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CT103A elicits responses after prior CAR T-cell relapse
BOSTON – CT103A, a chimeric antigen receptor (CAR) T-cell therapy, is “active and effective” in patients with relapsed/refractory multiple myeloma, according to a speaker at the International Myeloma Workshop, held by the International Myeloma Society.
The anti–B-cell maturation antigen (BCMA) CAR T-cell therapy produced a 100% response rate in patients with heavily pretreated multiple myeloma, and three of four patients who had failed a prior CAR T-cell therapy achieved a stringent complete response after CT103A.
Chunrui Li, MD, PhD, of Tongji Hospital and Tongji Medical College, Huazhong University of Science, Wuhan, China, presented these results at the workshop.
Dr. Li noted that anti-BCMA CAR T-cell therapy has produced responses in myeloma patients, but approximately half of patients typically relapse in about a year. CAR T-cell infusions after relapse have not been effective in these patients.
In an effort to change that, Dr. Li and his colleagues developed CT103A, a lentiviral vector containing a CAR structure with a fully human single-chain fragment variant; CD8a hinger; and transmembrane, 4-1BB co-stimulatory, and CD3z activation domains.
Dr. Li and his colleagues evaluated CT103A in a phase 0 trial (ChiCTR1800018137) of 18 patients who had received at least three prior lines of therapy and had disease refractory to a proteasome inhibitor and an immunomodulatory agent.
The patients’ median age was 53.3 years (range, 38-66 years), and their median time since diagnosis was 32 months (range, 8-92 months). They had received a median of 4 (range, 3-6) prior therapies. All had received prior bortezomib and lenalidomide, seven had undergone a transplant, and four had been treated on a trial of murine anti-BCMA CAR T-cell therapy.
For the current trial, patients received lymphodepletion with cyclophosphamide and fludarabine, followed by CT103A at 1x106, 3x106, or 6x106 CAR T cells/kg.
There was one dose-limiting toxicity at the highest dose level – grade 4 cytokine release syndrome (CRS) in a patient who died at day 19 after CT103A infusion.
In all, 17 patients developed CRS, four with grade 1, eight with grade 2, four with grade 3, and one with grade 4 CRS. None of the patients developed neurologic toxicity.
Serious adverse events related to lymphodepletion and/or CT103A included prolonged cytopenia (n = 3), pulmonary infection (n = 2), herpes zoster (n = 1), pleuritis (n = 1), and hypoxemia (n = 1).
There were 17 patients evaluable for efficacy, and all of them achieved a response at some point. In eight patients, responses have lasted more than 200 days.
At the data cutoff, there were 10 stringent complete responses, two complete responses, and three very good partial responses. One patient progressed after achieving a very good partial response, and one patient achieved a partial response but ultimately died (likely of respiratory failure attributable to a lung infection).
Of the four patients who had previously received murine CAR T-cell therapy, one progressed, and three achieved a stringent complete response.
This study was funded by Nanjing Iaso Biotherapeutics. Dr. Li did not disclose any conflicts of interest.
SOURCE: Li C et al. IMW 2019, Abstract OAB-033.
BOSTON – CT103A, a chimeric antigen receptor (CAR) T-cell therapy, is “active and effective” in patients with relapsed/refractory multiple myeloma, according to a speaker at the International Myeloma Workshop, held by the International Myeloma Society.
The anti–B-cell maturation antigen (BCMA) CAR T-cell therapy produced a 100% response rate in patients with heavily pretreated multiple myeloma, and three of four patients who had failed a prior CAR T-cell therapy achieved a stringent complete response after CT103A.
Chunrui Li, MD, PhD, of Tongji Hospital and Tongji Medical College, Huazhong University of Science, Wuhan, China, presented these results at the workshop.
Dr. Li noted that anti-BCMA CAR T-cell therapy has produced responses in myeloma patients, but approximately half of patients typically relapse in about a year. CAR T-cell infusions after relapse have not been effective in these patients.
In an effort to change that, Dr. Li and his colleagues developed CT103A, a lentiviral vector containing a CAR structure with a fully human single-chain fragment variant; CD8a hinger; and transmembrane, 4-1BB co-stimulatory, and CD3z activation domains.
Dr. Li and his colleagues evaluated CT103A in a phase 0 trial (ChiCTR1800018137) of 18 patients who had received at least three prior lines of therapy and had disease refractory to a proteasome inhibitor and an immunomodulatory agent.
The patients’ median age was 53.3 years (range, 38-66 years), and their median time since diagnosis was 32 months (range, 8-92 months). They had received a median of 4 (range, 3-6) prior therapies. All had received prior bortezomib and lenalidomide, seven had undergone a transplant, and four had been treated on a trial of murine anti-BCMA CAR T-cell therapy.
For the current trial, patients received lymphodepletion with cyclophosphamide and fludarabine, followed by CT103A at 1x106, 3x106, or 6x106 CAR T cells/kg.
There was one dose-limiting toxicity at the highest dose level – grade 4 cytokine release syndrome (CRS) in a patient who died at day 19 after CT103A infusion.
In all, 17 patients developed CRS, four with grade 1, eight with grade 2, four with grade 3, and one with grade 4 CRS. None of the patients developed neurologic toxicity.
Serious adverse events related to lymphodepletion and/or CT103A included prolonged cytopenia (n = 3), pulmonary infection (n = 2), herpes zoster (n = 1), pleuritis (n = 1), and hypoxemia (n = 1).
There were 17 patients evaluable for efficacy, and all of them achieved a response at some point. In eight patients, responses have lasted more than 200 days.
At the data cutoff, there were 10 stringent complete responses, two complete responses, and three very good partial responses. One patient progressed after achieving a very good partial response, and one patient achieved a partial response but ultimately died (likely of respiratory failure attributable to a lung infection).
Of the four patients who had previously received murine CAR T-cell therapy, one progressed, and three achieved a stringent complete response.
This study was funded by Nanjing Iaso Biotherapeutics. Dr. Li did not disclose any conflicts of interest.
SOURCE: Li C et al. IMW 2019, Abstract OAB-033.
BOSTON – CT103A, a chimeric antigen receptor (CAR) T-cell therapy, is “active and effective” in patients with relapsed/refractory multiple myeloma, according to a speaker at the International Myeloma Workshop, held by the International Myeloma Society.
The anti–B-cell maturation antigen (BCMA) CAR T-cell therapy produced a 100% response rate in patients with heavily pretreated multiple myeloma, and three of four patients who had failed a prior CAR T-cell therapy achieved a stringent complete response after CT103A.
Chunrui Li, MD, PhD, of Tongji Hospital and Tongji Medical College, Huazhong University of Science, Wuhan, China, presented these results at the workshop.
Dr. Li noted that anti-BCMA CAR T-cell therapy has produced responses in myeloma patients, but approximately half of patients typically relapse in about a year. CAR T-cell infusions after relapse have not been effective in these patients.
In an effort to change that, Dr. Li and his colleagues developed CT103A, a lentiviral vector containing a CAR structure with a fully human single-chain fragment variant; CD8a hinger; and transmembrane, 4-1BB co-stimulatory, and CD3z activation domains.
Dr. Li and his colleagues evaluated CT103A in a phase 0 trial (ChiCTR1800018137) of 18 patients who had received at least three prior lines of therapy and had disease refractory to a proteasome inhibitor and an immunomodulatory agent.
The patients’ median age was 53.3 years (range, 38-66 years), and their median time since diagnosis was 32 months (range, 8-92 months). They had received a median of 4 (range, 3-6) prior therapies. All had received prior bortezomib and lenalidomide, seven had undergone a transplant, and four had been treated on a trial of murine anti-BCMA CAR T-cell therapy.
For the current trial, patients received lymphodepletion with cyclophosphamide and fludarabine, followed by CT103A at 1x106, 3x106, or 6x106 CAR T cells/kg.
There was one dose-limiting toxicity at the highest dose level – grade 4 cytokine release syndrome (CRS) in a patient who died at day 19 after CT103A infusion.
In all, 17 patients developed CRS, four with grade 1, eight with grade 2, four with grade 3, and one with grade 4 CRS. None of the patients developed neurologic toxicity.
Serious adverse events related to lymphodepletion and/or CT103A included prolonged cytopenia (n = 3), pulmonary infection (n = 2), herpes zoster (n = 1), pleuritis (n = 1), and hypoxemia (n = 1).
There were 17 patients evaluable for efficacy, and all of them achieved a response at some point. In eight patients, responses have lasted more than 200 days.
At the data cutoff, there were 10 stringent complete responses, two complete responses, and three very good partial responses. One patient progressed after achieving a very good partial response, and one patient achieved a partial response but ultimately died (likely of respiratory failure attributable to a lung infection).
Of the four patients who had previously received murine CAR T-cell therapy, one progressed, and three achieved a stringent complete response.
This study was funded by Nanjing Iaso Biotherapeutics. Dr. Li did not disclose any conflicts of interest.
SOURCE: Li C et al. IMW 2019, Abstract OAB-033.
REPORTING FROM IMW 2019
Melflufen-dexamethasone active in patients with relapsed/refractory myeloma and EMD
BOSTON – Melflufen plus dexamethasone is active in patients with relapsed/refractory multiple myeloma, whether or not they have extramedullary disease (EMD), a phase 2 trial suggests.
In the HORIZON trial, melflufen-dexamethasone produced an overall response rate of 23% in patients with EMD and 27% in those without EMD.
Paul G. Richardson, MD, of Harvard Medical School and the Dana-Farber Cancer Institute, both in Boston, presented these results as a late-breaking abstract at the International Myeloma Workshop, held by the International Myeloma Society.
As of July 30, 2019, 136 patients had been treated on the HORIZON trial. The trial is enrolling patients with relapsed/refractory multiple myeloma refractory to pomalidomide, an anti-CD38 monoclonal antibody (mAb), or both. The patients must have received at least two prior lines of therapy, including a proteasome inhibitor (PI) and an immunomodulatory agent (IMiD).
Dr. Richardson presented results for 130 patients, 44 with EMD and 86 without it. The median age at baseline was 64 years in the EMD and non-EMD groups (overall range, 35-86 years). More than half of patients had high-risk cytogenetics (52% in the EMD group and 57% in the non-EMD group).
The median number of prior therapies was five in both the EMD and non-EMD groups. Most patients had received at least one prior transplant (73% in the EMD group and 69% in the non-EMD group). Most patients in both groups were refractory to an anti-CD38 mAb (93% EMD and 72% non-EMD); an IMiD and a PI (93% EMD and 90% non-EMD); an IMiD, a PI, and an anti-CD38 mAb (91% EMD and 63% non-EMD); and their last therapy (100% EMD and 95% non-EMD).
Dr. Richardson pointed out that the incidence of EMD in this trial is higher than has been reported previously. Of the 44 EMD patients, 26 had soft-tissue EMD, and 18 had bone-related EMD. Five patients had CNS involvement.
Another key finding, according to Dr. Richardson, was that EMD appeared to be associated with prior anti-CD38 therapy. Specifically, 40% of patients exposed to an anti-CD38 mAb had EMD, compared with 11% of patients who had not received an anti-CD38 mAb (P = .01).
“I don’t for a minute want to say that CD38-targeted therapy engenders extramedullary disease,” Dr. Richardson said. “I think what we can say, though, is that, once CD38 treatment fails a patient, extramedullary disease … is a very real challenge. Therefore, we need rationally targeted approaches, ideally in combination, to meet that challenge.”
The overall response rate was similar for EMD and non-EMD patients – 23% and 27%, respectively. The median duration of response was 3.4 months in the EMD patients and 4.4 months in the non-EMD group. The clinical benefit rate was 30% and 45%, respectively.
In the EMD group, the overall response rate was 19% in patients with soft-tissue EMD and 28% in bone-related EMD. None of the patients with CNS disease responded.
The median progression-free survival was 2.9 months for patients with EMD and 4.6 months for those without EMD. The median overall survival was 5.8 month and 11.6 months, respectively.
The median overall survival was 18.5 months in EMD responders and 17.2 months in non-EMD responders. The median overall survival was 5.1 months in EMD nonresponders and 8.5 months in non-EMD nonresponders.
In all, 54% of patients received subsequent therapy. There were no significant differences in outcomes between EMD and non-EMD patients.
The safety profiles were similar for EMD and non-EMD patients, Dr. Richardson said. Melflufen-dexamethasone was considered well tolerated overall, and there were no treatment-related deaths.
The most common treatment-emergent adverse events (grade 3 and 4, respectively) were thrombocytopenia (22% and 46%), neutropenia (32% and 35%), anemia (35% and 1%), white blood cell count decrease (10% and 7%), and pneumonia (7% and 1%).
This trial is sponsored by Oncopeptides. Dr. Richardson reported an advisory role and research funding from Oncopeptides.
SOURCE: Richardson PG et al. IMW 2019, Abstract OAB-086.
BOSTON – Melflufen plus dexamethasone is active in patients with relapsed/refractory multiple myeloma, whether or not they have extramedullary disease (EMD), a phase 2 trial suggests.
In the HORIZON trial, melflufen-dexamethasone produced an overall response rate of 23% in patients with EMD and 27% in those without EMD.
Paul G. Richardson, MD, of Harvard Medical School and the Dana-Farber Cancer Institute, both in Boston, presented these results as a late-breaking abstract at the International Myeloma Workshop, held by the International Myeloma Society.
