B Cell Lymphoma

Annual influenza vaccination rates and documentation of vaccination status appear to be suboptimal among patients with newly diagnosed diffuse large B-cell lymphoma, based on a retrospective analysis of data in the state of Georgia.

The researchers reviewed medical records of patients with a new diagnosis of diffuse large B-cell lymphoma at three Georgia hospitals. Documentation related to vaccine administration, refusal, and patient counseling was collected between Feb. 1, 2015, and Oct. 31, 2017, Andres Chang, MD, PhD, of Emory University, Atlanta, and colleagues wrote. The findings were published in Clinical Lymphoma, Myeloma & Leukemia.

Vaccination status within 1 year of diagnosis was documented for 61 of 107 patients. Among the 61 patients with documentation of influenza vaccination status, 35 (57%) were vaccinated. No reason was documented for vaccine refusal, and there was no follow-up documentation on vaccine counseling by nursing staff, physicians, or advanced practice providers in any of these admitted patients.

Nearly all documentation of influenza vaccination status came from the nursing staff. Only 4 of the 61 patients had documentation provided by primary oncologists or advanced practice providers, and those patients also had documentation from the outpatient nursing staff who subsequently administered the influenza vaccine.

“Routine outpatient vaccination screening and strategies for sharing and linking patient vaccination status between providers in different health care systems at the state and national levels could improve vaccination documentation in patients with lymphoma and provide opportunities to improve compliance,” the researchers wrote.

A key limitation of the study was the lack of adequate documentation, they explained. As a result, the reported vaccination rates were not more rigorously evaluated.

The study was funded by the Winship Cancer Institute and the National Institutes of Health. The authors reported financial affiliations with AbbVie, Acerta Pharma, Celgene, Gilead, Janssen, Pharmacyclics, and others.

SOURCE: Chang A et al. Clin Lymphoma Myeloma Leuk. 2019 Jan 2. doi: 10.1016/j.clml.2018.12.018.

Annual influenza vaccination rates and documentation of vaccination status appear to be suboptimal among patients with newly diagnosed diffuse large B-cell lymphoma, based on a retrospective analysis of data in the state of Georgia.

The researchers reviewed medical records of patients with a new diagnosis of diffuse large B-cell lymphoma at three Georgia hospitals. Documentation related to vaccine administration, refusal, and patient counseling was collected between Feb. 1, 2015, and Oct. 31, 2017, Andres Chang, MD, PhD, of Emory University, Atlanta, and colleagues wrote. The findings were published in Clinical Lymphoma, Myeloma & Leukemia.

Vaccination status within 1 year of diagnosis was documented for 61 of 107 patients. Among the 61 patients with documentation of influenza vaccination status, 35 (57%) were vaccinated. No reason was documented for vaccine refusal, and there was no follow-up documentation on vaccine counseling by nursing staff, physicians, or advanced practice providers in any of these admitted patients.

Nearly all documentation of influenza vaccination status came from the nursing staff. Only 4 of the 61 patients had documentation provided by primary oncologists or advanced practice providers, and those patients also had documentation from the outpatient nursing staff who subsequently administered the influenza vaccine.

“Routine outpatient vaccination screening and strategies for sharing and linking patient vaccination status between providers in different health care systems at the state and national levels could improve vaccination documentation in patients with lymphoma and provide opportunities to improve compliance,” the researchers wrote.

A key limitation of the study was the lack of adequate documentation, they explained. As a result, the reported vaccination rates were not more rigorously evaluated.

The study was funded by the Winship Cancer Institute and the National Institutes of Health. The authors reported financial affiliations with AbbVie, Acerta Pharma, Celgene, Gilead, Janssen, Pharmacyclics, and others.

SOURCE: Chang A et al. Clin Lymphoma Myeloma Leuk. 2019 Jan 2. doi: 10.1016/j.clml.2018.12.018.

Annual influenza vaccination rates and documentation of vaccination status appear to be suboptimal among patients with newly diagnosed diffuse large B-cell lymphoma, based on a retrospective analysis of data in the state of Georgia.

The researchers reviewed medical records of patients with a new diagnosis of diffuse large B-cell lymphoma at three Georgia hospitals. Documentation related to vaccine administration, refusal, and patient counseling was collected between Feb. 1, 2015, and Oct. 31, 2017, Andres Chang, MD, PhD, of Emory University, Atlanta, and colleagues wrote. The findings were published in Clinical Lymphoma, Myeloma & Leukemia.

Vaccination status within 1 year of diagnosis was documented for 61 of 107 patients. Among the 61 patients with documentation of influenza vaccination status, 35 (57%) were vaccinated. No reason was documented for vaccine refusal, and there was no follow-up documentation on vaccine counseling by nursing staff, physicians, or advanced practice providers in any of these admitted patients.

Nearly all documentation of influenza vaccination status came from the nursing staff. Only 4 of the 61 patients had documentation provided by primary oncologists or advanced practice providers, and those patients also had documentation from the outpatient nursing staff who subsequently administered the influenza vaccine.

“Routine outpatient vaccination screening and strategies for sharing and linking patient vaccination status between providers in different health care systems at the state and national levels could improve vaccination documentation in patients with lymphoma and provide opportunities to improve compliance,” the researchers wrote.

A key limitation of the study was the lack of adequate documentation, they explained. As a result, the reported vaccination rates were not more rigorously evaluated.

The study was funded by the Winship Cancer Institute and the National Institutes of Health. The authors reported financial affiliations with AbbVie, Acerta Pharma, Celgene, Gilead, Janssen, Pharmacyclics, and others.

SOURCE: Chang A et al. Clin Lymphoma Myeloma Leuk. 2019 Jan 2. doi: 10.1016/j.clml.2018.12.018.

AMSTERDAM – A combination of rituximab and the BRAF inhibitor vemurafenib could be the one-two punch needed for relapsed or refractory hairy cell leukemia (HCL), according to investigators.

Will Pass/MDedge News

Among evaluable patients treated with this combination, 96% achieved complete remission, reported lead author, Enrico Tiacci, MD, of the University and Hospital of Perugia, Italy.

This level of efficacy is “clearly superior to historical results with either agent alone,” Dr. Tiacci said during a presentation at the annual congress of the European Hematology Association, citing previous complete response rates with vemurafenib alone of 35%-40%. “[This combination] has potential for challenging chemotherapy in the frontline setting,” he said.

The phase 2 trial involved 31 patients with relapsed or refractory HCL who had received a median of three previous therapies. Eight of the patients (26%) had primary refractory disease. Patients received vemurafenib 960 mg, twice daily for 8 weeks and rituximab 375 mg/m², every 2 weeks. After finishing vemurafenib, patients received rituximab four more times, keeping the interval of 2 weeks. Complete remission was defined as a normal blood count, no leukemic cells in bone marrow biopsies and blood smears, and no palpable splenomegaly.

Out of 31 patients, 27 were evaluable at data cutoff. Of these, 26 (96%) achieved complete remission. The investigators noted that two complete responders had incomplete platelet recovery at the end of treatment that resolved soon after, and two patients had persistent splenomegaly, but were considered to be in complete remission at 22.5 and 25 months after finishing therapy.

All of the complete responders had previously received purine analogs, while a few had been refractory to a prior BRAF inhibitor (n = 7) and/or rituximab (n = 5).

The investigators also pointed out that 15 out of 24 evaluable patients (63%) achieved complete remission just 4 weeks after starting the trial regimen. Almost two-thirds of patients (65%) were negative for minimal residual disease (MRD). The rate of progression-free survival at a median follow-up of 29.5 months was 83%. Disease progression occurred exclusively in patients who were MRD positive.

The combination was well tolerated; most adverse events were of grade 1 or 2, overlapping with the safety profile of each agent alone.

Reflecting on the study findings, Dr. Tiacci suggested that the combination could be most effective if delivered immediately, instead of after BRAF failure.

“Interestingly,” he said, “the relapse-free survival in patients naive to a BRAF inhibitor remained significantly longer than the relapse-free interval that patients previously exposed to a BRAF inhibitor enjoyed, both following monotherapy with a BRAF inhibitor and following subsequent combination with rituximab, potentially suggesting that vemurafenib should be used directly in combination with rituximab rather than being delivered first as a monotherapy and then added to rituximab at relapse.”

Randomized testing of the combination against the chemotherapy-based standard of care in the frontline setting is warranted, the investigators concluded.

Dr. Tiacci reported financial relationships with Roche, AbbVie, and Shire.

SOURCE: Tiacci E et al. EHA Congress, Abstract S104.

AMSTERDAM – A combination of rituximab and the BRAF inhibitor vemurafenib could be the one-two punch needed for relapsed or refractory hairy cell leukemia (HCL), according to investigators.

Will Pass/MDedge News

Among evaluable patients treated with this combination, 96% achieved complete remission, reported lead author, Enrico Tiacci, MD, of the University and Hospital of Perugia, Italy.

This level of efficacy is “clearly superior to historical results with either agent alone,” Dr. Tiacci said during a presentation at the annual congress of the European Hematology Association, citing previous complete response rates with vemurafenib alone of 35%-40%. “[This combination] has potential for challenging chemotherapy in the frontline setting,” he said.

The phase 2 trial involved 31 patients with relapsed or refractory HCL who had received a median of three previous therapies. Eight of the patients (26%) had primary refractory disease. Patients received vemurafenib 960 mg, twice daily for 8 weeks and rituximab 375 mg/m², every 2 weeks. After finishing vemurafenib, patients received rituximab four more times, keeping the interval of 2 weeks. Complete remission was defined as a normal blood count, no leukemic cells in bone marrow biopsies and blood smears, and no palpable splenomegaly.

Out of 31 patients, 27 were evaluable at data cutoff. Of these, 26 (96%) achieved complete remission. The investigators noted that two complete responders had incomplete platelet recovery at the end of treatment that resolved soon after, and two patients had persistent splenomegaly, but were considered to be in complete remission at 22.5 and 25 months after finishing therapy.

All of the complete responders had previously received purine analogs, while a few had been refractory to a prior BRAF inhibitor (n = 7) and/or rituximab (n = 5).

The investigators also pointed out that 15 out of 24 evaluable patients (63%) achieved complete remission just 4 weeks after starting the trial regimen. Almost two-thirds of patients (65%) were negative for minimal residual disease (MRD). The rate of progression-free survival at a median follow-up of 29.5 months was 83%. Disease progression occurred exclusively in patients who were MRD positive.

The combination was well tolerated; most adverse events were of grade 1 or 2, overlapping with the safety profile of each agent alone.

Reflecting on the study findings, Dr. Tiacci suggested that the combination could be most effective if delivered immediately, instead of after BRAF failure.

“Interestingly,” he said, “the relapse-free survival in patients naive to a BRAF inhibitor remained significantly longer than the relapse-free interval that patients previously exposed to a BRAF inhibitor enjoyed, both following monotherapy with a BRAF inhibitor and following subsequent combination with rituximab, potentially suggesting that vemurafenib should be used directly in combination with rituximab rather than being delivered first as a monotherapy and then added to rituximab at relapse.”

Randomized testing of the combination against the chemotherapy-based standard of care in the frontline setting is warranted, the investigators concluded.

Dr. Tiacci reported financial relationships with Roche, AbbVie, and Shire.

SOURCE: Tiacci E et al. EHA Congress, Abstract S104.

AMSTERDAM – A combination of rituximab and the BRAF inhibitor vemurafenib could be the one-two punch needed for relapsed or refractory hairy cell leukemia (HCL), according to investigators.

Will Pass/MDedge News

Among evaluable patients treated with this combination, 96% achieved complete remission, reported lead author, Enrico Tiacci, MD, of the University and Hospital of Perugia, Italy.

This level of efficacy is “clearly superior to historical results with either agent alone,” Dr. Tiacci said during a presentation at the annual congress of the European Hematology Association, citing previous complete response rates with vemurafenib alone of 35%-40%. “[This combination] has potential for challenging chemotherapy in the frontline setting,” he said.

