3 or higher AEs occurred in 66% and 65% of patients, respectively. Serious AEs occurred in 39% and 38%, respectively.

Three percent of patients in the BV-CHP arm and 4% of those in the CHOP arm had fatal AEs.

The most common AEs of any grade occurring in at least 20% of patients (in the BV-CHP and CHOP arms, respectively) were:

• Nausea (46% and 38%)
• Peripheral sensory neuropathy (45% and 41%)
• Neutropenia (38% for both)
• Diarrhea (38% and 20%)
• Constipation (29% and 30%)
• Alopecia (26% and 25%)
• Pyrexia (26% and 19%)
• Vomiting (26% and 17%)
• Fatigue (24% and 20%)
• Anemia (21% and 16%).

This research was funded by Seattle Genetics Inc. and Millennium Pharmaceuticals Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited.

Dr. Horwitz disclosed relationships with Seattle Genetics, Aileron Therapeutics, Innate Pharma, Millennium/Takeda, Forty Seven, Corvus, Mundipharma, ADC Therapeutics, Trillium, Celgene, Portola, Infinity/Verastem, Spectrum, and Kyowa-Hakka-Kirin.

Photo courtesy of ASH

SAN DIEGO—A newly approved treatment regimen provides a survival benefit over standard therapy for patients with CD30-positive peripheral T-cell lymphomas (PTCLs), according to a presentation at the 2018 ASH Annual Meeting.

In the ECHELON-2 trial, patients who received brentuximab vedotin (BV) plus cyclophosphamide, doxorubicin, and prednisone (CHP) had superior progression-free survival (PFS) and overall survival (OS) compared to patients who received standard treatment with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP).

These results supported the recent U.S. approval of BV in combination with CHP for adults with previously untreated, systemic anaplastic large-cell lymphoma or other CD30-expressing PTCLs, including angioimmunoblastic T-cell lymphoma and PTCL not otherwise specified.

“ECHELON-2 is the first prospective trial in peripheral T-cell lymphoma to show an overall survival benefit over CHOP,” said Steven M. Horwitz, MD, of Memorial Sloan Kettering Cancer Center in Basking Ridge, New Jersey.

Dr. Horwitz presented results from this trial at ASH as abstract 997. Results were simultaneously published in The Lancet.

Patients and treatment

ECHELON-2 (NCT01777152) enrolled 452 patients with previously untreated, CD30-positive PTCL. Subtypes included ALK-positive (n=98) or -negative (n=218) systemic anaplastic large-cell lymphoma, PTCL not otherwise specified (n=72), angioimmunoblastic T-cell lymphoma (n=54), enteropathy-associated T-cell lymphoma (n=7), and adult T-cell leukemia/lymphoma (n=3).

Patients were randomized to receive BV-CHP plus placebo (n=226) or CHOP plus placebo (n=226) every 3 weeks for six to eight cycles.

At baseline, the median age was 58 in both the BV-CHP arm (range, 18-85) and the CHOP arm (range, 18-83). The majority of patients were male—59% in the BV-CHP arm and 67% in the CHOP arm—and most patients had stage III/IV disease—81% and 80%, respectively.

Eighty-nine percent of patients in the BV-CHP arm and 81% in the CHOP arm completed six or more cycles of their assigned treatment.

Twenty-seven percent of patients in the BV-CHP arm and 19% in the CHOP arm received consolidation consisting of radiotherapy (6% and 3%, respectively) and/or stem cell transplant (22% and 17%).

Twenty-six percent of patients in the BV-CHP arm and 42% in the CHOP arm received systemic therapy for residual or progressive disease, and 4% of patients in each arm received palliative radiation.

Efficacy

The overall response rate was 83% in the BV-CHP arm and 72% in the CHOP arm (P=0.0032). The complete response rates were 68% and 56%, respectively (P=0.0066).

At a median follow-up of 36.2 months, the median PFS was 48.2 months in the BV-CHP arm and 20.8 months in the CHOP arm. The rate of death or progression was 42% in the BV-CHP arm and 55% in the CHOP arm (hazard ratio=0.71, P=0.011).

At a median follow-up of 42.1 months, the median OS was not reached in either treatment arm. The rate of death was 23% in the BV-CHP arm and 32% in the CHOP arm (hazard ratio=0.66, P=0.0244).

Dr. Horwitz noted that this study was not powered to determine differences in OS or PFS according to PTCL subtypes.

Safety

BV-CHP had a comparable safety profile to CHOP, Dr. Horwitz said.

The rate of adverse events (AEs) was 99% in the BV-CHP arm and 98% in the CHOP arm. Grade 3 or higher AEs occurred in 66% and 65% of patients, respectively. Serious AEs occurred in 39% and 38%, respectively.

Three percent of patients in the BV-CHP arm and 4% of those in the CHOP arm had fatal AEs.

The most common AEs of any grade occurring in at least 20% of patients (in the BV-CHP and CHOP arms, respectively) were:

• Nausea (46% and 38%)
• Peripheral sensory neuropathy (45% and 41%)
• Neutropenia (38% for both)
• Diarrhea (38% and 20%)
• Constipation (29% and 30%)
• Alopecia (26% and 25%)
• Pyrexia (26% and 19%)
• Vomiting (26% and 17%)
• Fatigue (24% and 20%)
• Anemia (21% and 16%).

This research was funded by Seattle Genetics Inc. and Millennium Pharmaceuticals Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited.

Dr. Horwitz disclosed relationships with Seattle Genetics, Aileron Therapeutics, Innate Pharma, Millennium/Takeda, Forty Seven, Corvus, Mundipharma, ADC Therapeutics, Trillium, Celgene, Portola, Infinity/Verastem, Spectrum, and Kyowa-Hakka-Kirin.

© ASH/Luke Franke 2018

SAN DIEGO—An updated analysis of the JULIET trial showed that tisagenlecleucel produced a high rate of durable responses in adults with relapsed or refractory diffuse large B-cell lymphoma (DLBCL).

After a median follow-up of 19 months, two-thirds of adults with relapsed/refractory DLBCL who had early responses to the chimeric antigen receptor (CAR) T-cell therapy remained in remission with no evidence of minimal residual disease.

“Since the previous report, no new deaths have been reported due to any cause other than patient disease progression, no treatment-related mortality was seen throughout the study, and there were three early deaths, all related to lymphoma that progressed,” said study investigator Richard Thomas Maziarz, MD, of Oregon Health & Science University’s Knight Cancer Institute in Portland.

Dr. Maziarz and his colleagues reported the updated study results at the 2018 ASH Annual Meeting (abstract 1684). Results were published simultaneously in The New England Journal of Medicine. Data reported here are based on the ASH data.

JULIET then

In the phase 2, single-arm trial, investigators enrolled adults with DLBCL who had relapsed or were refractory after two or more prior lines of therapy and who were either ineligible for hematopoietic stem cell transplant (HSCT) or who experienced disease progression after HSCT.