As of July 30, 2019, 136 patients had been treated on the HORIZON trial. The trial is enrolling patients with relapsed/refractory multiple myeloma refractory to pomalidomide, an anti-CD38 monoclonal antibody (mAb), or both. The patients must have received at least two prior lines of therapy, including a proteasome inhibitor (PI) and an immunomodulatory agent (IMiD).
Dr. Richardson presented results for 130 patients, 44 with EMD and 86 without it. The median age at baseline was 64 years in the EMD and non-EMD groups (overall range, 35-86 years). More than half of patients had high-risk cytogenetics (52% in the EMD group and 57% in the non-EMD group).
The median number of prior therapies was five in both the EMD and non-EMD groups. Most patients had received at least one prior transplant (73% in the EMD group and 69% in the non-EMD group). Most patients in both groups were refractory to an anti-CD38 mAb (93% EMD and 72% non-EMD); an IMiD and a PI (93% EMD and 90% non-EMD); an IMiD, a PI, and an anti-CD38 mAb (91% EMD and 63% non-EMD); and their last therapy (100% EMD and 95% non-EMD).
Dr. Richardson pointed out that the incidence of EMD in this trial is higher than has been reported previously. Of the 44 EMD patients, 26 had soft-tissue EMD, and 18 had bone-related EMD. Five patients had CNS involvement.
Another key finding, according to Dr. Richardson, was that EMD appeared to be associated with prior anti-CD38 therapy. Specifically, 40% of patients exposed to an anti-CD38 mAb had EMD, compared with 11% of patients who had not received an anti-CD38 mAb (P = .01).
“I don’t for a minute want to say that CD38-targeted therapy engenders extramedullary disease,” Dr. Richardson said. “I think what we can say, though, is that, once CD38 treatment fails a patient, extramedullary disease … is a very real challenge. Therefore, we need rationally targeted approaches, ideally in combination, to meet that challenge.”
The overall response rate was similar for EMD and non-EMD patients – 23% and 27%, respectively. The median duration of response was 3.4 months in the EMD patients and 4.4 months in the non-EMD group. The clinical benefit rate was 30% and 45%, respectively.
In the EMD group, the overall response rate was 19% in patients with soft-tissue EMD and 28% in bone-related EMD. None of the patients with CNS disease responded.
The median progression-free survival was 2.9 months for patients with EMD and 4.6 months for those without EMD. The median overall survival was 5.8 month and 11.6 months, respectively.
The median overall survival was 18.5 months in EMD responders and 17.2 months in non-EMD responders. The median overall survival was 5.1 months in EMD nonresponders and 8.5 months in non-EMD nonresponders.
In all, 54% of patients received subsequent therapy. There were no significant differences in outcomes between EMD and non-EMD patients.
The safety profiles were similar for EMD and non-EMD patients, Dr. Richardson said. Melflufen-dexamethasone was considered well tolerated overall, and there were no treatment-related deaths.
The most common treatment-emergent adverse events (grade 3 and 4, respectively) were thrombocytopenia (22% and 46%), neutropenia (32% and 35%), anemia (35% and 1%), white blood cell count decrease (10% and 7%), and pneumonia (7% and 1%).
This trial is sponsored by Oncopeptides. Dr. Richardson reported an advisory role and research funding from Oncopeptides.
SOURCE: Richardson PG et al. IMW 2019, Abstract OAB-086.
BOSTON – Melflufen plus dexamethasone is active in patients with relapsed/refractory multiple myeloma, whether or not they have extramedullary disease (EMD), a phase 2 trial suggests.
In the HORIZON trial, melflufen-dexamethasone produced an overall response rate of 23% in patients with EMD and 27% in those without EMD.
Paul G. Richardson, MD, of Harvard Medical School and the Dana-Farber Cancer Institute, both in Boston, presented these results as a late-breaking abstract at the International Myeloma Workshop, held by the International Myeloma Society.
As of July 30, 2019, 136 patients had been treated on the HORIZON trial. The trial is enrolling patients with relapsed/refractory multiple myeloma refractory to pomalidomide, an anti-CD38 monoclonal antibody (mAb), or both. The patients must have received at least two prior lines of therapy, including a proteasome inhibitor (PI) and an immunomodulatory agent (IMiD).
Dr. Richardson presented results for 130 patients, 44 with EMD and 86 without it. The median age at baseline was 64 years in the EMD and non-EMD groups (overall range, 35-86 years). More than half of patients had high-risk cytogenetics (52% in the EMD group and 57% in the non-EMD group).
The median number of prior therapies was five in both the EMD and non-EMD groups. Most patients had received at least one prior transplant (73% in the EMD group and 69% in the non-EMD group). Most patients in both groups were refractory to an anti-CD38 mAb (93% EMD and 72% non-EMD); an IMiD and a PI (93% EMD and 90% non-EMD); an IMiD, a PI, and an anti-CD38 mAb (91% EMD and 63% non-EMD); and their last therapy (100% EMD and 95% non-EMD).
Dr. Richardson pointed out that the incidence of EMD in this trial is higher than has been reported previously. Of the 44 EMD patients, 26 had soft-tissue EMD, and 18 had bone-related EMD. Five patients had CNS involvement.
Another key finding, according to Dr. Richardson, was that EMD appeared to be associated with prior anti-CD38 therapy. Specifically, 40% of patients exposed to an anti-CD38 mAb had EMD, compared with 11% of patients who had not received an anti-CD38 mAb (P = .01).
“I don’t for a minute want to say that CD38-targeted therapy engenders extramedullary disease,” Dr. Richardson said. “I think what we can say, though, is that, once CD38 treatment fails a patient, extramedullary disease … is a very real challenge. Therefore, we need rationally targeted approaches, ideally in combination, to meet that challenge.”
The overall response rate was similar for EMD and non-EMD patients – 23% and 27%, respectively. The median duration of response was 3.4 months in the EMD patients and 4.4 months in the non-EMD group. The clinical benefit rate was 30% and 45%, respectively.
In the EMD group, the overall response rate was 19% in patients with soft-tissue EMD and 28% in bone-related EMD. None of the patients with CNS disease responded.
The median progression-free survival was 2.9 months for patients with EMD and 4.6 months for those without EMD. The median overall survival was 5.8 month and 11.6 months, respectively.
The median overall survival was 18.5 months in EMD responders and 17.2 months in non-EMD responders. The median overall survival was 5.1 months in EMD nonresponders and 8.5 months in non-EMD nonresponders.
In all, 54% of patients received subsequent therapy. There were no significant differences in outcomes between EMD and non-EMD patients.
The safety profiles were similar for EMD and non-EMD patients, Dr. Richardson said. Melflufen-dexamethasone was considered well tolerated overall, and there were no treatment-related deaths.
The most common treatment-emergent adverse events (grade 3 and 4, respectively) were thrombocytopenia (22% and 46%), neutropenia (32% and 35%), anemia (35% and 1%), white blood cell count decrease (10% and 7%), and pneumonia (7% and 1%).
This trial is sponsored by Oncopeptides. Dr. Richardson reported an advisory role and research funding from Oncopeptides.
SOURCE: Richardson PG et al. IMW 2019, Abstract OAB-086.
REPORTING FROM IMW 2019
VRD pretransplant induction deepens responses in myeloma
Pretransplant induction therapy with subcutaneous bortezomib, lenalidomide, and dexamethasone (VRD) deepened responses in patients with newly diagnosed multiple myeloma, according to an interim analysis of a phase 3 study.
Overall, the regimen was well tolerated, with a minimal number of patients discontinuing treatment because of treatment-emergent adverse events.
The ongoing, open-label, randomized, phase 3 study is designed to compare two transplant-conditioning regimens – intravenous busulfan plus melphalan versus melphalan – in patients who received VRD induction and consolidation, wrote Laura Rosiñol, MD, PhD, of the August Pi i Sunyer Biomedical Research Institute in Barcelona, and colleagues. The findings were published in Blood.
The PETHEMA/GEM2012 study included 458 patients with newly diagnosed multiple myeloma who were eligible for autologous stem cell transplantation. Study patients were previously untreated and aged younger than 65 years.
All patients received VRD induction, which consisted of subcutaneous bortezomib 1.3 mg/m2 on days 1, 4, 8, and 11 of each cycle; lenalidomide 25 mg/day on days 1-21; and dexamethasone 40 mg on days 1-4 and 9-12 at 4-week intervals for six cycles. Posttransplant consolidation consisted of two cycles of VRD.
The researchers conducted a grouped-response analysis of three different treatment phases: induction, transplant, and consolidation.
After analysis, the researchers found that responses deepened over the duration of treatment. In patients who started the sixth induction cycle, the response rates were 55.6%, 63.8%, 68.3%, and 70.4% after cycles 3, 4, 5, and post induction, respectively.
After six cycles of induction, the complete response rate was 33.4%, with a rate of undetectable minimal residual disease of 28.8%, which further increased at transplant (42.1%), and consolidation (45.2%).
With respect to safety, the most frequently reported grade 3 or higher treatment-emergent adverse events were neutropenia (12.9%) and infection (9.2%). The rate of grade 2 or higher peripheral neuropathy throughout induction was 17.0%, with lower rates of grade 3 (3.7%) and 4 (0.2%) toxicities.
“The regimen [used in the present study] has the highest lenalidomide and dexamethasone dose intensity per cycle and a lower bortezomib dose intensity per cycle than the 21-day regimens, which may offer high activity with low levels of toxicity, thereby enabling delivery of all planned induction cycles,” the researchers wrote, adding that “these results confirm that VRD is an effective pretransplant induction regimen and may be considered a new standard of care.”
The study was supported by Celgene, Janssen, Pierre Fabré, and the Instituto de Salud Carlos III. The authors reported financial affiliations with Celgene, Janssen, and several other companies.
SOURCE: Rosiñol L et al. Blood. 2019 Sep 4. doi: 10.1182/blood.2019000241.
Pretransplant induction therapy with subcutaneous bortezomib, lenalidomide, and dexamethasone (VRD) deepened responses in patients with newly diagnosed multiple myeloma, according to an interim analysis of a phase 3 study.
Overall, the regimen was well tolerated, with a minimal number of patients discontinuing treatment because of treatment-emergent adverse events.
The ongoing, open-label, randomized, phase 3 study is designed to compare two transplant-conditioning regimens – intravenous busulfan plus melphalan versus melphalan – in patients who received VRD induction and consolidation, wrote Laura Rosiñol, MD, PhD, of the August Pi i Sunyer Biomedical Research Institute in Barcelona, and colleagues. The findings were published in Blood.
The PETHEMA/GEM2012 study included 458 patients with newly diagnosed multiple myeloma who were eligible for autologous stem cell transplantation. Study patients were previously untreated and aged younger than 65 years.
All patients received VRD induction, which consisted of subcutaneous bortezomib 1.3 mg/m2 on days 1, 4, 8, and 11 of each cycle; lenalidomide 25 mg/day on days 1-21; and dexamethasone 40 mg on days 1-4 and 9-12 at 4-week intervals for six cycles. Posttransplant consolidation consisted of two cycles of VRD.
The researchers conducted a grouped-response analysis of three different treatment phases: induction, transplant, and consolidation.
After analysis, the researchers found that responses deepened over the duration of treatment. In patients who started the sixth induction cycle, the response rates were 55.6%, 63.8%, 68.3%, and 70.4% after cycles 3, 4, 5, and post induction, respectively.
After six cycles of induction, the complete response rate was 33.4%, with a rate of undetectable minimal residual disease of 28.8%, which further increased at transplant (42.1%), and consolidation (45.2%).
With respect to safety, the most frequently reported grade 3 or higher treatment-emergent adverse events were neutropenia (12.9%) and infection (9.2%). The rate of grade 2 or higher peripheral neuropathy throughout induction was 17.0%, with lower rates of grade 3 (3.7%) and 4 (0.2%) toxicities.
“The regimen [used in the present study] has the highest lenalidomide and dexamethasone dose intensity per cycle and a lower bortezomib dose intensity per cycle than the 21-day regimens, which may offer high activity with low levels of toxicity, thereby enabling delivery of all planned induction cycles,” the researchers wrote, adding that “these results confirm that VRD is an effective pretransplant induction regimen and may be considered a new standard of care.”
The study was supported by Celgene, Janssen, Pierre Fabré, and the Instituto de Salud Carlos III. The authors reported financial affiliations with Celgene, Janssen, and several other companies.
SOURCE: Rosiñol L et al. Blood. 2019 Sep 4. doi: 10.1182/blood.2019000241.
Pretransplant induction therapy with subcutaneous bortezomib, lenalidomide, and dexamethasone (VRD) deepened responses in patients with newly diagnosed multiple myeloma, according to an interim analysis of a phase 3 study.
Overall, the regimen was well tolerated, with a minimal number of patients discontinuing treatment because of treatment-emergent adverse events.
The ongoing, open-label, randomized, phase 3 study is designed to compare two transplant-conditioning regimens – intravenous busulfan plus melphalan versus melphalan – in patients who received VRD induction and consolidation, wrote Laura Rosiñol, MD, PhD, of the August Pi i Sunyer Biomedical Research Institute in Barcelona, and colleagues. The findings were published in Blood.
The PETHEMA/GEM2012 study included 458 patients with newly diagnosed multiple myeloma who were eligible for autologous stem cell transplantation. Study patients were previously untreated and aged younger than 65 years.