The phase 2 trial involved 31 patients with relapsed or refractory HCL who had received a median of three previous therapies. Eight of the patients (26%) had primary refractory disease. Patients received vemurafenib 960 mg, twice daily for 8 weeks and rituximab 375 mg/m², every 2 weeks. After finishing vemurafenib, patients received rituximab four more times, keeping the interval of 2 weeks. Complete remission was defined as a normal blood count, no leukemic cells in bone marrow biopsies and blood smears, and no palpable splenomegaly.

Out of 31 patients, 27 were evaluable at data cutoff. Of these, 26 (96%) achieved complete remission. The investigators noted that two complete responders had incomplete platelet recovery at the end of treatment that resolved soon after, and two patients had persistent splenomegaly, but were considered to be in complete remission at 22.5 and 25 months after finishing therapy.

All of the complete responders had previously received purine analogs, while a few had been refractory to a prior BRAF inhibitor (n = 7) and/or rituximab (n = 5).

The investigators also pointed out that 15 out of 24 evaluable patients (63%) achieved complete remission just 4 weeks after starting the trial regimen. Almost two-thirds of patients (65%) were negative for minimal residual disease (MRD). The rate of progression-free survival at a median follow-up of 29.5 months was 83%. Disease progression occurred exclusively in patients who were MRD positive.

The combination was well tolerated; most adverse events were of grade 1 or 2, overlapping with the safety profile of each agent alone.

Reflecting on the study findings, Dr. Tiacci suggested that the combination could be most effective if delivered immediately, instead of after BRAF failure.

“Interestingly,” he said, “the relapse-free survival in patients naive to a BRAF inhibitor remained significantly longer than the relapse-free interval that patients previously exposed to a BRAF inhibitor enjoyed, both following monotherapy with a BRAF inhibitor and following subsequent combination with rituximab, potentially suggesting that vemurafenib should be used directly in combination with rituximab rather than being delivered first as a monotherapy and then added to rituximab at relapse.”

Randomized testing of the combination against the chemotherapy-based standard of care in the frontline setting is warranted, the investigators concluded.

Dr. Tiacci reported financial relationships with Roche, AbbVie, and Shire.

SOURCE: Tiacci E et al. EHA Congress, Abstract S104.

AMSTERDAM – When predicting the risk of thromboembolism in lymphoma patients receiving chemotherapy, clinicians can rely on a routine diagnostic tool: complete blood count, investigators reported.

Will Pass/MDedge News

A recent study found that high neutrophil to lymphocyte (NLR) and platelet to lymphocyte (PLR) ratios were prognostic for thromboembolism in this setting, reported lead author Vladimir Otasevic, MD, of the Clinical Centre of Serbia in Belgrade.

“Because of the presence of a broad spectrum of risk factors [in patients with lymphoma undergoing chemotherapy], some authors have published risk-assessment models for prediction of thromboembolism,” Dr. Otasevic said during a presentation at the annual congress of the European Hematology Association. While the underlying pathophysiology that precedes thromboembolism is complex, Dr. Otasevic suggested that risk prediction may not have to be, noting that NLR and PLR were recently proposed as risk biomarkers.

To test the utility of these potential biomarkers, Dr. Otasevic and his colleagues retrospectively analyzed data from 484 patients with non-Hodgkin and Hodgkin lymphoma who had undergone at least one cycle of chemotherapy at the Clinic for Hematology, Clinical Centre of Serbia. Patients were followed for venous and arterial thromboembolic events from the time of diagnosis to 3 months beyond their final cycle of chemotherapy. NLR and PLR ratios were calculated from complete blood count. Thromboembolism was diagnosed by radiography, clinical exam, and laboratory evaluation, with probable diagnoses reviewed by an internist and radiologist.

The median patient age was 53 years with a range from 18 to 89 years. Most patients were recently diagnosed with advanced disease (21.1% stage III and 42.5% stage IV). Half of the population had high-grade non-Hodgkin lymphoma (50.0%) and slightly more than a quarter had low-grade non-Hodgkin lymphoma (28.3%). Low-grade Hodgkin lymphoma was less common (17.4%) and followed distantly by other forms (4.3%).

Thirty-five patients (7.2%) developed thromboembolic events; of these, 30 had venous thromboembolism (6.2%), 6 had arterial thromboembolism (1.2%), and 1 had both. Patients who experienced thromboembolic events had significantly higher NLR and PLR than patients without thromboembolism, and both ratios were significantly associated with one another.

A positive NLR, defined as a ratio of 3.1 or more, was associated with a relative risk of 4.1 for thromboembolism (P less than .001), while a positive PLR, defined as a ratio of 10 or more, was associated with a relative risk of 2.9 (P = .008). Using a multivariate model, a positive NLR was associated with an even higher relative risk (RR = 4.5; P less than .001).

“NLR and PLR demonstrated significant powerfulness in prediction of future risk of [thromboembolism] in lymphoma patients,” the investigators concluded. “Simplicity, effectiveness, modesty, and practicability qualify these new tools for routine [thromboembolism] prognostic assessment.”

Dr. Otasevic said that he and his colleagues have plans to build on these findings with further analysis involving progression-free and overall survival.

The investigators reported no disclosures.

SOURCE: Otasevic V et al. EHA Congress, Abstract S1645.

AMSTERDAM – When predicting the risk of thromboembolism in lymphoma patients receiving chemotherapy, clinicians can rely on a routine diagnostic tool: complete blood count, investigators reported.

Will Pass/MDedge News

A recent study found that high neutrophil to lymphocyte (NLR) and platelet to lymphocyte (PLR) ratios were prognostic for thromboembolism in this setting, reported lead author Vladimir Otasevic, MD, of the Clinical Centre of Serbia in Belgrade.

“Because of the presence of a broad spectrum of risk factors [in patients with lymphoma undergoing chemotherapy], some authors have published risk-assessment models for prediction of thromboembolism,” Dr. Otasevic said during a presentation at the annual congress of the European Hematology Association. While the underlying pathophysiology that precedes thromboembolism is complex, Dr. Otasevic suggested that risk prediction may not have to be, noting that NLR and PLR were recently proposed as risk biomarkers.

To test the utility of these potential biomarkers, Dr. Otasevic and his colleagues retrospectively analyzed data from 484 patients with non-Hodgkin and Hodgkin lymphoma who had undergone at least one cycle of chemotherapy at the Clinic for Hematology, Clinical Centre of Serbia. Patients were followed for venous and arterial thromboembolic events from the time of diagnosis to 3 months beyond their final cycle of chemotherapy. NLR and PLR ratios were calculated from complete blood count. Thromboembolism was diagnosed by radiography, clinical exam, and laboratory evaluation, with probable diagnoses reviewed by an internist and radiologist.

The median patient age was 53 years with a range from 18 to 89 years. Most patients were recently diagnosed with advanced disease (21.1% stage III and 42.5% stage IV). Half of the population had high-grade non-Hodgkin lymphoma (50.0%) and slightly more than a quarter had low-grade non-Hodgkin lymphoma (28.3%). Low-grade Hodgkin lymphoma was less common (17.4%) and followed distantly by other forms (4.3%).

Thirty-five patients (7.2%) developed thromboembolic events; of these, 30 had venous thromboembolism (6.2%), 6 had arterial thromboembolism (1.2%), and 1 had both. Patients who experienced thromboembolic events had significantly higher NLR and PLR than patients without thromboembolism, and both ratios were significantly associated with one another.

A positive NLR, defined as a ratio of 3.1 or more, was associated with a relative risk of 4.1 for thromboembolism (P less than .001), while a positive PLR, defined as a ratio of 10 or more, was associated with a relative risk of 2.9 (P = .008). Using a multivariate model, a positive NLR was associated with an even higher relative risk (RR = 4.5; P less than .001).

“NLR and PLR demonstrated significant powerfulness in prediction of future risk of [thromboembolism] in lymphoma patients,” the investigators concluded. “Simplicity, effectiveness, modesty, and practicability qualify these new tools for routine [thromboembolism] prognostic assessment.”

Dr. Otasevic said that he and his colleagues have plans to build on these findings with further analysis involving progression-free and overall survival.

The investigators reported no disclosures.

SOURCE: Otasevic V et al. EHA Congress, Abstract S1645.

AMSTERDAM – When predicting the risk of thromboembolism in lymphoma patients receiving chemotherapy, clinicians can rely on a routine diagnostic tool: complete blood count, investigators reported.

Will Pass/MDedge News

A recent study found that high neutrophil to lymphocyte (NLR) and platelet to lymphocyte (PLR) ratios were prognostic for thromboembolism in this setting, reported lead author Vladimir Otasevic, MD, of the Clinical Centre of Serbia in Belgrade.

“Because of the presence of a broad spectrum of risk factors [in patients with lymphoma undergoing chemotherapy], some authors have published risk-assessment models for prediction of thromboembolism,” Dr. Otasevic said during a presentation at the annual congress of the European Hematology Association. While the underlying pathophysiology that precedes thromboembolism is complex, Dr. Otasevic suggested that risk prediction may not have to be, noting that NLR and PLR were recently proposed as risk biomarkers.

To test the utility of these potential biomarkers, Dr. Otasevic and his colleagues retrospectively analyzed data from 484 patients with non-Hodgkin and Hodgkin lymphoma who had undergone at least one cycle of chemotherapy at the Clinic for Hematology, Clinical Centre of Serbia. Patients were followed for venous and arterial thromboembolic events from the time of diagnosis to 3 months beyond their final cycle of chemotherapy. NLR and PLR ratios were calculated from complete blood count. Thromboembolism was diagnosed by radiography, clinical exam, and laboratory evaluation, with probable diagnoses reviewed by an internist and radiologist.

The median patient age was 53 years with a range from 18 to 89 years. Most patients were recently diagnosed with advanced disease (21.1% stage III and 42.5% stage IV). Half of the population had high-grade non-Hodgkin lymphoma (50.0%) and slightly more than a quarter had low-grade non-Hodgkin lymphoma (28.3%). Low-grade Hodgkin lymphoma was less common (17.4%) and followed distantly by other forms (4.3%).

Thirty-five patients (7.2%) developed thromboembolic events; of these, 30 had venous thromboembolism (6.2%), 6 had arterial thromboembolism (1.2%), and 1 had both. Patients who experienced thromboembolic events had significantly higher NLR and PLR than patients without thromboembolism, and both ratios were significantly associated with one another.

A positive NLR, defined as a ratio of 3.1 or more, was associated with a relative risk of 4.1 for thromboembolism (P less than .001), while a positive PLR, defined as a ratio of 10 or more, was associated with a relative risk of 2.9 (P = .008). Using a multivariate model, a positive NLR was associated with an even higher relative risk (RR = 4.5; P less than .001).

“NLR and PLR demonstrated significant powerfulness in prediction of future risk of [thromboembolism] in lymphoma patients,” the investigators concluded. “Simplicity, effectiveness, modesty, and practicability qualify these new tools for routine [thromboembolism] prognostic assessment.”

Dr. Otasevic said that he and his colleagues have plans to build on these findings with further analysis involving progression-free and overall survival.

The investigators reported no disclosures.

SOURCE: Otasevic V et al. EHA Congress, Abstract S1645.

Activation of hedgehog (Hh) signaling could predict early disease progression in chronic lymphocytic leukemia (CLL) and offer a new therapeutic target, according to investigators.

Approximately 11% of treatment-naive patients had mutations associated with Hh signaling, reported lead author Emanuela M. Ghia, PhD, of the University of California, San Diego, and colleagues. In addition to early progression, Hh signaling was associated with expression of GLI1, which could be a future therapeutic target. In support of this possibility, in vitro experimentation with a GLI1 inhibitor showed high cytotoxicity for GLI1-positive CLL cells.

“Targeting GLI1 could block ligand-independent and ligand-dependent Hh pathway activation and perhaps overcome the apparent resistance to SMO inhibitors,” the investigators wrote in Blood.

Using the HALT Pan-Leukemia Gene Panel, which includes 103 genes, the investigators tested for mutations in cell samples from 841 patients with treatment-naive CLL. Specifically, the investigators focused on mutations that did not map to seven well-known signaling/metabolic pathways, such as Wnt and Notch.

