Hematology Times

Daratumumab is safe but ineffective for the treatment of patients with relapsed or refractory non-Hodgkin lymphoma (NHL) and CD38 expression of at least 50%, according to findings from a recent phase 2 trial.

Unfortunately, the study met headwinds early on, when initial screening of 112 patients with available tumor samples showed that only about half (56%) had CD38 expression of at least 50%, reported lead author Giles Salles, MD, PhD, of Claude Bernard University in Lyon, France, and his colleagues. The cutoff was based on preclinical models, suggesting that daratumumab-induced cytotoxicity depends on a high level of CD38 expression.

“Only 36 [patients] were eligible for study enrollment, questioning the generalizability of the study population,” the investigators wrote in Clinical Lymphoma, Myeloma & Leukemia.

Of these 36 patients, 15 had diffuse large B-cell lymphoma (DLBCL), 16 had follicular lymphoma (FL), and 5 had mantle cell lymphoma (MCL). Median CD38 expression was 70%. Patients were given 16 mg/kg of IV daratumumab once a week for two cycles, then every 2 weeks for four cycles, and finally on a monthly basis. Cycles were 28 days long. The primary endpoint was overall response rate. Safety and pharmacokinetics were also evaluated.

Results were generally disappointing, with ORR occurring in two patients (12.5%) with FL and one patient (6.7%) with DLBCL. No patients with MCL responded before the study was terminated. On a more encouraging note, 10 of 16 patients with FL maintained stable disease.

“All 16 patients in the FL cohort had progressed/relapsed on their prior treatment regimen; therefore, the maintenance of stable disease in the FL cohort may suggest some clinical benefit of daratumumab in this subset of NHL,” the investigators wrote.

Pharmacokinetics and safety data were similar to those from multiple myeloma studies of daratumumab; no new safety signals or instances of immunogenicity were encountered. The most common grade 3 or higher treatment-related adverse event was thrombocytopenia, which occurred in 11.1% of patients. Infusion-related reactions occurred in 72.2% of patients, but none were grade 4 and only three reactions were grade 3.

The investigators suggested that daratumumab may still play a role in NHL treatment, but not as a single agent.

“It is possible that daratumumab-based combination therapy would have allowed for more responses to be achieved within the current study,” the investigators wrote. “NHL is an extremely heterogeneous disease and the identification of predictive biomarkers and molecular genetics may provide new personalized therapies.”

The study was funded by Janssen Research & Development; two study authors reported employment by Janssen. Others reported financial ties to Janssen, Celgene, Roche, Gilead, Novartis, Amgen, and others.

SOURCE: Salles G et al. Clin Lymphoma Myeloma Leuk. 2019 Jan 2. doi: 10.1016/j.clml.2018.12.013.

Daratumumab is safe but ineffective for the treatment of patients with relapsed or refractory non-Hodgkin lymphoma (NHL) and CD38 expression of at least 50%, according to findings from a recent phase 2 trial.

Unfortunately, the study met headwinds early on, when initial screening of 112 patients with available tumor samples showed that only about half (56%) had CD38 expression of at least 50%, reported lead author Giles Salles, MD, PhD, of Claude Bernard University in Lyon, France, and his colleagues. The cutoff was based on preclinical models, suggesting that daratumumab-induced cytotoxicity depends on a high level of CD38 expression.

“Only 36 [patients] were eligible for study enrollment, questioning the generalizability of the study population,” the investigators wrote in Clinical Lymphoma, Myeloma & Leukemia.

Of these 36 patients, 15 had diffuse large B-cell lymphoma (DLBCL), 16 had follicular lymphoma (FL), and 5 had mantle cell lymphoma (MCL). Median CD38 expression was 70%. Patients were given 16 mg/kg of IV daratumumab once a week for two cycles, then every 2 weeks for four cycles, and finally on a monthly basis. Cycles were 28 days long. The primary endpoint was overall response rate. Safety and pharmacokinetics were also evaluated.

Results were generally disappointing, with ORR occurring in two patients (12.5%) with FL and one patient (6.7%) with DLBCL. No patients with MCL responded before the study was terminated. On a more encouraging note, 10 of 16 patients with FL maintained stable disease.

“All 16 patients in the FL cohort had progressed/relapsed on their prior treatment regimen; therefore, the maintenance of stable disease in the FL cohort may suggest some clinical benefit of daratumumab in this subset of NHL,” the investigators wrote.

Pharmacokinetics and safety data were similar to those from multiple myeloma studies of daratumumab; no new safety signals or instances of immunogenicity were encountered. The most common grade 3 or higher treatment-related adverse event was thrombocytopenia, which occurred in 11.1% of patients. Infusion-related reactions occurred in 72.2% of patients, but none were grade 4 and only three reactions were grade 3.

The investigators suggested that daratumumab may still play a role in NHL treatment, but not as a single agent.

“It is possible that daratumumab-based combination therapy would have allowed for more responses to be achieved within the current study,” the investigators wrote. “NHL is an extremely heterogeneous disease and the identification of predictive biomarkers and molecular genetics may provide new personalized therapies.”

The study was funded by Janssen Research & Development; two study authors reported employment by Janssen. Others reported financial ties to Janssen, Celgene, Roche, Gilead, Novartis, Amgen, and others.

SOURCE: Salles G et al. Clin Lymphoma Myeloma Leuk. 2019 Jan 2. doi: 10.1016/j.clml.2018.12.013.

Daratumumab is safe but ineffective for the treatment of patients with relapsed or refractory non-Hodgkin lymphoma (NHL) and CD38 expression of at least 50%, according to findings from a recent phase 2 trial.

Unfortunately, the study met headwinds early on, when initial screening of 112 patients with available tumor samples showed that only about half (56%) had CD38 expression of at least 50%, reported lead author Giles Salles, MD, PhD, of Claude Bernard University in Lyon, France, and his colleagues. The cutoff was based on preclinical models, suggesting that daratumumab-induced cytotoxicity depends on a high level of CD38 expression.

“Only 36 [patients] were eligible for study enrollment, questioning the generalizability of the study population,” the investigators wrote in Clinical Lymphoma, Myeloma & Leukemia.

Of these 36 patients, 15 had diffuse large B-cell lymphoma (DLBCL), 16 had follicular lymphoma (FL), and 5 had mantle cell lymphoma (MCL). Median CD38 expression was 70%. Patients were given 16 mg/kg of IV daratumumab once a week for two cycles, then every 2 weeks for four cycles, and finally on a monthly basis. Cycles were 28 days long. The primary endpoint was overall response rate. Safety and pharmacokinetics were also evaluated.

Results were generally disappointing, with ORR occurring in two patients (12.5%) with FL and one patient (6.7%) with DLBCL. No patients with MCL responded before the study was terminated. On a more encouraging note, 10 of 16 patients with FL maintained stable disease.

“All 16 patients in the FL cohort had progressed/relapsed on their prior treatment regimen; therefore, the maintenance of stable disease in the FL cohort may suggest some clinical benefit of daratumumab in this subset of NHL,” the investigators wrote.

Pharmacokinetics and safety data were similar to those from multiple myeloma studies of daratumumab; no new safety signals or instances of immunogenicity were encountered. The most common grade 3 or higher treatment-related adverse event was thrombocytopenia, which occurred in 11.1% of patients. Infusion-related reactions occurred in 72.2% of patients, but none were grade 4 and only three reactions were grade 3.

The investigators suggested that daratumumab may still play a role in NHL treatment, but not as a single agent.

“It is possible that daratumumab-based combination therapy would have allowed for more responses to be achieved within the current study,” the investigators wrote. “NHL is an extremely heterogeneous disease and the identification of predictive biomarkers and molecular genetics may provide new personalized therapies.”

The study was funded by Janssen Research & Development; two study authors reported employment by Janssen. Others reported financial ties to Janssen, Celgene, Roche, Gilead, Novartis, Amgen, and others.

SOURCE: Salles G et al. Clin Lymphoma Myeloma Leuk. 2019 Jan 2. doi: 10.1016/j.clml.2018.12.013.

Intensity of BCL2 expression, and to a lesser extent expression of t(14;18), may help distinguish common and indolent cutaneous lymphomas from poorer-prognosis cutaneous lesions secondary to systemic follicular lymphomas, results of a recent investigation show.

Strong expression of BCL2 was almost always associated with secondary cutaneous follicular lymphoma (SCFL), and infrequently associated with primary cutaneous follicular center-cell lymphoma (PCFCL), according to the study results.

The translocation t(14;18) was likewise linked to secondary lesions, occurring less frequently in PCFCL in the study, reported recently in the Journal of Cutaneous Pathology.

“BCL2 expression intensity is the single most valuable clue in differentiating PCFCL from SCFL cases on histopathological grounds,” said Ramon M. Pujol, MD, PhD, of Hospital del Mar, Barcelona, Spain, and colleagues.

One of the main cutaneous B-cell lymphoma subtypes, PCFCL is marked by frequent relapses, but little incidence of systemic spread, meaning that conservative, skin-based therapies are usually warranted. By contrast, patients with SCFLs have a poor prognosis and may require systemic therapy, the investigators noted in their report.

Previous investigations have yielded conflicting results on the role of BCL2 expression, CD10 expression, and presence of t(14;18) translocation in distinguishing PCFCL from SCFL.

While early studies suggested most PCFCLs were negative for these markers, some recent reports suggested BCL positivity in PCFCLs is as high as 86%, the investigators said.

Accordingly, Dr. Pujol and colleagues evaluated clinicopathologic and genetic features in a large series of patients, including 59 with PCFCL and 22 with SCFL.

Significant BCL2 expression was seen in 69% of PCFCLs and in 100% of SCFLs (P = .003) in this patient series; however, when looking at BCL2 intensity, investigators found strong expression almost exclusively in SCFL. Strong expression was seen in 46% of those patients with secondary lymphomas, versus just 4%, or two cases, in the PCFCL group (P = .001).

The t(14;18) translocation was seen in 64% of SCFLs and only 9.1% of PCFCLs (P = .001).

Similar to what was seen for BCL2, expression of CD10 was observed in 66% of PCFCLs and 91% of SCFLs, and again, intensity differences mattered. Strong CD10 expression was seen in 62% of secondary lymphomas and 16% of PCFCLs (P = .01). But the high number of positive PCFCLs made this marker less useful than BCL2, the investigators said.

“We believe that differences in BCL2 and CD10 expression between our results and older previous studies could reflect the improvement of antigen retrieval laboratory techniques,” they said.

The investigators did not report disclosures related to the research.

SOURCE: Servitje O et al. J Cutan Pathol. 2019;46:182-9.

Intensity of BCL2 expression, and to a lesser extent expression of t(14;18), may help distinguish common and indolent cutaneous lymphomas from poorer-prognosis cutaneous lesions secondary to systemic follicular lymphomas, results of a recent investigation show.

Strong expression of BCL2 was almost always associated with secondary cutaneous follicular lymphoma (SCFL), and infrequently associated with primary cutaneous follicular center-cell lymphoma (PCFCL), according to the study results.

