Lymphoma & Plasma Cell Disorders

Vials of drug

Mylan S.A.S. has withdrawn the European marketing authorization application for its pegfilgrastim biosimilar Fulphila, according to the European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP).

Fulphila was intended to be used to reduce the duration of neutropenia and the incidence of febrile neutropenia in adults receiving cytotoxic therapy for malignancy (except chronic myeloid leukemia and myelodysplastic syndromes).

Fulphila was intended to be highly similar to Neulasta, a solution for injection that contains the active substance pegfilgrastim.

To support the application for Fulphila, Mylan S.A.S. presented results of studies designed to show that Fulphila is highly similar to Neulasta in terms of chemical structure, purity, mechanism, safety, effectiveness, and immunogenicity.

Mylan S.A.S withdrew the application for Fulphila after the CHMP had evaluated the initial documentation the company provided on the drug and formulated a list of questions. The CHMP was assessing the company’s responses to the questions when the application was withdrawn.

At the time of the withdrawal, the CHMP had some concerns and was of the provisional opinion that Fulphila could not have been approved.

One of the CHMP’s main concerns was the lack of a certificate of Good Manufacturing Practice for the manufacturing site of the product. Other concerns related to the description of the manufacturing process, the control of impurities in the active substance, and the sterilization of the final product.

In a letter to the European Medicines Agency, Mylan S.A.S said it withdrew the application for Fulphila because a Good Manufacturing Practice certificate for the manufacturing site could not be obtained in the time available.

The application withdrawal does not impact ongoing clinical trials of Fulphila, and there are no compassionate use programs for the drug.

Mylan S.A.S said it plans to resubmit the application for Fulphila as soon as possible. The company is working to ensure “inspection readiness” at the Fulphila manufacturing site by October 2017.

Vials of drug

Mylan S.A.S. has withdrawn the European marketing authorization application for its pegfilgrastim biosimilar Fulphila, according to the European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP).

Fulphila was intended to be used to reduce the duration of neutropenia and the incidence of febrile neutropenia in adults receiving cytotoxic therapy for malignancy (except chronic myeloid leukemia and myelodysplastic syndromes).

Fulphila was intended to be highly similar to Neulasta, a solution for injection that contains the active substance pegfilgrastim.

To support the application for Fulphila, Mylan S.A.S. presented results of studies designed to show that Fulphila is highly similar to Neulasta in terms of chemical structure, purity, mechanism, safety, effectiveness, and immunogenicity.

Mylan S.A.S withdrew the application for Fulphila after the CHMP had evaluated the initial documentation the company provided on the drug and formulated a list of questions. The CHMP was assessing the company’s responses to the questions when the application was withdrawn.

At the time of the withdrawal, the CHMP had some concerns and was of the provisional opinion that Fulphila could not have been approved.

One of the CHMP’s main concerns was the lack of a certificate of Good Manufacturing Practice for the manufacturing site of the product. Other concerns related to the description of the manufacturing process, the control of impurities in the active substance, and the sterilization of the final product.

In a letter to the European Medicines Agency, Mylan S.A.S said it withdrew the application for Fulphila because a Good Manufacturing Practice certificate for the manufacturing site could not be obtained in the time available.

The application withdrawal does not impact ongoing clinical trials of Fulphila, and there are no compassionate use programs for the drug.

Mylan S.A.S said it plans to resubmit the application for Fulphila as soon as possible. The company is working to ensure “inspection readiness” at the Fulphila manufacturing site by October 2017.

Vials of drug

Mylan S.A.S. has withdrawn the European marketing authorization application for its pegfilgrastim biosimilar Fulphila, according to the European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP).

Fulphila was intended to be used to reduce the duration of neutropenia and the incidence of febrile neutropenia in adults receiving cytotoxic therapy for malignancy (except chronic myeloid leukemia and myelodysplastic syndromes).

Fulphila was intended to be highly similar to Neulasta, a solution for injection that contains the active substance pegfilgrastim.

To support the application for Fulphila, Mylan S.A.S. presented results of studies designed to show that Fulphila is highly similar to Neulasta in terms of chemical structure, purity, mechanism, safety, effectiveness, and immunogenicity.

Mylan S.A.S withdrew the application for Fulphila after the CHMP had evaluated the initial documentation the company provided on the drug and formulated a list of questions. The CHMP was assessing the company’s responses to the questions when the application was withdrawn.

At the time of the withdrawal, the CHMP had some concerns and was of the provisional opinion that Fulphila could not have been approved.

One of the CHMP’s main concerns was the lack of a certificate of Good Manufacturing Practice for the manufacturing site of the product. Other concerns related to the description of the manufacturing process, the control of impurities in the active substance, and the sterilization of the final product.

In a letter to the European Medicines Agency, Mylan S.A.S said it withdrew the application for Fulphila because a Good Manufacturing Practice certificate for the manufacturing site could not be obtained in the time available.

The application withdrawal does not impact ongoing clinical trials of Fulphila, and there are no compassionate use programs for the drug.

Mylan S.A.S said it plans to resubmit the application for Fulphila as soon as possible. The company is working to ensure “inspection readiness” at the Fulphila manufacturing site by October 2017.

Hodgkin lymphoma patients who received haploidentical (HAPLO) allogeneic hematopoietic cell transplantation after a nonmyeloablative regimen and posttransplantation cyclophosphamide had outcomes similar to those of patients who had conventional transplants, in a retrospective analysis of 709 adult patients in the European Society for Blood and Marrow Transplantation database.

In addition, patients who underwent HAPLO had a lower incidence of extensive chronic graft-versus host disease (cGVHD) compared with HLA-matched unrelated donor (MUD) transplantation and higher cGVHD-free/relapse-free survival compared with HLA-matched sibling donor (SIB) transplantation.

“Use of HAPLO donors may allow patients to proceed more rapidly to transplantation, avoiding the time needed to complete a formal MUD search and arrange for graft collection at a remote center,” wrote Carmen Martinez, MD, of the Institute of Hematology and Oncology, Hospital Clinic, Barcelona. The study was published online in the Journal of Clinical Oncology. Conventional donors are unavailable for a significant proportion of Hodgkin lymphoma patients.

Recommendations from the European Society for Blood and Marrow Transplantation consider alloHCT to be the standard treatment option for eligible patients with Hodgkin lymphoma who have relapsed after undergoing autologous hematopoietic cell transplantation and SIB or MUD. For the retrospective study, outcomes were compared for 338 patients who had SIB transplants, 273 patients who had MUD transplants, and 98 patients who received HAPLO transplants after a nonmyeloablative regimen and posttransplantation cyclophosphamide (PTCy) as GVHD prophylaxis.

The rate of grade II-IV acute GVHD after HAPLO was higher than after SIB (33% vs. 18%; P = .003), and was comparable to the rate with MUD (30%). The rates of grade III-IV acute GVHD were similar for all three cohorts (HAPLO, 9%; SIB, 6%; and MUD, 9%).

At 1 year, the cumulative rate of chronic GVHD was 26% after HAPLO and 25% after SIB; it was significantly higher at 41% after MUD (P = .017).

The cumulative incidence of nonrelapse mortality at 1 year was 17% with HAPLO, 13% with SIB, and significantly higher at 21% with MUD (P = .003). At 2 years, the cumulative incidence of relapse or progression was 39%, 49%, and 32%, respectively. The difference was significantly higher for SIB than HAPLO (P = .047) and MUD (P = .001).

There were no significant differences in 2-year overall survival, but MUD transplant recipients had lower overall survival (62%; 95% CI, 56 to 68; P = .039) compared with SIB transplant recipients.

“Whether HAPLO transplantation is the first choice instead of MUD transplantation and whether it can eventually substitute SIB transplantation in specific subgroups of patients must be assessed within the context of a randomized prospective clinical trial,” wrote Dr. Martinez and colleagues.

Hodgkin lymphoma patients who received haploidentical (HAPLO) allogeneic hematopoietic cell transplantation after a nonmyeloablative regimen and posttransplantation cyclophosphamide had outcomes similar to those of patients who had conventional transplants, in a retrospective analysis of 709 adult patients in the European Society for Blood and Marrow Transplantation database.

In addition, patients who underwent HAPLO had a lower incidence of extensive chronic graft-versus host disease (cGVHD) compared with HLA-matched unrelated donor (MUD) transplantation and higher cGVHD-free/relapse-free survival compared with HLA-matched sibling donor (SIB) transplantation.

“Use of HAPLO donors may allow patients to proceed more rapidly to transplantation, avoiding the time needed to complete a formal MUD search and arrange for graft collection at a remote center,” wrote Carmen Martinez, MD, of the Institute of Hematology and Oncology, Hospital Clinic, Barcelona. The study was published online in the Journal of Clinical Oncology. Conventional donors are unavailable for a significant proportion of Hodgkin lymphoma patients.

Recommendations from the European Society for Blood and Marrow Transplantation consider alloHCT to be the standard treatment option for eligible patients with Hodgkin lymphoma who have relapsed after undergoing autologous hematopoietic cell transplantation and SIB or MUD. For the retrospective study, outcomes were compared for 338 patients who had SIB transplants, 273 patients who had MUD transplants, and 98 patients who received HAPLO transplants after a nonmyeloablative regimen and posttransplantation cyclophosphamide (PTCy) as GVHD prophylaxis.

The rate of grade II-IV acute GVHD after HAPLO was higher than after SIB (33% vs. 18%; P = .003), and was comparable to the rate with MUD (30%). The rates of grade III-IV acute GVHD were similar for all three cohorts (HAPLO, 9%; SIB, 6%; and MUD, 9%).

At 1 year, the cumulative rate of chronic GVHD was 26% after HAPLO and 25% after SIB; it was significantly higher at 41% after MUD (P = .017).

The cumulative incidence of nonrelapse mortality at 1 year was 17% with HAPLO, 13% with SIB, and significantly higher at 21% with MUD (P = .003). At 2 years, the cumulative incidence of relapse or progression was 39%, 49%, and 32%, respectively. The difference was significantly higher for SIB than HAPLO (P = .047) and MUD (P = .001).

There were no significant differences in 2-year overall survival, but MUD transplant recipients had lower overall survival (62%; 95% CI, 56 to 68; P = .039) compared with SIB transplant recipients.

“Whether HAPLO transplantation is the first choice instead of MUD transplantation and whether it can eventually substitute SIB transplantation in specific subgroups of patients must be assessed within the context of a randomized prospective clinical trial,” wrote Dr. Martinez and colleagues.

Hodgkin lymphoma patients who received haploidentical (HAPLO) allogeneic hematopoietic cell transplantation after a nonmyeloablative regimen and posttransplantation cyclophosphamide had outcomes similar to those of patients who had conventional transplants, in a retrospective analysis of 709 adult patients in the European Society for Blood and Marrow Transplantation database.

