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Three-month response to CAR T-cells looks durable in DLBCL
ATLANTA – Responses 3 months after chimeric antigen receptor (CAR) T-cell therapy look durable in adults with transplant-ineligible relapsed/refractory diffuse large B-cell lymphoma (DLBCL), according to updated results from the single-arm, global, phase 2 JULIET trial.
Fully 95% of patients who had a complete response to CTL019 (tisagenlecleucel; Kymriah) at 3 months maintained that complete response at 6 months, Stephen J. Schuster, MD, said at the annual meeting of the American Society of Hematology.
Patients with relapsed/refractory DLBCL tend to face a very poor prognosis, noted Dr. Schuster of Perelman School of Medicine and Abramson Cancer Center, University of Pennsylvania, Philadelphia. High-dose chemotherapy followed by autologous stem cell transplantation “is capable of long-term survival, but in very few patients,” he said. A dismal 8% of patients completely respond to salvage treatment and only about one in five partially respond. Both levels of response are short-lived, with a median survival of about 4 months.
Meanwhile, CTL019 therapy has produced durable complete remissions in children with lymphoblastic leukemia and in adults with chronic lymphocytic leukemia, Dr. Schuster and his associates wrote in an article simultaneously published in the New England Journal of Medicine (2017 Dec 10. doi: 10.1056/NEJMoa1708566).
To test the CAR T-cell therapy in relapsed/refractory DLBCL, they enrolled affected adults who had received at least two prior lines of antineoplastic treatment and who were not candidates for autologous stem cell transplantation.
Treatment consisted of a single CTL019 infusion (median dose, 3.1 × 108 cells; range, 0.1 × 108 to 6.0 × 108 cells), usually after lymphodepleting chemotherapy. Previously, patients had received a median of three lines of therapy, and about half had undergone autologous stem cell transplantation.
Median time from infusion to data cutoff in March 2017 was 5.6 months. Among 81 patients followed for at least 3 months before data cutoff, best overall response rate was 53% and 40% had a complete response. Overall response rates were 38% at 3 months and 37% at 6 months. Rates of complete response as confirmed by 18F-fluorodeoxyglucose–positron-emission tomography (PET) were 32% at 3 months and 30% at 6 months.These findings highlight the predictive power of 3-month response to CTL019 therapy in relapsed/refractory DLBCL, Dr. Schuster said. Among all responders, 74% remained relapse free at 6 months, meaning that median duration of response and median overall survival were not reached at data cutoff.
Dr. Schuster also reported that 26% of patients were infused as outpatients, which he called “easy to do” and appropriate as long as patients who become febrile are admitted and monitored for cytokine release syndrome. Three-quarters of patients who were infused as outpatients were able to remain home for at least 3 days afterward, he said.
Adverse events typified those of CAR T-cell therapy, including cytokine release syndrome (all grades: 58%; grade 3-4: 23%) and neurological toxicities (all grades: 21%; grade 3-4: 12%). The current labeling for CTL019 in children and young adults with acute lymphoblastic leukemia also includes a boxed warning for these toxicities.Tisagenlecleucel, the first-ever approved CAR T-cell therapy, is made by using a lentiviral vector to genetically engineer a patient’s own T-cells to express a CAR for the pan-B-cell CD19 antigen. These anti-CD19 CAR T-cells are then expanded in the laboratory, frozen for shipping purposes, and infused back into patients. In October 2017, Novartis submitted a biologics license application to the Food and Drug Administration to expand the label for CTL019 to include transplant-ineligible relapsed/refractory DLBCL.
Novartis Pharmaceuticals anticipates large-scale production in 2018, Dr. Schuster said. Manufacturing time has been cut to 22 days from the 30-day turnaround used in the trial, he reported.
Dr. Schuster also said that he sees no point in retreating patients whose relapsed/refractory DLBCL doesn’t respond to tisagenlecleucel, and that JULIET did not test this approach. “If someone fails therapy and you retreat, you don’t see success, in my experience,” he said. “If patients respond and then fail later, then you retreat and you may succeed.”
Novartis Pharmaceuticals sponsored JULIET. Dr. Schuster disclosed consultancy and research funding from Novartis and ties to Celgene, Gilead, Genentech, and several other pharmaceutical companies.
SOURCE: Schuster S et al. ASH 2017 Abstract 577.
ATLANTA – Responses 3 months after chimeric antigen receptor (CAR) T-cell therapy look durable in adults with transplant-ineligible relapsed/refractory diffuse large B-cell lymphoma (DLBCL), according to updated results from the single-arm, global, phase 2 JULIET trial.
Fully 95% of patients who had a complete response to CTL019 (tisagenlecleucel; Kymriah) at 3 months maintained that complete response at 6 months, Stephen J. Schuster, MD, said at the annual meeting of the American Society of Hematology.
Patients with relapsed/refractory DLBCL tend to face a very poor prognosis, noted Dr. Schuster of Perelman School of Medicine and Abramson Cancer Center, University of Pennsylvania, Philadelphia. High-dose chemotherapy followed by autologous stem cell transplantation “is capable of long-term survival, but in very few patients,” he said. A dismal 8% of patients completely respond to salvage treatment and only about one in five partially respond. Both levels of response are short-lived, with a median survival of about 4 months.
Meanwhile, CTL019 therapy has produced durable complete remissions in children with lymphoblastic leukemia and in adults with chronic lymphocytic leukemia, Dr. Schuster and his associates wrote in an article simultaneously published in the New England Journal of Medicine (2017 Dec 10. doi: 10.1056/NEJMoa1708566).
To test the CAR T-cell therapy in relapsed/refractory DLBCL, they enrolled affected adults who had received at least two prior lines of antineoplastic treatment and who were not candidates for autologous stem cell transplantation.
Treatment consisted of a single CTL019 infusion (median dose, 3.1 × 108 cells; range, 0.1 × 108 to 6.0 × 108 cells), usually after lymphodepleting chemotherapy. Previously, patients had received a median of three lines of therapy, and about half had undergone autologous stem cell transplantation.
Median time from infusion to data cutoff in March 2017 was 5.6 months. Among 81 patients followed for at least 3 months before data cutoff, best overall response rate was 53% and 40% had a complete response. Overall response rates were 38% at 3 months and 37% at 6 months. Rates of complete response as confirmed by 18F-fluorodeoxyglucose–positron-emission tomography (PET) were 32% at 3 months and 30% at 6 months.These findings highlight the predictive power of 3-month response to CTL019 therapy in relapsed/refractory DLBCL, Dr. Schuster said. Among all responders, 74% remained relapse free at 6 months, meaning that median duration of response and median overall survival were not reached at data cutoff.
Dr. Schuster also reported that 26% of patients were infused as outpatients, which he called “easy to do” and appropriate as long as patients who become febrile are admitted and monitored for cytokine release syndrome. Three-quarters of patients who were infused as outpatients were able to remain home for at least 3 days afterward, he said.
Adverse events typified those of CAR T-cell therapy, including cytokine release syndrome (all grades: 58%; grade 3-4: 23%) and neurological toxicities (all grades: 21%; grade 3-4: 12%). The current labeling for CTL019 in children and young adults with acute lymphoblastic leukemia also includes a boxed warning for these toxicities.Tisagenlecleucel, the first-ever approved CAR T-cell therapy, is made by using a lentiviral vector to genetically engineer a patient’s own T-cells to express a CAR for the pan-B-cell CD19 antigen. These anti-CD19 CAR T-cells are then expanded in the laboratory, frozen for shipping purposes, and infused back into patients. In October 2017, Novartis submitted a biologics license application to the Food and Drug Administration to expand the label for CTL019 to include transplant-ineligible relapsed/refractory DLBCL.
Novartis Pharmaceuticals anticipates large-scale production in 2018, Dr. Schuster said. Manufacturing time has been cut to 22 days from the 30-day turnaround used in the trial, he reported.
Dr. Schuster also said that he sees no point in retreating patients whose relapsed/refractory DLBCL doesn’t respond to tisagenlecleucel, and that JULIET did not test this approach. “If someone fails therapy and you retreat, you don’t see success, in my experience,” he said. “If patients respond and then fail later, then you retreat and you may succeed.”
Novartis Pharmaceuticals sponsored JULIET. Dr. Schuster disclosed consultancy and research funding from Novartis and ties to Celgene, Gilead, Genentech, and several other pharmaceutical companies.
SOURCE: Schuster S et al. ASH 2017 Abstract 577.
ATLANTA – Responses 3 months after chimeric antigen receptor (CAR) T-cell therapy look durable in adults with transplant-ineligible relapsed/refractory diffuse large B-cell lymphoma (DLBCL), according to updated results from the single-arm, global, phase 2 JULIET trial.
Fully 95% of patients who had a complete response to CTL019 (tisagenlecleucel; Kymriah) at 3 months maintained that complete response at 6 months, Stephen J. Schuster, MD, said at the annual meeting of the American Society of Hematology.
Patients with relapsed/refractory DLBCL tend to face a very poor prognosis, noted Dr. Schuster of Perelman School of Medicine and Abramson Cancer Center, University of Pennsylvania, Philadelphia. High-dose chemotherapy followed by autologous stem cell transplantation “is capable of long-term survival, but in very few patients,” he said. A dismal 8% of patients completely respond to salvage treatment and only about one in five partially respond. Both levels of response are short-lived, with a median survival of about 4 months.
Meanwhile, CTL019 therapy has produced durable complete remissions in children with lymphoblastic leukemia and in adults with chronic lymphocytic leukemia, Dr. Schuster and his associates wrote in an article simultaneously published in the New England Journal of Medicine (2017 Dec 10. doi: 10.1056/NEJMoa1708566).
To test the CAR T-cell therapy in relapsed/refractory DLBCL, they enrolled affected adults who had received at least two prior lines of antineoplastic treatment and who were not candidates for autologous stem cell transplantation.
Treatment consisted of a single CTL019 infusion (median dose, 3.1 × 108 cells; range, 0.1 × 108 to 6.0 × 108 cells), usually after lymphodepleting chemotherapy. Previously, patients had received a median of three lines of therapy, and about half had undergone autologous stem cell transplantation.
Median time from infusion to data cutoff in March 2017 was 5.6 months. Among 81 patients followed for at least 3 months before data cutoff, best overall response rate was 53% and 40% had a complete response. Overall response rates were 38% at 3 months and 37% at 6 months. Rates of complete response as confirmed by 18F-fluorodeoxyglucose–positron-emission tomography (PET) were 32% at 3 months and 30% at 6 months.These findings highlight the predictive power of 3-month response to CTL019 therapy in relapsed/refractory DLBCL, Dr. Schuster said. Among all responders, 74% remained relapse free at 6 months, meaning that median duration of response and median overall survival were not reached at data cutoff.
Dr. Schuster also reported that 26% of patients were infused as outpatients, which he called “easy to do” and appropriate as long as patients who become febrile are admitted and monitored for cytokine release syndrome. Three-quarters of patients who were infused as outpatients were able to remain home for at least 3 days afterward, he said.
Adverse events typified those of CAR T-cell therapy, including cytokine release syndrome (all grades: 58%; grade 3-4: 23%) and neurological toxicities (all grades: 21%; grade 3-4: 12%). The current labeling for CTL019 in children and young adults with acute lymphoblastic leukemia also includes a boxed warning for these toxicities.Tisagenlecleucel, the first-ever approved CAR T-cell therapy, is made by using a lentiviral vector to genetically engineer a patient’s own T-cells to express a CAR for the pan-B-cell CD19 antigen. These anti-CD19 CAR T-cells are then expanded in the laboratory, frozen for shipping purposes, and infused back into patients. In October 2017, Novartis submitted a biologics license application to the Food and Drug Administration to expand the label for CTL019 to include transplant-ineligible relapsed/refractory DLBCL.
Novartis Pharmaceuticals anticipates large-scale production in 2018, Dr. Schuster said. Manufacturing time has been cut to 22 days from the 30-day turnaround used in the trial, he reported.
Dr. Schuster also said that he sees no point in retreating patients whose relapsed/refractory DLBCL doesn’t respond to tisagenlecleucel, and that JULIET did not test this approach. “If someone fails therapy and you retreat, you don’t see success, in my experience,” he said. “If patients respond and then fail later, then you retreat and you may succeed.”
Novartis Pharmaceuticals sponsored JULIET. Dr. Schuster disclosed consultancy and research funding from Novartis and ties to Celgene, Gilead, Genentech, and several other pharmaceutical companies.
SOURCE: Schuster S et al. ASH 2017 Abstract 577.
REPORTING FROM ASH 2017
Key clinical point:
Major finding: Among 81 patients with at least 3 months of follow-up, best overall response rate was 53% (95% CI, 42%-64%; P less than .0001) and rates of complete response were 32% at 3 months and 30% at 6 months.
Study details: JULIET is an international, single-arm, phase 2 study of adults with relapsed/refractory DLBCL.
Disclosures: Novartis Pharmaceuticals sponsored JULIET. Dr. Schuster reported consultancy and research funding from Novartis and ties to Celgene, Gilead, Genentech, and several other pharmaceutical companies.
Source: Schuster S et al. ASH 2017 Abstract 577.
CLL drug combinations induce MRD negativity
Atlanta – The potential of two- and three-drug combinations to induce deep, minimal residual disease (MRD)–negative responses in patients with chronic lymphocytic leukemia (CLL) was demonstrated in multiple studies presented at the annual meeting of the American Society of Hematology.
Previous studies have suggested that, in contrast to single-agent kinase inhibitor treatment, combinations of treatments, namely kinase or B-cell lyphoma 2 inhibitors combined with anti-CD20 antibodies, can induce MRD negativity at a high rate. For example, in a report on the CLL14 trial, 11 of 12 previously untreated patients were MRD negative after treatment with the BCL-2 inhibitor venetoclax and anti-CD20 antibody obinutuzumab (Blood. 2017;129:2702-5. doi:10.1182/blood-2017-01-761973).
This new batch of studies presented at ASH 2017 provided additional evidence for the venetoclax and obinutuzumab combination, as well as other combinations that appear to provide favorable rates of MRD-negative CLL, including obinutuzumab and venetoclax plus ibrutinib and, notably, a combination that included venetoclax and ibrutinib but no anti-CD20 antibody.
A phase II trial presented by Nitin Jain, MD, of MD Anderson Cancer Center, Houston, looked at the combination of venetoclax and ibrutinib for patients with previously untreated high-risk CLL or relapsed/refractory CLL. The regimen under evaluation starts with daily ibrutinib monotherapy for 3 months before venetoclax is added.
For the first line cohort of 36 patients, the bone marrow MRD-negativity proportion was 0% after 3 months of ibrutinib and 21% after 3 months of ibrutinib plus venetoclax, then 45%, 80%, and 100%, respectively, after 6, 9, and 12 months of combination therapy, Dr. Jain reported. In the relapsed/refractory cohort, MRD negativity was 8% after 3 months of combination therapy and 40% after 12 months. “Responses continue to improve with time, with many patients achieving bone marrow MRD-negative remission,” Dr. Jain said.