The translocation t(14;18) was likewise linked to secondary lesions, occurring less frequently in PCFCL in the study, reported recently in the Journal of Cutaneous Pathology.

“BCL2 expression intensity is the single most valuable clue in differentiating PCFCL from SCFL cases on histopathological grounds,” said Ramon M. Pujol, MD, PhD, of Hospital del Mar, Barcelona, Spain, and colleagues.

One of the main cutaneous B-cell lymphoma subtypes, PCFCL is marked by frequent relapses, but little incidence of systemic spread, meaning that conservative, skin-based therapies are usually warranted. By contrast, patients with SCFLs have a poor prognosis and may require systemic therapy, the investigators noted in their report.

Previous investigations have yielded conflicting results on the role of BCL2 expression, CD10 expression, and presence of t(14;18) translocation in distinguishing PCFCL from SCFL.

While early studies suggested most PCFCLs were negative for these markers, some recent reports suggested BCL positivity in PCFCLs is as high as 86%, the investigators said.

Accordingly, Dr. Pujol and colleagues evaluated clinicopathologic and genetic features in a large series of patients, including 59 with PCFCL and 22 with SCFL.

Significant BCL2 expression was seen in 69% of PCFCLs and in 100% of SCFLs (P = .003) in this patient series; however, when looking at BCL2 intensity, investigators found strong expression almost exclusively in SCFL. Strong expression was seen in 46% of those patients with secondary lymphomas, versus just 4%, or two cases, in the PCFCL group (P = .001).

The t(14;18) translocation was seen in 64% of SCFLs and only 9.1% of PCFCLs (P = .001).

Similar to what was seen for BCL2, expression of CD10 was observed in 66% of PCFCLs and 91% of SCFLs, and again, intensity differences mattered. Strong CD10 expression was seen in 62% of secondary lymphomas and 16% of PCFCLs (P = .01). But the high number of positive PCFCLs made this marker less useful than BCL2, the investigators said.

“We believe that differences in BCL2 and CD10 expression between our results and older previous studies could reflect the improvement of antigen retrieval laboratory techniques,” they said.

The investigators did not report disclosures related to the research.

SOURCE: Servitje O et al. J Cutan Pathol. 2019;46:182-9.

Intensity of BCL2 expression, and to a lesser extent expression of t(14;18), may help distinguish common and indolent cutaneous lymphomas from poorer-prognosis cutaneous lesions secondary to systemic follicular lymphomas, results of a recent investigation show.

Strong expression of BCL2 was almost always associated with secondary cutaneous follicular lymphoma (SCFL), and infrequently associated with primary cutaneous follicular center-cell lymphoma (PCFCL), according to the study results.

The translocation t(14;18) was likewise linked to secondary lesions, occurring less frequently in PCFCL in the study, reported recently in the Journal of Cutaneous Pathology.

“BCL2 expression intensity is the single most valuable clue in differentiating PCFCL from SCFL cases on histopathological grounds,” said Ramon M. Pujol, MD, PhD, of Hospital del Mar, Barcelona, Spain, and colleagues.

One of the main cutaneous B-cell lymphoma subtypes, PCFCL is marked by frequent relapses, but little incidence of systemic spread, meaning that conservative, skin-based therapies are usually warranted. By contrast, patients with SCFLs have a poor prognosis and may require systemic therapy, the investigators noted in their report.

Previous investigations have yielded conflicting results on the role of BCL2 expression, CD10 expression, and presence of t(14;18) translocation in distinguishing PCFCL from SCFL.

While early studies suggested most PCFCLs were negative for these markers, some recent reports suggested BCL positivity in PCFCLs is as high as 86%, the investigators said.

Accordingly, Dr. Pujol and colleagues evaluated clinicopathologic and genetic features in a large series of patients, including 59 with PCFCL and 22 with SCFL.

Significant BCL2 expression was seen in 69% of PCFCLs and in 100% of SCFLs (P = .003) in this patient series; however, when looking at BCL2 intensity, investigators found strong expression almost exclusively in SCFL. Strong expression was seen in 46% of those patients with secondary lymphomas, versus just 4%, or two cases, in the PCFCL group (P = .001).

The t(14;18) translocation was seen in 64% of SCFLs and only 9.1% of PCFCLs (P = .001).

Similar to what was seen for BCL2, expression of CD10 was observed in 66% of PCFCLs and 91% of SCFLs, and again, intensity differences mattered. Strong CD10 expression was seen in 62% of secondary lymphomas and 16% of PCFCLs (P = .01). But the high number of positive PCFCLs made this marker less useful than BCL2, the investigators said.

“We believe that differences in BCL2 and CD10 expression between our results and older previous studies could reflect the improvement of antigen retrieval laboratory techniques,” they said.

The investigators did not report disclosures related to the research.

SOURCE: Servitje O et al. J Cutan Pathol. 2019;46:182-9.

The thrombopoietic agent eltrombopag (Promacta) did more harm than good when given to adults with acute myeloid leukemia (AML) during standard induction chemotherapy, results of a randomized phase 2 trial show.

Patients who were randomly assigned to receive standard induction chemotherapy with daunorubicin and cytarabine plus eltrombopag had a higher incidence of serious adverse events and death from hemorrhage within 30 days of the last eltrombopag dose, compared with patients who received chemotherapy and placebo, reported Noelle Frey, MD, from the University of Pennsylvania in Philadelphia, and colleagues.

“Overall survival was also numerically longer in the placebo group, compared with the eltrombopag group. It remains unclear why there were more deaths, particularly due to hemorrhage within 30 days after the last dose of treatment, in the eltrombopag group,” they wrote in the Lancet Haematology.

The investigators had expected better results, based on eltrombopag’s demonstrated efficacy against thrombocytopenia (a common feature of AML, exacerbated by chemotherapy), and because of evidence suggesting that the thrombopoietin-receptor agonist might also have antileukemic properties.

They set out to test the safety, tolerability, and efficacy of eltrombopag added to standard induction therapy in patients with treatment-naive AML of any subtype except M3 (acute promyelocytic leukemia) or M7 (acute megakaryocytic leukemia).

Patients received chemotherapy with daunorubicin in a bolus intravenous infusion at a dose of 90 mg/m² on days 1-3 for patients 18-60 years of age, or 60 mg/m² for patients older than 60 years, plus cytarabine continuous intravenous infusion at a dose of 100 mg/m² on days 1-7. The 148 patients were randomized in groups of 74 each to receive either eltrombopag 200 mg (100 mg for patients of east Asian heritage) or placebo, once daily.

Eltrombopag was continued until platelet counts were 200 × 10⁹/L or higher, remission, or 42 days after the start of induction chemotherapy.

Grade 3 or 4 adverse events occurring in 10% or more of patients – a primary endpoint – were febrile neutropenia, which occurred in 42% of patients receiving eltrombopag, compared with 39% receiving placebo, decreased white blood cell count in 11% vs. 7%, and hypophosphatemia in 4% and 13%, respectively,

Serious adverse events occurred in 34% of patients on eltrombopag, compared with 20% on placebo. Similarly, 53% of patients receiving eltrombopag died, compared with 41% of patients receiving the placebo.

Most of the deaths were attributable to AML, including 19 patients (26%) on eltrombopag and 10 (14%) on placebo. Eleven patients on eltrombopag and four on placebo died within 30 days of the last dose of study treatment.

Hemorrhage accounted for the deaths of five patients on eltrombopag and three on placebo, and sepsis accounted for the deaths of five and six patients, respectively.

Both the incidence of thromboembolic events and mean change in left ventricular ejection fraction were similar between the groups.

Median overall survival was 15.4 months in the eltrombopag group vs. 25.7 months in the placebo group, although this difference was not statistically significant, likely because of the sample size.

The investigators were at a loss to explain why the eltrombopag-treated patients had numerically worse outcomes.

“In the present study, eltrombopag did not improve the time to platelet recovery or the incidences of grade 3-4 thrombocytopenia, neutropenia, or anemia, compared with placebo. Furthermore, the study did not reveal any differences in investigator-assessed response to treatment. These findings were unexpected given outcomes from previous studies of eltrombopag monotherapy in patients with myelodysplastic syndromes or acute myeloid leukemia,” they wrote.

Although the reasons behind the findings are unclear, “the data from this trial do not support a favorable benefit-risk profile for eltrombopag in combination with induction chemotherapy in patients with acute myeloid leukemia,” the investigators wrote.

The study was funded by Novartis. Dr. Frey reported nonfinancial support from Novartis during the conduct of the study and consultancy fees from Novartis outside of the submitted work. Multiple coauthors reported similar relationships with Novartis and/or other companies.

SOURCE: Frey N et al. Lancet Haematol. 2019 Jan 28. doi: 10.1016/S2352-3026(18)30231-X.

The thrombopoietic agent eltrombopag (Promacta) did more harm than good when given to adults with acute myeloid leukemia (AML) during standard induction chemotherapy, results of a randomized phase 2 trial show.

Patients who were randomly assigned to receive standard induction chemotherapy with daunorubicin and cytarabine plus eltrombopag had a higher incidence of serious adverse events and death from hemorrhage within 30 days of the last eltrombopag dose, compared with patients who received chemotherapy and placebo, reported Noelle Frey, MD, from the University of Pennsylvania in Philadelphia, and colleagues.

“Overall survival was also numerically longer in the placebo group, compared with the eltrombopag group. It remains unclear why there were more deaths, particularly due to hemorrhage within 30 days after the last dose of treatment, in the eltrombopag group,” they wrote in the Lancet Haematology.

The investigators had expected better results, based on eltrombopag’s demonstrated efficacy against thrombocytopenia (a common feature of AML, exacerbated by chemotherapy), and because of evidence suggesting that the thrombopoietin-receptor agonist might also have antileukemic properties.

They set out to test the safety, tolerability, and efficacy of eltrombopag added to standard induction therapy in patients with treatment-naive AML of any subtype except M3 (acute promyelocytic leukemia) or M7 (acute megakaryocytic leukemia).

Patients received chemotherapy with daunorubicin in a bolus intravenous infusion at a dose of 90 mg/m² on days 1-3 for patients 18-60 years of age, or 60 mg/m² for patients older than 60 years, plus cytarabine continuous intravenous infusion at a dose of 100 mg/m² on days 1-7. The 148 patients were randomized in groups of 74 each to receive either eltrombopag 200 mg (100 mg for patients of east Asian heritage) or placebo, once daily.

Eltrombopag was continued until platelet counts were 200 × 10⁹/L or higher, remission, or 42 days after the start of induction chemotherapy.

Grade 3 or 4 adverse events occurring in 10% or more of patients – a primary endpoint – were febrile neutropenia, which occurred in 42% of patients receiving eltrombopag, compared with 39% receiving placebo, decreased white blood cell count in 11% vs. 7%, and hypophosphatemia in 4% and 13%, respectively,

Serious adverse events occurred in 34% of patients on eltrombopag, compared with 20% on placebo. Similarly, 53% of patients receiving eltrombopag died, compared with 41% of patients receiving the placebo.