In addition, patients who underwent HAPLO had a lower incidence of extensive chronic graft-versus host disease (cGVHD) compared with HLA-matched unrelated donor (MUD) transplantation and higher cGVHD-free/relapse-free survival compared with HLA-matched sibling donor (SIB) transplantation.

“Use of HAPLO donors may allow patients to proceed more rapidly to transplantation, avoiding the time needed to complete a formal MUD search and arrange for graft collection at a remote center,” wrote Carmen Martinez, MD, of the Institute of Hematology and Oncology, Hospital Clinic, Barcelona. The study was published online in the Journal of Clinical Oncology. Conventional donors are unavailable for a significant proportion of Hodgkin lymphoma patients.

Recommendations from the European Society for Blood and Marrow Transplantation consider alloHCT to be the standard treatment option for eligible patients with Hodgkin lymphoma who have relapsed after undergoing autologous hematopoietic cell transplantation and SIB or MUD. For the retrospective study, outcomes were compared for 338 patients who had SIB transplants, 273 patients who had MUD transplants, and 98 patients who received HAPLO transplants after a nonmyeloablative regimen and posttransplantation cyclophosphamide (PTCy) as GVHD prophylaxis.

The rate of grade II-IV acute GVHD after HAPLO was higher than after SIB (33% vs. 18%; P = .003), and was comparable to the rate with MUD (30%). The rates of grade III-IV acute GVHD were similar for all three cohorts (HAPLO, 9%; SIB, 6%; and MUD, 9%).

At 1 year, the cumulative rate of chronic GVHD was 26% after HAPLO and 25% after SIB; it was significantly higher at 41% after MUD (P = .017).

The cumulative incidence of nonrelapse mortality at 1 year was 17% with HAPLO, 13% with SIB, and significantly higher at 21% with MUD (P = .003). At 2 years, the cumulative incidence of relapse or progression was 39%, 49%, and 32%, respectively. The difference was significantly higher for SIB than HAPLO (P = .047) and MUD (P = .001).

There were no significant differences in 2-year overall survival, but MUD transplant recipients had lower overall survival (62%; 95% CI, 56 to 68; P = .039) compared with SIB transplant recipients.

“Whether HAPLO transplantation is the first choice instead of MUD transplantation and whether it can eventually substitute SIB transplantation in specific subgroups of patients must be assessed within the context of a randomized prospective clinical trial,” wrote Dr. Martinez and colleagues.

PRNewsfoto/Bayer

The US Food and Drug Administration (FDA) has granted accelerated approval to copanlisib (Aliqopa), an intravenous PI3K inhibitor developed by Bayer.

The drug is now approved to treat adults with relapsed follicular lymphoma (FL) who have received at least 2 prior systemic therapies.

Copanlisib received accelerated approval from the FDA because it has not yet shown a clinical benefit in these patients.

The FDA’s accelerated approval program allows conditional approval of a drug that fills an unmet medical need for a serious condition.

Accelerated approval is based on a surrogate or intermediate endpoint—in this case, overall response rate—that is reasonably likely to predict clinical benefit.

Continued approval of copanlisib for the aforementioned indication may be contingent upon verification of clinical benefit in confirmatory trials.

The FDA previously granted copanlisib priority review, fast track designation, and orphan drug designation.

According to Bayer, copanlisib is now available. The prescribing information is available for download here.

In addition, Bayer has created the Aliqopa™ Resource Connections (ARC^TM) Program, which includes resources to help patients navigate the insurance process and identify sources of financial assistance.

The program offers free medication to patients who are uninsured or underinsured and meet the eligibility criteria. It includes a $0 co-pay program for covered patients.

Phase 2 results

The FDA’s approval of copanlisib is based on data from the phase 2 CHRONOS-1 trial. Data from this trial were presented at the AACR Annual Meeting 2017 and the 2017 ASCO Annual Meeting.

The trial included 104 patients with FL who had relapsed after at least 2 prior systemic therapies.

The median duration of treatment with copanlisib was 22 weeks (range, 1-105). Thirty-three patients (32%) were still on treatment at last follow-up.

The overall response rate was 59%, with 14% of patients achieving a complete response. The median duration of response was 12.2 months (range, 0+ to 22.6).

The most common treatment-emergent adverse events (in ≥25% of patients) were diarrhea (34% all grades, 5% ≥grade 3), reduced neutrophil count (30% all grades, 24% ≥grade 3), fatigue (30% all grades, 2% ≥grade 3), and fever (25% all grades, 4% ≥grade 3).

There were 6 deaths, and 3 of them were attributed to copanlisib. One patient died of lung infection, 1 died of respiratory failure, and 1 died of a thromboembolic event.

PRNewsfoto/Bayer

The US Food and Drug Administration (FDA) has granted accelerated approval to copanlisib (Aliqopa), an intravenous PI3K inhibitor developed by Bayer.

The drug is now approved to treat adults with relapsed follicular lymphoma (FL) who have received at least 2 prior systemic therapies.

Copanlisib received accelerated approval from the FDA because it has not yet shown a clinical benefit in these patients.

The FDA’s accelerated approval program allows conditional approval of a drug that fills an unmet medical need for a serious condition.

Accelerated approval is based on a surrogate or intermediate endpoint—in this case, overall response rate—that is reasonably likely to predict clinical benefit.

Continued approval of copanlisib for the aforementioned indication may be contingent upon verification of clinical benefit in confirmatory trials.

The FDA previously granted copanlisib priority review, fast track designation, and orphan drug designation.

According to Bayer, copanlisib is now available. The prescribing information is available for download here.

In addition, Bayer has created the Aliqopa™ Resource Connections (ARC^TM) Program, which includes resources to help patients navigate the insurance process and identify sources of financial assistance.

The program offers free medication to patients who are uninsured or underinsured and meet the eligibility criteria. It includes a $0 co-pay program for covered patients.

Phase 2 results

The FDA’s approval of copanlisib is based on data from the phase 2 CHRONOS-1 trial. Data from this trial were presented at the AACR Annual Meeting 2017 and the 2017 ASCO Annual Meeting.

The trial included 104 patients with FL who had relapsed after at least 2 prior systemic therapies.

The median duration of treatment with copanlisib was 22 weeks (range, 1-105). Thirty-three patients (32%) were still on treatment at last follow-up.

The overall response rate was 59%, with 14% of patients achieving a complete response. The median duration of response was 12.2 months (range, 0+ to 22.6).

The most common treatment-emergent adverse events (in ≥25% of patients) were diarrhea (34% all grades, 5% ≥grade 3), reduced neutrophil count (30% all grades, 24% ≥grade 3), fatigue (30% all grades, 2% ≥grade 3), and fever (25% all grades, 4% ≥grade 3).

There were 6 deaths, and 3 of them were attributed to copanlisib. One patient died of lung infection, 1 died of respiratory failure, and 1 died of a thromboembolic event.

PRNewsfoto/Bayer

The US Food and Drug Administration (FDA) has granted accelerated approval to copanlisib (Aliqopa), an intravenous PI3K inhibitor developed by Bayer.

The drug is now approved to treat adults with relapsed follicular lymphoma (FL) who have received at least 2 prior systemic therapies.

Copanlisib received accelerated approval from the FDA because it has not yet shown a clinical benefit in these patients.

The FDA’s accelerated approval program allows conditional approval of a drug that fills an unmet medical need for a serious condition.

Accelerated approval is based on a surrogate or intermediate endpoint—in this case, overall response rate—that is reasonably likely to predict clinical benefit.

Continued approval of copanlisib for the aforementioned indication may be contingent upon verification of clinical benefit in confirmatory trials.

The FDA previously granted copanlisib priority review, fast track designation, and orphan drug designation.

According to Bayer, copanlisib is now available. The prescribing information is available for download here.

In addition, Bayer has created the Aliqopa™ Resource Connections (ARC^TM) Program, which includes resources to help patients navigate the insurance process and identify sources of financial assistance.

The program offers free medication to patients who are uninsured or underinsured and meet the eligibility criteria. It includes a $0 co-pay program for covered patients.

Phase 2 results

The FDA’s approval of copanlisib is based on data from the phase 2 CHRONOS-1 trial. Data from this trial were presented at the AACR Annual Meeting 2017 and the 2017 ASCO Annual Meeting.

The trial included 104 patients with FL who had relapsed after at least 2 prior systemic therapies.

The median duration of treatment with copanlisib was 22 weeks (range, 1-105). Thirty-three patients (32%) were still on treatment at last follow-up.

The overall response rate was 59%, with 14% of patients achieving a complete response. The median duration of response was 12.2 months (range, 0+ to 22.6).

The most common treatment-emergent adverse events (in ≥25% of patients) were diarrhea (34% all grades, 5% ≥grade 3), reduced neutrophil count (30% all grades, 24% ≥grade 3), fatigue (30% all grades, 2% ≥grade 3), and fever (25% all grades, 4% ≥grade 3).

There were 6 deaths, and 3 of them were attributed to copanlisib. One patient died of lung infection, 1 died of respiratory failure, and 1 died of a thromboembolic event.

Micrograph showing DLBCL

MAINZ/FRANKFURT, GERMANY—Outcomes of treatment with a third-generation chimeric antigen receptor (CAR) T-cell therapy are associated with a patient’s immune status, according to a phase 1/2a trial.

The CD19-specific CAR T-cell therapy produced a complete response (CR) in 6 of 15 patients with relapsed/refractory CD19-positive leukemia or lymphoma.

Though all responders eventually relapsed, 4 patients—including 2 with stable disease (SD) after treatment—responded to subsequent therapy and are still alive, 1 of them beyond 36 months.

An analysis of blood samples taken throughout the study revealed that a patient’s immune status was associated with treatment failure and overall survival.

Tanja Lövgren, PhD, of Uppsala University in Sweden, and her colleagues presented these findings at the Third CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival (abstract B156).

“CD19-specific CAR T-cell therapy has yielded remarkable response rates for patients who have B-cell acute lymphoblastic leukemia,” Dr Lövgren said. “However, many patients relapse.”

“In addition, response rates are more variable for patients who have other CD19-positive B-cell malignancies, and many patients experience serious adverse events. We set out to investigate the safety and effectiveness of a third-generation CD19-specific CAR T-cell therapy and to identify potential biomarkers of treatment outcome.”

Dr Lövgren and her colleagues studied 15 patients (ages 24-72) who had relapsed or refractory CD19-positive B-cell malignancies:

• Six patients with diffuse large B-cell lymphoma (DLBCL), including 3 cases that were transformed from follicular lymphoma (FL)
• Four patients with pre-B acute lymphoblastic leukemia (ALL)
• Two patients with mantle cell lymphoma (MCL)
• Two patients with chronic lymphocytic leukemia (CLL)
• One patient with FL transformed from Burkitt lymphoma.

Eleven patients received preconditioning with cyclophosphamide (500 mg/m²) and fludarabine (3 doses at 25 mg/m²).