All patients received VRD induction, which consisted of subcutaneous bortezomib 1.3 mg/m2 on days 1, 4, 8, and 11 of each cycle; lenalidomide 25 mg/day on days 1-21; and dexamethasone 40 mg on days 1-4 and 9-12 at 4-week intervals for six cycles. Posttransplant consolidation consisted of two cycles of VRD.
The researchers conducted a grouped-response analysis of three different treatment phases: induction, transplant, and consolidation.
After analysis, the researchers found that responses deepened over the duration of treatment. In patients who started the sixth induction cycle, the response rates were 55.6%, 63.8%, 68.3%, and 70.4% after cycles 3, 4, 5, and post induction, respectively.
After six cycles of induction, the complete response rate was 33.4%, with a rate of undetectable minimal residual disease of 28.8%, which further increased at transplant (42.1%), and consolidation (45.2%).
With respect to safety, the most frequently reported grade 3 or higher treatment-emergent adverse events were neutropenia (12.9%) and infection (9.2%). The rate of grade 2 or higher peripheral neuropathy throughout induction was 17.0%, with lower rates of grade 3 (3.7%) and 4 (0.2%) toxicities.
“The regimen [used in the present study] has the highest lenalidomide and dexamethasone dose intensity per cycle and a lower bortezomib dose intensity per cycle than the 21-day regimens, which may offer high activity with low levels of toxicity, thereby enabling delivery of all planned induction cycles,” the researchers wrote, adding that “these results confirm that VRD is an effective pretransplant induction regimen and may be considered a new standard of care.”
The study was supported by Celgene, Janssen, Pierre Fabré, and the Instituto de Salud Carlos III. The authors reported financial affiliations with Celgene, Janssen, and several other companies.
SOURCE: Rosiñol L et al. Blood. 2019 Sep 4. doi: 10.1182/blood.2019000241.
FROM BLOOD
Progressive myeloma after induction? Go straight to transplant
Patients with multiple myeloma who don’t respond to induction therapy may be better off advancing straight to autologous stem cell therapy, rather than undergoing salvage therapy before transplant, according to findings of an analysis that included both real-world and clinical trial patients.
Joanna Blocka, MD, of the University Hospital of Heidelberg (Germany) and colleagues found similar progression-free and overall survival rates for patients who had progressive disease and underwent autologous stem cell therapy (ASCT), compared with patients who underwent salvage therapy and improved to at least stable disease before proceeding to transplant. The findings were published in Leukemia & Lymphoma.
The real-world analysis included 1,599 patients with multiple myeloma who had undergone ASCT between 1991 and 2016. More than half of the patients (58%) were not enrolled in clinical trials. The remainder were split between the German-Speaking Myeloma Multicenter Group (GMMG)-HD3 and GMMG-HD4 trials, which compared various induction regimens.
Just 23 patients in the analysis received salvage therapy because of progressive disease and deepened their response before ASCT. Of these patients, 12 received novel agents in induction therapy and 11 received older medications.
Looking across all 1,599 patients, 5.3% achieved complete remission before first ASCT. Most patients (71.8%) achieved partial remission, 9.7% had a minimal response, and 5.7% had stable disease. A group of 120 patients (7.5%) progressed between the last course of induction and ASCT.
The researchers compared the progression-free and overall survival rates of patients with progressive disease versus those who had stable disease or better before their first transplant. Both univariable and multivariable analysis showed no statistically significant differences in either survival outcome between the two groups.
In the multivariable analysis, there was a hazard ratio of 1.23 (95% confidence interval, 0.98-1.56) for progression-free survival for patients with progressive disease versus those who responded to induction therapy. Similarly, the HR for overall survival between the two groups was 1.24 (95% CI, 0.93-1.65).
The researchers also analyzed the groups based on whether they received novel or older agents during induction.
Patients with progressive disease who received novel agents had significantly worse progression-free survival (22.2 months), compared with patients who responded to treatment with novel agents (22.2 months vs. 29.1 months; P = .03). The same trend was seen with overall survival in these groups (54.4 months vs. 97.5 months; P less than .001).
Rates of survival were similar for patients with progressive disease and responders who had received older medications at induction.
“This might be explained by a prognostically disadvantageous disease biology in patients nonresponsive to novel agents,” the researchers wrote.
The researchers also compared survival outcomes for the 120 patients who underwent ASCT with progressive disease versus the 23 patients who received salvage therapy and improved their response to at least stable disease before transplant. Univariable analysis showed that salvage patients actually did worse than those with progressive disease who proceeded straight to transplant – 12.1 months versus 22.9 months of progression-free survival (P = .04) and 33.1 versus 69.5 months of overall survival (P = .08). But on multivariable analysis, there was no significant difference between the two groups for progression-free survival (HR, 0.71; 95% CI, 0.28-1.80; P = .5) or overall survival (HR, 0.77; 95% CI, 0.30-1.95; P = .6). The use of novel agents did not appear to affect the survival outcomes in these patients.
The worse outcomes seen among salvage patients observed in univariable analysis “might be due to a cumulative toxic effect of salvage therapy,” the researchers suggested. “An alternative explanation could be that the patients who were offered salvage therapy might have had more aggressive disease than those who did not undergo salvage therapy.”
Dr. Blocka reported having no relevant financial disclosures. Other coauthors reported relationships with Janssen, Amgen, Bristol-Myers Squibb, Celgene, and others.
SOURCE: Blocka J et al. Leuk Lymphoma. 2019 Aug 19. doi: 10.1080/10428194.2019.1646905.
Patients with multiple myeloma who don’t respond to induction therapy may be better off advancing straight to autologous stem cell therapy, rather than undergoing salvage therapy before transplant, according to findings of an analysis that included both real-world and clinical trial patients.
Joanna Blocka, MD, of the University Hospital of Heidelberg (Germany) and colleagues found similar progression-free and overall survival rates for patients who had progressive disease and underwent autologous stem cell therapy (ASCT), compared with patients who underwent salvage therapy and improved to at least stable disease before proceeding to transplant. The findings were published in Leukemia & Lymphoma.
The real-world analysis included 1,599 patients with multiple myeloma who had undergone ASCT between 1991 and 2016. More than half of the patients (58%) were not enrolled in clinical trials. The remainder were split between the German-Speaking Myeloma Multicenter Group (GMMG)-HD3 and GMMG-HD4 trials, which compared various induction regimens.
Just 23 patients in the analysis received salvage therapy because of progressive disease and deepened their response before ASCT. Of these patients, 12 received novel agents in induction therapy and 11 received older medications.
Looking across all 1,599 patients, 5.3% achieved complete remission before first ASCT. Most patients (71.8%) achieved partial remission, 9.7% had a minimal response, and 5.7% had stable disease. A group of 120 patients (7.5%) progressed between the last course of induction and ASCT.
The researchers compared the progression-free and overall survival rates of patients with progressive disease versus those who had stable disease or better before their first transplant. Both univariable and multivariable analysis showed no statistically significant differences in either survival outcome between the two groups.
In the multivariable analysis, there was a hazard ratio of 1.23 (95% confidence interval, 0.98-1.56) for progression-free survival for patients with progressive disease versus those who responded to induction therapy. Similarly, the HR for overall survival between the two groups was 1.24 (95% CI, 0.93-1.65).
The researchers also analyzed the groups based on whether they received novel or older agents during induction.
Patients with progressive disease who received novel agents had significantly worse progression-free survival (22.2 months), compared with patients who responded to treatment with novel agents (22.2 months vs. 29.1 months; P = .03). The same trend was seen with overall survival in these groups (54.4 months vs. 97.5 months; P less than .001).
Rates of survival were similar for patients with progressive disease and responders who had received older medications at induction.
“This might be explained by a prognostically disadvantageous disease biology in patients nonresponsive to novel agents,” the researchers wrote.
The researchers also compared survival outcomes for the 120 patients who underwent ASCT with progressive disease versus the 23 patients who received salvage therapy and improved their response to at least stable disease before transplant. Univariable analysis showed that salvage patients actually did worse than those with progressive disease who proceeded straight to transplant – 12.1 months versus 22.9 months of progression-free survival (P = .04) and 33.1 versus 69.5 months of overall survival (P = .08). But on multivariable analysis, there was no significant difference between the two groups for progression-free survival (HR, 0.71; 95% CI, 0.28-1.80; P = .5) or overall survival (HR, 0.77; 95% CI, 0.30-1.95; P = .6). The use of novel agents did not appear to affect the survival outcomes in these patients.
The worse outcomes seen among salvage patients observed in univariable analysis “might be due to a cumulative toxic effect of salvage therapy,” the researchers suggested. “An alternative explanation could be that the patients who were offered salvage therapy might have had more aggressive disease than those who did not undergo salvage therapy.”
Dr. Blocka reported having no relevant financial disclosures. Other coauthors reported relationships with Janssen, Amgen, Bristol-Myers Squibb, Celgene, and others.
SOURCE: Blocka J et al. Leuk Lymphoma. 2019 Aug 19. doi: 10.1080/10428194.2019.1646905.
Patients with multiple myeloma who don’t respond to induction therapy may be better off advancing straight to autologous stem cell therapy, rather than undergoing salvage therapy before transplant, according to findings of an analysis that included both real-world and clinical trial patients.
Joanna Blocka, MD, of the University Hospital of Heidelberg (Germany) and colleagues found similar progression-free and overall survival rates for patients who had progressive disease and underwent autologous stem cell therapy (ASCT), compared with patients who underwent salvage therapy and improved to at least stable disease before proceeding to transplant. The findings were published in Leukemia & Lymphoma.
The real-world analysis included 1,599 patients with multiple myeloma who had undergone ASCT between 1991 and 2016. More than half of the patients (58%) were not enrolled in clinical trials. The remainder were split between the German-Speaking Myeloma Multicenter Group (GMMG)-HD3 and GMMG-HD4 trials, which compared various induction regimens.
Just 23 patients in the analysis received salvage therapy because of progressive disease and deepened their response before ASCT. Of these patients, 12 received novel agents in induction therapy and 11 received older medications.
Looking across all 1,599 patients, 5.3% achieved complete remission before first ASCT. Most patients (71.8%) achieved partial remission, 9.7% had a minimal response, and 5.7% had stable disease. A group of 120 patients (7.5%) progressed between the last course of induction and ASCT.
The researchers compared the progression-free and overall survival rates of patients with progressive disease versus those who had stable disease or better before their first transplant. Both univariable and multivariable analysis showed no statistically significant differences in either survival outcome between the two groups.
In the multivariable analysis, there was a hazard ratio of 1.23 (95% confidence interval, 0.98-1.56) for progression-free survival for patients with progressive disease versus those who responded to induction therapy. Similarly, the HR for overall survival between the two groups was 1.24 (95% CI, 0.93-1.65).
The researchers also analyzed the groups based on whether they received novel or older agents during induction.
Patients with progressive disease who received novel agents had significantly worse progression-free survival (22.2 months), compared with patients who responded to treatment with novel agents (22.2 months vs. 29.1 months; P = .03). The same trend was seen with overall survival in these groups (54.4 months vs. 97.5 months; P less than .001).
Rates of survival were similar for patients with progressive disease and responders who had received older medications at induction.
“This might be explained by a prognostically disadvantageous disease biology in patients nonresponsive to novel agents,” the researchers wrote.
The researchers also compared survival outcomes for the 120 patients who underwent ASCT with progressive disease versus the 23 patients who received salvage therapy and improved their response to at least stable disease before transplant. Univariable analysis showed that salvage patients actually did worse than those with progressive disease who proceeded straight to transplant – 12.1 months versus 22.9 months of progression-free survival (P = .04) and 33.1 versus 69.5 months of overall survival (P = .08). But on multivariable analysis, there was no significant difference between the two groups for progression-free survival (HR, 0.71; 95% CI, 0.28-1.80; P = .5) or overall survival (HR, 0.77; 95% CI, 0.30-1.95; P = .6). The use of novel agents did not appear to affect the survival outcomes in these patients.
The worse outcomes seen among salvage patients observed in univariable analysis “might be due to a cumulative toxic effect of salvage therapy,” the researchers suggested. “An alternative explanation could be that the patients who were offered salvage therapy might have had more aggressive disease than those who did not undergo salvage therapy.”
Dr. Blocka reported having no relevant financial disclosures. Other coauthors reported relationships with Janssen, Amgen, Bristol-Myers Squibb, Celgene, and others.
SOURCE: Blocka J et al. Leuk Lymphoma. 2019 Aug 19. doi: 10.1080/10428194.2019.1646905.
FROM LEUKEMIA & LYMPHOMA
Key clinical point:
Major finding: There was no difference between patients with progressive disease who went straight to ASCT and patients who received salvage therapy, both in terms of progression-free survival (hazard ratio, 0.71; 95% confidence interval, 0.28-1.80; P = .5) and overall survival (HR, 0.77; 95% CI, 0.30-1.95; P = .6).
Study details: An analysis of 1,599 patients with multiple myeloma who underwent ASCT. A subanalysis compared 120 patients with progressive disease before ASCT with 23 patients who received salvage treatment before ASCT.
Disclosures: Dr. Blocka reported having no relevant financial disclosures. Other coauthors reported relationships with Janssen, Amgen, Bristol-Myers Squibb, Celgene, and others.
Source: Blocka J et al. Leuk Lymphoma. 2019 Aug 19. doi: 10.1080/10428194.2019.1646905.
