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Pembrolizumab sBLA receives priority review
The US Food and Drug Administration (FDA) has granted priority review to a supplemental biologics license application (sBLA) for the anti-PD-1 therapy pembrolizumab (KEYTRUDA).
With this sBLA, Merck is seeking approval for pembrolizumab to treat adult and pediatric patients with refractory primary mediastinal B-cell lymphoma (PMBCL) or patients with PMBCL who have relapsed after 2 or more prior lines of therapy.
The FDA expects to make a decision on the sBLA by April 3, 2018.
The agency’s goal is to take action on a priority review application within 6 months of receiving it, rather than the standard 10 months.
The FDA grants priority review to applications for products that may provide significant improvements in the treatment, diagnosis, or prevention of serious conditions.
Pembrolizumab is currently FDA-approved to treat classical Hodgkin lymphoma, melanoma, lung cancer, head and neck cancer, urothelial carcinoma, microsatellite instability-high cancer, and gastric cancer.
The sBLA for pembrolizumab as a treatment for PMBCL is supported by the phase 2 KEYNOTE-170 trial. Results from this trial were presented at the 2017 ASH Annual Meeting (abstract 2833).
KEYNOTE-170 is an ongoing study in which researchers are evaluating pembrolizumab (given at a 200 mg fixed dose every 3 weeks) in patients with relapsed/refractory PMBCL or relapsed/refractory Richter syndrome.
The PMBCL cohort enrolled patients who relapsed after autologous stem cell transplant (ASCT), were refractory to ASCT, or were ineligible for ASCT. Patients ineligible for ASCT had to have received 2 or more lines of prior therapy.
The median duration of follow-up was 10.5 months (range, 0.1-17.7).
In the efficacy population (n=29), the overall response rate was 41% (n=12), and the complete response rate was 24% (n=7).
The median time to response was 2.8 months (range, 2.4-5.5), and the median duration of response was not reached (range, 1.1+ to 13.6+ months).
Of the 53 patients evaluated for safety, 57% (n=30) experienced treatment-related adverse events (TRAEs), including 21% (n=11) who experienced grade 3-4 TRAEs.
The most common TRAEs (occurring in at least 5% of patients) were neutropenia (n=11), hypothyroidism (n=4), asthenia (n=3), and pyrexia (n=3).
Immune-mediated adverse events of all grades occurred in 11% (n=6) of patients. These include hypothyroidism (n=4), hyperthyroidism (n=2), pneumonitis (n=1), and thyroiditis (n=1). There were no treatment-related deaths. 
*Data in the abstract differ from the presentation.
The US Food and Drug Administration (FDA) has granted priority review to a supplemental biologics license application (sBLA) for the anti-PD-1 therapy pembrolizumab (KEYTRUDA).
With this sBLA, Merck is seeking approval for pembrolizumab to treat adult and pediatric patients with refractory primary mediastinal B-cell lymphoma (PMBCL) or patients with PMBCL who have relapsed after 2 or more prior lines of therapy.
The FDA expects to make a decision on the sBLA by April 3, 2018.
The agency’s goal is to take action on a priority review application within 6 months of receiving it, rather than the standard 10 months.
The FDA grants priority review to applications for products that may provide significant improvements in the treatment, diagnosis, or prevention of serious conditions.
Pembrolizumab is currently FDA-approved to treat classical Hodgkin lymphoma, melanoma, lung cancer, head and neck cancer, urothelial carcinoma, microsatellite instability-high cancer, and gastric cancer.
The sBLA for pembrolizumab as a treatment for PMBCL is supported by the phase 2 KEYNOTE-170 trial. Results from this trial were presented at the 2017 ASH Annual Meeting (abstract 2833).
KEYNOTE-170 is an ongoing study in which researchers are evaluating pembrolizumab (given at a 200 mg fixed dose every 3 weeks) in patients with relapsed/refractory PMBCL or relapsed/refractory Richter syndrome.
The PMBCL cohort enrolled patients who relapsed after autologous stem cell transplant (ASCT), were refractory to ASCT, or were ineligible for ASCT. Patients ineligible for ASCT had to have received 2 or more lines of prior therapy.
The median duration of follow-up was 10.5 months (range, 0.1-17.7).
In the efficacy population (n=29), the overall response rate was 41% (n=12), and the complete response rate was 24% (n=7).
The median time to response was 2.8 months (range, 2.4-5.5), and the median duration of response was not reached (range, 1.1+ to 13.6+ months).
Of the 53 patients evaluated for safety, 57% (n=30) experienced treatment-related adverse events (TRAEs), including 21% (n=11) who experienced grade 3-4 TRAEs.
The most common TRAEs (occurring in at least 5% of patients) were neutropenia (n=11), hypothyroidism (n=4), asthenia (n=3), and pyrexia (n=3).
Immune-mediated adverse events of all grades occurred in 11% (n=6) of patients. These include hypothyroidism (n=4), hyperthyroidism (n=2), pneumonitis (n=1), and thyroiditis (n=1). There were no treatment-related deaths.
*Data in the abstract differ from the presentation.
The US Food and Drug Administration (FDA) has granted priority review to a supplemental biologics license application (sBLA) for the anti-PD-1 therapy pembrolizumab (KEYTRUDA).
With this sBLA, Merck is seeking approval for pembrolizumab to treat adult and pediatric patients with refractory primary mediastinal B-cell lymphoma (PMBCL) or patients with PMBCL who have relapsed after 2 or more prior lines of therapy.
The FDA expects to make a decision on the sBLA by April 3, 2018.
The agency’s goal is to take action on a priority review application within 6 months of receiving it, rather than the standard 10 months.
The FDA grants priority review to applications for products that may provide significant improvements in the treatment, diagnosis, or prevention of serious conditions.
Pembrolizumab is currently FDA-approved to treat classical Hodgkin lymphoma, melanoma, lung cancer, head and neck cancer, urothelial carcinoma, microsatellite instability-high cancer, and gastric cancer.
The sBLA for pembrolizumab as a treatment for PMBCL is supported by the phase 2 KEYNOTE-170 trial. Results from this trial were presented at the 2017 ASH Annual Meeting (abstract 2833).
KEYNOTE-170 is an ongoing study in which researchers are evaluating pembrolizumab (given at a 200 mg fixed dose every 3 weeks) in patients with relapsed/refractory PMBCL or relapsed/refractory Richter syndrome.
The PMBCL cohort enrolled patients who relapsed after autologous stem cell transplant (ASCT), were refractory to ASCT, or were ineligible for ASCT. Patients ineligible for ASCT had to have received 2 or more lines of prior therapy.
The median duration of follow-up was 10.5 months (range, 0.1-17.7).
In the efficacy population (n=29), the overall response rate was 41% (n=12), and the complete response rate was 24% (n=7).
The median time to response was 2.8 months (range, 2.4-5.5), and the median duration of response was not reached (range, 1.1+ to 13.6+ months).
Of the 53 patients evaluated for safety, 57% (n=30) experienced treatment-related adverse events (TRAEs), including 21% (n=11) who experienced grade 3-4 TRAEs.
The most common TRAEs (occurring in at least 5% of patients) were neutropenia (n=11), hypothyroidism (n=4), asthenia (n=3), and pyrexia (n=3).
Immune-mediated adverse events of all grades occurred in 11% (n=6) of patients. These include hypothyroidism (n=4), hyperthyroidism (n=2), pneumonitis (n=1), and thyroiditis (n=1). There were no treatment-related deaths.
*Data in the abstract differ from the presentation.
Primary analysis confirms interim findings of CTL019 in DLBCL
ATLANTA—The first chimeric antigen receptor (CAR) T-cell therapy approved in the US to treat children and young adults with leukemia is also producing high response rates in lymphoma, according to investigators of the JULIET trial.
They reported that tisagenlecleucel (formerly CTL019) produced an overall response rate (ORR) of 53% and a complete response (CR) rate of 40% in patients with diffuse large B-cell lymphoma (DLBCL).
Additionally, researchers say the stability in the response rate at 3 and 6 months—38% and 37%, respectively—indicates the durability of the therapy.
At 3 months, 32% of patients who achieved CR remained in CR. At 6 months, 30% remained in CR.
Researchers believe these results confirm the durable clinical benefit reported previously.
Stephen J. Schuster, MD, of the University of Pennsylvania in Philadelphia, presented the JULIET data at the 2017 ASH Annual Meeting (abstract 577).
“Only about half of relapsed diffuse large B-cell lymphoma patients are eligible for transplant,” Dr Schuster said. “[O]f those patients, only about a half respond to salvage chemotherapy, and a significant number of patients relapse post-transplant. So there is really a large unmet need for these patients, and CAR T-cell therapy is a potential agent [for them].”
The JULIET trial was a global, single-arm, phase 2 trial evaluating tisagenlecleucel in DLBCL patients. Tisagenlecleucel (Kymriah™) consists of CAR T cells with a CD19 antigen-binding domain, a 4-1BB costimulatory domain, and a CD3-zeta signaling domain.
The trial was conducted at 27 sites in 10 countries across North America, Europe, Australia, and Asia. There were 2 centralized manufacturing sites, one in Europe and one in the US.
Patients had to be 18 years or older, have had 2 or more prior lines of therapy for DLBCL, and have progressive disease or be ineligible for autologous stem cell transplant (auto-SCT). They could not have had any prior anti-CD19 therapy, and they could not have any central nervous system involvement.
The primary endpoint was best ORR using Lugano criteria with assessment by an independent review committee. Secondary endpoints included duration of response, overall survival (OS), and safety.
Study design and enrollment
Patients were screened and underwent apheresis with cryopreservation of their leukapheresis products during screening, which “allowed for enrollment of all eligible patients,” Dr Schuster said.
Patients could receive bridging chemotherapy while they awaited the manufacture of the CAR T cells.
“What’s important to note is that, early on in the trial, there was a shortage of manufacturing capacity, and this led to a longer-than-anticipated interval between enrollment and treatment,” Dr Schuster said. “This interval decreased as manufacturing capacity improved throughout the trial.”
When their CAR T cells were ready, patients were restaged, lymphodepleted, and received the tisagenlecleucel infusion. The dose ranged from 0.6 x 108 to 6.0 x 108 CAR-positive T cells.
The infusion could be conducted on an inpatient or outpatient basis at the investigator’s discretion, Dr Schuster said.
As of the data cutoff in March 2017, investigators enrolled 147 patients and infused 99 with tisagenlecleucel.
Forty-three patients discontinued before infusion, 9 because of an inability to manufacture the T-cell product and 34 due to death (n=16), physician decision (n=12), patient decision (n=3), adverse event (n=2), and protocol deviation (n=1). Five patients were pending infusion.
There were 81 patients with at least 3 months of follow-up or earlier disease progression evaluable for response.
Patient characteristics
Patients were a median age of 56 (range, 22–76), and 23% were 65 or older. All had an ECOG performance status of 0 or 1, 80% had DLBCL, and 19% had transformed follicular lymphoma.
Fifteen percent had double or triple hits in CMYC, BCL2, and BCL6 genes, and 52% had germinal center B-cell type disease.
Forty-four percent had 2 prior lines of therapy, 31% had 3 prior lines of therapy, and 19% had 4 to 6 prior lines of therapy. All were either refractory to or relapsed from their last therapy.
Forty-seven percent had undergone prior auto-SCT.
Eighty-nine of the 99 patients infused with tisagenlecleucel received bridging therapy, and 92 received lymphodepleting therapy.
Twenty-six patients were infused as outpatients, and 20 remained as outpatients for 3 or more days after the infusion.
Efficacy
The trial met its primary endpoint with an ORR of 53% tested against the null hypothesis of 20% or less. Forty percent of patients achieved a CR, and 14% had a partial response.
The ORR was consistent across all subgroups, including age, sex, lines of prior antineoplastic therapy, cell of origin, and rearranged MYC/BCL2/BCL6.
“The durability of response, however, which is really the message, is shown by the stability between 3- and 6-month response rates, 38% and 37%, respectively,” Dr Schuster said. “The response rate at 3 months is really indicative of the long-term benefit of this treatment approach.”
The investigators observed no apparent relationship between tumor response at month 3 and dose. And they observed responses at all dose levels.
The very early response may be due, to a certain extent, to the chemotherapy, according to Dr Schuster.
“The effect of the T cells becomes evident as you follow these patients over time,” he said.
The median duration of response and overall response have not been reached. And 74% of patients were relapse-free at 6 months.
“Importantly, almost all the complete responders at month 3 remained in complete response,” Dr Schuster said.