This strategy revealed that 89 patients (11%) had nonsynonymous mutations in genes that drive Hh signaling. These mutations were highly associated with GLI1 expression (x² test; P less than .0001), which stands to reason, as GLI1 is the main effector of the Hh signaling pathway. Of note, 62 of the 161 patients (38%) who did not test positive for an Hh pathway mutation still tested positive for GLI1, suggesting that they had Hh pathway activation, albeit without an identifiable mutational cause.

These findings are clinically significant, as GLI1 overexpression has been linked to numerous types of cancer and is an adverse prognostic indicator for acute myeloid leukemia and several carcinomas, the investigators wrote.

Considering these associations with other cancer types, the investigators looked for a relationship between GLI1 expression and outcomes in CLL. Comparing 103 patients with GLI1-positive disease with 107 GLI-negative patients revealed that GLI1 positivity was significantly associated with shorter median treatment-free survival (4.7 vs. 6.4 years; P = .002). Additional analysis showed that this prognostic relationship was present regardless of IgVH mutational status.

Based on these findings, the investigators concluded that “[a]ctivation of the Hh pathway can strongly influence disease progression in CLL.”

Two additional tests showed that GLI1-positivity was associated with cell survival. First, silencing GLI1 with a GLI1-specific small interfering RNA led to decreased cell viability. Second, GANT61, a small molecule inhibitor of GLI1, was highly cytotoxic for GLI1-positive cells. According to the investigators, these findings suggest that GLI1 could be a future therapeutic target.

“[T]his report shows that the Hh pathway frequently is activated in CLL and associated with relatively rapid disease progression, while identifying a new avenue for therapeutic intervention for patients with this disease,” they concluded.

The study was funded by the National Institutes of Health, the Cancer Stem Cell Consortium, the Canadian Institutes of Health Research, the Ontario Institute for Cancer Research, and other groups. The investigators reported having no competing financial interests.

SOURCE: Ghia EM et al. Blood. 2019 Jun 20;133(25):2651-63.

Activation of hedgehog (Hh) signaling could predict early disease progression in chronic lymphocytic leukemia (CLL) and offer a new therapeutic target, according to investigators.

Approximately 11% of treatment-naive patients had mutations associated with Hh signaling, reported lead author Emanuela M. Ghia, PhD, of the University of California, San Diego, and colleagues. In addition to early progression, Hh signaling was associated with expression of GLI1, which could be a future therapeutic target. In support of this possibility, in vitro experimentation with a GLI1 inhibitor showed high cytotoxicity for GLI1-positive CLL cells.

“Targeting GLI1 could block ligand-independent and ligand-dependent Hh pathway activation and perhaps overcome the apparent resistance to SMO inhibitors,” the investigators wrote in Blood.

Using the HALT Pan-Leukemia Gene Panel, which includes 103 genes, the investigators tested for mutations in cell samples from 841 patients with treatment-naive CLL. Specifically, the investigators focused on mutations that did not map to seven well-known signaling/metabolic pathways, such as Wnt and Notch.

This strategy revealed that 89 patients (11%) had nonsynonymous mutations in genes that drive Hh signaling. These mutations were highly associated with GLI1 expression (x² test; P less than .0001), which stands to reason, as GLI1 is the main effector of the Hh signaling pathway. Of note, 62 of the 161 patients (38%) who did not test positive for an Hh pathway mutation still tested positive for GLI1, suggesting that they had Hh pathway activation, albeit without an identifiable mutational cause.

These findings are clinically significant, as GLI1 overexpression has been linked to numerous types of cancer and is an adverse prognostic indicator for acute myeloid leukemia and several carcinomas, the investigators wrote.

Considering these associations with other cancer types, the investigators looked for a relationship between GLI1 expression and outcomes in CLL. Comparing 103 patients with GLI1-positive disease with 107 GLI-negative patients revealed that GLI1 positivity was significantly associated with shorter median treatment-free survival (4.7 vs. 6.4 years; P = .002). Additional analysis showed that this prognostic relationship was present regardless of IgVH mutational status.

Based on these findings, the investigators concluded that “[a]ctivation of the Hh pathway can strongly influence disease progression in CLL.”

Two additional tests showed that GLI1-positivity was associated with cell survival. First, silencing GLI1 with a GLI1-specific small interfering RNA led to decreased cell viability. Second, GANT61, a small molecule inhibitor of GLI1, was highly cytotoxic for GLI1-positive cells. According to the investigators, these findings suggest that GLI1 could be a future therapeutic target.

“[T]his report shows that the Hh pathway frequently is activated in CLL and associated with relatively rapid disease progression, while identifying a new avenue for therapeutic intervention for patients with this disease,” they concluded.

The study was funded by the National Institutes of Health, the Cancer Stem Cell Consortium, the Canadian Institutes of Health Research, the Ontario Institute for Cancer Research, and other groups. The investigators reported having no competing financial interests.

SOURCE: Ghia EM et al. Blood. 2019 Jun 20;133(25):2651-63.

Activation of hedgehog (Hh) signaling could predict early disease progression in chronic lymphocytic leukemia (CLL) and offer a new therapeutic target, according to investigators.

Approximately 11% of treatment-naive patients had mutations associated with Hh signaling, reported lead author Emanuela M. Ghia, PhD, of the University of California, San Diego, and colleagues. In addition to early progression, Hh signaling was associated with expression of GLI1, which could be a future therapeutic target. In support of this possibility, in vitro experimentation with a GLI1 inhibitor showed high cytotoxicity for GLI1-positive CLL cells.

“Targeting GLI1 could block ligand-independent and ligand-dependent Hh pathway activation and perhaps overcome the apparent resistance to SMO inhibitors,” the investigators wrote in Blood.

Using the HALT Pan-Leukemia Gene Panel, which includes 103 genes, the investigators tested for mutations in cell samples from 841 patients with treatment-naive CLL. Specifically, the investigators focused on mutations that did not map to seven well-known signaling/metabolic pathways, such as Wnt and Notch.

This strategy revealed that 89 patients (11%) had nonsynonymous mutations in genes that drive Hh signaling. These mutations were highly associated with GLI1 expression (x² test; P less than .0001), which stands to reason, as GLI1 is the main effector of the Hh signaling pathway. Of note, 62 of the 161 patients (38%) who did not test positive for an Hh pathway mutation still tested positive for GLI1, suggesting that they had Hh pathway activation, albeit without an identifiable mutational cause.

These findings are clinically significant, as GLI1 overexpression has been linked to numerous types of cancer and is an adverse prognostic indicator for acute myeloid leukemia and several carcinomas, the investigators wrote.

Considering these associations with other cancer types, the investigators looked for a relationship between GLI1 expression and outcomes in CLL. Comparing 103 patients with GLI1-positive disease with 107 GLI-negative patients revealed that GLI1 positivity was significantly associated with shorter median treatment-free survival (4.7 vs. 6.4 years; P = .002). Additional analysis showed that this prognostic relationship was present regardless of IgVH mutational status.

Based on these findings, the investigators concluded that “[a]ctivation of the Hh pathway can strongly influence disease progression in CLL.”

Two additional tests showed that GLI1-positivity was associated with cell survival. First, silencing GLI1 with a GLI1-specific small interfering RNA led to decreased cell viability. Second, GANT61, a small molecule inhibitor of GLI1, was highly cytotoxic for GLI1-positive cells. According to the investigators, these findings suggest that GLI1 could be a future therapeutic target.

“[T]his report shows that the Hh pathway frequently is activated in CLL and associated with relatively rapid disease progression, while identifying a new avenue for therapeutic intervention for patients with this disease,” they concluded.

The study was funded by the National Institutes of Health, the Cancer Stem Cell Consortium, the Canadian Institutes of Health Research, the Ontario Institute for Cancer Research, and other groups. The investigators reported having no competing financial interests.

SOURCE: Ghia EM et al. Blood. 2019 Jun 20;133(25):2651-63.

A preclinical study supports the use of BET inhibitors to treat activated B-cell–like diffuse large B-cell lymphoma (ABC-like DLBCL).

Courtesy Green Lab, UT MD Anderson

Researchers found the TCF4 (E2-2) transcription factor is an oncogene in ABC-like DLBCL, and TCF4 can be targeted via BET inhibition.

The BET protein degrader ARV771 reduced TCF4 expression and exhibited activity against ABC-like DLBCL in vitro and in vivo.

Neeraj Jain, PhD, of the University of Texas MD Anderson Cancer Center in Houston and colleagues reported these findings in Science Translational Medicine.

The researchers performed a genomic analysis of 1,000 DLBCL tumors and discovered that gains of 18q21.2 were the most frequent genetic alteration in ABC-like DLBCL. In analyzing another 249 tumors, the researchers found that TCF4 was the target of the 18q21.2 gains.

Additional experiments with primary DLBCL tumors and DLBCL cell lines indicated that TCF4 regulates IGHM and MYC expression. The researchers also found that the TCF4 gene was “one of the most highly BRD4-loaded genes in DLBCL,” and knocking down BRD4 in DLBCL cell lines reduced TCF4 expression.

These findings prompted the team to test small-molecule BET inhibitors – JQ1 and OTX015 – and a BET protein degrader – ARV771 – in ABC-like DLBCL cell lines with a high TCF4 copy number.

Treatment with JQ1 and OTX015 resulted in upregulation of BRD4, but ARV771 treatment did not. As a result, subsequent experiments were performed with ARV771.

The researchers found that ARV771 induced apoptosis in the cell lines and reduced the expression of TCF4, IgM, and MYC. However, enforced TCF4 expression during ARV771 treatment rescued IgM and MYC expression. This suggests that “reduction of TCF4 is one of the mechanisms by which BET inhibition reduces IgM and MYC expression and induces apoptosis,” according to the researchers.

The team also tested ARV771 in mouse models of ABC-like DLBCL with high TCF4 expression. ARV771 significantly reduced tumor growth and prolonged survival (P less than .05 for both), and there were no signs of toxicity in ARV771-treated mice.

“Our data provide a clear functional rationale for BET inhibition in ABC-like DLBCL,” the researchers wrote. They did note, however, that BCL2 overexpression is associated with resistance to BET inhibitors, and most of the 18q DNA copy number gains the researchers observed in DLBCL encompass TCF4 and BCL2. The team therefore theorized that combining a BET inhibitor with a BCL2 inhibitor could be a promising treatment approach in ABC-like DLBCL and is worthy of further investigation.

This research was supported by the Nebraska Department of Health & Human Services, the Schweitzer Family Fund, the Fred & Pamela Buffet Cancer Center Support Grant, and the MD Anderson Cancer Center NCI CORE Grant. The authors reported having no conflicts of interest related to the study.

[email protected]

SOURCE: Jain N et al. Sci. Transl. Med. 2019 Jun 19. doi: 10.1126/scitranslmed.aav5599.

A preclinical study supports the use of BET inhibitors to treat activated B-cell–like diffuse large B-cell lymphoma (ABC-like DLBCL).

Courtesy Green Lab, UT MD Anderson

Researchers found the TCF4 (E2-2) transcription factor is an oncogene in ABC-like DLBCL, and TCF4 can be targeted via BET inhibition.

The BET protein degrader ARV771 reduced TCF4 expression and exhibited activity against ABC-like DLBCL in vitro and in vivo.

Neeraj Jain, PhD, of the University of Texas MD Anderson Cancer Center in Houston and colleagues reported these findings in Science Translational Medicine.

The researchers performed a genomic analysis of 1,000 DLBCL tumors and discovered that gains of 18q21.2 were the most frequent genetic alteration in ABC-like DLBCL. In analyzing another 249 tumors, the researchers found that TCF4 was the target of the 18q21.2 gains.

Additional experiments with primary DLBCL tumors and DLBCL cell lines indicated that TCF4 regulates IGHM and MYC expression. The researchers also found that the TCF4 gene was “one of the most highly BRD4-loaded genes in DLBCL,” and knocking down BRD4 in DLBCL cell lines reduced TCF4 expression.

These findings prompted the team to test small-molecule BET inhibitors – JQ1 and OTX015 – and a BET protein degrader – ARV771 – in ABC-like DLBCL cell lines with a high TCF4 copy number.

Treatment with JQ1 and OTX015 resulted in upregulation of BRD4, but ARV771 treatment did not. As a result, subsequent experiments were performed with ARV771.