The study showed “very impressive MRD rates,” commented Ian W. Flinn, MD, of Sarah Cannon Research Institute, Nashville, Tenn. “I think it’s still up for further discussion and research to find which is the best combination.”
Dr. Flinn presented results from a phase Ib GP28331 study of venetoclax and obinutuzumab in patients with previously untreated CLL in which MRD was assessed in peripheral blood and bone marrow.
All 32 patients achieved peripheral blood negativity at some point on study, Dr. Flinn said, and 75% achieved bone marrow negativity. The complete response rate was 72% (23/32), but notably, high rates of undetectable bone marrow MRD were seen irrespective of response status, Dr. Flinn said.
All patients had at least one adverse event, with grade 3-4 neutropenia, febrile neutropenia, and thrombocytopenia reported most commonly.
Preliminary progression-free survival data (PFS) suggested “durable clinical outcomes” for the combination, with an estimated 18-month PFS of 90.5%, he said.
A third study assessed the combination of obinutuzumab, ibrutinib, and venetoclax, finding that the combination induced MRD negativity in 14 of 24 (58%) treatment-naive CLL patients, according to Kerry A. Rogers, MD, of Ohio State University, Columbus.
The combination had a 96% response rate and is “extremely effective at eliminating detectable CLL,” Dr. Rogers noted.
Most adverse events were hematologic, and high-grade adverse events were rare, she said.
Results for the study’s primary endpoint, rate of MRD-negative complete remission, are expected by May 2018, Dr. Rogers said, adding that further follow-up will be needed to determine PFS for the combination.
Session attendees asked presenters whether they felt there was scientific justification for inclusion of the anti-CD20 antibody rituximab in future trials designed in part to assess MRD negativity.
“I think that obinutuzumab has greater efficacy in patients with CLL, compared to rituximab, and so our hypothesis is that it is a superior antibody to combine with venetoclax,” Dr. Flinn said.
AbbVie provided funding for the study on venetoclax and ibrutinib. Dr. Jain reported disclosures from venetoclax makers AbbVie and Genentech, ibrutinib makers Janssen and Pharmacyclics, and others.
Genentech and AbbVie provided support for the study on venetoclax and obinutuzumab. Dr. Flinn reported disclosures related to both companies and others.
Dr. Rogers reported no conflicts related to the study on obinutuzumab, ibrutinib, and venetoclax. One of her associates reported disclosures related to ibrutinib makers Novartis and Pharmacylics, among others.
SOURCE: Jain N et al. ASH 2017 Abstract 429; Flinn I et al. ASH 2017 Abstract 430; Rogers K et al. ASH 2017 Abstract 431.
Atlanta – The potential of two- and three-drug combinations to induce deep, minimal residual disease (MRD)–negative responses in patients with chronic lymphocytic leukemia (CLL) was demonstrated in multiple studies presented at the annual meeting of the American Society of Hematology.
Previous studies have suggested that, in contrast to single-agent kinase inhibitor treatment, combinations of treatments, namely kinase or B-cell lyphoma 2 inhibitors combined with anti-CD20 antibodies, can induce MRD negativity at a high rate. For example, in a report on the CLL14 trial, 11 of 12 previously untreated patients were MRD negative after treatment with the BCL-2 inhibitor venetoclax and anti-CD20 antibody obinutuzumab (Blood. 2017;129:2702-5. doi:10.1182/blood-2017-01-761973).
This new batch of studies presented at ASH 2017 provided additional evidence for the venetoclax and obinutuzumab combination, as well as other combinations that appear to provide favorable rates of MRD-negative CLL, including obinutuzumab and venetoclax plus ibrutinib and, notably, a combination that included venetoclax and ibrutinib but no anti-CD20 antibody.
A phase II trial presented by Nitin Jain, MD, of MD Anderson Cancer Center, Houston, looked at the combination of venetoclax and ibrutinib for patients with previously untreated high-risk CLL or relapsed/refractory CLL. The regimen under evaluation starts with daily ibrutinib monotherapy for 3 months before venetoclax is added.
For the first line cohort of 36 patients, the bone marrow MRD-negativity proportion was 0% after 3 months of ibrutinib and 21% after 3 months of ibrutinib plus venetoclax, then 45%, 80%, and 100%, respectively, after 6, 9, and 12 months of combination therapy, Dr. Jain reported. In the relapsed/refractory cohort, MRD negativity was 8% after 3 months of combination therapy and 40% after 12 months. “Responses continue to improve with time, with many patients achieving bone marrow MRD-negative remission,” Dr. Jain said.
The study showed “very impressive MRD rates,” commented Ian W. Flinn, MD, of Sarah Cannon Research Institute, Nashville, Tenn. “I think it’s still up for further discussion and research to find which is the best combination.”
Dr. Flinn presented results from a phase Ib GP28331 study of venetoclax and obinutuzumab in patients with previously untreated CLL in which MRD was assessed in peripheral blood and bone marrow.
All 32 patients achieved peripheral blood negativity at some point on study, Dr. Flinn said, and 75% achieved bone marrow negativity. The complete response rate was 72% (23/32), but notably, high rates of undetectable bone marrow MRD were seen irrespective of response status, Dr. Flinn said.
All patients had at least one adverse event, with grade 3-4 neutropenia, febrile neutropenia, and thrombocytopenia reported most commonly.
Preliminary progression-free survival data (PFS) suggested “durable clinical outcomes” for the combination, with an estimated 18-month PFS of 90.5%, he said.
A third study assessed the combination of obinutuzumab, ibrutinib, and venetoclax, finding that the combination induced MRD negativity in 14 of 24 (58%) treatment-naive CLL patients, according to Kerry A. Rogers, MD, of Ohio State University, Columbus.
The combination had a 96% response rate and is “extremely effective at eliminating detectable CLL,” Dr. Rogers noted.
Most adverse events were hematologic, and high-grade adverse events were rare, she said.
Results for the study’s primary endpoint, rate of MRD-negative complete remission, are expected by May 2018, Dr. Rogers said, adding that further follow-up will be needed to determine PFS for the combination.
Session attendees asked presenters whether they felt there was scientific justification for inclusion of the anti-CD20 antibody rituximab in future trials designed in part to assess MRD negativity.
“I think that obinutuzumab has greater efficacy in patients with CLL, compared to rituximab, and so our hypothesis is that it is a superior antibody to combine with venetoclax,” Dr. Flinn said.
AbbVie provided funding for the study on venetoclax and ibrutinib. Dr. Jain reported disclosures from venetoclax makers AbbVie and Genentech, ibrutinib makers Janssen and Pharmacyclics, and others.
Genentech and AbbVie provided support for the study on venetoclax and obinutuzumab. Dr. Flinn reported disclosures related to both companies and others.
Dr. Rogers reported no conflicts related to the study on obinutuzumab, ibrutinib, and venetoclax. One of her associates reported disclosures related to ibrutinib makers Novartis and Pharmacylics, among others.
SOURCE: Jain N et al. ASH 2017 Abstract 429; Flinn I et al. ASH 2017 Abstract 430; Rogers K et al. ASH 2017 Abstract 431.
Atlanta – The potential of two- and three-drug combinations to induce deep, minimal residual disease (MRD)–negative responses in patients with chronic lymphocytic leukemia (CLL) was demonstrated in multiple studies presented at the annual meeting of the American Society of Hematology.
Previous studies have suggested that, in contrast to single-agent kinase inhibitor treatment, combinations of treatments, namely kinase or B-cell lyphoma 2 inhibitors combined with anti-CD20 antibodies, can induce MRD negativity at a high rate. For example, in a report on the CLL14 trial, 11 of 12 previously untreated patients were MRD negative after treatment with the BCL-2 inhibitor venetoclax and anti-CD20 antibody obinutuzumab (Blood. 2017;129:2702-5. doi:10.1182/blood-2017-01-761973).
This new batch of studies presented at ASH 2017 provided additional evidence for the venetoclax and obinutuzumab combination, as well as other combinations that appear to provide favorable rates of MRD-negative CLL, including obinutuzumab and venetoclax plus ibrutinib and, notably, a combination that included venetoclax and ibrutinib but no anti-CD20 antibody.
A phase II trial presented by Nitin Jain, MD, of MD Anderson Cancer Center, Houston, looked at the combination of venetoclax and ibrutinib for patients with previously untreated high-risk CLL or relapsed/refractory CLL. The regimen under evaluation starts with daily ibrutinib monotherapy for 3 months before venetoclax is added.
For the first line cohort of 36 patients, the bone marrow MRD-negativity proportion was 0% after 3 months of ibrutinib and 21% after 3 months of ibrutinib plus venetoclax, then 45%, 80%, and 100%, respectively, after 6, 9, and 12 months of combination therapy, Dr. Jain reported. In the relapsed/refractory cohort, MRD negativity was 8% after 3 months of combination therapy and 40% after 12 months. “Responses continue to improve with time, with many patients achieving bone marrow MRD-negative remission,” Dr. Jain said.
The study showed “very impressive MRD rates,” commented Ian W. Flinn, MD, of Sarah Cannon Research Institute, Nashville, Tenn. “I think it’s still up for further discussion and research to find which is the best combination.”
Dr. Flinn presented results from a phase Ib GP28331 study of venetoclax and obinutuzumab in patients with previously untreated CLL in which MRD was assessed in peripheral blood and bone marrow.
All 32 patients achieved peripheral blood negativity at some point on study, Dr. Flinn said, and 75% achieved bone marrow negativity. The complete response rate was 72% (23/32), but notably, high rates of undetectable bone marrow MRD were seen irrespective of response status, Dr. Flinn said.
All patients had at least one adverse event, with grade 3-4 neutropenia, febrile neutropenia, and thrombocytopenia reported most commonly.
Preliminary progression-free survival data (PFS) suggested “durable clinical outcomes” for the combination, with an estimated 18-month PFS of 90.5%, he said.
A third study assessed the combination of obinutuzumab, ibrutinib, and venetoclax, finding that the combination induced MRD negativity in 14 of 24 (58%) treatment-naive CLL patients, according to Kerry A. Rogers, MD, of Ohio State University, Columbus.
The combination had a 96% response rate and is “extremely effective at eliminating detectable CLL,” Dr. Rogers noted.
Most adverse events were hematologic, and high-grade adverse events were rare, she said.
Results for the study’s primary endpoint, rate of MRD-negative complete remission, are expected by May 2018, Dr. Rogers said, adding that further follow-up will be needed to determine PFS for the combination.
Session attendees asked presenters whether they felt there was scientific justification for inclusion of the anti-CD20 antibody rituximab in future trials designed in part to assess MRD negativity.
“I think that obinutuzumab has greater efficacy in patients with CLL, compared to rituximab, and so our hypothesis is that it is a superior antibody to combine with venetoclax,” Dr. Flinn said.
AbbVie provided funding for the study on venetoclax and ibrutinib. Dr. Jain reported disclosures from venetoclax makers AbbVie and Genentech, ibrutinib makers Janssen and Pharmacyclics, and others.
Genentech and AbbVie provided support for the study on venetoclax and obinutuzumab. Dr. Flinn reported disclosures related to both companies and others.
Dr. Rogers reported no conflicts related to the study on obinutuzumab, ibrutinib, and venetoclax. One of her associates reported disclosures related to ibrutinib makers Novartis and Pharmacylics, among others.
SOURCE: Jain N et al. ASH 2017 Abstract 429; Flinn I et al. ASH 2017 Abstract 430; Rogers K et al. ASH 2017 Abstract 431.
REPORTING FROM ASH 2017
MAVORIC: Mogamulizumab tops vorinostat in pretreated CTCL
ATLANTA – Intravenous treatment with mogamulizumab, an investigational antibody targeting CC chemokine receptor 4, more than doubled progression-free survival (PFS), compared with oral vorinostat in a phase 3 trial of 372 patients with heavily pretreated cutaneous T-cell lymphoma (CTCL).
After a median of three treatment cycles, median PFS with mogamulizumab was 7.7 months vs. 3.1 months with vorinostat (hazard ratio, 0.53; 95% confidence interval, 0.41-0.69; P less than .0001), Youn H. Kim, MD, reported at the annual meeting of the American Society of Hematology.
, said Dr. Kim, the Joanne and Peter Haas, Jr. Professor for Cutaneous Lymphoma Research at Stanford (Calif.) University. Adverse effects, such as infusion reactions, were expected and manageable, she added.
Mogamulizumab is approved in Japan for treating CTCL and received an FDA breakthrough therapy designation in August 2017.
Based on audits so far, the agency might green-light mogamulizumab for previously treated CTCL by early 2018 – its first approval in the United States, Dr. Kim said in an interview.
Cutaneous T-cell lymphoma responds poorly to treatments that work in other, more common types of non-Hodgkin lymphoma. Moreover, extensive disease can destroy quality of life.
“There’s a major psychosocial impact because if you’re infected, you smell bad,” Dr. Kim said during a press briefing. “Itch is very severe – patients often cannot sleep because of it.”
Mogamulizumab is a humanized monoclonal antibody that targets CC chemokine receptor 4 (CCR4), which facilitates trafficking of lymphocytes to skin and other organs. It is defucosylated, augmenting its toxicity against malignant T cells. In a prior phase 1/2 study in the United States, mogamulizumab showed a tolerable safety profile and a 37% overall response rate – “a good response, considering that other CTCL drugs are usually in the 30% range,” Dr. Kim said.
For the phase 3 study (MAVORIC), 372 patients with previously treated stage IB to stage IVB CTCL (mycosis fungoides or Sézary syndrome) without large-cell transformation received mogamulizumab (1.0 mg/kg IV weekly for 28 days; days 1 and 15 of subsequent 28-day cycles) or vorinostat (400 mg per oral daily). Treatment continued until disease progression or intolerable toxicity. Researchers evaluated PFS based on a global composite response score that covers the skin, blood, lymph nodes, and viscera, in accordance with international consensus guidelines (J Clin Oncol. 2011 Jun 20;29(18):2598-607; doi: 10.1200/JCO.2010.32.0630).
Treatment groups resembled each other at baseline. Most had received three systemic therapies for CTCL, and some had received as many as 18. Median duration of response was 14 months in the mogamulizumab arm and 9 months in the vorinostat arm. Patients tended to respond to mogamulizumab 2 months sooner than to vorinostat (3.3 vs. 5.1 months), Dr. Kim said.
Mogamulizumab also significantly improved quality of life on the Skindex-29 Symptoms (P less than .05), Skindex-29 Function (P less than 05), and FACT-G Functional Well-Being (P less than .05) quality of life scales, which is part of what earned it a breakthrough therapy designation, Dr. Kim said.