All patients received CAR T cells at 1 x 10⁸, 2 x 10⁷, or 2 x 10⁸ cells/m². These were autologous, CD19-targeting CAR T cells with 3 intracellular signaling domains derived from CD3 zeta, CD28, and 4-1BB.

The researchers assessed tumor responses via bone marrow/blood analysis and/or radiology, depending on the type of malignancy. The team also collected blood samples before CAR T-cell infusion and at multiple times after infusion.

Efficacy and safety

Six patients achieved a CR to treatment—3 with DLBCL (1 transformed), 2 with ALL, and 1 with CLL. Two patients had SD—1 with MCL and 1 with CLL. The remaining patients progressed.

All patients with a CR eventually relapsed. The median duration of CR was 5 months (range, 3-24 months).

Four patients—2 complete responders and 2 with SD—responded well to subsequent therapy and are still alive with 27 to 36 months of follow-up. This includes 1 patient with DLBCL, 1 with MCL, and 2 with CLL.

Four patients had serious adverse events. Three had cytokine-release syndrome, and 2 had neurological toxicity.

All cases of cytokine-release syndrome resolved after treatment with corticosteroids/anti-IL6R therapy. The neurological toxicity resolved spontaneously.

Immune status

An analysis of the blood samples taken throughout the study showed that high levels of monocytic myeloid-derived suppressor cells (MDSCs) prior to treatment was associated with decreased overall survival. In addition, increased levels of MDSCs after treatment preceded treatment failure.

Furthermore, high plasma levels of immunosuppressive factors—such as PD-L1 and PD-L2—after treatment were associated with decreased overall survival.

High plasma levels of biomarkers of an immunostimulatory environment—including IL-12, DC-LAMP, TRAIL, and FasL—before the administration of CAR T-cell therapy was associated with increased overall survival.

“[A]n immunostimulatory environment was associated with improved overall survival, while immunosuppressive cells and factors were associated with treatment failure and decreased overall survival,” Dr Lövgren said.

“We are hoping to follow up this study with another clinical trial that will combine CAR T-cell therapy with chemotherapy known to decrease the number of monocytic myeloid-derived suppressive cells. We are also looking to further optimize the CAR T-cell therapy.”

Dr Lövgren said the main limitations of this study are that it only included 15 patients, the patients had several different malignancies, and some patients may have been too sick to respond to any treatment.

This study was supported by funds from AFA Insurance AB, the Swedish Cancer Society, the Swedish Research Council, the Lions Fund at Uppsala University Hospital, and the Swedish State Support for Clinical Research. Dr Lövgren declared no conflicts of interest.

Micrograph showing DLBCL

MAINZ/FRANKFURT, GERMANY—Outcomes of treatment with a third-generation chimeric antigen receptor (CAR) T-cell therapy are associated with a patient’s immune status, according to a phase 1/2a trial.

The CD19-specific CAR T-cell therapy produced a complete response (CR) in 6 of 15 patients with relapsed/refractory CD19-positive leukemia or lymphoma.

Though all responders eventually relapsed, 4 patients—including 2 with stable disease (SD) after treatment—responded to subsequent therapy and are still alive, 1 of them beyond 36 months.

An analysis of blood samples taken throughout the study revealed that a patient’s immune status was associated with treatment failure and overall survival.

Tanja Lövgren, PhD, of Uppsala University in Sweden, and her colleagues presented these findings at the Third CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival (abstract B156).

“CD19-specific CAR T-cell therapy has yielded remarkable response rates for patients who have B-cell acute lymphoblastic leukemia,” Dr Lövgren said. “However, many patients relapse.”

“In addition, response rates are more variable for patients who have other CD19-positive B-cell malignancies, and many patients experience serious adverse events. We set out to investigate the safety and effectiveness of a third-generation CD19-specific CAR T-cell therapy and to identify potential biomarkers of treatment outcome.”

Dr Lövgren and her colleagues studied 15 patients (ages 24-72) who had relapsed or refractory CD19-positive B-cell malignancies:

• Six patients with diffuse large B-cell lymphoma (DLBCL), including 3 cases that were transformed from follicular lymphoma (FL)
• Four patients with pre-B acute lymphoblastic leukemia (ALL)
• Two patients with mantle cell lymphoma (MCL)
• Two patients with chronic lymphocytic leukemia (CLL)
• One patient with FL transformed from Burkitt lymphoma.

Eleven patients received preconditioning with cyclophosphamide (500 mg/m²) and fludarabine (3 doses at 25 mg/m²).

All patients received CAR T cells at 1 x 10⁸, 2 x 10⁷, or 2 x 10⁸ cells/m². These were autologous, CD19-targeting CAR T cells with 3 intracellular signaling domains derived from CD3 zeta, CD28, and 4-1BB.

The researchers assessed tumor responses via bone marrow/blood analysis and/or radiology, depending on the type of malignancy. The team also collected blood samples before CAR T-cell infusion and at multiple times after infusion.

Efficacy and safety

Six patients achieved a CR to treatment—3 with DLBCL (1 transformed), 2 with ALL, and 1 with CLL. Two patients had SD—1 with MCL and 1 with CLL. The remaining patients progressed.

All patients with a CR eventually relapsed. The median duration of CR was 5 months (range, 3-24 months).

Four patients—2 complete responders and 2 with SD—responded well to subsequent therapy and are still alive with 27 to 36 months of follow-up. This includes 1 patient with DLBCL, 1 with MCL, and 2 with CLL.

Four patients had serious adverse events. Three had cytokine-release syndrome, and 2 had neurological toxicity.

All cases of cytokine-release syndrome resolved after treatment with corticosteroids/anti-IL6R therapy. The neurological toxicity resolved spontaneously.

Immune status

An analysis of the blood samples taken throughout the study showed that high levels of monocytic myeloid-derived suppressor cells (MDSCs) prior to treatment was associated with decreased overall survival. In addition, increased levels of MDSCs after treatment preceded treatment failure.

Furthermore, high plasma levels of immunosuppressive factors—such as PD-L1 and PD-L2—after treatment were associated with decreased overall survival.

High plasma levels of biomarkers of an immunostimulatory environment—including IL-12, DC-LAMP, TRAIL, and FasL—before the administration of CAR T-cell therapy was associated with increased overall survival.

“[A]n immunostimulatory environment was associated with improved overall survival, while immunosuppressive cells and factors were associated with treatment failure and decreased overall survival,” Dr Lövgren said.

“We are hoping to follow up this study with another clinical trial that will combine CAR T-cell therapy with chemotherapy known to decrease the number of monocytic myeloid-derived suppressive cells. We are also looking to further optimize the CAR T-cell therapy.”

Dr Lövgren said the main limitations of this study are that it only included 15 patients, the patients had several different malignancies, and some patients may have been too sick to respond to any treatment.

This study was supported by funds from AFA Insurance AB, the Swedish Cancer Society, the Swedish Research Council, the Lions Fund at Uppsala University Hospital, and the Swedish State Support for Clinical Research. Dr Lövgren declared no conflicts of interest.

Micrograph showing DLBCL

MAINZ/FRANKFURT, GERMANY—Outcomes of treatment with a third-generation chimeric antigen receptor (CAR) T-cell therapy are associated with a patient’s immune status, according to a phase 1/2a trial.

The CD19-specific CAR T-cell therapy produced a complete response (CR) in 6 of 15 patients with relapsed/refractory CD19-positive leukemia or lymphoma.

Though all responders eventually relapsed, 4 patients—including 2 with stable disease (SD) after treatment—responded to subsequent therapy and are still alive, 1 of them beyond 36 months.

An analysis of blood samples taken throughout the study revealed that a patient’s immune status was associated with treatment failure and overall survival.

Tanja Lövgren, PhD, of Uppsala University in Sweden, and her colleagues presented these findings at the Third CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival (abstract B156).

“CD19-specific CAR T-cell therapy has yielded remarkable response rates for patients who have B-cell acute lymphoblastic leukemia,” Dr Lövgren said. “However, many patients relapse.”

“In addition, response rates are more variable for patients who have other CD19-positive B-cell malignancies, and many patients experience serious adverse events. We set out to investigate the safety and effectiveness of a third-generation CD19-specific CAR T-cell therapy and to identify potential biomarkers of treatment outcome.”

Dr Lövgren and her colleagues studied 15 patients (ages 24-72) who had relapsed or refractory CD19-positive B-cell malignancies:

• Six patients with diffuse large B-cell lymphoma (DLBCL), including 3 cases that were transformed from follicular lymphoma (FL)
• Four patients with pre-B acute lymphoblastic leukemia (ALL)
• Two patients with mantle cell lymphoma (MCL)
• Two patients with chronic lymphocytic leukemia (CLL)
• One patient with FL transformed from Burkitt lymphoma.

Eleven patients received preconditioning with cyclophosphamide (500 mg/m²) and fludarabine (3 doses at 25 mg/m²).

All patients received CAR T cells at 1 x 10⁸, 2 x 10⁷, or 2 x 10⁸ cells/m². These were autologous, CD19-targeting CAR T cells with 3 intracellular signaling domains derived from CD3 zeta, CD28, and 4-1BB.

The researchers assessed tumor responses via bone marrow/blood analysis and/or radiology, depending on the type of malignancy. The team also collected blood samples before CAR T-cell infusion and at multiple times after infusion.

Efficacy and safety

Six patients achieved a CR to treatment—3 with DLBCL (1 transformed), 2 with ALL, and 1 with CLL. Two patients had SD—1 with MCL and 1 with CLL. The remaining patients progressed.

All patients with a CR eventually relapsed. The median duration of CR was 5 months (range, 3-24 months).

Four patients—2 complete responders and 2 with SD—responded well to subsequent therapy and are still alive with 27 to 36 months of follow-up. This includes 1 patient with DLBCL, 1 with MCL, and 2 with CLL.

Four patients had serious adverse events. Three had cytokine-release syndrome, and 2 had neurological toxicity.

All cases of cytokine-release syndrome resolved after treatment with corticosteroids/anti-IL6R therapy. The neurological toxicity resolved spontaneously.

Immune status

An analysis of the blood samples taken throughout the study showed that high levels of monocytic myeloid-derived suppressor cells (MDSCs) prior to treatment was associated with decreased overall survival. In addition, increased levels of MDSCs after treatment preceded treatment failure.

Furthermore, high plasma levels of immunosuppressive factors—such as PD-L1 and PD-L2—after treatment were associated with decreased overall survival.

High plasma levels of biomarkers of an immunostimulatory environment—including IL-12, DC-LAMP, TRAIL, and FasL—before the administration of CAR T-cell therapy was associated with increased overall survival.

“[A]n immunostimulatory environment was associated with improved overall survival, while immunosuppressive cells and factors were associated with treatment failure and decreased overall survival,” Dr Lövgren said.

“We are hoping to follow up this study with another clinical trial that will combine CAR T-cell therapy with chemotherapy known to decrease the number of monocytic myeloid-derived suppressive cells. We are also looking to further optimize the CAR T-cell therapy.”