Combo produces responses in triple-class refractory myeloma
Selinexor plus low-dose dexamethasone can produce responses in patients with triple-class refractory multiple myeloma, according to the phase 2 STORM trial.
The combination produced a response rate of 26% in patients who were refractory to at least one proteasome inhibitor, one immunomodulatory agent, and daratumumab.
The most common grade 3/4 adverse events in this trial were thrombocytopenia (59%), anemia (44%), hyponatremia (22%), and neutropenia (21%).
Ajai Chari, MD, of the Mount Sinai School of Medicine, New York, and colleagues reported these results in the New England Journal of Medicine.
The STORM trial included 123 patients with multiple myeloma who had previously received bortezomib, carfilzomib, lenalidomide, pomalidomide, daratumumab, and an alkylating agent. Their disease was refractory to at least one proteasome inhibitor, one immunomodulatory drug, and daratumumab.
The patients had received a median of 7 (range, 3-18) prior treatment regimens, and their median time since diagnosis was 6.6 years (range, 1.1-23.4 years). The median age at baseline was 65.2 years (range, 40-86 years), 58% of patients were men, and 53% had high-risk cytogenetics. In addition, 36% of patients had thrombocytopenia and 16% had neutropenia at baseline.
The patients received oral selinexor at 80 mg twice weekly plus dexamethasone at 20 mg twice weekly until disease progression, death, or discontinuation. Doses were modified in response to adverse events.
Results
In total, 96% of patients (118/123) discontinued treatment. The most common reasons for discontinuation were disease progression (n = 65) and adverse events (n = 38).
Of the 122 patients evaluable for efficacy, 26% achieved a partial response or better, and 39% had a minimal response or better. There were 24 partial responses, 16 minimal responses, 6 very good partial responses, and 2 stringent complete responses. Forty-eight patients had stable disease.
The median duration of response was 4.4 months, the median progression-free survival was 3.7 months, and the median overall survival was 8.6 months.
The median overall survival was 15.6 months in responders, 5.9 months in patients with stable disease, and 1.7 months in those who progressed.
All 123 patients were evaluable for safety, and 63% of them experienced serious adverse events. Pneumonia (11%) and sepsis (9%) were the most common serious events.
The most common treatment-emergent nonhematologic adverse events were fatigue (73%), nausea (72%), decreased appetite (56%), decreased weight (50%), diarrhea (46%), vomiting (38%), hyponatremia (37%), upper respiratory tract infection (23%), constipation (22%), and dyspnea (22%).
Treatment-emergent hematologic adverse events included thrombocytopenia (73%), anemia (67%), neutropenia (40%), leukopenia (33%), and lymphopenia (16%).
Eighty percent of patients had adverse events leading to dose modification or interruption. The most common of these were thrombocytopenia (43%), fatigue (16%), and neutropenia (11%).
“Because most patients involved in the study were older and frail, with limited end-organ reserve and at increased risk for adverse events, dose modifications were anticipated and were specified along with supportive care in the protocol,” the researchers wrote.
“The adverse events that were observed in the study were a function of dose, schedule, and baseline clinical characteristics (e.g., cytopenias). Thrombocytopenia … was reversible and was managed with dose interruptions and thrombopoietin-receptor agonists.”
There were 28 deaths on study, with 16 patients dying of disease progression and 12 dying from an adverse event. Two of the fatal adverse events were considered treatment related – sepsis in one patient and pneumonia with concurrent disease progression in another patient.
The researchers reported ties with Karyopharm Therapeutics, which sponsored the study, and many other companies.
SOURCE: Chari A et al. N Engl J Med 2019;381:727-38.
Selinexor plus low-dose dexamethasone can produce responses in patients with triple-class refractory multiple myeloma, according to the phase 2 STORM trial.
The combination produced a response rate of 26% in patients who were refractory to at least one proteasome inhibitor, one immunomodulatory agent, and daratumumab.
The most common grade 3/4 adverse events in this trial were thrombocytopenia (59%), anemia (44%), hyponatremia (22%), and neutropenia (21%).
Ajai Chari, MD, of the Mount Sinai School of Medicine, New York, and colleagues reported these results in the New England Journal of Medicine.
The STORM trial included 123 patients with multiple myeloma who had previously received bortezomib, carfilzomib, lenalidomide, pomalidomide, daratumumab, and an alkylating agent. Their disease was refractory to at least one proteasome inhibitor, one immunomodulatory drug, and daratumumab.
The patients had received a median of 7 (range, 3-18) prior treatment regimens, and their median time since diagnosis was 6.6 years (range, 1.1-23.4 years). The median age at baseline was 65.2 years (range, 40-86 years), 58% of patients were men, and 53% had high-risk cytogenetics. In addition, 36% of patients had thrombocytopenia and 16% had neutropenia at baseline.
The patients received oral selinexor at 80 mg twice weekly plus dexamethasone at 20 mg twice weekly until disease progression, death, or discontinuation. Doses were modified in response to adverse events.
Results
In total, 96% of patients (118/123) discontinued treatment. The most common reasons for discontinuation were disease progression (n = 65) and adverse events (n = 38).
Of the 122 patients evaluable for efficacy, 26% achieved a partial response or better, and 39% had a minimal response or better. There were 24 partial responses, 16 minimal responses, 6 very good partial responses, and 2 stringent complete responses. Forty-eight patients had stable disease.
The median duration of response was 4.4 months, the median progression-free survival was 3.7 months, and the median overall survival was 8.6 months.
The median overall survival was 15.6 months in responders, 5.9 months in patients with stable disease, and 1.7 months in those who progressed.
All 123 patients were evaluable for safety, and 63% of them experienced serious adverse events. Pneumonia (11%) and sepsis (9%) were the most common serious events.
The most common treatment-emergent nonhematologic adverse events were fatigue (73%), nausea (72%), decreased appetite (56%), decreased weight (50%), diarrhea (46%), vomiting (38%), hyponatremia (37%), upper respiratory tract infection (23%), constipation (22%), and dyspnea (22%).
Treatment-emergent hematologic adverse events included thrombocytopenia (73%), anemia (67%), neutropenia (40%), leukopenia (33%), and lymphopenia (16%).
Eighty percent of patients had adverse events leading to dose modification or interruption. The most common of these were thrombocytopenia (43%), fatigue (16%), and neutropenia (11%).
“Because most patients involved in the study were older and frail, with limited end-organ reserve and at increased risk for adverse events, dose modifications were anticipated and were specified along with supportive care in the protocol,” the researchers wrote.
“The adverse events that were observed in the study were a function of dose, schedule, and baseline clinical characteristics (e.g., cytopenias). Thrombocytopenia … was reversible and was managed with dose interruptions and thrombopoietin-receptor agonists.”
There were 28 deaths on study, with 16 patients dying of disease progression and 12 dying from an adverse event. Two of the fatal adverse events were considered treatment related – sepsis in one patient and pneumonia with concurrent disease progression in another patient.
The researchers reported ties with Karyopharm Therapeutics, which sponsored the study, and many other companies.
SOURCE: Chari A et al. N Engl J Med 2019;381:727-38.
Selinexor plus low-dose dexamethasone can produce responses in patients with triple-class refractory multiple myeloma, according to the phase 2 STORM trial.
The combination produced a response rate of 26% in patients who were refractory to at least one proteasome inhibitor, one immunomodulatory agent, and daratumumab.
The most common grade 3/4 adverse events in this trial were thrombocytopenia (59%), anemia (44%), hyponatremia (22%), and neutropenia (21%).
Ajai Chari, MD, of the Mount Sinai School of Medicine, New York, and colleagues reported these results in the New England Journal of Medicine.
The STORM trial included 123 patients with multiple myeloma who had previously received bortezomib, carfilzomib, lenalidomide, pomalidomide, daratumumab, and an alkylating agent. Their disease was refractory to at least one proteasome inhibitor, one immunomodulatory drug, and daratumumab.
The patients had received a median of 7 (range, 3-18) prior treatment regimens, and their median time since diagnosis was 6.6 years (range, 1.1-23.4 years). The median age at baseline was 65.2 years (range, 40-86 years), 58% of patients were men, and 53% had high-risk cytogenetics. In addition, 36% of patients had thrombocytopenia and 16% had neutropenia at baseline.
The patients received oral selinexor at 80 mg twice weekly plus dexamethasone at 20 mg twice weekly until disease progression, death, or discontinuation. Doses were modified in response to adverse events.
Results
In total, 96% of patients (118/123) discontinued treatment. The most common reasons for discontinuation were disease progression (n = 65) and adverse events (n = 38).
Of the 122 patients evaluable for efficacy, 26% achieved a partial response or better, and 39% had a minimal response or better. There were 24 partial responses, 16 minimal responses, 6 very good partial responses, and 2 stringent complete responses. Forty-eight patients had stable disease.
The median duration of response was 4.4 months, the median progression-free survival was 3.7 months, and the median overall survival was 8.6 months.
The median overall survival was 15.6 months in responders, 5.9 months in patients with stable disease, and 1.7 months in those who progressed.
All 123 patients were evaluable for safety, and 63% of them experienced serious adverse events. Pneumonia (11%) and sepsis (9%) were the most common serious events.
The most common treatment-emergent nonhematologic adverse events were fatigue (73%), nausea (72%), decreased appetite (56%), decreased weight (50%), diarrhea (46%), vomiting (38%), hyponatremia (37%), upper respiratory tract infection (23%), constipation (22%), and dyspnea (22%).
Treatment-emergent hematologic adverse events included thrombocytopenia (73%), anemia (67%), neutropenia (40%), leukopenia (33%), and lymphopenia (16%).
Eighty percent of patients had adverse events leading to dose modification or interruption. The most common of these were thrombocytopenia (43%), fatigue (16%), and neutropenia (11%).
“Because most patients involved in the study were older and frail, with limited end-organ reserve and at increased risk for adverse events, dose modifications were anticipated and were specified along with supportive care in the protocol,” the researchers wrote.
“The adverse events that were observed in the study were a function of dose, schedule, and baseline clinical characteristics (e.g., cytopenias). Thrombocytopenia … was reversible and was managed with dose interruptions and thrombopoietin-receptor agonists.”
There were 28 deaths on study, with 16 patients dying of disease progression and 12 dying from an adverse event. Two of the fatal adverse events were considered treatment related – sepsis in one patient and pneumonia with concurrent disease progression in another patient.
The researchers reported ties with Karyopharm Therapeutics, which sponsored the study, and many other companies.
SOURCE: Chari A et al. N Engl J Med 2019;381:727-38.
FROM NEW ENGLAND JOURNAL OF MEDICINE
Key clinical point:
Major finding: The response rate was 26%, which included 24 partial responses, 6 very good partial responses, and 2 stringent complete responses.
Study details: A phase 2 trial of 123 patients with multiple myeloma refractory to at least one proteasome inhibitor, one immunomodulatory drug, and daratumumab (triple-class refractory).
Disclosures: The researchers reported ties with Karyopharm Therapeutics, which sponsored the study, and many other companies.
Source: Chari A et al. N Engl J Med 2019;381:727-38.
Cardiovascular complications most common with carfilzomib in relapsed myeloma
Cardiovascular (CV) adverse events were common in patients receiving proteasome inhibitor therapy for relapsed multiple myeloma, especially with carfilzomib-based therapy, according to results from the PROTECT study.
While prior studies have shown an increased risk for CV toxicities with proteasome inhibitor therapy, detailed descriptions of the events and risk factors have been lacking. “Furthermore, there is no validated protocol to help determine which patients are at highest risk of CV toxicity during therapy, nor is there management guidance for patients who experience a [CV adverse event],” wrote Robert F. Cornell, MD, of Vanderbilt University, Nashville, Tenn., and colleagues in the Journal of Clinical Oncology.
The PROTECT (Prospective Observation of Cardiac Safety with Proteasome Inhibitor) study was conducted at Vanderbilt University Medical Center and the University of Pennsylvania Abramson Cancer Center, Philadelphia, between September 2015 and March 2018.
Researchers followed 95 patients with relapsed multiple myeloma who were treated with either bortezomib or carfilzomib for a total duration of 18 months. A total of 65 patients received a carfilzomib-based therapy and 30 patients received a bortezomib-based therapy.
Study patients received a CV assessment at baseline and at the beginning of each treatment cycle for the initial six cycles of proteasome inhibitor therapy. Subsequently, patients were monitored for the development of CV adverse events. CV assessments included ECG, echocardiography, and measurement of other cardiac biomarkers, such as NTproBNP and troponin I or T.
CV toxicities were reported among 5 patients (16.7%) of patients treated with bortezomib and 33 patients (50.7%) treated with carfilzomib (P = .005).
In total, there were 64 CV adverse events reported, most of which were grade 2 or 3, and 56 of which occurred while on carfilzomib-based therapy. For carfilzomib, the most common complications were heart failure (23 cases), followed by grade 3 or 4 hypertension (13 cases). Cardiac chest pain, atrial fibrillation, and acute coronary syndrome were reported in fewer cases.
The researchers also found that elevated natriuretic peptides that occurred before starting carfilzomib therapy or within the first 3 weeks of carfilzomib therapy were associated with a substantially higher risk of CV adverse events.
Patients who have multiple CV risk factors, and especially patients with a history of CV complications and elevated baseline natriuretic peptides, should be referred for a comprehensive cardiac evaluation, the researchers advised. “Such patients are at highest risk of CV [adverse events] with carfilzomib-based therapy, and optimization of CV therapy seems to improve overall care, allow continuation of potentially lifesaving cancer treatment, and affect severity or development of CV [adverse events],” they wrote.