The researchers found that ARV771 induced apoptosis in the cell lines and reduced the expression of TCF4, IgM, and MYC. However, enforced TCF4 expression during ARV771 treatment rescued IgM and MYC expression. This suggests that “reduction of TCF4 is one of the mechanisms by which BET inhibition reduces IgM and MYC expression and induces apoptosis,” according to the researchers.

The team also tested ARV771 in mouse models of ABC-like DLBCL with high TCF4 expression. ARV771 significantly reduced tumor growth and prolonged survival (P less than .05 for both), and there were no signs of toxicity in ARV771-treated mice.

“Our data provide a clear functional rationale for BET inhibition in ABC-like DLBCL,” the researchers wrote. They did note, however, that BCL2 overexpression is associated with resistance to BET inhibitors, and most of the 18q DNA copy number gains the researchers observed in DLBCL encompass TCF4 and BCL2. The team therefore theorized that combining a BET inhibitor with a BCL2 inhibitor could be a promising treatment approach in ABC-like DLBCL and is worthy of further investigation.

This research was supported by the Nebraska Department of Health & Human Services, the Schweitzer Family Fund, the Fred & Pamela Buffet Cancer Center Support Grant, and the MD Anderson Cancer Center NCI CORE Grant. The authors reported having no conflicts of interest related to the study.

[email protected]

SOURCE: Jain N et al. Sci. Transl. Med. 2019 Jun 19. doi: 10.1126/scitranslmed.aav5599.

A preclinical study supports the use of BET inhibitors to treat activated B-cell–like diffuse large B-cell lymphoma (ABC-like DLBCL).

Courtesy Green Lab, UT MD Anderson

Researchers found the TCF4 (E2-2) transcription factor is an oncogene in ABC-like DLBCL, and TCF4 can be targeted via BET inhibition.

The BET protein degrader ARV771 reduced TCF4 expression and exhibited activity against ABC-like DLBCL in vitro and in vivo.

Neeraj Jain, PhD, of the University of Texas MD Anderson Cancer Center in Houston and colleagues reported these findings in Science Translational Medicine.

The researchers performed a genomic analysis of 1,000 DLBCL tumors and discovered that gains of 18q21.2 were the most frequent genetic alteration in ABC-like DLBCL. In analyzing another 249 tumors, the researchers found that TCF4 was the target of the 18q21.2 gains.

Additional experiments with primary DLBCL tumors and DLBCL cell lines indicated that TCF4 regulates IGHM and MYC expression. The researchers also found that the TCF4 gene was “one of the most highly BRD4-loaded genes in DLBCL,” and knocking down BRD4 in DLBCL cell lines reduced TCF4 expression.

These findings prompted the team to test small-molecule BET inhibitors – JQ1 and OTX015 – and a BET protein degrader – ARV771 – in ABC-like DLBCL cell lines with a high TCF4 copy number.

Treatment with JQ1 and OTX015 resulted in upregulation of BRD4, but ARV771 treatment did not. As a result, subsequent experiments were performed with ARV771.

The researchers found that ARV771 induced apoptosis in the cell lines and reduced the expression of TCF4, IgM, and MYC. However, enforced TCF4 expression during ARV771 treatment rescued IgM and MYC expression. This suggests that “reduction of TCF4 is one of the mechanisms by which BET inhibition reduces IgM and MYC expression and induces apoptosis,” according to the researchers.

The team also tested ARV771 in mouse models of ABC-like DLBCL with high TCF4 expression. ARV771 significantly reduced tumor growth and prolonged survival (P less than .05 for both), and there were no signs of toxicity in ARV771-treated mice.

“Our data provide a clear functional rationale for BET inhibition in ABC-like DLBCL,” the researchers wrote. They did note, however, that BCL2 overexpression is associated with resistance to BET inhibitors, and most of the 18q DNA copy number gains the researchers observed in DLBCL encompass TCF4 and BCL2. The team therefore theorized that combining a BET inhibitor with a BCL2 inhibitor could be a promising treatment approach in ABC-like DLBCL and is worthy of further investigation.

This research was supported by the Nebraska Department of Health & Human Services, the Schweitzer Family Fund, the Fred & Pamela Buffet Cancer Center Support Grant, and the MD Anderson Cancer Center NCI CORE Grant. The authors reported having no conflicts of interest related to the study.

[email protected]

SOURCE: Jain N et al. Sci. Transl. Med. 2019 Jun 19. doi: 10.1126/scitranslmed.aav5599.

CHICAGO – A bispecific anti-CD19, anti-CD20 chimeric antigen receptor (CAR) T cell approach is safe and produced complete responses in the majority of patients with relapsed or refractory non-Hodgkin lymphoma in a phase 1 study, an investigator reported.

Eleven of 17 assessable patients had a response to treatment with the bispecific lentiviral CAR T cell (LV20.19CAR) at day 28, and of those 11 patients, 9 had complete responses, all of which are ongoing, said Nirav Niranjan Shah, MD, of the Medical College of Wisconsin in Milwaukee.

“To date, there’s no dose-limiting toxicity, no ICU-level care, no deaths attributed to treatment, no grade 3 to 4 cytokine release syndrome, and only two patients had reversible grade 3 neurotoxicity,” Dr. Shah said at the annual meeting of the American Society of Clinical Oncology.

Patients who did relapse or progress on treatment maintained CD19 or CD20 positivity, with no observed downregulation of target receptors, he reported in an oral abstract session.

Of note, the CAR T cells were produced locally at the point of care, with a 100% success rate and a set 14-day manufacturing time, he added.

Bispecific targeting of CD19 and CD20 is a new approach being investigated at a time when there are already two CD19-specific CAR T cell therapies approved for aggressive B-cell non-Hodgkin lymphomas, Dr. Shah told attendees.

“Despite the great promise of CD19 CAR T cell therapies, very quickly after the development of these therapies, we discovered mechanisms of resistance—specifically, the development of a CD19 negative relapse,” he said.

The hypothesis that targeting more than one B-cell antigen could potentially mitigate that effect stemmed from preclinical studies showing that targeting both CD19 and CD20 decreased downregulation of CD19 but not other B-cell antigens, he added.

In the present phase 1 study of the first-in-human, bispecific tandem CAR T cell against CD19 and CD20, patients have been treated at several dose levels, some with a split infusion over 2 days to evaluate safety, and some with a single infusion, Dr. Shah said.

A total of 17 patients have been treated with a lymphodepletion regimen followed by LV20.19CAR: 8 patients with diffuse large B-cell lymphoma, 6 with mantle cell lymphoma, 2 with chronic lymphocytic leukemia, and 1 with follicular lymphoma, according to the investigator. The median age of patients is 59 years, and patients had received at least 3 and up to 11 prior lines of therapy.

There have been no dose-limiting toxicities to date with dosing up to the target of 2.5 x 106 cells/kg, Dr. Shah reported, adding that there has been no grade 3-4 cytokine release syndrome and no grade 4 neurotoxicity. Grade 1-2 cytokine release syndrome has been seen in 11 patients, while grade 3 neurotoxicity occurred in 2 patients.

Fourteen of 17 patients had a response, including 11 complete responses and 3 partial responses. Eleven patients were treated at the target dose of 2.5 x 106 cells/kg, and of those, 9 had a complete response and 1 had a partial response (overall response rate, Dr. Shah said.

To date, all patients in complete response have remained in a complete response, with durations of response of 1 to 18 months.

Next, investigators plan to conduct phase 2 studies in more specific cohorts, including patients with mantle cell lymphoma, and patients who have relapsed after CD19 CAR T cell therapy, Dr. Shah said.

Dr. Shah reported disclosures related to Cidara Therapeutics, Exelixis, Geron, Oncosec, Incyte, Jazz Pharmaceuticals, Juno Therapeutics, Kite Pharma, and Miltenyi Biotec.

SOURCE: Shah NN et al. ASCO 2019. Abstract 2510.

This article was updated on 7/8/2019

CHICAGO – A bispecific anti-CD19, anti-CD20 chimeric antigen receptor (CAR) T cell approach is safe and produced complete responses in the majority of patients with relapsed or refractory non-Hodgkin lymphoma in a phase 1 study, an investigator reported.

Eleven of 17 assessable patients had a response to treatment with the bispecific lentiviral CAR T cell (LV20.19CAR) at day 28, and of those 11 patients, 9 had complete responses, all of which are ongoing, said Nirav Niranjan Shah, MD, of the Medical College of Wisconsin in Milwaukee.

“To date, there’s no dose-limiting toxicity, no ICU-level care, no deaths attributed to treatment, no grade 3 to 4 cytokine release syndrome, and only two patients had reversible grade 3 neurotoxicity,” Dr. Shah said at the annual meeting of the American Society of Clinical Oncology.

Patients who did relapse or progress on treatment maintained CD19 or CD20 positivity, with no observed downregulation of target receptors, he reported in an oral abstract session.

Of note, the CAR T cells were produced locally at the point of care, with a 100% success rate and a set 14-day manufacturing time, he added.

Bispecific targeting of CD19 and CD20 is a new approach being investigated at a time when there are already two CD19-specific CAR T cell therapies approved for aggressive B-cell non-Hodgkin lymphomas, Dr. Shah told attendees.

“Despite the great promise of CD19 CAR T cell therapies, very quickly after the development of these therapies, we discovered mechanisms of resistance—specifically, the development of a CD19 negative relapse,” he said.

The hypothesis that targeting more than one B-cell antigen could potentially mitigate that effect stemmed from preclinical studies showing that targeting both CD19 and CD20 decreased downregulation of CD19 but not other B-cell antigens, he added.

In the present phase 1 study of the first-in-human, bispecific tandem CAR T cell against CD19 and CD20, patients have been treated at several dose levels, some with a split infusion over 2 days to evaluate safety, and some with a single infusion, Dr. Shah said.

A total of 17 patients have been treated with a lymphodepletion regimen followed by LV20.19CAR: 8 patients with diffuse large B-cell lymphoma, 6 with mantle cell lymphoma, 2 with chronic lymphocytic leukemia, and 1 with follicular lymphoma, according to the investigator. The median age of patients is 59 years, and patients had received at least 3 and up to 11 prior lines of therapy.

There have been no dose-limiting toxicities to date with dosing up to the target of 2.5 x 106 cells/kg, Dr. Shah reported, adding that there has been no grade 3-4 cytokine release syndrome and no grade 4 neurotoxicity. Grade 1-2 cytokine release syndrome has been seen in 11 patients, while grade 3 neurotoxicity occurred in 2 patients.

Fourteen of 17 patients had a response, including 11 complete responses and 3 partial responses. Eleven patients were treated at the target dose of 2.5 x 106 cells/kg, and of those, 9 had a complete response and 1 had a partial response (overall response rate, Dr. Shah said.

To date, all patients in complete response have remained in a complete response, with durations of response of 1 to 18 months.

Next, investigators plan to conduct phase 2 studies in more specific cohorts, including patients with mantle cell lymphoma, and patients who have relapsed after CD19 CAR T cell therapy, Dr. Shah said.

Dr. Shah reported disclosures related to Cidara Therapeutics, Exelixis, Geron, Oncosec, Incyte, Jazz Pharmaceuticals, Juno Therapeutics, Kite Pharma, and Miltenyi Biotec.

SOURCE: Shah NN et al. ASCO 2019. Abstract 2510.

This article was updated on 7/8/2019

CHICAGO – A bispecific anti-CD19, anti-CD20 chimeric antigen receptor (CAR) T cell approach is safe and produced complete responses in the majority of patients with relapsed or refractory non-Hodgkin lymphoma in a phase 1 study, an investigator reported.

Eleven of 17 assessable patients had a response to treatment with the bispecific lentiviral CAR T cell (LV20.19CAR) at day 28, and of those 11 patients, 9 had complete responses, all of which are ongoing, said Nirav Niranjan Shah, MD, of the Medical College of Wisconsin in Milwaukee.

“To date, there’s no dose-limiting toxicity, no ICU-level care, no deaths attributed to treatment, no grade 3 to 4 cytokine release syndrome, and only two patients had reversible grade 3 neurotoxicity,” Dr. Shah said at the annual meeting of the American Society of Clinical Oncology.