Interim results of the study were previously reported at the 22nd Congress of the European Hematology Association in 2017.

At that meeting, Gilles Salles, MD, PhD, of the University of Lyon in France, presented results of an analysis of available efficacy data on 51 patients with at least 3 months of follow-up.

In this population, the best overall response rate (ORR) was 59%. Three-month ORR was 45%, consisting of 37% complete responses (CR) and 8% partial responses (PR).

Relapse-free survival at 6 months was 79%, and all patients who had responses at 3 months continued to have responses at the time of data cutoff.

JULIET now

The current analysis was completed after a median time from infusion to data cutoff of 19 months as of May 21, 2018. The analysis included 115 patients who received CAR T-cell infusions, 99 of whom were evaluable for efficacy.

As reported at ASH, the best ORR, the primary endpoint, was 54%, comprised of 40% CR and 13% PR.

Fifty-four percent of patients who had achieved PR converted to CR.

The response rates were consistent across all subgroups, regardless of age, sex, previous response status, International Prognostic Index score at enrollment, prior therapy, molecular subtype, and other factors.

Estimated relapse-free survival 12 months after documentation of an initial response was 64%.

The median duration of response had not been reached at the time of data cutoff, and the median overall survival had not been reached for patients with a CR.

Median overall survival in this heavily pretreated population as a whole (all patients who received CAR T-cell infusions) was 11.1 months and not reached for patients in CR.

Adverse events of special interest included grade 3 or 4 cytokine release syndrome (CRS) in 23% of patients, prolonged cytopenia in 34%, infections in 19%, neurologic events in 11%, febrile neutropenia in 15%, and tumor lysis syndrome in 2%.

There were no deaths attributable to the treatment, CRS, or to cerebral edema, a complication of CAR T-cell therapy that appears to be related to the costimulatory molecule used in various constructs.

The JULIET trial is supported by Novartis. Dr. Maziarz disclosed honoraria, consultancy fees, and/or research funding from Novartis, Incyte, Juno Therapeutics, and Kite Therapeutics as well as patents/royalties from Athersys, Inc. 

© ASH/Luke Franke 2018

SAN DIEGO—An updated analysis of the JULIET trial showed that tisagenlecleucel produced a high rate of durable responses in adults with relapsed or refractory diffuse large B-cell lymphoma (DLBCL).

After a median follow-up of 19 months, two-thirds of adults with relapsed/refractory DLBCL who had early responses to the chimeric antigen receptor (CAR) T-cell therapy remained in remission with no evidence of minimal residual disease.

“Since the previous report, no new deaths have been reported due to any cause other than patient disease progression, no treatment-related mortality was seen throughout the study, and there were three early deaths, all related to lymphoma that progressed,” said study investigator Richard Thomas Maziarz, MD, of Oregon Health & Science University’s Knight Cancer Institute in Portland.

Dr. Maziarz and his colleagues reported the updated study results at the 2018 ASH Annual Meeting (abstract 1684). Results were published simultaneously in The New England Journal of Medicine. Data reported here are based on the ASH data.

JULIET then

In the phase 2, single-arm trial, investigators enrolled adults with DLBCL who had relapsed or were refractory after two or more prior lines of therapy and who were either ineligible for hematopoietic stem cell transplant (HSCT) or who experienced disease progression after HSCT.

Interim results of the study were previously reported at the 22nd Congress of the European Hematology Association in 2017.

At that meeting, Gilles Salles, MD, PhD, of the University of Lyon in France, presented results of an analysis of available efficacy data on 51 patients with at least 3 months of follow-up.

In this population, the best overall response rate (ORR) was 59%. Three-month ORR was 45%, consisting of 37% complete responses (CR) and 8% partial responses (PR).

Relapse-free survival at 6 months was 79%, and all patients who had responses at 3 months continued to have responses at the time of data cutoff.

JULIET now

The current analysis was completed after a median time from infusion to data cutoff of 19 months as of May 21, 2018. The analysis included 115 patients who received CAR T-cell infusions, 99 of whom were evaluable for efficacy.

As reported at ASH, the best ORR, the primary endpoint, was 54%, comprised of 40% CR and 13% PR.

Fifty-four percent of patients who had achieved PR converted to CR.

The response rates were consistent across all subgroups, regardless of age, sex, previous response status, International Prognostic Index score at enrollment, prior therapy, molecular subtype, and other factors.

Estimated relapse-free survival 12 months after documentation of an initial response was 64%.

The median duration of response had not been reached at the time of data cutoff, and the median overall survival had not been reached for patients with a CR.

Median overall survival in this heavily pretreated population as a whole (all patients who received CAR T-cell infusions) was 11.1 months and not reached for patients in CR.

Adverse events of special interest included grade 3 or 4 cytokine release syndrome (CRS) in 23% of patients, prolonged cytopenia in 34%, infections in 19%, neurologic events in 11%, febrile neutropenia in 15%, and tumor lysis syndrome in 2%.

There were no deaths attributable to the treatment, CRS, or to cerebral edema, a complication of CAR T-cell therapy that appears to be related to the costimulatory molecule used in various constructs.

The JULIET trial is supported by Novartis. Dr. Maziarz disclosed honoraria, consultancy fees, and/or research funding from Novartis, Incyte, Juno Therapeutics, and Kite Therapeutics as well as patents/royalties from Athersys, Inc. 

© ASH/Luke Franke 2018

SAN DIEGO—An updated analysis of the JULIET trial showed that tisagenlecleucel produced a high rate of durable responses in adults with relapsed or refractory diffuse large B-cell lymphoma (DLBCL).

After a median follow-up of 19 months, two-thirds of adults with relapsed/refractory DLBCL who had early responses to the chimeric antigen receptor (CAR) T-cell therapy remained in remission with no evidence of minimal residual disease.

“Since the previous report, no new deaths have been reported due to any cause other than patient disease progression, no treatment-related mortality was seen throughout the study, and there were three early deaths, all related to lymphoma that progressed,” said study investigator Richard Thomas Maziarz, MD, of Oregon Health & Science University’s Knight Cancer Institute in Portland.

Dr. Maziarz and his colleagues reported the updated study results at the 2018 ASH Annual Meeting (abstract 1684). Results were published simultaneously in The New England Journal of Medicine. Data reported here are based on the ASH data.

JULIET then

In the phase 2, single-arm trial, investigators enrolled adults with DLBCL who had relapsed or were refractory after two or more prior lines of therapy and who were either ineligible for hematopoietic stem cell transplant (HSCT) or who experienced disease progression after HSCT.

Interim results of the study were previously reported at the 22nd Congress of the European Hematology Association in 2017.

At that meeting, Gilles Salles, MD, PhD, of the University of Lyon in France, presented results of an analysis of available efficacy data on 51 patients with at least 3 months of follow-up.

In this population, the best overall response rate (ORR) was 59%. Three-month ORR was 45%, consisting of 37% complete responses (CR) and 8% partial responses (PR).

