ALL

Despite improvements in prevention of graft-versus-host disease, chronic GVHD still occurs in 10%-50% of patients who undergo an allogeneic hematopoietic stem cell transplant, and these patients may require prolonged treatment with multiple lines of therapy, said a hematologist and transplant researcher.

“More effective, less toxic therapies for chronic GVHD are needed,” Stephanie Lee, MD, MPH, from the Fred Hutchinson Cancer Research Center in Seattle said at the Transplant & Cellular Therapies Meetings.

Dr. Lee reviewed clinical trials for chronic GVHD at the meeting held by the American Society for Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research.

Although the incidence of chronic GVHD has gradually declined over the last 40 years and both relapse-free and overall survival following a chronic GVHD diagnosis have improved, “for patients who are diagnosed with chronic GVHD, they still will see many lines of therapy and many years of therapy,” she said.

Among 148 patients with chronic GVHD treated at her center, for example, 66% went on to two lines of therapy, 50% went on to three lines, 37% required four lines of therapy, and 20% needed five lines or more.

Salvage therapies for patients with chronic GVHD have evolved away from immunomodulators and immunosuppressants in the early 1990s, toward monoclonal antibodies such as rituximab in the early 2000s, to interleukin-2 and to tyrosine kinase inhibitors such as ruxolitinib (Jakafi) and ibrutinib (Imbruvica).

There are currently 36 agents that are FDA approved for at least one indication and can also be prescribed for the treatment of chronic GVHD, Dr. Lee noted.
 

Treatment goals

Dr. Lee laid out six goals for treating patients with chronic GVHD. They include:

• Controlling current signs and symptoms, measured by response rates and patient-reported outcomes
• Preventing further tissue and organ damage
• Minimizing toxicity
• Maintaining graft-versus-tumor effect
• Achieving graft tolerance and stopping immunosuppression
• Decreasing nonrelapse mortality and improving survival

Active trials

Dr. Lee identified 33 trials with chronic GVHD as an indication that are currently recruiting, and an additional 13 trials that are active but closed to recruiting. The trials can be generally grouped by mechanism of action, and involve agents targeting T-regulatory cells, B cells and/or B-cell receptor (BCR) signaling, monocytes/macrophages, costimulatory blockage, a proteasome inhibition, Janus kinase (JAK) 1/2 inhibitors, ROCK2 inhibitors, hedgehog pathway inhibition, cellular therapy, and organ-targeted therapy.

Most of the trials have overall response rate as the primary endpoint, and all but five are currently in phase 1 or 2. The currently active phase 3 trials include two with ibrutinib, one with the investigational agent itacitinib, one with ruxolitinib, and one with mesenchymal stem cells.

“I’ll note that, when results are reported, the denominator really matters for the overall response rate, especially if you’re talking about small trials, because if you require the patient to be treated with an agent for a certain period of time, and you take out all the people who didn’t make it to that time point, then your overall response rate looks better,” she said.
 

BTK inhibitors

The first-in-class Bruton tyrosine kinase (BTK) inhibitor ibrutinib was the first and thus far only agent approved by the Food and Drug Administration for chronic GVHD. The approval was based on a single-arm, multicenter trial with 42 patients.

The ORR in this trial was 69%, consisting of 31% complete responses and 38% partial responses, with a duration of response longer than 10 months in slightly more than half of all patients. In all, 24% of patients had improvement of symptoms in two consecutive visits, and 29% continued on ibrutinib at the time of the primary analysis in 2017.

Based on these promising results, acalabrutinib, which is more potent and selective for BTK than ibrutinib, with no effect on either platelets or natural killer cells, is currently under investigation in a phase 2 trial in 50 patients at a dose of 100 mg orally twice daily.
 

JAK1/2 inhibition

The JAK1 inhibitor itacitinib failed to meet its primary ORR endpoint in the phase 3 GRAVITAS-301 study, according to a press release, but the manufacturer (Incyte) said that it is continuing its commitment to JAK inhibitors with ruxolitinib, which has shown activity against acute, steroid-refractory GVHD, and is being explored for prevention of chronic GVHD in the randomized, phase 3 REACH3 study.

The trial met its primary endpoint for a higher ORR at week 24 with ruxolitinib versus best available therapy, at 49.7% versus 25.6%, respectively, which translated into an odds ratio for response with the JAK inhibitor of 2.99 (P < .0001).
 

Selective T-cell expansion

Efavaleukin alfa is an IL-2-mutated protein (mutein), with a mutation in the IL-2RB-binding portion of IL-2 causing increased selectivity for regulatory T-cell expansion. It is bound to an IgG-Fc domain that is itself mutated, with reduced Fc receptor binding and IgG effector function to give it a longer half life. This agent is being studied in a phase 1/2 trial in a subcutaneous formulation delivered every 1 or 2 weeks to 68 patients.

Monocyte/macrophage depletion

Axatilimab is a high-affinity antibody targeting colony stimulating factor–1 receptor (CSF-1R) expressed on monocytes and macrophages. By blocking CSF-1R, it depletes circulation of nonclassical monocytes and prevents the differentiation and survival of M2 macrophages in tissue.

It is currently being investigated 30 patients in a phase 1/2 study in an intravenous formulation delivered over 30 minutes every 2-4 weeks.
 

Hedgehog pathway inhibition

There is evidence suggesting that hedgehog pathway inhibition can lessen fibrosis. Glasdegib (Daurismo) a potent selective oral inhibitor of the hedgehog signaling pathway, is approved for use with low-dose cytarabine for patients with newly diagnosed acute myeloid leukemia aged older than 75 years or have comorbidities precluding intensive chemotherapy.

This agent is associated with drug intolerance because of muscle spasms, dysgeusia, and alopecia, however.

The drug is currently in phase 1/2 at a dose of 50 mg orally per day in 20 patients.
 

ROCK2 inhibition

Belumosudil (formerly KD025) “appears to rebalance the immune system,” Dr. Lee said. Investigators think that the drug dampens an autoaggressive inflammatory response by selective inhibition of ROCK2.

This drug has been studied in a dose-escalation study and a phase 2 trial, in which 132 participants were randomized to receive belumosudil 200 mg either once or twice daily.

At a median follow-up of 8 months, the ORR with belumosudil 200 mg once and twice daily was 73% and 74%, respectively. Similar results were seen in patients who had previously received either ruxolitinib or ibrutinib. High response rates were seen in patients with severe chronic GVHD, involvement of four or more organs and a refractory response to their last line of therapy.
 

Hard-to-manage patients

“We’re very hopeful for many of these agents, but we have to acknowledge that there are still many management dilemmas, patients that we just don’t really know what to do with,” Dr. Lee said. “These include patients who have bad sclerosis and fasciitis, nonhealing skin ulcers, bronchiolitis obliterans, serositis that can be very difficult to manage, severe keratoconjunctivitis that can be eyesight threatening, nonhealing mouth ulcers, esophageal structures, and always patients who have frequent infections.

“We are hopeful that some these agents will be useful for our patients who have severe manifestations, but often the number of patients with these manifestations in the trials is too low to say something specific about them,” she added.
 

‘Exciting time’

“It’s an exciting time because there are a lot of different drugs that are being studied for chronic GVHD,” commented Betty Hamilton, MD, a hematologist/oncologist at the Cleveland Clinic.

“I think that where the field is going in terms of treatment is recognizing that chronic GVHD is a pretty heterogeneous disease, and we have to learn even more about the underlying biologic pathways to be able to determine which class of drugs to use and when,” she said in an interview.

She agreed with Dr. Lee that the goals of treating patients with chronic GVHD include improving symptoms and quality, preventing progression, ideally tapering patients off immunosuppression, and achieving a balance between preventing negative consequences of GVHD while maintain the benefits of a graft-versus-leukemia effect.

“In our center, drug choice is based on physician preference and comfort with how often they’ve used the drug, patients’ comorbidities, toxicities of the drug, and logistical considerations,” Dr. Hamilton said.