Patients who did relapse or progress on treatment maintained CD19 or CD20 positivity, with no observed downregulation of target receptors, he reported in an oral abstract session.

Of note, the CAR T cells were produced locally at the point of care, with a 100% success rate and a set 14-day manufacturing time, he added.

Bispecific targeting of CD19 and CD20 is a new approach being investigated at a time when there are already two CD19-specific CAR T cell therapies approved for aggressive B-cell non-Hodgkin lymphomas, Dr. Shah told attendees.

“Despite the great promise of CD19 CAR T cell therapies, very quickly after the development of these therapies, we discovered mechanisms of resistance—specifically, the development of a CD19 negative relapse,” he said.

The hypothesis that targeting more than one B-cell antigen could potentially mitigate that effect stemmed from preclinical studies showing that targeting both CD19 and CD20 decreased downregulation of CD19 but not other B-cell antigens, he added.

In the present phase 1 study of the first-in-human, bispecific tandem CAR T cell against CD19 and CD20, patients have been treated at several dose levels, some with a split infusion over 2 days to evaluate safety, and some with a single infusion, Dr. Shah said.

A total of 17 patients have been treated with a lymphodepletion regimen followed by LV20.19CAR: 8 patients with diffuse large B-cell lymphoma, 6 with mantle cell lymphoma, 2 with chronic lymphocytic leukemia, and 1 with follicular lymphoma, according to the investigator. The median age of patients is 59 years, and patients had received at least 3 and up to 11 prior lines of therapy.

There have been no dose-limiting toxicities to date with dosing up to the target of 2.5 x 106 cells/kg, Dr. Shah reported, adding that there has been no grade 3-4 cytokine release syndrome and no grade 4 neurotoxicity. Grade 1-2 cytokine release syndrome has been seen in 11 patients, while grade 3 neurotoxicity occurred in 2 patients.

Fourteen of 17 patients had a response, including 11 complete responses and 3 partial responses. Eleven patients were treated at the target dose of 2.5 x 106 cells/kg, and of those, 9 had a complete response and 1 had a partial response (overall response rate, Dr. Shah said.

To date, all patients in complete response have remained in a complete response, with durations of response of 1 to 18 months.

Next, investigators plan to conduct phase 2 studies in more specific cohorts, including patients with mantle cell lymphoma, and patients who have relapsed after CD19 CAR T cell therapy, Dr. Shah said.

Dr. Shah reported disclosures related to Cidara Therapeutics, Exelixis, Geron, Oncosec, Incyte, Jazz Pharmaceuticals, Juno Therapeutics, Kite Pharma, and Miltenyi Biotec.

SOURCE: Shah NN et al. ASCO 2019. Abstract 2510.

This article was updated on 7/8/2019

AMSTERDAM – The novel monoclonal antibody Hu5F9, when combined with rituximab, effectively tells macrophages that it’s okay to chow down on lymphoma cells but lay off munching on normal cells, thereby thwarting a mechanism that non-Hodgkin lymphomas (NHL) use to evade immune surveillance, investigators report.

Among 97 patients with relapsed or refractory aggressive or indolent lymphomas in a phase 1b/2 trial who were treated with Hu5F9 (5F9) plus rituximab, the objective response rate (ORR) was 45%, reported Mark Roschewski, MD, of the National Cancer Institute’s Center for Cancer Research in Bethesda, Md.

5F9 is an immune checkpoint inhibitor that targets CD47, the “don’t eat me” signal that inhibits macrophages from carrying out their crucial phagocytosis role.

“Rituximab, through its activity on the Fc receptor, places an extrinsic ‘eat me’ signal, so when you give these two things together you’re blocking the ‘don’t eat me’ signal and you’re placing the ‘eat me’ signal, and then the cell becomes susceptible to phagocytosis,” he said in a briefing prior to his presentation of the data at the annual congress of the European Hematology Association.

5F9 is the first agent in its class and the most advanced in clinical trials, but several similar agents are also in development. As previously reported, a similar molecule labeled TTI-621 has shown early activity in the treatment of T-cell lymphomas.

In an interview, Dr. Roschewski explained that the therapeutic approach shows promise for the treatment of NHL and nonmalignant diseases.

“This target isn’t even specific to cancer. There is rationale for using this to treat infections or other conditions. Basically, anything that your innate immune system should normally chew up, if that cell has always been evading it using that signal, this removes that [evasion] mechanism,” he said.

In preclinical studies, 5F9 showed the most activity against NHL and acute myeloid leukemia, he noted.

Results of the phase 1b portion of the study were reported in the New England Journal of Medicine (2018;379:1711-21). At the EHA Congress, Dr. Roschewski reported on extended follow-up of the phase 1b cohort and preliminary phase 2 data.

In phase 2, the investigators enrolled patients with diffuse large B-cell lymphoma (DLBCL) that was either primary refractory to standard therapy or relapsed/refractory after two or more prior lines of therapy and who were not eligible for chimeric antigen receptor T-cell therapy. They also enrolled a smaller cohort of patients with the indolent lymphoma histologies follicular lymphoma and marginal zone lymphoma (MZL) whose disease was relapsed or refractory to at least two prior lines.

Dr. Roschewski reported on pooled data for 115 patients enrolled in phases 1b and 2: 70 with DLBCL, 41 with FL, and 4 with MZL.


The patients were heavily pretreated with a median of three prior lines of therapy. Of the patients with DLBCL, 59% had primary refractory disease, and 89% of the patients with DLBCL in phase 2 were not eligible for CAR T-cell therapy.

Among all patients in this analysis, 85% had disease that was refractory to a prior rituximab-containing regimen, and the majority had disease that was refractory to the last rituximab-containing regimen.

Among 97 patients evaluable for response (59 with DLBCL, 35 with FL, and 3 with MZL), the ORR was 45%, including 19% CR and 27% partial responses (PR). An additional 17% of patients had stable disease, and 38% experienced disease progression.

The ORR for DLBCL patients was 35%, consisting of 15% CR and 20% PR. An additional 12% of patients with DLBCL had stable disease, and 53% experienced progression.

Of the patients with indolent lymphomas, the ORR was 61%, including 24% CR and 37% PR. Of this group, 24% had stable disease, and 16% had disease progression.

For all patients, the median time to response was 1.8 months (range 1.6-7.3 months).

Efficacy among patients with DLBCL was similar across subtypes and for patients with primary refractory vs. acquired refractory disease. The responses also were similar irrespective of prior lines of therapy.

Patients tolerated the combination well, with no maximum tolerated dose at up to 45 mg/kg of 5F9, and no significant dose-related toxicities.

Most adverse events were grade 1 or 2. The most common adverse events included expected on-target anemia, caused by clearance of aging red blood cells, which are cleared by the CD47-blocking effects of 5F9. This anemia can be mitigated with an initial priming dose of 1 mg/kg 5FP that causes a transient mild decline in hemoglobin and a temporary reticulocytosis that soon resolves. Hemoglobin levels return to baseline even with continued 5F9 at doses much higher than the priming dose, Dr. Roschewski said.

Other adverse events were infusion reactions and related symptoms. There were no autoimmune adverse events, and just 8 of the 115 patients available for the safety analysis (7%) had to discontinue therapy.

Enrollment in the phase 2 trial is continuing, and a 30-mg/kg maintenance dose of 5F9 has been selected for a trial in patients with DLBCL who are either ineligible for CAR T-cell therapy or have disease that progressed on three or more prior lines of therapy.

The study is funded by Forty Seven and the Leukemia and Lymphoma Society. Dr. Roschewski reported having no financial disclosures.

SOURCE: Roschewski M et al. EHA Congress, Abstract S867.

AMSTERDAM – The novel monoclonal antibody Hu5F9, when combined with rituximab, effectively tells macrophages that it’s okay to chow down on lymphoma cells but lay off munching on normal cells, thereby thwarting a mechanism that non-Hodgkin lymphomas (NHL) use to evade immune surveillance, investigators report.

Among 97 patients with relapsed or refractory aggressive or indolent lymphomas in a phase 1b/2 trial who were treated with Hu5F9 (5F9) plus rituximab, the objective response rate (ORR) was 45%, reported Mark Roschewski, MD, of the National Cancer Institute’s Center for Cancer Research in Bethesda, Md.

5F9 is an immune checkpoint inhibitor that targets CD47, the “don’t eat me” signal that inhibits macrophages from carrying out their crucial phagocytosis role.

“Rituximab, through its activity on the Fc receptor, places an extrinsic ‘eat me’ signal, so when you give these two things together you’re blocking the ‘don’t eat me’ signal and you’re placing the ‘eat me’ signal, and then the cell becomes susceptible to phagocytosis,” he said in a briefing prior to his presentation of the data at the annual congress of the European Hematology Association.

5F9 is the first agent in its class and the most advanced in clinical trials, but several similar agents are also in development. As previously reported, a similar molecule labeled TTI-621 has shown early activity in the treatment of T-cell lymphomas.

In an interview, Dr. Roschewski explained that the therapeutic approach shows promise for the treatment of NHL and nonmalignant diseases.

“This target isn’t even specific to cancer. There is rationale for using this to treat infections or other conditions. Basically, anything that your innate immune system should normally chew up, if that cell has always been evading it using that signal, this removes that [evasion] mechanism,” he said.

In preclinical studies, 5F9 showed the most activity against NHL and acute myeloid leukemia, he noted.

Results of the phase 1b portion of the study were reported in the New England Journal of Medicine (2018;379:1711-21). At the EHA Congress, Dr. Roschewski reported on extended follow-up of the phase 1b cohort and preliminary phase 2 data.

In phase 2, the investigators enrolled patients with diffuse large B-cell lymphoma (DLBCL) that was either primary refractory to standard therapy or relapsed/refractory after two or more prior lines of therapy and who were not eligible for chimeric antigen receptor T-cell therapy. They also enrolled a smaller cohort of patients with the indolent lymphoma histologies follicular lymphoma and marginal zone lymphoma (MZL) whose disease was relapsed or refractory to at least two prior lines.

Dr. Roschewski reported on pooled data for 115 patients enrolled in phases 1b and 2: 70 with DLBCL, 41 with FL, and 4 with MZL.


The patients were heavily pretreated with a median of three prior lines of therapy. Of the patients with DLBCL, 59% had primary refractory disease, and 89% of the patients with DLBCL in phase 2 were not eligible for CAR T-cell therapy.

Among all patients in this analysis, 85% had disease that was refractory to a prior rituximab-containing regimen, and the majority had disease that was refractory to the last rituximab-containing regimen.

Among 97 patients evaluable for response (59 with DLBCL, 35 with FL, and 3 with MZL), the ORR was 45%, including 19% CR and 27% partial responses (PR). An additional 17% of patients had stable disease, and 38% experienced disease progression.

The ORR for DLBCL patients was 35%, consisting of 15% CR and 20% PR. An additional 12% of patients with DLBCL had stable disease, and 53% experienced progression.

Of the patients with indolent lymphomas, the ORR was 61%, including 24% CR and 37% PR. Of this group, 24% had stable disease, and 16% had disease progression.

For all patients, the median time to response was 1.8 months (range 1.6-7.3 months).

Efficacy among patients with DLBCL was similar across subtypes and for patients with primary refractory vs. acquired refractory disease. The responses also were similar irrespective of prior lines of therapy.

Patients tolerated the combination well, with no maximum tolerated dose at up to 45 mg/kg of 5F9, and no significant dose-related toxicities.

Most adverse events were grade 1 or 2. The most common adverse events included expected on-target anemia, caused by clearance of aging red blood cells, which are cleared by the CD47-blocking effects of 5F9. This anemia can be mitigated with an initial priming dose of 1 mg/kg 5FP that causes a transient mild decline in hemoglobin and a temporary reticulocytosis that soon resolves. Hemoglobin levels return to baseline even with continued 5F9 at doses much higher than the priming dose, Dr. Roschewski said.

Other adverse events were infusion reactions and related symptoms. There were no autoimmune adverse events, and just 8 of the 115 patients available for the safety analysis (7%) had to discontinue therapy.

Enrollment in the phase 2 trial is continuing, and a 30-mg/kg maintenance dose of 5F9 has been selected for a trial in patients with DLBCL who are either ineligible for CAR T-cell therapy or have disease that progressed on three or more prior lines of therapy.