Safety
Adverse events of special interest that occurred within 8 weeks of the infusion included:
- Cytokine release syndrome (CRS)—58% all grades, 15% grade 3, 8% grade 4
- Neurologic events—21% all grades, 8% grade 3, 4% grade 4
- Prolonged cytopenia—36% all grades, 15% grade 3, 12% grade 4
- Infections—34% all grades, 18% grade 3, 2% grade 4
- Febrile neutropenia—13% all grades, 11% grade 3, 2% grade 4
No deaths occurred due to tisagenlecleucel, CRS, or cerebral edema.
Fifty-seven patients developed CRS. The median time to onset of CRS was 3 days (range, 1–9), and the median duration of CRS was 7 days (range, 2–30).
Twenty-eight percent of patients developed hypotension that required intervention, 6% requiring high-dose vasopressors. Eight percent were intubated, and 16% received anticytokine therapy—15% with tocilizumab and 11% with corticosteroids.
Investigators did not observe a relationship between dose and neurological events. However, they did detect a higher probability of CRS with the higher doses of tisagenlecleucel.
They also noted that dose and exposure were independent.
Dr Schuster indicated that these data are the basis for global regulatory submissions.
Manufacture of tisagenlecleucel was centralized, and investigators believe the trial shows the feasibility of global distribution of CAR T-cell therapy using cryopreserved apheresis and centralized manufacturing.
Novartis Pharmaceuticals, the sponsor of the trial, is now able to commercially manufacture the CAR T cells in 22 days.
Dr Schuster disclosed research funding and consulting fees from Novartis and Celgene.
ATLANTA—The first chimeric antigen receptor (CAR) T-cell therapy approved in the US to treat children and young adults with leukemia is also producing high response rates in lymphoma, according to investigators of the JULIET trial.
They reported that tisagenlecleucel (formerly CTL019) produced an overall response rate (ORR) of 53% and a complete response (CR) rate of 40% in patients with diffuse large B-cell lymphoma (DLBCL).
Additionally, researchers say the stability in the response rate at 3 and 6 months—38% and 37%, respectively—indicates the durability of the therapy.
At 3 months, 32% of patients who achieved CR remained in CR. At 6 months, 30% remained in CR.
Researchers believe these results confirm the durable clinical benefit reported previously.
Stephen J. Schuster, MD, of the University of Pennsylvania in Philadelphia, presented the JULIET data at the 2017 ASH Annual Meeting (abstract 577).
“Only about half of relapsed diffuse large B-cell lymphoma patients are eligible for transplant,” Dr Schuster said. “[O]f those patients, only about a half respond to salvage chemotherapy, and a significant number of patients relapse post-transplant. So there is really a large unmet need for these patients, and CAR T-cell therapy is a potential agent [for them].”
The JULIET trial was a global, single-arm, phase 2 trial evaluating tisagenlecleucel in DLBCL patients. Tisagenlecleucel (Kymriah™) consists of CAR T cells with a CD19 antigen-binding domain, a 4-1BB costimulatory domain, and a CD3-zeta signaling domain.
The trial was conducted at 27 sites in 10 countries across North America, Europe, Australia, and Asia. There were 2 centralized manufacturing sites, one in Europe and one in the US.
Patients had to be 18 years or older, have had 2 or more prior lines of therapy for DLBCL, and have progressive disease or be ineligible for autologous stem cell transplant (auto-SCT). They could not have had any prior anti-CD19 therapy, and they could not have any central nervous system involvement.
The primary endpoint was best ORR using Lugano criteria with assessment by an independent review committee. Secondary endpoints included duration of response, overall survival (OS), and safety.
Study design and enrollment
Patients were screened and underwent apheresis with cryopreservation of their leukapheresis products during screening, which “allowed for enrollment of all eligible patients,” Dr Schuster said.
Patients could receive bridging chemotherapy while they awaited the manufacture of the CAR T cells.
“What’s important to note is that, early on in the trial, there was a shortage of manufacturing capacity, and this led to a longer-than-anticipated interval between enrollment and treatment,” Dr Schuster said. “This interval decreased as manufacturing capacity improved throughout the trial.”
When their CAR T cells were ready, patients were restaged, lymphodepleted, and received the tisagenlecleucel infusion. The dose ranged from 0.6 x 108 to 6.0 x 108 CAR-positive T cells.
The infusion could be conducted on an inpatient or outpatient basis at the investigator’s discretion, Dr Schuster said.
As of the data cutoff in March 2017, investigators enrolled 147 patients and infused 99 with tisagenlecleucel.
Forty-three patients discontinued before infusion, 9 because of an inability to manufacture the T-cell product and 34 due to death (n=16), physician decision (n=12), patient decision (n=3), adverse event (n=2), and protocol deviation (n=1). Five patients were pending infusion.
There were 81 patients with at least 3 months of follow-up or earlier disease progression evaluable for response.
Patient characteristics
Patients were a median age of 56 (range, 22–76), and 23% were 65 or older. All had an ECOG performance status of 0 or 1, 80% had DLBCL, and 19% had transformed follicular lymphoma.
Fifteen percent had double or triple hits in CMYC, BCL2, and BCL6 genes, and 52% had germinal center B-cell type disease.
Forty-four percent had 2 prior lines of therapy, 31% had 3 prior lines of therapy, and 19% had 4 to 6 prior lines of therapy. All were either refractory to or relapsed from their last therapy.
Forty-seven percent had undergone prior auto-SCT.
Eighty-nine of the 99 patients infused with tisagenlecleucel received bridging therapy, and 92 received lymphodepleting therapy.
Twenty-six patients were infused as outpatients, and 20 remained as outpatients for 3 or more days after the infusion.
Efficacy
The trial met its primary endpoint with an ORR of 53% tested against the null hypothesis of 20% or less. Forty percent of patients achieved a CR, and 14% had a partial response.
The ORR was consistent across all subgroups, including age, sex, lines of prior antineoplastic therapy, cell of origin, and rearranged MYC/BCL2/BCL6.
“The durability of response, however, which is really the message, is shown by the stability between 3- and 6-month response rates, 38% and 37%, respectively,” Dr Schuster said. “The response rate at 3 months is really indicative of the long-term benefit of this treatment approach.”
The investigators observed no apparent relationship between tumor response at month 3 and dose. And they observed responses at all dose levels.
The very early response may be due, to a certain extent, to the chemotherapy, according to Dr Schuster.
“The effect of the T cells becomes evident as you follow these patients over time,” he said.
The median duration of response and overall response have not been reached. And 74% of patients were relapse-free at 6 months.
“Importantly, almost all the complete responders at month 3 remained in complete response,” Dr Schuster said.
Safety
Adverse events of special interest that occurred within 8 weeks of the infusion included:
- Cytokine release syndrome (CRS)—58% all grades, 15% grade 3, 8% grade 4
- Neurologic events—21% all grades, 8% grade 3, 4% grade 4
- Prolonged cytopenia—36% all grades, 15% grade 3, 12% grade 4
- Infections—34% all grades, 18% grade 3, 2% grade 4
- Febrile neutropenia—13% all grades, 11% grade 3, 2% grade 4
No deaths occurred due to tisagenlecleucel, CRS, or cerebral edema.
Fifty-seven patients developed CRS. The median time to onset of CRS was 3 days (range, 1–9), and the median duration of CRS was 7 days (range, 2–30).
Twenty-eight percent of patients developed hypotension that required intervention, 6% requiring high-dose vasopressors. Eight percent were intubated, and 16% received anticytokine therapy—15% with tocilizumab and 11% with corticosteroids.
Investigators did not observe a relationship between dose and neurological events. However, they did detect a higher probability of CRS with the higher doses of tisagenlecleucel.
They also noted that dose and exposure were independent.
Dr Schuster indicated that these data are the basis for global regulatory submissions.
Manufacture of tisagenlecleucel was centralized, and investigators believe the trial shows the feasibility of global distribution of CAR T-cell therapy using cryopreserved apheresis and centralized manufacturing.
Novartis Pharmaceuticals, the sponsor of the trial, is now able to commercially manufacture the CAR T cells in 22 days.
Dr Schuster disclosed research funding and consulting fees from Novartis and Celgene.
ATLANTA—The first chimeric antigen receptor (CAR) T-cell therapy approved in the US to treat children and young adults with leukemia is also producing high response rates in lymphoma, according to investigators of the JULIET trial.
They reported that tisagenlecleucel (formerly CTL019) produced an overall response rate (ORR) of 53% and a complete response (CR) rate of 40% in patients with diffuse large B-cell lymphoma (DLBCL).
Additionally, researchers say the stability in the response rate at 3 and 6 months—38% and 37%, respectively—indicates the durability of the therapy.
At 3 months, 32% of patients who achieved CR remained in CR. At 6 months, 30% remained in CR.
Researchers believe these results confirm the durable clinical benefit reported previously.
Stephen J. Schuster, MD, of the University of Pennsylvania in Philadelphia, presented the JULIET data at the 2017 ASH Annual Meeting (abstract 577).
“Only about half of relapsed diffuse large B-cell lymphoma patients are eligible for transplant,” Dr Schuster said. “[O]f those patients, only about a half respond to salvage chemotherapy, and a significant number of patients relapse post-transplant. So there is really a large unmet need for these patients, and CAR T-cell therapy is a potential agent [for them].”
The JULIET trial was a global, single-arm, phase 2 trial evaluating tisagenlecleucel in DLBCL patients. Tisagenlecleucel (Kymriah™) consists of CAR T cells with a CD19 antigen-binding domain, a 4-1BB costimulatory domain, and a CD3-zeta signaling domain.
The trial was conducted at 27 sites in 10 countries across North America, Europe, Australia, and Asia. There were 2 centralized manufacturing sites, one in Europe and one in the US.
Patients had to be 18 years or older, have had 2 or more prior lines of therapy for DLBCL, and have progressive disease or be ineligible for autologous stem cell transplant (auto-SCT). They could not have had any prior anti-CD19 therapy, and they could not have any central nervous system involvement.
The primary endpoint was best ORR using Lugano criteria with assessment by an independent review committee. Secondary endpoints included duration of response, overall survival (OS), and safety.
Study design and enrollment
Patients were screened and underwent apheresis with cryopreservation of their leukapheresis products during screening, which “allowed for enrollment of all eligible patients,” Dr Schuster said.
Patients could receive bridging chemotherapy while they awaited the manufacture of the CAR T cells.
“What’s important to note is that, early on in the trial, there was a shortage of manufacturing capacity, and this led to a longer-than-anticipated interval between enrollment and treatment,” Dr Schuster said. “This interval decreased as manufacturing capacity improved throughout the trial.”
When their CAR T cells were ready, patients were restaged, lymphodepleted, and received the tisagenlecleucel infusion. The dose ranged from 0.6 x 108 to 6.0 x 108 CAR-positive T cells.
The infusion could be conducted on an inpatient or outpatient basis at the investigator’s discretion, Dr Schuster said.
As of the data cutoff in March 2017, investigators enrolled 147 patients and infused 99 with tisagenlecleucel.
Forty-three patients discontinued before infusion, 9 because of an inability to manufacture the T-cell product and 34 due to death (n=16), physician decision (n=12), patient decision (n=3), adverse event (n=2), and protocol deviation (n=1). Five patients were pending infusion.
There were 81 patients with at least 3 months of follow-up or earlier disease progression evaluable for response.
Patient characteristics
Patients were a median age of 56 (range, 22–76), and 23% were 65 or older. All had an ECOG performance status of 0 or 1, 80% had DLBCL, and 19% had transformed follicular lymphoma.
Fifteen percent had double or triple hits in CMYC, BCL2, and BCL6 genes, and 52% had germinal center B-cell type disease.
Forty-four percent had 2 prior lines of therapy, 31% had 3 prior lines of therapy, and 19% had 4 to 6 prior lines of therapy. All were either refractory to or relapsed from their last therapy.
Forty-seven percent had undergone prior auto-SCT.
Eighty-nine of the 99 patients infused with tisagenlecleucel received bridging therapy, and 92 received lymphodepleting therapy.
Twenty-six patients were infused as outpatients, and 20 remained as outpatients for 3 or more days after the infusion.
Efficacy
The trial met its primary endpoint with an ORR of 53% tested against the null hypothesis of 20% or less. Forty percent of patients achieved a CR, and 14% had a partial response.
The ORR was consistent across all subgroups, including age, sex, lines of prior antineoplastic therapy, cell of origin, and rearranged MYC/BCL2/BCL6.