A key limitation of the study was the lack of standardized treatment regimens. As a result, there was a broad dosing range for carfilzomib, in comparison to bortezomib.
Some authors reported financial relationships with carfilzomib maker Amgen and bortezomib maker Takeda, as well as with other companies.
SOURCE: Cornell RF et al. J Clin Oncol. 2019 Jun 12. doi: 10.1200/JCO.19.00231.
Cardiovascular (CV) adverse events were common in patients receiving proteasome inhibitor therapy for relapsed multiple myeloma, especially with carfilzomib-based therapy, according to results from the PROTECT study.
While prior studies have shown an increased risk for CV toxicities with proteasome inhibitor therapy, detailed descriptions of the events and risk factors have been lacking. “Furthermore, there is no validated protocol to help determine which patients are at highest risk of CV toxicity during therapy, nor is there management guidance for patients who experience a [CV adverse event],” wrote Robert F. Cornell, MD, of Vanderbilt University, Nashville, Tenn., and colleagues in the Journal of Clinical Oncology.
The PROTECT (Prospective Observation of Cardiac Safety with Proteasome Inhibitor) study was conducted at Vanderbilt University Medical Center and the University of Pennsylvania Abramson Cancer Center, Philadelphia, between September 2015 and March 2018.
Researchers followed 95 patients with relapsed multiple myeloma who were treated with either bortezomib or carfilzomib for a total duration of 18 months. A total of 65 patients received a carfilzomib-based therapy and 30 patients received a bortezomib-based therapy.
Study patients received a CV assessment at baseline and at the beginning of each treatment cycle for the initial six cycles of proteasome inhibitor therapy. Subsequently, patients were monitored for the development of CV adverse events. CV assessments included ECG, echocardiography, and measurement of other cardiac biomarkers, such as NTproBNP and troponin I or T.
CV toxicities were reported among 5 patients (16.7%) of patients treated with bortezomib and 33 patients (50.7%) treated with carfilzomib (P = .005).
In total, there were 64 CV adverse events reported, most of which were grade 2 or 3, and 56 of which occurred while on carfilzomib-based therapy. For carfilzomib, the most common complications were heart failure (23 cases), followed by grade 3 or 4 hypertension (13 cases). Cardiac chest pain, atrial fibrillation, and acute coronary syndrome were reported in fewer cases.
The researchers also found that elevated natriuretic peptides that occurred before starting carfilzomib therapy or within the first 3 weeks of carfilzomib therapy were associated with a substantially higher risk of CV adverse events.
Patients who have multiple CV risk factors, and especially patients with a history of CV complications and elevated baseline natriuretic peptides, should be referred for a comprehensive cardiac evaluation, the researchers advised. “Such patients are at highest risk of CV [adverse events] with carfilzomib-based therapy, and optimization of CV therapy seems to improve overall care, allow continuation of potentially lifesaving cancer treatment, and affect severity or development of CV [adverse events],” they wrote.
A key limitation of the study was the lack of standardized treatment regimens. As a result, there was a broad dosing range for carfilzomib, in comparison to bortezomib.
Some authors reported financial relationships with carfilzomib maker Amgen and bortezomib maker Takeda, as well as with other companies.
SOURCE: Cornell RF et al. J Clin Oncol. 2019 Jun 12. doi: 10.1200/JCO.19.00231.
Cardiovascular (CV) adverse events were common in patients receiving proteasome inhibitor therapy for relapsed multiple myeloma, especially with carfilzomib-based therapy, according to results from the PROTECT study.
While prior studies have shown an increased risk for CV toxicities with proteasome inhibitor therapy, detailed descriptions of the events and risk factors have been lacking. “Furthermore, there is no validated protocol to help determine which patients are at highest risk of CV toxicity during therapy, nor is there management guidance for patients who experience a [CV adverse event],” wrote Robert F. Cornell, MD, of Vanderbilt University, Nashville, Tenn., and colleagues in the Journal of Clinical Oncology.
The PROTECT (Prospective Observation of Cardiac Safety with Proteasome Inhibitor) study was conducted at Vanderbilt University Medical Center and the University of Pennsylvania Abramson Cancer Center, Philadelphia, between September 2015 and March 2018.
Researchers followed 95 patients with relapsed multiple myeloma who were treated with either bortezomib or carfilzomib for a total duration of 18 months. A total of 65 patients received a carfilzomib-based therapy and 30 patients received a bortezomib-based therapy.
Study patients received a CV assessment at baseline and at the beginning of each treatment cycle for the initial six cycles of proteasome inhibitor therapy. Subsequently, patients were monitored for the development of CV adverse events. CV assessments included ECG, echocardiography, and measurement of other cardiac biomarkers, such as NTproBNP and troponin I or T.
CV toxicities were reported among 5 patients (16.7%) of patients treated with bortezomib and 33 patients (50.7%) treated with carfilzomib (P = .005).
In total, there were 64 CV adverse events reported, most of which were grade 2 or 3, and 56 of which occurred while on carfilzomib-based therapy. For carfilzomib, the most common complications were heart failure (23 cases), followed by grade 3 or 4 hypertension (13 cases). Cardiac chest pain, atrial fibrillation, and acute coronary syndrome were reported in fewer cases.
The researchers also found that elevated natriuretic peptides that occurred before starting carfilzomib therapy or within the first 3 weeks of carfilzomib therapy were associated with a substantially higher risk of CV adverse events.
Patients who have multiple CV risk factors, and especially patients with a history of CV complications and elevated baseline natriuretic peptides, should be referred for a comprehensive cardiac evaluation, the researchers advised. “Such patients are at highest risk of CV [adverse events] with carfilzomib-based therapy, and optimization of CV therapy seems to improve overall care, allow continuation of potentially lifesaving cancer treatment, and affect severity or development of CV [adverse events],” they wrote.
A key limitation of the study was the lack of standardized treatment regimens. As a result, there was a broad dosing range for carfilzomib, in comparison to bortezomib.
Some authors reported financial relationships with carfilzomib maker Amgen and bortezomib maker Takeda, as well as with other companies.
SOURCE: Cornell RF et al. J Clin Oncol. 2019 Jun 12. doi: 10.1200/JCO.19.00231.
FROM THE JOURNAL OF CLINICAL ONCOLOGY
TP53 double hit predicts aggressive myeloma
Relapsed multiple myeloma becomes increasingly aggressive and difficult to treat with each additional TP53 alteration, according to investigators.
Findings from the study help illuminate the mechanics of myeloma disease progression and demonstrate the value of clonal competition assays, reported lead author Umair Munawar of the University Hospital Würzburg (Germany) and colleagues.
“The implications of mono-allelic TP53 lesions for the clinical outcome remain controversial, but clonal selection and evolution is a common feature of myeloma progression, and patients with TP53 wild-type or mono-allelic inactivation may present a double hit on relapse,” the investigators wrote in Blood. “Here, we addressed the hypothesis that sequential acquisition of TP53 hits lead to a gain of proliferative fitness of [multiple myeloma] cancer cells, inducing the expansion and domination of the affected clones within the patient’s bone marrow.”
The investigators used sleeping beauty and CRISPR/Cas9 techniques to create double- and single-hit multiple myeloma cell lines that were stably transfected with fluorescent proteins. By observing coculture pairings of wild-type, single-hit, and double-hit cells, the investigators found a hierarchy of proliferation that depended on the number of TP53 alterations. For instance, when double-hit cells were cocultured with wild-type cells in a 1:3 ratio, it took 21 days for the double-hit cells to reach 50% of the total culture population. Similarly, single-hit cells outcompeted wild-type cells after 38 days, while double-hit cells took 35 days to overcome the single-hit population.
Further testing showed that comparatively smaller initial populations of TP53-aberrant cells required longer to outcompete larger wild-type populations, which could explain why deeper responses in the clinic are often followed by longer periods without disease progression, the investigators suggested.
A comparison of transcriptomes between wild-type cells and TP53 mutants revealed differences in about 900 genes, including 14 signaling pathways. Specifically, downregulation impacted antigen processing and presentation, chemokine signaling, and oxidative phosphorylation.
“These differences on the transcriptomic level well reflect the biology of ultra–high risk disease,” the investigators wrote, referring to increased glucose uptake on PET, resistance to immunotherapies, and extramedullary disease.
“[This study] underscores the power of clonal competition assays to decipher the effect of genomic lesions in tumors to better understand their impact on progression and disease relapse in [multiple myeloma],” the investigators concluded.
The study was funded by Deutsche Forschungsgemeinschaft, the CDW Stiftung, and the IZKF Würzburg. The investigators reported additional support from the CRIS foundation, the German Cancer Aid, and the University of Würzburg.
SOURCE: Munawar U et al. Blood. 2019 Jul 24. doi: 10.1182/blood.2019000080.
Relapsed multiple myeloma becomes increasingly aggressive and difficult to treat with each additional TP53 alteration, according to investigators.
Findings from the study help illuminate the mechanics of myeloma disease progression and demonstrate the value of clonal competition assays, reported lead author Umair Munawar of the University Hospital Würzburg (Germany) and colleagues.
“The implications of mono-allelic TP53 lesions for the clinical outcome remain controversial, but clonal selection and evolution is a common feature of myeloma progression, and patients with TP53 wild-type or mono-allelic inactivation may present a double hit on relapse,” the investigators wrote in Blood. “Here, we addressed the hypothesis that sequential acquisition of TP53 hits lead to a gain of proliferative fitness of [multiple myeloma] cancer cells, inducing the expansion and domination of the affected clones within the patient’s bone marrow.”
The investigators used sleeping beauty and CRISPR/Cas9 techniques to create double- and single-hit multiple myeloma cell lines that were stably transfected with fluorescent proteins. By observing coculture pairings of wild-type, single-hit, and double-hit cells, the investigators found a hierarchy of proliferation that depended on the number of TP53 alterations. For instance, when double-hit cells were cocultured with wild-type cells in a 1:3 ratio, it took 21 days for the double-hit cells to reach 50% of the total culture population. Similarly, single-hit cells outcompeted wild-type cells after 38 days, while double-hit cells took 35 days to overcome the single-hit population.
Further testing showed that comparatively smaller initial populations of TP53-aberrant cells required longer to outcompete larger wild-type populations, which could explain why deeper responses in the clinic are often followed by longer periods without disease progression, the investigators suggested.
A comparison of transcriptomes between wild-type cells and TP53 mutants revealed differences in about 900 genes, including 14 signaling pathways. Specifically, downregulation impacted antigen processing and presentation, chemokine signaling, and oxidative phosphorylation.
“These differences on the transcriptomic level well reflect the biology of ultra–high risk disease,” the investigators wrote, referring to increased glucose uptake on PET, resistance to immunotherapies, and extramedullary disease.
“[This study] underscores the power of clonal competition assays to decipher the effect of genomic lesions in tumors to better understand their impact on progression and disease relapse in [multiple myeloma],” the investigators concluded.
The study was funded by Deutsche Forschungsgemeinschaft, the CDW Stiftung, and the IZKF Würzburg. The investigators reported additional support from the CRIS foundation, the German Cancer Aid, and the University of Würzburg.
SOURCE: Munawar U et al. Blood. 2019 Jul 24. doi: 10.1182/blood.2019000080.
Relapsed multiple myeloma becomes increasingly aggressive and difficult to treat with each additional TP53 alteration, according to investigators.
Findings from the study help illuminate the mechanics of myeloma disease progression and demonstrate the value of clonal competition assays, reported lead author Umair Munawar of the University Hospital Würzburg (Germany) and colleagues.
“The implications of mono-allelic TP53 lesions for the clinical outcome remain controversial, but clonal selection and evolution is a common feature of myeloma progression, and patients with TP53 wild-type or mono-allelic inactivation may present a double hit on relapse,” the investigators wrote in Blood. “Here, we addressed the hypothesis that sequential acquisition of TP53 hits lead to a gain of proliferative fitness of [multiple myeloma] cancer cells, inducing the expansion and domination of the affected clones within the patient’s bone marrow.”
The investigators used sleeping beauty and CRISPR/Cas9 techniques to create double- and single-hit multiple myeloma cell lines that were stably transfected with fluorescent proteins. By observing coculture pairings of wild-type, single-hit, and double-hit cells, the investigators found a hierarchy of proliferation that depended on the number of TP53 alterations. For instance, when double-hit cells were cocultured with wild-type cells in a 1:3 ratio, it took 21 days for the double-hit cells to reach 50% of the total culture population. Similarly, single-hit cells outcompeted wild-type cells after 38 days, while double-hit cells took 35 days to overcome the single-hit population.
Further testing showed that comparatively smaller initial populations of TP53-aberrant cells required longer to outcompete larger wild-type populations, which could explain why deeper responses in the clinic are often followed by longer periods without disease progression, the investigators suggested.
A comparison of transcriptomes between wild-type cells and TP53 mutants revealed differences in about 900 genes, including 14 signaling pathways. Specifically, downregulation impacted antigen processing and presentation, chemokine signaling, and oxidative phosphorylation.
“These differences on the transcriptomic level well reflect the biology of ultra–high risk disease,” the investigators wrote, referring to increased glucose uptake on PET, resistance to immunotherapies, and extramedullary disease.