Relapse-free survival at 6 months was 79%, and all patients who had responses at 3 months continued to have responses at the time of data cutoff.

JULIET now

The current analysis was completed after a median time from infusion to data cutoff of 19 months as of May 21, 2018. The analysis included 115 patients who received CAR T-cell infusions, 99 of whom were evaluable for efficacy.

As reported at ASH, the best ORR, the primary endpoint, was 54%, comprised of 40% CR and 13% PR.

Fifty-four percent of patients who had achieved PR converted to CR.

The response rates were consistent across all subgroups, regardless of age, sex, previous response status, International Prognostic Index score at enrollment, prior therapy, molecular subtype, and other factors.

Estimated relapse-free survival 12 months after documentation of an initial response was 64%.

The median duration of response had not been reached at the time of data cutoff, and the median overall survival had not been reached for patients with a CR.

Median overall survival in this heavily pretreated population as a whole (all patients who received CAR T-cell infusions) was 11.1 months and not reached for patients in CR.

Adverse events of special interest included grade 3 or 4 cytokine release syndrome (CRS) in 23% of patients, prolonged cytopenia in 34%, infections in 19%, neurologic events in 11%, febrile neutropenia in 15%, and tumor lysis syndrome in 2%.

There were no deaths attributable to the treatment, CRS, or to cerebral edema, a complication of CAR T-cell therapy that appears to be related to the costimulatory molecule used in various constructs.

The JULIET trial is supported by Novartis. Dr. Maziarz disclosed honoraria, consultancy fees, and/or research funding from Novartis, Incyte, Juno Therapeutics, and Kite Therapeutics as well as patents/royalties from Athersys, Inc. 

SAN DIEGO – Two-thirds of adults with relapsed or refractory diffuse large B-cell lymphoma who had early responses to chimeric antigen receptor T-cell (CAR T) therapy with tisagenlecleucel (Kymriah) remain in remission with no evidence of minimal residual disease, according to an updated analysis of the JULIET trial.

In the single-arm, open-label trial, the overall response rate after 19 months of follow-up was 54%, including 40% complete remissions and 14% partial remissions. The median duration of response had not been reached at the time of data cutoff, and the median overall survival had not been reached for patients with a complete remission. Overall survival in this heavily pretreated population as a whole (all patients who received CAR T-cell infusions) was 11.1 months.

Adverse events were similar to those previously reported and were manageable, according to investigator Richard Thomas Maziarz, MD, from the Oregon Health & Science Knight Cancer Institute in Portland.

In this video interview at the annual meeting of the American Society of Hematology, Dr. Maziarz discusses the promising results using CAR T cells in this difficult to treat population.

SAN DIEGO – Two-thirds of adults with relapsed or refractory diffuse large B-cell lymphoma who had early responses to chimeric antigen receptor T-cell (CAR T) therapy with tisagenlecleucel (Kymriah) remain in remission with no evidence of minimal residual disease, according to an updated analysis of the JULIET trial.

In the single-arm, open-label trial, the overall response rate after 19 months of follow-up was 54%, including 40% complete remissions and 14% partial remissions. The median duration of response had not been reached at the time of data cutoff, and the median overall survival had not been reached for patients with a complete remission. Overall survival in this heavily pretreated population as a whole (all patients who received CAR T-cell infusions) was 11.1 months.

Adverse events were similar to those previously reported and were manageable, according to investigator Richard Thomas Maziarz, MD, from the Oregon Health & Science Knight Cancer Institute in Portland.

In this video interview at the annual meeting of the American Society of Hematology, Dr. Maziarz discusses the promising results using CAR T cells in this difficult to treat population.

SAN DIEGO – Two-thirds of adults with relapsed or refractory diffuse large B-cell lymphoma who had early responses to chimeric antigen receptor T-cell (CAR T) therapy with tisagenlecleucel (Kymriah) remain in remission with no evidence of minimal residual disease, according to an updated analysis of the JULIET trial.

In the single-arm, open-label trial, the overall response rate after 19 months of follow-up was 54%, including 40% complete remissions and 14% partial remissions. The median duration of response had not been reached at the time of data cutoff, and the median overall survival had not been reached for patients with a complete remission. Overall survival in this heavily pretreated population as a whole (all patients who received CAR T-cell infusions) was 11.1 months.

Adverse events were similar to those previously reported and were manageable, according to investigator Richard Thomas Maziarz, MD, from the Oregon Health & Science Knight Cancer Institute in Portland.

In this video interview at the annual meeting of the American Society of Hematology, Dr. Maziarz discusses the promising results using CAR T cells in this difficult to treat population.

SAN DIEGO – Chimeric antigen receptor T-cell therapy with tisagenlecleucel (Kymriah) is associated with a high rate of durable responses in adults with relapsed or refractory diffuse large B-cell lymphoma, an updated analysis of the JULIET trial showed.

Neil Osterweil/MDedge News

After a median follow-up of 19 months, two-thirds of adults with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) who had early responses to chimeric antigen receptor (CAR) T-cell therapy with tisagenlecleucel remained in remission with no evidence of minimal residual disease, reported Richard Thomas Maziarz, MD, from the Oregon Health & Science Knight Cancer Institute in Portland, at the annual meeting of the American Society of Hematology.

“Since the previous report, no new deaths have been reported due to any cause other than patient disease progression. No treatment-related mortality was seen throughout the study, and there were three early deaths, all related to lymphoma that progressed,” he said in a briefing prior to presentation of the data in a scientific poster.

The updated study results were published simultaneously online in the New England Journal of Medicine.

JULIET then

In the phase 2, single-arm trial, investigators enrolled adults with DLBCL that had relapsed or was refractory after two or more prior lines of therapy and who were either ineligible for hematopoietic stem cell transplant or who experienced disease progression after transplant.

Interim results of the study were previously reported at the European Hematology Association Congress in 2017.

At that meeting, Gilles Salles, MD, PhD, from the University of Lyon (France), presented results of an analysis of available efficacy data on 51 patients with at least 3 months of follow-up. In this population, the best overall response rate was 59%. The 3-month overall response rate was 45%, consisting of 37% complete responses and 8% partial responses. Relapse-free survival at 6 months was 79% and all patients who had responses at 3 months continued to have responses at the time of data cutoff.

JULIET now

In the most recent analysis, completed after a median time from infusion to data cutoff of 14 months, the investigators reported on efficacy in 93 patients who received CAR T-cell infusions.

The best overall response rate, the primary endpoint, was 52%, comprising 40% complete responses and 12% partial responses. The response rates were consistent across all prognostic subgroups, including age, sex, previous response status, International Prognostic Index score at enrollment, prior therapy, molecular subtype, and other factors.

Estimated relapse-free survival 12 months after documentation of an initial response was 65%, and was 79% among patients who had complete responses.

The median duration of response had not been reached at the time of data cutoff; the median overall survival had not been reached for patients with a complete remission. Overall survival in this heavily pretreated population as a whole (all patients who received CAR T-cell infusions) was 11.1 months.