Dr. Lee disclosed consulting activities for Pfizer and Kadmon, travel and lodging from Amgen, and research funding from those companies and others. Dr. Hamilton disclosed consulting for Syndax and Incyte.

Despite improvements in prevention of graft-versus-host disease, chronic GVHD still occurs in 10%-50% of patients who undergo an allogeneic hematopoietic stem cell transplant, and these patients may require prolonged treatment with multiple lines of therapy, said a hematologist and transplant researcher.

“More effective, less toxic therapies for chronic GVHD are needed,” Stephanie Lee, MD, MPH, from the Fred Hutchinson Cancer Research Center in Seattle said at the Transplant & Cellular Therapies Meetings.

Dr. Lee reviewed clinical trials for chronic GVHD at the meeting held by the American Society for Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research.

Although the incidence of chronic GVHD has gradually declined over the last 40 years and both relapse-free and overall survival following a chronic GVHD diagnosis have improved, “for patients who are diagnosed with chronic GVHD, they still will see many lines of therapy and many years of therapy,” she said.

Among 148 patients with chronic GVHD treated at her center, for example, 66% went on to two lines of therapy, 50% went on to three lines, 37% required four lines of therapy, and 20% needed five lines or more.

Salvage therapies for patients with chronic GVHD have evolved away from immunomodulators and immunosuppressants in the early 1990s, toward monoclonal antibodies such as rituximab in the early 2000s, to interleukin-2 and to tyrosine kinase inhibitors such as ruxolitinib (Jakafi) and ibrutinib (Imbruvica).

There are currently 36 agents that are FDA approved for at least one indication and can also be prescribed for the treatment of chronic GVHD, Dr. Lee noted.
 

Treatment goals

Dr. Lee laid out six goals for treating patients with chronic GVHD. They include:

• Controlling current signs and symptoms, measured by response rates and patient-reported outcomes
• Preventing further tissue and organ damage
• Minimizing toxicity
• Maintaining graft-versus-tumor effect
• Achieving graft tolerance and stopping immunosuppression
• Decreasing nonrelapse mortality and improving survival

Active trials

Dr. Lee identified 33 trials with chronic GVHD as an indication that are currently recruiting, and an additional 13 trials that are active but closed to recruiting. The trials can be generally grouped by mechanism of action, and involve agents targeting T-regulatory cells, B cells and/or B-cell receptor (BCR) signaling, monocytes/macrophages, costimulatory blockage, a proteasome inhibition, Janus kinase (JAK) 1/2 inhibitors, ROCK2 inhibitors, hedgehog pathway inhibition, cellular therapy, and organ-targeted therapy.

Most of the trials have overall response rate as the primary endpoint, and all but five are currently in phase 1 or 2. The currently active phase 3 trials include two with ibrutinib, one with the investigational agent itacitinib, one with ruxolitinib, and one with mesenchymal stem cells.

“I’ll note that, when results are reported, the denominator really matters for the overall response rate, especially if you’re talking about small trials, because if you require the patient to be treated with an agent for a certain period of time, and you take out all the people who didn’t make it to that time point, then your overall response rate looks better,” she said.
 

BTK inhibitors

The first-in-class Bruton tyrosine kinase (BTK) inhibitor ibrutinib was the first and thus far only agent approved by the Food and Drug Administration for chronic GVHD. The approval was based on a single-arm, multicenter trial with 42 patients.

The ORR in this trial was 69%, consisting of 31% complete responses and 38% partial responses, with a duration of response longer than 10 months in slightly more than half of all patients. In all, 24% of patients had improvement of symptoms in two consecutive visits, and 29% continued on ibrutinib at the time of the primary analysis in 2017.

Based on these promising results, acalabrutinib, which is more potent and selective for BTK than ibrutinib, with no effect on either platelets or natural killer cells, is currently under investigation in a phase 2 trial in 50 patients at a dose of 100 mg orally twice daily.
 

JAK1/2 inhibition

The JAK1 inhibitor itacitinib failed to meet its primary ORR endpoint in the phase 3 GRAVITAS-301 study, according to a press release, but the manufacturer (Incyte) said that it is continuing its commitment to JAK inhibitors with ruxolitinib, which has shown activity against acute, steroid-refractory GVHD, and is being explored for prevention of chronic GVHD in the randomized, phase 3 REACH3 study.

The trial met its primary endpoint for a higher ORR at week 24 with ruxolitinib versus best available therapy, at 49.7% versus 25.6%, respectively, which translated into an odds ratio for response with the JAK inhibitor of 2.99 (P < .0001).
 

Selective T-cell expansion

Efavaleukin alfa is an IL-2-mutated protein (mutein), with a mutation in the IL-2RB-binding portion of IL-2 causing increased selectivity for regulatory T-cell expansion. It is bound to an IgG-Fc domain that is itself mutated, with reduced Fc receptor binding and IgG effector function to give it a longer half life. This agent is being studied in a phase 1/2 trial in a subcutaneous formulation delivered every 1 or 2 weeks to 68 patients.

Monocyte/macrophage depletion

Axatilimab is a high-affinity antibody targeting colony stimulating factor–1 receptor (CSF-1R) expressed on monocytes and macrophages. By blocking CSF-1R, it depletes circulation of nonclassical monocytes and prevents the differentiation and survival of M2 macrophages in tissue.

It is currently being investigated 30 patients in a phase 1/2 study in an intravenous formulation delivered over 30 minutes every 2-4 weeks.
 

Hedgehog pathway inhibition

There is evidence suggesting that hedgehog pathway inhibition can lessen fibrosis. Glasdegib (Daurismo) a potent selective oral inhibitor of the hedgehog signaling pathway, is approved for use with low-dose cytarabine for patients with newly diagnosed acute myeloid leukemia aged older than 75 years or have comorbidities precluding intensive chemotherapy.

This agent is associated with drug intolerance because of muscle spasms, dysgeusia, and alopecia, however.

The drug is currently in phase 1/2 at a dose of 50 mg orally per day in 20 patients.
 

ROCK2 inhibition

Belumosudil (formerly KD025) “appears to rebalance the immune system,” Dr. Lee said. Investigators think that the drug dampens an autoaggressive inflammatory response by selective inhibition of ROCK2.

This drug has been studied in a dose-escalation study and a phase 2 trial, in which 132 participants were randomized to receive belumosudil 200 mg either once or twice daily.

At a median follow-up of 8 months, the ORR with belumosudil 200 mg once and twice daily was 73% and 74%, respectively. Similar results were seen in patients who had previously received either ruxolitinib or ibrutinib. High response rates were seen in patients with severe chronic GVHD, involvement of four or more organs and a refractory response to their last line of therapy.
 

Hard-to-manage patients

“We’re very hopeful for many of these agents, but we have to acknowledge that there are still many management dilemmas, patients that we just don’t really know what to do with,” Dr. Lee said. “These include patients who have bad sclerosis and fasciitis, nonhealing skin ulcers, bronchiolitis obliterans, serositis that can be very difficult to manage, severe keratoconjunctivitis that can be eyesight threatening, nonhealing mouth ulcers, esophageal structures, and always patients who have frequent infections.

“We are hopeful that some these agents will be useful for our patients who have severe manifestations, but often the number of patients with these manifestations in the trials is too low to say something specific about them,” she added.
 

‘Exciting time’

“It’s an exciting time because there are a lot of different drugs that are being studied for chronic GVHD,” commented Betty Hamilton, MD, a hematologist/oncologist at the Cleveland Clinic.

“I think that where the field is going in terms of treatment is recognizing that chronic GVHD is a pretty heterogeneous disease, and we have to learn even more about the underlying biologic pathways to be able to determine which class of drugs to use and when,” she said in an interview.

She agreed with Dr. Lee that the goals of treating patients with chronic GVHD include improving symptoms and quality, preventing progression, ideally tapering patients off immunosuppression, and achieving a balance between preventing negative consequences of GVHD while maintain the benefits of a graft-versus-leukemia effect.

“In our center, drug choice is based on physician preference and comfort with how often they’ve used the drug, patients’ comorbidities, toxicities of the drug, and logistical considerations,” Dr. Hamilton said.