MAVORIC is the largest randomized study to compare systemic therapies in CTCL and the first to use PFS as the primary endpoint, Dr. Kim noted. Patients’ level of CCR4 expression was not a criterion for enrollment because CCR4 is consistently and highly expressed in this disease, she noted. Thus, using mogamulizumab to treat CTCL in the United States would not require CCR4 testing.
Joseph M. Connors, MD, who specializes in lymphoid cancers at the BC Cancer Agency, a division of the British Columbia Provincial Health Services Authority, and who was not involved in the study, agreed that these data represent real headway in treating CTCL.
“I can state unequivocally that we just haven’t had effective therapy for CTCL,” he said at the press briefing. “We’ve had treatments that might help patients feel somewhat better, but we’ve had no consensus on a treatment that is right for this disease. These data provide an opportunity to have that consensus. They could create a platform for making further progress.”
Kyowa Kirin Pharmaceutical Development provided funding. Dr. Kim disclosed research and advisory relationships with Kyowa Kirin and ties to Millennium Pharmaceuticals, Seattle Genetics, Soligenix, and other companies.
SOURCE: Kim YH et al. ASH 2017 Abstract 817.
ATLANTA – Intravenous treatment with mogamulizumab, an investigational antibody targeting CC chemokine receptor 4, more than doubled progression-free survival (PFS), compared with oral vorinostat in a phase 3 trial of 372 patients with heavily pretreated cutaneous T-cell lymphoma (CTCL).
After a median of three treatment cycles, median PFS with mogamulizumab was 7.7 months vs. 3.1 months with vorinostat (hazard ratio, 0.53; 95% confidence interval, 0.41-0.69; P less than .0001), Youn H. Kim, MD, reported at the annual meeting of the American Society of Hematology.
, said Dr. Kim, the Joanne and Peter Haas, Jr. Professor for Cutaneous Lymphoma Research at Stanford (Calif.) University. Adverse effects, such as infusion reactions, were expected and manageable, she added.
Mogamulizumab is approved in Japan for treating CTCL and received an FDA breakthrough therapy designation in August 2017.
Based on audits so far, the agency might green-light mogamulizumab for previously treated CTCL by early 2018 – its first approval in the United States, Dr. Kim said in an interview.
Cutaneous T-cell lymphoma responds poorly to treatments that work in other, more common types of non-Hodgkin lymphoma. Moreover, extensive disease can destroy quality of life.
“There’s a major psychosocial impact because if you’re infected, you smell bad,” Dr. Kim said during a press briefing. “Itch is very severe – patients often cannot sleep because of it.”
Mogamulizumab is a humanized monoclonal antibody that targets CC chemokine receptor 4 (CCR4), which facilitates trafficking of lymphocytes to skin and other organs. It is defucosylated, augmenting its toxicity against malignant T cells. In a prior phase 1/2 study in the United States, mogamulizumab showed a tolerable safety profile and a 37% overall response rate – “a good response, considering that other CTCL drugs are usually in the 30% range,” Dr. Kim said.
For the phase 3 study (MAVORIC), 372 patients with previously treated stage IB to stage IVB CTCL (mycosis fungoides or Sézary syndrome) without large-cell transformation received mogamulizumab (1.0 mg/kg IV weekly for 28 days; days 1 and 15 of subsequent 28-day cycles) or vorinostat (400 mg per oral daily). Treatment continued until disease progression or intolerable toxicity. Researchers evaluated PFS based on a global composite response score that covers the skin, blood, lymph nodes, and viscera, in accordance with international consensus guidelines (J Clin Oncol. 2011 Jun 20;29(18):2598-607; doi: 10.1200/JCO.2010.32.0630).
Treatment groups resembled each other at baseline. Most had received three systemic therapies for CTCL, and some had received as many as 18. Median duration of response was 14 months in the mogamulizumab arm and 9 months in the vorinostat arm. Patients tended to respond to mogamulizumab 2 months sooner than to vorinostat (3.3 vs. 5.1 months), Dr. Kim said.
Mogamulizumab also significantly improved quality of life on the Skindex-29 Symptoms (P less than .05), Skindex-29 Function (P less than 05), and FACT-G Functional Well-Being (P less than .05) quality of life scales, which is part of what earned it a breakthrough therapy designation, Dr. Kim said.
MAVORIC is the largest randomized study to compare systemic therapies in CTCL and the first to use PFS as the primary endpoint, Dr. Kim noted. Patients’ level of CCR4 expression was not a criterion for enrollment because CCR4 is consistently and highly expressed in this disease, she noted. Thus, using mogamulizumab to treat CTCL in the United States would not require CCR4 testing.
Joseph M. Connors, MD, who specializes in lymphoid cancers at the BC Cancer Agency, a division of the British Columbia Provincial Health Services Authority, and who was not involved in the study, agreed that these data represent real headway in treating CTCL.
“I can state unequivocally that we just haven’t had effective therapy for CTCL,” he said at the press briefing. “We’ve had treatments that might help patients feel somewhat better, but we’ve had no consensus on a treatment that is right for this disease. These data provide an opportunity to have that consensus. They could create a platform for making further progress.”
Kyowa Kirin Pharmaceutical Development provided funding. Dr. Kim disclosed research and advisory relationships with Kyowa Kirin and ties to Millennium Pharmaceuticals, Seattle Genetics, Soligenix, and other companies.
SOURCE: Kim YH et al. ASH 2017 Abstract 817.
ATLANTA – Intravenous treatment with mogamulizumab, an investigational antibody targeting CC chemokine receptor 4, more than doubled progression-free survival (PFS), compared with oral vorinostat in a phase 3 trial of 372 patients with heavily pretreated cutaneous T-cell lymphoma (CTCL).
After a median of three treatment cycles, median PFS with mogamulizumab was 7.7 months vs. 3.1 months with vorinostat (hazard ratio, 0.53; 95% confidence interval, 0.41-0.69; P less than .0001), Youn H. Kim, MD, reported at the annual meeting of the American Society of Hematology.
, said Dr. Kim, the Joanne and Peter Haas, Jr. Professor for Cutaneous Lymphoma Research at Stanford (Calif.) University. Adverse effects, such as infusion reactions, were expected and manageable, she added.
Mogamulizumab is approved in Japan for treating CTCL and received an FDA breakthrough therapy designation in August 2017.
Based on audits so far, the agency might green-light mogamulizumab for previously treated CTCL by early 2018 – its first approval in the United States, Dr. Kim said in an interview.
Cutaneous T-cell lymphoma responds poorly to treatments that work in other, more common types of non-Hodgkin lymphoma. Moreover, extensive disease can destroy quality of life.
“There’s a major psychosocial impact because if you’re infected, you smell bad,” Dr. Kim said during a press briefing. “Itch is very severe – patients often cannot sleep because of it.”
Mogamulizumab is a humanized monoclonal antibody that targets CC chemokine receptor 4 (CCR4), which facilitates trafficking of lymphocytes to skin and other organs. It is defucosylated, augmenting its toxicity against malignant T cells. In a prior phase 1/2 study in the United States, mogamulizumab showed a tolerable safety profile and a 37% overall response rate – “a good response, considering that other CTCL drugs are usually in the 30% range,” Dr. Kim said.
For the phase 3 study (MAVORIC), 372 patients with previously treated stage IB to stage IVB CTCL (mycosis fungoides or Sézary syndrome) without large-cell transformation received mogamulizumab (1.0 mg/kg IV weekly for 28 days; days 1 and 15 of subsequent 28-day cycles) or vorinostat (400 mg per oral daily). Treatment continued until disease progression or intolerable toxicity. Researchers evaluated PFS based on a global composite response score that covers the skin, blood, lymph nodes, and viscera, in accordance with international consensus guidelines (J Clin Oncol. 2011 Jun 20;29(18):2598-607; doi: 10.1200/JCO.2010.32.0630).
Treatment groups resembled each other at baseline. Most had received three systemic therapies for CTCL, and some had received as many as 18. Median duration of response was 14 months in the mogamulizumab arm and 9 months in the vorinostat arm. Patients tended to respond to mogamulizumab 2 months sooner than to vorinostat (3.3 vs. 5.1 months), Dr. Kim said.
Mogamulizumab also significantly improved quality of life on the Skindex-29 Symptoms (P less than .05), Skindex-29 Function (P less than 05), and FACT-G Functional Well-Being (P less than .05) quality of life scales, which is part of what earned it a breakthrough therapy designation, Dr. Kim said.
MAVORIC is the largest randomized study to compare systemic therapies in CTCL and the first to use PFS as the primary endpoint, Dr. Kim noted. Patients’ level of CCR4 expression was not a criterion for enrollment because CCR4 is consistently and highly expressed in this disease, she noted. Thus, using mogamulizumab to treat CTCL in the United States would not require CCR4 testing.
Joseph M. Connors, MD, who specializes in lymphoid cancers at the BC Cancer Agency, a division of the British Columbia Provincial Health Services Authority, and who was not involved in the study, agreed that these data represent real headway in treating CTCL.
“I can state unequivocally that we just haven’t had effective therapy for CTCL,” he said at the press briefing. “We’ve had treatments that might help patients feel somewhat better, but we’ve had no consensus on a treatment that is right for this disease. These data provide an opportunity to have that consensus. They could create a platform for making further progress.”
Kyowa Kirin Pharmaceutical Development provided funding. Dr. Kim disclosed research and advisory relationships with Kyowa Kirin and ties to Millennium Pharmaceuticals, Seattle Genetics, Soligenix, and other companies.
SOURCE: Kim YH et al. ASH 2017 Abstract 817.
REPORTING FROM ASH 2017
Key clinical point: Mogamulizumab more than doubled median progression-free survival, compared with vorinostat in patients with previously treated cutaneous T-cell lymphoma.
Major finding: Median progression-free survival was 7.7 months vs. 3.1 months (HR, 0.53; 95% CI, 0.41 to 0.69; P less than .0001).
Data source: An open-label phase 3 trial of 372 patients with previously treated cutaneous T-cell lymphoma (MAVORIC).
Disclosures: Kyowa Kirin Pharmaceutical Development provided funding. Dr. Kim disclosed research and advisory relationships with Kyowa Kirin and ties to Millennium Pharmaceuticals, Seattle Genetics, Soligenix, and other companies.
Source: Kim YH et al. ASH 2017 Abstract 817.
CLARITY: Ibrutinib/venetoclax combo results look promising for relapsed/refractory CLL
ATLANTA – Combination therapy with ibrutinib and venetoclax is well tolerated and shows promise for the treatment of relapsed/refractory chronic lymphocytic leukemia (CLL), according to initial results from the CLARITY feasibility trial.
Of 38 patients who received at least 6 months of treatment with combination ibrutinib (Imbruvica)/venetoclax (Venclexta) and reached month 8 – and therefore had computed tomography, clinical data, and peripheral blood and marrow assessments available – 15 (37%) achieved peripheral blood minimal residual disease (MRD) negativity, and 12 (32%) achieved bone marrow MRD negativity, Peter Hillmen, MBChB, PhD, reported during a press briefing at the annual meeting of the American Society of Hematology.
The rates of MRD negativity in the blood and marrow, and of normal trephine biopsy, were similar in subsets of patients who relapsed within 36 months of prior treatment with fludarabine/cyclophosphamide/rituximab (FCR) or bendamustine/rituximab (BR), and with prior idelalisib exposure, he noted.
“In terms of [International Workshop on Chronic Lymphocytic Leukemia] response criteria, which is a secondary endpoint, 47% of patients achieved a [complete remission or complete remission with incomplete hematologic recovery] and every patient has had an overall response, which for this group of patients is impressive,” he said.
Again, the findings were similar in those who were refractory to prior FCR/BR or to previous idelalisib, he noted.
Both ibrutinib and venetoclax are approved as single agents for the treatment of CLL. Ibrutinib is a Bruton’s tyrosine kinase inhibitor that has had a major effect on patient outcomes, showing overall survival advantages in numerous trials, Dr. Hillmen said.
“However, ibrutinib does not eradicate disease, and patients remain on treatment indefinitely or until progression,” he said.
Venetoclax is a highly selective B cell lymphoma–2 inhibitor approved for refractory CLL in patients with 17p deletion. It has a rapid effect, which can lead to tumor lysis syndrome, but also leads to eradication of MRD in some patients, which can lead to prolonged survival, he said.
The CLARITY trial was designed to investigate the safety and efficacy of the two in combination in relapsed/refractory CLL patients.
The primary endpoint of the study is MRD eradication in the marrow after 12 months of treatment. The current analysis looks at a key secondary endpoint of the study – MRD eradication in the marrow after 6 months of treatment.
The study enrolled 54 patients, including 37 men and 17 women with a median age of 64 years; 20% have 17p deletion, and the population was heavily pretreated, with 81% having prior FCR or BR (44% with relapse within 3 years of treatment), and 20% with previous idelalisib exposure. Patients were excluded if they had prior exposure to ibrutinib or venetoclax.
Treatment involves ibrutinib monotherapy at a dose of 420 mg/day for 2 months to debulk the disease, after which venetoclax is added at a dose escalating from 20 mg to 400 mg/day over 2 months to reduce the risk of tumor lysis syndrome.
Bone marrow biopsies are performed at 6, 12, and 24 months. Treatment is discontinued at 12 months in those who achieve MRD negativity at 6 months, and is discontinued at 24 months in those who achieve MRD negativity at 12 months.
The combination treatment was well tolerated in the first 38 patients. Bruising (mainly grade 1) occurred in 33 patients, and neutropenia (including 16 grade 3 cases and 6 grade 4 cases) occurred in 25, and some GI toxicity occurred, but was largely grade 1 or 2, Dr. Hillmen said.
“There really was otherwise very acceptable toxicity,” he added, noting that a single case of tumor lysis syndrome occurred, but was managed successfully by delaying venetoclax.
“That patient re-escalated back onto treatment and is doing well,” he said.
No patients stopped treatment, and only seven had treatment interruption, and then only for a few days, he noted.
The findings are encouraging, and suggest a potent synergy between ibrutinib and venetoclax, said Dr. Hillmen.
“We’re seeing, even at this very early stage, over 30% of patients achieving MRD negative remission, which was our target at the 12-month bone marrow stage with this combination,” he said.
In light of these results, the ongoing phase 3 FLAIR trial, which is actively recruiting, has been modified to include combination ibrutinib and venetoclax in front-line CLL, he said.
Dr. Hillmen reported financial relationships with AbbVie and several other pharmaceutical companies. The CLARITY trial is supported by AbbVie, Bloodwise, Experimental Cancer Medicine Centre, Janssen-Cilag, the National Institute for Health Research Clinical Research Network: Cancer, and the University of Birmingham (England).
[email protected]
SOURCE: Hillmen P et al., ASH abstract 428.
ATLANTA – Combination therapy with ibrutinib and venetoclax is well tolerated and shows promise for the treatment of relapsed/refractory chronic lymphocytic leukemia (CLL), according to initial results from the CLARITY feasibility trial.