Adverse events of special interest included grade 3 or 4 cytokine release syndrome (CRS) in 23% of patients, prolonged cytopenia in 34%, infections in 19%, neurologic events in 11%, febrile neutropenia in 15%, and tumor lysis syndrome in 2%.

There were no deaths attributable to CRS or to cerebral edema, a complication of CAR T-cell therapy that appears to be related to the costimulatory molecule used in various constructs.

“Patients with relapsed or refractory DLBCL who are not eligible for high-dose therapy and hematopoietic cell transplantation or for whom such therapy was not successful have very few treatment options. For these patients, tisagenlecleucel shows promise that will need to be confirmed through larger studies with longer follow-up,” the investigators wrote in the New England Journal of Medicine.

The JULIET Trial is supported by Novartis. Dr. Maziar reported personal fees from Incyte, Kite Therapeutics, and Athersys.

SOURCE: Maziarz RT et al. N Engl J Med. 2018 Dec 1. doi: 10.1056/NEJMoa1804980.
 

SAN DIEGO – Chimeric antigen receptor T-cell therapy with tisagenlecleucel (Kymriah) is associated with a high rate of durable responses in adults with relapsed or refractory diffuse large B-cell lymphoma, an updated analysis of the JULIET trial showed.

Neil Osterweil/MDedge News

After a median follow-up of 19 months, two-thirds of adults with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) who had early responses to chimeric antigen receptor (CAR) T-cell therapy with tisagenlecleucel remained in remission with no evidence of minimal residual disease, reported Richard Thomas Maziarz, MD, from the Oregon Health & Science Knight Cancer Institute in Portland, at the annual meeting of the American Society of Hematology.

“Since the previous report, no new deaths have been reported due to any cause other than patient disease progression. No treatment-related mortality was seen throughout the study, and there were three early deaths, all related to lymphoma that progressed,” he said in a briefing prior to presentation of the data in a scientific poster.

The updated study results were published simultaneously online in the New England Journal of Medicine.

JULIET then

In the phase 2, single-arm trial, investigators enrolled adults with DLBCL that had relapsed or was refractory after two or more prior lines of therapy and who were either ineligible for hematopoietic stem cell transplant or who experienced disease progression after transplant.

Interim results of the study were previously reported at the European Hematology Association Congress in 2017.

At that meeting, Gilles Salles, MD, PhD, from the University of Lyon (France), presented results of an analysis of available efficacy data on 51 patients with at least 3 months of follow-up. In this population, the best overall response rate was 59%. The 3-month overall response rate was 45%, consisting of 37% complete responses and 8% partial responses. Relapse-free survival at 6 months was 79% and all patients who had responses at 3 months continued to have responses at the time of data cutoff.

JULIET now

In the most recent analysis, completed after a median time from infusion to data cutoff of 14 months, the investigators reported on efficacy in 93 patients who received CAR T-cell infusions.

The best overall response rate, the primary endpoint, was 52%, comprising 40% complete responses and 12% partial responses. The response rates were consistent across all prognostic subgroups, including age, sex, previous response status, International Prognostic Index score at enrollment, prior therapy, molecular subtype, and other factors.

Estimated relapse-free survival 12 months after documentation of an initial response was 65%, and was 79% among patients who had complete responses.

The median duration of response had not been reached at the time of data cutoff; the median overall survival had not been reached for patients with a complete remission. Overall survival in this heavily pretreated population as a whole (all patients who received CAR T-cell infusions) was 11.1 months.

Adverse events of special interest included grade 3 or 4 cytokine release syndrome (CRS) in 23% of patients, prolonged cytopenia in 34%, infections in 19%, neurologic events in 11%, febrile neutropenia in 15%, and tumor lysis syndrome in 2%.

There were no deaths attributable to CRS or to cerebral edema, a complication of CAR T-cell therapy that appears to be related to the costimulatory molecule used in various constructs.

“Patients with relapsed or refractory DLBCL who are not eligible for high-dose therapy and hematopoietic cell transplantation or for whom such therapy was not successful have very few treatment options. For these patients, tisagenlecleucel shows promise that will need to be confirmed through larger studies with longer follow-up,” the investigators wrote in the New England Journal of Medicine.

The JULIET Trial is supported by Novartis. Dr. Maziar reported personal fees from Incyte, Kite Therapeutics, and Athersys.

SOURCE: Maziarz RT et al. N Engl J Med. 2018 Dec 1. doi: 10.1056/NEJMoa1804980.
 

SAN DIEGO – Chimeric antigen receptor T-cell therapy with tisagenlecleucel (Kymriah) is associated with a high rate of durable responses in adults with relapsed or refractory diffuse large B-cell lymphoma, an updated analysis of the JULIET trial showed.

Neil Osterweil/MDedge News

After a median follow-up of 19 months, two-thirds of adults with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) who had early responses to chimeric antigen receptor (CAR) T-cell therapy with tisagenlecleucel remained in remission with no evidence of minimal residual disease, reported Richard Thomas Maziarz, MD, from the Oregon Health & Science Knight Cancer Institute in Portland, at the annual meeting of the American Society of Hematology.

“Since the previous report, no new deaths have been reported due to any cause other than patient disease progression. No treatment-related mortality was seen throughout the study, and there were three early deaths, all related to lymphoma that progressed,” he said in a briefing prior to presentation of the data in a scientific poster.

The updated study results were published simultaneously online in the New England Journal of Medicine.

JULIET then

In the phase 2, single-arm trial, investigators enrolled adults with DLBCL that had relapsed or was refractory after two or more prior lines of therapy and who were either ineligible for hematopoietic stem cell transplant or who experienced disease progression after transplant.

Interim results of the study were previously reported at the European Hematology Association Congress in 2017.

At that meeting, Gilles Salles, MD, PhD, from the University of Lyon (France), presented results of an analysis of available efficacy data on 51 patients with at least 3 months of follow-up. In this population, the best overall response rate was 59%. The 3-month overall response rate was 45%, consisting of 37% complete responses and 8% partial responses. Relapse-free survival at 6 months was 79% and all patients who had responses at 3 months continued to have responses at the time of data cutoff.

JULIET now

In the most recent analysis, completed after a median time from infusion to data cutoff of 14 months, the investigators reported on efficacy in 93 patients who received CAR T-cell infusions.

The best overall response rate, the primary endpoint, was 52%, comprising 40% complete responses and 12% partial responses. The response rates were consistent across all prognostic subgroups, including age, sex, previous response status, International Prognostic Index score at enrollment, prior therapy, molecular subtype, and other factors.

Estimated relapse-free survival 12 months after documentation of an initial response was 65%, and was 79% among patients who had complete responses.

The median duration of response had not been reached at the time of data cutoff; the median overall survival had not been reached for patients with a complete remission. Overall survival in this heavily pretreated population as a whole (all patients who received CAR T-cell infusions) was 11.1 months.