“[This study] underscores the power of clonal competition assays to decipher the effect of genomic lesions in tumors to better understand their impact on progression and disease relapse in [multiple myeloma],” the investigators concluded.
The study was funded by Deutsche Forschungsgemeinschaft, the CDW Stiftung, and the IZKF Würzburg. The investigators reported additional support from the CRIS foundation, the German Cancer Aid, and the University of Würzburg.
SOURCE: Munawar U et al. Blood. 2019 Jul 24. doi: 10.1182/blood.2019000080.
FROM BLOOD
Potential improvements in convenience, tolerability of hematologic treatment
In this edition of “How I will treat my next patient,” I highlight two recent presentations regarding potential improvements in the convenience and tolerability of treatment for two hematologic malignancies: multiple myeloma and chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL).
SC-Dara in myeloma
At the 2019 annual meeting of the American Society of Clinical Oncology, Maria-Victoria Mateos, MD, PhD, and colleagues, reported the results of COLUMBA, a phase 3 evaluation in 522 patients with multiple myeloma who were randomized to subcutaneous daratumumab (SC-Dara) or standard intravenous infusions of daratumumab (IV-Dara). A previous phase 1b study (Blood. 2017;130:838) had suggested comparable efficacy from the more convenient SC regime. Whereas conventional infusions of IV-Dara (16 mg/kg) take several hours, the SC formulation (1,800 mg–flat dose) is delivered in minutes. In COLUMBA, patients were randomized between SC- and IV-Dara weekly (cycles 1-2), then every 2 weeks (cycles 3-6), then every 4 weeks until disease progression.
Among the IV-Dara patients, the median duration of the first infusion was 421 minutes in cycle 1, 255 minutes in cycle 2, and 205 minutes in subsequent cycles – compatible with standard practice in the United States. As reported, at a median follow-up of 7.46 months, the efficacy (overall response rate, complete response rate, stringent-complete response rate, very good-partial response rate, progression-free survival, and 6-month overall survival) and safety profile were non-inferior for SC-Dara. SC-Dara patients also reported higher satisfaction with therapy.
What this means in practice
It is always a good idea to await publication of the manuscript because there may be study details and statistical nuances that make SC-Dara appear better than it will prove to be. For example, patient characteristics were slightly different between the two arms. Peer review of the final manuscript could be important in placing these results in context.
However, for treatments that demand frequent office visits over many months, reducing treatment burden for patients has value. Based on COLUMBA, it appears likely that SC-Dara will be a major convenience for patients, without obvious drawbacks in efficacy or toxicity. Meanwhile, flat dosing will be a time-saver for physicians, nursing, and pharmacy staff. If the price of the SC formulation is not exorbitant, I would expect a “win-win” that will support converting from IV- to SC-Dara as standard practice.
Acalabrutinib in CLL/SLL
Preclinical studies have shown acalabrutinib (Acala) to be more selective for Bruton’s tyrosine kinase (BTK) than the first-in-class agent ibrutinib, with less off-target kinase inhibition. As reported at the 2019 annual congress of the European Hematology Association by Paolo Ghia, MD, PhD, and colleagues in the phase 3 ASCEND trial, 310 patients with previously treated CLL were randomized between oral Acala twice daily and treatment of physician’s choice (TPC) – either idelalisib plus rituximab (maximum of seven infusions) or bendamustine plus rituximab (maximum of six cycles).
Progression-free survival was the primary endpoint. At a median of 16.1 months, progression-free survival had not been reached for Acala, in comparison with 16.5 months for TPC. Significant benefit of Acala was observed in all prognostic subsets.
Although there was no difference in overall survival at a median follow-up of about 16 months, 85% of Acala patients had a response lasting at least 12 months, compared with 60% of TPC patients. Adverse events of any grade occurred in 94% of patients treated with Acala, with 45% being grade 3-4 toxicities and six treatment-related deaths.
What this means in practice
The vast majority of CLL/SLL patients will relapse after primary therapy and will require further treatment, so the progression-free survival improvement associated with Acala in ASCEND is eye-catching. However, there are important considerations that demand closer scrutiny.
With oral agents administered until progression or unacceptable toxicity, low-grade toxicities can influence patient adherence, quality of life, and potentially the need for dose reduction or treatment interruptions. Regimens of finite duration and easy adherence monitoring may be, on balance, preferred by patients and providers – especially if the oral agent can be given in later-line with comparable overall survival.
With ibrutinib (Blood. 2017;129:2612-5), Paul M. Barr, MD, and colleagues demonstrated that higher dose intensity was associated with improved progression-free survival and that holds were associated with worsened progression-free survival. Acala’s promise of high efficacy and lower off-target toxicity will be solidified if the large (more than 500 patients) phase 3 ACE-CL-006 study (Acala vs. ibrutinib) demonstrates its relative benefit from efficacy, toxicity, and adherence perspectives, in comparison with a standard therapy that similarly demands adherence until disease progression or unacceptable toxicity.
Dr. Lyss has been a community-based medical oncologist and clinical researcher for more than 35 years, practicing in St. Louis. His clinical and research interests are in the prevention, diagnosis, and treatment of breast and lung cancers and in expanding access to clinical trials to medically underserved populations.
In this edition of “How I will treat my next patient,” I highlight two recent presentations regarding potential improvements in the convenience and tolerability of treatment for two hematologic malignancies: multiple myeloma and chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL).
SC-Dara in myeloma
At the 2019 annual meeting of the American Society of Clinical Oncology, Maria-Victoria Mateos, MD, PhD, and colleagues, reported the results of COLUMBA, a phase 3 evaluation in 522 patients with multiple myeloma who were randomized to subcutaneous daratumumab (SC-Dara) or standard intravenous infusions of daratumumab (IV-Dara). A previous phase 1b study (Blood. 2017;130:838) had suggested comparable efficacy from the more convenient SC regime. Whereas conventional infusions of IV-Dara (16 mg/kg) take several hours, the SC formulation (1,800 mg–flat dose) is delivered in minutes. In COLUMBA, patients were randomized between SC- and IV-Dara weekly (cycles 1-2), then every 2 weeks (cycles 3-6), then every 4 weeks until disease progression.
Among the IV-Dara patients, the median duration of the first infusion was 421 minutes in cycle 1, 255 minutes in cycle 2, and 205 minutes in subsequent cycles – compatible with standard practice in the United States. As reported, at a median follow-up of 7.46 months, the efficacy (overall response rate, complete response rate, stringent-complete response rate, very good-partial response rate, progression-free survival, and 6-month overall survival) and safety profile were non-inferior for SC-Dara. SC-Dara patients also reported higher satisfaction with therapy.
What this means in practice
It is always a good idea to await publication of the manuscript because there may be study details and statistical nuances that make SC-Dara appear better than it will prove to be. For example, patient characteristics were slightly different between the two arms. Peer review of the final manuscript could be important in placing these results in context.
However, for treatments that demand frequent office visits over many months, reducing treatment burden for patients has value. Based on COLUMBA, it appears likely that SC-Dara will be a major convenience for patients, without obvious drawbacks in efficacy or toxicity. Meanwhile, flat dosing will be a time-saver for physicians, nursing, and pharmacy staff. If the price of the SC formulation is not exorbitant, I would expect a “win-win” that will support converting from IV- to SC-Dara as standard practice.
Acalabrutinib in CLL/SLL
Preclinical studies have shown acalabrutinib (Acala) to be more selective for Bruton’s tyrosine kinase (BTK) than the first-in-class agent ibrutinib, with less off-target kinase inhibition. As reported at the 2019 annual congress of the European Hematology Association by Paolo Ghia, MD, PhD, and colleagues in the phase 3 ASCEND trial, 310 patients with previously treated CLL were randomized between oral Acala twice daily and treatment of physician’s choice (TPC) – either idelalisib plus rituximab (maximum of seven infusions) or bendamustine plus rituximab (maximum of six cycles).
Progression-free survival was the primary endpoint. At a median of 16.1 months, progression-free survival had not been reached for Acala, in comparison with 16.5 months for TPC. Significant benefit of Acala was observed in all prognostic subsets.
Although there was no difference in overall survival at a median follow-up of about 16 months, 85% of Acala patients had a response lasting at least 12 months, compared with 60% of TPC patients. Adverse events of any grade occurred in 94% of patients treated with Acala, with 45% being grade 3-4 toxicities and six treatment-related deaths.
What this means in practice
The vast majority of CLL/SLL patients will relapse after primary therapy and will require further treatment, so the progression-free survival improvement associated with Acala in ASCEND is eye-catching. However, there are important considerations that demand closer scrutiny.
With oral agents administered until progression or unacceptable toxicity, low-grade toxicities can influence patient adherence, quality of life, and potentially the need for dose reduction or treatment interruptions. Regimens of finite duration and easy adherence monitoring may be, on balance, preferred by patients and providers – especially if the oral agent can be given in later-line with comparable overall survival.
With ibrutinib (Blood. 2017;129:2612-5), Paul M. Barr, MD, and colleagues demonstrated that higher dose intensity was associated with improved progression-free survival and that holds were associated with worsened progression-free survival. Acala’s promise of high efficacy and lower off-target toxicity will be solidified if the large (more than 500 patients) phase 3 ACE-CL-006 study (Acala vs. ibrutinib) demonstrates its relative benefit from efficacy, toxicity, and adherence perspectives, in comparison with a standard therapy that similarly demands adherence until disease progression or unacceptable toxicity.
Dr. Lyss has been a community-based medical oncologist and clinical researcher for more than 35 years, practicing in St. Louis. His clinical and research interests are in the prevention, diagnosis, and treatment of breast and lung cancers and in expanding access to clinical trials to medically underserved populations.
In this edition of “How I will treat my next patient,” I highlight two recent presentations regarding potential improvements in the convenience and tolerability of treatment for two hematologic malignancies: multiple myeloma and chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL).
SC-Dara in myeloma
At the 2019 annual meeting of the American Society of Clinical Oncology, Maria-Victoria Mateos, MD, PhD, and colleagues, reported the results of COLUMBA, a phase 3 evaluation in 522 patients with multiple myeloma who were randomized to subcutaneous daratumumab (SC-Dara) or standard intravenous infusions of daratumumab (IV-Dara). A previous phase 1b study (Blood. 2017;130:838) had suggested comparable efficacy from the more convenient SC regime. Whereas conventional infusions of IV-Dara (16 mg/kg) take several hours, the SC formulation (1,800 mg–flat dose) is delivered in minutes. In COLUMBA, patients were randomized between SC- and IV-Dara weekly (cycles 1-2), then every 2 weeks (cycles 3-6), then every 4 weeks until disease progression.
Among the IV-Dara patients, the median duration of the first infusion was 421 minutes in cycle 1, 255 minutes in cycle 2, and 205 minutes in subsequent cycles – compatible with standard practice in the United States. As reported, at a median follow-up of 7.46 months, the efficacy (overall response rate, complete response rate, stringent-complete response rate, very good-partial response rate, progression-free survival, and 6-month overall survival) and safety profile were non-inferior for SC-Dara. SC-Dara patients also reported higher satisfaction with therapy.
What this means in practice
It is always a good idea to await publication of the manuscript because there may be study details and statistical nuances that make SC-Dara appear better than it will prove to be. For example, patient characteristics were slightly different between the two arms. Peer review of the final manuscript could be important in placing these results in context.
However, for treatments that demand frequent office visits over many months, reducing treatment burden for patients has value. Based on COLUMBA, it appears likely that SC-Dara will be a major convenience for patients, without obvious drawbacks in efficacy or toxicity. Meanwhile, flat dosing will be a time-saver for physicians, nursing, and pharmacy staff. If the price of the SC formulation is not exorbitant, I would expect a “win-win” that will support converting from IV- to SC-Dara as standard practice.
Acalabrutinib in CLL/SLL
Preclinical studies have shown acalabrutinib (Acala) to be more selective for Bruton’s tyrosine kinase (BTK) than the first-in-class agent ibrutinib, with less off-target kinase inhibition. As reported at the 2019 annual congress of the European Hematology Association by Paolo Ghia, MD, PhD, and colleagues in the phase 3 ASCEND trial, 310 patients with previously treated CLL were randomized between oral Acala twice daily and treatment of physician’s choice (TPC) – either idelalisib plus rituximab (maximum of seven infusions) or bendamustine plus rituximab (maximum of six cycles).
Progression-free survival was the primary endpoint. At a median of 16.1 months, progression-free survival had not been reached for Acala, in comparison with 16.5 months for TPC. Significant benefit of Acala was observed in all prognostic subsets.
Although there was no difference in overall survival at a median follow-up of about 16 months, 85% of Acala patients had a response lasting at least 12 months, compared with 60% of TPC patients. Adverse events of any grade occurred in 94% of patients treated with Acala, with 45% being grade 3-4 toxicities and six treatment-related deaths.
What this means in practice
The vast majority of CLL/SLL patients will relapse after primary therapy and will require further treatment, so the progression-free survival improvement associated with Acala in ASCEND is eye-catching. However, there are important considerations that demand closer scrutiny.
With oral agents administered until progression or unacceptable toxicity, low-grade toxicities can influence patient adherence, quality of life, and potentially the need for dose reduction or treatment interruptions. Regimens of finite duration and easy adherence monitoring may be, on balance, preferred by patients and providers – especially if the oral agent can be given in later-line with comparable overall survival.