Dr Lövgren said the main limitations of this study are that it only included 15 patients, the patients had several different malignancies, and some patients may have been too sick to respond to any treatment.

This study was supported by funds from AFA Insurance AB, the Swedish Cancer Society, the Swedish Research Council, the Lions Fund at Uppsala University Hospital, and the Swedish State Support for Clinical Research. Dr Lövgren declared no conflicts of interest.

Photo by Rhoda Baer

MADRID—New research indicates there is a lack of specialized care in Europe for adolescents and young adults (AYAs) with cancer.

In a survey of more than 200 European healthcare professionals, more than two-thirds of respondents said they did not have access to specialized services where adult and pediatric cancer specialists work together to plan treatment and deliver care to AYAs with cancer.

This lack of services was more pronounced in Eastern and Southern Europe than Western and Northern Europe.

“The survey found gaps and disparities in cancer care for adolescents and young adults across Europe,” said study author Emmanouil Saloustros, MD, a consultant medical oncologist at General Hospital of Heraklion “Venizelio” in Heraklion, Crete, Greece.

Dr Saloustros and his colleagues presented these findings at the ESMO 2017 Congress (abstract 1438O_PR) and reported them in ESMO Open.

The researchers sent an online survey on the status of care and research in AYAs (ages 15-39) to members of the European Society for Medical Oncology (ESMO) and the European Society for Paediatric Oncology (SIOPE).

The team received responses from 266 healthcare professionals across Europe—55% of them female. Eleven percent were age 20–29, 29% were age 30–39, 26% were age 40–49, 25% were age 50–59, and 9% were age 60 and older.

Forty-eight percent were medical oncologists, 21% were pediatric oncologists, 8% were in training, 5% were hematologists, 4% were radiation oncologists, and 2% were surgical oncologists. The rest were other types of healthcare professionals, such as oncology nurses.

Fifty-two percent of respondents worked in general academic centers, 19% in specialized cancer hospitals, and 11% in pediatric hospitals. Sixty percent of respondents had been trained to treat adults with cancer, 25% to treat pediatric cancer patients, and 15% were trained to treat both.

In the past year, 32% of respondents had treated between 1 and 10 AYAs, 28% had treated 11 to 20, 17% had treated between 21 and 50, and 16% had treated more than 50 AYAs.

Results

The following results are based on data from 242 survey respondents. (The other respondents did not provide complete information.)

More than two-thirds (67%) of the respondents said they did not have access to specialized services for AYAs with cancer. This was true for 88% of respondents in Southern Europe, 87% in Eastern Europe, 55% in Western Europe, and 40% in Northern Europe.

Sixty-two percent of hematologists said they had access to AYA services, as did 44% of pediatric oncologists and 27% of medical oncologists.

Eighty-six percent of respondents said their AYA patients had access to professional psychological support. This was true for 97% of respondents in Western Europe, 82% in Southern Europe, 81% in Northern Europe, and 74% in Eastern Europe.

Fifty-four percent of all respondents said their AYAs had access to a support group with other young people. This was true for 81% of respondents in Northern Europe, 60% in Western Europe, 48% in Eastern Europe, and 34% in Southern Europe.

Thirty-six percent of all respondents said their AYAs had access to an age-specific specialist nurse. This was true for 53% of respondents in Western Europe, 51% in Northern Europe, 32% in Eastern Europe, and 10% in Southern Europe.

Sixty-two percent of respondents said their institution provided AYAs with access to a fertility specialist. This was true for 78% of respondents in Western Europe, 72% in Northern Europe, 52% in Southern Europe, and 24% in Eastern Europe.

“These patients have specific needs that are not covered by pediatric or general oncology centers or classical medical oncology centers, and this survey shows that most do not have access to the recommended special care,” said Gilles Vassal, director of clinical research at Gustave Roussy in Villejuif, France, and past president of SIOPE (who was not involved in this study).

“Countries without these services can look at existing examples—such as in the UK and France—to build teams equipped to improve survival and survivorship for adolescents and young adults with cancer.”

Photo by Rhoda Baer

MADRID—New research indicates there is a lack of specialized care in Europe for adolescents and young adults (AYAs) with cancer.

In a survey of more than 200 European healthcare professionals, more than two-thirds of respondents said they did not have access to specialized services where adult and pediatric cancer specialists work together to plan treatment and deliver care to AYAs with cancer.

This lack of services was more pronounced in Eastern and Southern Europe than Western and Northern Europe.

“The survey found gaps and disparities in cancer care for adolescents and young adults across Europe,” said study author Emmanouil Saloustros, MD, a consultant medical oncologist at General Hospital of Heraklion “Venizelio” in Heraklion, Crete, Greece.

Dr Saloustros and his colleagues presented these findings at the ESMO 2017 Congress (abstract 1438O_PR) and reported them in ESMO Open.

The researchers sent an online survey on the status of care and research in AYAs (ages 15-39) to members of the European Society for Medical Oncology (ESMO) and the European Society for Paediatric Oncology (SIOPE).

The team received responses from 266 healthcare professionals across Europe—55% of them female. Eleven percent were age 20–29, 29% were age 30–39, 26% were age 40–49, 25% were age 50–59, and 9% were age 60 and older.

Forty-eight percent were medical oncologists, 21% were pediatric oncologists, 8% were in training, 5% were hematologists, 4% were radiation oncologists, and 2% were surgical oncologists. The rest were other types of healthcare professionals, such as oncology nurses.

Fifty-two percent of respondents worked in general academic centers, 19% in specialized cancer hospitals, and 11% in pediatric hospitals. Sixty percent of respondents had been trained to treat adults with cancer, 25% to treat pediatric cancer patients, and 15% were trained to treat both.

In the past year, 32% of respondents had treated between 1 and 10 AYAs, 28% had treated 11 to 20, 17% had treated between 21 and 50, and 16% had treated more than 50 AYAs.

Results

The following results are based on data from 242 survey respondents. (The other respondents did not provide complete information.)

More than two-thirds (67%) of the respondents said they did not have access to specialized services for AYAs with cancer. This was true for 88% of respondents in Southern Europe, 87% in Eastern Europe, 55% in Western Europe, and 40% in Northern Europe.

Sixty-two percent of hematologists said they had access to AYA services, as did 44% of pediatric oncologists and 27% of medical oncologists.

Eighty-six percent of respondents said their AYA patients had access to professional psychological support. This was true for 97% of respondents in Western Europe, 82% in Southern Europe, 81% in Northern Europe, and 74% in Eastern Europe.

Fifty-four percent of all respondents said their AYAs had access to a support group with other young people. This was true for 81% of respondents in Northern Europe, 60% in Western Europe, 48% in Eastern Europe, and 34% in Southern Europe.

Thirty-six percent of all respondents said their AYAs had access to an age-specific specialist nurse. This was true for 53% of respondents in Western Europe, 51% in Northern Europe, 32% in Eastern Europe, and 10% in Southern Europe.

Sixty-two percent of respondents said their institution provided AYAs with access to a fertility specialist. This was true for 78% of respondents in Western Europe, 72% in Northern Europe, 52% in Southern Europe, and 24% in Eastern Europe.

“These patients have specific needs that are not covered by pediatric or general oncology centers or classical medical oncology centers, and this survey shows that most do not have access to the recommended special care,” said Gilles Vassal, director of clinical research at Gustave Roussy in Villejuif, France, and past president of SIOPE (who was not involved in this study).

“Countries without these services can look at existing examples—such as in the UK and France—to build teams equipped to improve survival and survivorship for adolescents and young adults with cancer.”

Photo by Rhoda Baer

MADRID—New research indicates there is a lack of specialized care in Europe for adolescents and young adults (AYAs) with cancer.

In a survey of more than 200 European healthcare professionals, more than two-thirds of respondents said they did not have access to specialized services where adult and pediatric cancer specialists work together to plan treatment and deliver care to AYAs with cancer.

This lack of services was more pronounced in Eastern and Southern Europe than Western and Northern Europe.

“The survey found gaps and disparities in cancer care for adolescents and young adults across Europe,” said study author Emmanouil Saloustros, MD, a consultant medical oncologist at General Hospital of Heraklion “Venizelio” in Heraklion, Crete, Greece.

Dr Saloustros and his colleagues presented these findings at the ESMO 2017 Congress (abstract 1438O_PR) and reported them in ESMO Open.

The researchers sent an online survey on the status of care and research in AYAs (ages 15-39) to members of the European Society for Medical Oncology (ESMO) and the European Society for Paediatric Oncology (SIOPE).

The team received responses from 266 healthcare professionals across Europe—55% of them female. Eleven percent were age 20–29, 29% were age 30–39, 26% were age 40–49, 25% were age 50–59, and 9% were age 60 and older.

Forty-eight percent were medical oncologists, 21% were pediatric oncologists, 8% were in training, 5% were hematologists, 4% were radiation oncologists, and 2% were surgical oncologists. The rest were other types of healthcare professionals, such as oncology nurses.

Fifty-two percent of respondents worked in general academic centers, 19% in specialized cancer hospitals, and 11% in pediatric hospitals. Sixty percent of respondents had been trained to treat adults with cancer, 25% to treat pediatric cancer patients, and 15% were trained to treat both.

In the past year, 32% of respondents had treated between 1 and 10 AYAs, 28% had treated 11 to 20, 17% had treated between 21 and 50, and 16% had treated more than 50 AYAs.

Results

The following results are based on data from 242 survey respondents. (The other respondents did not provide complete information.)

More than two-thirds (67%) of the respondents said they did not have access to specialized services for AYAs with cancer. This was true for 88% of respondents in Southern Europe, 87% in Eastern Europe, 55% in Western Europe, and 40% in Northern Europe.

Sixty-two percent of hematologists said they had access to AYA services, as did 44% of pediatric oncologists and 27% of medical oncologists.

Eighty-six percent of respondents said their AYA patients had access to professional psychological support. This was true for 97% of respondents in Western Europe, 82% in Southern Europe, 81% in Northern Europe, and 74% in Eastern Europe.

Fifty-four percent of all respondents said their AYAs had access to a support group with other young people. This was true for 81% of respondents in Northern Europe, 60% in Western Europe, 48% in Eastern Europe, and 34% in Southern Europe.

Thirty-six percent of all respondents said their AYAs had access to an age-specific specialist nurse. This was true for 53% of respondents in Western Europe, 51% in Northern Europe, 32% in Eastern Europe, and 10% in Southern Europe.

Sixty-two percent of respondents said their institution provided AYAs with access to a fertility specialist. This was true for 78% of respondents in Western Europe, 72% in Northern Europe, 52% in Southern Europe, and 24% in Eastern Europe.

“These patients have specific needs that are not covered by pediatric or general oncology centers or classical medical oncology centers, and this survey shows that most do not have access to the recommended special care,” said Gilles Vassal, director of clinical research at Gustave Roussy in Villejuif, France, and past president of SIOPE (who was not involved in this study).