“The durability of response, however, which is really the message, is shown by the stability between 3- and 6-month response rates, 38% and 37%, respectively,” Dr Schuster said. “The response rate at 3 months is really indicative of the long-term benefit of this treatment approach.”
The investigators observed no apparent relationship between tumor response at month 3 and dose. And they observed responses at all dose levels.
The very early response may be due, to a certain extent, to the chemotherapy, according to Dr Schuster.
“The effect of the T cells becomes evident as you follow these patients over time,” he said.
The median duration of response and overall response have not been reached. And 74% of patients were relapse-free at 6 months.
“Importantly, almost all the complete responders at month 3 remained in complete response,” Dr Schuster said.
Safety
Adverse events of special interest that occurred within 8 weeks of the infusion included:
- Cytokine release syndrome (CRS)—58% all grades, 15% grade 3, 8% grade 4
- Neurologic events—21% all grades, 8% grade 3, 4% grade 4
- Prolonged cytopenia—36% all grades, 15% grade 3, 12% grade 4
- Infections—34% all grades, 18% grade 3, 2% grade 4
- Febrile neutropenia—13% all grades, 11% grade 3, 2% grade 4
No deaths occurred due to tisagenlecleucel, CRS, or cerebral edema.
Fifty-seven patients developed CRS. The median time to onset of CRS was 3 days (range, 1–9), and the median duration of CRS was 7 days (range, 2–30).
Twenty-eight percent of patients developed hypotension that required intervention, 6% requiring high-dose vasopressors. Eight percent were intubated, and 16% received anticytokine therapy—15% with tocilizumab and 11% with corticosteroids.
Investigators did not observe a relationship between dose and neurological events. However, they did detect a higher probability of CRS with the higher doses of tisagenlecleucel.
They also noted that dose and exposure were independent.
Dr Schuster indicated that these data are the basis for global regulatory submissions.
Manufacture of tisagenlecleucel was centralized, and investigators believe the trial shows the feasibility of global distribution of CAR T-cell therapy using cryopreserved apheresis and centralized manufacturing.
Novartis Pharmaceuticals, the sponsor of the trial, is now able to commercially manufacture the CAR T cells in 22 days.
Dr Schuster disclosed research funding and consulting fees from Novartis and Celgene.
CRP drives bone destruction in myeloma, team says
New research suggests that C-reactive protein (CRP) drives multiple myeloma (MM) to destroy bone.
Researchers found that CRP accelerated the onset of bone destruction and made bone damage more severe in mouse models of MM.
The team also observed an association between elevated serum CRP levels and greater degree of bone damage in newly diagnosed MM patients.
The researchers therefore believe that CRP might be targeted to prevent or treat MM-associated bone disease.
Qing Yi, MD, PhD, of the Lerner Research Institute at the Cleveland Clinic in Ohio, and his colleagues conducted this research and reported the results in Science Translational Medicine.
The researchers noted that high levels of circulating CRP have been associated with poor prognosis in many cancers, including MM.
In a previous study, the team found that CRP enhanced MM cell proliferation under stressed conditions and protected MM cells from chemotherapy-induced apoptosis.
Now, the researchers have found that CRP activates MM cells to promote osteoclastogenesis and bone destruction.
In experiments with mouse models, the team found that CRP promoted MM-cell-mediated lytic bone disease. The researchers said CRP enhanced osteoclast differentiation and bone resorption activity.
In vitro experiments showed that CRP stimulates MM cells to produce osteoclast activators such as RANKL, MCP-1, and MIP-1a.
Further investigation revealed that CRP binds to CD32 on MM cells. This activates a pathway mediated by the kinase p38 MAPK and the transcription factor Twist, which increases MM cells’ production of osteolytic cytokines.
Finally, the researchers analyzed samples from newly diagnosed MM patients.
The team found that serum CRP levels “significantly and positively” correlated with the number of bone lesions patients had. And CRP was abundant in lesion biopsies from individuals with severe skeletal disease.
New research suggests that C-reactive protein (CRP) drives multiple myeloma (MM) to destroy bone.
Researchers found that CRP accelerated the onset of bone destruction and made bone damage more severe in mouse models of MM.
The team also observed an association between elevated serum CRP levels and greater degree of bone damage in newly diagnosed MM patients.
The researchers therefore believe that CRP might be targeted to prevent or treat MM-associated bone disease.
Qing Yi, MD, PhD, of the Lerner Research Institute at the Cleveland Clinic in Ohio, and his colleagues conducted this research and reported the results in Science Translational Medicine.
The researchers noted that high levels of circulating CRP have been associated with poor prognosis in many cancers, including MM.
In a previous study, the team found that CRP enhanced MM cell proliferation under stressed conditions and protected MM cells from chemotherapy-induced apoptosis.
Now, the researchers have found that CRP activates MM cells to promote osteoclastogenesis and bone destruction.
In experiments with mouse models, the team found that CRP promoted MM-cell-mediated lytic bone disease. The researchers said CRP enhanced osteoclast differentiation and bone resorption activity.
In vitro experiments showed that CRP stimulates MM cells to produce osteoclast activators such as RANKL, MCP-1, and MIP-1a.
Further investigation revealed that CRP binds to CD32 on MM cells. This activates a pathway mediated by the kinase p38 MAPK and the transcription factor Twist, which increases MM cells’ production of osteolytic cytokines.
Finally, the researchers analyzed samples from newly diagnosed MM patients.
The team found that serum CRP levels “significantly and positively” correlated with the number of bone lesions patients had. And CRP was abundant in lesion biopsies from individuals with severe skeletal disease.
New research suggests that C-reactive protein (CRP) drives multiple myeloma (MM) to destroy bone.
Researchers found that CRP accelerated the onset of bone destruction and made bone damage more severe in mouse models of MM.
The team also observed an association between elevated serum CRP levels and greater degree of bone damage in newly diagnosed MM patients.
The researchers therefore believe that CRP might be targeted to prevent or treat MM-associated bone disease.
Qing Yi, MD, PhD, of the Lerner Research Institute at the Cleveland Clinic in Ohio, and his colleagues conducted this research and reported the results in Science Translational Medicine.
The researchers noted that high levels of circulating CRP have been associated with poor prognosis in many cancers, including MM.
In a previous study, the team found that CRP enhanced MM cell proliferation under stressed conditions and protected MM cells from chemotherapy-induced apoptosis.
Now, the researchers have found that CRP activates MM cells to promote osteoclastogenesis and bone destruction.
In experiments with mouse models, the team found that CRP promoted MM-cell-mediated lytic bone disease. The researchers said CRP enhanced osteoclast differentiation and bone resorption activity.
In vitro experiments showed that CRP stimulates MM cells to produce osteoclast activators such as RANKL, MCP-1, and MIP-1a.
Further investigation revealed that CRP binds to CD32 on MM cells. This activates a pathway mediated by the kinase p38 MAPK and the transcription factor Twist, which increases MM cells’ production of osteolytic cytokines.
Finally, the researchers analyzed samples from newly diagnosed MM patients.
The team found that serum CRP levels “significantly and positively” correlated with the number of bone lesions patients had. And CRP was abundant in lesion biopsies from individuals with severe skeletal disease.
Providers endorse medical marijuana for kids with cancer
A survey of nearly 300 US medical providers revealed that many were open to helping children with cancer access medical marijuana (MM).
However, most of the providers surveyed did not know state-specific regulations pertaining to MM.
Providers who were legally eligible to certify (ETC) for MM were less open to endorsing its use.
The lack of standards on formulations, dosing, and potency of MM was identified as the greatest barrier to recommending MM for children with cancer.
Kelly Michelson, MD, of Ann & Robert H. Lurie Children’s Hospital of Chicago in Illinois, and her colleagues reported these findings in Pediatrics.
The researchers used a 32-item survey to assess MM practices, knowledge, attitudes, and barriers for pediatric oncology providers in Illinois, Massachusetts, and Washington.
The survey was sent to providers at Dana-Farber/Boston Children’s Cancer and Blood Disorders Center, Seattle Children’s Cancer and Blood Disorders Center, and Lurie Children’s Center for Cancer and Blood Disorders.
There were 288 respondents, and 33% were legally ETC for MM. Eighty-six percent of ETC providers were physicians, and 14% were nurse practitioners or physician assistants.
Of the non-ETC providers, 89% were nurses, 8% were nurse practitioners or physician assistants, 2% were psychosocial providers, and 2% were “other” providers.
Thirty percent of all providers said they had received at least 1 request for MM in the previous month. And 14% of these providers facilitated patient access to MM.
Ninety-two percent of providers said they were willing to help pediatric cancer patients access MM. Fifty-seven percent of providers approved of patients smoking MM, 89% approved of oral formulations, 67% approved of using MM as cancer-directed therapy, and 92% approved of using MM to manage symptoms.
Fifty-nine percent of providers knew that MM is against federal laws, and 86% knew that their state had legalized MM, but only 5% knew state-specific regulations.
ETC providers were less likely to report willingness to help patients access MM. These providers were also less likely to approve of MM use by smoking, oral formulations, as cancer-directed therapy, or to manage symptoms.
“It is not surprising that providers who are eligible to certify for medical marijuana were more cautious about recommending it, given that their licensure could be jeopardized due to federal prohibition,” Dr Michelson said.
“Institutional policies also may have influenced their attitudes. Lurie Children’s, for example, prohibits pediatric providers from facilitating medical marijuana access in accordance with the federal law, even though it is legal in Illinois.”
Most providers considered MM more permissible for use in children with advanced cancer or near the end of life than in earlier stages of cancer treatment. This is consistent with the current American Academy of Pediatrics position that sanctions MM use for “children with life-limiting or seriously debilitating conditions.”
Only 2% of providers reported that MM was never appropriate for a child with cancer.
Most providers (63%) were not concerned about substance abuse in children who receive MM or about being prosecuted for helping patients access MM (80%).
The greatest concern (listed by 46% of providers) was the absence of standards around prescribing MM to children with cancer.
“In addition to unclear dosage guidelines, the lack of high quality scientific data that medical marijuana benefits outweigh possible harm is a huge concern for providers accustomed to evidence-based practice,” Dr Michelson said. “We need rigorously designed clinical trials on the use of medical marijuana in children with cancer.”
A survey of nearly 300 US medical providers revealed that many were open to helping children with cancer access medical marijuana (MM).
However, most of the providers surveyed did not know state-specific regulations pertaining to MM.
Providers who were legally eligible to certify (ETC) for MM were less open to endorsing its use.
The lack of standards on formulations, dosing, and potency of MM was identified as the greatest barrier to recommending MM for children with cancer.
Kelly Michelson, MD, of Ann & Robert H. Lurie Children’s Hospital of Chicago in Illinois, and her colleagues reported these findings in Pediatrics.
The researchers used a 32-item survey to assess MM practices, knowledge, attitudes, and barriers for pediatric oncology providers in Illinois, Massachusetts, and Washington.
The survey was sent to providers at Dana-Farber/Boston Children’s Cancer and Blood Disorders Center, Seattle Children’s Cancer and Blood Disorders Center, and Lurie Children’s Center for Cancer and Blood Disorders.
There were 288 respondents, and 33% were legally ETC for MM. Eighty-six percent of ETC providers were physicians, and 14% were nurse practitioners or physician assistants.
Of the non-ETC providers, 89% were nurses, 8% were nurse practitioners or physician assistants, 2% were psychosocial providers, and 2% were “other” providers.
Thirty percent of all providers said they had received at least 1 request for MM in the previous month. And 14% of these providers facilitated patient access to MM.
Ninety-two percent of providers said they were willing to help pediatric cancer patients access MM. Fifty-seven percent of providers approved of patients smoking MM, 89% approved of oral formulations, 67% approved of using MM as cancer-directed therapy, and 92% approved of using MM to manage symptoms.
Fifty-nine percent of providers knew that MM is against federal laws, and 86% knew that their state had legalized MM, but only 5% knew state-specific regulations.
ETC providers were less likely to report willingness to help patients access MM. These providers were also less likely to approve of MM use by smoking, oral formulations, as cancer-directed therapy, or to manage symptoms.
“It is not surprising that providers who are eligible to certify for medical marijuana were more cautious about recommending it, given that their licensure could be jeopardized due to federal prohibition,” Dr Michelson said.
“Institutional policies also may have influenced their attitudes. Lurie Children’s, for example, prohibits pediatric providers from facilitating medical marijuana access in accordance with the federal law, even though it is legal in Illinois.”
Most providers considered MM more permissible for use in children with advanced cancer or near the end of life than in earlier stages of cancer treatment. This is consistent with the current American Academy of Pediatrics position that sanctions MM use for “children with life-limiting or seriously debilitating conditions.”