Adverse events of special interest included grade 3 or 4 cytokine release syndrome (CRS) in 23% of patients, prolonged cytopenia in 34%, infections in 19%, neurologic events in 11%, febrile neutropenia in 15%, and tumor lysis syndrome in 2%.

There were no deaths attributable to CRS or to cerebral edema, a complication of CAR T-cell therapy that appears to be related to the costimulatory molecule used in various constructs.

“Patients with relapsed or refractory DLBCL who are not eligible for high-dose therapy and hematopoietic cell transplantation or for whom such therapy was not successful have very few treatment options. For these patients, tisagenlecleucel shows promise that will need to be confirmed through larger studies with longer follow-up,” the investigators wrote in the New England Journal of Medicine.

The JULIET Trial is supported by Novartis. Dr. Maziar reported personal fees from Incyte, Kite Therapeutics, and Athersys.

SOURCE: Maziarz RT et al. N Engl J Med. 2018 Dec 1. doi: 10.1056/NEJMoa1804980.
 

Infection with certain viruses has been causally linked to the development of cancer. In recent years, an improved understanding of the unique pathology and molecular underpinnings of these virally associated cancers has prompted the development of more personalized treatment strategies, with a particular focus on immunotherapy. Here, we describe some of the latest developments.

The link between viruses and cancer

Suspicions about a possible role of viral infections in the development of cancer were first aroused in the early 1900s. The seminal discovery is traced back to Peyton Rous, who showed that a malignant tumor growing in a chicken could be transferred to a healthy bird by injecting it with tumor extracts that contained no actual tumor cells.¹

The infectious etiology of human cancer, however, remained controversial until many years later when the first cancer-causing virus, Epstein-Barr virus (EBV), was identified in cell cultures from patients with Burkitt lymphoma. Shortly afterward, the Rous sarcoma virus was unveiled as the oncogenic agent behind Rous’ observations.²Seven viruses have now been linked to the development of cancers and are thought to be responsible for around 12% of all cancer cases worldwide. The burden is likely to increase as technological advancements make it easier to establish a causal link between viruses and cancer development.³

In addition to making these links, researchers have also made significant headway in understanding how viruses cause cancer. Cancerous transformation of host cells occurs in only a minority of those who are infected with oncogenic viruses and often occurs in the setting of chronic infection.

Viruses can mediate carcinogenesis by direct and/or indirect mechanisms (Figure 1). Many of the hallmarks of cancer, the key attributes that drive the transformation from a normal cell to a malignant one, are compatible with the virus’s needs, such as needing to avoid cell death, increasing cell proliferation, and avoiding detection by the immune system.

Vaccines lead the charge in HPV-driven cancers

German virologist Harald zur Hausen received the Nobel Prize in 2008 for his discovery of the oncogenic role of human papillomaviruses (HPVs), a large family of more than 100 DNA viruses that infect the epithelial cells of the skin and mucous membranes. They are responsible for the largest number of virally associated cancer cases globally – around 5% (Table 1).

A number of different cancer types are linked to HPV infection, but it is best known as the cause of cervical cancer. The development of diagnostic blood tests and prophylactic vaccines for prevention and early intervention in HPV infection has helped to reduce the incidence of cervical cancer. Conversely, another type of HPV-associated cancer, head and neck squamous cell carcinoma (HNSCC), has seen increased incidence in recent years.

HPVs are categorized according to their oncogenic potential as high, intermediate, or low risk. The high-risk HPV16 and HPV18 strains are most commonly associated with cancer. They are thought to cause cancer predominantly through integration into the host genome. The HPV genome is composed of 8 genes encoding proteins that regulate viral replication and assembly. The E6 and E7 genes are the most highly oncogenic; as the HPV DNA is inserted into the host genome, the transcriptional regulator of E6/E7 is lost, leading to their increased expression. These genes have significant oncogenic potential because of their interaction with 2 tumor suppressor proteins, p53 and pRb.^6,7

The largest investment in therapeutic development for HPV-positive cancers has been in the realm of immunotherapy in an effort to boost the anti-tumor immune response. In particular, there has been a focus on the development of therapeutic vaccines, designed to prime the anti-tumor immune response to recognize viral antigens. A variety of different types of vaccines are being developed, including live, attenuated and inactivated vaccines that are protein, DNA, or peptide based. Most developed to date target the E6/E7 proteins from the HPV16/18 strains (Table 2).^8,9

Hepatocellular carcinoma: a tale of two viruses

The hepatitis viruses are a group of 5 unrelated viruses that causes inflammation of the liver. Hepatitis B (HBV), a DNA virus, and hepatitis C (HCV), an RNA virus, are also oncoviruses; HBV in particular is one of the main causes of hepatocellular carcinoma (HCC), the most common type of liver cancer.

The highly inflammatory environment fostered by HBV and HCV infection causes liver damage that often leads to cirrhosis. Continued infection can drive permanent damage to the hepatocytes, leading to genetic and epigenetic damage and driving oncogenesis. As an RNA virus, HCV doesn’t integrate into the genome and no confirmed viral oncoproteins have been identified to date, therefore it mostly drives cancer through these indirect mechanisms, which is also reflected in the fact that HCV-associated HCC predominantly occurs against a backdrop of liver cirrhosis.

HBV does integrate into the host genome. Genome sequencing studies revealed hundreds of integration sites, but most commonly they disrupted host genes involved in telomere stability and cell cycle regulation, providing some insight into the mechanisms by which HBV-associated HCC develops. In addition, HBV produces several oncoproteins, including HBx, which disrupts gene transcription, cell signaling pathways, cell cycle progress, apoptosis and other cellular processes.^15,16

Multitargeted tyrosine kinase inhibitors (TKIs) have been the focal point of therapeutic development in HCC. However, following the approval of sorafenib in 2008, there was a dearth of effective new treatment options despite substantial efforts and numerous phase 3 trials. More recently, immunotherapy has also come to the forefront, especially immune checkpoint inhibitors.

Last year marked the first new drug approvals in nearly a decade – the TKI regorafenib (Stivarga) and immune checkpoint inhibitor nivolumab (Opdivo), both in the second-line setting after failure of sorafenib. Treatment options in this setting may continue to expand, with the TKIs cabozantinib and lenvatinib and the immune checkpoint inhibitor pembrolizumab and the combination of durvalumab and tremelimumab hot on their heels.^17-20 Many of these drugs are also being evaluated in the front-line setting in comparison with sorafenib (Table 3).

Adoptive cell therapy promising in EBV-positive cancers

More than 90% of the global population is infected with EBV, making it one of the most common human viruses. It is a member of the herpesvirus family that is probably best known as the cause of infectious mononucleosis. On rare occasions, however, EBV can cause tumor development, though our understanding of its exact pathogenic role in cancer is still incomplete.