Dr. Lee disclosed consulting activities for Pfizer and Kadmon, travel and lodging from Amgen, and research funding from those companies and others. Dr. Hamilton disclosed consulting for Syndax and Incyte.

Despite improvements in prevention of graft-versus-host disease, chronic GVHD still occurs in 10%-50% of patients who undergo an allogeneic hematopoietic stem cell transplant, and these patients may require prolonged treatment with multiple lines of therapy, said a hematologist and transplant researcher.

“More effective, less toxic therapies for chronic GVHD are needed,” Stephanie Lee, MD, MPH, from the Fred Hutchinson Cancer Research Center in Seattle said at the Transplant & Cellular Therapies Meetings.

Dr. Lee reviewed clinical trials for chronic GVHD at the meeting held by the American Society for Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research.

Although the incidence of chronic GVHD has gradually declined over the last 40 years and both relapse-free and overall survival following a chronic GVHD diagnosis have improved, “for patients who are diagnosed with chronic GVHD, they still will see many lines of therapy and many years of therapy,” she said.

Among 148 patients with chronic GVHD treated at her center, for example, 66% went on to two lines of therapy, 50% went on to three lines, 37% required four lines of therapy, and 20% needed five lines or more.

Salvage therapies for patients with chronic GVHD have evolved away from immunomodulators and immunosuppressants in the early 1990s, toward monoclonal antibodies such as rituximab in the early 2000s, to interleukin-2 and to tyrosine kinase inhibitors such as ruxolitinib (Jakafi) and ibrutinib (Imbruvica).

There are currently 36 agents that are FDA approved for at least one indication and can also be prescribed for the treatment of chronic GVHD, Dr. Lee noted.
 

Treatment goals

Dr. Lee laid out six goals for treating patients with chronic GVHD. They include:

• Controlling current signs and symptoms, measured by response rates and patient-reported outcomes
• Preventing further tissue and organ damage
• Minimizing toxicity
• Maintaining graft-versus-tumor effect
• Achieving graft tolerance and stopping immunosuppression
• Decreasing nonrelapse mortality and improving survival

Active trials

Dr. Lee identified 33 trials with chronic GVHD as an indication that are currently recruiting, and an additional 13 trials that are active but closed to recruiting. The trials can be generally grouped by mechanism of action, and involve agents targeting T-regulatory cells, B cells and/or B-cell receptor (BCR) signaling, monocytes/macrophages, costimulatory blockage, a proteasome inhibition, Janus kinase (JAK) 1/2 inhibitors, ROCK2 inhibitors, hedgehog pathway inhibition, cellular therapy, and organ-targeted therapy.

Most of the trials have overall response rate as the primary endpoint, and all but five are currently in phase 1 or 2. The currently active phase 3 trials include two with ibrutinib, one with the investigational agent itacitinib, one with ruxolitinib, and one with mesenchymal stem cells.

“I’ll note that, when results are reported, the denominator really matters for the overall response rate, especially if you’re talking about small trials, because if you require the patient to be treated with an agent for a certain period of time, and you take out all the people who didn’t make it to that time point, then your overall response rate looks better,” she said.
 

BTK inhibitors

The first-in-class Bruton tyrosine kinase (BTK) inhibitor ibrutinib was the first and thus far only agent approved by the Food and Drug Administration for chronic GVHD. The approval was based on a single-arm, multicenter trial with 42 patients.

The ORR in this trial was 69%, consisting of 31% complete responses and 38% partial responses, with a duration of response longer than 10 months in slightly more than half of all patients. In all, 24% of patients had improvement of symptoms in two consecutive visits, and 29% continued on ibrutinib at the time of the primary analysis in 2017.

Based on these promising results, acalabrutinib, which is more potent and selective for BTK than ibrutinib, with no effect on either platelets or natural killer cells, is currently under investigation in a phase 2 trial in 50 patients at a dose of 100 mg orally twice daily.
 

JAK1/2 inhibition

The JAK1 inhibitor itacitinib failed to meet its primary ORR endpoint in the phase 3 GRAVITAS-301 study, according to a press release, but the manufacturer (Incyte) said that it is continuing its commitment to JAK inhibitors with ruxolitinib, which has shown activity against acute, steroid-refractory GVHD, and is being explored for prevention of chronic GVHD in the randomized, phase 3 REACH3 study.

The trial met its primary endpoint for a higher ORR at week 24 with ruxolitinib versus best available therapy, at 49.7% versus 25.6%, respectively, which translated into an odds ratio for response with the JAK inhibitor of 2.99 (P < .0001).
 

Selective T-cell expansion

Efavaleukin alfa is an IL-2-mutated protein (mutein), with a mutation in the IL-2RB-binding portion of IL-2 causing increased selectivity for regulatory T-cell expansion. It is bound to an IgG-Fc domain that is itself mutated, with reduced Fc receptor binding and IgG effector function to give it a longer half life. This agent is being studied in a phase 1/2 trial in a subcutaneous formulation delivered every 1 or 2 weeks to 68 patients.

Monocyte/macrophage depletion

Axatilimab is a high-affinity antibody targeting colony stimulating factor–1 receptor (CSF-1R) expressed on monocytes and macrophages. By blocking CSF-1R, it depletes circulation of nonclassical monocytes and prevents the differentiation and survival of M2 macrophages in tissue.

It is currently being investigated 30 patients in a phase 1/2 study in an intravenous formulation delivered over 30 minutes every 2-4 weeks.
 

Hedgehog pathway inhibition

There is evidence suggesting that hedgehog pathway inhibition can lessen fibrosis. Glasdegib (Daurismo) a potent selective oral inhibitor of the hedgehog signaling pathway, is approved for use with low-dose cytarabine for patients with newly diagnosed acute myeloid leukemia aged older than 75 years or have comorbidities precluding intensive chemotherapy.

This agent is associated with drug intolerance because of muscle spasms, dysgeusia, and alopecia, however.

The drug is currently in phase 1/2 at a dose of 50 mg orally per day in 20 patients.
 

ROCK2 inhibition

Belumosudil (formerly KD025) “appears to rebalance the immune system,” Dr. Lee said. Investigators think that the drug dampens an autoaggressive inflammatory response by selective inhibition of ROCK2.

This drug has been studied in a dose-escalation study and a phase 2 trial, in which 132 participants were randomized to receive belumosudil 200 mg either once or twice daily.

At a median follow-up of 8 months, the ORR with belumosudil 200 mg once and twice daily was 73% and 74%, respectively. Similar results were seen in patients who had previously received either ruxolitinib or ibrutinib. High response rates were seen in patients with severe chronic GVHD, involvement of four or more organs and a refractory response to their last line of therapy.
 

Hard-to-manage patients

“We’re very hopeful for many of these agents, but we have to acknowledge that there are still many management dilemmas, patients that we just don’t really know what to do with,” Dr. Lee said. “These include patients who have bad sclerosis and fasciitis, nonhealing skin ulcers, bronchiolitis obliterans, serositis that can be very difficult to manage, severe keratoconjunctivitis that can be eyesight threatening, nonhealing mouth ulcers, esophageal structures, and always patients who have frequent infections.

“We are hopeful that some these agents will be useful for our patients who have severe manifestations, but often the number of patients with these manifestations in the trials is too low to say something specific about them,” she added.
 

‘Exciting time’

“It’s an exciting time because there are a lot of different drugs that are being studied for chronic GVHD,” commented Betty Hamilton, MD, a hematologist/oncologist at the Cleveland Clinic.

“I think that where the field is going in terms of treatment is recognizing that chronic GVHD is a pretty heterogeneous disease, and we have to learn even more about the underlying biologic pathways to be able to determine which class of drugs to use and when,” she said in an interview.

She agreed with Dr. Lee that the goals of treating patients with chronic GVHD include improving symptoms and quality, preventing progression, ideally tapering patients off immunosuppression, and achieving a balance between preventing negative consequences of GVHD while maintain the benefits of a graft-versus-leukemia effect.