The study is funded by Forty Seven and the Leukemia and Lymphoma Society. Dr. Roschewski reported having no financial disclosures.

SOURCE: Roschewski M et al. EHA Congress, Abstract S867.

AMSTERDAM – The novel monoclonal antibody Hu5F9, when combined with rituximab, effectively tells macrophages that it’s okay to chow down on lymphoma cells but lay off munching on normal cells, thereby thwarting a mechanism that non-Hodgkin lymphomas (NHL) use to evade immune surveillance, investigators report.

Among 97 patients with relapsed or refractory aggressive or indolent lymphomas in a phase 1b/2 trial who were treated with Hu5F9 (5F9) plus rituximab, the objective response rate (ORR) was 45%, reported Mark Roschewski, MD, of the National Cancer Institute’s Center for Cancer Research in Bethesda, Md.

5F9 is an immune checkpoint inhibitor that targets CD47, the “don’t eat me” signal that inhibits macrophages from carrying out their crucial phagocytosis role.

“Rituximab, through its activity on the Fc receptor, places an extrinsic ‘eat me’ signal, so when you give these two things together you’re blocking the ‘don’t eat me’ signal and you’re placing the ‘eat me’ signal, and then the cell becomes susceptible to phagocytosis,” he said in a briefing prior to his presentation of the data at the annual congress of the European Hematology Association.

5F9 is the first agent in its class and the most advanced in clinical trials, but several similar agents are also in development. As previously reported, a similar molecule labeled TTI-621 has shown early activity in the treatment of T-cell lymphomas.

In an interview, Dr. Roschewski explained that the therapeutic approach shows promise for the treatment of NHL and nonmalignant diseases.

“This target isn’t even specific to cancer. There is rationale for using this to treat infections or other conditions. Basically, anything that your innate immune system should normally chew up, if that cell has always been evading it using that signal, this removes that [evasion] mechanism,” he said.

In preclinical studies, 5F9 showed the most activity against NHL and acute myeloid leukemia, he noted.

Results of the phase 1b portion of the study were reported in the New England Journal of Medicine (2018;379:1711-21). At the EHA Congress, Dr. Roschewski reported on extended follow-up of the phase 1b cohort and preliminary phase 2 data.

In phase 2, the investigators enrolled patients with diffuse large B-cell lymphoma (DLBCL) that was either primary refractory to standard therapy or relapsed/refractory after two or more prior lines of therapy and who were not eligible for chimeric antigen receptor T-cell therapy. They also enrolled a smaller cohort of patients with the indolent lymphoma histologies follicular lymphoma and marginal zone lymphoma (MZL) whose disease was relapsed or refractory to at least two prior lines.

Dr. Roschewski reported on pooled data for 115 patients enrolled in phases 1b and 2: 70 with DLBCL, 41 with FL, and 4 with MZL.


The patients were heavily pretreated with a median of three prior lines of therapy. Of the patients with DLBCL, 59% had primary refractory disease, and 89% of the patients with DLBCL in phase 2 were not eligible for CAR T-cell therapy.

Among all patients in this analysis, 85% had disease that was refractory to a prior rituximab-containing regimen, and the majority had disease that was refractory to the last rituximab-containing regimen.

Among 97 patients evaluable for response (59 with DLBCL, 35 with FL, and 3 with MZL), the ORR was 45%, including 19% CR and 27% partial responses (PR). An additional 17% of patients had stable disease, and 38% experienced disease progression.

The ORR for DLBCL patients was 35%, consisting of 15% CR and 20% PR. An additional 12% of patients with DLBCL had stable disease, and 53% experienced progression.

Of the patients with indolent lymphomas, the ORR was 61%, including 24% CR and 37% PR. Of this group, 24% had stable disease, and 16% had disease progression.

For all patients, the median time to response was 1.8 months (range 1.6-7.3 months).

Efficacy among patients with DLBCL was similar across subtypes and for patients with primary refractory vs. acquired refractory disease. The responses also were similar irrespective of prior lines of therapy.

Patients tolerated the combination well, with no maximum tolerated dose at up to 45 mg/kg of 5F9, and no significant dose-related toxicities.

Most adverse events were grade 1 or 2. The most common adverse events included expected on-target anemia, caused by clearance of aging red blood cells, which are cleared by the CD47-blocking effects of 5F9. This anemia can be mitigated with an initial priming dose of 1 mg/kg 5FP that causes a transient mild decline in hemoglobin and a temporary reticulocytosis that soon resolves. Hemoglobin levels return to baseline even with continued 5F9 at doses much higher than the priming dose, Dr. Roschewski said.

Other adverse events were infusion reactions and related symptoms. There were no autoimmune adverse events, and just 8 of the 115 patients available for the safety analysis (7%) had to discontinue therapy.

Enrollment in the phase 2 trial is continuing, and a 30-mg/kg maintenance dose of 5F9 has been selected for a trial in patients with DLBCL who are either ineligible for CAR T-cell therapy or have disease that progressed on three or more prior lines of therapy.

The study is funded by Forty Seven and the Leukemia and Lymphoma Society. Dr. Roschewski reported having no financial disclosures.

SOURCE: Roschewski M et al. EHA Congress, Abstract S867.

Amsterdam – For patients with untreated mantle cell lymphoma (MCL), the anti-CD20 monoclonal antibody obinutuzumab may one day offer an alternative to rituximab, according to investigators.

Patients in the LYMA-101 trial were given four cycles of obinutuzumab in combination with dexamethasone, high-dose aracytine, and platinum chemotherapy (O-DHAP), followed by autologous stem cell transplantation (ASCT) and maintenance obinutuzumab. After a median follow-up of 14.6 months, ranging from 3.8 to 24.4 months, 85% of evaluable patients had achieved minimal residual disease (MRD) in bone marrow, reported lead author Steven Le Gouill, MD, PhD, of the University Hospital of Nantes, and his colleagues.

In this disease population, an MRD rate of 85% is “unprecedented,” Dr. Le Gouill said during his presentation at the annual congress of the European Hematology Association. Based on findings from LYMA-101 and preclinical data, Dr. Le Gouill suggested that obinutuzumab may become an alternative to rituximab, the current standard anti-CD20 antibody.

“There are few data of interest for obinutuzumab in MCL, but there is a strong rationale in the lab as obinutuzumab has a different mechanism of action against tumor cells [than rituximab], with more efficacy against MCL cells,” Dr. Le Gouill said.

Data from the ongoing phase 2 trial were drawn from 85 patients with untreated MCL who were 65 years or younger at the time of enrollment. More specifically, median patient age was 55.5 years and 17.4% of patients had blastoid disease. All patients were given the O-DHAP/ASCT/obinutuzumab protocol, with a maintenance period of 3 years. Thereafter, MRD-positive patients may receive obinutuzumab on-demand.

The primary endpoint was MRD in bone marrow after induction therapy, measured by quantitative PCR (qPCR) and droplet digital PCR (ddPCR). Secondary endpoints included response rates, survival measures, incidence of stem cell collection failure after O-DHAP, and MRD rates at additional therapeutic time points.

Owing to the ongoing nature of the study, Dr. Le Gouill focused on the primary endpoint during his presentation.

Analysis showed that 75% and 85% of evaluable patients had achieved negative MRD in bone marrow after induction, according to qPCR and ddPCR, respectively.

These early findings give “a flavor of the results in terms of efficacy,” Dr. Le Gouill said, noting that “the median follow-up is pretty short.”

Still, 1-year findings were “very promising,” he said, with a progression-free survival of 93.4% and overall survival of 96%.

Twelve patients stopped treatment before ASCT, three prior to maintenance, and nine during maintenance. Of these 24 patients, 13 stopped treatment because of adverse events. The remaining 11 patients halted therapy because of disease progression, other malignancies, or death.

From the original 85 patients, 3 patients died and 3 progressed. Considering all of these findings, and that no major toxicities were encountered, the investigators concluded that the regimen was safe.

Overall, the results suggest that further research is needed, Dr. Le Gouill concluded. “Maybe this is where obinutuzumab may have stronger efficacy in MCL, as compared to rituximab,” he said.

The study is sponsored by the Lymphoma Academic Research Organisation. The investigators reported relationships with Roche, Janssen-Cilag, Gilead, Servier, and Novartis.

SOURCE: Le Gouill S et al. EHA Congress, Abstract S103.

Amsterdam – For patients with untreated mantle cell lymphoma (MCL), the anti-CD20 monoclonal antibody obinutuzumab may one day offer an alternative to rituximab, according to investigators.

Patients in the LYMA-101 trial were given four cycles of obinutuzumab in combination with dexamethasone, high-dose aracytine, and platinum chemotherapy (O-DHAP), followed by autologous stem cell transplantation (ASCT) and maintenance obinutuzumab. After a median follow-up of 14.6 months, ranging from 3.8 to 24.4 months, 85% of evaluable patients had achieved minimal residual disease (MRD) in bone marrow, reported lead author Steven Le Gouill, MD, PhD, of the University Hospital of Nantes, and his colleagues.

In this disease population, an MRD rate of 85% is “unprecedented,” Dr. Le Gouill said during his presentation at the annual congress of the European Hematology Association. Based on findings from LYMA-101 and preclinical data, Dr. Le Gouill suggested that obinutuzumab may become an alternative to rituximab, the current standard anti-CD20 antibody.

“There are few data of interest for obinutuzumab in MCL, but there is a strong rationale in the lab as obinutuzumab has a different mechanism of action against tumor cells [than rituximab], with more efficacy against MCL cells,” Dr. Le Gouill said.

Data from the ongoing phase 2 trial were drawn from 85 patients with untreated MCL who were 65 years or younger at the time of enrollment. More specifically, median patient age was 55.5 years and 17.4% of patients had blastoid disease. All patients were given the O-DHAP/ASCT/obinutuzumab protocol, with a maintenance period of 3 years. Thereafter, MRD-positive patients may receive obinutuzumab on-demand.

The primary endpoint was MRD in bone marrow after induction therapy, measured by quantitative PCR (qPCR) and droplet digital PCR (ddPCR). Secondary endpoints included response rates, survival measures, incidence of stem cell collection failure after O-DHAP, and MRD rates at additional therapeutic time points.

Owing to the ongoing nature of the study, Dr. Le Gouill focused on the primary endpoint during his presentation.

Analysis showed that 75% and 85% of evaluable patients had achieved negative MRD in bone marrow after induction, according to qPCR and ddPCR, respectively.

These early findings give “a flavor of the results in terms of efficacy,” Dr. Le Gouill said, noting that “the median follow-up is pretty short.”

Still, 1-year findings were “very promising,” he said, with a progression-free survival of 93.4% and overall survival of 96%.

Twelve patients stopped treatment before ASCT, three prior to maintenance, and nine during maintenance. Of these 24 patients, 13 stopped treatment because of adverse events. The remaining 11 patients halted therapy because of disease progression, other malignancies, or death.

From the original 85 patients, 3 patients died and 3 progressed. Considering all of these findings, and that no major toxicities were encountered, the investigators concluded that the regimen was safe.

Overall, the results suggest that further research is needed, Dr. Le Gouill concluded. “Maybe this is where obinutuzumab may have stronger efficacy in MCL, as compared to rituximab,” he said.

The study is sponsored by the Lymphoma Academic Research Organisation. The investigators reported relationships with Roche, Janssen-Cilag, Gilead, Servier, and Novartis.

SOURCE: Le Gouill S et al. EHA Congress, Abstract S103.

Amsterdam – For patients with untreated mantle cell lymphoma (MCL), the anti-CD20 monoclonal antibody obinutuzumab may one day offer an alternative to rituximab, according to investigators.

Patients in the LYMA-101 trial were given four cycles of obinutuzumab in combination with dexamethasone, high-dose aracytine, and platinum chemotherapy (O-DHAP), followed by autologous stem cell transplantation (ASCT) and maintenance obinutuzumab. After a median follow-up of 14.6 months, ranging from 3.8 to 24.4 months, 85% of evaluable patients had achieved minimal residual disease (MRD) in bone marrow, reported lead author Steven Le Gouill, MD, PhD, of the University Hospital of Nantes, and his colleagues.