Most of the deaths were attributable to AML, including 19 patients (26%) on eltrombopag and 10 (14%) on placebo. Eleven patients on eltrombopag and four on placebo died within 30 days of the last dose of study treatment.

Hemorrhage accounted for the deaths of five patients on eltrombopag and three on placebo, and sepsis accounted for the deaths of five and six patients, respectively.

Both the incidence of thromboembolic events and mean change in left ventricular ejection fraction were similar between the groups.

Median overall survival was 15.4 months in the eltrombopag group vs. 25.7 months in the placebo group, although this difference was not statistically significant, likely because of the sample size.

The investigators were at a loss to explain why the eltrombopag-treated patients had numerically worse outcomes.

“In the present study, eltrombopag did not improve the time to platelet recovery or the incidences of grade 3-4 thrombocytopenia, neutropenia, or anemia, compared with placebo. Furthermore, the study did not reveal any differences in investigator-assessed response to treatment. These findings were unexpected given outcomes from previous studies of eltrombopag monotherapy in patients with myelodysplastic syndromes or acute myeloid leukemia,” they wrote.

Although the reasons behind the findings are unclear, “the data from this trial do not support a favorable benefit-risk profile for eltrombopag in combination with induction chemotherapy in patients with acute myeloid leukemia,” the investigators wrote.

The study was funded by Novartis. Dr. Frey reported nonfinancial support from Novartis during the conduct of the study and consultancy fees from Novartis outside of the submitted work. Multiple coauthors reported similar relationships with Novartis and/or other companies.

SOURCE: Frey N et al. Lancet Haematol. 2019 Jan 28. doi: 10.1016/S2352-3026(18)30231-X.

The thrombopoietic agent eltrombopag (Promacta) did more harm than good when given to adults with acute myeloid leukemia (AML) during standard induction chemotherapy, results of a randomized phase 2 trial show.

Patients who were randomly assigned to receive standard induction chemotherapy with daunorubicin and cytarabine plus eltrombopag had a higher incidence of serious adverse events and death from hemorrhage within 30 days of the last eltrombopag dose, compared with patients who received chemotherapy and placebo, reported Noelle Frey, MD, from the University of Pennsylvania in Philadelphia, and colleagues.

“Overall survival was also numerically longer in the placebo group, compared with the eltrombopag group. It remains unclear why there were more deaths, particularly due to hemorrhage within 30 days after the last dose of treatment, in the eltrombopag group,” they wrote in the Lancet Haematology.

The investigators had expected better results, based on eltrombopag’s demonstrated efficacy against thrombocytopenia (a common feature of AML, exacerbated by chemotherapy), and because of evidence suggesting that the thrombopoietin-receptor agonist might also have antileukemic properties.

They set out to test the safety, tolerability, and efficacy of eltrombopag added to standard induction therapy in patients with treatment-naive AML of any subtype except M3 (acute promyelocytic leukemia) or M7 (acute megakaryocytic leukemia).

Patients received chemotherapy with daunorubicin in a bolus intravenous infusion at a dose of 90 mg/m² on days 1-3 for patients 18-60 years of age, or 60 mg/m² for patients older than 60 years, plus cytarabine continuous intravenous infusion at a dose of 100 mg/m² on days 1-7. The 148 patients were randomized in groups of 74 each to receive either eltrombopag 200 mg (100 mg for patients of east Asian heritage) or placebo, once daily.

Eltrombopag was continued until platelet counts were 200 × 10⁹/L or higher, remission, or 42 days after the start of induction chemotherapy.

Grade 3 or 4 adverse events occurring in 10% or more of patients – a primary endpoint – were febrile neutropenia, which occurred in 42% of patients receiving eltrombopag, compared with 39% receiving placebo, decreased white blood cell count in 11% vs. 7%, and hypophosphatemia in 4% and 13%, respectively,

Serious adverse events occurred in 34% of patients on eltrombopag, compared with 20% on placebo. Similarly, 53% of patients receiving eltrombopag died, compared with 41% of patients receiving the placebo.

Most of the deaths were attributable to AML, including 19 patients (26%) on eltrombopag and 10 (14%) on placebo. Eleven patients on eltrombopag and four on placebo died within 30 days of the last dose of study treatment.

Hemorrhage accounted for the deaths of five patients on eltrombopag and three on placebo, and sepsis accounted for the deaths of five and six patients, respectively.

Both the incidence of thromboembolic events and mean change in left ventricular ejection fraction were similar between the groups.

Median overall survival was 15.4 months in the eltrombopag group vs. 25.7 months in the placebo group, although this difference was not statistically significant, likely because of the sample size.

The investigators were at a loss to explain why the eltrombopag-treated patients had numerically worse outcomes.

“In the present study, eltrombopag did not improve the time to platelet recovery or the incidences of grade 3-4 thrombocytopenia, neutropenia, or anemia, compared with placebo. Furthermore, the study did not reveal any differences in investigator-assessed response to treatment. These findings were unexpected given outcomes from previous studies of eltrombopag monotherapy in patients with myelodysplastic syndromes or acute myeloid leukemia,” they wrote.

Although the reasons behind the findings are unclear, “the data from this trial do not support a favorable benefit-risk profile for eltrombopag in combination with induction chemotherapy in patients with acute myeloid leukemia,” the investigators wrote.

The study was funded by Novartis. Dr. Frey reported nonfinancial support from Novartis during the conduct of the study and consultancy fees from Novartis outside of the submitted work. Multiple coauthors reported similar relationships with Novartis and/or other companies.

SOURCE: Frey N et al. Lancet Haematol. 2019 Jan 28. doi: 10.1016/S2352-3026(18)30231-X.

SAN DIEGO – Checkpoint inhibition can be used safely and effectively with CD19-directed chimeric antigen receptor (CAR) T-cell therapy in children with relapsed B-cell acute lymphoblastic leukemia (ALL), and it may bolster CAR T-cell effects and persistence, suggest the findings in a series of 14 patients at the Children’s Hospital of Philadelphia.

Combined programmed death-1 (PD-1) blockade and CAR T-cell therapy appeared to have particular benefit in patients with early B-cell recovery and in those with bulky extramedullary disease, Shannon Maude, MD, PhD, reported during a press conference at the annual meeting of the American Society of Hematology.

The patients, aged 4-17 years with heavily pretreated relapsed B-ALL (13 patients) or B lymphoblastic lymphoma (1 patient), were treated with CD19-directed CAR T-cell therapy, including CTL019 in 4 patients and CTL119 in 10 patients, followed by pembrolizumab (in 13 patients) or nivolumab (in 1 patient).

Six patients received the combination therapy because of early B-cell recovery after initial CAR T-cell infusion, four patients had relapsed or refractory (R/R) bulky extramedullary disease, and four patients had failed to respond or relapsed after initial CAR T-cell therapy.

Three of the six with poor persistence of response reestablished B-cell aplasia (a reflection of CAR T-cell function) after reinfusion of the CAR T-cell product followed by infusion with PD-1 blockade, and they have “sustained CR [complete response] with B-cell aplasia, showing continued persistence of their CAR T cells,” said Dr. Maude, an attending physician in the Cancer Center at Children’s Hospital of Philadelphia.

Of the four patients with R/R bulky extramedullary disease, two patients had a partial response and two patients had CR, she said, explaining that it was hypothesized that the “PD-1 checkpoint pathway may be activated through the microenvironment in that extramedullary situation.”

However, all four patients who had partial or no response to initial CAR T-cell therapy progressed after PD-1 administration, she said, noting that “in one patient, this progression was marked by reduced CD19 expression, which was probably the mode of escape from CD19 CAR T cells.”

Prior studies have shown that patients who respond to CAR T-cell therapy have persistence of CD19 CAR T cells, whereas those with loss of CD19 CAR T cells within 6 months of infusion have a higher rate of relapse, Dr. Maude explained.

“Our hypothesis was that T cells, upon activation, may become exhausted through activation of immune checkpoint pathways, that one such pathway – PD-1 – may be involved in early loss of CD19 CAR T cells and therefore that the combination [of CD19 CAR T-cell therapy] with PD-1 checkpoint blockade may improve the function of the CAR T cells and their persistence,” she said.

The combined approach was well tolerated in this study, she said, noting that mild cytokine release syndrome symptoms and fever typical of CAR T-cell proliferative responses were observed in three patients within 2 days of starting pembrolizumab.

Other adverse effects associated with PD-1 inhibition, including acute pancreatitis, hypothyroidism, arthralgias, and urticaria, occurred in one patient each. There were four cases of grade 3-4 cytopenias that were deemed tolerable or reversible upon discontinuation.

“We show that PD-1 checkpoint inhibitors can be safely combined with CD19 CAR T-cell therapy and that this mechanism may be useful to improve CAR T-cell persistence,” Dr. Maude said.

These findings, which showed particular benefit in patients with poor persistence marked by early B-cell recovery and in those with R/R bulky extramedullary disease, should help inform future use of checkpoint inhibitors after CAR T-cell therapy, she added.

Dr. Maude reported financial ties to Novartis.

[email protected]

SOURCE: Li AM et al. ASH 2018, Abstract 556.

SAN DIEGO – Checkpoint inhibition can be used safely and effectively with CD19-directed chimeric antigen receptor (CAR) T-cell therapy in children with relapsed B-cell acute lymphoblastic leukemia (ALL), and it may bolster CAR T-cell effects and persistence, suggest the findings in a series of 14 patients at the Children’s Hospital of Philadelphia.

Combined programmed death-1 (PD-1) blockade and CAR T-cell therapy appeared to have particular benefit in patients with early B-cell recovery and in those with bulky extramedullary disease, Shannon Maude, MD, PhD, reported during a press conference at the annual meeting of the American Society of Hematology.

The patients, aged 4-17 years with heavily pretreated relapsed B-ALL (13 patients) or B lymphoblastic lymphoma (1 patient), were treated with CD19-directed CAR T-cell therapy, including CTL019 in 4 patients and CTL119 in 10 patients, followed by pembrolizumab (in 13 patients) or nivolumab (in 1 patient).

Six patients received the combination therapy because of early B-cell recovery after initial CAR T-cell infusion, four patients had relapsed or refractory (R/R) bulky extramedullary disease, and four patients had failed to respond or relapsed after initial CAR T-cell therapy.

Three of the six with poor persistence of response reestablished B-cell aplasia (a reflection of CAR T-cell function) after reinfusion of the CAR T-cell product followed by infusion with PD-1 blockade, and they have “sustained CR [complete response] with B-cell aplasia, showing continued persistence of their CAR T cells,” said Dr. Maude, an attending physician in the Cancer Center at Children’s Hospital of Philadelphia.

Of the four patients with R/R bulky extramedullary disease, two patients had a partial response and two patients had CR, she said, explaining that it was hypothesized that the “PD-1 checkpoint pathway may be activated through the microenvironment in that extramedullary situation.”