Of 38 patients who received at least 6 months of treatment with combination ibrutinib (Imbruvica)/venetoclax (Venclexta) and reached month 8 – and therefore had computed tomography, clinical data, and peripheral blood and marrow assessments available – 15 (37%) achieved peripheral blood minimal residual disease (MRD) negativity, and 12 (32%) achieved bone marrow MRD negativity, Peter Hillmen, MBChB, PhD, reported during a press briefing at the annual meeting of the American Society of Hematology.
The rates of MRD negativity in the blood and marrow, and of normal trephine biopsy, were similar in subsets of patients who relapsed within 36 months of prior treatment with fludarabine/cyclophosphamide/rituximab (FCR) or bendamustine/rituximab (BR), and with prior idelalisib exposure, he noted.
“In terms of [International Workshop on Chronic Lymphocytic Leukemia] response criteria, which is a secondary endpoint, 47% of patients achieved a [complete remission or complete remission with incomplete hematologic recovery] and every patient has had an overall response, which for this group of patients is impressive,” he said.
Again, the findings were similar in those who were refractory to prior FCR/BR or to previous idelalisib, he noted.
Both ibrutinib and venetoclax are approved as single agents for the treatment of CLL. Ibrutinib is a Bruton’s tyrosine kinase inhibitor that has had a major effect on patient outcomes, showing overall survival advantages in numerous trials, Dr. Hillmen said.
“However, ibrutinib does not eradicate disease, and patients remain on treatment indefinitely or until progression,” he said.
Venetoclax is a highly selective B cell lymphoma–2 inhibitor approved for refractory CLL in patients with 17p deletion. It has a rapid effect, which can lead to tumor lysis syndrome, but also leads to eradication of MRD in some patients, which can lead to prolonged survival, he said.
The CLARITY trial was designed to investigate the safety and efficacy of the two in combination in relapsed/refractory CLL patients.
The primary endpoint of the study is MRD eradication in the marrow after 12 months of treatment. The current analysis looks at a key secondary endpoint of the study – MRD eradication in the marrow after 6 months of treatment.
The study enrolled 54 patients, including 37 men and 17 women with a median age of 64 years; 20% have 17p deletion, and the population was heavily pretreated, with 81% having prior FCR or BR (44% with relapse within 3 years of treatment), and 20% with previous idelalisib exposure. Patients were excluded if they had prior exposure to ibrutinib or venetoclax.
Treatment involves ibrutinib monotherapy at a dose of 420 mg/day for 2 months to debulk the disease, after which venetoclax is added at a dose escalating from 20 mg to 400 mg/day over 2 months to reduce the risk of tumor lysis syndrome.
Bone marrow biopsies are performed at 6, 12, and 24 months. Treatment is discontinued at 12 months in those who achieve MRD negativity at 6 months, and is discontinued at 24 months in those who achieve MRD negativity at 12 months.
The combination treatment was well tolerated in the first 38 patients. Bruising (mainly grade 1) occurred in 33 patients, and neutropenia (including 16 grade 3 cases and 6 grade 4 cases) occurred in 25, and some GI toxicity occurred, but was largely grade 1 or 2, Dr. Hillmen said.
“There really was otherwise very acceptable toxicity,” he added, noting that a single case of tumor lysis syndrome occurred, but was managed successfully by delaying venetoclax.
“That patient re-escalated back onto treatment and is doing well,” he said.
No patients stopped treatment, and only seven had treatment interruption, and then only for a few days, he noted.
The findings are encouraging, and suggest a potent synergy between ibrutinib and venetoclax, said Dr. Hillmen.
“We’re seeing, even at this very early stage, over 30% of patients achieving MRD negative remission, which was our target at the 12-month bone marrow stage with this combination,” he said.
In light of these results, the ongoing phase 3 FLAIR trial, which is actively recruiting, has been modified to include combination ibrutinib and venetoclax in front-line CLL, he said.
Dr. Hillmen reported financial relationships with AbbVie and several other pharmaceutical companies. The CLARITY trial is supported by AbbVie, Bloodwise, Experimental Cancer Medicine Centre, Janssen-Cilag, the National Institute for Health Research Clinical Research Network: Cancer, and the University of Birmingham (England).
[email protected]
SOURCE: Hillmen P et al., ASH abstract 428.
ATLANTA – Combination therapy with ibrutinib and venetoclax is well tolerated and shows promise for the treatment of relapsed/refractory chronic lymphocytic leukemia (CLL), according to initial results from the CLARITY feasibility trial.
Of 38 patients who received at least 6 months of treatment with combination ibrutinib (Imbruvica)/venetoclax (Venclexta) and reached month 8 – and therefore had computed tomography, clinical data, and peripheral blood and marrow assessments available – 15 (37%) achieved peripheral blood minimal residual disease (MRD) negativity, and 12 (32%) achieved bone marrow MRD negativity, Peter Hillmen, MBChB, PhD, reported during a press briefing at the annual meeting of the American Society of Hematology.
The rates of MRD negativity in the blood and marrow, and of normal trephine biopsy, were similar in subsets of patients who relapsed within 36 months of prior treatment with fludarabine/cyclophosphamide/rituximab (FCR) or bendamustine/rituximab (BR), and with prior idelalisib exposure, he noted.
“In terms of [International Workshop on Chronic Lymphocytic Leukemia] response criteria, which is a secondary endpoint, 47% of patients achieved a [complete remission or complete remission with incomplete hematologic recovery] and every patient has had an overall response, which for this group of patients is impressive,” he said.
Again, the findings were similar in those who were refractory to prior FCR/BR or to previous idelalisib, he noted.
Both ibrutinib and venetoclax are approved as single agents for the treatment of CLL. Ibrutinib is a Bruton’s tyrosine kinase inhibitor that has had a major effect on patient outcomes, showing overall survival advantages in numerous trials, Dr. Hillmen said.
“However, ibrutinib does not eradicate disease, and patients remain on treatment indefinitely or until progression,” he said.
Venetoclax is a highly selective B cell lymphoma–2 inhibitor approved for refractory CLL in patients with 17p deletion. It has a rapid effect, which can lead to tumor lysis syndrome, but also leads to eradication of MRD in some patients, which can lead to prolonged survival, he said.
The CLARITY trial was designed to investigate the safety and efficacy of the two in combination in relapsed/refractory CLL patients.
The primary endpoint of the study is MRD eradication in the marrow after 12 months of treatment. The current analysis looks at a key secondary endpoint of the study – MRD eradication in the marrow after 6 months of treatment.
The study enrolled 54 patients, including 37 men and 17 women with a median age of 64 years; 20% have 17p deletion, and the population was heavily pretreated, with 81% having prior FCR or BR (44% with relapse within 3 years of treatment), and 20% with previous idelalisib exposure. Patients were excluded if they had prior exposure to ibrutinib or venetoclax.
Treatment involves ibrutinib monotherapy at a dose of 420 mg/day for 2 months to debulk the disease, after which venetoclax is added at a dose escalating from 20 mg to 400 mg/day over 2 months to reduce the risk of tumor lysis syndrome.
Bone marrow biopsies are performed at 6, 12, and 24 months. Treatment is discontinued at 12 months in those who achieve MRD negativity at 6 months, and is discontinued at 24 months in those who achieve MRD negativity at 12 months.
The combination treatment was well tolerated in the first 38 patients. Bruising (mainly grade 1) occurred in 33 patients, and neutropenia (including 16 grade 3 cases and 6 grade 4 cases) occurred in 25, and some GI toxicity occurred, but was largely grade 1 or 2, Dr. Hillmen said.
“There really was otherwise very acceptable toxicity,” he added, noting that a single case of tumor lysis syndrome occurred, but was managed successfully by delaying venetoclax.
“That patient re-escalated back onto treatment and is doing well,” he said.
No patients stopped treatment, and only seven had treatment interruption, and then only for a few days, he noted.
The findings are encouraging, and suggest a potent synergy between ibrutinib and venetoclax, said Dr. Hillmen.
“We’re seeing, even at this very early stage, over 30% of patients achieving MRD negative remission, which was our target at the 12-month bone marrow stage with this combination,” he said.
In light of these results, the ongoing phase 3 FLAIR trial, which is actively recruiting, has been modified to include combination ibrutinib and venetoclax in front-line CLL, he said.
Dr. Hillmen reported financial relationships with AbbVie and several other pharmaceutical companies. The CLARITY trial is supported by AbbVie, Bloodwise, Experimental Cancer Medicine Centre, Janssen-Cilag, the National Institute for Health Research Clinical Research Network: Cancer, and the University of Birmingham (England).
[email protected]
SOURCE: Hillmen P et al., ASH abstract 428.
REPORTING FROM ASH 2017
Key clinical point:
Major finding: 37% and 32% of patients achieved peripheral blood and marrow MRD negativity, respectively.
Study details: Initial results from 38 patients in the CLARITY feasibility trial.
Disclosures: Dr. Hillmen reported financial relationships with AbbVie and several other pharmaceutical companies. The CLARITY trial is supported by AbbVie, Bloodwise, Experimental Cancer Medicine Centre, Janssen-Cilag, the National Institute for Health Research Clinical Research Network: Cancer, and the University of Birmingham.
Source: Hillmen P et al. ASH Abstract 428.
Updated ZUMA-1 data show durable CAR-T responses in B-cell lymphomas
ATLANTA – More than one-third of patients with refractory large B-cell lymphomas treated with the chimeric antigen receptor (CAR) T-cell product axicabtagene ciloleucel (Yescarta), often called axi-cel, had durable responses, with some patients having complete responses lasting more than 1 year after a single infusion, according to investigators in the ZUMA-1 trial.
Updated combined phase 1 and phase 2 results in 108 patients with diffuse large B-cell lymphoma (DLBCL), primary mediastinal B-cell lymphoma (PMBCL), or transformed follicular lymphoma (TFL) showed an objective response rate (ORR) of 82%, including 58% complete responses, after a median follow-up of 15.4 months, reported Sattva S. Neelapu, MD, from the University of Texas MD Anderson Cancer Center in Houston.
“Axi-cel is highly effective in patients with large B-cell lymphoma who otherwise have no curative treatment options,” he said in a briefing at the annual meeting of the American Society of Hematology, prior to his presentation of the data in an oral session.
The trial results were also published simultaneously in the New England Journal of Medicine.As previously reported, in the multicenter phase 2 ZUMA-1 trial, 111 patients with treatment refractory DLBCL, PMBCL, or TFL were enrolled and treated with axi-cel at a target dose of 2 x 106 cells/kg, following a conditioning regimen with low-dose cyclophosphamide and fludarabine.
The median patient age was 58 years. Patients had stage III or IV disease, 48% had International Prognostic Index scores of 3-4, 76% had disease that was refractory to third-line therapies or beyond, and 21% had disease that relapsed within 12 months of an autologous bone marrow transplant
Axi-cel was successfully manufactured with sufficient cells for transfusion in all but one of the 111 patients, and 101 patients eventually received infusions in phase 2 (modified intention-to-treat population). The average turnaround time from apheresis to the clinical site was 17 days.
Dr. Neelapu also presented data on seven patients enrolled in phase 1; the data were combined with the phase 2 results for an updated analysis of those patients who had at least 1 year of follow-up.
The phase 2 trial met its primary endpoint at the time of the primary analysis, with an 82% ORR, consisting of 54% complete responses and 28% partial responses at a median follow-up of 8.7 months.
In the updated analysis, the ORR and respective remission rates were 82%, 58%, and 34%, at a median of 15.4 months follow-up.
The median duration of response in the updated analysis was 11.1 months. The median duration of complete responses had not been reached at the time of data cutoff in August 2017. The median duration of partial responses was 1.9 months.
At the 15.4-month mark, 42% of patients remained free of disease progression, and 56% were alive, with the median overall survival not yet reached.
The treatment had generally acceptable toxicities, with only 13% of patients in phase 2 experiencing grade 3 or greater cytokine release syndrome (CRS), although one patient with CRS died from hemophagocytic lymphohistiocytosis, and one with CRS died from cardiac arrest. Grade 3 or greater neurologic events occurred in 28% of patients, and included encephalopathy, confusional state, aphasia, and somnolence.
The events were generally reversible, and the rates of each declined over time. The use of tocilizumab or steroids to control adverse events did not have a negative effect on responses.
Since the primary analysis with at least 6 months of follow-up, there have been no new axi-cel–related cases of CRS, neurologic events, or deaths.
Dr. Neelapu also presented safety data on serious adverse events occurring more than 6 months after therapy in 10 patients who developed symptoms after the data cutoff.
Grade 3 events in these patients included lung infection, recurrent upper respiratory viral infection, and rotavirus infection, pneumonias, atrial fibrillation with rapid ventricular response, lung infection, febrile neutropenia, and influenza B infection. One patient had grade 4 sepsis.
In an editorial accompanying the study in the New England Journal of Medicine, Eric Tran, PhD, and Walter J. Urba, MD, PhD, from the Earle A. Chiles Research Institute and the Providence Portland (Ore.) Medical Center, and Dan L. Longo, MD, deputy editor of the journal, praised ZUMA-1 as “a landmark study because it involved 22 institutions and showed that a personalized gene-engineered T-cell product could be rapidly generated at a centralized cell-manufacturing facility and safely administered to patients at transplantation-capable medical centers.”
They noted, however, that about half of all patients with relapsed or refractory large B-cell lymphomas will not have durable responses to CAR T-cell therapy directed against CD19, and that new strategies will be needed to improve responses (N Engl J Med. 2017 Dec 10; doi: 10.1056/NEJMe1714680).
In the question and answer session at the end of the briefing, Dr. Neelapu said the preliminary observations of mechanisms of relapse or disease progression in some patients may be related to the loss of the CD19 antigen, which occurs in about one-third of patients who experience relapse, and to high expression of the programmed death ligand-1, which can potentially inhibit CAR-T cell function. A clinical trial is currently underway to evaluate potential strategies for improving response rates to CAR-T therapies, he said.
ZUMA-1 is supported by Kite Pharma and the Leukemia and Lymphoma Society Therapy Acceleration Program. Dr. Neelapu reported receiving advisory board fees from the company. Myriad coauthors also reported financial relationship with multiple companies.
SOURCE: Neelapu S et al. ASH 2017 Abstract 578.
ATLANTA – More than one-third of patients with refractory large B-cell lymphomas treated with the chimeric antigen receptor (CAR) T-cell product axicabtagene ciloleucel (Yescarta), often called axi-cel, had durable responses, with some patients having complete responses lasting more than 1 year after a single infusion, according to investigators in the ZUMA-1 trial.