In this disease population, an MRD rate of 85% is “unprecedented,” Dr. Le Gouill said during his presentation at the annual congress of the European Hematology Association. Based on findings from LYMA-101 and preclinical data, Dr. Le Gouill suggested that obinutuzumab may become an alternative to rituximab, the current standard anti-CD20 antibody.

“There are few data of interest for obinutuzumab in MCL, but there is a strong rationale in the lab as obinutuzumab has a different mechanism of action against tumor cells [than rituximab], with more efficacy against MCL cells,” Dr. Le Gouill said.

Data from the ongoing phase 2 trial were drawn from 85 patients with untreated MCL who were 65 years or younger at the time of enrollment. More specifically, median patient age was 55.5 years and 17.4% of patients had blastoid disease. All patients were given the O-DHAP/ASCT/obinutuzumab protocol, with a maintenance period of 3 years. Thereafter, MRD-positive patients may receive obinutuzumab on-demand.

The primary endpoint was MRD in bone marrow after induction therapy, measured by quantitative PCR (qPCR) and droplet digital PCR (ddPCR). Secondary endpoints included response rates, survival measures, incidence of stem cell collection failure after O-DHAP, and MRD rates at additional therapeutic time points.

Owing to the ongoing nature of the study, Dr. Le Gouill focused on the primary endpoint during his presentation.

Analysis showed that 75% and 85% of evaluable patients had achieved negative MRD in bone marrow after induction, according to qPCR and ddPCR, respectively.

These early findings give “a flavor of the results in terms of efficacy,” Dr. Le Gouill said, noting that “the median follow-up is pretty short.”

Still, 1-year findings were “very promising,” he said, with a progression-free survival of 93.4% and overall survival of 96%.

Twelve patients stopped treatment before ASCT, three prior to maintenance, and nine during maintenance. Of these 24 patients, 13 stopped treatment because of adverse events. The remaining 11 patients halted therapy because of disease progression, other malignancies, or death.

From the original 85 patients, 3 patients died and 3 progressed. Considering all of these findings, and that no major toxicities were encountered, the investigators concluded that the regimen was safe.

Overall, the results suggest that further research is needed, Dr. Le Gouill concluded. “Maybe this is where obinutuzumab may have stronger efficacy in MCL, as compared to rituximab,” he said.

The study is sponsored by the Lymphoma Academic Research Organisation. The investigators reported relationships with Roche, Janssen-Cilag, Gilead, Servier, and Novartis.

SOURCE: Le Gouill S et al. EHA Congress, Abstract S103.

CHICAGO – A six-drug combination produced complete responses in previously untreated, high-risk diffuse large B-cell lymphoma (DLBCL) patients in a phase 2 trial.

Jennifer Smith/ MDedge News

Induction with durvalumab and R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone) produced complete response rates of 54% in the entire cohort and 41% in patients with double- or triple-hit lymphoma. Immune-related adverse events (AEs) were common with this regimen, but no unexpected AEs occurred, according to researchers.

Grzegorz S. Nowakowski, MD, of the Mayo Clinic in Rochester, Minn., and colleagues presented these results in a poster at the annual meeting of the American Society of Clinical Oncology.

Treatment

The phase 2 trial (NCT03003520) was designed to assess durvalumab plus R-CHOP as well as durvalumab plus R-CHOP and lenalidomide (R2-CHOP) in patients with previously untreated, high-risk DLBCL. However, the R2-CHOP arm was closed early.

In cycle one, all patients received durvalumab plus R-CHOP. For subsequent cycles, patients with activated B-cell (ABC) DLBCL were assigned to durvalumab plus R2-CHOP, while patients with non-ABC DLBCL continued on durvalumab plus R-CHOP.

The R2-CHOP arm was closed early due to safety issues observed in trials combining checkpoint inhibitors with immunomodulatory agents. A partial clinical hold was placed on the R2-CHOP arm, but patients could continue on the regimen if they experienced a clinical benefit. Any patients with ABC DLBCL who were enrolled after the partial hold received treatment with durvalumab plus R-CHOP.

Induction was given for up to eight cycles and was followed by consolidation with durvalumab alone for up to 12 months from the start of induction.

Patient characteristics

The researchers presented data on 43 patients in the durvalumab plus R-CHOP arm. The patients’ median age was 62 years, and 61% were men.

“I think it’s worth noting that 46% of patients in the durvalumab plus R-CHOP group had very high-risk features, including double-hit or triple-hit genetic features,” said Justin Kline, MD, of the University of Chicago Medicine who reviewed this study in a poster discussion session.

Specifically, 30% of patients had double-hit lymphoma, and 16% had triple-hit lymphoma. Most patients had a high-intermediate-risk (49%) or high-risk (21%) International Prognostic Index score, and 79% of patients had Ann Arbor stage IV disease.

Efficacy

As of Aug. 2, 2018, 70% of patients had completed induction, 2% had completed consolidation, 44% remained on treatment, and 54% had discontinued therapy. The most common reasons for stopping treatment were progression (16%), AEs (14%), and consent withdrawal (12%).

“The combination of durvalumab plus R-CHOP demonstrated encouraging response rates … in subjects with high-risk DLBCL, including double- and triple-hit lymphomas,” Dr. Kline said.

The complete response rate was 54% (20/37) at the end of induction and 68% (n = 25) at the end of consolidation. The partial response rate at the end of consolidation was 30% (n = 11).

In patients with double- or triple-hit lymphoma, the complete response rate at the end of induction was 41% (7/17). The overall response rate in this group was 88% (n = 15).

Safety

“The safety profile was as expected for the components of the combination, and no new safety signals were observed,” Dr. Kline said.

He noted that AEs of special interest, or immune-related AEs, occurred in 61% of patients, but most of these events were grade 1 or 2.

AEs of special interest included diarrhea (28%), rash (23%), infusion-related reactions (16%), dermatitis (12%), hypothyroidism (5%), myocarditis (5%), adrenal insufficiency (2%), and hepatitis (2%).

Grade 3 or 4 AEs of special interest included infusion-related reactions (5%), rash (2%), diarrhea (2%), and hepatitis (2%).

The safety and efficacy results support further evaluation of durvalumab plus R-CHOP, although it will be important to identify DLBCL patients who are more likely to derive a clinical benefit from PD-1 or PD-L1 blockade, Dr. Kline said.

“This early study showed that the combination is feasible,” Dr. Nowakowski added. “I think, down the road, we’ll need to identify patients who can actually benefit from this combination. We definitely have clinical evidence of exceptional responses to PD-1 blockade.”

The trial was sponsored by Celgene. Dr. Nowakowski reported relationships with Celgene, Genentech, MorphoSys, and NanoString Technologies. Dr. Kline reported relationships with Cardinal Health, Merck, Seattle Genetics, Kite/Gilead, ITeos Therapeutics, and Bristol-Myers Squibb.

[email protected]

SOURCE: Nowakowski GS et al. ASCO 2019, Abstract 7520.

CHICAGO – A six-drug combination produced complete responses in previously untreated, high-risk diffuse large B-cell lymphoma (DLBCL) patients in a phase 2 trial.

Jennifer Smith/ MDedge News

Induction with durvalumab and R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone) produced complete response rates of 54% in the entire cohort and 41% in patients with double- or triple-hit lymphoma. Immune-related adverse events (AEs) were common with this regimen, but no unexpected AEs occurred, according to researchers.

Grzegorz S. Nowakowski, MD, of the Mayo Clinic in Rochester, Minn., and colleagues presented these results in a poster at the annual meeting of the American Society of Clinical Oncology.

Treatment

The phase 2 trial (NCT03003520) was designed to assess durvalumab plus R-CHOP as well as durvalumab plus R-CHOP and lenalidomide (R2-CHOP) in patients with previously untreated, high-risk DLBCL. However, the R2-CHOP arm was closed early.

In cycle one, all patients received durvalumab plus R-CHOP. For subsequent cycles, patients with activated B-cell (ABC) DLBCL were assigned to durvalumab plus R2-CHOP, while patients with non-ABC DLBCL continued on durvalumab plus R-CHOP.

The R2-CHOP arm was closed early due to safety issues observed in trials combining checkpoint inhibitors with immunomodulatory agents. A partial clinical hold was placed on the R2-CHOP arm, but patients could continue on the regimen if they experienced a clinical benefit. Any patients with ABC DLBCL who were enrolled after the partial hold received treatment with durvalumab plus R-CHOP.

Induction was given for up to eight cycles and was followed by consolidation with durvalumab alone for up to 12 months from the start of induction.

Patient characteristics

The researchers presented data on 43 patients in the durvalumab plus R-CHOP arm. The patients’ median age was 62 years, and 61% were men.

“I think it’s worth noting that 46% of patients in the durvalumab plus R-CHOP group had very high-risk features, including double-hit or triple-hit genetic features,” said Justin Kline, MD, of the University of Chicago Medicine who reviewed this study in a poster discussion session.

Specifically, 30% of patients had double-hit lymphoma, and 16% had triple-hit lymphoma. Most patients had a high-intermediate-risk (49%) or high-risk (21%) International Prognostic Index score, and 79% of patients had Ann Arbor stage IV disease.

Efficacy

As of Aug. 2, 2018, 70% of patients had completed induction, 2% had completed consolidation, 44% remained on treatment, and 54% had discontinued therapy. The most common reasons for stopping treatment were progression (16%), AEs (14%), and consent withdrawal (12%).

“The combination of durvalumab plus R-CHOP demonstrated encouraging response rates … in subjects with high-risk DLBCL, including double- and triple-hit lymphomas,” Dr. Kline said.

The complete response rate was 54% (20/37) at the end of induction and 68% (n = 25) at the end of consolidation. The partial response rate at the end of consolidation was 30% (n = 11).

In patients with double- or triple-hit lymphoma, the complete response rate at the end of induction was 41% (7/17). The overall response rate in this group was 88% (n = 15).

Safety

“The safety profile was as expected for the components of the combination, and no new safety signals were observed,” Dr. Kline said.

He noted that AEs of special interest, or immune-related AEs, occurred in 61% of patients, but most of these events were grade 1 or 2.

AEs of special interest included diarrhea (28%), rash (23%), infusion-related reactions (16%), dermatitis (12%), hypothyroidism (5%), myocarditis (5%), adrenal insufficiency (2%), and hepatitis (2%).

Grade 3 or 4 AEs of special interest included infusion-related reactions (5%), rash (2%), diarrhea (2%), and hepatitis (2%).

The safety and efficacy results support further evaluation of durvalumab plus R-CHOP, although it will be important to identify DLBCL patients who are more likely to derive a clinical benefit from PD-1 or PD-L1 blockade, Dr. Kline said.

“This early study showed that the combination is feasible,” Dr. Nowakowski added. “I think, down the road, we’ll need to identify patients who can actually benefit from this combination. We definitely have clinical evidence of exceptional responses to PD-1 blockade.”

The trial was sponsored by Celgene. Dr. Nowakowski reported relationships with Celgene, Genentech, MorphoSys, and NanoString Technologies. Dr. Kline reported relationships with Cardinal Health, Merck, Seattle Genetics, Kite/Gilead, ITeos Therapeutics, and Bristol-Myers Squibb.

[email protected]

SOURCE: Nowakowski GS et al. ASCO 2019, Abstract 7520.

CHICAGO – A six-drug combination produced complete responses in previously untreated, high-risk diffuse large B-cell lymphoma (DLBCL) patients in a phase 2 trial.

Jennifer Smith/ MDedge News

Induction with durvalumab and R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone) produced complete response rates of 54% in the entire cohort and 41% in patients with double- or triple-hit lymphoma. Immune-related adverse events (AEs) were common with this regimen, but no unexpected AEs occurred, according to researchers.

Grzegorz S. Nowakowski, MD, of the Mayo Clinic in Rochester, Minn., and colleagues presented these results in a poster at the annual meeting of the American Society of Clinical Oncology.

Treatment

The phase 2 trial (NCT03003520) was designed to assess durvalumab plus R-CHOP as well as durvalumab plus R-CHOP and lenalidomide (R2-CHOP) in patients with previously untreated, high-risk DLBCL. However, the R2-CHOP arm was closed early.