However, all four patients who had partial or no response to initial CAR T-cell therapy progressed after PD-1 administration, she said, noting that “in one patient, this progression was marked by reduced CD19 expression, which was probably the mode of escape from CD19 CAR T cells.”

Prior studies have shown that patients who respond to CAR T-cell therapy have persistence of CD19 CAR T cells, whereas those with loss of CD19 CAR T cells within 6 months of infusion have a higher rate of relapse, Dr. Maude explained.

“Our hypothesis was that T cells, upon activation, may become exhausted through activation of immune checkpoint pathways, that one such pathway – PD-1 – may be involved in early loss of CD19 CAR T cells and therefore that the combination [of CD19 CAR T-cell therapy] with PD-1 checkpoint blockade may improve the function of the CAR T cells and their persistence,” she said.

The combined approach was well tolerated in this study, she said, noting that mild cytokine release syndrome symptoms and fever typical of CAR T-cell proliferative responses were observed in three patients within 2 days of starting pembrolizumab.

Other adverse effects associated with PD-1 inhibition, including acute pancreatitis, hypothyroidism, arthralgias, and urticaria, occurred in one patient each. There were four cases of grade 3-4 cytopenias that were deemed tolerable or reversible upon discontinuation.

“We show that PD-1 checkpoint inhibitors can be safely combined with CD19 CAR T-cell therapy and that this mechanism may be useful to improve CAR T-cell persistence,” Dr. Maude said.

These findings, which showed particular benefit in patients with poor persistence marked by early B-cell recovery and in those with R/R bulky extramedullary disease, should help inform future use of checkpoint inhibitors after CAR T-cell therapy, she added.

Dr. Maude reported financial ties to Novartis.

[email protected]

SOURCE: Li AM et al. ASH 2018, Abstract 556.

SAN DIEGO – Checkpoint inhibition can be used safely and effectively with CD19-directed chimeric antigen receptor (CAR) T-cell therapy in children with relapsed B-cell acute lymphoblastic leukemia (ALL), and it may bolster CAR T-cell effects and persistence, suggest the findings in a series of 14 patients at the Children’s Hospital of Philadelphia.

Combined programmed death-1 (PD-1) blockade and CAR T-cell therapy appeared to have particular benefit in patients with early B-cell recovery and in those with bulky extramedullary disease, Shannon Maude, MD, PhD, reported during a press conference at the annual meeting of the American Society of Hematology.

The patients, aged 4-17 years with heavily pretreated relapsed B-ALL (13 patients) or B lymphoblastic lymphoma (1 patient), were treated with CD19-directed CAR T-cell therapy, including CTL019 in 4 patients and CTL119 in 10 patients, followed by pembrolizumab (in 13 patients) or nivolumab (in 1 patient).

Six patients received the combination therapy because of early B-cell recovery after initial CAR T-cell infusion, four patients had relapsed or refractory (R/R) bulky extramedullary disease, and four patients had failed to respond or relapsed after initial CAR T-cell therapy.

Three of the six with poor persistence of response reestablished B-cell aplasia (a reflection of CAR T-cell function) after reinfusion of the CAR T-cell product followed by infusion with PD-1 blockade, and they have “sustained CR [complete response] with B-cell aplasia, showing continued persistence of their CAR T cells,” said Dr. Maude, an attending physician in the Cancer Center at Children’s Hospital of Philadelphia.

Of the four patients with R/R bulky extramedullary disease, two patients had a partial response and two patients had CR, she said, explaining that it was hypothesized that the “PD-1 checkpoint pathway may be activated through the microenvironment in that extramedullary situation.”

However, all four patients who had partial or no response to initial CAR T-cell therapy progressed after PD-1 administration, she said, noting that “in one patient, this progression was marked by reduced CD19 expression, which was probably the mode of escape from CD19 CAR T cells.”

Prior studies have shown that patients who respond to CAR T-cell therapy have persistence of CD19 CAR T cells, whereas those with loss of CD19 CAR T cells within 6 months of infusion have a higher rate of relapse, Dr. Maude explained.

“Our hypothesis was that T cells, upon activation, may become exhausted through activation of immune checkpoint pathways, that one such pathway – PD-1 – may be involved in early loss of CD19 CAR T cells and therefore that the combination [of CD19 CAR T-cell therapy] with PD-1 checkpoint blockade may improve the function of the CAR T cells and their persistence,” she said.

The combined approach was well tolerated in this study, she said, noting that mild cytokine release syndrome symptoms and fever typical of CAR T-cell proliferative responses were observed in three patients within 2 days of starting pembrolizumab.

Other adverse effects associated with PD-1 inhibition, including acute pancreatitis, hypothyroidism, arthralgias, and urticaria, occurred in one patient each. There were four cases of grade 3-4 cytopenias that were deemed tolerable or reversible upon discontinuation.

“We show that PD-1 checkpoint inhibitors can be safely combined with CD19 CAR T-cell therapy and that this mechanism may be useful to improve CAR T-cell persistence,” Dr. Maude said.

These findings, which showed particular benefit in patients with poor persistence marked by early B-cell recovery and in those with R/R bulky extramedullary disease, should help inform future use of checkpoint inhibitors after CAR T-cell therapy, she added.

Dr. Maude reported financial ties to Novartis.

[email protected]

SOURCE: Li AM et al. ASH 2018, Abstract 556.

For patients with multiple myeloma that remains symptomatic within a year of starting therapy, neither a second autologous stem cell transplant nor more intensive consolidation therapy offered survival benefits superior to those seen with a single first autologous transplant and lenalidomide maintenance, reported investigators in a multicenter U.S. trial.

Courtesy Wikimedia Commons/KGH/Creative Commons License

Among 758 patients with multiple myeloma (MM) who underwent standard induction therapy, followed by melphalan conditioning and autologous hematopoietic cell transplant (AHCT), there were no differences in either progression-free survival (PFS) or overall survival (OS) between the three treatment arms, reported Edward A. Stadtmauer, MD, from the University of Pennsylvania, Philadelphia, and his colleagues.

Patients were randomized to either lenalidomide (Revlimid) maintenance alone; consolidation therapy with four cycles of lenalidomide, bortezomib (Velcade), and dexamethasone (RVD), followed by lenalidomide maintenance; or second transplant followed by lenalidomide maintenance.

“Single AHCT followed by len[alidomide] remains the standard of care. Greater than 80% of patients were alive at 38 months, which highlights excellent contemporary outcomes of patients with MM when treated with a standard approach of a multidrug induction followed by AHCT consolidation and maintenance,” they wrote in the Journal of Clinical Oncology.

The investigators hypothesized that the use of thalidomide analogues and proteasome inhibitors used in first-line therapy, consolidation, and long-term maintenance after high-dose melphalan and AHCT would improve survival, compared with a second AHCT.

To test this idea, they enrolled 758 patients from 54 U.S. centers and randomized them to one of three post-transplant strategies prior to transplant conditioning with high-dose melphalan (200 mg/m²) and AHCT.


Roughly 25% of patients in each treatment arm had high-risk disease, defined as beta-2 microglobulin levels greater than 5.5 mg/L, high-risk cytogenetics, and deletion 13 detected by standard cytogenetics only. The remaining patients in each arm had standard-risk disease.

The patients, who were a median age of 56 years old, had symptomatic multiple myeloma 12 months from the start of therapy without disease progression. They were randomly assigned to either AHCT followed by a second transplant and lenalidomide maintenance (247 patients), single transplant followed by RVD and lenalidomide maintenance (254), or single AHCT plus lenalidomide maintenance (257).

There were no significant differences between the groups in the primary endpoint of PFS at 38 months, with rates of 58.5% for the dual AHCT plus lenalidomide group, 57.8% for AHCT/RVD/lenalidomide, and 53.9% for AHCT/lenalidomide. Respective OS rates also did not differ significantly, at 81.8%, 85.4%, and 83.7%.

Complete response rates at 1 year were 50.5%, 58.4%, and 47.1%, respectively.

The three regimens also were similar in their toxicity profiles and in the risk of second malignancies.

The trial was supported by grants from the National Institutes of Health, research groups, Celgene, and Millennium (Takeda) Pharmaceuticals. Dr. Stadtmauer reported ties to Celgene, Takeda, and other companies. Multiple coauthors reported relationships with industry.

SOURCE: Stadtmauer E et al. J Clin Oncol. 2019 Jan 17. doi: 10.1200/JCO.18.00685.

For patients with multiple myeloma that remains symptomatic within a year of starting therapy, neither a second autologous stem cell transplant nor more intensive consolidation therapy offered survival benefits superior to those seen with a single first autologous transplant and lenalidomide maintenance, reported investigators in a multicenter U.S. trial.

Courtesy Wikimedia Commons/KGH/Creative Commons License

Among 758 patients with multiple myeloma (MM) who underwent standard induction therapy, followed by melphalan conditioning and autologous hematopoietic cell transplant (AHCT), there were no differences in either progression-free survival (PFS) or overall survival (OS) between the three treatment arms, reported Edward A. Stadtmauer, MD, from the University of Pennsylvania, Philadelphia, and his colleagues.

Patients were randomized to either lenalidomide (Revlimid) maintenance alone; consolidation therapy with four cycles of lenalidomide, bortezomib (Velcade), and dexamethasone (RVD), followed by lenalidomide maintenance; or second transplant followed by lenalidomide maintenance.

“Single AHCT followed by len[alidomide] remains the standard of care. Greater than 80% of patients were alive at 38 months, which highlights excellent contemporary outcomes of patients with MM when treated with a standard approach of a multidrug induction followed by AHCT consolidation and maintenance,” they wrote in the Journal of Clinical Oncology.

The investigators hypothesized that the use of thalidomide analogues and proteasome inhibitors used in first-line therapy, consolidation, and long-term maintenance after high-dose melphalan and AHCT would improve survival, compared with a second AHCT.

To test this idea, they enrolled 758 patients from 54 U.S. centers and randomized them to one of three post-transplant strategies prior to transplant conditioning with high-dose melphalan (200 mg/m²) and AHCT.


Roughly 25% of patients in each treatment arm had high-risk disease, defined as beta-2 microglobulin levels greater than 5.5 mg/L, high-risk cytogenetics, and deletion 13 detected by standard cytogenetics only. The remaining patients in each arm had standard-risk disease.

The patients, who were a median age of 56 years old, had symptomatic multiple myeloma 12 months from the start of therapy without disease progression. They were randomly assigned to either AHCT followed by a second transplant and lenalidomide maintenance (247 patients), single transplant followed by RVD and lenalidomide maintenance (254), or single AHCT plus lenalidomide maintenance (257).

There were no significant differences between the groups in the primary endpoint of PFS at 38 months, with rates of 58.5% for the dual AHCT plus lenalidomide group, 57.8% for AHCT/RVD/lenalidomide, and 53.9% for AHCT/lenalidomide. Respective OS rates also did not differ significantly, at 81.8%, 85.4%, and 83.7%.