EBV is a DNA virus that doesn’t tend to integrate into the host genome, but instead remains in the nucleus in the form of episomes and produces several oncoproteins, including latent membrane protein-1. It is associated with a range of different cancer types, including Burkitt lymphoma and other B-cell malignancies. It also infects epithelial cells and can cause nasopharyngeal carcinoma and gastric cancer, however, much less is known about the molecular underpinnings of these EBV-positive cancer types.^26,27Gastric cancers actually comprise the largest group of EBV-associated tumors because of the global incidence of this cancer type. The Cancer Genome Atlas Research Network recently characterized gastric cancer on a molecular level and identified an EBV-positive subgroup as a distinct clinical entity with unique molecular characteristics.²⁹

The focus of therapeutic development has again been on immunotherapy, however in this case the idea of collecting the patients T cells, engineering them to recognize EBV, and then reinfusing them into the patient – adoptive cell therapy – has gained the most traction (Table 4).

Newest oncovirus on the block

The most recently discovered cancer-associated virus is Merkel cell polyomavirus (MCV), a DNA virus that was identified in 2008. Like EBV, virtually the whole global adult population is infected with MCV. It is linked to the development of a highly aggressive and lethal, though rare, form of skin cancer – Merkel cell carcinoma.

MCV is found in around 80% of MCC cases and in fewer than 10% of melanomas and other skin cancers. Thus far, several direct mechanisms of oncogenesis have been described, including integration of MCV into the host genome and the production of viral oncogenes, though their precise function is as yet unclear.^32-34

The American Cancer Society estimates that only 1500 cases of MCC are diagnosed each year in the United States.³⁵ Its rarity makes it difficult to conduct clinical trials with sufficient power, yet some headway has still been made.

Around half of MCCs express the programmed cell death ligand 1 (PD-L1) on their surface, making them a logical candidate for immune checkpoint inhibition. In 2017, avelumab became the first FDA-approved drug for the treatment of MCC. Approval was based on the JAVELIN Merkel 200 study in which 88 patients received avelumab. After 1 year of follow-up the ORR was 31.8%, with a CR rate of 9%.³⁶

Genome sequencing studies suggest that the mutational profile of MCV-positive tumors is quite different to those that are MCV-negative, which could have therapeutic implications. To date, these implications have not been delineated, given the challenge of small patient numbers, however an ongoing phase 1/2 trial is evaluating the combination of avelumab and radiation therapy or recombinant interferon beta, with or without MCV-specific cytotoxic T cells in patients with MCC and MCV infection.

The 2 other known cancer-causing viruses are human T-lymphotropic virus 1 (HTLV-1), a retrovirus associated with adult T-cell leukemia/lymphoma (ATL) and Kaposi sarcoma herpesvirus (KSHV). The latter is the causative agent of Kaposi sarcoma, often in combination with human immunodeficiency virus (HIV), a rare skin tumor that became renowned in the 1980s as an AIDS-defining illness.

The incidence of HTLV-1- and KSHV-positive tumors is substantially lower than the other virally associated cancers and, like MCC, this makes studying them and conducting clinical trials of novel therapeutic options a challenge. Nonetheless, several trials of targeted therapies and immunotherapies are underway.

Infection with certain viruses has been causally linked to the development of cancer. In recent years, an improved understanding of the unique pathology and molecular underpinnings of these virally associated cancers has prompted the development of more personalized treatment strategies, with a particular focus on immunotherapy. Here, we describe some of the latest developments.

The link between viruses and cancer

Suspicions about a possible role of viral infections in the development of cancer were first aroused in the early 1900s. The seminal discovery is traced back to Peyton Rous, who showed that a malignant tumor growing in a chicken could be transferred to a healthy bird by injecting it with tumor extracts that contained no actual tumor cells.¹

The infectious etiology of human cancer, however, remained controversial until many years later when the first cancer-causing virus, Epstein-Barr virus (EBV), was identified in cell cultures from patients with Burkitt lymphoma. Shortly afterward, the Rous sarcoma virus was unveiled as the oncogenic agent behind Rous’ observations.²Seven viruses have now been linked to the development of cancers and are thought to be responsible for around 12% of all cancer cases worldwide. The burden is likely to increase as technological advancements make it easier to establish a causal link between viruses and cancer development.³

In addition to making these links, researchers have also made significant headway in understanding how viruses cause cancer. Cancerous transformation of host cells occurs in only a minority of those who are infected with oncogenic viruses and often occurs in the setting of chronic infection.

Viruses can mediate carcinogenesis by direct and/or indirect mechanisms (Figure 1). Many of the hallmarks of cancer, the key attributes that drive the transformation from a normal cell to a malignant one, are compatible with the virus’s needs, such as needing to avoid cell death, increasing cell proliferation, and avoiding detection by the immune system.

Vaccines lead the charge in HPV-driven cancers

German virologist Harald zur Hausen received the Nobel Prize in 2008 for his discovery of the oncogenic role of human papillomaviruses (HPVs), a large family of more than 100 DNA viruses that infect the epithelial cells of the skin and mucous membranes. They are responsible for the largest number of virally associated cancer cases globally – around 5% (Table 1).

A number of different cancer types are linked to HPV infection, but it is best known as the cause of cervical cancer. The development of diagnostic blood tests and prophylactic vaccines for prevention and early intervention in HPV infection has helped to reduce the incidence of cervical cancer. Conversely, another type of HPV-associated cancer, head and neck squamous cell carcinoma (HNSCC), has seen increased incidence in recent years.

HPVs are categorized according to their oncogenic potential as high, intermediate, or low risk. The high-risk HPV16 and HPV18 strains are most commonly associated with cancer. They are thought to cause cancer predominantly through integration into the host genome. The HPV genome is composed of 8 genes encoding proteins that regulate viral replication and assembly. The E6 and E7 genes are the most highly oncogenic; as the HPV DNA is inserted into the host genome, the transcriptional regulator of E6/E7 is lost, leading to their increased expression. These genes have significant oncogenic potential because of their interaction with 2 tumor suppressor proteins, p53 and pRb.^6,7

The largest investment in therapeutic development for HPV-positive cancers has been in the realm of immunotherapy in an effort to boost the anti-tumor immune response. In particular, there has been a focus on the development of therapeutic vaccines, designed to prime the anti-tumor immune response to recognize viral antigens. A variety of different types of vaccines are being developed, including live, attenuated and inactivated vaccines that are protein, DNA, or peptide based. Most developed to date target the E6/E7 proteins from the HPV16/18 strains (Table 2).^8,9

Hepatocellular carcinoma: a tale of two viruses

The hepatitis viruses are a group of 5 unrelated viruses that causes inflammation of the liver. Hepatitis B (HBV), a DNA virus, and hepatitis C (HCV), an RNA virus, are also oncoviruses; HBV in particular is one of the main causes of hepatocellular carcinoma (HCC), the most common type of liver cancer.

The highly inflammatory environment fostered by HBV and HCV infection causes liver damage that often leads to cirrhosis. Continued infection can drive permanent damage to the hepatocytes, leading to genetic and epigenetic damage and driving oncogenesis. As an RNA virus, HCV doesn’t integrate into the genome and no confirmed viral oncoproteins have been identified to date, therefore it mostly drives cancer through these indirect mechanisms, which is also reflected in the fact that HCV-associated HCC predominantly occurs against a backdrop of liver cirrhosis.