“Countries without these services can look at existing examples—such as in the UK and France—to build teams equipped to improve survival and survivorship for adolescents and young adults with cancer.”

MADRID – The high rate of infusion-related reactions at first daratumumab infusion may be related to treatment duration, based on data from the CASTOR and POLLUX studies presented at the European Society for Medical Oncology Congress.

Infusion-related reactions occur in half of relapsed or refractory multiple myeloma patients who receive daratumumab, but nearly all reactions are grade 2 or less and rarely lead to treatment discontinuation, reported Philippe Moreau, MD, of University Hospital, Nantes, France.

“In the two phase 3 trials, CASTOR and POLLUX, infusion-related reactions occurred in 45% and 48% of patients, respectively. Of these, 98% and 96%, respectively, occurred during the first infusion,” he said. Treatment duration was 7 hours for first infusion vs. 4 hours and 3 hours for the second and third infusions, respectively. Grade 3 infusion-related reactions occurred in 5.3% and 8.6% of patients in CASTOR and POLLUX, respectively. No grade 4 infusion-related reactions were observed in either trial.

(In CASTOR [NCT02136134], daratumumab was combined with bortezomib and dexamethasone. In POLLUX [NCT02076009], it was combined with lenalidomide and dexamethasone. Based on improvements in progression-free survival relative to the background drugs alone, daratumumab was approved for relapsed or refractory multiple myeloma.)

All patients in the trials received some form of preinfusion medications. These included 650-1,000 mg of paracetamol by intravenous or oral administration, 25-50 mg of diphenhydramine, 10 mg of montelukast, and 20 mg of dexamethasone. Patients thought to be at high risk of respiratory complications were candidates for postinfusion medications such as diphenhydramine or a short-acting beta agonist. However, only about 10% of high-risk patients received these therapies, so the impact of this potentially preventive approach is not clear, Dr. Moreau said.

In grade 1 reactions, Dr. Moreau recommended that infusions be paused at the first sign of an infusion-related reaction and then restarted at half the infusion rate when the condition is considered stable. Daratumumab treatment should be withdrawn in grade 2 or higher infusion-related reactions associated with laryngeal edema or grade 2 or higher bronchospasm that does not respond to systemic therapy and resolves within 6 hours of onset.

In grade 3 infusion-related reactions, the recommendation is to stop the daratumumab infusion and closely observe the patient. The infusion should be restarted only if the severity drops to grade 1. Again, the rate of infusion after the interruption should be half the rate provided prior to the infusion-related reaction. Therapy should be withdrawn if the infusion-related reaction recurs for a second time, according to Dr. Moreau.

Infusion-related reactions involving the upper respiratory tract – such as dyspnea, cough, bronchospasm, or throat irritation – may be related to the physiologic function of CD38, Dr. Moreau said. For this reason, grade 3 upper respiratory-related events deserve close attention and persisting symptoms warrant halting treatment.

The evidence is “reassuring” that the majority of infusion-related reactions are confined to the first infusion, said the ESMO-invited discussant, Evangelos Terpos, MD, PhD, of the University of Athens. He noted that the specific treatment recommendations outlined by Dr. Moreau could be helpful for minimizing nuisance infusion-related reactions as well as reducing the risk of more serious infusion-related reactions, particularly those involving respiratory events.

Prophylactic strategies for infusion-related reactions are particularly important in patients with risk factors for respiratory complications, Dr. Terpos added.
 

op@frontlinemedcom.com

MADRID – The high rate of infusion-related reactions at first daratumumab infusion may be related to treatment duration, based on data from the CASTOR and POLLUX studies presented at the European Society for Medical Oncology Congress.

Infusion-related reactions occur in half of relapsed or refractory multiple myeloma patients who receive daratumumab, but nearly all reactions are grade 2 or less and rarely lead to treatment discontinuation, reported Philippe Moreau, MD, of University Hospital, Nantes, France.

“In the two phase 3 trials, CASTOR and POLLUX, infusion-related reactions occurred in 45% and 48% of patients, respectively. Of these, 98% and 96%, respectively, occurred during the first infusion,” he said. Treatment duration was 7 hours for first infusion vs. 4 hours and 3 hours for the second and third infusions, respectively. Grade 3 infusion-related reactions occurred in 5.3% and 8.6% of patients in CASTOR and POLLUX, respectively. No grade 4 infusion-related reactions were observed in either trial.

(In CASTOR [NCT02136134], daratumumab was combined with bortezomib and dexamethasone. In POLLUX [NCT02076009], it was combined with lenalidomide and dexamethasone. Based on improvements in progression-free survival relative to the background drugs alone, daratumumab was approved for relapsed or refractory multiple myeloma.)

All patients in the trials received some form of preinfusion medications. These included 650-1,000 mg of paracetamol by intravenous or oral administration, 25-50 mg of diphenhydramine, 10 mg of montelukast, and 20 mg of dexamethasone. Patients thought to be at high risk of respiratory complications were candidates for postinfusion medications such as diphenhydramine or a short-acting beta agonist. However, only about 10% of high-risk patients received these therapies, so the impact of this potentially preventive approach is not clear, Dr. Moreau said.

In grade 1 reactions, Dr. Moreau recommended that infusions be paused at the first sign of an infusion-related reaction and then restarted at half the infusion rate when the condition is considered stable. Daratumumab treatment should be withdrawn in grade 2 or higher infusion-related reactions associated with laryngeal edema or grade 2 or higher bronchospasm that does not respond to systemic therapy and resolves within 6 hours of onset.

In grade 3 infusion-related reactions, the recommendation is to stop the daratumumab infusion and closely observe the patient. The infusion should be restarted only if the severity drops to grade 1. Again, the rate of infusion after the interruption should be half the rate provided prior to the infusion-related reaction. Therapy should be withdrawn if the infusion-related reaction recurs for a second time, according to Dr. Moreau.

Infusion-related reactions involving the upper respiratory tract – such as dyspnea, cough, bronchospasm, or throat irritation – may be related to the physiologic function of CD38, Dr. Moreau said. For this reason, grade 3 upper respiratory-related events deserve close attention and persisting symptoms warrant halting treatment.

The evidence is “reassuring” that the majority of infusion-related reactions are confined to the first infusion, said the ESMO-invited discussant, Evangelos Terpos, MD, PhD, of the University of Athens. He noted that the specific treatment recommendations outlined by Dr. Moreau could be helpful for minimizing nuisance infusion-related reactions as well as reducing the risk of more serious infusion-related reactions, particularly those involving respiratory events.

Prophylactic strategies for infusion-related reactions are particularly important in patients with risk factors for respiratory complications, Dr. Terpos added.
 

op@frontlinemedcom.com

MADRID – The high rate of infusion-related reactions at first daratumumab infusion may be related to treatment duration, based on data from the CASTOR and POLLUX studies presented at the European Society for Medical Oncology Congress.

Infusion-related reactions occur in half of relapsed or refractory multiple myeloma patients who receive daratumumab, but nearly all reactions are grade 2 or less and rarely lead to treatment discontinuation, reported Philippe Moreau, MD, of University Hospital, Nantes, France.

“In the two phase 3 trials, CASTOR and POLLUX, infusion-related reactions occurred in 45% and 48% of patients, respectively. Of these, 98% and 96%, respectively, occurred during the first infusion,” he said. Treatment duration was 7 hours for first infusion vs. 4 hours and 3 hours for the second and third infusions, respectively. Grade 3 infusion-related reactions occurred in 5.3% and 8.6% of patients in CASTOR and POLLUX, respectively. No grade 4 infusion-related reactions were observed in either trial.

(In CASTOR [NCT02136134], daratumumab was combined with bortezomib and dexamethasone. In POLLUX [NCT02076009], it was combined with lenalidomide and dexamethasone. Based on improvements in progression-free survival relative to the background drugs alone, daratumumab was approved for relapsed or refractory multiple myeloma.)

All patients in the trials received some form of preinfusion medications. These included 650-1,000 mg of paracetamol by intravenous or oral administration, 25-50 mg of diphenhydramine, 10 mg of montelukast, and 20 mg of dexamethasone. Patients thought to be at high risk of respiratory complications were candidates for postinfusion medications such as diphenhydramine or a short-acting beta agonist. However, only about 10% of high-risk patients received these therapies, so the impact of this potentially preventive approach is not clear, Dr. Moreau said.

In grade 1 reactions, Dr. Moreau recommended that infusions be paused at the first sign of an infusion-related reaction and then restarted at half the infusion rate when the condition is considered stable. Daratumumab treatment should be withdrawn in grade 2 or higher infusion-related reactions associated with laryngeal edema or grade 2 or higher bronchospasm that does not respond to systemic therapy and resolves within 6 hours of onset.

In grade 3 infusion-related reactions, the recommendation is to stop the daratumumab infusion and closely observe the patient. The infusion should be restarted only if the severity drops to grade 1. Again, the rate of infusion after the interruption should be half the rate provided prior to the infusion-related reaction. Therapy should be withdrawn if the infusion-related reaction recurs for a second time, according to Dr. Moreau.

Infusion-related reactions involving the upper respiratory tract – such as dyspnea, cough, bronchospasm, or throat irritation – may be related to the physiologic function of CD38, Dr. Moreau said. For this reason, grade 3 upper respiratory-related events deserve close attention and persisting symptoms warrant halting treatment.

The evidence is “reassuring” that the majority of infusion-related reactions are confined to the first infusion, said the ESMO-invited discussant, Evangelos Terpos, MD, PhD, of the University of Athens. He noted that the specific treatment recommendations outlined by Dr. Moreau could be helpful for minimizing nuisance infusion-related reactions as well as reducing the risk of more serious infusion-related reactions, particularly those involving respiratory events.

Prophylactic strategies for infusion-related reactions are particularly important in patients with risk factors for respiratory complications, Dr. Terpos added.
 

op@frontlinemedcom.com

Photo by Rhoda Baer

Deaths from cancer are on the decline in the US, but new cases of cancer are on the rise, according to the 7th annual American Association for Cancer Research (AACR) Cancer Progress Report.

The data suggest the cancer death rate declined by 35% from 1991 to 2014 for children and by 25% for adults, a reduction that translates to 2.1 million cancer deaths avoided.

However, 600,920 people in the US are projected to die from cancer in 2017.

And the number of new cancer cases is predicted to rise from 1.7 million in 2017 to 2.3 million in 2030.

The report also estimates there will be 62,130 new cases of leukemia in 2017 and 24,500 leukemia deaths this year.

This includes:

• 5970 cases of acute lymphocytic leukemia and 1440 deaths
• 20,110 cases of chronic lymphocytic leukemia and 4660 deaths
• 21,380 cases of acute myeloid leukemia (AML) and 10,590 deaths
• 8950 cases of chronic myeloid leukemia and 1080 deaths.

The estimate for lymphomas is 80,500 new cases and 21,210 deaths.