Complete response rates at 1 year were 50.5%, 58.4%, and 47.1%, respectively.

The three regimens also were similar in their toxicity profiles and in the risk of second malignancies.

The trial was supported by grants from the National Institutes of Health, research groups, Celgene, and Millennium (Takeda) Pharmaceuticals. Dr. Stadtmauer reported ties to Celgene, Takeda, and other companies. Multiple coauthors reported relationships with industry.

SOURCE: Stadtmauer E et al. J Clin Oncol. 2019 Jan 17. doi: 10.1200/JCO.18.00685.

For patients with multiple myeloma that remains symptomatic within a year of starting therapy, neither a second autologous stem cell transplant nor more intensive consolidation therapy offered survival benefits superior to those seen with a single first autologous transplant and lenalidomide maintenance, reported investigators in a multicenter U.S. trial.

Courtesy Wikimedia Commons/KGH/Creative Commons License

Among 758 patients with multiple myeloma (MM) who underwent standard induction therapy, followed by melphalan conditioning and autologous hematopoietic cell transplant (AHCT), there were no differences in either progression-free survival (PFS) or overall survival (OS) between the three treatment arms, reported Edward A. Stadtmauer, MD, from the University of Pennsylvania, Philadelphia, and his colleagues.

Patients were randomized to either lenalidomide (Revlimid) maintenance alone; consolidation therapy with four cycles of lenalidomide, bortezomib (Velcade), and dexamethasone (RVD), followed by lenalidomide maintenance; or second transplant followed by lenalidomide maintenance.

“Single AHCT followed by len[alidomide] remains the standard of care. Greater than 80% of patients were alive at 38 months, which highlights excellent contemporary outcomes of patients with MM when treated with a standard approach of a multidrug induction followed by AHCT consolidation and maintenance,” they wrote in the Journal of Clinical Oncology.

The investigators hypothesized that the use of thalidomide analogues and proteasome inhibitors used in first-line therapy, consolidation, and long-term maintenance after high-dose melphalan and AHCT would improve survival, compared with a second AHCT.

To test this idea, they enrolled 758 patients from 54 U.S. centers and randomized them to one of three post-transplant strategies prior to transplant conditioning with high-dose melphalan (200 mg/m²) and AHCT.


Roughly 25% of patients in each treatment arm had high-risk disease, defined as beta-2 microglobulin levels greater than 5.5 mg/L, high-risk cytogenetics, and deletion 13 detected by standard cytogenetics only. The remaining patients in each arm had standard-risk disease.

The patients, who were a median age of 56 years old, had symptomatic multiple myeloma 12 months from the start of therapy without disease progression. They were randomly assigned to either AHCT followed by a second transplant and lenalidomide maintenance (247 patients), single transplant followed by RVD and lenalidomide maintenance (254), or single AHCT plus lenalidomide maintenance (257).

There were no significant differences between the groups in the primary endpoint of PFS at 38 months, with rates of 58.5% for the dual AHCT plus lenalidomide group, 57.8% for AHCT/RVD/lenalidomide, and 53.9% for AHCT/lenalidomide. Respective OS rates also did not differ significantly, at 81.8%, 85.4%, and 83.7%.

Complete response rates at 1 year were 50.5%, 58.4%, and 47.1%, respectively.

The three regimens also were similar in their toxicity profiles and in the risk of second malignancies.

The trial was supported by grants from the National Institutes of Health, research groups, Celgene, and Millennium (Takeda) Pharmaceuticals. Dr. Stadtmauer reported ties to Celgene, Takeda, and other companies. Multiple coauthors reported relationships with industry.

SOURCE: Stadtmauer E et al. J Clin Oncol. 2019 Jan 17. doi: 10.1200/JCO.18.00685.

Some patients with aggressive leukemic nonnodal mantle cell lymphoma (L-NN-MCL) respond very well to combination therapy with rituximab and ibrutinib, according to two case reports.

Both patients, who had aggressive L-NN-MCL and P53 abnormalities, remain free of disease 18 months after treatment with rituximab/ibrutinib and autologous stem cell transplantation (ASCT), reported Shahram Mori, MD, PhD, of the Florida Hospital Cancer Institute in Orlando, and his colleagues.

The findings suggest that P53 gene status in L-NN-MCL may have a significant impact on prognosis and treatment planning. There are currently no guidelines for risk stratifying L-NN-MCL patients.

“Although the recognition of L-NN-MCL is important to avoid overtreatment, there appears to be a subset of patients who either have a more aggressive form or disease that has transformed to a more aggressive form who present with symptomatic disease and/or cytopenias,” the investigators wrote in Clinical Lymphoma, Myeloma & Leukemia.

The investigators described two such cases in their report. Both patients had leukocytosis with various other blood cell derangements and splenomegaly without lymphadenopathy.

The first patient was a 53-year-old African American man with L-NN-MCL and a number of genetic aberrations, including loss of the P53 gene. After two cycles of rituximab with bendamustine proved ineffective, he was switched to rituxan with cyclophosphamide, vincristine, adriamycin, and dexamethasone with high-dose methotrexate and cytarabine. This regimen was also ineffective and his white blood cell count kept rising.

His story changed for the better when the patient was switched to ibrutinib 560 mg daily and rituximab 375 mg/m² monthly. Within 2 months of starting therapy, his blood abnormalities normalized, and bone marrow biopsy at the end of treatment revealed complete remission without evidence of minimal residual disease. The patient remains in complete remission 18 months after ASCT.

The second patient was a 49-year-old Hispanic man with L-NN-MCL. He had missense mutations in TP53 and KMT2A (MLL), a frameshift mutation in BCOR, and a t(11;14) translocation. Ibrutinib/rituximab was started immediately. After 1 month, his blood levels began to normalize. After five cycles, bone marrow biopsy showed complete remission with no evidence of minimal residual disease. Like the first patient, the second patient remains in complete remission 18 months after ASCT.

“To our knowledge, these are the first two cases of L-NN-MCL with P53 gene mutations/alterations that were successfully treated with a combination of rituximab and ibrutinib,” the investigators wrote. “Our two cases confirm the previous studies by Chapman-Fredricks et al, who also noted P53 gene mutation or deletion is associated with the aggressive course.”

The researchers reported having no financial disclosures.

SOURCE: Mori S et al. Clin Lymphoma Myeloma Leuk. 2019 Feb;19(2):e93-7.

Some patients with aggressive leukemic nonnodal mantle cell lymphoma (L-NN-MCL) respond very well to combination therapy with rituximab and ibrutinib, according to two case reports.

Both patients, who had aggressive L-NN-MCL and P53 abnormalities, remain free of disease 18 months after treatment with rituximab/ibrutinib and autologous stem cell transplantation (ASCT), reported Shahram Mori, MD, PhD, of the Florida Hospital Cancer Institute in Orlando, and his colleagues.

The findings suggest that P53 gene status in L-NN-MCL may have a significant impact on prognosis and treatment planning. There are currently no guidelines for risk stratifying L-NN-MCL patients.

“Although the recognition of L-NN-MCL is important to avoid overtreatment, there appears to be a subset of patients who either have a more aggressive form or disease that has transformed to a more aggressive form who present with symptomatic disease and/or cytopenias,” the investigators wrote in Clinical Lymphoma, Myeloma & Leukemia.

The investigators described two such cases in their report. Both patients had leukocytosis with various other blood cell derangements and splenomegaly without lymphadenopathy.

The first patient was a 53-year-old African American man with L-NN-MCL and a number of genetic aberrations, including loss of the P53 gene. After two cycles of rituximab with bendamustine proved ineffective, he was switched to rituxan with cyclophosphamide, vincristine, adriamycin, and dexamethasone with high-dose methotrexate and cytarabine. This regimen was also ineffective and his white blood cell count kept rising.

His story changed for the better when the patient was switched to ibrutinib 560 mg daily and rituximab 375 mg/m² monthly. Within 2 months of starting therapy, his blood abnormalities normalized, and bone marrow biopsy at the end of treatment revealed complete remission without evidence of minimal residual disease. The patient remains in complete remission 18 months after ASCT.

The second patient was a 49-year-old Hispanic man with L-NN-MCL. He had missense mutations in TP53 and KMT2A (MLL), a frameshift mutation in BCOR, and a t(11;14) translocation. Ibrutinib/rituximab was started immediately. After 1 month, his blood levels began to normalize. After five cycles, bone marrow biopsy showed complete remission with no evidence of minimal residual disease. Like the first patient, the second patient remains in complete remission 18 months after ASCT.

“To our knowledge, these are the first two cases of L-NN-MCL with P53 gene mutations/alterations that were successfully treated with a combination of rituximab and ibrutinib,” the investigators wrote. “Our two cases confirm the previous studies by Chapman-Fredricks et al, who also noted P53 gene mutation or deletion is associated with the aggressive course.”

The researchers reported having no financial disclosures.

SOURCE: Mori S et al. Clin Lymphoma Myeloma Leuk. 2019 Feb;19(2):e93-7.

Some patients with aggressive leukemic nonnodal mantle cell lymphoma (L-NN-MCL) respond very well to combination therapy with rituximab and ibrutinib, according to two case reports.

Both patients, who had aggressive L-NN-MCL and P53 abnormalities, remain free of disease 18 months after treatment with rituximab/ibrutinib and autologous stem cell transplantation (ASCT), reported Shahram Mori, MD, PhD, of the Florida Hospital Cancer Institute in Orlando, and his colleagues.

The findings suggest that P53 gene status in L-NN-MCL may have a significant impact on prognosis and treatment planning. There are currently no guidelines for risk stratifying L-NN-MCL patients.

“Although the recognition of L-NN-MCL is important to avoid overtreatment, there appears to be a subset of patients who either have a more aggressive form or disease that has transformed to a more aggressive form who present with symptomatic disease and/or cytopenias,” the investigators wrote in Clinical Lymphoma, Myeloma & Leukemia.

The investigators described two such cases in their report. Both patients had leukocytosis with various other blood cell derangements and splenomegaly without lymphadenopathy.

The first patient was a 53-year-old African American man with L-NN-MCL and a number of genetic aberrations, including loss of the P53 gene. After two cycles of rituximab with bendamustine proved ineffective, he was switched to rituxan with cyclophosphamide, vincristine, adriamycin, and dexamethasone with high-dose methotrexate and cytarabine. This regimen was also ineffective and his white blood cell count kept rising.

His story changed for the better when the patient was switched to ibrutinib 560 mg daily and rituximab 375 mg/m² monthly. Within 2 months of starting therapy, his blood abnormalities normalized, and bone marrow biopsy at the end of treatment revealed complete remission without evidence of minimal residual disease. The patient remains in complete remission 18 months after ASCT.

The second patient was a 49-year-old Hispanic man with L-NN-MCL. He had missense mutations in TP53 and KMT2A (MLL), a frameshift mutation in BCOR, and a t(11;14) translocation. Ibrutinib/rituximab was started immediately. After 1 month, his blood levels began to normalize. After five cycles, bone marrow biopsy showed complete remission with no evidence of minimal residual disease. Like the first patient, the second patient remains in complete remission 18 months after ASCT.