HBV does integrate into the host genome. Genome sequencing studies revealed hundreds of integration sites, but most commonly they disrupted host genes involved in telomere stability and cell cycle regulation, providing some insight into the mechanisms by which HBV-associated HCC develops. In addition, HBV produces several oncoproteins, including HBx, which disrupts gene transcription, cell signaling pathways, cell cycle progress, apoptosis and other cellular processes.^15,16

Multitargeted tyrosine kinase inhibitors (TKIs) have been the focal point of therapeutic development in HCC. However, following the approval of sorafenib in 2008, there was a dearth of effective new treatment options despite substantial efforts and numerous phase 3 trials. More recently, immunotherapy has also come to the forefront, especially immune checkpoint inhibitors.

Last year marked the first new drug approvals in nearly a decade – the TKI regorafenib (Stivarga) and immune checkpoint inhibitor nivolumab (Opdivo), both in the second-line setting after failure of sorafenib. Treatment options in this setting may continue to expand, with the TKIs cabozantinib and lenvatinib and the immune checkpoint inhibitor pembrolizumab and the combination of durvalumab and tremelimumab hot on their heels.^17-20 Many of these drugs are also being evaluated in the front-line setting in comparison with sorafenib (Table 3).

Adoptive cell therapy promising in EBV-positive cancers

More than 90% of the global population is infected with EBV, making it one of the most common human viruses. It is a member of the herpesvirus family that is probably best known as the cause of infectious mononucleosis. On rare occasions, however, EBV can cause tumor development, though our understanding of its exact pathogenic role in cancer is still incomplete.

EBV is a DNA virus that doesn’t tend to integrate into the host genome, but instead remains in the nucleus in the form of episomes and produces several oncoproteins, including latent membrane protein-1. It is associated with a range of different cancer types, including Burkitt lymphoma and other B-cell malignancies. It also infects epithelial cells and can cause nasopharyngeal carcinoma and gastric cancer, however, much less is known about the molecular underpinnings of these EBV-positive cancer types.^26,27Gastric cancers actually comprise the largest group of EBV-associated tumors because of the global incidence of this cancer type. The Cancer Genome Atlas Research Network recently characterized gastric cancer on a molecular level and identified an EBV-positive subgroup as a distinct clinical entity with unique molecular characteristics.²⁹

The focus of therapeutic development has again been on immunotherapy, however in this case the idea of collecting the patients T cells, engineering them to recognize EBV, and then reinfusing them into the patient – adoptive cell therapy – has gained the most traction (Table 4).

Newest oncovirus on the block

The most recently discovered cancer-associated virus is Merkel cell polyomavirus (MCV), a DNA virus that was identified in 2008. Like EBV, virtually the whole global adult population is infected with MCV. It is linked to the development of a highly aggressive and lethal, though rare, form of skin cancer – Merkel cell carcinoma.

MCV is found in around 80% of MCC cases and in fewer than 10% of melanomas and other skin cancers. Thus far, several direct mechanisms of oncogenesis have been described, including integration of MCV into the host genome and the production of viral oncogenes, though their precise function is as yet unclear.^32-34

The American Cancer Society estimates that only 1500 cases of MCC are diagnosed each year in the United States.³⁵ Its rarity makes it difficult to conduct clinical trials with sufficient power, yet some headway has still been made.

Around half of MCCs express the programmed cell death ligand 1 (PD-L1) on their surface, making them a logical candidate for immune checkpoint inhibition. In 2017, avelumab became the first FDA-approved drug for the treatment of MCC. Approval was based on the JAVELIN Merkel 200 study in which 88 patients received avelumab. After 1 year of follow-up the ORR was 31.8%, with a CR rate of 9%.³⁶

Genome sequencing studies suggest that the mutational profile of MCV-positive tumors is quite different to those that are MCV-negative, which could have therapeutic implications. To date, these implications have not been delineated, given the challenge of small patient numbers, however an ongoing phase 1/2 trial is evaluating the combination of avelumab and radiation therapy or recombinant interferon beta, with or without MCV-specific cytotoxic T cells in patients with MCC and MCV infection.

The 2 other known cancer-causing viruses are human T-lymphotropic virus 1 (HTLV-1), a retrovirus associated with adult T-cell leukemia/lymphoma (ATL) and Kaposi sarcoma herpesvirus (KSHV). The latter is the causative agent of Kaposi sarcoma, often in combination with human immunodeficiency virus (HIV), a rare skin tumor that became renowned in the 1980s as an AIDS-defining illness.

The incidence of HTLV-1- and KSHV-positive tumors is substantially lower than the other virally associated cancers and, like MCC, this makes studying them and conducting clinical trials of novel therapeutic options a challenge. Nonetheless, several trials of targeted therapies and immunotherapies are underway.

Infection with certain viruses has been causally linked to the development of cancer. In recent years, an improved understanding of the unique pathology and molecular underpinnings of these virally associated cancers has prompted the development of more personalized treatment strategies, with a particular focus on immunotherapy. Here, we describe some of the latest developments.

The link between viruses and cancer

Suspicions about a possible role of viral infections in the development of cancer were first aroused in the early 1900s. The seminal discovery is traced back to Peyton Rous, who showed that a malignant tumor growing in a chicken could be transferred to a healthy bird by injecting it with tumor extracts that contained no actual tumor cells.¹

The infectious etiology of human cancer, however, remained controversial until many years later when the first cancer-causing virus, Epstein-Barr virus (EBV), was identified in cell cultures from patients with Burkitt lymphoma. Shortly afterward, the Rous sarcoma virus was unveiled as the oncogenic agent behind Rous’ observations.²Seven viruses have now been linked to the development of cancers and are thought to be responsible for around 12% of all cancer cases worldwide. The burden is likely to increase as technological advancements make it easier to establish a causal link between viruses and cancer development.³

In addition to making these links, researchers have also made significant headway in understanding how viruses cause cancer. Cancerous transformation of host cells occurs in only a minority of those who are infected with oncogenic viruses and often occurs in the setting of chronic infection.

Viruses can mediate carcinogenesis by direct and/or indirect mechanisms (Figure 1). Many of the hallmarks of cancer, the key attributes that drive the transformation from a normal cell to a malignant one, are compatible with the virus’s needs, such as needing to avoid cell death, increasing cell proliferation, and avoiding detection by the immune system.

Vaccines lead the charge in HPV-driven cancers

German virologist Harald zur Hausen received the Nobel Prize in 2008 for his discovery of the oncogenic role of human papillomaviruses (HPVs), a large family of more than 100 DNA viruses that infect the epithelial cells of the skin and mucous membranes. They are responsible for the largest number of virally associated cancer cases globally – around 5% (Table 1).