“In our center, drug choice is based on physician preference and comfort with how often they’ve used the drug, patients’ comorbidities, toxicities of the drug, and logistical considerations,” Dr. Hamilton said.

Dr. Lee disclosed consulting activities for Pfizer and Kadmon, travel and lodging from Amgen, and research funding from those companies and others. Dr. Hamilton disclosed consulting for Syndax and Incyte.

For now at least, total body irradiation (TBI) plus etoposide remains the conditioning regimen of choice for children undergoing allogeneic hematopoietic stem cell transplant for acute lymphoblastic leukemia (ALL), according to an open-label, phase 3 trial from Europe.

The investigators sought to answer a question many physicians have raised: With improvements in human leukocyte antigen typing, better graft-versus-host disease prophylaxis, and other advances, can myeloablative chemotherapy conditioning replace TBI, which is more toxic?

The downstream effects of TBI can include secondary malignancies and cataracts, as well as impaired growth and impaired gonadal and cognitive function.

But the answer to that question is no, or at least, not yet.

The phase 3 trial included individuals with ALL who were aged 4-21 years at time of transplant. They were randomly assigned to receive either fractionated TBI at 12 Gy plus etoposide or chemotherapy based on a myeloablative regimen: fludarabine, thiotepa, and either busulfan or treosulfan.

The trial was stopped after 413 patients had undergone randomization – quite a bit short of the 1,000-patient goal. The trial was terminated because TBI proved clearly superior on an interim analysis at a median follow-up of 2.1 years.

The results showed that 72% of the TBI group – but only 51% of the chemotherapy arm – were relapse free at 2 years with no graft-versus-host disease (P = .0003).

The 2-year treatment-related mortality rate was 2% in the TBI group but 9% with chemotherapy conditioning (P = .03).

The study was published Feb. 1, 2020, in the Journal of Clinical Oncology.

“We recommend TBI plus etoposide conditioning for patients [aged over] 4 years old with high-risk ALL undergoing allogeneic HSCT [hematopoietic stem cell transplant],” they concluded. The investigators were led by Christina Peters, MD, a pediatrics professor at the St. Anna Children’s Cancer Research Institute, Vienna.

The benefits of TBI held on multivariate analysis and across subgroups, including children in their first and second remissions and among those with high-risk cytogenetics. Relapse risk factors, such as age at transplant, leukemic phenotype, and molecular aberrations, did not significantly affect outcomes, the authors reported.

Given that relapses plateaued with TBI at 2.5 years but were still on the upswing for patients who underwent chemoconditioning, “it is unlikely that secondary malignancies after TBI could jeopardize the survival advantage,” they wrote.

“So does this mean that the HCT community is forever chained to TBI as a standard of care? Certainly, it means that without very sound rationale to deviate, a TBI-based preparative regimen is the preferred therapy at present,” Michael Pulsipher, MD, head of blood and marrow transplantation at Children’s Hospital Los Angeles, commented in an accompanying editorial.

However, “there are approaches under study currently that may define patients who do not need TBI for high rates of cure,” he suggested. Those approaches include selecting patients with the deepest remissions and using KIR-favorable haplotype to harness natural killer cell activity.

“In our new world of chimeric antigen receptor T-cells and immunotherapies, surely we can find safer paths to success,” Dr. Pulsipher wrote.

With regard to patient selection, the investigators noted that a recent review that included more than 3,000 children with ALL found no overall survival benefit with TBI versus chemoconditioning for patients in first complete remission but worse outcomes with chemoconditioning among patients in second complete remission. “A similar trend was observed in our subgroup analyses; however, our study was not powered to assess statistical significance in a sample size of 413 patients,” they wrote.

Minimal residual disease did not influence survival outcomes, probably because the investigators were aggressive in inducing deep remission in their patients before transplant, so for most patients, MRD was undetectable or very low beforehand.

The study was funded by Amgen, Jazz Pharmaceuticals, Neovii, Medac, and others. Dr. Peters and coauthors, as well as Dr. Pulsipher have disclosed numerous ties with those and/or other companies.

A version of this article first appeared on Medscape.com.

For now at least, total body irradiation (TBI) plus etoposide remains the conditioning regimen of choice for children undergoing allogeneic hematopoietic stem cell transplant for acute lymphoblastic leukemia (ALL), according to an open-label, phase 3 trial from Europe.

The investigators sought to answer a question many physicians have raised: With improvements in human leukocyte antigen typing, better graft-versus-host disease prophylaxis, and other advances, can myeloablative chemotherapy conditioning replace TBI, which is more toxic?

The downstream effects of TBI can include secondary malignancies and cataracts, as well as impaired growth and impaired gonadal and cognitive function.

But the answer to that question is no, or at least, not yet.

The phase 3 trial included individuals with ALL who were aged 4-21 years at time of transplant. They were randomly assigned to receive either fractionated TBI at 12 Gy plus etoposide or chemotherapy based on a myeloablative regimen: fludarabine, thiotepa, and either busulfan or treosulfan.

The trial was stopped after 413 patients had undergone randomization – quite a bit short of the 1,000-patient goal. The trial was terminated because TBI proved clearly superior on an interim analysis at a median follow-up of 2.1 years.

The results showed that 72% of the TBI group – but only 51% of the chemotherapy arm – were relapse free at 2 years with no graft-versus-host disease (P = .0003).

The 2-year treatment-related mortality rate was 2% in the TBI group but 9% with chemotherapy conditioning (P = .03).

The study was published Feb. 1, 2020, in the Journal of Clinical Oncology.

“We recommend TBI plus etoposide conditioning for patients [aged over] 4 years old with high-risk ALL undergoing allogeneic HSCT [hematopoietic stem cell transplant],” they concluded. The investigators were led by Christina Peters, MD, a pediatrics professor at the St. Anna Children’s Cancer Research Institute, Vienna.

The benefits of TBI held on multivariate analysis and across subgroups, including children in their first and second remissions and among those with high-risk cytogenetics. Relapse risk factors, such as age at transplant, leukemic phenotype, and molecular aberrations, did not significantly affect outcomes, the authors reported.

Given that relapses plateaued with TBI at 2.5 years but were still on the upswing for patients who underwent chemoconditioning, “it is unlikely that secondary malignancies after TBI could jeopardize the survival advantage,” they wrote.

“So does this mean that the HCT community is forever chained to TBI as a standard of care? Certainly, it means that without very sound rationale to deviate, a TBI-based preparative regimen is the preferred therapy at present,” Michael Pulsipher, MD, head of blood and marrow transplantation at Children’s Hospital Los Angeles, commented in an accompanying editorial.

However, “there are approaches under study currently that may define patients who do not need TBI for high rates of cure,” he suggested. Those approaches include selecting patients with the deepest remissions and using KIR-favorable haplotype to harness natural killer cell activity.

“In our new world of chimeric antigen receptor T-cells and immunotherapies, surely we can find safer paths to success,” Dr. Pulsipher wrote.

With regard to patient selection, the investigators noted that a recent review that included more than 3,000 children with ALL found no overall survival benefit with TBI versus chemoconditioning for patients in first complete remission but worse outcomes with chemoconditioning among patients in second complete remission. “A similar trend was observed in our subgroup analyses; however, our study was not powered to assess statistical significance in a sample size of 413 patients,” they wrote.

Minimal residual disease did not influence survival outcomes, probably because the investigators were aggressive in inducing deep remission in their patients before transplant, so for most patients, MRD was undetectable or very low beforehand.

The study was funded by Amgen, Jazz Pharmaceuticals, Neovii, Medac, and others. Dr. Peters and coauthors, as well as Dr. Pulsipher have disclosed numerous ties with those and/or other companies.

A version of this article first appeared on Medscape.com.

For now at least, total body irradiation (TBI) plus etoposide remains the conditioning regimen of choice for children undergoing allogeneic hematopoietic stem cell transplant for acute lymphoblastic leukemia (ALL), according to an open-label, phase 3 trial from Europe.

The investigators sought to answer a question many physicians have raised: With improvements in human leukocyte antigen typing, better graft-versus-host disease prophylaxis, and other advances, can myeloablative chemotherapy conditioning replace TBI, which is more toxic?