Only 2% of providers reported that MM was never appropriate for a child with cancer.
Most providers (63%) were not concerned about substance abuse in children who receive MM or about being prosecuted for helping patients access MM (80%).
The greatest concern (listed by 46% of providers) was the absence of standards around prescribing MM to children with cancer.
“In addition to unclear dosage guidelines, the lack of high quality scientific data that medical marijuana benefits outweigh possible harm is a huge concern for providers accustomed to evidence-based practice,” Dr Michelson said. “We need rigorously designed clinical trials on the use of medical marijuana in children with cancer.”
A survey of nearly 300 US medical providers revealed that many were open to helping children with cancer access medical marijuana (MM).
However, most of the providers surveyed did not know state-specific regulations pertaining to MM.
Providers who were legally eligible to certify (ETC) for MM were less open to endorsing its use.
The lack of standards on formulations, dosing, and potency of MM was identified as the greatest barrier to recommending MM for children with cancer.
Kelly Michelson, MD, of Ann & Robert H. Lurie Children’s Hospital of Chicago in Illinois, and her colleagues reported these findings in Pediatrics.
The researchers used a 32-item survey to assess MM practices, knowledge, attitudes, and barriers for pediatric oncology providers in Illinois, Massachusetts, and Washington.
The survey was sent to providers at Dana-Farber/Boston Children’s Cancer and Blood Disorders Center, Seattle Children’s Cancer and Blood Disorders Center, and Lurie Children’s Center for Cancer and Blood Disorders.
There were 288 respondents, and 33% were legally ETC for MM. Eighty-six percent of ETC providers were physicians, and 14% were nurse practitioners or physician assistants.
Of the non-ETC providers, 89% were nurses, 8% were nurse practitioners or physician assistants, 2% were psychosocial providers, and 2% were “other” providers.
Thirty percent of all providers said they had received at least 1 request for MM in the previous month. And 14% of these providers facilitated patient access to MM.
Ninety-two percent of providers said they were willing to help pediatric cancer patients access MM. Fifty-seven percent of providers approved of patients smoking MM, 89% approved of oral formulations, 67% approved of using MM as cancer-directed therapy, and 92% approved of using MM to manage symptoms.
Fifty-nine percent of providers knew that MM is against federal laws, and 86% knew that their state had legalized MM, but only 5% knew state-specific regulations.
ETC providers were less likely to report willingness to help patients access MM. These providers were also less likely to approve of MM use by smoking, oral formulations, as cancer-directed therapy, or to manage symptoms.
“It is not surprising that providers who are eligible to certify for medical marijuana were more cautious about recommending it, given that their licensure could be jeopardized due to federal prohibition,” Dr Michelson said.
“Institutional policies also may have influenced their attitudes. Lurie Children’s, for example, prohibits pediatric providers from facilitating medical marijuana access in accordance with the federal law, even though it is legal in Illinois.”
Most providers considered MM more permissible for use in children with advanced cancer or near the end of life than in earlier stages of cancer treatment. This is consistent with the current American Academy of Pediatrics position that sanctions MM use for “children with life-limiting or seriously debilitating conditions.”
Only 2% of providers reported that MM was never appropriate for a child with cancer.
Most providers (63%) were not concerned about substance abuse in children who receive MM or about being prosecuted for helping patients access MM (80%).
The greatest concern (listed by 46% of providers) was the absence of standards around prescribing MM to children with cancer.
“In addition to unclear dosage guidelines, the lack of high quality scientific data that medical marijuana benefits outweigh possible harm is a huge concern for providers accustomed to evidence-based practice,” Dr Michelson said. “We need rigorously designed clinical trials on the use of medical marijuana in children with cancer.”
A+AVD improves modified PFS in advanced HL
ATLANTA—Phase 3 trial results suggest one 4-drug combination may be more effective than another as frontline treatment for advanced Hodgkin lymphoma (HL).
In the ECHELON-1 trial, treatment with brentuximab vedotin, doxorubicin, vinblastine, and dacarbazine (A+AVD) staved off progression, death, and the need for subsequent therapy more effectively than treatment with doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD).
However, there was no significant difference between the treatment arms when it came to response rates or overall survival.
Neutropenia, febrile neutropenia, and peripheral neuropathy were more common with A+AVD, while pulmonary toxicity was more common with ABVD.
These data were presented at the 2017 ASH Annual Meeting (abstract 6) and simultaneously published in The New England Journal of Medicine. The trial was funded by Millennium Pharmaceuticals and Seattle Genetics, Inc.
“The standard of care in the treatment of Hodgkin lymphoma has not changed over the last several decades, and there remains an unmet need for additional regimens in frontline treatment,” said Joseph M. Connors, MD, of BC Cancer in Vancouver, British Columbia, Canada.
With this in mind, he and his colleagues conducted ECHELON-1. The study enrolled 1334 patients who had stage III or IV HL and had not previously received systemic chemotherapy or radiotherapy.
Fifty-eight percent of patients were male, and the median age was 36 (range, 18-83). Sixty-four percent of patients had stage IV disease, 62% had extranodal involvement at diagnosis, and 58% had B symptoms.
The patients were randomized to receive A+AVD (n=664) or ABVD (n=670) on days 1 and 15 of each 28-day cycle for up to 6 cycles. Baseline characteristics were well-balanced between the treatment arms.
The median follow-up was 24.9 months (range, 0-49.3).
Primary endpoint
The study’s primary endpoint is modified progression-free survival (PFS), which is defined as time to progression, death, or evidence of non-complete response after completion of frontline therapy followed by subsequent anticancer therapy.
According to an independent review facility, A+AVD provided a significant improvement in modified PFS compared to ABVD. The hazard ratio was 0.77 (P=0.035), which corresponds to a 23% reduction in the risk of progression, death, or the need for additional anticancer therapy.
“Reducing the risk of relapse is an important concern for patients and their physicians,” Dr Connors noted. “In the trial, 33% fewer patients [in the A+AVD arm] required subsequent salvage chemotherapy or high-dose chemotherapy and transplant compared to the patients treated with ABVD.”
According to the independent review facility, the 2-year modified PFS rate was 82.1% in the A+AVD arm and 77.2% in the ABVD arm.
Certain pre-specified subgroups of patients appeared to benefit more with A+AVD than with ABVD, including:
- Males
- Patients treated in North America
- Patients with involvement of more than 1 extranodal site
- Patients with International Prognostic Scores of 4 to 7
- Patients with stage IV disease
- Patients younger than 60.
Secondary endpoints
Secondary endpoints trended in favor of the A+AVD arm, although there were no significant differences between the treatment arms.
The objective response rate at the end of the randomized regimen was 86% in the A+AVD arm and 83% in the ABVD arm (P=0.12). The complete response rate was 73% and 70%, respectively (P=0.22).
The proportion of patients with a Deauville score ≤2 after the completion of frontline therapy was 85% in the A+AVD arm and 80% in the ABVD arm (P=0.03).
The interim 2-year overall survival rate was 97% in the A+AVD arm and 95% in the ABVD arm (hazard ratio=0.72; P=0.19).
Safety
“[T]he safety profile [of A+AVD] was generally consistent with that known for the single-agent components of the regimen,” Dr Connors said.
The overall incidence of adverse events (AEs) was 99% in the A+AVD arm and 98% in the ABVD arm. The incidence of grade 3 or higher AEs was 83% and 66%, respectively, and the incidence of serious AEs was 43% and 27%, respectively.
Common AEs (in the A+AVD and ABVD arms, respectively) included neutropenia (58% and 45%), constipation (42% and 37%), vomiting (33% and 28%), fatigue (both 32%), diarrhea (27% and 18%), pyrexia (27% and 22%), abdominal pain (21% and 10%), and stomatitis (21% and 16%).
Peripheral neuropathy events were observed in 67% of patients in the A+AVD arm and 43% in the ABVD arm. Grade 3 or higher peripheral neuropathy was reported in 11% and 2%, respectively.
Febrile neutropenia occurred in 19% of patients in the A+AVD arm and 8% of those in the ABVD arm. However, prophylaxis with granulocyte colony-stimulating factor (G-CSF) was able to reduce the incidence of febrile neutropenia. In the A+AVD arm, the rate of febrile neutropenia was 11% among patients who received G-CSF and 21% among patients who did not.
Pulmonary toxicity occurred in 2% of patients in the A+AVD arm and 7% of those in the ABVD arm. Grade 3 or higher pulmonary toxicity was reported in 0.76% and 3%, respectively.
There were 9 deaths during treatment in the A+AVD arm. Seven were due to neutropenia or associated complications, and 2 were due to myocardial infarction. One of the patients who died of neutropenia had the condition prior to trial enrollment. The remaining 6 patients did not receive G-CSF prophylaxis.
In the ABVD arm, there were 13 deaths during treatment. Eleven were due to or associated with pulmonary-related toxicity, 1 was due to cardiopulmonary failure, and 1 death had an unknown cause.
ATLANTA—Phase 3 trial results suggest one 4-drug combination may be more effective than another as frontline treatment for advanced Hodgkin lymphoma (HL).
In the ECHELON-1 trial, treatment with brentuximab vedotin, doxorubicin, vinblastine, and dacarbazine (A+AVD) staved off progression, death, and the need for subsequent therapy more effectively than treatment with doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD).
However, there was no significant difference between the treatment arms when it came to response rates or overall survival.
Neutropenia, febrile neutropenia, and peripheral neuropathy were more common with A+AVD, while pulmonary toxicity was more common with ABVD.
These data were presented at the 2017 ASH Annual Meeting (abstract 6) and simultaneously published in The New England Journal of Medicine. The trial was funded by Millennium Pharmaceuticals and Seattle Genetics, Inc.
“The standard of care in the treatment of Hodgkin lymphoma has not changed over the last several decades, and there remains an unmet need for additional regimens in frontline treatment,” said Joseph M. Connors, MD, of BC Cancer in Vancouver, British Columbia, Canada.
With this in mind, he and his colleagues conducted ECHELON-1. The study enrolled 1334 patients who had stage III or IV HL and had not previously received systemic chemotherapy or radiotherapy.
Fifty-eight percent of patients were male, and the median age was 36 (range, 18-83). Sixty-four percent of patients had stage IV disease, 62% had extranodal involvement at diagnosis, and 58% had B symptoms.
The patients were randomized to receive A+AVD (n=664) or ABVD (n=670) on days 1 and 15 of each 28-day cycle for up to 6 cycles. Baseline characteristics were well-balanced between the treatment arms.
The median follow-up was 24.9 months (range, 0-49.3).
Primary endpoint
The study’s primary endpoint is modified progression-free survival (PFS), which is defined as time to progression, death, or evidence of non-complete response after completion of frontline therapy followed by subsequent anticancer therapy.
According to an independent review facility, A+AVD provided a significant improvement in modified PFS compared to ABVD. The hazard ratio was 0.77 (P=0.035), which corresponds to a 23% reduction in the risk of progression, death, or the need for additional anticancer therapy.
“Reducing the risk of relapse is an important concern for patients and their physicians,” Dr Connors noted. “In the trial, 33% fewer patients [in the A+AVD arm] required subsequent salvage chemotherapy or high-dose chemotherapy and transplant compared to the patients treated with ABVD.”
According to the independent review facility, the 2-year modified PFS rate was 82.1% in the A+AVD arm and 77.2% in the ABVD arm.
Certain pre-specified subgroups of patients appeared to benefit more with A+AVD than with ABVD, including:
- Males
- Patients treated in North America
- Patients with involvement of more than 1 extranodal site
- Patients with International Prognostic Scores of 4 to 7
- Patients with stage IV disease
- Patients younger than 60.
Secondary endpoints
Secondary endpoints trended in favor of the A+AVD arm, although there were no significant differences between the treatment arms.
The objective response rate at the end of the randomized regimen was 86% in the A+AVD arm and 83% in the ABVD arm (P=0.12). The complete response rate was 73% and 70%, respectively (P=0.22).
The proportion of patients with a Deauville score ≤2 after the completion of frontline therapy was 85% in the A+AVD arm and 80% in the ABVD arm (P=0.03).
The interim 2-year overall survival rate was 97% in the A+AVD arm and 95% in the ABVD arm (hazard ratio=0.72; P=0.19).
Safety
“[T]he safety profile [of A+AVD] was generally consistent with that known for the single-agent components of the regimen,” Dr Connors said.