This includes:

• 8260 cases of Hodgkin lymphoma (HL) and 1070 deaths
• 72,240 cases of non-Hodgkin lymphoma and 20,140 deaths.

The estimate for myeloma is 30,280 new cases and 12,590 deaths.

The report says the estimated new cases of cancer are based on cancer incidence rates from 49 states and the District of Columbia from 1995 through 2013, as reported by the North American Association of Central Cancer Registries. This represents about 98% of the US population.

The estimated deaths are based on US mortality data from 1997 through 2013, taken from the National Center for Health Statistics of the Centers for Disease Control and Prevention.

Drug approvals

The AACR report notes that, between August 1, 2016, and July 31, 2017, the US Food and Drug Administration (FDA) approved new uses for 15 anticancer agents, 9 of which had no previous FDA approval.

Five of the agents are immunotherapies, which the report dubs “revolutionary treatments that are increasing survival and improving quality of life for patients.”

Among the recently approved therapies are 3 used for hematology indications:

• Ibrutinib (Imbruvica), approved to treat patients with relapsed/refractory marginal zone lymphoma who require systemic therapy and have received at least 1 prior anti-CD20-based therapy
• Midostaurin (Rydapt), approved as monotherapy for adults with advanced systemic mastocytosis and for use in combination with standard cytarabine and daunorubicin induction, followed by cytarabine consolidation, in adults with newly diagnosed AML who are FLT3 mutation-positive, as detected by an FDA-approved test.
• Pembrolizumab (Keytruda), approved to treat adult and pediatric patients with refractory classical HL or those with classical HL who have relapsed after 3 or more prior lines of therapy.

Disparities and costs

The AACR report points out that advances against cancer have not benefited everyone equally, and cancer health disparities are some of the most pressing challenges.

Among the disparities listed is the fact that adolescents and young adults (ages 15 to 39) with AML have a 5-year relative survival rate that is 22% lower than that of children (ages 1 to 14) with AML.

And Hispanic children are 24% more likely to develop leukemia than non-Hispanic children.

Another concern mentioned in the report is the cost of cancer care. The direct medical costs of cancer care in 2014 were estimated to be nearly $87.6 billion. This number does not include the indirect costs of lost productivity due to cancer-related morbidity and mortality.

With this in mind, the AACR is calling for a $2 billion increase in funding for the National Institutes of Health in fiscal year 2018, for a total funding level of $36.2 billion.

The AACR also recommends an $80 million increase in the FDA budget, bringing it to $2.8 billion for fiscal year 2018.

Photo by Rhoda Baer

Deaths from cancer are on the decline in the US, but new cases of cancer are on the rise, according to the 7th annual American Association for Cancer Research (AACR) Cancer Progress Report.

The data suggest the cancer death rate declined by 35% from 1991 to 2014 for children and by 25% for adults, a reduction that translates to 2.1 million cancer deaths avoided.

However, 600,920 people in the US are projected to die from cancer in 2017.

And the number of new cancer cases is predicted to rise from 1.7 million in 2017 to 2.3 million in 2030.

The report also estimates there will be 62,130 new cases of leukemia in 2017 and 24,500 leukemia deaths this year.

This includes:

• 5970 cases of acute lymphocytic leukemia and 1440 deaths
• 20,110 cases of chronic lymphocytic leukemia and 4660 deaths
• 21,380 cases of acute myeloid leukemia (AML) and 10,590 deaths
• 8950 cases of chronic myeloid leukemia and 1080 deaths.

The estimate for lymphomas is 80,500 new cases and 21,210 deaths.

This includes:

• 8260 cases of Hodgkin lymphoma (HL) and 1070 deaths
• 72,240 cases of non-Hodgkin lymphoma and 20,140 deaths.

The estimate for myeloma is 30,280 new cases and 12,590 deaths.

The report says the estimated new cases of cancer are based on cancer incidence rates from 49 states and the District of Columbia from 1995 through 2013, as reported by the North American Association of Central Cancer Registries. This represents about 98% of the US population.

The estimated deaths are based on US mortality data from 1997 through 2013, taken from the National Center for Health Statistics of the Centers for Disease Control and Prevention.

Drug approvals

The AACR report notes that, between August 1, 2016, and July 31, 2017, the US Food and Drug Administration (FDA) approved new uses for 15 anticancer agents, 9 of which had no previous FDA approval.

Five of the agents are immunotherapies, which the report dubs “revolutionary treatments that are increasing survival and improving quality of life for patients.”

Among the recently approved therapies are 3 used for hematology indications:

• Ibrutinib (Imbruvica), approved to treat patients with relapsed/refractory marginal zone lymphoma who require systemic therapy and have received at least 1 prior anti-CD20-based therapy
• Midostaurin (Rydapt), approved as monotherapy for adults with advanced systemic mastocytosis and for use in combination with standard cytarabine and daunorubicin induction, followed by cytarabine consolidation, in adults with newly diagnosed AML who are FLT3 mutation-positive, as detected by an FDA-approved test.
• Pembrolizumab (Keytruda), approved to treat adult and pediatric patients with refractory classical HL or those with classical HL who have relapsed after 3 or more prior lines of therapy.

Disparities and costs

The AACR report points out that advances against cancer have not benefited everyone equally, and cancer health disparities are some of the most pressing challenges.

Among the disparities listed is the fact that adolescents and young adults (ages 15 to 39) with AML have a 5-year relative survival rate that is 22% lower than that of children (ages 1 to 14) with AML.

And Hispanic children are 24% more likely to develop leukemia than non-Hispanic children.

Another concern mentioned in the report is the cost of cancer care. The direct medical costs of cancer care in 2014 were estimated to be nearly $87.6 billion. This number does not include the indirect costs of lost productivity due to cancer-related morbidity and mortality.

With this in mind, the AACR is calling for a $2 billion increase in funding for the National Institutes of Health in fiscal year 2018, for a total funding level of $36.2 billion.

The AACR also recommends an $80 million increase in the FDA budget, bringing it to $2.8 billion for fiscal year 2018.

Photo by Rhoda Baer

Deaths from cancer are on the decline in the US, but new cases of cancer are on the rise, according to the 7th annual American Association for Cancer Research (AACR) Cancer Progress Report.

The data suggest the cancer death rate declined by 35% from 1991 to 2014 for children and by 25% for adults, a reduction that translates to 2.1 million cancer deaths avoided.

However, 600,920 people in the US are projected to die from cancer in 2017.

And the number of new cancer cases is predicted to rise from 1.7 million in 2017 to 2.3 million in 2030.

The report also estimates there will be 62,130 new cases of leukemia in 2017 and 24,500 leukemia deaths this year.

This includes:

• 5970 cases of acute lymphocytic leukemia and 1440 deaths
• 20,110 cases of chronic lymphocytic leukemia and 4660 deaths
• 21,380 cases of acute myeloid leukemia (AML) and 10,590 deaths
• 8950 cases of chronic myeloid leukemia and 1080 deaths.

The estimate for lymphomas is 80,500 new cases and 21,210 deaths.

This includes:

• 8260 cases of Hodgkin lymphoma (HL) and 1070 deaths
• 72,240 cases of non-Hodgkin lymphoma and 20,140 deaths.

The estimate for myeloma is 30,280 new cases and 12,590 deaths.

The report says the estimated new cases of cancer are based on cancer incidence rates from 49 states and the District of Columbia from 1995 through 2013, as reported by the North American Association of Central Cancer Registries. This represents about 98% of the US population.

The estimated deaths are based on US mortality data from 1997 through 2013, taken from the National Center for Health Statistics of the Centers for Disease Control and Prevention.

Drug approvals

The AACR report notes that, between August 1, 2016, and July 31, 2017, the US Food and Drug Administration (FDA) approved new uses for 15 anticancer agents, 9 of which had no previous FDA approval.

Five of the agents are immunotherapies, which the report dubs “revolutionary treatments that are increasing survival and improving quality of life for patients.”

Among the recently approved therapies are 3 used for hematology indications:

• Ibrutinib (Imbruvica), approved to treat patients with relapsed/refractory marginal zone lymphoma who require systemic therapy and have received at least 1 prior anti-CD20-based therapy
• Midostaurin (Rydapt), approved as monotherapy for adults with advanced systemic mastocytosis and for use in combination with standard cytarabine and daunorubicin induction, followed by cytarabine consolidation, in adults with newly diagnosed AML who are FLT3 mutation-positive, as detected by an FDA-approved test.
• Pembrolizumab (Keytruda), approved to treat adult and pediatric patients with refractory classical HL or those with classical HL who have relapsed after 3 or more prior lines of therapy.

Disparities and costs

The AACR report points out that advances against cancer have not benefited everyone equally, and cancer health disparities are some of the most pressing challenges.

Among the disparities listed is the fact that adolescents and young adults (ages 15 to 39) with AML have a 5-year relative survival rate that is 22% lower than that of children (ages 1 to 14) with AML.

And Hispanic children are 24% more likely to develop leukemia than non-Hispanic children.

Another concern mentioned in the report is the cost of cancer care. The direct medical costs of cancer care in 2014 were estimated to be nearly $87.6 billion. This number does not include the indirect costs of lost productivity due to cancer-related morbidity and mortality.

With this in mind, the AACR is calling for a $2 billion increase in funding for the National Institutes of Health in fiscal year 2018, for a total funding level of $36.2 billion.

The AACR also recommends an $80 million increase in the FDA budget, bringing it to $2.8 billion for fiscal year 2018.

Bortezomib and KW-2478, a novel nonansamycin heat shock protein 90 (Hsp90) inhibitor, had modest activity and was well tolerated in an open-label phase 1/2 study of patients with relapsed or refractory multiple myeloma.

The objective response rate in 79 evaluable patients treated with the combination was 39.2%, and the clinical benefit rate was 51.9%. Median progression-free survival was 6.7 months, and median duration of response was 5.5 months, according to a report by Jamie Cavenagh, MD, of St. Bartholomew’s Hospital, West Smithfield, London, and colleagues. The results were published online in the British Journal of Cancer.

Peter Anderson/ Pathology Education Informational Resource Digital Library/copyright University of Alabama at Birmingham, Department of Pathology

sworcester@frontlinemedcom.com

Bortezomib and KW-2478, a novel nonansamycin heat shock protein 90 (Hsp90) inhibitor, had modest activity and was well tolerated in an open-label phase 1/2 study of patients with relapsed or refractory multiple myeloma.

The objective response rate in 79 evaluable patients treated with the combination was 39.2%, and the clinical benefit rate was 51.9%. Median progression-free survival was 6.7 months, and median duration of response was 5.5 months, according to a report by Jamie Cavenagh, MD, of St. Bartholomew’s Hospital, West Smithfield, London, and colleagues. The results were published online in the British Journal of Cancer.

Peter Anderson/ Pathology Education Informational Resource Digital Library/copyright University of Alabama at Birmingham, Department of Pathology

sworcester@frontlinemedcom.com

Bortezomib and KW-2478, a novel nonansamycin heat shock protein 90 (Hsp90) inhibitor, had modest activity and was well tolerated in an open-label phase 1/2 study of patients with relapsed or refractory multiple myeloma.