Updated combined phase 1 and phase 2 results in 108 patients with diffuse large B-cell lymphoma (DLBCL), primary mediastinal B-cell lymphoma (PMBCL), or transformed follicular lymphoma (TFL) showed an objective response rate (ORR) of 82%, including 58% complete responses, after a median follow-up of 15.4 months, reported Sattva S. Neelapu, MD, from the University of Texas MD Anderson Cancer Center in Houston.
“Axi-cel is highly effective in patients with large B-cell lymphoma who otherwise have no curative treatment options,” he said in a briefing at the annual meeting of the American Society of Hematology, prior to his presentation of the data in an oral session.
The trial results were also published simultaneously in the New England Journal of Medicine.As previously reported, in the multicenter phase 2 ZUMA-1 trial, 111 patients with treatment refractory DLBCL, PMBCL, or TFL were enrolled and treated with axi-cel at a target dose of 2 x 106 cells/kg, following a conditioning regimen with low-dose cyclophosphamide and fludarabine.
The median patient age was 58 years. Patients had stage III or IV disease, 48% had International Prognostic Index scores of 3-4, 76% had disease that was refractory to third-line therapies or beyond, and 21% had disease that relapsed within 12 months of an autologous bone marrow transplant
Axi-cel was successfully manufactured with sufficient cells for transfusion in all but one of the 111 patients, and 101 patients eventually received infusions in phase 2 (modified intention-to-treat population). The average turnaround time from apheresis to the clinical site was 17 days.
Dr. Neelapu also presented data on seven patients enrolled in phase 1; the data were combined with the phase 2 results for an updated analysis of those patients who had at least 1 year of follow-up.
The phase 2 trial met its primary endpoint at the time of the primary analysis, with an 82% ORR, consisting of 54% complete responses and 28% partial responses at a median follow-up of 8.7 months.
In the updated analysis, the ORR and respective remission rates were 82%, 58%, and 34%, at a median of 15.4 months follow-up.
The median duration of response in the updated analysis was 11.1 months. The median duration of complete responses had not been reached at the time of data cutoff in August 2017. The median duration of partial responses was 1.9 months.
At the 15.4-month mark, 42% of patients remained free of disease progression, and 56% were alive, with the median overall survival not yet reached.
The treatment had generally acceptable toxicities, with only 13% of patients in phase 2 experiencing grade 3 or greater cytokine release syndrome (CRS), although one patient with CRS died from hemophagocytic lymphohistiocytosis, and one with CRS died from cardiac arrest. Grade 3 or greater neurologic events occurred in 28% of patients, and included encephalopathy, confusional state, aphasia, and somnolence.
The events were generally reversible, and the rates of each declined over time. The use of tocilizumab or steroids to control adverse events did not have a negative effect on responses.
Since the primary analysis with at least 6 months of follow-up, there have been no new axi-cel–related cases of CRS, neurologic events, or deaths.
Dr. Neelapu also presented safety data on serious adverse events occurring more than 6 months after therapy in 10 patients who developed symptoms after the data cutoff.
Grade 3 events in these patients included lung infection, recurrent upper respiratory viral infection, and rotavirus infection, pneumonias, atrial fibrillation with rapid ventricular response, lung infection, febrile neutropenia, and influenza B infection. One patient had grade 4 sepsis.
In an editorial accompanying the study in the New England Journal of Medicine, Eric Tran, PhD, and Walter J. Urba, MD, PhD, from the Earle A. Chiles Research Institute and the Providence Portland (Ore.) Medical Center, and Dan L. Longo, MD, deputy editor of the journal, praised ZUMA-1 as “a landmark study because it involved 22 institutions and showed that a personalized gene-engineered T-cell product could be rapidly generated at a centralized cell-manufacturing facility and safely administered to patients at transplantation-capable medical centers.”
They noted, however, that about half of all patients with relapsed or refractory large B-cell lymphomas will not have durable responses to CAR T-cell therapy directed against CD19, and that new strategies will be needed to improve responses (N Engl J Med. 2017 Dec 10; doi: 10.1056/NEJMe1714680).
In the question and answer session at the end of the briefing, Dr. Neelapu said the preliminary observations of mechanisms of relapse or disease progression in some patients may be related to the loss of the CD19 antigen, which occurs in about one-third of patients who experience relapse, and to high expression of the programmed death ligand-1, which can potentially inhibit CAR-T cell function. A clinical trial is currently underway to evaluate potential strategies for improving response rates to CAR-T therapies, he said.
ZUMA-1 is supported by Kite Pharma and the Leukemia and Lymphoma Society Therapy Acceleration Program. Dr. Neelapu reported receiving advisory board fees from the company. Myriad coauthors also reported financial relationship with multiple companies.
SOURCE: Neelapu S et al. ASH 2017 Abstract 578.
ATLANTA – More than one-third of patients with refractory large B-cell lymphomas treated with the chimeric antigen receptor (CAR) T-cell product axicabtagene ciloleucel (Yescarta), often called axi-cel, had durable responses, with some patients having complete responses lasting more than 1 year after a single infusion, according to investigators in the ZUMA-1 trial.
Updated combined phase 1 and phase 2 results in 108 patients with diffuse large B-cell lymphoma (DLBCL), primary mediastinal B-cell lymphoma (PMBCL), or transformed follicular lymphoma (TFL) showed an objective response rate (ORR) of 82%, including 58% complete responses, after a median follow-up of 15.4 months, reported Sattva S. Neelapu, MD, from the University of Texas MD Anderson Cancer Center in Houston.
“Axi-cel is highly effective in patients with large B-cell lymphoma who otherwise have no curative treatment options,” he said in a briefing at the annual meeting of the American Society of Hematology, prior to his presentation of the data in an oral session.
The trial results were also published simultaneously in the New England Journal of Medicine.As previously reported, in the multicenter phase 2 ZUMA-1 trial, 111 patients with treatment refractory DLBCL, PMBCL, or TFL were enrolled and treated with axi-cel at a target dose of 2 x 106 cells/kg, following a conditioning regimen with low-dose cyclophosphamide and fludarabine.
The median patient age was 58 years. Patients had stage III or IV disease, 48% had International Prognostic Index scores of 3-4, 76% had disease that was refractory to third-line therapies or beyond, and 21% had disease that relapsed within 12 months of an autologous bone marrow transplant
Axi-cel was successfully manufactured with sufficient cells for transfusion in all but one of the 111 patients, and 101 patients eventually received infusions in phase 2 (modified intention-to-treat population). The average turnaround time from apheresis to the clinical site was 17 days.
Dr. Neelapu also presented data on seven patients enrolled in phase 1; the data were combined with the phase 2 results for an updated analysis of those patients who had at least 1 year of follow-up.
The phase 2 trial met its primary endpoint at the time of the primary analysis, with an 82% ORR, consisting of 54% complete responses and 28% partial responses at a median follow-up of 8.7 months.
In the updated analysis, the ORR and respective remission rates were 82%, 58%, and 34%, at a median of 15.4 months follow-up.
The median duration of response in the updated analysis was 11.1 months. The median duration of complete responses had not been reached at the time of data cutoff in August 2017. The median duration of partial responses was 1.9 months.
At the 15.4-month mark, 42% of patients remained free of disease progression, and 56% were alive, with the median overall survival not yet reached.
The treatment had generally acceptable toxicities, with only 13% of patients in phase 2 experiencing grade 3 or greater cytokine release syndrome (CRS), although one patient with CRS died from hemophagocytic lymphohistiocytosis, and one with CRS died from cardiac arrest. Grade 3 or greater neurologic events occurred in 28% of patients, and included encephalopathy, confusional state, aphasia, and somnolence.
The events were generally reversible, and the rates of each declined over time. The use of tocilizumab or steroids to control adverse events did not have a negative effect on responses.
Since the primary analysis with at least 6 months of follow-up, there have been no new axi-cel–related cases of CRS, neurologic events, or deaths.
Dr. Neelapu also presented safety data on serious adverse events occurring more than 6 months after therapy in 10 patients who developed symptoms after the data cutoff.
Grade 3 events in these patients included lung infection, recurrent upper respiratory viral infection, and rotavirus infection, pneumonias, atrial fibrillation with rapid ventricular response, lung infection, febrile neutropenia, and influenza B infection. One patient had grade 4 sepsis.
In an editorial accompanying the study in the New England Journal of Medicine, Eric Tran, PhD, and Walter J. Urba, MD, PhD, from the Earle A. Chiles Research Institute and the Providence Portland (Ore.) Medical Center, and Dan L. Longo, MD, deputy editor of the journal, praised ZUMA-1 as “a landmark study because it involved 22 institutions and showed that a personalized gene-engineered T-cell product could be rapidly generated at a centralized cell-manufacturing facility and safely administered to patients at transplantation-capable medical centers.”
They noted, however, that about half of all patients with relapsed or refractory large B-cell lymphomas will not have durable responses to CAR T-cell therapy directed against CD19, and that new strategies will be needed to improve responses (N Engl J Med. 2017 Dec 10; doi: 10.1056/NEJMe1714680).
In the question and answer session at the end of the briefing, Dr. Neelapu said the preliminary observations of mechanisms of relapse or disease progression in some patients may be related to the loss of the CD19 antigen, which occurs in about one-third of patients who experience relapse, and to high expression of the programmed death ligand-1, which can potentially inhibit CAR-T cell function. A clinical trial is currently underway to evaluate potential strategies for improving response rates to CAR-T therapies, he said.
ZUMA-1 is supported by Kite Pharma and the Leukemia and Lymphoma Society Therapy Acceleration Program. Dr. Neelapu reported receiving advisory board fees from the company. Myriad coauthors also reported financial relationship with multiple companies.
SOURCE: Neelapu S et al. ASH 2017 Abstract 578.
REPORTING FROM ASH 2017
Key clinical point:.
Major finding: The objective response rate was 82%, including 58% complete responses at a median of 15.4 months of follow-up.
Data source: Update analysis of phase 1 and 2 data from the ZUMA-1 trial in 108 patients with large B-cell lymphomas.
Disclosures: ZUMA-1 is supported by Kite Pharma and the Leukemia and Lymphoma Society Therapy Acceleration Program. Dr. Neelapu reported receiving advisory board fees from the company. Myriad coauthors also reported financial relationship with multiple companies.
Source: Neelapu S et al. ASH 2017 Abstract 578
Guideline preview: ASH to recommend against VTE prophylaxis for lower-risk cancer patients
ATLANTA – An expert panel convened by the American Society of Hematology will recommend against routine venous thromboembolism (VTE) prophylaxis with low-molecular-weight heparin, except in patients deemed high risk, the panel chair told attendees at the group’s annual meeting.
The recommendations will be posted for public comment in early 2018 and are expected to be finalized and published later in the year.
The panel found strong evidence to recommend against prophylaxis in cancer patients at low risk of VTE, said Gary H. Lyman, MD, of the Fred Hutchinson Cancer Research Center and the University of Washington, both in Seattle.
For cancer patients at high risk of VTE, the panel will make a conditional recommendation – based on weaker evidence – in favor of low-molecular-weight thromboprophylaxis (LMWH) “with a caveat that patients should have no major bleeding risk or other contraindication to anticoagulation,” Dr. Lyman said.
The panel also found weaker evidence to support a conditional recommendation against routine prophylaxis in patients at intermediate risk of VTE, based on results from a systematic review.
These recommendations, which were described during a special education session at the annual meeting of the American Society of Hematology, are just one piece of a larger effort by ASH to develop evidence-based guidelines on VTE management. More than 100 thrombosis experts have reviewed evidence and drafted more than 200 recommendations on diagnosis, prevention, and treatment of VTE, according to ASH.
The cancer-specific recommendations described by Dr. Lyman are based in part on a meta-analysis of 17 randomized controlled trials of cancer patients receiving LMWH thromboprophylaxis that were published between 2008 and 2017. Across cancer types and settings, LMWH prophylaxis in these trials was associated with a reduced risk of VTE and an increased risk of bleeding, Dr. Lyman said.
For all cancer types, relative risk (RR) of VTE was 0.55 (95% confidence interval, 0.46-0.65), with an absolute risk reduction of just 2.7% “because of the low baseline risk of VTE in this setting,” Dr. Lyman said.
However, the baseline risk increased for certain cancer types, including lung cancer, which had a similar relative risk of 0.53 (95% CI, 0.41-0.69) but an absolute risk reduction of 4.3%, according to data Dr. Lyman presented. Likewise, pancreatic cancer was associated with a relative risk of 0.43 (95% CI, 0.25-0.73) but an absolute risk reduction of 10.1%.
Major bleeding across all trials was significantly increased (RR 1.40; 95% CI, 1.01-1.92), but the presented data show that, in absolute terms, the increase was just 0.7% overall and similarly, 0.7% and 0.9% for lung and pancreatic cancer, respectively.
However, VTE risk depends on more than the site of the cancer, Dr. Lyman noted. In their deliberations, the panel considered the validated Khorana Risk Score, which incorporates factors such as body mass index, platelet count, leukocyte count, and hemoglobin level.
Specific analysis of high-risk patients suggested a pronounced risk reduction associated with LMWH prophylaxis, according to Dr. Lyman, who noted that a patient-level analysis including nearly 8,000 patients from 13 randomized, controlled trials showed a relative risk of 0.58, with VTE events seen in 4.0% patients in the LMWH group versus 7.0% of controls.
The forthcoming ASH guidelines also will address other aspects of cancer-associated VTE, according to Dr. Lyman, including initial treatment, secondary prophylaxis, perioperative prophylaxis, and prophylaxis or treatment in patients with a central venous catheter.
“The risk of venous thromboembolism in patients with cancer is well recognized, and that risk is especially notable in patients receiving cancer treatment,” Dr. Lyman said.
Dr. Lyman reported having no relevant financial disclosures.
ATLANTA – An expert panel convened by the American Society of Hematology will recommend against routine venous thromboembolism (VTE) prophylaxis with low-molecular-weight heparin, except in patients deemed high risk, the panel chair told attendees at the group’s annual meeting.
The recommendations will be posted for public comment in early 2018 and are expected to be finalized and published later in the year.
The panel found strong evidence to recommend against prophylaxis in cancer patients at low risk of VTE, said Gary H. Lyman, MD, of the Fred Hutchinson Cancer Research Center and the University of Washington, both in Seattle.
For cancer patients at high risk of VTE, the panel will make a conditional recommendation – based on weaker evidence – in favor of low-molecular-weight thromboprophylaxis (LMWH) “with a caveat that patients should have no major bleeding risk or other contraindication to anticoagulation,” Dr. Lyman said.
The panel also found weaker evidence to support a conditional recommendation against routine prophylaxis in patients at intermediate risk of VTE, based on results from a systematic review.
These recommendations, which were described during a special education session at the annual meeting of the American Society of Hematology, are just one piece of a larger effort by ASH to develop evidence-based guidelines on VTE management. More than 100 thrombosis experts have reviewed evidence and drafted more than 200 recommendations on diagnosis, prevention, and treatment of VTE, according to ASH.