The overall incidence of adverse events (AEs) was 99% in the A+AVD arm and 98% in the ABVD arm. The incidence of grade 3 or higher AEs was 83% and 66%, respectively, and the incidence of serious AEs was 43% and 27%, respectively.
Common AEs (in the A+AVD and ABVD arms, respectively) included neutropenia (58% and 45%), constipation (42% and 37%), vomiting (33% and 28%), fatigue (both 32%), diarrhea (27% and 18%), pyrexia (27% and 22%), abdominal pain (21% and 10%), and stomatitis (21% and 16%).
Peripheral neuropathy events were observed in 67% of patients in the A+AVD arm and 43% in the ABVD arm. Grade 3 or higher peripheral neuropathy was reported in 11% and 2%, respectively.
Febrile neutropenia occurred in 19% of patients in the A+AVD arm and 8% of those in the ABVD arm. However, prophylaxis with granulocyte colony-stimulating factor (G-CSF) was able to reduce the incidence of febrile neutropenia. In the A+AVD arm, the rate of febrile neutropenia was 11% among patients who received G-CSF and 21% among patients who did not.
Pulmonary toxicity occurred in 2% of patients in the A+AVD arm and 7% of those in the ABVD arm. Grade 3 or higher pulmonary toxicity was reported in 0.76% and 3%, respectively.
There were 9 deaths during treatment in the A+AVD arm. Seven were due to neutropenia or associated complications, and 2 were due to myocardial infarction. One of the patients who died of neutropenia had the condition prior to trial enrollment. The remaining 6 patients did not receive G-CSF prophylaxis.
In the ABVD arm, there were 13 deaths during treatment. Eleven were due to or associated with pulmonary-related toxicity, 1 was due to cardiopulmonary failure, and 1 death had an unknown cause.
ATLANTA—Phase 3 trial results suggest one 4-drug combination may be more effective than another as frontline treatment for advanced Hodgkin lymphoma (HL).
In the ECHELON-1 trial, treatment with brentuximab vedotin, doxorubicin, vinblastine, and dacarbazine (A+AVD) staved off progression, death, and the need for subsequent therapy more effectively than treatment with doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD).
However, there was no significant difference between the treatment arms when it came to response rates or overall survival.
Neutropenia, febrile neutropenia, and peripheral neuropathy were more common with A+AVD, while pulmonary toxicity was more common with ABVD.
These data were presented at the 2017 ASH Annual Meeting (abstract 6) and simultaneously published in The New England Journal of Medicine. The trial was funded by Millennium Pharmaceuticals and Seattle Genetics, Inc.
“The standard of care in the treatment of Hodgkin lymphoma has not changed over the last several decades, and there remains an unmet need for additional regimens in frontline treatment,” said Joseph M. Connors, MD, of BC Cancer in Vancouver, British Columbia, Canada.
With this in mind, he and his colleagues conducted ECHELON-1. The study enrolled 1334 patients who had stage III or IV HL and had not previously received systemic chemotherapy or radiotherapy.
Fifty-eight percent of patients were male, and the median age was 36 (range, 18-83). Sixty-four percent of patients had stage IV disease, 62% had extranodal involvement at diagnosis, and 58% had B symptoms.
The patients were randomized to receive A+AVD (n=664) or ABVD (n=670) on days 1 and 15 of each 28-day cycle for up to 6 cycles. Baseline characteristics were well-balanced between the treatment arms.
The median follow-up was 24.9 months (range, 0-49.3).
Primary endpoint
The study’s primary endpoint is modified progression-free survival (PFS), which is defined as time to progression, death, or evidence of non-complete response after completion of frontline therapy followed by subsequent anticancer therapy.
According to an independent review facility, A+AVD provided a significant improvement in modified PFS compared to ABVD. The hazard ratio was 0.77 (P=0.035), which corresponds to a 23% reduction in the risk of progression, death, or the need for additional anticancer therapy.
“Reducing the risk of relapse is an important concern for patients and their physicians,” Dr Connors noted. “In the trial, 33% fewer patients [in the A+AVD arm] required subsequent salvage chemotherapy or high-dose chemotherapy and transplant compared to the patients treated with ABVD.”
According to the independent review facility, the 2-year modified PFS rate was 82.1% in the A+AVD arm and 77.2% in the ABVD arm.
Certain pre-specified subgroups of patients appeared to benefit more with A+AVD than with ABVD, including:
- Males
- Patients treated in North America
- Patients with involvement of more than 1 extranodal site
- Patients with International Prognostic Scores of 4 to 7
- Patients with stage IV disease
- Patients younger than 60.
Secondary endpoints
Secondary endpoints trended in favor of the A+AVD arm, although there were no significant differences between the treatment arms.
The objective response rate at the end of the randomized regimen was 86% in the A+AVD arm and 83% in the ABVD arm (P=0.12). The complete response rate was 73% and 70%, respectively (P=0.22).
The proportion of patients with a Deauville score ≤2 after the completion of frontline therapy was 85% in the A+AVD arm and 80% in the ABVD arm (P=0.03).
The interim 2-year overall survival rate was 97% in the A+AVD arm and 95% in the ABVD arm (hazard ratio=0.72; P=0.19).
Safety
“[T]he safety profile [of A+AVD] was generally consistent with that known for the single-agent components of the regimen,” Dr Connors said.
The overall incidence of adverse events (AEs) was 99% in the A+AVD arm and 98% in the ABVD arm. The incidence of grade 3 or higher AEs was 83% and 66%, respectively, and the incidence of serious AEs was 43% and 27%, respectively.
Common AEs (in the A+AVD and ABVD arms, respectively) included neutropenia (58% and 45%), constipation (42% and 37%), vomiting (33% and 28%), fatigue (both 32%), diarrhea (27% and 18%), pyrexia (27% and 22%), abdominal pain (21% and 10%), and stomatitis (21% and 16%).
Peripheral neuropathy events were observed in 67% of patients in the A+AVD arm and 43% in the ABVD arm. Grade 3 or higher peripheral neuropathy was reported in 11% and 2%, respectively.
Febrile neutropenia occurred in 19% of patients in the A+AVD arm and 8% of those in the ABVD arm. However, prophylaxis with granulocyte colony-stimulating factor (G-CSF) was able to reduce the incidence of febrile neutropenia. In the A+AVD arm, the rate of febrile neutropenia was 11% among patients who received G-CSF and 21% among patients who did not.
Pulmonary toxicity occurred in 2% of patients in the A+AVD arm and 7% of those in the ABVD arm. Grade 3 or higher pulmonary toxicity was reported in 0.76% and 3%, respectively.
There were 9 deaths during treatment in the A+AVD arm. Seven were due to neutropenia or associated complications, and 2 were due to myocardial infarction. One of the patients who died of neutropenia had the condition prior to trial enrollment. The remaining 6 patients did not receive G-CSF prophylaxis.
In the ABVD arm, there were 13 deaths during treatment. Eleven were due to or associated with pulmonary-related toxicity, 1 was due to cardiopulmonary failure, and 1 death had an unknown cause.
EC approves new formulation of pegaspargase
The European Commission (EC) has granted marketing authorization for a lyophilized formulation of pegaspargase (ONCASPAR).
The product is intended for use as a component of antineoplastic combination therapy in acute lymphoblastic leukemia patients of all ages.
The EC’s approval authorizes Shire to market lyophilized pegaspargase in the 28 member states of the European Union as well as Iceland, Liechtenstein, and Norway.
Lyophilized pegaspargase works the same way as the liquid formulation. By depleting serum L-asparagine levels and thereby interfering with protein synthesis, pegaspargase deprives lymphoblasts of L-asparagine, resulting in cell death.
The lyophilized formulation offers the same dosing regimen as liquid pegaspargase but also provides a shelf life of up to 24 months—3 times longer than that of the liquid formulation.
Shire expects lyophilized pegaspargase to be available in European markets beginning in the first half of 2018.
“With this lyophilized formulation, we aim to make pegylated asparaginase, part of the pediatric standard therapy in acute lymphoblastic leukemia, available to patients in countries where liquid ONCASPAR is not currently offered,” said Howard B. Mayer, MD, senior vice-president and ad-interim head of global research and development at Shire.
“Additionally, with extended shelf life up to 24 months, treatment centers will have flexibility in inventory management to help ensure continuous treatment supply for patients.”
The European Commission (EC) has granted marketing authorization for a lyophilized formulation of pegaspargase (ONCASPAR).
The product is intended for use as a component of antineoplastic combination therapy in acute lymphoblastic leukemia patients of all ages.
The EC’s approval authorizes Shire to market lyophilized pegaspargase in the 28 member states of the European Union as well as Iceland, Liechtenstein, and Norway.
Lyophilized pegaspargase works the same way as the liquid formulation. By depleting serum L-asparagine levels and thereby interfering with protein synthesis, pegaspargase deprives lymphoblasts of L-asparagine, resulting in cell death.
The lyophilized formulation offers the same dosing regimen as liquid pegaspargase but also provides a shelf life of up to 24 months—3 times longer than that of the liquid formulation.
Shire expects lyophilized pegaspargase to be available in European markets beginning in the first half of 2018.
“With this lyophilized formulation, we aim to make pegylated asparaginase, part of the pediatric standard therapy in acute lymphoblastic leukemia, available to patients in countries where liquid ONCASPAR is not currently offered,” said Howard B. Mayer, MD, senior vice-president and ad-interim head of global research and development at Shire.
“Additionally, with extended shelf life up to 24 months, treatment centers will have flexibility in inventory management to help ensure continuous treatment supply for patients.”
The European Commission (EC) has granted marketing authorization for a lyophilized formulation of pegaspargase (ONCASPAR).
The product is intended for use as a component of antineoplastic combination therapy in acute lymphoblastic leukemia patients of all ages.
The EC’s approval authorizes Shire to market lyophilized pegaspargase in the 28 member states of the European Union as well as Iceland, Liechtenstein, and Norway.
Lyophilized pegaspargase works the same way as the liquid formulation. By depleting serum L-asparagine levels and thereby interfering with protein synthesis, pegaspargase deprives lymphoblasts of L-asparagine, resulting in cell death.
The lyophilized formulation offers the same dosing regimen as liquid pegaspargase but also provides a shelf life of up to 24 months—3 times longer than that of the liquid formulation.
Shire expects lyophilized pegaspargase to be available in European markets beginning in the first half of 2018.
“With this lyophilized formulation, we aim to make pegylated asparaginase, part of the pediatric standard therapy in acute lymphoblastic leukemia, available to patients in countries where liquid ONCASPAR is not currently offered,” said Howard B. Mayer, MD, senior vice-president and ad-interim head of global research and development at Shire.
“Additionally, with extended shelf life up to 24 months, treatment centers will have flexibility in inventory management to help ensure continuous treatment supply for patients.”
Technique may be effective for diagnosing NHL
Preclinical research suggests infrared spectroscopy could be used to diagnose non-Hodgkin lymphoma (NHL).
Researchers used mid-infrared spectroscopy to analyze blood serum derived from mice and differentiate mice with NHL and subcutaneous melanoma from each other and from healthy control mice.
The findings suggest infrared spectroscopy can detect biochemical changes induced by NHL and melanoma and therefore has diagnostic potential as a screening technique for these cancers.
A.G. Unil Perera, PhD, of Georgia State University in Atlanta, and his colleagues detailed these findings in Scientific Reports.
The researchers said that Fourier Transform Infrared (FTIR) spectroscopy in Attenuated Total Reflection (ATR) sampling mode provides high-quality results with better reproducibility compared to other vibrational spectroscopy.
With previous work, Dr Perera and his colleagues discovered that a blood test for ulcerative colitis using ATR-FTIR spectroscopy could provide a cheaper, less invasive alternative for screening compared to colonoscopy.
In the current study, the researchers tested ATR-FTIR spectroscopy in mouse models of malignancy—EL4 NHL and B16 subcutaneous melanoma.
The team extracted blood serum from these mice and control mice. Droplets of serum were placed on an ATR crystal of the FTIR instrument.
Incident infrared beams were absorbed and reflected by the serum, creating a wave that was recorded and used to produce an absorbance curve with peaks that identified the presence of certain biomarkers in the sample.
The researchers compared the absorbance curves from the control and cancer mice and assessed biochemical changes induced by NHL and melanoma.
The team found “remarkable” differences between the ATR-FTIR spectra of serum samples from tumor-bearing mice and control mice.
Dr Perera said these findings are applicable to humans because mice and humans have some biomarkers and chemicals in common.
Using the data collected on the biomarkers for NHL and melanoma, the researchers could develop detectors for these particular absorbance peaks, which doctors could use to test patients’ blood samples for these cancers.