The downstream effects of TBI can include secondary malignancies and cataracts, as well as impaired growth and impaired gonadal and cognitive function.

But the answer to that question is no, or at least, not yet.

The phase 3 trial included individuals with ALL who were aged 4-21 years at time of transplant. They were randomly assigned to receive either fractionated TBI at 12 Gy plus etoposide or chemotherapy based on a myeloablative regimen: fludarabine, thiotepa, and either busulfan or treosulfan.

The trial was stopped after 413 patients had undergone randomization – quite a bit short of the 1,000-patient goal. The trial was terminated because TBI proved clearly superior on an interim analysis at a median follow-up of 2.1 years.

The results showed that 72% of the TBI group – but only 51% of the chemotherapy arm – were relapse free at 2 years with no graft-versus-host disease (P = .0003).

The 2-year treatment-related mortality rate was 2% in the TBI group but 9% with chemotherapy conditioning (P = .03).

The study was published Feb. 1, 2020, in the Journal of Clinical Oncology.

“We recommend TBI plus etoposide conditioning for patients [aged over] 4 years old with high-risk ALL undergoing allogeneic HSCT [hematopoietic stem cell transplant],” they concluded. The investigators were led by Christina Peters, MD, a pediatrics professor at the St. Anna Children’s Cancer Research Institute, Vienna.

The benefits of TBI held on multivariate analysis and across subgroups, including children in their first and second remissions and among those with high-risk cytogenetics. Relapse risk factors, such as age at transplant, leukemic phenotype, and molecular aberrations, did not significantly affect outcomes, the authors reported.

Given that relapses plateaued with TBI at 2.5 years but were still on the upswing for patients who underwent chemoconditioning, “it is unlikely that secondary malignancies after TBI could jeopardize the survival advantage,” they wrote.

“So does this mean that the HCT community is forever chained to TBI as a standard of care? Certainly, it means that without very sound rationale to deviate, a TBI-based preparative regimen is the preferred therapy at present,” Michael Pulsipher, MD, head of blood and marrow transplantation at Children’s Hospital Los Angeles, commented in an accompanying editorial.

However, “there are approaches under study currently that may define patients who do not need TBI for high rates of cure,” he suggested. Those approaches include selecting patients with the deepest remissions and using KIR-favorable haplotype to harness natural killer cell activity.

“In our new world of chimeric antigen receptor T-cells and immunotherapies, surely we can find safer paths to success,” Dr. Pulsipher wrote.

With regard to patient selection, the investigators noted that a recent review that included more than 3,000 children with ALL found no overall survival benefit with TBI versus chemoconditioning for patients in first complete remission but worse outcomes with chemoconditioning among patients in second complete remission. “A similar trend was observed in our subgroup analyses; however, our study was not powered to assess statistical significance in a sample size of 413 patients,” they wrote.

Minimal residual disease did not influence survival outcomes, probably because the investigators were aggressive in inducing deep remission in their patients before transplant, so for most patients, MRD was undetectable or very low beforehand.

The study was funded by Amgen, Jazz Pharmaceuticals, Neovii, Medac, and others. Dr. Peters and coauthors, as well as Dr. Pulsipher have disclosed numerous ties with those and/or other companies.

A version of this article first appeared on Medscape.com.

Allogeneic hematopoietic stem-cell transplantation (AHSCT) improved disease-free survival (DFS), compared with pediatric-inspired Berlin-Frankfurt-Münster (BFM-95) chemotherapy in adults with acute lymphoblastic leukemia (ALL), according to the results of retrospective study published in Clinical Lymphoma, Myeloma & Leukemia. However, overall survival (OS) was not significantly different between the two groups, as reported by Elifcan Aladag, MD, of the Hacettepe University Faculty of Medicine, Ankara, Turkey, and colleagues.

VashiDonsk/Wikimedia Commons/Creative Commons 3.0

Despite this, “AHSCT is recommended for all patients with suitable donors, but the risk of transplant-related mortality should be kept in mind,” according to the researchers.

The multicenter study compared two different treatment approaches (BFM-95 chemotherapy regimen and AHSCT). The BFM-95 chemotherapy group comprised 47 newly diagnosed ALL patients. The transplant cohort comprised 83 patients with ALL in first complete remission who received AHSCT from fully matched human leukocyte antigen (HLA)-identical siblings. Thirty-five of the AHSCT patients (42.1%) received chemotherapy at least until the M stage of the BFM-95 protocol.

The primary endpoints of the study were OS and duration of DFS. OS was defined from the day of starting BFM-95 chemotherapy until death from any cause, and DFS was calculated from the date of complete remission until the date of first relapse or death from any cause, whichever occurred first, according to the authors.
 

Study results

The median OS was 68 months in patients who underwent AHSCT and 46 months in patients treated only with BFM-95 (P = .3). Two- and 5-year OS rates were 78% and 60% , respectively, in the AHSCT group, and 69% and 64% in the BFM-95 group (P = .06 and .13, respectively).

The median DFS was 36.6 months in patients who underwent AHSCT and 28 months in patients treated with BFM-95 (P = .033). Two- and 5-year DFS rates were 68.5% and 57%, respectively, in the AHSCT group, and 63% and 38% respectively, in the BFM-95 group (P = .12 and .029, respectively).

Mortality in the BFM-95 group was the result of sepsis due to infections (fungal infection in two patients, resistant bacterial infections in four patients). In the AHSCT group, respectively, three and seven patients died of graft-versus-host disease and bacterial infections (with fungal infections in four patients and resistant bacterial infections in three patients), according to the researchers.

“In our study, no 2-year OS and DFS difference was observed in any treatment group; however, a significant difference occurred in 5-year DFS in favor of AHSCT. This may be due to transplant-related mortality in the first 2 years, which led to no statistically significant difference,” the authors stated.

“In order to further elucidate the role of AHSCT when pediatric-derived regimens are used for the treatment of adult lymphoblastic leukemia, higher-powered randomized prospective studies are needed,” they concluded.

The authors reported that they had no conflicts of interest.

[email protected]

Allogeneic hematopoietic stem-cell transplantation (AHSCT) improved disease-free survival (DFS), compared with pediatric-inspired Berlin-Frankfurt-Münster (BFM-95) chemotherapy in adults with acute lymphoblastic leukemia (ALL), according to the results of retrospective study published in Clinical Lymphoma, Myeloma & Leukemia. However, overall survival (OS) was not significantly different between the two groups, as reported by Elifcan Aladag, MD, of the Hacettepe University Faculty of Medicine, Ankara, Turkey, and colleagues.

VashiDonsk/Wikimedia Commons/Creative Commons 3.0

Despite this, “AHSCT is recommended for all patients with suitable donors, but the risk of transplant-related mortality should be kept in mind,” according to the researchers.

The multicenter study compared two different treatment approaches (BFM-95 chemotherapy regimen and AHSCT). The BFM-95 chemotherapy group comprised 47 newly diagnosed ALL patients. The transplant cohort comprised 83 patients with ALL in first complete remission who received AHSCT from fully matched human leukocyte antigen (HLA)-identical siblings. Thirty-five of the AHSCT patients (42.1%) received chemotherapy at least until the M stage of the BFM-95 protocol.

The primary endpoints of the study were OS and duration of DFS. OS was defined from the day of starting BFM-95 chemotherapy until death from any cause, and DFS was calculated from the date of complete remission until the date of first relapse or death from any cause, whichever occurred first, according to the authors.
 

Study results

The median OS was 68 months in patients who underwent AHSCT and 46 months in patients treated only with BFM-95 (P = .3). Two- and 5-year OS rates were 78% and 60% , respectively, in the AHSCT group, and 69% and 64% in the BFM-95 group (P = .06 and .13, respectively).

The median DFS was 36.6 months in patients who underwent AHSCT and 28 months in patients treated with BFM-95 (P = .033). Two- and 5-year DFS rates were 68.5% and 57%, respectively, in the AHSCT group, and 63% and 38% respectively, in the BFM-95 group (P = .12 and .029, respectively).