The cancer-specific recommendations described by Dr. Lyman are based in part on a meta-analysis of 17 randomized controlled trials of cancer patients receiving LMWH thromboprophylaxis that were published between 2008 and 2017. Across cancer types and settings, LMWH prophylaxis in these trials was associated with a reduced risk of VTE and an increased risk of bleeding, Dr. Lyman said.
For all cancer types, relative risk (RR) of VTE was 0.55 (95% confidence interval, 0.46-0.65), with an absolute risk reduction of just 2.7% “because of the low baseline risk of VTE in this setting,” Dr. Lyman said.
However, the baseline risk increased for certain cancer types, including lung cancer, which had a similar relative risk of 0.53 (95% CI, 0.41-0.69) but an absolute risk reduction of 4.3%, according to data Dr. Lyman presented. Likewise, pancreatic cancer was associated with a relative risk of 0.43 (95% CI, 0.25-0.73) but an absolute risk reduction of 10.1%.
Major bleeding across all trials was significantly increased (RR 1.40; 95% CI, 1.01-1.92), but the presented data show that, in absolute terms, the increase was just 0.7% overall and similarly, 0.7% and 0.9% for lung and pancreatic cancer, respectively.
However, VTE risk depends on more than the site of the cancer, Dr. Lyman noted. In their deliberations, the panel considered the validated Khorana Risk Score, which incorporates factors such as body mass index, platelet count, leukocyte count, and hemoglobin level.
Specific analysis of high-risk patients suggested a pronounced risk reduction associated with LMWH prophylaxis, according to Dr. Lyman, who noted that a patient-level analysis including nearly 8,000 patients from 13 randomized, controlled trials showed a relative risk of 0.58, with VTE events seen in 4.0% patients in the LMWH group versus 7.0% of controls.
The forthcoming ASH guidelines also will address other aspects of cancer-associated VTE, according to Dr. Lyman, including initial treatment, secondary prophylaxis, perioperative prophylaxis, and prophylaxis or treatment in patients with a central venous catheter.
“The risk of venous thromboembolism in patients with cancer is well recognized, and that risk is especially notable in patients receiving cancer treatment,” Dr. Lyman said.
Dr. Lyman reported having no relevant financial disclosures.
ATLANTA – An expert panel convened by the American Society of Hematology will recommend against routine venous thromboembolism (VTE) prophylaxis with low-molecular-weight heparin, except in patients deemed high risk, the panel chair told attendees at the group’s annual meeting.
The recommendations will be posted for public comment in early 2018 and are expected to be finalized and published later in the year.
The panel found strong evidence to recommend against prophylaxis in cancer patients at low risk of VTE, said Gary H. Lyman, MD, of the Fred Hutchinson Cancer Research Center and the University of Washington, both in Seattle.
For cancer patients at high risk of VTE, the panel will make a conditional recommendation – based on weaker evidence – in favor of low-molecular-weight thromboprophylaxis (LMWH) “with a caveat that patients should have no major bleeding risk or other contraindication to anticoagulation,” Dr. Lyman said.
The panel also found weaker evidence to support a conditional recommendation against routine prophylaxis in patients at intermediate risk of VTE, based on results from a systematic review.
These recommendations, which were described during a special education session at the annual meeting of the American Society of Hematology, are just one piece of a larger effort by ASH to develop evidence-based guidelines on VTE management. More than 100 thrombosis experts have reviewed evidence and drafted more than 200 recommendations on diagnosis, prevention, and treatment of VTE, according to ASH.
The cancer-specific recommendations described by Dr. Lyman are based in part on a meta-analysis of 17 randomized controlled trials of cancer patients receiving LMWH thromboprophylaxis that were published between 2008 and 2017. Across cancer types and settings, LMWH prophylaxis in these trials was associated with a reduced risk of VTE and an increased risk of bleeding, Dr. Lyman said.
For all cancer types, relative risk (RR) of VTE was 0.55 (95% confidence interval, 0.46-0.65), with an absolute risk reduction of just 2.7% “because of the low baseline risk of VTE in this setting,” Dr. Lyman said.
However, the baseline risk increased for certain cancer types, including lung cancer, which had a similar relative risk of 0.53 (95% CI, 0.41-0.69) but an absolute risk reduction of 4.3%, according to data Dr. Lyman presented. Likewise, pancreatic cancer was associated with a relative risk of 0.43 (95% CI, 0.25-0.73) but an absolute risk reduction of 10.1%.
Major bleeding across all trials was significantly increased (RR 1.40; 95% CI, 1.01-1.92), but the presented data show that, in absolute terms, the increase was just 0.7% overall and similarly, 0.7% and 0.9% for lung and pancreatic cancer, respectively.
However, VTE risk depends on more than the site of the cancer, Dr. Lyman noted. In their deliberations, the panel considered the validated Khorana Risk Score, which incorporates factors such as body mass index, platelet count, leukocyte count, and hemoglobin level.
Specific analysis of high-risk patients suggested a pronounced risk reduction associated with LMWH prophylaxis, according to Dr. Lyman, who noted that a patient-level analysis including nearly 8,000 patients from 13 randomized, controlled trials showed a relative risk of 0.58, with VTE events seen in 4.0% patients in the LMWH group versus 7.0% of controls.
The forthcoming ASH guidelines also will address other aspects of cancer-associated VTE, according to Dr. Lyman, including initial treatment, secondary prophylaxis, perioperative prophylaxis, and prophylaxis or treatment in patients with a central venous catheter.
“The risk of venous thromboembolism in patients with cancer is well recognized, and that risk is especially notable in patients receiving cancer treatment,” Dr. Lyman said.
Dr. Lyman reported having no relevant financial disclosures.
REPORTING FROM ASH 2017
Avapritinib yields high response rate in patients with systemic mastocytosis
ATLANTA – An oral investigational drug with specific activity against a mutation frequently found in advanced systemic mastocytosis (ASM) produced clinical responses in the majority treated patients, according to preliminary data presented at the annual meeting of the American Society of Hematology.
that included a 56% rate of complete or partial response, according to lead study author Daniel J. DeAngelo, MD, PhD, director of clinical and translational research at Dana-Farber Cancer Institute, Boston.
Currently, midostaurin, a multikinase inhibitor, is the only Food and Drug Administration–approved drug for the treatment of systemic mastocytosis. That approval, announced in April 2017, was based in part on a 17% rate of complete or partial response, Dr. DeAngelo noted at a press briefing.
The primary goal of the phase 1 trial was to evaluate the safety profile and establish a maximum-tolerated dose for once-daily oral avapritinib administration. Treatment-emergent side effects were primarily grade 1-2, according to Dr. DeAngelo. Most hematologic toxicities were mild to moderate, and the most common grade 3 nonhematologic toxicities were periorbital edema and fatigue.
This part of the phase 1 trial enrolled 18 patients with ASM, systemic mastocytosis with associated hematologic neoplasm (SM-AHN), and mantle cell lymphoma (MCL). Efficacy of avapritinib was assessed on International Working Group criteria for response rate in myelodysplasia.
The overall response rate was 72% (13 of 18 patients saw complete response, partial response, or clinical improvement), and a 56% rate of complete and partial response (10 of 18 patients), Dr. DeAngelo said.
Avapritinib was active in all ASM subtypes evaluated, including in patients who had previously been treated with midostaurin or chemotherapy, according to the investigators.
The data on avapritinib suggests the drug “has a potent and clinically important activity in systemic mastocytosis,” he said. “It has been a wonderful success in terms of getting the majority of patients into complete and partial remissions, and so as this evolves, having better targeted agents, I think, can improve the outcome for these patients.”
More patients are being enrolled as the phase 1 study continues into the dose-expansion phase at 300 mg once daily, and 30 of 32 patients remain on treatment with median duration of 9 months, Dr. DeAngelo said.
A phase 2 study in advanced systemic mastocytosis is planned for 2018, as well as phase 1 and phase 2 studies that will include patients with indolent or smoldering disease, he added.
Avapritinib is manufactured by Blueprint Medicines, which also supported the study. Dr. DeAngelo reported disclosures from Blueprint and several other companies in the hematologic space.
SOURCE: DeAngelo D et al. ASH 2017 Abstract 2.
ATLANTA – An oral investigational drug with specific activity against a mutation frequently found in advanced systemic mastocytosis (ASM) produced clinical responses in the majority treated patients, according to preliminary data presented at the annual meeting of the American Society of Hematology.
that included a 56% rate of complete or partial response, according to lead study author Daniel J. DeAngelo, MD, PhD, director of clinical and translational research at Dana-Farber Cancer Institute, Boston.
Currently, midostaurin, a multikinase inhibitor, is the only Food and Drug Administration–approved drug for the treatment of systemic mastocytosis. That approval, announced in April 2017, was based in part on a 17% rate of complete or partial response, Dr. DeAngelo noted at a press briefing.
The primary goal of the phase 1 trial was to evaluate the safety profile and establish a maximum-tolerated dose for once-daily oral avapritinib administration. Treatment-emergent side effects were primarily grade 1-2, according to Dr. DeAngelo. Most hematologic toxicities were mild to moderate, and the most common grade 3 nonhematologic toxicities were periorbital edema and fatigue.
This part of the phase 1 trial enrolled 18 patients with ASM, systemic mastocytosis with associated hematologic neoplasm (SM-AHN), and mantle cell lymphoma (MCL). Efficacy of avapritinib was assessed on International Working Group criteria for response rate in myelodysplasia.
The overall response rate was 72% (13 of 18 patients saw complete response, partial response, or clinical improvement), and a 56% rate of complete and partial response (10 of 18 patients), Dr. DeAngelo said.
Avapritinib was active in all ASM subtypes evaluated, including in patients who had previously been treated with midostaurin or chemotherapy, according to the investigators.
The data on avapritinib suggests the drug “has a potent and clinically important activity in systemic mastocytosis,” he said. “It has been a wonderful success in terms of getting the majority of patients into complete and partial remissions, and so as this evolves, having better targeted agents, I think, can improve the outcome for these patients.”
More patients are being enrolled as the phase 1 study continues into the dose-expansion phase at 300 mg once daily, and 30 of 32 patients remain on treatment with median duration of 9 months, Dr. DeAngelo said.
A phase 2 study in advanced systemic mastocytosis is planned for 2018, as well as phase 1 and phase 2 studies that will include patients with indolent or smoldering disease, he added.
Avapritinib is manufactured by Blueprint Medicines, which also supported the study. Dr. DeAngelo reported disclosures from Blueprint and several other companies in the hematologic space.
SOURCE: DeAngelo D et al. ASH 2017 Abstract 2.
ATLANTA – An oral investigational drug with specific activity against a mutation frequently found in advanced systemic mastocytosis (ASM) produced clinical responses in the majority treated patients, according to preliminary data presented at the annual meeting of the American Society of Hematology.
that included a 56% rate of complete or partial response, according to lead study author Daniel J. DeAngelo, MD, PhD, director of clinical and translational research at Dana-Farber Cancer Institute, Boston.
Currently, midostaurin, a multikinase inhibitor, is the only Food and Drug Administration–approved drug for the treatment of systemic mastocytosis. That approval, announced in April 2017, was based in part on a 17% rate of complete or partial response, Dr. DeAngelo noted at a press briefing.
The primary goal of the phase 1 trial was to evaluate the safety profile and establish a maximum-tolerated dose for once-daily oral avapritinib administration. Treatment-emergent side effects were primarily grade 1-2, according to Dr. DeAngelo. Most hematologic toxicities were mild to moderate, and the most common grade 3 nonhematologic toxicities were periorbital edema and fatigue.
This part of the phase 1 trial enrolled 18 patients with ASM, systemic mastocytosis with associated hematologic neoplasm (SM-AHN), and mantle cell lymphoma (MCL). Efficacy of avapritinib was assessed on International Working Group criteria for response rate in myelodysplasia.
The overall response rate was 72% (13 of 18 patients saw complete response, partial response, or clinical improvement), and a 56% rate of complete and partial response (10 of 18 patients), Dr. DeAngelo said.
Avapritinib was active in all ASM subtypes evaluated, including in patients who had previously been treated with midostaurin or chemotherapy, according to the investigators.
The data on avapritinib suggests the drug “has a potent and clinically important activity in systemic mastocytosis,” he said. “It has been a wonderful success in terms of getting the majority of patients into complete and partial remissions, and so as this evolves, having better targeted agents, I think, can improve the outcome for these patients.”
More patients are being enrolled as the phase 1 study continues into the dose-expansion phase at 300 mg once daily, and 30 of 32 patients remain on treatment with median duration of 9 months, Dr. DeAngelo said.
A phase 2 study in advanced systemic mastocytosis is planned for 2018, as well as phase 1 and phase 2 studies that will include patients with indolent or smoldering disease, he added.
Avapritinib is manufactured by Blueprint Medicines, which also supported the study. Dr. DeAngelo reported disclosures from Blueprint and several other companies in the hematologic space.
SOURCE: DeAngelo D et al. ASH 2017 Abstract 2.
REPORTING FROM ASH 2017
Key clinical point: Avapritinib produced complete or partial responses in the majority of patients with advanced systemic mastocytosis.
Major finding: The overall response rate was 72%, including a 56% rate of complete or partial response.
Data source: Phase 1 dose-escalation study of 18 patients with advanced systemic mastocytosis.
Disclosures: The study was supported by Blueprint Medicines. Dr. DeAngelo reported disclosures from Blueprint and several other companies in the hematologic space.
Source: DeAngelo D et al. ASH 2017 Abstract 2
Intrabone gene therapy shows promise in beta-thalassemia
ATLANTA – Intrabone gene therapy could offer long-term hope for patients with beta thalassemia who cannot be treated by allogeneic hematopoietic stem cell transplant (HSCT), suggest the results of a phase 1/2 trial.
After a median of 16 months of follow-up, five of seven patients who received this novel gene therapy needed markedly fewer blood transfusions than at baseline, lead investigator Sarah Marktel, MD, reported at the annual meeting of the American Society of Hematology.
Even more strikingly, (indicating severe disease), said Dr. Marktel of San Raffaele Scientific Institute and San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), Milan.
All patients met the trial’s primary safety endpoint and experienced no treatment-related adverse effects except those caused by conditioning chemotherapy, such as infections, Dr. Marktel said. She and her coinvestigators are expanding the study by administering intrabone gene therapy to three more children.
Beta-thalassemia is a genetic anemia linked to multiple mutations of the beta-globin gene. Patients who can’t undergo allogeneic HSCT face a lifetime of blood transfusions and iron chelation. This is the reality for most because they lack a compatible donor, have exclusionary risk factors for allogeneic transplant, or cannot access treatment, Dr. Marktel said during a press briefing.
Although this is not the first human study of gene therapy in beta-thalassemia, it is the first to infuse treatment directly into bone marrow instead of peripheral blood.