“Our final goal is to say we can use this infrared technique to identify various diseases,” Dr Perera said. “This study shows infrared spectroscopy can identify cancer. Right now, when you go to the doctor, they do blood tests for sugar and several other things but not for serious diseases like cancer and colitis.”
“One day, we hope that even these serious diseases can be rapidly screened. Your primary doctor could keep a record of your number and check that every time you come back. Then, if there is some indication of cancer or colitis, they can do biopsies, colonoscopies, etc.”
Preclinical research suggests infrared spectroscopy could be used to diagnose non-Hodgkin lymphoma (NHL).
Researchers used mid-infrared spectroscopy to analyze blood serum derived from mice and differentiate mice with NHL and subcutaneous melanoma from each other and from healthy control mice.
The findings suggest infrared spectroscopy can detect biochemical changes induced by NHL and melanoma and therefore has diagnostic potential as a screening technique for these cancers.
A.G. Unil Perera, PhD, of Georgia State University in Atlanta, and his colleagues detailed these findings in Scientific Reports.
The researchers said that Fourier Transform Infrared (FTIR) spectroscopy in Attenuated Total Reflection (ATR) sampling mode provides high-quality results with better reproducibility compared to other vibrational spectroscopy.
With previous work, Dr Perera and his colleagues discovered that a blood test for ulcerative colitis using ATR-FTIR spectroscopy could provide a cheaper, less invasive alternative for screening compared to colonoscopy.
In the current study, the researchers tested ATR-FTIR spectroscopy in mouse models of malignancy—EL4 NHL and B16 subcutaneous melanoma.
The team extracted blood serum from these mice and control mice. Droplets of serum were placed on an ATR crystal of the FTIR instrument.
Incident infrared beams were absorbed and reflected by the serum, creating a wave that was recorded and used to produce an absorbance curve with peaks that identified the presence of certain biomarkers in the sample.
The researchers compared the absorbance curves from the control and cancer mice and assessed biochemical changes induced by NHL and melanoma.
The team found “remarkable” differences between the ATR-FTIR spectra of serum samples from tumor-bearing mice and control mice.
Dr Perera said these findings are applicable to humans because mice and humans have some biomarkers and chemicals in common.
Using the data collected on the biomarkers for NHL and melanoma, the researchers could develop detectors for these particular absorbance peaks, which doctors could use to test patients’ blood samples for these cancers.
“Our final goal is to say we can use this infrared technique to identify various diseases,” Dr Perera said. “This study shows infrared spectroscopy can identify cancer. Right now, when you go to the doctor, they do blood tests for sugar and several other things but not for serious diseases like cancer and colitis.”
“One day, we hope that even these serious diseases can be rapidly screened. Your primary doctor could keep a record of your number and check that every time you come back. Then, if there is some indication of cancer or colitis, they can do biopsies, colonoscopies, etc.”
Preclinical research suggests infrared spectroscopy could be used to diagnose non-Hodgkin lymphoma (NHL).
Researchers used mid-infrared spectroscopy to analyze blood serum derived from mice and differentiate mice with NHL and subcutaneous melanoma from each other and from healthy control mice.
The findings suggest infrared spectroscopy can detect biochemical changes induced by NHL and melanoma and therefore has diagnostic potential as a screening technique for these cancers.
A.G. Unil Perera, PhD, of Georgia State University in Atlanta, and his colleagues detailed these findings in Scientific Reports.
The researchers said that Fourier Transform Infrared (FTIR) spectroscopy in Attenuated Total Reflection (ATR) sampling mode provides high-quality results with better reproducibility compared to other vibrational spectroscopy.
With previous work, Dr Perera and his colleagues discovered that a blood test for ulcerative colitis using ATR-FTIR spectroscopy could provide a cheaper, less invasive alternative for screening compared to colonoscopy.
In the current study, the researchers tested ATR-FTIR spectroscopy in mouse models of malignancy—EL4 NHL and B16 subcutaneous melanoma.
The team extracted blood serum from these mice and control mice. Droplets of serum were placed on an ATR crystal of the FTIR instrument.
Incident infrared beams were absorbed and reflected by the serum, creating a wave that was recorded and used to produce an absorbance curve with peaks that identified the presence of certain biomarkers in the sample.
The researchers compared the absorbance curves from the control and cancer mice and assessed biochemical changes induced by NHL and melanoma.
The team found “remarkable” differences between the ATR-FTIR spectra of serum samples from tumor-bearing mice and control mice.
Dr Perera said these findings are applicable to humans because mice and humans have some biomarkers and chemicals in common.
Using the data collected on the biomarkers for NHL and melanoma, the researchers could develop detectors for these particular absorbance peaks, which doctors could use to test patients’ blood samples for these cancers.
“Our final goal is to say we can use this infrared technique to identify various diseases,” Dr Perera said. “This study shows infrared spectroscopy can identify cancer. Right now, when you go to the doctor, they do blood tests for sugar and several other things but not for serious diseases like cancer and colitis.”
“One day, we hope that even these serious diseases can be rapidly screened. Your primary doctor could keep a record of your number and check that every time you come back. Then, if there is some indication of cancer or colitis, they can do biopsies, colonoscopies, etc.”
Combo should be standard in MM, doc says
ATLANTA—Study results “strongly support” a new standard of care for transplant-ineligible patients with newly diagnosed multiple myeloma (MM), according to a speaker at the 2017 ASH Annual Meeting.
The study, ALCYONE, suggests treatment with bortezomib, melphalan, and prednisone (VMP) can be improved by the addition of daratumumab (D).
D-VMP produced deeper responses and prolonged progression-free survival (PFS) when compared to VMP.
“In this first phase 3, randomized study with a monoclonal antibody in newly diagnosed multiple myeloma, daratumumab reduced the risk of progression or death by 50%,” said Maria-Victoria Mateos, MD, PhD, of University Hospital of Salamanca in Spain.
“No new safety signals were observed [with D-VMP], except for higher infectious events that resolved. I would say the results of this study strongly support daratumumab in combination with VMP as a standard of care in transplant-ineligible, newly diagnosed multiple myeloma.”
Dr Mateos presented results from ALCYONE as a late-breaking abstract (LBA-4) at the ASH Annual Meeting. The study was simultaneously published in NEJM. The research was supported by Janssen Research and Development.
Patients and treatment
ALCYONE enrolled 706 patients with newly diagnosed MM who were not eligible for high-dose chemotherapy with autologous stem cell transplant.
Patients were randomized to receive VMP or D-VMP. They were stratified by International Staging System (I, II, III), region (Europe vs other), and age (<75 vs ≥75 years).
All patients received up to 9 cycles of VMP:
- Bortezomib at 1.3 mg/m2 twice weekly on weeks 1, 2, 4, and 5 of cycle 1 and once weekly on weeks 1, 2, 4, and 5 of cycles 2 through 9
- Melphalan at 9 mg/m2 once daily on days 1 to 4 of each cycle
- Prednisone at 60 mg/m2 once daily on days 1 to 4 of each cycle.
Patients in the daratumumab arm received the drug at 16 mg/kg once-weekly for the first cycle, every 3 weeks for cycles 2 to 9, and every 4 weeks thereafter, until disease progression. These patients also received dexamethasone (to manage infusion reactions) at 20 mg on the same schedule.
Baseline characteristics were similar between the VMP (n=356) and D-VMP (n=350) arms. The median age was 71 in both arms (range, 50-91 in the VMP arm and 40-93 in the D-VMP arm). Males made up 47% of the VMP arm and 46% of the D-VMP arm.
Forty-nine percent of patients in the VMP arm and 52% in the D-VMP arm had an ECOG performance status of 1. Twenty-eight percent and 22%, respectively, had a status of 0.
The median follow-up was 16.5 months (range, 0.1-28.1). At the clinical cutoff date (June 12, 2017), 5% of patients in the VMP arm were still on study treatment, as were 71% of patients in the D-VMP arm.
Response and survival
“I would like to note that the benefit of the addition of daratumumab was observed since the beginning of the treatment,” Dr Mateos said.
The overall response rate was 74% in the VMP arm and 91% in the D-VMP arm (P<0.0001). The median duration of response was 21.3 months in the VMP arm and was not reached in the D-VMP arm.
The rate of complete response was 24% in the VMP arm and 43% in the D-VMP arm (P<0.0001). Six percent of patients in the VMP arm and 22% in the D-VMP arm were negative for minimal residual disease (P<0.0001).
The hazard ratio for disease progression or death in the D-VMP arm versus the VMP arm was 0.50 (P<0.0001).
The median PFS was 18.1 months in the VMP arm and was not reached in the D-VMP arm. The 12-month PFS was 76% and 87%, respectively. And the 18-month PFS was 50% and 72%, respectively.
D-VMP prolonged PFS regardless of patient sex, age, cytogenetic risk, ECOG performance status, baseline renal function, and other factors.
The median overall survival was not reached in either treatment arm. There were 48 deaths in the VMP arm and 45 in the D-VMP arm.
Adverse events
The most common treatment-emergent adverse events (TEAEs; in the D-VMP and VMP arms, respectively) were neutropenia (50% and 53%), thrombocytopenia (49% and 54%), anemia (28% and 38%), peripheral sensory neuropathy (28% and 34%), upper respiratory tract infection (26% and 14%), diarrhea (24% and 25%), pyrexia (23% and 21%), and nausea (21% and 22%).
The most common grade 3/4 TEAEs (in the D-VMP and VMP arms, respectively) were neutropenia (40% and 39%), thrombocytopenia (34% and 38%), and anemia (16% and 20%).
There were 6 deaths due to TEAEs in the D-VMP arm and 5 such deaths in the VMP arm.
The rate of grade 3/4 infections was higher in the D-VMP arm than the VMP arm—23% and 15%, respectively. The most common of these was pneumonia, with rates of 11% and 4%, respectively.
Infections resolved in 88% of cases in the D-VMP arm and 87% of cases in the VMP arm. Rates of treatment discontinuation due to infection were 0.9% and 1.4%, respectively. One patient in each group stopped treatment due to pneumonia.
Twenty-eight percent of patients in the D-VMP arm had infusion-related reactions (15% grade 3 and 2% grade 4). Most of these reactions occurred during the first infusion. Five patients (1.4%) discontinued daratumumab due to infusion-related reactions.
ATLANTA—Study results “strongly support” a new standard of care for transplant-ineligible patients with newly diagnosed multiple myeloma (MM), according to a speaker at the 2017 ASH Annual Meeting.
The study, ALCYONE, suggests treatment with bortezomib, melphalan, and prednisone (VMP) can be improved by the addition of daratumumab (D).
D-VMP produced deeper responses and prolonged progression-free survival (PFS) when compared to VMP.
“In this first phase 3, randomized study with a monoclonal antibody in newly diagnosed multiple myeloma, daratumumab reduced the risk of progression or death by 50%,” said Maria-Victoria Mateos, MD, PhD, of University Hospital of Salamanca in Spain.
“No new safety signals were observed [with D-VMP], except for higher infectious events that resolved. I would say the results of this study strongly support daratumumab in combination with VMP as a standard of care in transplant-ineligible, newly diagnosed multiple myeloma.”
Dr Mateos presented results from ALCYONE as a late-breaking abstract (LBA-4) at the ASH Annual Meeting. The study was simultaneously published in NEJM. The research was supported by Janssen Research and Development.
Patients and treatment
ALCYONE enrolled 706 patients with newly diagnosed MM who were not eligible for high-dose chemotherapy with autologous stem cell transplant.
Patients were randomized to receive VMP or D-VMP. They were stratified by International Staging System (I, II, III), region (Europe vs other), and age (<75 vs ≥75 years).
All patients received up to 9 cycles of VMP:
- Bortezomib at 1.3 mg/m2 twice weekly on weeks 1, 2, 4, and 5 of cycle 1 and once weekly on weeks 1, 2, 4, and 5 of cycles 2 through 9
- Melphalan at 9 mg/m2 once daily on days 1 to 4 of each cycle
- Prednisone at 60 mg/m2 once daily on days 1 to 4 of each cycle.
Patients in the daratumumab arm received the drug at 16 mg/kg once-weekly for the first cycle, every 3 weeks for cycles 2 to 9, and every 4 weeks thereafter, until disease progression. These patients also received dexamethasone (to manage infusion reactions) at 20 mg on the same schedule.
Baseline characteristics were similar between the VMP (n=356) and D-VMP (n=350) arms. The median age was 71 in both arms (range, 50-91 in the VMP arm and 40-93 in the D-VMP arm). Males made up 47% of the VMP arm and 46% of the D-VMP arm.