The objective response rate in 79 evaluable patients treated with the combination was 39.2%, and the clinical benefit rate was 51.9%. Median progression-free survival was 6.7 months, and median duration of response was 5.5 months, according to a report by Jamie Cavenagh, MD, of St. Bartholomew’s Hospital, West Smithfield, London, and colleagues. The results were published online in the British Journal of Cancer.

Peter Anderson/ Pathology Education Informational Resource Digital Library/copyright University of Alabama at Birmingham, Department of Pathology

sworcester@frontlinemedcom.com

MADRID – The biosimilar GP2013 met the criteria for therapeutic equivalence to rituximab in a large comparator trial of previously untreated patients with aggressive follicular lymphoma.

Based on results presented at the European Society for Medical Oncology Congress, “there is absolutely no difference in the objective response rates for GP2013 and rituximab,” the primary endpoint of the trial, reported Wojciech Jurczak, MD, PhD, head of lymphoma, department of hematology, Jagiellonian University, Krakow, Poland.

Dr. Jurczak characterized the double-blind, randomized phase 3 trial ASSIST_FL (NCT01419665) as the “largest biosimilar trial in hematology.” For the study, 629 patients with previously untreated, advanced-stage follicular lymphoma were randomized to GP2013 and the conventional regimen of cyclophosphamide, vincristine, and prednisone (G-CVP) or rituximab and the same three-agent regimen (R-CVP). Each regimen was given for eight cycles followed by maintenance monotherapy with the assigned monoclonal antibody for up to 2 years.

The primary endpoint, objective response rate (ORR), was 87.1% and 87.5% for G-CVP and R-CVP, respectively. There were no differences in ORR among the subgroups evaluated, which included patients aged 60 years and older vs. younger patients, presence or absence of bulky disease, high or low FLIPI (Follicular Lymphoma International Prognostic Index) score, gender, and the geographic region where treatment was given.

Safety was a secondary endpoint evaluated at the end of eight cycles and again after a year of maintenance therapy. The proportion of patients with any adverse event and the proportion with grade 3 or greater adverse events were not statistically different at any time point. There were also no significant differences in any of the other secondary endpoints evaluated, which included pharmacokinetic, pharmacodynamic, and immune measures.

The results are consistent with those of a related randomized bioequivalence trial comparing GP2013 and rituximab in 312 patients with rheumatoid arthritis (Ann Rheum Dis. 2017;76:1598-1602). The primary endpoint in that trial was area-under-the-curve serum concentration time.

The two studies are mutually reinforcing, and “the ASSIST_FL trial ends the story. We have the totality of evidence that GP2013 can be considered a biosimilar,” said Dr. Jurczak, who anticipates “major price differences” for this agent relative to rituximab.

“We may, based on the results of the follicular lymphoma trial, use the biosimilar in all registered indications for rituximab,” said Dr. Jurczak. This is also the conclusion of the European Medicine Agency, which approved this agent in June 2017 for all rituximab indications.

In explaining the process for approval of biosimilars, Dr. Jurczak emphasized that demonstrating bioequivalence is not the same as the approval process for a new therapeutic agent, for which regulatory agents require a demonstration of efficacy on a meaningful clinical endpoint, such as progression-free survival. For biosimilars, it is not necessary to show clinical benefits. Biosimilars must demonstrate the same biological activity, and ORR is considered an acceptable measure.

The ESMO-invited discussant, Michele Ghielmini, MD, PhD, medical director at the Oncology Institute of Southern Switzerland, Bellinzona, agreed. “We can reasonably speculate that (when rituximab and the biosimilar are associated with the same) response rate, they will lead to the same clinical benefits.”

MADRID – The biosimilar GP2013 met the criteria for therapeutic equivalence to rituximab in a large comparator trial of previously untreated patients with aggressive follicular lymphoma.

Based on results presented at the European Society for Medical Oncology Congress, “there is absolutely no difference in the objective response rates for GP2013 and rituximab,” the primary endpoint of the trial, reported Wojciech Jurczak, MD, PhD, head of lymphoma, department of hematology, Jagiellonian University, Krakow, Poland.

Dr. Jurczak characterized the double-blind, randomized phase 3 trial ASSIST_FL (NCT01419665) as the “largest biosimilar trial in hematology.” For the study, 629 patients with previously untreated, advanced-stage follicular lymphoma were randomized to GP2013 and the conventional regimen of cyclophosphamide, vincristine, and prednisone (G-CVP) or rituximab and the same three-agent regimen (R-CVP). Each regimen was given for eight cycles followed by maintenance monotherapy with the assigned monoclonal antibody for up to 2 years.

The primary endpoint, objective response rate (ORR), was 87.1% and 87.5% for G-CVP and R-CVP, respectively. There were no differences in ORR among the subgroups evaluated, which included patients aged 60 years and older vs. younger patients, presence or absence of bulky disease, high or low FLIPI (Follicular Lymphoma International Prognostic Index) score, gender, and the geographic region where treatment was given.

Safety was a secondary endpoint evaluated at the end of eight cycles and again after a year of maintenance therapy. The proportion of patients with any adverse event and the proportion with grade 3 or greater adverse events were not statistically different at any time point. There were also no significant differences in any of the other secondary endpoints evaluated, which included pharmacokinetic, pharmacodynamic, and immune measures.

The results are consistent with those of a related randomized bioequivalence trial comparing GP2013 and rituximab in 312 patients with rheumatoid arthritis (Ann Rheum Dis. 2017;76:1598-1602). The primary endpoint in that trial was area-under-the-curve serum concentration time.

The two studies are mutually reinforcing, and “the ASSIST_FL trial ends the story. We have the totality of evidence that GP2013 can be considered a biosimilar,” said Dr. Jurczak, who anticipates “major price differences” for this agent relative to rituximab.

“We may, based on the results of the follicular lymphoma trial, use the biosimilar in all registered indications for rituximab,” said Dr. Jurczak. This is also the conclusion of the European Medicine Agency, which approved this agent in June 2017 for all rituximab indications.

In explaining the process for approval of biosimilars, Dr. Jurczak emphasized that demonstrating bioequivalence is not the same as the approval process for a new therapeutic agent, for which regulatory agents require a demonstration of efficacy on a meaningful clinical endpoint, such as progression-free survival. For biosimilars, it is not necessary to show clinical benefits. Biosimilars must demonstrate the same biological activity, and ORR is considered an acceptable measure.

The ESMO-invited discussant, Michele Ghielmini, MD, PhD, medical director at the Oncology Institute of Southern Switzerland, Bellinzona, agreed. “We can reasonably speculate that (when rituximab and the biosimilar are associated with the same) response rate, they will lead to the same clinical benefits.”

MADRID – The biosimilar GP2013 met the criteria for therapeutic equivalence to rituximab in a large comparator trial of previously untreated patients with aggressive follicular lymphoma.

Based on results presented at the European Society for Medical Oncology Congress, “there is absolutely no difference in the objective response rates for GP2013 and rituximab,” the primary endpoint of the trial, reported Wojciech Jurczak, MD, PhD, head of lymphoma, department of hematology, Jagiellonian University, Krakow, Poland.

Dr. Jurczak characterized the double-blind, randomized phase 3 trial ASSIST_FL (NCT01419665) as the “largest biosimilar trial in hematology.” For the study, 629 patients with previously untreated, advanced-stage follicular lymphoma were randomized to GP2013 and the conventional regimen of cyclophosphamide, vincristine, and prednisone (G-CVP) or rituximab and the same three-agent regimen (R-CVP). Each regimen was given for eight cycles followed by maintenance monotherapy with the assigned monoclonal antibody for up to 2 years.

The primary endpoint, objective response rate (ORR), was 87.1% and 87.5% for G-CVP and R-CVP, respectively. There were no differences in ORR among the subgroups evaluated, which included patients aged 60 years and older vs. younger patients, presence or absence of bulky disease, high or low FLIPI (Follicular Lymphoma International Prognostic Index) score, gender, and the geographic region where treatment was given.

Safety was a secondary endpoint evaluated at the end of eight cycles and again after a year of maintenance therapy. The proportion of patients with any adverse event and the proportion with grade 3 or greater adverse events were not statistically different at any time point. There were also no significant differences in any of the other secondary endpoints evaluated, which included pharmacokinetic, pharmacodynamic, and immune measures.

The results are consistent with those of a related randomized bioequivalence trial comparing GP2013 and rituximab in 312 patients with rheumatoid arthritis (Ann Rheum Dis. 2017;76:1598-1602). The primary endpoint in that trial was area-under-the-curve serum concentration time.

The two studies are mutually reinforcing, and “the ASSIST_FL trial ends the story. We have the totality of evidence that GP2013 can be considered a biosimilar,” said Dr. Jurczak, who anticipates “major price differences” for this agent relative to rituximab.

“We may, based on the results of the follicular lymphoma trial, use the biosimilar in all registered indications for rituximab,” said Dr. Jurczak. This is also the conclusion of the European Medicine Agency, which approved this agent in June 2017 for all rituximab indications.

In explaining the process for approval of biosimilars, Dr. Jurczak emphasized that demonstrating bioequivalence is not the same as the approval process for a new therapeutic agent, for which regulatory agents require a demonstration of efficacy on a meaningful clinical endpoint, such as progression-free survival. For biosimilars, it is not necessary to show clinical benefits. Biosimilars must demonstrate the same biological activity, and ORR is considered an acceptable measure.

The ESMO-invited discussant, Michele Ghielmini, MD, PhD, medical director at the Oncology Institute of Southern Switzerland, Bellinzona, agreed. “We can reasonably speculate that (when rituximab and the biosimilar are associated with the same) response rate, they will lead to the same clinical benefits.”

Photo by Bill Branson

MADRID—The biosimilar GP2013 has demonstrated equivalence to its reference drug rituximab in patients with previously untreated, advanced-stage follicular lymphoma (FL), according to researchers.

Treatment with GP2013 plus cyclophosphamide, vincristine, and prednisone (CVP) produced a similar overall response rate (ORR) as rituximab plus CVP in the phase 3 ASSIST-FL trial.

Survival rates were also similar between the treatment arms, as were adverse events (AEs).

Results from this study were published in The Lancet Haematology and presented at ESMO 2017 Congress (abstract 994O).

The study was funded by Hexal AG, a Sandoz company (part of the Novartis group), which is marketing GP2013 as Rixathon in Europe.

Patients and treatment

The trial included 629 patients with previously untreated, advanced-stage FL. They were randomized to receive 8 cycles of GP2013-CVP (n=314) or rituximab-CVP (n=315). Responders in either arm could receive monotherapy maintenance for up to 2 years.

The mean age was 57.5 in the GP2013 arm and 56.4 in the rituximab arm. Fifty-eight percent and 54% of patients, respectively, were female.