A number of different cancer types are linked to HPV infection, but it is best known as the cause of cervical cancer. The development of diagnostic blood tests and prophylactic vaccines for prevention and early intervention in HPV infection has helped to reduce the incidence of cervical cancer. Conversely, another type of HPV-associated cancer, head and neck squamous cell carcinoma (HNSCC), has seen increased incidence in recent years.

HPVs are categorized according to their oncogenic potential as high, intermediate, or low risk. The high-risk HPV16 and HPV18 strains are most commonly associated with cancer. They are thought to cause cancer predominantly through integration into the host genome. The HPV genome is composed of 8 genes encoding proteins that regulate viral replication and assembly. The E6 and E7 genes are the most highly oncogenic; as the HPV DNA is inserted into the host genome, the transcriptional regulator of E6/E7 is lost, leading to their increased expression. These genes have significant oncogenic potential because of their interaction with 2 tumor suppressor proteins, p53 and pRb.^6,7

The largest investment in therapeutic development for HPV-positive cancers has been in the realm of immunotherapy in an effort to boost the anti-tumor immune response. In particular, there has been a focus on the development of therapeutic vaccines, designed to prime the anti-tumor immune response to recognize viral antigens. A variety of different types of vaccines are being developed, including live, attenuated and inactivated vaccines that are protein, DNA, or peptide based. Most developed to date target the E6/E7 proteins from the HPV16/18 strains (Table 2).^8,9

Hepatocellular carcinoma: a tale of two viruses

The hepatitis viruses are a group of 5 unrelated viruses that causes inflammation of the liver. Hepatitis B (HBV), a DNA virus, and hepatitis C (HCV), an RNA virus, are also oncoviruses; HBV in particular is one of the main causes of hepatocellular carcinoma (HCC), the most common type of liver cancer.

The highly inflammatory environment fostered by HBV and HCV infection causes liver damage that often leads to cirrhosis. Continued infection can drive permanent damage to the hepatocytes, leading to genetic and epigenetic damage and driving oncogenesis. As an RNA virus, HCV doesn’t integrate into the genome and no confirmed viral oncoproteins have been identified to date, therefore it mostly drives cancer through these indirect mechanisms, which is also reflected in the fact that HCV-associated HCC predominantly occurs against a backdrop of liver cirrhosis.

HBV does integrate into the host genome. Genome sequencing studies revealed hundreds of integration sites, but most commonly they disrupted host genes involved in telomere stability and cell cycle regulation, providing some insight into the mechanisms by which HBV-associated HCC develops. In addition, HBV produces several oncoproteins, including HBx, which disrupts gene transcription, cell signaling pathways, cell cycle progress, apoptosis and other cellular processes.^15,16

Multitargeted tyrosine kinase inhibitors (TKIs) have been the focal point of therapeutic development in HCC. However, following the approval of sorafenib in 2008, there was a dearth of effective new treatment options despite substantial efforts and numerous phase 3 trials. More recently, immunotherapy has also come to the forefront, especially immune checkpoint inhibitors.

Last year marked the first new drug approvals in nearly a decade – the TKI regorafenib (Stivarga) and immune checkpoint inhibitor nivolumab (Opdivo), both in the second-line setting after failure of sorafenib. Treatment options in this setting may continue to expand, with the TKIs cabozantinib and lenvatinib and the immune checkpoint inhibitor pembrolizumab and the combination of durvalumab and tremelimumab hot on their heels.^17-20 Many of these drugs are also being evaluated in the front-line setting in comparison with sorafenib (Table 3).

Adoptive cell therapy promising in EBV-positive cancers

More than 90% of the global population is infected with EBV, making it one of the most common human viruses. It is a member of the herpesvirus family that is probably best known as the cause of infectious mononucleosis. On rare occasions, however, EBV can cause tumor development, though our understanding of its exact pathogenic role in cancer is still incomplete.

EBV is a DNA virus that doesn’t tend to integrate into the host genome, but instead remains in the nucleus in the form of episomes and produces several oncoproteins, including latent membrane protein-1. It is associated with a range of different cancer types, including Burkitt lymphoma and other B-cell malignancies. It also infects epithelial cells and can cause nasopharyngeal carcinoma and gastric cancer, however, much less is known about the molecular underpinnings of these EBV-positive cancer types.^26,27Gastric cancers actually comprise the largest group of EBV-associated tumors because of the global incidence of this cancer type. The Cancer Genome Atlas Research Network recently characterized gastric cancer on a molecular level and identified an EBV-positive subgroup as a distinct clinical entity with unique molecular characteristics.²⁹

The focus of therapeutic development has again been on immunotherapy, however in this case the idea of collecting the patients T cells, engineering them to recognize EBV, and then reinfusing them into the patient – adoptive cell therapy – has gained the most traction (Table 4).

Newest oncovirus on the block

The most recently discovered cancer-associated virus is Merkel cell polyomavirus (MCV), a DNA virus that was identified in 2008. Like EBV, virtually the whole global adult population is infected with MCV. It is linked to the development of a highly aggressive and lethal, though rare, form of skin cancer – Merkel cell carcinoma.

MCV is found in around 80% of MCC cases and in fewer than 10% of melanomas and other skin cancers. Thus far, several direct mechanisms of oncogenesis have been described, including integration of MCV into the host genome and the production of viral oncogenes, though their precise function is as yet unclear.^32-34

The American Cancer Society estimates that only 1500 cases of MCC are diagnosed each year in the United States.³⁵ Its rarity makes it difficult to conduct clinical trials with sufficient power, yet some headway has still been made.

Around half of MCCs express the programmed cell death ligand 1 (PD-L1) on their surface, making them a logical candidate for immune checkpoint inhibition. In 2017, avelumab became the first FDA-approved drug for the treatment of MCC. Approval was based on the JAVELIN Merkel 200 study in which 88 patients received avelumab. After 1 year of follow-up the ORR was 31.8%, with a CR rate of 9%.³⁶

Genome sequencing studies suggest that the mutational profile of MCV-positive tumors is quite different to those that are MCV-negative, which could have therapeutic implications. To date, these implications have not been delineated, given the challenge of small patient numbers, however an ongoing phase 1/2 trial is evaluating the combination of avelumab and radiation therapy or recombinant interferon beta, with or without MCV-specific cytotoxic T cells in patients with MCC and MCV infection.

The 2 other known cancer-causing viruses are human T-lymphotropic virus 1 (HTLV-1), a retrovirus associated with adult T-cell leukemia/lymphoma (ATL) and Kaposi sarcoma herpesvirus (KSHV). The latter is the causative agent of Kaposi sarcoma, often in combination with human immunodeficiency virus (HIV), a rare skin tumor that became renowned in the 1980s as an AIDS-defining illness.

The incidence of HTLV-1- and KSHV-positive tumors is substantially lower than the other virally associated cancers and, like MCC, this makes studying them and conducting clinical trials of novel therapeutic options a challenge. Nonetheless, several trials of targeted therapies and immunotherapies are underway.