Forty-nine percent of patients in the VMP arm and 52% in the D-VMP arm had an ECOG performance status of 1. Twenty-eight percent and 22%, respectively, had a status of 0.
The median follow-up was 16.5 months (range, 0.1-28.1). At the clinical cutoff date (June 12, 2017), 5% of patients in the VMP arm were still on study treatment, as were 71% of patients in the D-VMP arm.
Response and survival
“I would like to note that the benefit of the addition of daratumumab was observed since the beginning of the treatment,” Dr Mateos said.
The overall response rate was 74% in the VMP arm and 91% in the D-VMP arm (P<0.0001). The median duration of response was 21.3 months in the VMP arm and was not reached in the D-VMP arm.
The rate of complete response was 24% in the VMP arm and 43% in the D-VMP arm (P<0.0001). Six percent of patients in the VMP arm and 22% in the D-VMP arm were negative for minimal residual disease (P<0.0001).
The hazard ratio for disease progression or death in the D-VMP arm versus the VMP arm was 0.50 (P<0.0001).
The median PFS was 18.1 months in the VMP arm and was not reached in the D-VMP arm. The 12-month PFS was 76% and 87%, respectively. And the 18-month PFS was 50% and 72%, respectively.
D-VMP prolonged PFS regardless of patient sex, age, cytogenetic risk, ECOG performance status, baseline renal function, and other factors.
The median overall survival was not reached in either treatment arm. There were 48 deaths in the VMP arm and 45 in the D-VMP arm.
Adverse events
The most common treatment-emergent adverse events (TEAEs; in the D-VMP and VMP arms, respectively) were neutropenia (50% and 53%), thrombocytopenia (49% and 54%), anemia (28% and 38%), peripheral sensory neuropathy (28% and 34%), upper respiratory tract infection (26% and 14%), diarrhea (24% and 25%), pyrexia (23% and 21%), and nausea (21% and 22%).
The most common grade 3/4 TEAEs (in the D-VMP and VMP arms, respectively) were neutropenia (40% and 39%), thrombocytopenia (34% and 38%), and anemia (16% and 20%).
There were 6 deaths due to TEAEs in the D-VMP arm and 5 such deaths in the VMP arm.
The rate of grade 3/4 infections was higher in the D-VMP arm than the VMP arm—23% and 15%, respectively. The most common of these was pneumonia, with rates of 11% and 4%, respectively.
Infections resolved in 88% of cases in the D-VMP arm and 87% of cases in the VMP arm. Rates of treatment discontinuation due to infection were 0.9% and 1.4%, respectively. One patient in each group stopped treatment due to pneumonia.
Twenty-eight percent of patients in the D-VMP arm had infusion-related reactions (15% grade 3 and 2% grade 4). Most of these reactions occurred during the first infusion. Five patients (1.4%) discontinued daratumumab due to infusion-related reactions.
ATLANTA—Study results “strongly support” a new standard of care for transplant-ineligible patients with newly diagnosed multiple myeloma (MM), according to a speaker at the 2017 ASH Annual Meeting.
The study, ALCYONE, suggests treatment with bortezomib, melphalan, and prednisone (VMP) can be improved by the addition of daratumumab (D).
D-VMP produced deeper responses and prolonged progression-free survival (PFS) when compared to VMP.
“In this first phase 3, randomized study with a monoclonal antibody in newly diagnosed multiple myeloma, daratumumab reduced the risk of progression or death by 50%,” said Maria-Victoria Mateos, MD, PhD, of University Hospital of Salamanca in Spain.
“No new safety signals were observed [with D-VMP], except for higher infectious events that resolved. I would say the results of this study strongly support daratumumab in combination with VMP as a standard of care in transplant-ineligible, newly diagnosed multiple myeloma.”
Dr Mateos presented results from ALCYONE as a late-breaking abstract (LBA-4) at the ASH Annual Meeting. The study was simultaneously published in NEJM. The research was supported by Janssen Research and Development.
Patients and treatment
ALCYONE enrolled 706 patients with newly diagnosed MM who were not eligible for high-dose chemotherapy with autologous stem cell transplant.
Patients were randomized to receive VMP or D-VMP. They were stratified by International Staging System (I, II, III), region (Europe vs other), and age (<75 vs ≥75 years).
All patients received up to 9 cycles of VMP:
- Bortezomib at 1.3 mg/m2 twice weekly on weeks 1, 2, 4, and 5 of cycle 1 and once weekly on weeks 1, 2, 4, and 5 of cycles 2 through 9
- Melphalan at 9 mg/m2 once daily on days 1 to 4 of each cycle
- Prednisone at 60 mg/m2 once daily on days 1 to 4 of each cycle.
Patients in the daratumumab arm received the drug at 16 mg/kg once-weekly for the first cycle, every 3 weeks for cycles 2 to 9, and every 4 weeks thereafter, until disease progression. These patients also received dexamethasone (to manage infusion reactions) at 20 mg on the same schedule.
Baseline characteristics were similar between the VMP (n=356) and D-VMP (n=350) arms. The median age was 71 in both arms (range, 50-91 in the VMP arm and 40-93 in the D-VMP arm). Males made up 47% of the VMP arm and 46% of the D-VMP arm.
Forty-nine percent of patients in the VMP arm and 52% in the D-VMP arm had an ECOG performance status of 1. Twenty-eight percent and 22%, respectively, had a status of 0.
The median follow-up was 16.5 months (range, 0.1-28.1). At the clinical cutoff date (June 12, 2017), 5% of patients in the VMP arm were still on study treatment, as were 71% of patients in the D-VMP arm.
Response and survival
“I would like to note that the benefit of the addition of daratumumab was observed since the beginning of the treatment,” Dr Mateos said.
The overall response rate was 74% in the VMP arm and 91% in the D-VMP arm (P<0.0001). The median duration of response was 21.3 months in the VMP arm and was not reached in the D-VMP arm.
The rate of complete response was 24% in the VMP arm and 43% in the D-VMP arm (P<0.0001). Six percent of patients in the VMP arm and 22% in the D-VMP arm were negative for minimal residual disease (P<0.0001).
The hazard ratio for disease progression or death in the D-VMP arm versus the VMP arm was 0.50 (P<0.0001).
The median PFS was 18.1 months in the VMP arm and was not reached in the D-VMP arm. The 12-month PFS was 76% and 87%, respectively. And the 18-month PFS was 50% and 72%, respectively.
D-VMP prolonged PFS regardless of patient sex, age, cytogenetic risk, ECOG performance status, baseline renal function, and other factors.
The median overall survival was not reached in either treatment arm. There were 48 deaths in the VMP arm and 45 in the D-VMP arm.
Adverse events
The most common treatment-emergent adverse events (TEAEs; in the D-VMP and VMP arms, respectively) were neutropenia (50% and 53%), thrombocytopenia (49% and 54%), anemia (28% and 38%), peripheral sensory neuropathy (28% and 34%), upper respiratory tract infection (26% and 14%), diarrhea (24% and 25%), pyrexia (23% and 21%), and nausea (21% and 22%).
The most common grade 3/4 TEAEs (in the D-VMP and VMP arms, respectively) were neutropenia (40% and 39%), thrombocytopenia (34% and 38%), and anemia (16% and 20%).
There were 6 deaths due to TEAEs in the D-VMP arm and 5 such deaths in the VMP arm.
The rate of grade 3/4 infections was higher in the D-VMP arm than the VMP arm—23% and 15%, respectively. The most common of these was pneumonia, with rates of 11% and 4%, respectively.
Infections resolved in 88% of cases in the D-VMP arm and 87% of cases in the VMP arm. Rates of treatment discontinuation due to infection were 0.9% and 1.4%, respectively. One patient in each group stopped treatment due to pneumonia.
Twenty-eight percent of patients in the D-VMP arm had infusion-related reactions (15% grade 3 and 2% grade 4). Most of these reactions occurred during the first infusion. Five patients (1.4%) discontinued daratumumab due to infusion-related reactions.
Emicizumab reduces bleeds in kids with hemophilia A and inhibitors
ATLANTA—Updated results from the HAVEN 2 trial have shown that emicizumab prophylaxis can reduce bleeds in children with hemophilia A and factor VIII inhibitors.
Sixty-five percent of all patients enrolled in HAVEN 2 had no bleeds while on emicizumab, and 95% had no treated bleeds.
Among patients who had been on emicizumab for at least 12 weeks, 35% had no bleeds, and 87% had no treated bleeds.
The most common adverse events (AEs) in this trial were viral upper respiratory tract infections and injection site reactions.
Guy Young, MD, of Children’s Hospital Los Angeles in California, presented these results at the 2017 ASH Annual Meeting (abstract 85). The trial was sponsored by Hoffmann-La Roche.
HAVEN 2 enrolled 60 patients, ages 1 to 17, who had hemophilia A and inhibitors. Most patients (95%) had severe hemophilia, 3.3% (n=2) had mild disease, and 1.7% (n=1) had moderate disease.
Nearly a quarter of patients (73.3%) had previously received prophylaxis, and 26.7% had previously received episodic treatment.
The median number of bleeds in the previous 24 weeks was 6.0 (range, 0-155), and 38.3% of patients had target joints.
Patients received emicizumab prophylaxis at 3 mg/kg/week for 4 weeks and 1.5 mg/kg/week thereafter. The median observation time was 9 weeks (range, 1.6 to 41.6 weeks).
Efficacy
The efficacy analysis included 57 patients who were younger than 12. The 3 older patients were only included in the safety analysis.
Of the 57 patients, 64.9% had 0 bleeds, 94.7% had 0 treated bleeds, and 98.2% had 0 treated spontaneous bleeds and 0 treated joint bleeds. None of the patients had treated target joint bleeds.
There were a total of 65 bleeds in 20 patients. Eight were joint bleeds, 2 were muscle bleeds, and the rest were classified as “other.” Of the 55 “other’’ bleeds, 26 (40.0%) were spontaneous, 36 (55.4%) were traumatic, and 3 (4.6%) were due to a procedure/surgery.
A subset of 23 patients received emicizumab for at least 12 weeks. They had a median treatment duration of 38.1 weeks (range, 12.7 to 41.6 weeks).
Of these patients, 34.8% had 0 bleeds, 87.0% had 0 treated bleeds, and 95.7% had 0 treated spontaneous bleeds and 0 treated joint bleeds. There were a total of 41 bleeds in 15 of these patients. Three bleeds (joint, muscle, and hip) were treated.
The median annualized bleeding rate (ABR) for the 23 patients was 1.5 for all bleeds and 0.0 for all types of treated bleeds.
There were 13 patients who had participated in a non-interventional study prior to enrolling in HAVEN 2, so these patients could serve as their own controls. The patients had an overall reduction in ABR of 99% with emicizumab.
Safety
All 60 patients were evaluated for safety. Forty patients had a total of 201 AEs. The most common AEs were viral upper respiratory tract infection (16.7%) and injection site reactions (16.7%)
There were 7 serious AEs in 6 patients—muscle hemorrhage (n=2), eye pain, catheter site injection, device-related infection, mouth hemorrhage, and appendicitis. None of these events were considered treatment-related.
There were no thromboembolic or thrombotic microangiopathy events, and none of the patients tested positive for anti-drug antibodies.
“The safety profile of emicizumab was favorable and well-tolerated,” Dr Young said. “And these updated results from the HAVEN 2 study confirm our prior efficacy results, presented at ISTH, that emicizumab successfully prevents or reduces bleeds.”
ATLANTA—Updated results from the HAVEN 2 trial have shown that emicizumab prophylaxis can reduce bleeds in children with hemophilia A and factor VIII inhibitors.
Sixty-five percent of all patients enrolled in HAVEN 2 had no bleeds while on emicizumab, and 95% had no treated bleeds.
Among patients who had been on emicizumab for at least 12 weeks, 35% had no bleeds, and 87% had no treated bleeds.
The most common adverse events (AEs) in this trial were viral upper respiratory tract infections and injection site reactions.
Guy Young, MD, of Children’s Hospital Los Angeles in California, presented these results at the 2017 ASH Annual Meeting (abstract 85). The trial was sponsored by Hoffmann-La Roche.
HAVEN 2 enrolled 60 patients, ages 1 to 17, who had hemophilia A and inhibitors. Most patients (95%) had severe hemophilia, 3.3% (n=2) had mild disease, and 1.7% (n=1) had moderate disease.