Mortality in the BFM-95 group was the result of sepsis due to infections (fungal infection in two patients, resistant bacterial infections in four patients). In the AHSCT group, respectively, three and seven patients died of graft-versus-host disease and bacterial infections (with fungal infections in four patients and resistant bacterial infections in three patients), according to the researchers.

“In our study, no 2-year OS and DFS difference was observed in any treatment group; however, a significant difference occurred in 5-year DFS in favor of AHSCT. This may be due to transplant-related mortality in the first 2 years, which led to no statistically significant difference,” the authors stated.

“In order to further elucidate the role of AHSCT when pediatric-derived regimens are used for the treatment of adult lymphoblastic leukemia, higher-powered randomized prospective studies are needed,” they concluded.

The authors reported that they had no conflicts of interest.

[email protected]

Allogeneic hematopoietic stem-cell transplantation (AHSCT) improved disease-free survival (DFS), compared with pediatric-inspired Berlin-Frankfurt-Münster (BFM-95) chemotherapy in adults with acute lymphoblastic leukemia (ALL), according to the results of retrospective study published in Clinical Lymphoma, Myeloma & Leukemia. However, overall survival (OS) was not significantly different between the two groups, as reported by Elifcan Aladag, MD, of the Hacettepe University Faculty of Medicine, Ankara, Turkey, and colleagues.

VashiDonsk/Wikimedia Commons/Creative Commons 3.0

Despite this, “AHSCT is recommended for all patients with suitable donors, but the risk of transplant-related mortality should be kept in mind,” according to the researchers.

The multicenter study compared two different treatment approaches (BFM-95 chemotherapy regimen and AHSCT). The BFM-95 chemotherapy group comprised 47 newly diagnosed ALL patients. The transplant cohort comprised 83 patients with ALL in first complete remission who received AHSCT from fully matched human leukocyte antigen (HLA)-identical siblings. Thirty-five of the AHSCT patients (42.1%) received chemotherapy at least until the M stage of the BFM-95 protocol.

The primary endpoints of the study were OS and duration of DFS. OS was defined from the day of starting BFM-95 chemotherapy until death from any cause, and DFS was calculated from the date of complete remission until the date of first relapse or death from any cause, whichever occurred first, according to the authors.
 

Study results

The median OS was 68 months in patients who underwent AHSCT and 46 months in patients treated only with BFM-95 (P = .3). Two- and 5-year OS rates were 78% and 60% , respectively, in the AHSCT group, and 69% and 64% in the BFM-95 group (P = .06 and .13, respectively).

The median DFS was 36.6 months in patients who underwent AHSCT and 28 months in patients treated with BFM-95 (P = .033). Two- and 5-year DFS rates were 68.5% and 57%, respectively, in the AHSCT group, and 63% and 38% respectively, in the BFM-95 group (P = .12 and .029, respectively).

Mortality in the BFM-95 group was the result of sepsis due to infections (fungal infection in two patients, resistant bacterial infections in four patients). In the AHSCT group, respectively, three and seven patients died of graft-versus-host disease and bacterial infections (with fungal infections in four patients and resistant bacterial infections in three patients), according to the researchers.

“In our study, no 2-year OS and DFS difference was observed in any treatment group; however, a significant difference occurred in 5-year DFS in favor of AHSCT. This may be due to transplant-related mortality in the first 2 years, which led to no statistically significant difference,” the authors stated.

“In order to further elucidate the role of AHSCT when pediatric-derived regimens are used for the treatment of adult lymphoblastic leukemia, higher-powered randomized prospective studies are needed,” they concluded.

The authors reported that they had no conflicts of interest.

[email protected]

Blinatumomab was superior to high-risk consolidation (HC) 3 chemotherapy in a phase 3 clinical trial among children with high-risk first-relapse acute lymphoblastic leukemia (ALL), according to Franco Locatelli, MD, PhD, Ospedale Pediatrico Bambino Gesú and Sapienza, Rome.

Blinatumomab constitutes a new standard of care because of superior event-free survival (EFS) and other comparative benefits, including fewer and less severe toxicities, he said in a presentation at theannual meeting of the American Society of Hematology, which was held virtually.

About 15% of children with B-cell precursor (BCP) ALL relapse after standard treatment. Prognosis depends largely on time from diagnosis to relapse and the site of relapse. After relapse, when a second morphological complete remission (M1 marrow) is achieved, most are candidates for allogeneic hematopoietic stem cell transplant (alloHSCT), Dr. Locatelli noted. Immuno-oncotherapy with blinatumomab, a bispecific T-cell–engager molecule, has been shown to be efficacious in children with relapsed/refractory BCP-ALL.

In the open-label, controlled trial, investigators randomized children with M1 (<5% blasts) or M2 (<25% and 5% or greater blasts) marrow 1:1 after induction therapy and cycles of HC1 and HC2 chemotherapy to a third consolidation course with blinatumomab (15 µg/m²/day for 4 weeks) or HC3 (dexamethasone, vincristine, daunorubicin, methotrexate, ifosfamide, PEG-asparaginase); intrathecal chemotherapy (methotrexate/cytarabine/prednisolone) was administered before treatment. Patients achieving a second complete morphological remission (M1 marrow) after blinatumomab or HC3 proceeded to alloHSCT. EFS was the primary endpoint (from randomization until relapse date or M2 marrow after a complete response [CR], failure to achieve CR at end of treatment, second malignancy, or death from any cause).

Investigators had enrolled 108 (54 received HC3; 54 received blinatumomab) out of a target of about 202 patients when the data-monitoring committee recommended termination because of blinatumomab benefit observed at the first interim analysis. Median age was around 5.5 years (1-17), with the mean time from first diagnosis to relapse at approximately 22 months.

Dr. Locatelli reported events for 18/54 (33.3%) in the blinatumomab arm and 31/54 (57.4%) in the HC3 arm, with a median EFS of “not reached” and 7.4 months, respectively. The risk of relapse with blinatumomab was reduced by 64% versus HC3 (hazard ratio, 0.36; 95% confidence interval, 0.19-0.66, P < .001). Overall survival (OS) favored blinatumomab over HC3, as well, with a hazard ratio of 0.43 (95% CI, 0.18-1.01). Minimal residual disease (MRD) remission (MRD < 10-4) was seen in 43/46 (93.5%) blinatumomab-randomized and 25/46 (54.3%) HC3-randomized patients.

Relapses occurred more often in the HC3 group (blinatumomab 13, 24%; HC3 29, 54%) overall, and at each of the assessments at 6 months, 12 months, and 24 months. Also, MRD remissions by PCR (polymerase chain reaction) were superior in the blinatumomab arm overall (90% versus 54%) and according to baseline MRD status with strikingly divergent rates in those with MRD greater than or equal to 104 at baseline (93% blinatumomab/24% HC3). Rates were relatively similar in patients with MRD less than 104 at baseline (85% blinatumomab/87% HC3).

Grade 3 or greater treatment-emergent adverse events were reported by 30/53 (57%) and 41/51 (80%) patients in the blinatumomab and HC3 groups, respectively, with several markedly lower in the blinatumomab group (neutropenia/neutrophil count decrease 17 versus 31; anemia 15 versus 41; febrile neutropenia 4 versus 26). As expected, grade 3 or greater neurologic events occurred more frequently with blinatumomab than with HC3 (48% versus 29%); no grade 3 or greater cytokine release syndrome events were reported.

Tallying the blinatumomab benefits (superior EFS and MRD negativity prior to alloHSCT, improved OS, fewer relapses, fewer and less severe toxicities), Dr. Locatelli concluded, “Blinatumomab constitutes a new standard of care in children with high-risk first-relapse ALL.”

In the postpresentation discussion, Dr. Locatelli underscored the blinatumomab benefit versus a third course of chemotherapy: “Monotherapy with blinatumomab was able to present a higher proportion of patients in CR2 who could proceed to transplant.”

Dr. Locatelli disclosed relationships with multiple companies.