“Compared to previous trials, patients showed evidence of successful engraftment [proliferation in bone marrow] sooner after receiving the therapy,” Dr. Marktel said. Researchers saw evidence of engraftment as soon as 10 days after treatment – noticeably faster than in prior gene therapy studies of beta-thalassemia, she added.
To develop this treatment, investigators created a self-inactivating lentiviral vector (dubbed GLOBE) that carries a normal beta-globin gene. The vector posted encouraging safety and efficacy signals in studies of human thalassemic cells and in a mouse model, Dr. Marktel said.
For the phase 1/2 trial, the researchers extracted circulating CD34+ stem cells from the peripheral blood from three adults and four children with transfusion-dependent beta-thalassemia. For each patient, they transduced these stem cells with GLOBE. Next, patients underwent a 3-day conditioning regimen of treosulfan and thiotepa, after which their individual cell-gene product was infused into their own bone marrow.
This is a small study, but if results hold up in more patients, gene therapy “could represent an alternative to bone marrow transplantation that does not require a matched donor or immunosuppression and that carries no risk of graft-versus-host disease or transplant rejection,” Dr. Marktel said. Children in this study might have had better results because their younger stem cells are more amenable to gene transduction and engraftment, she hypothesized.
Both beta-0/beta-0 patients in the study are children. One continues to need blood transfusions because he experiences a drop in genetically modified cells and vector copy numbers soon after each infusion of gene therapy. The other was treated more than a year ago and remains transfusion free.
“The beta-0/beta-0 genotype is toughest to treat with gene therapy,” Dr. Marktel noted. “In comparison, beta-0/beta+ or beta+/beta+ patients have the highest chances of becoming transfusion independent because they can contribute their own hemoglobin to the total hemoglobin output.”
Telethon Foundation provided funding. Dr. Marktel disclosed research funding from GlaxoSmithKline, which has licensed the therapy.
SOURCE: Marktel S et al. ASH 2017 Abstract 355.
ATLANTA – Intrabone gene therapy could offer long-term hope for patients with beta thalassemia who cannot be treated by allogeneic hematopoietic stem cell transplant (HSCT), suggest the results of a phase 1/2 trial.
After a median of 16 months of follow-up, five of seven patients who received this novel gene therapy needed markedly fewer blood transfusions than at baseline, lead investigator Sarah Marktel, MD, reported at the annual meeting of the American Society of Hematology.
Even more strikingly, (indicating severe disease), said Dr. Marktel of San Raffaele Scientific Institute and San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), Milan.
All patients met the trial’s primary safety endpoint and experienced no treatment-related adverse effects except those caused by conditioning chemotherapy, such as infections, Dr. Marktel said. She and her coinvestigators are expanding the study by administering intrabone gene therapy to three more children.
Beta-thalassemia is a genetic anemia linked to multiple mutations of the beta-globin gene. Patients who can’t undergo allogeneic HSCT face a lifetime of blood transfusions and iron chelation. This is the reality for most because they lack a compatible donor, have exclusionary risk factors for allogeneic transplant, or cannot access treatment, Dr. Marktel said during a press briefing.
Although this is not the first human study of gene therapy in beta-thalassemia, it is the first to infuse treatment directly into bone marrow instead of peripheral blood.
“Compared to previous trials, patients showed evidence of successful engraftment [proliferation in bone marrow] sooner after receiving the therapy,” Dr. Marktel said. Researchers saw evidence of engraftment as soon as 10 days after treatment – noticeably faster than in prior gene therapy studies of beta-thalassemia, she added.
To develop this treatment, investigators created a self-inactivating lentiviral vector (dubbed GLOBE) that carries a normal beta-globin gene. The vector posted encouraging safety and efficacy signals in studies of human thalassemic cells and in a mouse model, Dr. Marktel said.
For the phase 1/2 trial, the researchers extracted circulating CD34+ stem cells from the peripheral blood from three adults and four children with transfusion-dependent beta-thalassemia. For each patient, they transduced these stem cells with GLOBE. Next, patients underwent a 3-day conditioning regimen of treosulfan and thiotepa, after which their individual cell-gene product was infused into their own bone marrow.
This is a small study, but if results hold up in more patients, gene therapy “could represent an alternative to bone marrow transplantation that does not require a matched donor or immunosuppression and that carries no risk of graft-versus-host disease or transplant rejection,” Dr. Marktel said. Children in this study might have had better results because their younger stem cells are more amenable to gene transduction and engraftment, she hypothesized.
Both beta-0/beta-0 patients in the study are children. One continues to need blood transfusions because he experiences a drop in genetically modified cells and vector copy numbers soon after each infusion of gene therapy. The other was treated more than a year ago and remains transfusion free.
“The beta-0/beta-0 genotype is toughest to treat with gene therapy,” Dr. Marktel noted. “In comparison, beta-0/beta+ or beta+/beta+ patients have the highest chances of becoming transfusion independent because they can contribute their own hemoglobin to the total hemoglobin output.”
Telethon Foundation provided funding. Dr. Marktel disclosed research funding from GlaxoSmithKline, which has licensed the therapy.
SOURCE: Marktel S et al. ASH 2017 Abstract 355.
ATLANTA – Intrabone gene therapy could offer long-term hope for patients with beta thalassemia who cannot be treated by allogeneic hematopoietic stem cell transplant (HSCT), suggest the results of a phase 1/2 trial.
After a median of 16 months of follow-up, five of seven patients who received this novel gene therapy needed markedly fewer blood transfusions than at baseline, lead investigator Sarah Marktel, MD, reported at the annual meeting of the American Society of Hematology.
Even more strikingly, (indicating severe disease), said Dr. Marktel of San Raffaele Scientific Institute and San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), Milan.
All patients met the trial’s primary safety endpoint and experienced no treatment-related adverse effects except those caused by conditioning chemotherapy, such as infections, Dr. Marktel said. She and her coinvestigators are expanding the study by administering intrabone gene therapy to three more children.
Beta-thalassemia is a genetic anemia linked to multiple mutations of the beta-globin gene. Patients who can’t undergo allogeneic HSCT face a lifetime of blood transfusions and iron chelation. This is the reality for most because they lack a compatible donor, have exclusionary risk factors for allogeneic transplant, or cannot access treatment, Dr. Marktel said during a press briefing.
Although this is not the first human study of gene therapy in beta-thalassemia, it is the first to infuse treatment directly into bone marrow instead of peripheral blood.
“Compared to previous trials, patients showed evidence of successful engraftment [proliferation in bone marrow] sooner after receiving the therapy,” Dr. Marktel said. Researchers saw evidence of engraftment as soon as 10 days after treatment – noticeably faster than in prior gene therapy studies of beta-thalassemia, she added.
To develop this treatment, investigators created a self-inactivating lentiviral vector (dubbed GLOBE) that carries a normal beta-globin gene. The vector posted encouraging safety and efficacy signals in studies of human thalassemic cells and in a mouse model, Dr. Marktel said.
For the phase 1/2 trial, the researchers extracted circulating CD34+ stem cells from the peripheral blood from three adults and four children with transfusion-dependent beta-thalassemia. For each patient, they transduced these stem cells with GLOBE. Next, patients underwent a 3-day conditioning regimen of treosulfan and thiotepa, after which their individual cell-gene product was infused into their own bone marrow.
This is a small study, but if results hold up in more patients, gene therapy “could represent an alternative to bone marrow transplantation that does not require a matched donor or immunosuppression and that carries no risk of graft-versus-host disease or transplant rejection,” Dr. Marktel said. Children in this study might have had better results because their younger stem cells are more amenable to gene transduction and engraftment, she hypothesized.
Both beta-0/beta-0 patients in the study are children. One continues to need blood transfusions because he experiences a drop in genetically modified cells and vector copy numbers soon after each infusion of gene therapy. The other was treated more than a year ago and remains transfusion free.
“The beta-0/beta-0 genotype is toughest to treat with gene therapy,” Dr. Marktel noted. “In comparison, beta-0/beta+ or beta+/beta+ patients have the highest chances of becoming transfusion independent because they can contribute their own hemoglobin to the total hemoglobin output.”
Telethon Foundation provided funding. Dr. Marktel disclosed research funding from GlaxoSmithKline, which has licensed the therapy.
SOURCE: Marktel S et al. ASH 2017 Abstract 355.
REPORTING FROM ASH 2017
Key clinical point: Gene therapy engraftment was achieved sooner using intrabone delivery.
Major finding: After a median of 16 months of follow-up, five of seven patients who received this novel gene therapy needed markedly fewer blood transfusions than at baseline.
Data source: An interventional phase 1/2 trial of seven patients with transfusion-dependent beta thalassemia.
Disclosures: Telethon Foundation provided funding. Dr. Marktel disclosed research funding from GlaxoSmithKline, which has licensed the therapy.
Source: Marktel S et al. ASH 2017 Abstract 355.
Gene therapy normalized or near-normalized factor VIII in hemophilia A
ATLANTA – A single infusion of valoctocogene roxaparvovec normalized or nearly normalized factor VIII levels in 11 of 13 adults with severe hemophilia A, eliminated spontaneous bleeds and the need for factor VIII infusions, showed durable effects for up to 72 weeks of follow-up, K. John Pasi, MD, said at the annual meeting of the American Society of Hematology.
Nicknamed valrox and designated as a breakthrough therapy by the Food and Drug Administration in October 2017, valoctocogene roxaparvovec uses an adenoviral vector to deliver a functional copy of the factor VIII gene to patients with hemophilia A, said Dr. Pasi of Barts and The London School of Medicine and Dentistry.
Gene therapy has long been the “holy grail” for managing hemophilia because it is a single-gene disorder with a clear relationship between clotting factor level and bleeding severity, Dr. Pasi said. In a mouse model of hemophilia A, valrox restored factor VIII plasma concentrations to levels thought to be adequate to support normal clotting in humans.
Accordingly, the phase 2/3 enrolled 13 patients with severe hemophilia A whose baseline factor VIII levels were less than 1 IU/dL. Patients started at the lowest dose of gene therapy (4 x 1013 vector genomes/kg) and then received a higher dose ( 6 x 1013 VG/kg) if their factor VIII level remained under 5 IU/dL at week 3. Six patients received the lower dose and seven received the higher dose.
At 78 weeks, median factor VIII level in the higher-dose cohort was 90 IU/mL, as Dr. Pasi and his associates reported simultaneously in the New England Journal of Medicine (2017 Dec 9. doi: 10. 1056/NEJMoa1708483).
Before undergoing gene therapy, study participants had endured up to 41 breakthrough bleeds per year despite often receiving more than 150 infusions of factor VIII annually. Median annualized bleeding rates, which at baseline were 16.5 in the higher dose group and 8 in the lower dose group, zeroed out in both groups after factor VIII activity rose above 5%. Quality of life was evaluated in five patients, who reported substantial improvements across all domains.
All patients began producing factor VIII several weeks after infusion. Median levels plateaued within normal range by 20 weeks in the higher-dose group. At the lower dose, median levels rose steadily to a median of 34 IU/dL by 20 weeks. Additionally, three recipients of the lower dose who were followed for 32 weeks achieved factor VIII levels within normal range (median 51 IU/dL). Levels of factor VIII remained within normal range for up to 78 weeks of posttreatment follow-up, Dr. Pasi said.
No patients developed inhibitors or signs of immune-related adverse effects, nor were adverse events qualitatively different between dose groups, Dr. Pasi said. The most common adverse effects were transient increases in alanine transaminase (ALT), which peaked between 44 IU/L and 141 IU/L and lasted anywhere from several days to 15 weeks. Patients whose ALT rose 1.5-fold above baseline received short-term corticosteroids with no adverse effects. All but one was tapered off. There were two serious adverse events – one elective knee surgery and one case of transient fever, headache, and myalgia at time of infusion.
So far, valrox appears to be long lasting, but “durability is a huge question for any gene therapy approach,” Dr. Pasi said. “The only way to answer it is to follow patients through.”
In hemophilia B, studies indicate that some patients continue expressing factor IX years after a single infusion of gene therapy (N Engl J Med. 2017 Dec 7;377:2215-27).
Two phase 3 trials will further evaluate safety and optimal dosing of valrox, Dr. Pasi said. The GENEr8-1 trial will use the 6 x 1013 VG/kg dose and the GENEr8-2 trial will use the 4 x 1013 VG/kg dose. Like the pilot study, these trials will exclude patients with inhibitors, but they may include patients with comorbidities such as liver disease, he said.
Valrox was previously known as BMN 270.
The study was sponsored by BioMarin. Dr. Pasi disclosed research funding, consultancy fees, and speaker and advisory relationships with BioMarin. He disclosed ties to many other companies that develop hemophilia therapies.
SOURCE: Pasi KJ et al. ASH 2017 Abstract 603
ATLANTA – A single infusion of valoctocogene roxaparvovec normalized or nearly normalized factor VIII levels in 11 of 13 adults with severe hemophilia A, eliminated spontaneous bleeds and the need for factor VIII infusions, showed durable effects for up to 72 weeks of follow-up, K. John Pasi, MD, said at the annual meeting of the American Society of Hematology.
Nicknamed valrox and designated as a breakthrough therapy by the Food and Drug Administration in October 2017, valoctocogene roxaparvovec uses an adenoviral vector to deliver a functional copy of the factor VIII gene to patients with hemophilia A, said Dr. Pasi of Barts and The London School of Medicine and Dentistry.
Gene therapy has long been the “holy grail” for managing hemophilia because it is a single-gene disorder with a clear relationship between clotting factor level and bleeding severity, Dr. Pasi said. In a mouse model of hemophilia A, valrox restored factor VIII plasma concentrations to levels thought to be adequate to support normal clotting in humans.
Accordingly, the phase 2/3 enrolled 13 patients with severe hemophilia A whose baseline factor VIII levels were less than 1 IU/dL. Patients started at the lowest dose of gene therapy (4 x 1013 vector genomes/kg) and then received a higher dose ( 6 x 1013 VG/kg) if their factor VIII level remained under 5 IU/dL at week 3. Six patients received the lower dose and seven received the higher dose.
At 78 weeks, median factor VIII level in the higher-dose cohort was 90 IU/mL, as Dr. Pasi and his associates reported simultaneously in the New England Journal of Medicine (2017 Dec 9. doi: 10. 1056/NEJMoa1708483).
Before undergoing gene therapy, study participants had endured up to 41 breakthrough bleeds per year despite often receiving more than 150 infusions of factor VIII annually. Median annualized bleeding rates, which at baseline were 16.5 in the higher dose group and 8 in the lower dose group, zeroed out in both groups after factor VIII activity rose above 5%. Quality of life was evaluated in five patients, who reported substantial improvements across all domains.
All patients began producing factor VIII several weeks after infusion. Median levels plateaued within normal range by 20 weeks in the higher-dose group. At the lower dose, median levels rose steadily to a median of 34 IU/dL by 20 weeks. Additionally, three recipients of the lower dose who were followed for 32 weeks achieved factor VIII levels within normal range (median 51 IU/dL). Levels of factor VIII remained within normal range for up to 78 weeks of posttreatment follow-up, Dr. Pasi said.