Nearly a quarter of patients (73.3%) had previously received prophylaxis, and 26.7% had previously received episodic treatment.
The median number of bleeds in the previous 24 weeks was 6.0 (range, 0-155), and 38.3% of patients had target joints.
Patients received emicizumab prophylaxis at 3 mg/kg/week for 4 weeks and 1.5 mg/kg/week thereafter. The median observation time was 9 weeks (range, 1.6 to 41.6 weeks).
Efficacy
The efficacy analysis included 57 patients who were younger than 12. The 3 older patients were only included in the safety analysis.
Of the 57 patients, 64.9% had 0 bleeds, 94.7% had 0 treated bleeds, and 98.2% had 0 treated spontaneous bleeds and 0 treated joint bleeds. None of the patients had treated target joint bleeds.
There were a total of 65 bleeds in 20 patients. Eight were joint bleeds, 2 were muscle bleeds, and the rest were classified as “other.” Of the 55 “other’’ bleeds, 26 (40.0%) were spontaneous, 36 (55.4%) were traumatic, and 3 (4.6%) were due to a procedure/surgery.
A subset of 23 patients received emicizumab for at least 12 weeks. They had a median treatment duration of 38.1 weeks (range, 12.7 to 41.6 weeks).
Of these patients, 34.8% had 0 bleeds, 87.0% had 0 treated bleeds, and 95.7% had 0 treated spontaneous bleeds and 0 treated joint bleeds. There were a total of 41 bleeds in 15 of these patients. Three bleeds (joint, muscle, and hip) were treated.
The median annualized bleeding rate (ABR) for the 23 patients was 1.5 for all bleeds and 0.0 for all types of treated bleeds.
There were 13 patients who had participated in a non-interventional study prior to enrolling in HAVEN 2, so these patients could serve as their own controls. The patients had an overall reduction in ABR of 99% with emicizumab.
Safety
All 60 patients were evaluated for safety. Forty patients had a total of 201 AEs. The most common AEs were viral upper respiratory tract infection (16.7%) and injection site reactions (16.7%)
There were 7 serious AEs in 6 patients—muscle hemorrhage (n=2), eye pain, catheter site injection, device-related infection, mouth hemorrhage, and appendicitis. None of these events were considered treatment-related.
There were no thromboembolic or thrombotic microangiopathy events, and none of the patients tested positive for anti-drug antibodies.
“The safety profile of emicizumab was favorable and well-tolerated,” Dr Young said. “And these updated results from the HAVEN 2 study confirm our prior efficacy results, presented at ISTH, that emicizumab successfully prevents or reduces bleeds.”
ATLANTA—Updated results from the HAVEN 2 trial have shown that emicizumab prophylaxis can reduce bleeds in children with hemophilia A and factor VIII inhibitors.
Sixty-five percent of all patients enrolled in HAVEN 2 had no bleeds while on emicizumab, and 95% had no treated bleeds.
Among patients who had been on emicizumab for at least 12 weeks, 35% had no bleeds, and 87% had no treated bleeds.
The most common adverse events (AEs) in this trial were viral upper respiratory tract infections and injection site reactions.
Guy Young, MD, of Children’s Hospital Los Angeles in California, presented these results at the 2017 ASH Annual Meeting (abstract 85). The trial was sponsored by Hoffmann-La Roche.
HAVEN 2 enrolled 60 patients, ages 1 to 17, who had hemophilia A and inhibitors. Most patients (95%) had severe hemophilia, 3.3% (n=2) had mild disease, and 1.7% (n=1) had moderate disease.
Nearly a quarter of patients (73.3%) had previously received prophylaxis, and 26.7% had previously received episodic treatment.
The median number of bleeds in the previous 24 weeks was 6.0 (range, 0-155), and 38.3% of patients had target joints.
Patients received emicizumab prophylaxis at 3 mg/kg/week for 4 weeks and 1.5 mg/kg/week thereafter. The median observation time was 9 weeks (range, 1.6 to 41.6 weeks).
Efficacy
The efficacy analysis included 57 patients who were younger than 12. The 3 older patients were only included in the safety analysis.
Of the 57 patients, 64.9% had 0 bleeds, 94.7% had 0 treated bleeds, and 98.2% had 0 treated spontaneous bleeds and 0 treated joint bleeds. None of the patients had treated target joint bleeds.
There were a total of 65 bleeds in 20 patients. Eight were joint bleeds, 2 were muscle bleeds, and the rest were classified as “other.” Of the 55 “other’’ bleeds, 26 (40.0%) were spontaneous, 36 (55.4%) were traumatic, and 3 (4.6%) were due to a procedure/surgery.
A subset of 23 patients received emicizumab for at least 12 weeks. They had a median treatment duration of 38.1 weeks (range, 12.7 to 41.6 weeks).
Of these patients, 34.8% had 0 bleeds, 87.0% had 0 treated bleeds, and 95.7% had 0 treated spontaneous bleeds and 0 treated joint bleeds. There were a total of 41 bleeds in 15 of these patients. Three bleeds (joint, muscle, and hip) were treated.
The median annualized bleeding rate (ABR) for the 23 patients was 1.5 for all bleeds and 0.0 for all types of treated bleeds.
There were 13 patients who had participated in a non-interventional study prior to enrolling in HAVEN 2, so these patients could serve as their own controls. The patients had an overall reduction in ABR of 99% with emicizumab.
Safety
All 60 patients were evaluated for safety. Forty patients had a total of 201 AEs. The most common AEs were viral upper respiratory tract infection (16.7%) and injection site reactions (16.7%)
There were 7 serious AEs in 6 patients—muscle hemorrhage (n=2), eye pain, catheter site injection, device-related infection, mouth hemorrhage, and appendicitis. None of these events were considered treatment-related.
There were no thromboembolic or thrombotic microangiopathy events, and none of the patients tested positive for anti-drug antibodies.
“The safety profile of emicizumab was favorable and well-tolerated,” Dr Young said. “And these updated results from the HAVEN 2 study confirm our prior efficacy results, presented at ISTH, that emicizumab successfully prevents or reduces bleeds.”
Method may improve HSC mobilization, engraftment
New research suggests a 2-drug combination might improve hematopoietic stem cell transplant (HSCT) for donors and recipients.
Researchers found that a single dose of the drugs provides HSC mobilization that rivals 5-day treatment with granulocyte colony-stimulating factor (G-CSF).
And the combination mobilizes HSCs that have higher engraftment efficiency than HSCs mobilized by G-CSF.
Jonathan Hoggatt, PhD, of Massachusetts General Hospital in Boston, and his colleagues reported these findings in Cell.
“Our new method of harvesting stem cells requires only a single injection and mobilizes the cells needed in 15 minutes,” Dr Hoggatt said. “So in the time it takes to boil an egg, we are able to acquire the number of stem cells produced by the current standard 5-day protocol. This means less pain, time off work, and lifestyle disruption for the donor, more convenience for the clinical staff, and more predictability for the harvesting procedure.”
Dr Hoggatt and his colleagues have investigated ways to enhance HSC donation for several years. In a previous study, the researchers found that a CXCR2 agonist called GRO-beta induced rapid movement of HSCs from the marrow into the blood in animal models.
Initial experiments in the current study revealed that GRO-beta injections were safe and well tolerated in human volunteers but had only a modest effect in mobilizing HSCs. Therefore, the team tried combining GRO-beta with the CXCR4 antagonist AMD3100 (plerixafor).
The researchers found that simultaneous administration of both drugs rapidly (within 15 minutes) produced a quantity of HSCs equal to that provided by the 5-day G-CSF protocol.
When transplanted in mice, the HSCs mobilized by AMD3100 and GRO-beta prompted faster reconstitution of bone marrow and recovery of immune cell populations than HSCs mobilized by G-CSF.
The HSCs mobilized by AMD3100 and GRO-beta showed patterns of gene expression similar to those of fetal HSCs.
“These highly engraftable hematopoietic stem cells produced by our new strategy are essentially the A+ students of bone marrow stem cells,” Dr Hoggatt said. “Finding that they express genes similar to those of fetal liver HSCs . . . suggests that they will be very good at moving into an empty bone marrow space and rapidly dividing to fill the marrow and produce blood. Now, we need to test the combination in a clinical trial to confirm its safety and effectiveness in humans.”
New research suggests a 2-drug combination might improve hematopoietic stem cell transplant (HSCT) for donors and recipients.
Researchers found that a single dose of the drugs provides HSC mobilization that rivals 5-day treatment with granulocyte colony-stimulating factor (G-CSF).
And the combination mobilizes HSCs that have higher engraftment efficiency than HSCs mobilized by G-CSF.
Jonathan Hoggatt, PhD, of Massachusetts General Hospital in Boston, and his colleagues reported these findings in Cell.
“Our new method of harvesting stem cells requires only a single injection and mobilizes the cells needed in 15 minutes,” Dr Hoggatt said. “So in the time it takes to boil an egg, we are able to acquire the number of stem cells produced by the current standard 5-day protocol. This means less pain, time off work, and lifestyle disruption for the donor, more convenience for the clinical staff, and more predictability for the harvesting procedure.”
Dr Hoggatt and his colleagues have investigated ways to enhance HSC donation for several years. In a previous study, the researchers found that a CXCR2 agonist called GRO-beta induced rapid movement of HSCs from the marrow into the blood in animal models.
Initial experiments in the current study revealed that GRO-beta injections were safe and well tolerated in human volunteers but had only a modest effect in mobilizing HSCs. Therefore, the team tried combining GRO-beta with the CXCR4 antagonist AMD3100 (plerixafor).
The researchers found that simultaneous administration of both drugs rapidly (within 15 minutes) produced a quantity of HSCs equal to that provided by the 5-day G-CSF protocol.
When transplanted in mice, the HSCs mobilized by AMD3100 and GRO-beta prompted faster reconstitution of bone marrow and recovery of immune cell populations than HSCs mobilized by G-CSF.
The HSCs mobilized by AMD3100 and GRO-beta showed patterns of gene expression similar to those of fetal HSCs.
“These highly engraftable hematopoietic stem cells produced by our new strategy are essentially the A+ students of bone marrow stem cells,” Dr Hoggatt said. “Finding that they express genes similar to those of fetal liver HSCs . . . suggests that they will be very good at moving into an empty bone marrow space and rapidly dividing to fill the marrow and produce blood. Now, we need to test the combination in a clinical trial to confirm its safety and effectiveness in humans.”
New research suggests a 2-drug combination might improve hematopoietic stem cell transplant (HSCT) for donors and recipients.
Researchers found that a single dose of the drugs provides HSC mobilization that rivals 5-day treatment with granulocyte colony-stimulating factor (G-CSF).
And the combination mobilizes HSCs that have higher engraftment efficiency than HSCs mobilized by G-CSF.
Jonathan Hoggatt, PhD, of Massachusetts General Hospital in Boston, and his colleagues reported these findings in Cell.
“Our new method of harvesting stem cells requires only a single injection and mobilizes the cells needed in 15 minutes,” Dr Hoggatt said. “So in the time it takes to boil an egg, we are able to acquire the number of stem cells produced by the current standard 5-day protocol. This means less pain, time off work, and lifestyle disruption for the donor, more convenience for the clinical staff, and more predictability for the harvesting procedure.”
Dr Hoggatt and his colleagues have investigated ways to enhance HSC donation for several years. In a previous study, the researchers found that a CXCR2 agonist called GRO-beta induced rapid movement of HSCs from the marrow into the blood in animal models.
Initial experiments in the current study revealed that GRO-beta injections were safe and well tolerated in human volunteers but had only a modest effect in mobilizing HSCs. Therefore, the team tried combining GRO-beta with the CXCR4 antagonist AMD3100 (plerixafor).
The researchers found that simultaneous administration of both drugs rapidly (within 15 minutes) produced a quantity of HSCs equal to that provided by the 5-day G-CSF protocol.
When transplanted in mice, the HSCs mobilized by AMD3100 and GRO-beta prompted faster reconstitution of bone marrow and recovery of immune cell populations than HSCs mobilized by G-CSF.
The HSCs mobilized by AMD3100 and GRO-beta showed patterns of gene expression similar to those of fetal HSCs.
“These highly engraftable hematopoietic stem cells produced by our new strategy are essentially the A+ students of bone marrow stem cells,” Dr Hoggatt said. “Finding that they express genes similar to those of fetal liver HSCs . . . suggests that they will be very good at moving into an empty bone marrow space and rapidly dividing to fill the marrow and produce blood. Now, we need to test the combination in a clinical trial to confirm its safety and effectiveness in humans.”