SOURCE: Locatelli F et al. ASH 2020, Abstract 268.

Blinatumomab was superior to high-risk consolidation (HC) 3 chemotherapy in a phase 3 clinical trial among children with high-risk first-relapse acute lymphoblastic leukemia (ALL), according to Franco Locatelli, MD, PhD, Ospedale Pediatrico Bambino Gesú and Sapienza, Rome.

Blinatumomab constitutes a new standard of care because of superior event-free survival (EFS) and other comparative benefits, including fewer and less severe toxicities, he said in a presentation at theannual meeting of the American Society of Hematology, which was held virtually.

About 15% of children with B-cell precursor (BCP) ALL relapse after standard treatment. Prognosis depends largely on time from diagnosis to relapse and the site of relapse. After relapse, when a second morphological complete remission (M1 marrow) is achieved, most are candidates for allogeneic hematopoietic stem cell transplant (alloHSCT), Dr. Locatelli noted. Immuno-oncotherapy with blinatumomab, a bispecific T-cell–engager molecule, has been shown to be efficacious in children with relapsed/refractory BCP-ALL.

In the open-label, controlled trial, investigators randomized children with M1 (<5% blasts) or M2 (<25% and 5% or greater blasts) marrow 1:1 after induction therapy and cycles of HC1 and HC2 chemotherapy to a third consolidation course with blinatumomab (15 µg/m²/day for 4 weeks) or HC3 (dexamethasone, vincristine, daunorubicin, methotrexate, ifosfamide, PEG-asparaginase); intrathecal chemotherapy (methotrexate/cytarabine/prednisolone) was administered before treatment. Patients achieving a second complete morphological remission (M1 marrow) after blinatumomab or HC3 proceeded to alloHSCT. EFS was the primary endpoint (from randomization until relapse date or M2 marrow after a complete response [CR], failure to achieve CR at end of treatment, second malignancy, or death from any cause).

Investigators had enrolled 108 (54 received HC3; 54 received blinatumomab) out of a target of about 202 patients when the data-monitoring committee recommended termination because of blinatumomab benefit observed at the first interim analysis. Median age was around 5.5 years (1-17), with the mean time from first diagnosis to relapse at approximately 22 months.

Dr. Locatelli reported events for 18/54 (33.3%) in the blinatumomab arm and 31/54 (57.4%) in the HC3 arm, with a median EFS of “not reached” and 7.4 months, respectively. The risk of relapse with blinatumomab was reduced by 64% versus HC3 (hazard ratio, 0.36; 95% confidence interval, 0.19-0.66, P < .001). Overall survival (OS) favored blinatumomab over HC3, as well, with a hazard ratio of 0.43 (95% CI, 0.18-1.01). Minimal residual disease (MRD) remission (MRD < 10-4) was seen in 43/46 (93.5%) blinatumomab-randomized and 25/46 (54.3%) HC3-randomized patients.

Relapses occurred more often in the HC3 group (blinatumomab 13, 24%; HC3 29, 54%) overall, and at each of the assessments at 6 months, 12 months, and 24 months. Also, MRD remissions by PCR (polymerase chain reaction) were superior in the blinatumomab arm overall (90% versus 54%) and according to baseline MRD status with strikingly divergent rates in those with MRD greater than or equal to 104 at baseline (93% blinatumomab/24% HC3). Rates were relatively similar in patients with MRD less than 104 at baseline (85% blinatumomab/87% HC3).

Grade 3 or greater treatment-emergent adverse events were reported by 30/53 (57%) and 41/51 (80%) patients in the blinatumomab and HC3 groups, respectively, with several markedly lower in the blinatumomab group (neutropenia/neutrophil count decrease 17 versus 31; anemia 15 versus 41; febrile neutropenia 4 versus 26). As expected, grade 3 or greater neurologic events occurred more frequently with blinatumomab than with HC3 (48% versus 29%); no grade 3 or greater cytokine release syndrome events were reported.

Tallying the blinatumomab benefits (superior EFS and MRD negativity prior to alloHSCT, improved OS, fewer relapses, fewer and less severe toxicities), Dr. Locatelli concluded, “Blinatumomab constitutes a new standard of care in children with high-risk first-relapse ALL.”

In the postpresentation discussion, Dr. Locatelli underscored the blinatumomab benefit versus a third course of chemotherapy: “Monotherapy with blinatumomab was able to present a higher proportion of patients in CR2 who could proceed to transplant.”

Dr. Locatelli disclosed relationships with multiple companies.

SOURCE: Locatelli F et al. ASH 2020, Abstract 268.

Blinatumomab was superior to high-risk consolidation (HC) 3 chemotherapy in a phase 3 clinical trial among children with high-risk first-relapse acute lymphoblastic leukemia (ALL), according to Franco Locatelli, MD, PhD, Ospedale Pediatrico Bambino Gesú and Sapienza, Rome.

Blinatumomab constitutes a new standard of care because of superior event-free survival (EFS) and other comparative benefits, including fewer and less severe toxicities, he said in a presentation at theannual meeting of the American Society of Hematology, which was held virtually.

About 15% of children with B-cell precursor (BCP) ALL relapse after standard treatment. Prognosis depends largely on time from diagnosis to relapse and the site of relapse. After relapse, when a second morphological complete remission (M1 marrow) is achieved, most are candidates for allogeneic hematopoietic stem cell transplant (alloHSCT), Dr. Locatelli noted. Immuno-oncotherapy with blinatumomab, a bispecific T-cell–engager molecule, has been shown to be efficacious in children with relapsed/refractory BCP-ALL.

In the open-label, controlled trial, investigators randomized children with M1 (<5% blasts) or M2 (<25% and 5% or greater blasts) marrow 1:1 after induction therapy and cycles of HC1 and HC2 chemotherapy to a third consolidation course with blinatumomab (15 µg/m²/day for 4 weeks) or HC3 (dexamethasone, vincristine, daunorubicin, methotrexate, ifosfamide, PEG-asparaginase); intrathecal chemotherapy (methotrexate/cytarabine/prednisolone) was administered before treatment. Patients achieving a second complete morphological remission (M1 marrow) after blinatumomab or HC3 proceeded to alloHSCT. EFS was the primary endpoint (from randomization until relapse date or M2 marrow after a complete response [CR], failure to achieve CR at end of treatment, second malignancy, or death from any cause).

Investigators had enrolled 108 (54 received HC3; 54 received blinatumomab) out of a target of about 202 patients when the data-monitoring committee recommended termination because of blinatumomab benefit observed at the first interim analysis. Median age was around 5.5 years (1-17), with the mean time from first diagnosis to relapse at approximately 22 months.

Dr. Locatelli reported events for 18/54 (33.3%) in the blinatumomab arm and 31/54 (57.4%) in the HC3 arm, with a median EFS of “not reached” and 7.4 months, respectively. The risk of relapse with blinatumomab was reduced by 64% versus HC3 (hazard ratio, 0.36; 95% confidence interval, 0.19-0.66, P < .001). Overall survival (OS) favored blinatumomab over HC3, as well, with a hazard ratio of 0.43 (95% CI, 0.18-1.01). Minimal residual disease (MRD) remission (MRD < 10-4) was seen in 43/46 (93.5%) blinatumomab-randomized and 25/46 (54.3%) HC3-randomized patients.

Relapses occurred more often in the HC3 group (blinatumomab 13, 24%; HC3 29, 54%) overall, and at each of the assessments at 6 months, 12 months, and 24 months. Also, MRD remissions by PCR (polymerase chain reaction) were superior in the blinatumomab arm overall (90% versus 54%) and according to baseline MRD status with strikingly divergent rates in those with MRD greater than or equal to 104 at baseline (93% blinatumomab/24% HC3). Rates were relatively similar in patients with MRD less than 104 at baseline (85% blinatumomab/87% HC3).