No patients developed inhibitors or signs of immune-related adverse effects, nor were adverse events qualitatively different between dose groups, Dr. Pasi said. The most common adverse effects were transient increases in alanine transaminase (ALT), which peaked between 44 IU/L and 141 IU/L and lasted anywhere from several days to 15 weeks. Patients whose ALT rose 1.5-fold above baseline received short-term corticosteroids with no adverse effects. All but one was tapered off. There were two serious adverse events – one elective knee surgery and one case of transient fever, headache, and myalgia at time of infusion.
So far, valrox appears to be long lasting, but “durability is a huge question for any gene therapy approach,” Dr. Pasi said. “The only way to answer it is to follow patients through.”
In hemophilia B, studies indicate that some patients continue expressing factor IX years after a single infusion of gene therapy (N Engl J Med. 2017 Dec 7;377:2215-27).
Two phase 3 trials will further evaluate safety and optimal dosing of valrox, Dr. Pasi said. The GENEr8-1 trial will use the 6 x 1013 VG/kg dose and the GENEr8-2 trial will use the 4 x 1013 VG/kg dose. Like the pilot study, these trials will exclude patients with inhibitors, but they may include patients with comorbidities such as liver disease, he said.
Valrox was previously known as BMN 270.
The study was sponsored by BioMarin. Dr. Pasi disclosed research funding, consultancy fees, and speaker and advisory relationships with BioMarin. He disclosed ties to many other companies that develop hemophilia therapies.
SOURCE: Pasi KJ et al. ASH 2017 Abstract 603
ATLANTA – A single infusion of valoctocogene roxaparvovec normalized or nearly normalized factor VIII levels in 11 of 13 adults with severe hemophilia A, eliminated spontaneous bleeds and the need for factor VIII infusions, showed durable effects for up to 72 weeks of follow-up, K. John Pasi, MD, said at the annual meeting of the American Society of Hematology.
Nicknamed valrox and designated as a breakthrough therapy by the Food and Drug Administration in October 2017, valoctocogene roxaparvovec uses an adenoviral vector to deliver a functional copy of the factor VIII gene to patients with hemophilia A, said Dr. Pasi of Barts and The London School of Medicine and Dentistry.
Gene therapy has long been the “holy grail” for managing hemophilia because it is a single-gene disorder with a clear relationship between clotting factor level and bleeding severity, Dr. Pasi said. In a mouse model of hemophilia A, valrox restored factor VIII plasma concentrations to levels thought to be adequate to support normal clotting in humans.
Accordingly, the phase 2/3 enrolled 13 patients with severe hemophilia A whose baseline factor VIII levels were less than 1 IU/dL. Patients started at the lowest dose of gene therapy (4 x 1013 vector genomes/kg) and then received a higher dose ( 6 x 1013 VG/kg) if their factor VIII level remained under 5 IU/dL at week 3. Six patients received the lower dose and seven received the higher dose.
At 78 weeks, median factor VIII level in the higher-dose cohort was 90 IU/mL, as Dr. Pasi and his associates reported simultaneously in the New England Journal of Medicine (2017 Dec 9. doi: 10. 1056/NEJMoa1708483).
Before undergoing gene therapy, study participants had endured up to 41 breakthrough bleeds per year despite often receiving more than 150 infusions of factor VIII annually. Median annualized bleeding rates, which at baseline were 16.5 in the higher dose group and 8 in the lower dose group, zeroed out in both groups after factor VIII activity rose above 5%. Quality of life was evaluated in five patients, who reported substantial improvements across all domains.
All patients began producing factor VIII several weeks after infusion. Median levels plateaued within normal range by 20 weeks in the higher-dose group. At the lower dose, median levels rose steadily to a median of 34 IU/dL by 20 weeks. Additionally, three recipients of the lower dose who were followed for 32 weeks achieved factor VIII levels within normal range (median 51 IU/dL). Levels of factor VIII remained within normal range for up to 78 weeks of posttreatment follow-up, Dr. Pasi said.
No patients developed inhibitors or signs of immune-related adverse effects, nor were adverse events qualitatively different between dose groups, Dr. Pasi said. The most common adverse effects were transient increases in alanine transaminase (ALT), which peaked between 44 IU/L and 141 IU/L and lasted anywhere from several days to 15 weeks. Patients whose ALT rose 1.5-fold above baseline received short-term corticosteroids with no adverse effects. All but one was tapered off. There were two serious adverse events – one elective knee surgery and one case of transient fever, headache, and myalgia at time of infusion.
So far, valrox appears to be long lasting, but “durability is a huge question for any gene therapy approach,” Dr. Pasi said. “The only way to answer it is to follow patients through.”
In hemophilia B, studies indicate that some patients continue expressing factor IX years after a single infusion of gene therapy (N Engl J Med. 2017 Dec 7;377:2215-27).
Two phase 3 trials will further evaluate safety and optimal dosing of valrox, Dr. Pasi said. The GENEr8-1 trial will use the 6 x 1013 VG/kg dose and the GENEr8-2 trial will use the 4 x 1013 VG/kg dose. Like the pilot study, these trials will exclude patients with inhibitors, but they may include patients with comorbidities such as liver disease, he said.
Valrox was previously known as BMN 270.
The study was sponsored by BioMarin. Dr. Pasi disclosed research funding, consultancy fees, and speaker and advisory relationships with BioMarin. He disclosed ties to many other companies that develop hemophilia therapies.
SOURCE: Pasi KJ et al. ASH 2017 Abstract 603
REPORTING FROM ASH 2017
Key clinical point: The investigational gene therapy BMN 270 (valoctocogene roxaparvovec; valrox) eliminated spontaneous bleeds and the need for factor VIII infusions in patients with hemophilia A, and the effects persisted for up to 78 weeks.
Major finding: Median FVIII level was 90 IU/dL at 78 weeks in the higher (6 x 1013 VG/kg) dose cohort.
Data source: A phase I/II, first-in-human study of adenoassociated viral factor VIII gene transfer in 15 patients with severe hemophilia A without inhibitors.
Disclosures: The study was sponsored by BioMarin. Dr. Pasi disclosed research funding, consultancy fees, and speaker and advisory relationships with BioMarin. He disclosed ties to many other companies that develop hemophilia therapies.
Source: Pasi KJ et al. ASH 2017 Abstract 603
Gene therapy regimen for XSCID shows rapid results in newly diagnosed infants
ATLANTA – A new approach to gene therapy produced rapid T cell reconstruction and normal markers of B-cell and natural killer (NK)-cell function in newly diagnosed infants with X-linked Severe Combined Immunodeficiency (XSCID), according to initial results from a phase 1/2 trial.
Researchers used a regimen of safety-modified lentiviral vector plus reduced-exposure busulfan conditioning in seven newly diagnosed infants and found that it was well tolerated in all patients and quickly improved T-cell immunity in five of seven patients.
Initial gene therapy trials used a mouse vector without busulfan conditioning. These trials produced T-cell correction but were unable to restore B-cell function, NK-cell function, or myeloid-cell function. As a result, patients continued to experience viral infections and required monthly, life-long intravenous immunoglobulin infusions, Dr. Mamcarz said.
The phase 1/2 multicenter safety and efficacy study tested the gene therapy regimen for the first time in seven newly diagnosed infants. The regimen involved transducing purified bone marrow CD34+ cells with the lentiviral vector, which was generated by a stable producer cell line and then cryopreserved. The busulfan was given as two single daily doses, which were tailored based on patient age and weight.
In total, seven patients have been treated and all tolerated the low-dose busulfan chemotherapy well. Five patients had normal numbers of previously defective cells (T cells, B cells, and NK cells) and were taken off protective isolation and prophylactic medications. Those infants appear to have functioning immune systems, Dr. Mamcarz said. One infant has stopped monthly intravenous immunoglobulin infusions and has received normal pediatric vaccines, but responses have not yet been tested.
For the two infants who did not show responses, one is early in the trial and there is not yet adequate follow-up data to assess the immune system reconstitution, Dr. Mamcarz said.
The other infant had high levels of maternal T cell engraftment, severe neutropenia, and ongoing cytomegalovirus infection, resulting in delayed and partial T-cell reconstitution. The researchers sought to boost the patient’s immunity through an infusion of corrected cells – without busulfan – at 1 year after receiving the initial therapy. Three months after the second treatment, the infant has normal functioning of T cells and NK cells, but he is not yet engrafting B cells, Dr. Mamcarz said.
Overall, there was no evidence of vector-mediated effects on blood formation, Dr. Mamcarz reported.
The ultimate evaluation of the efficacy of the trial would be to assess vaccine responses in the infants treated with gene therapy, she said.
The study was supported by the Assisi Foundation of Memphis and the California Institute of Regenerative Medicine. Dr. Mamcarz reported having no relevant financial disclosures. Her coauthors reported financial relationships with InsightRX, UpToDate, Invitae, and Homology Medicines.
[email protected]
SOURCE: Mamcarz E et al. Abstract 523.
ATLANTA – A new approach to gene therapy produced rapid T cell reconstruction and normal markers of B-cell and natural killer (NK)-cell function in newly diagnosed infants with X-linked Severe Combined Immunodeficiency (XSCID), according to initial results from a phase 1/2 trial.
Researchers used a regimen of safety-modified lentiviral vector plus reduced-exposure busulfan conditioning in seven newly diagnosed infants and found that it was well tolerated in all patients and quickly improved T-cell immunity in five of seven patients.
Initial gene therapy trials used a mouse vector without busulfan conditioning. These trials produced T-cell correction but were unable to restore B-cell function, NK-cell function, or myeloid-cell function. As a result, patients continued to experience viral infections and required monthly, life-long intravenous immunoglobulin infusions, Dr. Mamcarz said.
The phase 1/2 multicenter safety and efficacy study tested the gene therapy regimen for the first time in seven newly diagnosed infants. The regimen involved transducing purified bone marrow CD34+ cells with the lentiviral vector, which was generated by a stable producer cell line and then cryopreserved. The busulfan was given as two single daily doses, which were tailored based on patient age and weight.
In total, seven patients have been treated and all tolerated the low-dose busulfan chemotherapy well. Five patients had normal numbers of previously defective cells (T cells, B cells, and NK cells) and were taken off protective isolation and prophylactic medications. Those infants appear to have functioning immune systems, Dr. Mamcarz said. One infant has stopped monthly intravenous immunoglobulin infusions and has received normal pediatric vaccines, but responses have not yet been tested.
For the two infants who did not show responses, one is early in the trial and there is not yet adequate follow-up data to assess the immune system reconstitution, Dr. Mamcarz said.
The other infant had high levels of maternal T cell engraftment, severe neutropenia, and ongoing cytomegalovirus infection, resulting in delayed and partial T-cell reconstitution. The researchers sought to boost the patient’s immunity through an infusion of corrected cells – without busulfan – at 1 year after receiving the initial therapy. Three months after the second treatment, the infant has normal functioning of T cells and NK cells, but he is not yet engrafting B cells, Dr. Mamcarz said.
Overall, there was no evidence of vector-mediated effects on blood formation, Dr. Mamcarz reported.
The ultimate evaluation of the efficacy of the trial would be to assess vaccine responses in the infants treated with gene therapy, she said.
The study was supported by the Assisi Foundation of Memphis and the California Institute of Regenerative Medicine. Dr. Mamcarz reported having no relevant financial disclosures. Her coauthors reported financial relationships with InsightRX, UpToDate, Invitae, and Homology Medicines.
[email protected]
SOURCE: Mamcarz E et al. Abstract 523.
ATLANTA – A new approach to gene therapy produced rapid T cell reconstruction and normal markers of B-cell and natural killer (NK)-cell function in newly diagnosed infants with X-linked Severe Combined Immunodeficiency (XSCID), according to initial results from a phase 1/2 trial.
Researchers used a regimen of safety-modified lentiviral vector plus reduced-exposure busulfan conditioning in seven newly diagnosed infants and found that it was well tolerated in all patients and quickly improved T-cell immunity in five of seven patients.
Initial gene therapy trials used a mouse vector without busulfan conditioning. These trials produced T-cell correction but were unable to restore B-cell function, NK-cell function, or myeloid-cell function. As a result, patients continued to experience viral infections and required monthly, life-long intravenous immunoglobulin infusions, Dr. Mamcarz said.
The phase 1/2 multicenter safety and efficacy study tested the gene therapy regimen for the first time in seven newly diagnosed infants. The regimen involved transducing purified bone marrow CD34+ cells with the lentiviral vector, which was generated by a stable producer cell line and then cryopreserved. The busulfan was given as two single daily doses, which were tailored based on patient age and weight.
In total, seven patients have been treated and all tolerated the low-dose busulfan chemotherapy well. Five patients had normal numbers of previously defective cells (T cells, B cells, and NK cells) and were taken off protective isolation and prophylactic medications. Those infants appear to have functioning immune systems, Dr. Mamcarz said. One infant has stopped monthly intravenous immunoglobulin infusions and has received normal pediatric vaccines, but responses have not yet been tested.
For the two infants who did not show responses, one is early in the trial and there is not yet adequate follow-up data to assess the immune system reconstitution, Dr. Mamcarz said.
The other infant had high levels of maternal T cell engraftment, severe neutropenia, and ongoing cytomegalovirus infection, resulting in delayed and partial T-cell reconstitution. The researchers sought to boost the patient’s immunity through an infusion of corrected cells – without busulfan – at 1 year after receiving the initial therapy. Three months after the second treatment, the infant has normal functioning of T cells and NK cells, but he is not yet engrafting B cells, Dr. Mamcarz said.
Overall, there was no evidence of vector-mediated effects on blood formation, Dr. Mamcarz reported.
The ultimate evaluation of the efficacy of the trial would be to assess vaccine responses in the infants treated with gene therapy, she said.
The study was supported by the Assisi Foundation of Memphis and the California Institute of Regenerative Medicine. Dr. Mamcarz reported having no relevant financial disclosures. Her coauthors reported financial relationships with InsightRX, UpToDate, Invitae, and Homology Medicines.
[email protected]
SOURCE: Mamcarz E et al. Abstract 523.
REPORTING FROM ASH 2017
Key clinical point:
Major finding: In total, five of seven infants with XSCID had normal functioning of T cells, B cells, and NK cells.
Study details: A phase 1/2 multicenter study of seven infants with newly diagnosed XSCID.
Disclosures: The study was supported by the Assisi Foundation of Memphis and the California Institute of Regenerative Medicine. Dr. Mamcarz reported having no relevant financial disclosures. Her coauthors reported financial relationships with InsightRX, UpToDate, Invitae, and Homology Medicines.
Source: Mamcarz E et al. Abstract 523.