“To our knowledge, these are the first two cases of L-NN-MCL with P53 gene mutations/alterations that were successfully treated with a combination of rituximab and ibrutinib,” the investigators wrote. “Our two cases confirm the previous studies by Chapman-Fredricks et al, who also noted P53 gene mutation or deletion is associated with the aggressive course.”

The researchers reported having no financial disclosures.

SOURCE: Mori S et al. Clin Lymphoma Myeloma Leuk. 2019 Feb;19(2):e93-7.

LA JOLLA, CALIF. – A retrospective study suggests patients with mycosis fungoides (MF) have an increased risk of developing hematologic and solid tumor malignancies.

Vidyard Video

Researchers found the risk of second malignancy was highest among MF patients aged 30 to 50 years and patients who had tumor stage or advanced stage MF.

The increased risk was present during the entire period after MF diagnosis, but it was greatest in the first 6 months after diagnosis and roughly a dozen years later.

Amrita Goyal, MD, of the University of Minnesota in Minneapolis, and her colleagues presented these findings at the annual T-cell Lymphoma Forum.

The researchers first assessed the risk of second malignancy in 172 MF patients treated at UMN from 2005 to 2017, comparing this cohort to a control group of 172 patients with seborrheic dermatitis.

Second malignancies occurred in 24 MF patients and three controls, which was a significant difference (P = .0045). The most common second malignancies among the MF patients were melanoma (n = 4), prostate cancer (n = 3), and renal cell carcinoma (n = 3).

Further analyses revealed that MF patients were more likely to develop a second malignancy if they had tumor stage disease (P = .0024) or stage IIB or higher disease (P = .03).

To corroborate and expand upon these results, Dr. Goyal and her colleagues analyzed data from the Surveillance, Epidemiology, and End Results (SEER) database on patients diagnosed with MF from 2000 to 2014.

Among the 6,196 MF patients in this cohort, there were 514 second cancers.

“We found that MF patients were, overall, 10 times more likely to develop a second malignancy [compared with the general population],” Dr. Goyal said.

Specifically, the standardized incidence ratio was 10.15 for all malignancies, 7.33 for solid tumors, and 41.72 for hematologic malignancies.

Standardized incidence ratios for individual malignancies were:

• 69.8 for Hodgkin lymphoma.
• 46.5 for non-Hodgkin lymphoma.
• 8.6 for leukemia.
• 7.2 for melanoma.
• 6.2 for lung cancer.
• 7.9 for female breast cancer.
• 5.2 for colon cancer.
• 4.1 for prostate cancer.
• 3.9 for renal cell carcinoma.
• 3.8 for pancreatic cancer.
• 3.6 for bladder cancer.

“We found there is an increased risk [of second malignancy] during the first 6 months after diagnosis of MF, likely related to patients being in contact with the health care system more,” Dr. Goyal said. “Over time, patients have about a 7- to 10-fold increased risk over baseline, until they reach about 12 or 13 years after diagnosis, at which point, there is an increase in risk.”

The researchers found the greatest risk of second malignancy was among patients aged 30 to 50 years, although there was an increased risk for all age groups.

“The reason we think patients are experiencing an increased risk of cancers is we believe this may be due to immune suppression secondary to the mycosis fungoides, although further studies need to be performed to determine if that’s accurate,” Dr. Goyal said.

To that end, she and her colleagues are planning gene expression studies in patients from the UMN cohort. The researchers plan to examine genes involved in the pathogenesis of second malignancies and MF progression in tissue samples from 36 MF patients, 12 who developed second malignancies and 24 who did not.

The current research was funded by the American Society of Hematology. Dr. Goyal reported having no relevant financial disclosures. The T-cell Lymphoma Forum is organized by Jonathan Wood & Associates, which is owned by the same company as this news organization.

[email protected]

LA JOLLA, CALIF. – A retrospective study suggests patients with mycosis fungoides (MF) have an increased risk of developing hematologic and solid tumor malignancies.

Vidyard Video

Researchers found the risk of second malignancy was highest among MF patients aged 30 to 50 years and patients who had tumor stage or advanced stage MF.

The increased risk was present during the entire period after MF diagnosis, but it was greatest in the first 6 months after diagnosis and roughly a dozen years later.

Amrita Goyal, MD, of the University of Minnesota in Minneapolis, and her colleagues presented these findings at the annual T-cell Lymphoma Forum.

The researchers first assessed the risk of second malignancy in 172 MF patients treated at UMN from 2005 to 2017, comparing this cohort to a control group of 172 patients with seborrheic dermatitis.

Second malignancies occurred in 24 MF patients and three controls, which was a significant difference (P = .0045). The most common second malignancies among the MF patients were melanoma (n = 4), prostate cancer (n = 3), and renal cell carcinoma (n = 3).

Further analyses revealed that MF patients were more likely to develop a second malignancy if they had tumor stage disease (P = .0024) or stage IIB or higher disease (P = .03).

To corroborate and expand upon these results, Dr. Goyal and her colleagues analyzed data from the Surveillance, Epidemiology, and End Results (SEER) database on patients diagnosed with MF from 2000 to 2014.

Among the 6,196 MF patients in this cohort, there were 514 second cancers.

“We found that MF patients were, overall, 10 times more likely to develop a second malignancy [compared with the general population],” Dr. Goyal said.

Specifically, the standardized incidence ratio was 10.15 for all malignancies, 7.33 for solid tumors, and 41.72 for hematologic malignancies.

Standardized incidence ratios for individual malignancies were:

• 69.8 for Hodgkin lymphoma.
• 46.5 for non-Hodgkin lymphoma.
• 8.6 for leukemia.
• 7.2 for melanoma.
• 6.2 for lung cancer.
• 7.9 for female breast cancer.
• 5.2 for colon cancer.
• 4.1 for prostate cancer.
• 3.9 for renal cell carcinoma.
• 3.8 for pancreatic cancer.
• 3.6 for bladder cancer.

“We found there is an increased risk [of second malignancy] during the first 6 months after diagnosis of MF, likely related to patients being in contact with the health care system more,” Dr. Goyal said. “Over time, patients have about a 7- to 10-fold increased risk over baseline, until they reach about 12 or 13 years after diagnosis, at which point, there is an increase in risk.”

The researchers found the greatest risk of second malignancy was among patients aged 30 to 50 years, although there was an increased risk for all age groups.

“The reason we think patients are experiencing an increased risk of cancers is we believe this may be due to immune suppression secondary to the mycosis fungoides, although further studies need to be performed to determine if that’s accurate,” Dr. Goyal said.

To that end, she and her colleagues are planning gene expression studies in patients from the UMN cohort. The researchers plan to examine genes involved in the pathogenesis of second malignancies and MF progression in tissue samples from 36 MF patients, 12 who developed second malignancies and 24 who did not.

The current research was funded by the American Society of Hematology. Dr. Goyal reported having no relevant financial disclosures. The T-cell Lymphoma Forum is organized by Jonathan Wood & Associates, which is owned by the same company as this news organization.

[email protected]

LA JOLLA, CALIF. – A retrospective study suggests patients with mycosis fungoides (MF) have an increased risk of developing hematologic and solid tumor malignancies.

Vidyard Video

Researchers found the risk of second malignancy was highest among MF patients aged 30 to 50 years and patients who had tumor stage or advanced stage MF.

The increased risk was present during the entire period after MF diagnosis, but it was greatest in the first 6 months after diagnosis and roughly a dozen years later.

Amrita Goyal, MD, of the University of Minnesota in Minneapolis, and her colleagues presented these findings at the annual T-cell Lymphoma Forum.

The researchers first assessed the risk of second malignancy in 172 MF patients treated at UMN from 2005 to 2017, comparing this cohort to a control group of 172 patients with seborrheic dermatitis.

Second malignancies occurred in 24 MF patients and three controls, which was a significant difference (P = .0045). The most common second malignancies among the MF patients were melanoma (n = 4), prostate cancer (n = 3), and renal cell carcinoma (n = 3).

Further analyses revealed that MF patients were more likely to develop a second malignancy if they had tumor stage disease (P = .0024) or stage IIB or higher disease (P = .03).

To corroborate and expand upon these results, Dr. Goyal and her colleagues analyzed data from the Surveillance, Epidemiology, and End Results (SEER) database on patients diagnosed with MF from 2000 to 2014.

Among the 6,196 MF patients in this cohort, there were 514 second cancers.

“We found that MF patients were, overall, 10 times more likely to develop a second malignancy [compared with the general population],” Dr. Goyal said.

Specifically, the standardized incidence ratio was 10.15 for all malignancies, 7.33 for solid tumors, and 41.72 for hematologic malignancies.

Standardized incidence ratios for individual malignancies were:

• 69.8 for Hodgkin lymphoma.
• 46.5 for non-Hodgkin lymphoma.
• 8.6 for leukemia.
• 7.2 for melanoma.
• 6.2 for lung cancer.
• 7.9 for female breast cancer.
• 5.2 for colon cancer.
• 4.1 for prostate cancer.
• 3.9 for renal cell carcinoma.
• 3.8 for pancreatic cancer.
• 3.6 for bladder cancer.

“We found there is an increased risk [of second malignancy] during the first 6 months after diagnosis of MF, likely related to patients being in contact with the health care system more,” Dr. Goyal said. “Over time, patients have about a 7- to 10-fold increased risk over baseline, until they reach about 12 or 13 years after diagnosis, at which point, there is an increase in risk.”

The researchers found the greatest risk of second malignancy was among patients aged 30 to 50 years, although there was an increased risk for all age groups.

“The reason we think patients are experiencing an increased risk of cancers is we believe this may be due to immune suppression secondary to the mycosis fungoides, although further studies need to be performed to determine if that’s accurate,” Dr. Goyal said.

To that end, she and her colleagues are planning gene expression studies in patients from the UMN cohort. The researchers plan to examine genes involved in the pathogenesis of second malignancies and MF progression in tissue samples from 36 MF patients, 12 who developed second malignancies and 24 who did not.

The current research was funded by the American Society of Hematology. Dr. Goyal reported having no relevant financial disclosures. The T-cell Lymphoma Forum is organized by Jonathan Wood & Associates, which is owned by the same company as this news organization.

[email protected]

The Food and Drug Administration has identified 457 unique cases of breast implant–associated anaplastic large cell lymphoma (BIA-ALCL) and 9 related deaths since 2010, and received 246 new medical device reports (MDRs) regarding BIA-ALCL between September 2017 and September 2018, according to an update from the agency’s Center for Devices and Radiological Health.

gorodenkoff/iStock/Getty Images Plus

That brings the total number of reports to 660; however, that number reflects duplicative cases, Binita Ashar, MD, a general surgeon and the director of the division of surgical devices at the center, said in a statement.