With ibrutinib (Blood. 2017;129:2612-5), Paul M. Barr, MD, and colleagues demonstrated that higher dose intensity was associated with improved progression-free survival and that holds were associated with worsened progression-free survival. Acala’s promise of high efficacy and lower off-target toxicity will be solidified if the large (more than 500 patients) phase 3 ACE-CL-006 study (Acala vs. ibrutinib) demonstrates its relative benefit from efficacy, toxicity, and adherence perspectives, in comparison with a standard therapy that similarly demands adherence until disease progression or unacceptable toxicity.
Dr. Lyss has been a community-based medical oncologist and clinical researcher for more than 35 years, practicing in St. Louis. His clinical and research interests are in the prevention, diagnosis, and treatment of breast and lung cancers and in expanding access to clinical trials to medically underserved populations.
SC daratumumab deemed feasible for every multiple myeloma patient
CHICAGO – Subcutaneous (SC) daratumumab is noninferior to intravenous (IV) daratumumab for patients with relapsed or refractory multiple myeloma (MM), according findings from a phase 3 trial.
In the COLUMBA trial, SC daratumumab proved noninferior to IV daratumumab with regard to overall response rate and maximum trough concentration (Ctrough).
The safety profiles of the two formulations were similar, although patients who received SC daratumumab had a lower rate of infusion-related reactions. SC daratumumab also had a lower treatment burden.
“The COLUMBA study shows that [SC daratumumab] can be used in every myeloma patient [as a] single agent or, maybe in the future, in combination with the different backbones,” said Maria-Victoria Mateos, MD, PhD, of University Hospital of Salamanca (Spain).
Dr. Mateos presented results from the COLUMBA trial at the annual meeting of the American Society of Clinical Oncology.
Dr. Mateos cited a previous phase 1b study that had suggested that SC daratumumab might produce similar results as IV daratumumab (Blood. 2017;130:838) while providing a more convenient delivery method. She pointed out that infusions of IV daratumumab can last hours, while the SC formulation can be delivered in minutes.
The aim of the phase 3 COLUMBA study was to compare the IV and SC formulations head-to-head. The trial enrolled 522 patients with relapsed/refractory multiple myeloma. They were randomized to receive daratumumab SC (n = 263) or IV (n = 259).
The median patient age was 68 years (range, 33-92 years) in the IV arm and 65 years (range, 42-84 years) in the SC arm. Patients had received a median of four prior lines of therapy (range, 1-15 in the IV arm and 2-12 in the SC arm). Most patients were refractory to their last line of therapy – 85% in the IV arm and 80% in the SC arm – and most patients had standard-risk cytogenetics – 83% and 74%, respectively.
Treatment
Patients received SC daratumumab at 1,800 mg and IV daratumumab at 16 mg/kg. Both were given weekly for cycles 1-2, every 2 weeks for cycles 3-6, and every 4 weeks thereafter until disease progression.
The median duration of the first infusion was 421 minutes in the IV arm and 5 minutes in the SC arm. The median duration of the second infusion was 255 minutes and 5 minutes, respectively, and the median duration of subsequent infusions was 205 minutes and 5 minutes, respectively.
At a median follow-up of 7.46 months, 57% of patients in each arm had discontinued the study treatment. The most common reasons for discontinuation were progression – 44% of the IV arm and 43% of the SC arm – and adverse events (AEs) – 8% and 7%, respectively.
Safety
Dr. Mateos said the safety profiles of IV and SC daratumumab were comparable. However, infusion-related reactions were significantly less likely in the SC arm, occurring in 12.7% of those patients and 34.5% of patients in the IV arm (P less than .0001).
Grade 3 or higher treatment-emergent AEs occurred in 49% of patients in the IV arm and 46% of those in the SC arm. Rates of grade 5 AEs were 7% and 5%, respectively. The most common grade 3/4 AEs (in the IV and SC arms, respectively) were anemia (14% and 13%), thrombocytopenia (14% for both), neutropenia (8% and 13%), lymphopenia (6% and 5%), and hypertension (6% and 3%).
Efficacy
One of the study’s primary endpoints was overall response rate, which was 37.1% in the IV arm and 41.1% in the SC arm (relative risk, 1.11; 95% CI, 0.89-1.37; P less than .0001). This met the criteria for noninferiority, and overall response rates were comparable across all patient subgroups, Dr. Mateos noted.
The rates of complete response or stringent complete response were also comparable at 2.7% in the IV arm and 1.9% in the SC arm. Rates of very good partial response were 17.0% and 19.0%, respectively.
The study’s other primary endpoint was maximum Ctrough predose on day 1 of cycle 3. The ratio of maximum Ctrough for daratumumab SC over IV was 107.93% (90% CI, 95.74%-121.67%), which met the noninferiority criterion.
Survival outcomes were also similar between the IV and SC arms. The median progression-free survival was 6.1 months and 5.6 months, respectively (P = .9258). The rate of overall survival at 6 months was 83.0% and 87.5%, respectively (P = .6032).
Considering these results together, Dr. Mateos and colleagues concluded that SC daratumumab is noninferior to IV daratumumab.
“[SC daratumumab] has a reduced treatment burden due to a considerably shorter administration duration, and patients treated with [SC daratumumab] reported higher satisfaction with therapy,” Dr. Mateos said.
The results support the use of flat-dose 1,800-mg SC daratumumab, which is comparable with the IV formulation, she said.
The COLUMBA trial was sponsored by Janssen Research & Development. Dr. Mateos reported relationships with Amgen, Celgene, Janssen-Cilag, and Takeda.
SOURCE: Mateos MV et al. ASCO 2019, Abstract 8005.
CHICAGO – Subcutaneous (SC) daratumumab is noninferior to intravenous (IV) daratumumab for patients with relapsed or refractory multiple myeloma (MM), according findings from a phase 3 trial.
In the COLUMBA trial, SC daratumumab proved noninferior to IV daratumumab with regard to overall response rate and maximum trough concentration (Ctrough).
The safety profiles of the two formulations were similar, although patients who received SC daratumumab had a lower rate of infusion-related reactions. SC daratumumab also had a lower treatment burden.
“The COLUMBA study shows that [SC daratumumab] can be used in every myeloma patient [as a] single agent or, maybe in the future, in combination with the different backbones,” said Maria-Victoria Mateos, MD, PhD, of University Hospital of Salamanca (Spain).
Dr. Mateos presented results from the COLUMBA trial at the annual meeting of the American Society of Clinical Oncology.
Dr. Mateos cited a previous phase 1b study that had suggested that SC daratumumab might produce similar results as IV daratumumab (Blood. 2017;130:838) while providing a more convenient delivery method. She pointed out that infusions of IV daratumumab can last hours, while the SC formulation can be delivered in minutes.
The aim of the phase 3 COLUMBA study was to compare the IV and SC formulations head-to-head. The trial enrolled 522 patients with relapsed/refractory multiple myeloma. They were randomized to receive daratumumab SC (n = 263) or IV (n = 259).
The median patient age was 68 years (range, 33-92 years) in the IV arm and 65 years (range, 42-84 years) in the SC arm. Patients had received a median of four prior lines of therapy (range, 1-15 in the IV arm and 2-12 in the SC arm). Most patients were refractory to their last line of therapy – 85% in the IV arm and 80% in the SC arm – and most patients had standard-risk cytogenetics – 83% and 74%, respectively.
Treatment
Patients received SC daratumumab at 1,800 mg and IV daratumumab at 16 mg/kg. Both were given weekly for cycles 1-2, every 2 weeks for cycles 3-6, and every 4 weeks thereafter until disease progression.
The median duration of the first infusion was 421 minutes in the IV arm and 5 minutes in the SC arm. The median duration of the second infusion was 255 minutes and 5 minutes, respectively, and the median duration of subsequent infusions was 205 minutes and 5 minutes, respectively.
At a median follow-up of 7.46 months, 57% of patients in each arm had discontinued the study treatment. The most common reasons for discontinuation were progression – 44% of the IV arm and 43% of the SC arm – and adverse events (AEs) – 8% and 7%, respectively.
Safety
Dr. Mateos said the safety profiles of IV and SC daratumumab were comparable. However, infusion-related reactions were significantly less likely in the SC arm, occurring in 12.7% of those patients and 34.5% of patients in the IV arm (P less than .0001).
Grade 3 or higher treatment-emergent AEs occurred in 49% of patients in the IV arm and 46% of those in the SC arm. Rates of grade 5 AEs were 7% and 5%, respectively. The most common grade 3/4 AEs (in the IV and SC arms, respectively) were anemia (14% and 13%), thrombocytopenia (14% for both), neutropenia (8% and 13%), lymphopenia (6% and 5%), and hypertension (6% and 3%).
Efficacy
One of the study’s primary endpoints was overall response rate, which was 37.1% in the IV arm and 41.1% in the SC arm (relative risk, 1.11; 95% CI, 0.89-1.37; P less than .0001). This met the criteria for noninferiority, and overall response rates were comparable across all patient subgroups, Dr. Mateos noted.
The rates of complete response or stringent complete response were also comparable at 2.7% in the IV arm and 1.9% in the SC arm. Rates of very good partial response were 17.0% and 19.0%, respectively.
The study’s other primary endpoint was maximum Ctrough predose on day 1 of cycle 3. The ratio of maximum Ctrough for daratumumab SC over IV was 107.93% (90% CI, 95.74%-121.67%), which met the noninferiority criterion.
Survival outcomes were also similar between the IV and SC arms. The median progression-free survival was 6.1 months and 5.6 months, respectively (P = .9258). The rate of overall survival at 6 months was 83.0% and 87.5%, respectively (P = .6032).
Considering these results together, Dr. Mateos and colleagues concluded that SC daratumumab is noninferior to IV daratumumab.
“[SC daratumumab] has a reduced treatment burden due to a considerably shorter administration duration, and patients treated with [SC daratumumab] reported higher satisfaction with therapy,” Dr. Mateos said.
The results support the use of flat-dose 1,800-mg SC daratumumab, which is comparable with the IV formulation, she said.
The COLUMBA trial was sponsored by Janssen Research & Development. Dr. Mateos reported relationships with Amgen, Celgene, Janssen-Cilag, and Takeda.
SOURCE: Mateos MV et al. ASCO 2019, Abstract 8005.
CHICAGO – Subcutaneous (SC) daratumumab is noninferior to intravenous (IV) daratumumab for patients with relapsed or refractory multiple myeloma (MM), according findings from a phase 3 trial.
In the COLUMBA trial, SC daratumumab proved noninferior to IV daratumumab with regard to overall response rate and maximum trough concentration (Ctrough).
The safety profiles of the two formulations were similar, although patients who received SC daratumumab had a lower rate of infusion-related reactions. SC daratumumab also had a lower treatment burden.
“The COLUMBA study shows that [SC daratumumab] can be used in every myeloma patient [as a] single agent or, maybe in the future, in combination with the different backbones,” said Maria-Victoria Mateos, MD, PhD, of University Hospital of Salamanca (Spain).
Dr. Mateos presented results from the COLUMBA trial at the annual meeting of the American Society of Clinical Oncology.
Dr. Mateos cited a previous phase 1b study that had suggested that SC daratumumab might produce similar results as IV daratumumab (Blood. 2017;130:838) while providing a more convenient delivery method. She pointed out that infusions of IV daratumumab can last hours, while the SC formulation can be delivered in minutes.
The aim of the phase 3 COLUMBA study was to compare the IV and SC formulations head-to-head. The trial enrolled 522 patients with relapsed/refractory multiple myeloma. They were randomized to receive daratumumab SC (n = 263) or IV (n = 259).
The median patient age was 68 years (range, 33-92 years) in the IV arm and 65 years (range, 42-84 years) in the SC arm. Patients had received a median of four prior lines of therapy (range, 1-15 in the IV arm and 2-12 in the SC arm). Most patients were refractory to their last line of therapy – 85% in the IV arm and 80% in the SC arm – and most patients had standard-risk cytogenetics – 83% and 74%, respectively.
Treatment
Patients received SC daratumumab at 1,800 mg and IV daratumumab at 16 mg/kg. Both were given weekly for cycles 1-2, every 2 weeks for cycles 3-6, and every 4 weeks thereafter until disease progression.
The median duration of the first infusion was 421 minutes in the IV arm and 5 minutes in the SC arm. The median duration of the second infusion was 255 minutes and 5 minutes, respectively, and the median duration of subsequent infusions was 205 minutes and 5 minutes, respectively.
At a median follow-up of 7.46 months, 57% of patients in each arm had discontinued the study treatment. The most common reasons for discontinuation were progression – 44% of the IV arm and 43% of the SC arm – and adverse events (AEs) – 8% and 7%, respectively.
Safety
Dr. Mateos said the safety profiles of IV and SC daratumumab were comparable. However, infusion-related reactions were significantly less likely in the SC arm, occurring in 12.7% of those patients and 34.5% of patients in the IV arm (P less than .0001).
Grade 3 or higher treatment-emergent AEs occurred in 49% of patients in the IV arm and 46% of those in the SC arm. Rates of grade 5 AEs were 7% and 5%, respectively. The most common grade 3/4 AEs (in the IV and SC arms, respectively) were anemia (14% and 13%), thrombocytopenia (14% for both), neutropenia (8% and 13%), lymphopenia (6% and 5%), and hypertension (6% and 3%).