In cycle one, all patients received durvalumab plus R-CHOP. For subsequent cycles, patients with activated B-cell (ABC) DLBCL were assigned to durvalumab plus R2-CHOP, while patients with non-ABC DLBCL continued on durvalumab plus R-CHOP.

The R2-CHOP arm was closed early due to safety issues observed in trials combining checkpoint inhibitors with immunomodulatory agents. A partial clinical hold was placed on the R2-CHOP arm, but patients could continue on the regimen if they experienced a clinical benefit. Any patients with ABC DLBCL who were enrolled after the partial hold received treatment with durvalumab plus R-CHOP.

Induction was given for up to eight cycles and was followed by consolidation with durvalumab alone for up to 12 months from the start of induction.

Patient characteristics

The researchers presented data on 43 patients in the durvalumab plus R-CHOP arm. The patients’ median age was 62 years, and 61% were men.

“I think it’s worth noting that 46% of patients in the durvalumab plus R-CHOP group had very high-risk features, including double-hit or triple-hit genetic features,” said Justin Kline, MD, of the University of Chicago Medicine who reviewed this study in a poster discussion session.

Specifically, 30% of patients had double-hit lymphoma, and 16% had triple-hit lymphoma. Most patients had a high-intermediate-risk (49%) or high-risk (21%) International Prognostic Index score, and 79% of patients had Ann Arbor stage IV disease.

Efficacy

As of Aug. 2, 2018, 70% of patients had completed induction, 2% had completed consolidation, 44% remained on treatment, and 54% had discontinued therapy. The most common reasons for stopping treatment were progression (16%), AEs (14%), and consent withdrawal (12%).

“The combination of durvalumab plus R-CHOP demonstrated encouraging response rates … in subjects with high-risk DLBCL, including double- and triple-hit lymphomas,” Dr. Kline said.

The complete response rate was 54% (20/37) at the end of induction and 68% (n = 25) at the end of consolidation. The partial response rate at the end of consolidation was 30% (n = 11).

In patients with double- or triple-hit lymphoma, the complete response rate at the end of induction was 41% (7/17). The overall response rate in this group was 88% (n = 15).

Safety

“The safety profile was as expected for the components of the combination, and no new safety signals were observed,” Dr. Kline said.

He noted that AEs of special interest, or immune-related AEs, occurred in 61% of patients, but most of these events were grade 1 or 2.

AEs of special interest included diarrhea (28%), rash (23%), infusion-related reactions (16%), dermatitis (12%), hypothyroidism (5%), myocarditis (5%), adrenal insufficiency (2%), and hepatitis (2%).

Grade 3 or 4 AEs of special interest included infusion-related reactions (5%), rash (2%), diarrhea (2%), and hepatitis (2%).

The safety and efficacy results support further evaluation of durvalumab plus R-CHOP, although it will be important to identify DLBCL patients who are more likely to derive a clinical benefit from PD-1 or PD-L1 blockade, Dr. Kline said.

“This early study showed that the combination is feasible,” Dr. Nowakowski added. “I think, down the road, we’ll need to identify patients who can actually benefit from this combination. We definitely have clinical evidence of exceptional responses to PD-1 blockade.”

The trial was sponsored by Celgene. Dr. Nowakowski reported relationships with Celgene, Genentech, MorphoSys, and NanoString Technologies. Dr. Kline reported relationships with Cardinal Health, Merck, Seattle Genetics, Kite/Gilead, ITeos Therapeutics, and Bristol-Myers Squibb.

[email protected]

SOURCE: Nowakowski GS et al. ASCO 2019, Abstract 7520.

CHICAGO – Lenalidomide plus rituximab (R²) demonstrated activity against relapsed or refractory follicular lymphoma (FL) and marginal zone lymphoma (MZL) in the phase 3b MAGNIFY trial.

Jennifer Smith/MDedge News

R² produced responses in FL and MZL patients, including those who had previously experienced early relapse and patients who were refractory to rituximab or both lenalidomide and rituximab at baseline.

David Jacob Andorsky, MD, of Rocky Mountain Cancer Centers in Boulder, Colo., and colleagues presented these results in a poster at the annual meeting of the American Society of Clinical Oncology.

The ongoing MAGNIFY trial has enrolled 370 patients with relapsed/refractory FL (grade 1-3a) or MZL.

For induction, patients receive lenalidomide (20 mg per day on days 1-21 for 12 cycles) and rituximab (375 mg/m² per week in cycle 1 and then on day 1 of cycles 3, 5, 7, 9, and 11). Patients who achieve stable disease or better on R² induction are randomized to maintenance with R² or rituximab alone.

Dr. Andorsky and colleagues presented results of R² induction in 310 evaluable patients – 247 with FL and 63 with MZL.

The patients had a median age of 66 years (range, 35-91 years) at baseline, and they had received a median of two prior therapies (range, one to eight). Some patients had experienced early relapse (37%, n = 115), were refractory to rituximab (36%, n = 113), or were refractory to both rituximab and lenalidomide (20%, n = 63) at baseline.

Results

At a median follow-up of 16.7 months, the overall response rate was 73%, and the complete response rate was 45%. The overall response rate was 74% in FL patients, 65% in MZL patients, 63% in rituximab-refractory patients, 51% in double-refractory patients, and 68% in patients with an early relapse.

The median duration of response was 36.8 months in all patients, 35.8 months in MZL patients, and not reached in FL patients. The median duration of response was 35.8 months in patients who were rituximab refractory and was not reached in patients who were not refractory to rituximab.

The median progression-free survival was 36 months overall, 30 months in FL patients, 38 months in MZL patients, 23 months in patients with early relapse, and 15.5 months in double-refractory patients.

“While these [subgroup analyses of efficacy] were exploratory endpoints, I think this suggests that [R²] is a promising regimen for patients that are in the high-risk subgroup,” said Carla Casulo, MD, of the University of Rochester (N.Y.), who reviewed this study in a poster discussion session.

The most common adverse events in this trial were fatigue (48%), neutropenia (40%), diarrhea (35%), nausea (30%), and constipation (29%). The most common grade 3/4 adverse event was neutropenia (34%).

The MAGNIFY trial is sponsored by Celgene. Dr. Andorsky reported financial relationships with Celgene, CTI BioPharma, and Gilead Sciences. Dr. Casulo reported financial relationships with Gilead Sciences, Celgene, and Roche.

[email protected]

SOURCE: Andorsky DJ et al. ASCO 2019, Abstract 7513.

CHICAGO – Lenalidomide plus rituximab (R²) demonstrated activity against relapsed or refractory follicular lymphoma (FL) and marginal zone lymphoma (MZL) in the phase 3b MAGNIFY trial.

Jennifer Smith/MDedge News

R² produced responses in FL and MZL patients, including those who had previously experienced early relapse and patients who were refractory to rituximab or both lenalidomide and rituximab at baseline.

David Jacob Andorsky, MD, of Rocky Mountain Cancer Centers in Boulder, Colo., and colleagues presented these results in a poster at the annual meeting of the American Society of Clinical Oncology.

The ongoing MAGNIFY trial has enrolled 370 patients with relapsed/refractory FL (grade 1-3a) or MZL.

For induction, patients receive lenalidomide (20 mg per day on days 1-21 for 12 cycles) and rituximab (375 mg/m² per week in cycle 1 and then on day 1 of cycles 3, 5, 7, 9, and 11). Patients who achieve stable disease or better on R² induction are randomized to maintenance with R² or rituximab alone.

Dr. Andorsky and colleagues presented results of R² induction in 310 evaluable patients – 247 with FL and 63 with MZL.

The patients had a median age of 66 years (range, 35-91 years) at baseline, and they had received a median of two prior therapies (range, one to eight). Some patients had experienced early relapse (37%, n = 115), were refractory to rituximab (36%, n = 113), or were refractory to both rituximab and lenalidomide (20%, n = 63) at baseline.

Results

At a median follow-up of 16.7 months, the overall response rate was 73%, and the complete response rate was 45%. The overall response rate was 74% in FL patients, 65% in MZL patients, 63% in rituximab-refractory patients, 51% in double-refractory patients, and 68% in patients with an early relapse.

The median duration of response was 36.8 months in all patients, 35.8 months in MZL patients, and not reached in FL patients. The median duration of response was 35.8 months in patients who were rituximab refractory and was not reached in patients who were not refractory to rituximab.

The median progression-free survival was 36 months overall, 30 months in FL patients, 38 months in MZL patients, 23 months in patients with early relapse, and 15.5 months in double-refractory patients.

“While these [subgroup analyses of efficacy] were exploratory endpoints, I think this suggests that [R²] is a promising regimen for patients that are in the high-risk subgroup,” said Carla Casulo, MD, of the University of Rochester (N.Y.), who reviewed this study in a poster discussion session.

The most common adverse events in this trial were fatigue (48%), neutropenia (40%), diarrhea (35%), nausea (30%), and constipation (29%). The most common grade 3/4 adverse event was neutropenia (34%).

The MAGNIFY trial is sponsored by Celgene. Dr. Andorsky reported financial relationships with Celgene, CTI BioPharma, and Gilead Sciences. Dr. Casulo reported financial relationships with Gilead Sciences, Celgene, and Roche.

[email protected]

SOURCE: Andorsky DJ et al. ASCO 2019, Abstract 7513.

CHICAGO – Lenalidomide plus rituximab (R²) demonstrated activity against relapsed or refractory follicular lymphoma (FL) and marginal zone lymphoma (MZL) in the phase 3b MAGNIFY trial.

Jennifer Smith/MDedge News

R² produced responses in FL and MZL patients, including those who had previously experienced early relapse and patients who were refractory to rituximab or both lenalidomide and rituximab at baseline.

David Jacob Andorsky, MD, of Rocky Mountain Cancer Centers in Boulder, Colo., and colleagues presented these results in a poster at the annual meeting of the American Society of Clinical Oncology.

The ongoing MAGNIFY trial has enrolled 370 patients with relapsed/refractory FL (grade 1-3a) or MZL.

For induction, patients receive lenalidomide (20 mg per day on days 1-21 for 12 cycles) and rituximab (375 mg/m² per week in cycle 1 and then on day 1 of cycles 3, 5, 7, 9, and 11). Patients who achieve stable disease or better on R² induction are randomized to maintenance with R² or rituximab alone.

Dr. Andorsky and colleagues presented results of R² induction in 310 evaluable patients – 247 with FL and 63 with MZL.

The patients had a median age of 66 years (range, 35-91 years) at baseline, and they had received a median of two prior therapies (range, one to eight). Some patients had experienced early relapse (37%, n = 115), were refractory to rituximab (36%, n = 113), or were refractory to both rituximab and lenalidomide (20%, n = 63) at baseline.

Results

At a median follow-up of 16.7 months, the overall response rate was 73%, and the complete response rate was 45%. The overall response rate was 74% in FL patients, 65% in MZL patients, 63% in rituximab-refractory patients, 51% in double-refractory patients, and 68% in patients with an early relapse.

The median duration of response was 36.8 months in all patients, 35.8 months in MZL patients, and not reached in FL patients. The median duration of response was 35.8 months in patients who were rituximab refractory and was not reached in patients who were not refractory to rituximab.

The median progression-free survival was 36 months overall, 30 months in FL patients, 38 months in MZL patients, 23 months in patients with early relapse, and 15.5 months in double-refractory patients.

“While these [subgroup analyses of efficacy] were exploratory endpoints, I think this suggests that [R²] is a promising regimen for patients that are in the high-risk subgroup,” said Carla Casulo, MD, of the University of Rochester (N.Y.), who reviewed this study in a poster discussion session.

The most common adverse events in this trial were fatigue (48%), neutropenia (40%), diarrhea (35%), nausea (30%), and constipation (29%). The most common grade 3/4 adverse event was neutropenia (34%).

The MAGNIFY trial is sponsored by Celgene. Dr. Andorsky reported financial relationships with Celgene, CTI BioPharma, and Gilead Sciences. Dr. Casulo reported financial relationships with Gilead Sciences, Celgene, and Roche.

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SOURCE: Andorsky DJ et al. ASCO 2019, Abstract 7513.