“These types of increases in the MDRs are to be expected and may include past cases that were not previously reported to the FDA,” Dr. Ashar said, addressing the high number of new reports. “The increased number of MDRs contributes to our evolving understanding of BIA-ALCL and represents a more thorough and comprehensive analysis.”

BIA-ALCL is a type of non-Hodgkin lymphoma and a known risk from breast implants that was first communicated by the FDA in 2011. Regular updates have been provided with respect to related medical device reports, cases, deaths, and known risks.

“We hope that this information prompts providers and patients to have important, informed conversations about breast implants and the risk of BIA-ALCL. At the same time, we remain committed to working in partnership with all stakeholders to continue to study, understand, and provide updates about this important public health issue,” Dr. Ashar said.

To that end, the center also issued a Letter to Health Care Providers to “encourage those who regularly treat patients, including primary care physicians and gynecologists, to learn about BIA-ALCL in patients with breast implants.”

Patients and providers are encouraged to file MDRs with the FDA via MedWatch, the FDA Safety Information and Adverse Event Reporting program, she said.

[email protected]

The Food and Drug Administration has identified 457 unique cases of breast implant–associated anaplastic large cell lymphoma (BIA-ALCL) and 9 related deaths since 2010, and received 246 new medical device reports (MDRs) regarding BIA-ALCL between September 2017 and September 2018, according to an update from the agency’s Center for Devices and Radiological Health.

gorodenkoff/iStock/Getty Images Plus

That brings the total number of reports to 660; however, that number reflects duplicative cases, Binita Ashar, MD, a general surgeon and the director of the division of surgical devices at the center, said in a statement.

“These types of increases in the MDRs are to be expected and may include past cases that were not previously reported to the FDA,” Dr. Ashar said, addressing the high number of new reports. “The increased number of MDRs contributes to our evolving understanding of BIA-ALCL and represents a more thorough and comprehensive analysis.”

BIA-ALCL is a type of non-Hodgkin lymphoma and a known risk from breast implants that was first communicated by the FDA in 2011. Regular updates have been provided with respect to related medical device reports, cases, deaths, and known risks.

“We hope that this information prompts providers and patients to have important, informed conversations about breast implants and the risk of BIA-ALCL. At the same time, we remain committed to working in partnership with all stakeholders to continue to study, understand, and provide updates about this important public health issue,” Dr. Ashar said.

To that end, the center also issued a Letter to Health Care Providers to “encourage those who regularly treat patients, including primary care physicians and gynecologists, to learn about BIA-ALCL in patients with breast implants.”

Patients and providers are encouraged to file MDRs with the FDA via MedWatch, the FDA Safety Information and Adverse Event Reporting program, she said.

[email protected]

The Food and Drug Administration has identified 457 unique cases of breast implant–associated anaplastic large cell lymphoma (BIA-ALCL) and 9 related deaths since 2010, and received 246 new medical device reports (MDRs) regarding BIA-ALCL between September 2017 and September 2018, according to an update from the agency’s Center for Devices and Radiological Health.

gorodenkoff/iStock/Getty Images Plus

That brings the total number of reports to 660; however, that number reflects duplicative cases, Binita Ashar, MD, a general surgeon and the director of the division of surgical devices at the center, said in a statement.

“These types of increases in the MDRs are to be expected and may include past cases that were not previously reported to the FDA,” Dr. Ashar said, addressing the high number of new reports. “The increased number of MDRs contributes to our evolving understanding of BIA-ALCL and represents a more thorough and comprehensive analysis.”

BIA-ALCL is a type of non-Hodgkin lymphoma and a known risk from breast implants that was first communicated by the FDA in 2011. Regular updates have been provided with respect to related medical device reports, cases, deaths, and known risks.

“We hope that this information prompts providers and patients to have important, informed conversations about breast implants and the risk of BIA-ALCL. At the same time, we remain committed to working in partnership with all stakeholders to continue to study, understand, and provide updates about this important public health issue,” Dr. Ashar said.

To that end, the center also issued a Letter to Health Care Providers to “encourage those who regularly treat patients, including primary care physicians and gynecologists, to learn about BIA-ALCL in patients with breast implants.”

Patients and providers are encouraged to file MDRs with the FDA via MedWatch, the FDA Safety Information and Adverse Event Reporting program, she said.

[email protected]

LA JOLLA, CALIF. – Phase 1 results suggest cobomarsen is well tolerated and can maintain or improve responses in patients with previously treated adult T-cell leukemia/lymphoma (ATLL).

Five of eight ATLL patients studied experienced disease stabilization or improvement while receiving cobomarsen (MRG-106), an inhibitor of microRNA-155.

There were no grade 3/4 adverse events (AEs) or serious AEs related to cobomarsen in these patients.

Francine Foss, MD, of Yale Cancer Center in New Haven, Conn., and her colleagues presented these results at the annual T-cell Lymphoma Forum.

In this ongoing trial (NCT02580552), researchers are evaluating cobomarsen in patients with B- and T-cell lymphomas, including mycosis fungoides and ATLL.

Results are available for eight patients with previously treated ATLL. These patients had received a median of 4 (range, 1-10) prior systemic therapies, and they had a median age of 51 years (range, 40-68).

The patients received three loading doses of cobomarsen during the first week of cycle 1, followed by weekly dosing. All patients have received cobomarsen as a 600 mg intravenous infusion. They can remain on cobomarsen until they progress, experience clinically significant side effects, cannot tolerate the drug, or the trial is terminated.

The researchers have measured efficacy at least monthly by monitoring tumor cell burden in the peripheral blood and lymph nodes, as well as evaluating changes in skin involvement.

Stabilization and response

“Initially, we saw some very good responses in patients who had escalating disease. In other words, their disease was progressing after conventional chemotherapy,” Dr. Foss said. “They went on this microRNA, [and] their disease stabilized and then regressed. We saw, subsequently, in another three or four patients, the same pattern of activity.”

In all, five patients achieved or maintained a response while on cobomarsen. All five were still receiving the drug at the data cutoff on Dec. 13, 2018.

Two of these patients had acute disease and were in partial response (PR) at baseline. These patients had received cobomarsen for 87 days and 401 days as of the data cutoff.

The other three patients still receiving cobomarsen at the cutoff had lymphomatous disease. At baseline, two of the patients were in PR and one had stable disease.

The two patients in PR at baseline had received cobomarsen for 80 days and 366 days at the data cutoff. The patient with stable disease had received the drug for 161 days.
 

Progression and withdrawal

There were three patients who withdrew from the study because of disease progression. Two of these patients were relapsing with significant skin involvement at baseline.

One of the patients discontinued cobomarsen after 23 days of treatment. The other patient received cobomarsen for 91 days and left the study, then re-enrolled and received cobomarsen for another 42 days before withdrawing from the study again.

The third patient had relapsed lymphomatous disease at baseline. This patient had a mixed response to cobomarsen, with some nodes decreasing in size and others increasing. She discontinued cobomarsen after 9 days.

“It’s still early on in our experience with ATLL, so we don’t really know yet who the patient is that’s going to respond – what are the clinical features that would predict response in these patients,” Dr. Foss said. “And we’re still really trying to understand how we give the drug to these patients, for how long, and whether or not we can change the dosing interval. But, nevertheless, we have some very interesting data.”
 

Safety

There were no dose-limiting toxicities, AE-related discontinuations, treatment-related grade 3/4 AEs, or new opportunistic infections observed.

“[I] have to say, in using this drug now for over a year in two of my patients – and that’s with weekly administration – we really haven’t seen anything as far as adverse events,” Dr. Foss said.

She noted that one patient has reported transient diarrhea after dosing.

Two serious AEs – febrile neutropenia and pyrexia – occurred in one patient, but neither of these events were considered related to cobomarsen. The AEs occurred after the patient had stopped cobomarsen, and both events resolved.

There were no on-treatment deaths. One patient (the one who received cobomarsen for 9 days) died from disease progression approximately 2 months after stopping cobomarsen and while on a different therapy.

Dr. Foss said, based on their results, she and her colleagues are hoping to accrue more ATLL patients in this trial.

The trial is sponsored by miRagen Therapeutics. Dr. Foss is a cochair of the T-cell Lymphoma Forum. The T-cell Lymphoma Forum is organized by Jonathan Wood & Associates, which is owned by the same company as this news organization.

[email protected]

LA JOLLA, CALIF. – Phase 1 results suggest cobomarsen is well tolerated and can maintain or improve responses in patients with previously treated adult T-cell leukemia/lymphoma (ATLL).

Five of eight ATLL patients studied experienced disease stabilization or improvement while receiving cobomarsen (MRG-106), an inhibitor of microRNA-155.

There were no grade 3/4 adverse events (AEs) or serious AEs related to cobomarsen in these patients.

Francine Foss, MD, of Yale Cancer Center in New Haven, Conn., and her colleagues presented these results at the annual T-cell Lymphoma Forum.

In this ongoing trial (NCT02580552), researchers are evaluating cobomarsen in patients with B- and T-cell lymphomas, including mycosis fungoides and ATLL.

Results are available for eight patients with previously treated ATLL. These patients had received a median of 4 (range, 1-10) prior systemic therapies, and they had a median age of 51 years (range, 40-68).

The patients received three loading doses of cobomarsen during the first week of cycle 1, followed by weekly dosing. All patients have received cobomarsen as a 600 mg intravenous infusion. They can remain on cobomarsen until they progress, experience clinically significant side effects, cannot tolerate the drug, or the trial is terminated.

The researchers have measured efficacy at least monthly by monitoring tumor cell burden in the peripheral blood and lymph nodes, as well as evaluating changes in skin involvement.

Stabilization and response

“Initially, we saw some very good responses in patients who had escalating disease. In other words, their disease was progressing after conventional chemotherapy,” Dr. Foss said. “They went on this microRNA, [and] their disease stabilized and then regressed. We saw, subsequently, in another three or four patients, the same pattern of activity.”

In all, five patients achieved or maintained a response while on cobomarsen. All five were still receiving the drug at the data cutoff on Dec. 13, 2018.

Two of these patients had acute disease and were in partial response (PR) at baseline. These patients had received cobomarsen for 87 days and 401 days as of the data cutoff.

The other three patients still receiving cobomarsen at the cutoff had lymphomatous disease. At baseline, two of the patients were in PR and one had stable disease.

The two patients in PR at baseline had received cobomarsen for 80 days and 366 days at the data cutoff. The patient with stable disease had received the drug for 161 days.
 

Progression and withdrawal

There were three patients who withdrew from the study because of disease progression. Two of these patients were relapsing with significant skin involvement at baseline.

One of the patients discontinued cobomarsen after 23 days of treatment. The other patient received cobomarsen for 91 days and left the study, then re-enrolled and received cobomarsen for another 42 days before withdrawing from the study again.

The third patient had relapsed lymphomatous disease at baseline. This patient had a mixed response to cobomarsen, with some nodes decreasing in size and others increasing. She discontinued cobomarsen after 9 days.