Fifty-seven percent of patients in the GP2013 arm and 56% in the rituximab arm had an ECOG performance status of 0. Forty percent and 39%, respectively, had a status of 1. Two percent and 4%, respectively, had a status of 2. (For the remaining 1% of patients in each arm, data on performance status were missing.)

Patients had an Ann Arbor stage of III—46% in the GP2013 arm and 43% in the GP2013 arm—or IV—54% in the GP2013 arm and 57% in the rituximab arm.

Fifty-six percent of patients in each arm were high-risk according to FLIPI. Thirty-four percent in the GP2013 arm and 33% in the rituximab arm were intermediate-risk. Ten percent and 11%, respectively, were low-risk.

Fourteen percent of patients in the GP2013 arm and 18% in the rituximab arm had bulky disease. Fifteen percent and 13%, respectively, had splenic involvement.

ORR and survival

The patients had a median follow-up of 23.8 months. The primary efficacy endpoint was equivalence in ORR, defined by a 95% confidence interval (CI) with a margin of ± 12% standard deviation.

The primary endpoint was met, as the ORR was 87% in the GP2013 arm and 88% in the rituximab arm, with a difference of –0.40% (95% CI –5.94%, 5.14%).

The complete response rate was 15% in the GP2013 arm and 13% in the rituximab arm. The partial response rates were 72% and 74%, respectively.

The median progression-free survival and overall survival have not been reached. However, the progression-free survival rate was 70% in the GP2013 arm and 76% in the rituximab arm (hazard ratio [HR]=1.31; 95% CI 1.02, 1.69).

The overall survival rate was 93% in the GP2013 arm and 91% in the rituximab arm (HR=0.77; 95% CI 0.49, 1.22).

Safety

During the combination phase, the incidence of AEs was 93% in the GP2013 arm and 91% in the rituximab arm. The incidence of serious AEs was 23% and 20%, respectively.

The most frequent AEs (in the GP2013 and rituximab arms, respectively) were neutropenia (26% and 30%), constipation (22% and 20%), and nausea (16% and 13%). The most common grade 3/4 AE was neutropenia (18% and 21%).

There were 11 deaths reported during the combination phase—4 in the GP2013 arm and 7 in the rituximab arm.

Three deaths in the GP2013 arm (sudden death, septic shock, and respiratory failure) and 2 deaths in the rituximab arm (multiple organ dysfunction syndrome and sepsis) were suspected to be related to study treatment.

During the maintenance phase, the incidence of AEs was 63% in the GP2013 arm and 57% in the rituximab arm. The incidence of serious AEs was 6% and 4%, respectively.

The most frequent AEs (in the GP2013 and rituximab arms, respectively) were infections and infestations (20% and 27%), neutropenia (10% and 6%), cough (9% and 6%), and upper respiratory tract infection (3% and 6%). The most common grade 3/4 AE was neutropenia (7% and 4%).

There were 4 deaths reported during the maintenance phase, 2 in each treatment arm.

Photo by Bill Branson

MADRID—The biosimilar GP2013 has demonstrated equivalence to its reference drug rituximab in patients with previously untreated, advanced-stage follicular lymphoma (FL), according to researchers.

Treatment with GP2013 plus cyclophosphamide, vincristine, and prednisone (CVP) produced a similar overall response rate (ORR) as rituximab plus CVP in the phase 3 ASSIST-FL trial.

Survival rates were also similar between the treatment arms, as were adverse events (AEs).

Results from this study were published in The Lancet Haematology and presented at ESMO 2017 Congress (abstract 994O).

The study was funded by Hexal AG, a Sandoz company (part of the Novartis group), which is marketing GP2013 as Rixathon in Europe.

Patients and treatment

The trial included 629 patients with previously untreated, advanced-stage FL. They were randomized to receive 8 cycles of GP2013-CVP (n=314) or rituximab-CVP (n=315). Responders in either arm could receive monotherapy maintenance for up to 2 years.

The mean age was 57.5 in the GP2013 arm and 56.4 in the rituximab arm. Fifty-eight percent and 54% of patients, respectively, were female.

Fifty-seven percent of patients in the GP2013 arm and 56% in the rituximab arm had an ECOG performance status of 0. Forty percent and 39%, respectively, had a status of 1. Two percent and 4%, respectively, had a status of 2. (For the remaining 1% of patients in each arm, data on performance status were missing.)

Patients had an Ann Arbor stage of III—46% in the GP2013 arm and 43% in the GP2013 arm—or IV—54% in the GP2013 arm and 57% in the rituximab arm.

Fifty-six percent of patients in each arm were high-risk according to FLIPI. Thirty-four percent in the GP2013 arm and 33% in the rituximab arm were intermediate-risk. Ten percent and 11%, respectively, were low-risk.

Fourteen percent of patients in the GP2013 arm and 18% in the rituximab arm had bulky disease. Fifteen percent and 13%, respectively, had splenic involvement.

ORR and survival

The patients had a median follow-up of 23.8 months. The primary efficacy endpoint was equivalence in ORR, defined by a 95% confidence interval (CI) with a margin of ± 12% standard deviation.

The primary endpoint was met, as the ORR was 87% in the GP2013 arm and 88% in the rituximab arm, with a difference of –0.40% (95% CI –5.94%, 5.14%).

The complete response rate was 15% in the GP2013 arm and 13% in the rituximab arm. The partial response rates were 72% and 74%, respectively.

The median progression-free survival and overall survival have not been reached. However, the progression-free survival rate was 70% in the GP2013 arm and 76% in the rituximab arm (hazard ratio [HR]=1.31; 95% CI 1.02, 1.69).

The overall survival rate was 93% in the GP2013 arm and 91% in the rituximab arm (HR=0.77; 95% CI 0.49, 1.22).

Safety

During the combination phase, the incidence of AEs was 93% in the GP2013 arm and 91% in the rituximab arm. The incidence of serious AEs was 23% and 20%, respectively.

The most frequent AEs (in the GP2013 and rituximab arms, respectively) were neutropenia (26% and 30%), constipation (22% and 20%), and nausea (16% and 13%). The most common grade 3/4 AE was neutropenia (18% and 21%).

There were 11 deaths reported during the combination phase—4 in the GP2013 arm and 7 in the rituximab arm.

Three deaths in the GP2013 arm (sudden death, septic shock, and respiratory failure) and 2 deaths in the rituximab arm (multiple organ dysfunction syndrome and sepsis) were suspected to be related to study treatment.

During the maintenance phase, the incidence of AEs was 63% in the GP2013 arm and 57% in the rituximab arm. The incidence of serious AEs was 6% and 4%, respectively.

The most frequent AEs (in the GP2013 and rituximab arms, respectively) were infections and infestations (20% and 27%), neutropenia (10% and 6%), cough (9% and 6%), and upper respiratory tract infection (3% and 6%). The most common grade 3/4 AE was neutropenia (7% and 4%).

There were 4 deaths reported during the maintenance phase, 2 in each treatment arm.

Photo by Bill Branson

MADRID—The biosimilar GP2013 has demonstrated equivalence to its reference drug rituximab in patients with previously untreated, advanced-stage follicular lymphoma (FL), according to researchers.

Treatment with GP2013 plus cyclophosphamide, vincristine, and prednisone (CVP) produced a similar overall response rate (ORR) as rituximab plus CVP in the phase 3 ASSIST-FL trial.

Survival rates were also similar between the treatment arms, as were adverse events (AEs).

Results from this study were published in The Lancet Haematology and presented at ESMO 2017 Congress (abstract 994O).

The study was funded by Hexal AG, a Sandoz company (part of the Novartis group), which is marketing GP2013 as Rixathon in Europe.

Patients and treatment

The trial included 629 patients with previously untreated, advanced-stage FL. They were randomized to receive 8 cycles of GP2013-CVP (n=314) or rituximab-CVP (n=315). Responders in either arm could receive monotherapy maintenance for up to 2 years.

The mean age was 57.5 in the GP2013 arm and 56.4 in the rituximab arm. Fifty-eight percent and 54% of patients, respectively, were female.

Fifty-seven percent of patients in the GP2013 arm and 56% in the rituximab arm had an ECOG performance status of 0. Forty percent and 39%, respectively, had a status of 1. Two percent and 4%, respectively, had a status of 2. (For the remaining 1% of patients in each arm, data on performance status were missing.)

Patients had an Ann Arbor stage of III—46% in the GP2013 arm and 43% in the GP2013 arm—or IV—54% in the GP2013 arm and 57% in the rituximab arm.

Fifty-six percent of patients in each arm were high-risk according to FLIPI. Thirty-four percent in the GP2013 arm and 33% in the rituximab arm were intermediate-risk. Ten percent and 11%, respectively, were low-risk.

Fourteen percent of patients in the GP2013 arm and 18% in the rituximab arm had bulky disease. Fifteen percent and 13%, respectively, had splenic involvement.

ORR and survival

The patients had a median follow-up of 23.8 months. The primary efficacy endpoint was equivalence in ORR, defined by a 95% confidence interval (CI) with a margin of ± 12% standard deviation.

The primary endpoint was met, as the ORR was 87% in the GP2013 arm and 88% in the rituximab arm, with a difference of –0.40% (95% CI –5.94%, 5.14%).

The complete response rate was 15% in the GP2013 arm and 13% in the rituximab arm. The partial response rates were 72% and 74%, respectively.

The median progression-free survival and overall survival have not been reached. However, the progression-free survival rate was 70% in the GP2013 arm and 76% in the rituximab arm (hazard ratio [HR]=1.31; 95% CI 1.02, 1.69).

The overall survival rate was 93% in the GP2013 arm and 91% in the rituximab arm (HR=0.77; 95% CI 0.49, 1.22).

Safety

During the combination phase, the incidence of AEs was 93% in the GP2013 arm and 91% in the rituximab arm. The incidence of serious AEs was 23% and 20%, respectively.

The most frequent AEs (in the GP2013 and rituximab arms, respectively) were neutropenia (26% and 30%), constipation (22% and 20%), and nausea (16% and 13%). The most common grade 3/4 AE was neutropenia (18% and 21%).

There were 11 deaths reported during the combination phase—4 in the GP2013 arm and 7 in the rituximab arm.

Three deaths in the GP2013 arm (sudden death, septic shock, and respiratory failure) and 2 deaths in the rituximab arm (multiple organ dysfunction syndrome and sepsis) were suspected to be related to study treatment.

During the maintenance phase, the incidence of AEs was 63% in the GP2013 arm and 57% in the rituximab arm. The incidence of serious AEs was 6% and 4%, respectively.

The most frequent AEs (in the GP2013 and rituximab arms, respectively) were infections and infestations (20% and 27%), neutropenia (10% and 6%), cough (9% and 6%), and upper respiratory tract infection (3% and 6%). The most common grade 3/4 AE was neutropenia (7% and 4%).

There were 4 deaths reported during the maintenance phase, 2 in each treatment arm.