Efficacy
One of the study’s primary endpoints was overall response rate, which was 37.1% in the IV arm and 41.1% in the SC arm (relative risk, 1.11; 95% CI, 0.89-1.37; P less than .0001). This met the criteria for noninferiority, and overall response rates were comparable across all patient subgroups, Dr. Mateos noted.
The rates of complete response or stringent complete response were also comparable at 2.7% in the IV arm and 1.9% in the SC arm. Rates of very good partial response were 17.0% and 19.0%, respectively.
The study’s other primary endpoint was maximum Ctrough predose on day 1 of cycle 3. The ratio of maximum Ctrough for daratumumab SC over IV was 107.93% (90% CI, 95.74%-121.67%), which met the noninferiority criterion.
Survival outcomes were also similar between the IV and SC arms. The median progression-free survival was 6.1 months and 5.6 months, respectively (P = .9258). The rate of overall survival at 6 months was 83.0% and 87.5%, respectively (P = .6032).
Considering these results together, Dr. Mateos and colleagues concluded that SC daratumumab is noninferior to IV daratumumab.
“[SC daratumumab] has a reduced treatment burden due to a considerably shorter administration duration, and patients treated with [SC daratumumab] reported higher satisfaction with therapy,” Dr. Mateos said.
The results support the use of flat-dose 1,800-mg SC daratumumab, which is comparable with the IV formulation, she said.
The COLUMBA trial was sponsored by Janssen Research & Development. Dr. Mateos reported relationships with Amgen, Celgene, Janssen-Cilag, and Takeda.
SOURCE: Mateos MV et al. ASCO 2019, Abstract 8005.
REPORTING FROM ASCO 2019
Recombinant vaccine cut herpes zoster rate in immunocompromised patients
Two doses of recombinant zoster vaccine significantly reduced incidence of herpes zoster in adults who had undergone autologous hematopoietic stem cell transplantation (HSCT), results of a randomized, placebo-controlled trial indicate.
The incidence of herpes zoster was 30 per 1,000 person-years for patients who received the adjuvanted recombinant zoster vaccine (Shingrix) versus 94 per 1,000 person-years for those who received placebo, according to study results.
Recombinant zoster vaccine induced humoral and cellular responses that were strong and occurring at a rate higher than what was seen in the placebo group, said senior author Keith M. Sullivan, MD, of Duke University Medical Center, Durham, N.C., and coauthors, who reported findings on behalf of the Zoster Efficacy Study in Patients Undergoing HSCT (ZOE-HSCT) Study Group.
“The vaccinations were generally well tolerated, and most symptoms were mild and transient and did not substantially deter participants from receiving their second dose,” Dr. Sullivan and colleagues wrote in JAMA.
The risk of herpes zoster is increased for 2-3 years after autologous HSCT because of diminished T-cell immunity, according to the authors.
“Antiviral prophylaxis is commonly administered to patients after HSCT to prevent such complications, but the efficacy depends on adherence to treatment,” they said.
While vaccines could provide long-term protection, immunocompromised individuals receiving live attenuated vaccine would be at increased risk of varicella caused by spread of the vaccine strain, they added.
There have been a few encouraging recent studies of non-live vaccines in this setting, including one large phase 3 trial of a heat-inactivated varicella-zoster virus vaccine that showed patients undergoing autologous HSCT had a 63.8% estimated efficacy in preventing herpes zoster, investigators from that study said in The Lancet (2018 May 26;391[10135]:2116-27).
A phase 1/2a study of the adjuvanted recombinant zoster vaccine in patients undergoing HSCT demonstrated strong humoral and cell-mediated immunity responses, which provided the rationale for studying the vaccine further in the randomized ZOE-HSCT study, according to Dr. Sullivan and coauthors.
Their study included a total of 1,846 adults who had undergone autologous HSCT. They were randomized to receive two doses of the recombinant zoster vaccine, the first at 50-70 days after the procedure and the second 1-2 months later.
Herpes zoster cases were seen in 49 and 136 individuals in the vaccine and placebo groups, respectively, which resulted in overall incidences of 30 and 94 per 1,000 person-years.
The incidence rate ratio of a first episode of herpes zoster was 0.36 for individuals receiving at least one dose, which authors said was equivalent to a vaccine efficacy of 63.7%.
That efficacy rate is “very similar” to the estimated efficacy reported for the heat-inactivated varicella-zoster virus vaccine reported in The Lancet, said Dr. Sullivan and coauthors.
However, the heat-inactivated vaccine achieved that level of protection with a four-dose schedule, including one dose given prior to autologous HSCT.
“An advantage of the short 2-dose posttransplantation schedule is that more patients might complete the vaccination program,” they said in a discussion of the results, noting that 94.7% of the recombinant zoster vaccine recipients completed two doses, compared with 81.9% of recipients who received the heat-inactivated herpes zoster vaccine in the previous report.
The study was funded and sponsored by GlaxoSmithKline Biologicals SA. Dr. Sullivan reported disclosures related to GlaxoSmithKline (GSK), Kiadis Pharmaceutical, Roche Genentech, and the National Institute of Allergy and Infectious Diseases. Coauthors provided disclosures related to GSK, AbbVie, Roche, Gilead, Janssen, Pharmacyclics, Morphosys, Helsinn, Celgene, and others.
SOURCE: Bastidas A et al. JAMA. 2019 July 9. doi: 10.1001/jama.2019.9053.
Two doses of recombinant zoster vaccine significantly reduced incidence of herpes zoster in adults who had undergone autologous hematopoietic stem cell transplantation (HSCT), results of a randomized, placebo-controlled trial indicate.
The incidence of herpes zoster was 30 per 1,000 person-years for patients who received the adjuvanted recombinant zoster vaccine (Shingrix) versus 94 per 1,000 person-years for those who received placebo, according to study results.
Recombinant zoster vaccine induced humoral and cellular responses that were strong and occurring at a rate higher than what was seen in the placebo group, said senior author Keith M. Sullivan, MD, of Duke University Medical Center, Durham, N.C., and coauthors, who reported findings on behalf of the Zoster Efficacy Study in Patients Undergoing HSCT (ZOE-HSCT) Study Group.
“The vaccinations were generally well tolerated, and most symptoms were mild and transient and did not substantially deter participants from receiving their second dose,” Dr. Sullivan and colleagues wrote in JAMA.
The risk of herpes zoster is increased for 2-3 years after autologous HSCT because of diminished T-cell immunity, according to the authors.
“Antiviral prophylaxis is commonly administered to patients after HSCT to prevent such complications, but the efficacy depends on adherence to treatment,” they said.
While vaccines could provide long-term protection, immunocompromised individuals receiving live attenuated vaccine would be at increased risk of varicella caused by spread of the vaccine strain, they added.
There have been a few encouraging recent studies of non-live vaccines in this setting, including one large phase 3 trial of a heat-inactivated varicella-zoster virus vaccine that showed patients undergoing autologous HSCT had a 63.8% estimated efficacy in preventing herpes zoster, investigators from that study said in The Lancet (2018 May 26;391[10135]:2116-27).
A phase 1/2a study of the adjuvanted recombinant zoster vaccine in patients undergoing HSCT demonstrated strong humoral and cell-mediated immunity responses, which provided the rationale for studying the vaccine further in the randomized ZOE-HSCT study, according to Dr. Sullivan and coauthors.
Their study included a total of 1,846 adults who had undergone autologous HSCT. They were randomized to receive two doses of the recombinant zoster vaccine, the first at 50-70 days after the procedure and the second 1-2 months later.
Herpes zoster cases were seen in 49 and 136 individuals in the vaccine and placebo groups, respectively, which resulted in overall incidences of 30 and 94 per 1,000 person-years.
The incidence rate ratio of a first episode of herpes zoster was 0.36 for individuals receiving at least one dose, which authors said was equivalent to a vaccine efficacy of 63.7%.
That efficacy rate is “very similar” to the estimated efficacy reported for the heat-inactivated varicella-zoster virus vaccine reported in The Lancet, said Dr. Sullivan and coauthors.
However, the heat-inactivated vaccine achieved that level of protection with a four-dose schedule, including one dose given prior to autologous HSCT.
“An advantage of the short 2-dose posttransplantation schedule is that more patients might complete the vaccination program,” they said in a discussion of the results, noting that 94.7% of the recombinant zoster vaccine recipients completed two doses, compared with 81.9% of recipients who received the heat-inactivated herpes zoster vaccine in the previous report.
The study was funded and sponsored by GlaxoSmithKline Biologicals SA. Dr. Sullivan reported disclosures related to GlaxoSmithKline (GSK), Kiadis Pharmaceutical, Roche Genentech, and the National Institute of Allergy and Infectious Diseases. Coauthors provided disclosures related to GSK, AbbVie, Roche, Gilead, Janssen, Pharmacyclics, Morphosys, Helsinn, Celgene, and others.
SOURCE: Bastidas A et al. JAMA. 2019 July 9. doi: 10.1001/jama.2019.9053.
Two doses of recombinant zoster vaccine significantly reduced incidence of herpes zoster in adults who had undergone autologous hematopoietic stem cell transplantation (HSCT), results of a randomized, placebo-controlled trial indicate.
The incidence of herpes zoster was 30 per 1,000 person-years for patients who received the adjuvanted recombinant zoster vaccine (Shingrix) versus 94 per 1,000 person-years for those who received placebo, according to study results.
Recombinant zoster vaccine induced humoral and cellular responses that were strong and occurring at a rate higher than what was seen in the placebo group, said senior author Keith M. Sullivan, MD, of Duke University Medical Center, Durham, N.C., and coauthors, who reported findings on behalf of the Zoster Efficacy Study in Patients Undergoing HSCT (ZOE-HSCT) Study Group.
“The vaccinations were generally well tolerated, and most symptoms were mild and transient and did not substantially deter participants from receiving their second dose,” Dr. Sullivan and colleagues wrote in JAMA.
The risk of herpes zoster is increased for 2-3 years after autologous HSCT because of diminished T-cell immunity, according to the authors.
“Antiviral prophylaxis is commonly administered to patients after HSCT to prevent such complications, but the efficacy depends on adherence to treatment,” they said.
While vaccines could provide long-term protection, immunocompromised individuals receiving live attenuated vaccine would be at increased risk of varicella caused by spread of the vaccine strain, they added.
There have been a few encouraging recent studies of non-live vaccines in this setting, including one large phase 3 trial of a heat-inactivated varicella-zoster virus vaccine that showed patients undergoing autologous HSCT had a 63.8% estimated efficacy in preventing herpes zoster, investigators from that study said in The Lancet (2018 May 26;391[10135]:2116-27).
A phase 1/2a study of the adjuvanted recombinant zoster vaccine in patients undergoing HSCT demonstrated strong humoral and cell-mediated immunity responses, which provided the rationale for studying the vaccine further in the randomized ZOE-HSCT study, according to Dr. Sullivan and coauthors.
Their study included a total of 1,846 adults who had undergone autologous HSCT. They were randomized to receive two doses of the recombinant zoster vaccine, the first at 50-70 days after the procedure and the second 1-2 months later.
Herpes zoster cases were seen in 49 and 136 individuals in the vaccine and placebo groups, respectively, which resulted in overall incidences of 30 and 94 per 1,000 person-years.
The incidence rate ratio of a first episode of herpes zoster was 0.36 for individuals receiving at least one dose, which authors said was equivalent to a vaccine efficacy of 63.7%.
That efficacy rate is “very similar” to the estimated efficacy reported for the heat-inactivated varicella-zoster virus vaccine reported in The Lancet, said Dr. Sullivan and coauthors.
However, the heat-inactivated vaccine achieved that level of protection with a four-dose schedule, including one dose given prior to autologous HSCT.
“An advantage of the short 2-dose posttransplantation schedule is that more patients might complete the vaccination program,” they said in a discussion of the results, noting that 94.7% of the recombinant zoster vaccine recipients completed two doses, compared with 81.9% of recipients who received the heat-inactivated herpes zoster vaccine in the previous report.
The study was funded and sponsored by GlaxoSmithKline Biologicals SA. Dr. Sullivan reported disclosures related to GlaxoSmithKline (GSK), Kiadis Pharmaceutical, Roche Genentech, and the National Institute of Allergy and Infectious Diseases. Coauthors provided disclosures related to GSK, AbbVie, Roche, Gilead, Janssen, Pharmacyclics, Morphosys, Helsinn, Celgene, and others.
SOURCE: Bastidas A et al. JAMA. 2019 July 9. doi: 10.1001/jama.2019.9053.
FROM JAMA
Key clinical point: Two doses of recombinant zoster vaccine significantly reduced incidence of herpes zoster versus placebo in adults who had undergone autologous hematopoietic stem cell transplantation (HSCT).
Major finding: Herpes zoster cases were seen in 49 and 136 individuals in the vaccine and placebo groups, respectively, resulting in overall incidences of 30 and 94 per 1,000 person-years.
Study details: A randomized clinical trial (ZOE-HSCT) including 1,846 adults who had undergone autologous HSCT.
Disclosures: The study was funded and sponsored by GlaxoSmithKline Biologicals SA. Study authors reported disclosures related to GlaxoSmithKline, Kiadis Pharmaceutical, Roche Genentech, AbbVie, Roche, Gilead, Janssen, Pharmacyclics, Morphosys, Helsinn, Celgene, and others.
Source: Bastidas A et al. JAMA. 2019 July 9. doi: 10.1001/jama.2019.9053.