“It’s still early on in our experience with ATLL, so we don’t really know yet who the patient is that’s going to respond – what are the clinical features that would predict response in these patients,” Dr. Foss said. “And we’re still really trying to understand how we give the drug to these patients, for how long, and whether or not we can change the dosing interval. But, nevertheless, we have some very interesting data.”
 

Safety

There were no dose-limiting toxicities, AE-related discontinuations, treatment-related grade 3/4 AEs, or new opportunistic infections observed.

“[I] have to say, in using this drug now for over a year in two of my patients – and that’s with weekly administration – we really haven’t seen anything as far as adverse events,” Dr. Foss said.

She noted that one patient has reported transient diarrhea after dosing.

Two serious AEs – febrile neutropenia and pyrexia – occurred in one patient, but neither of these events were considered related to cobomarsen. The AEs occurred after the patient had stopped cobomarsen, and both events resolved.

There were no on-treatment deaths. One patient (the one who received cobomarsen for 9 days) died from disease progression approximately 2 months after stopping cobomarsen and while on a different therapy.

Dr. Foss said, based on their results, she and her colleagues are hoping to accrue more ATLL patients in this trial.

The trial is sponsored by miRagen Therapeutics. Dr. Foss is a cochair of the T-cell Lymphoma Forum. The T-cell Lymphoma Forum is organized by Jonathan Wood & Associates, which is owned by the same company as this news organization.

[email protected]

LA JOLLA, CALIF. – Phase 1 results suggest cobomarsen is well tolerated and can maintain or improve responses in patients with previously treated adult T-cell leukemia/lymphoma (ATLL).

Five of eight ATLL patients studied experienced disease stabilization or improvement while receiving cobomarsen (MRG-106), an inhibitor of microRNA-155.

There were no grade 3/4 adverse events (AEs) or serious AEs related to cobomarsen in these patients.

Francine Foss, MD, of Yale Cancer Center in New Haven, Conn., and her colleagues presented these results at the annual T-cell Lymphoma Forum.

In this ongoing trial (NCT02580552), researchers are evaluating cobomarsen in patients with B- and T-cell lymphomas, including mycosis fungoides and ATLL.

Results are available for eight patients with previously treated ATLL. These patients had received a median of 4 (range, 1-10) prior systemic therapies, and they had a median age of 51 years (range, 40-68).

The patients received three loading doses of cobomarsen during the first week of cycle 1, followed by weekly dosing. All patients have received cobomarsen as a 600 mg intravenous infusion. They can remain on cobomarsen until they progress, experience clinically significant side effects, cannot tolerate the drug, or the trial is terminated.

The researchers have measured efficacy at least monthly by monitoring tumor cell burden in the peripheral blood and lymph nodes, as well as evaluating changes in skin involvement.

Stabilization and response

“Initially, we saw some very good responses in patients who had escalating disease. In other words, their disease was progressing after conventional chemotherapy,” Dr. Foss said. “They went on this microRNA, [and] their disease stabilized and then regressed. We saw, subsequently, in another three or four patients, the same pattern of activity.”

In all, five patients achieved or maintained a response while on cobomarsen. All five were still receiving the drug at the data cutoff on Dec. 13, 2018.

Two of these patients had acute disease and were in partial response (PR) at baseline. These patients had received cobomarsen for 87 days and 401 days as of the data cutoff.

The other three patients still receiving cobomarsen at the cutoff had lymphomatous disease. At baseline, two of the patients were in PR and one had stable disease.

The two patients in PR at baseline had received cobomarsen for 80 days and 366 days at the data cutoff. The patient with stable disease had received the drug for 161 days.
 

Progression and withdrawal

There were three patients who withdrew from the study because of disease progression. Two of these patients were relapsing with significant skin involvement at baseline.

One of the patients discontinued cobomarsen after 23 days of treatment. The other patient received cobomarsen for 91 days and left the study, then re-enrolled and received cobomarsen for another 42 days before withdrawing from the study again.

The third patient had relapsed lymphomatous disease at baseline. This patient had a mixed response to cobomarsen, with some nodes decreasing in size and others increasing. She discontinued cobomarsen after 9 days.

“It’s still early on in our experience with ATLL, so we don’t really know yet who the patient is that’s going to respond – what are the clinical features that would predict response in these patients,” Dr. Foss said. “And we’re still really trying to understand how we give the drug to these patients, for how long, and whether or not we can change the dosing interval. But, nevertheless, we have some very interesting data.”
 

Safety

There were no dose-limiting toxicities, AE-related discontinuations, treatment-related grade 3/4 AEs, or new opportunistic infections observed.

“[I] have to say, in using this drug now for over a year in two of my patients – and that’s with weekly administration – we really haven’t seen anything as far as adverse events,” Dr. Foss said.

She noted that one patient has reported transient diarrhea after dosing.

Two serious AEs – febrile neutropenia and pyrexia – occurred in one patient, but neither of these events were considered related to cobomarsen. The AEs occurred after the patient had stopped cobomarsen, and both events resolved.

There were no on-treatment deaths. One patient (the one who received cobomarsen for 9 days) died from disease progression approximately 2 months after stopping cobomarsen and while on a different therapy.

Dr. Foss said, based on their results, she and her colleagues are hoping to accrue more ATLL patients in this trial.

The trial is sponsored by miRagen Therapeutics. Dr. Foss is a cochair of the T-cell Lymphoma Forum. The T-cell Lymphoma Forum is organized by Jonathan Wood & Associates, which is owned by the same company as this news organization.

[email protected]

The Food and Drug Administration has approved caplacizumab (Cablivi) in combination with plasma exchange and immunosuppressive therapy for the treatment of adults with acquired thrombotic thrombocytopenic purpura (aTTP).

Caplacizumab is an anti–von Willebrand factor nanobody designed to inhibit the interaction between von Willebrand factor and platelets. The injection previously received orphan drug designation from the FDA and was approved under priority review.

The FDA’s approval of caplacizumab was based on results from the phase 3 HERCULES trial (N Engl J Med 2019 Jan 24;380:335-46).

The trial (NCT02553317) included 145 adults with aTTP. They were randomized to receive caplacizumab (n = 72) or placebo (n = 73), in addition to plasma exchange and immunosuppression.

The study’s primary endpoint was the time to platelet count response (normalization), which was defined as a platelet count of at least 150 x 10⁹/L with subsequent stop of daily plasma exchange within 5 days.

There was a significant reduction in time to platelet count response in the caplacizumab arm, compared with the placebo arm – 2.69 days and 2.88 days, respectively. The platelet normalization rate ratio was 1.55 (P less than .01).

A secondary endpoint was the combination of aTTP-related death, aTTP recurrence, and at least one major thromboembolic event during study treatment. The incidence of this combined endpoint was 12% in the caplacizumab arm and 49% in the placebo arm (P less than .001).

The most common treatment-emergent adverse events (occurring in at least 15% of patients in the caplacizumab and placebo arms, respectively) were epistaxis (32% and 3%), headache (23% and 8%), urticaria (17% and 7%), and hypokalemia (9% and 19%).

During the treatment period, there were no deaths in the caplacizumab arm and three deaths in the placebo arm. There was one death (from cerebral ischemia) in the caplacizumab arm during the follow-up period, but it was considered unrelated to caplacizumab.

For more details on caplacizumab, see the full prescribing information.

[email protected]

The Food and Drug Administration has approved caplacizumab (Cablivi) in combination with plasma exchange and immunosuppressive therapy for the treatment of adults with acquired thrombotic thrombocytopenic purpura (aTTP).

Caplacizumab is an anti–von Willebrand factor nanobody designed to inhibit the interaction between von Willebrand factor and platelets. The injection previously received orphan drug designation from the FDA and was approved under priority review.

The FDA’s approval of caplacizumab was based on results from the phase 3 HERCULES trial (N Engl J Med 2019 Jan 24;380:335-46).

The trial (NCT02553317) included 145 adults with aTTP. They were randomized to receive caplacizumab (n = 72) or placebo (n = 73), in addition to plasma exchange and immunosuppression.

The study’s primary endpoint was the time to platelet count response (normalization), which was defined as a platelet count of at least 150 x 10⁹/L with subsequent stop of daily plasma exchange within 5 days.

There was a significant reduction in time to platelet count response in the caplacizumab arm, compared with the placebo arm – 2.69 days and 2.88 days, respectively. The platelet normalization rate ratio was 1.55 (P less than .01).

A secondary endpoint was the combination of aTTP-related death, aTTP recurrence, and at least one major thromboembolic event during study treatment. The incidence of this combined endpoint was 12% in the caplacizumab arm and 49% in the placebo arm (P less than .001).

The most common treatment-emergent adverse events (occurring in at least 15% of patients in the caplacizumab and placebo arms, respectively) were epistaxis (32% and 3%), headache (23% and 8%), urticaria (17% and 7%), and hypokalemia (9% and 19%).

During the treatment period, there were no deaths in the caplacizumab arm and three deaths in the placebo arm. There was one death (from cerebral ischemia) in the caplacizumab arm during the follow-up period, but it was considered unrelated to caplacizumab.

For more details on caplacizumab, see the full prescribing information.

[email protected]

The Food and Drug Administration has approved caplacizumab (Cablivi) in combination with plasma exchange and immunosuppressive therapy for the treatment of adults with acquired thrombotic thrombocytopenic purpura (aTTP).

Caplacizumab is an anti–von Willebrand factor nanobody designed to inhibit the interaction between von Willebrand factor and platelets. The injection previously received orphan drug designation from the FDA and was approved under priority review.

The FDA’s approval of caplacizumab was based on results from the phase 3 HERCULES trial (N Engl J Med 2019 Jan 24;380:335-46).

The trial (NCT02553317) included 145 adults with aTTP. They were randomized to receive caplacizumab (n = 72) or placebo (n = 73), in addition to plasma exchange and immunosuppression.

The study’s primary endpoint was the time to platelet count response (normalization), which was defined as a platelet count of at least 150 x 10⁹/L with subsequent stop of daily plasma exchange within 5 days.

There was a significant reduction in time to platelet count response in the caplacizumab arm, compared with the placebo arm – 2.69 days and 2.88 days, respectively. The platelet normalization rate ratio was 1.55 (P less than .01).

A secondary endpoint was the combination of aTTP-related death, aTTP recurrence, and at least one major thromboembolic event during study treatment. The incidence of this combined endpoint was 12% in the caplacizumab arm and 49% in the placebo arm (P less than .001).

The most common treatment-emergent adverse events (occurring in at least 15% of patients in the caplacizumab and placebo arms, respectively) were epistaxis (32% and 3%), headache (23% and 8%), urticaria (17% and 7%), and hypokalemia (9% and 19%).

During the treatment period, there were no deaths in the caplacizumab arm and three deaths in the placebo arm. There was one death (from cerebral ischemia) in the caplacizumab arm during the follow-up period, but it was considered unrelated to caplacizumab.

For more details on caplacizumab, see the full prescribing information.

[email protected]