Grade 3 or greater treatment-emergent adverse events were reported by 30/53 (57%) and 41/51 (80%) patients in the blinatumomab and HC3 groups, respectively, with several markedly lower in the blinatumomab group (neutropenia/neutrophil count decrease 17 versus 31; anemia 15 versus 41; febrile neutropenia 4 versus 26). As expected, grade 3 or greater neurologic events occurred more frequently with blinatumomab than with HC3 (48% versus 29%); no grade 3 or greater cytokine release syndrome events were reported.

Tallying the blinatumomab benefits (superior EFS and MRD negativity prior to alloHSCT, improved OS, fewer relapses, fewer and less severe toxicities), Dr. Locatelli concluded, “Blinatumomab constitutes a new standard of care in children with high-risk first-relapse ALL.”

In the postpresentation discussion, Dr. Locatelli underscored the blinatumomab benefit versus a third course of chemotherapy: “Monotherapy with blinatumomab was able to present a higher proportion of patients in CR2 who could proceed to transplant.”

Dr. Locatelli disclosed relationships with multiple companies.

SOURCE: Locatelli F et al. ASH 2020, Abstract 268.

In heavily pretreated pediatric patients with relapsed or refractory acute lymphoblastic leukemia (ALL) or lymphoblastic lymphoma (LL), venetoclax plus navitoclax with chemotherapy was well tolerated with promising responses, according to results of a phase 1 trial. Delayed count recovery, however, stated lead author Jeffrey E. Rubnitz, MD, PhD, St. Jude’s Children’s Research Hospital, Memphis, remained a key safety concern.
 

Unmet medical need

Despite intensive chemotherapy and novel therapeutics, Dr. Rubnitz said in a virtual oral presentation at the annual meeting of the American Society of Hematology, patients with relapsed or refractory ALL and LL have a poor prognosis and represent an unmet medical need. Venetoclax, a potent, highly selective oral B-cell lymphoma 2 inhibitor, and navitoclax, an oral BCL-2, BCL-XL, and BCL-W inhibitor, directly bind their BCL-2 family member targets to promote apoptosis. In ALL preclinical models, venetoclax and navitoclax have demonstrated antileukemic effects, which suggests dependence on BCL-2 family members. Venetoclax efficacy associated with BCL-2 family inhibition may be potentiated and dose-limiting thrombocytopenia associated with standard-dose navitoclax monotherapy may be avoided by adding venetoclax to low-dose navitoclax. Previous reports of an ongoing phase 1, multicenter, open-label, dose-escalation study in an adult and pediatric population (NCT03181126), Dr. Rubnitz noted, showed the venetoclax/navitoclax/chemotherapy combination to be well tolerated with promising response rates. In the current report, Dr. Rubnitz presented data on the safety, tolerability, pharmacokinetics, and antitumor activity of the triplet regimen in the subgroup of pediatric patients.

The study included pediatric patients (ages, 4-18 years and weight ≥20 kg) receiving venetoclax (weight-adjusted equivalent of 400 mg daily) and navitoclax at three dose levels (25, 50, 100 mg) for patients weighing ≥45 kg and two dose levels (25, 50 mg) for patients weighing <45 kg. At investigator’s discretion, patients could receive chemotherapy (polyethylene glycosylated–asparaginase, vincristine, and dexamethasone). The primary outcomes were safety (including incidence of dose-limiting toxicities and adverse events) and pharmacokinetics. A safety expansion cohort assessed a 21-day dosing schedule of venetoclax at 400 mg followed by 7 days off plus navitoclax at 50 mg (patients ≥45 kg) or 25 mg (patients <45 kg).

Investigators enrolled 18 patients <18 years (median age, 10 years; range, 6-16; 56% male), with 12 in the dose-escalation cohort and 6 in the safety-expansion cohort. Three patients had prior chimeric antigen receptor (CAR) T treatment and four had received prior stem cell transplantation. In the overall cohort, B-cell ALL was most common (n = 13, 72%), with T-cell ALL (n = 3, 17%) and LL (n = 2, 11%) following. The median number of prior therapies was 2 (range 1-6). All patients received chemotherapy.
 

Grade 3-4 adverse events

Venetoclax-related grade 3-4 adverse events occurred in 56% of patients. Similarly, navitoclax-related grade 3-4 events were reported in 56% of patients. Navitoclax dose-limiting toxicities occurred in two patients (11%), delayed count recovery on 25 mg and sepsis on 50 mg. No grade 5 adverse events and tumor lysis syndrome were reported.

Among secondary endpoint efficacy parameters, complete responses, CRs with incomplete marrow recovery (CRi) and CRs without platelet recovery (CRp) combined occurred in 62% of B-ALL patients (8/13), 33% of T-cell ALL patients (1/3) and in 50% of LL patients (1/2). Separately, CRs/CRis/CRps occurred in 33%/22%/0% of all patients, respectively.

Subsequently, 5 of 18 (28%) of patients proceeded to stem cell transplantation and 3 (17%) to CAR T. Eight patients (44%) died from disease progression.
 

BH3 profiling

BH3 profiling revealed that at baseline, patients with B-cell ALL had more diversity in BCL-2 and BCL-XL dependency than did patients with T-cell ALL or early T-cell precursor ALL. The fact that responses were observed in patients who were BCL-2 or BCL-XL dependent, Dr. Rubnitz said, supports the use of venetoclax plus navitoclax in these patients. Analysis of these results led to a recommended phase 2 dose for pediatric patients of 400 mg venetoclax with 25 mg navitoclax (for patients weighing <45 kg) or 50 mg navitoclax (for patients weighing 45 kg or more).

Dr. Rubnitz concluded: “Venetoclax plus navitoclax plus chemotherapy was well tolerated in pediatric patients with relapsed/refractory ALL or LL, with promising response rates observed in a heavily pretreated pediatric population.”

Asked whether the combination might be used also before the refractory setting, in a minimal residual disease (MRD) setting, Dr. Rubnitz replied: “We have a lot of safety data on venetoclax but very little on navitoclax. The next trial, being developed by Seth Karol, MD, will include relapsed patients. MRD-positive patients will also be eligible for enrollment.” To a further question as to whether guiding titration via BH3 profiling would lead to improved outcomes, Dr. Rubnitz said, “I think BH3 profiling can be used to identify which patients will respond to these drugs, but we are still a long way from using it for titrating the doses and dose ratios for the two drugs.”

Dr. Rubnitz disclosed research funding from AbbVie.

SOURCE: Rubnitz JE et al. ASH 2020, Abstract 466.

In heavily pretreated pediatric patients with relapsed or refractory acute lymphoblastic leukemia (ALL) or lymphoblastic lymphoma (LL), venetoclax plus navitoclax with chemotherapy was well tolerated with promising responses, according to results of a phase 1 trial. Delayed count recovery, however, stated lead author Jeffrey E. Rubnitz, MD, PhD, St. Jude’s Children’s Research Hospital, Memphis, remained a key safety concern.
 

Unmet medical need

Despite intensive chemotherapy and novel therapeutics, Dr. Rubnitz said in a virtual oral presentation at the annual meeting of the American Society of Hematology, patients with relapsed or refractory ALL and LL have a poor prognosis and represent an unmet medical need. Venetoclax, a potent, highly selective oral B-cell lymphoma 2 inhibitor, and navitoclax, an oral BCL-2, BCL-XL, and BCL-W inhibitor, directly bind their BCL-2 family member targets to promote apoptosis. In ALL preclinical models, venetoclax and navitoclax have demonstrated antileukemic effects, which suggests dependence on BCL-2 family members. Venetoclax efficacy associated with BCL-2 family inhibition may be potentiated and dose-limiting thrombocytopenia associated with standard-dose navitoclax monotherapy may be avoided by adding venetoclax to low-dose navitoclax. Previous reports of an ongoing phase 1, multicenter, open-label, dose-escalation study in an adult and pediatric population (NCT03181126), Dr. Rubnitz noted, showed the venetoclax/navitoclax/chemotherapy combination to be well tolerated with promising response rates. In the current report, Dr. Rubnitz presented data on the safety, tolerability, pharmacokinetics, and antitumor activity of the triplet regimen in the subgroup of pediatric patients.

The study included pediatric patients (ages, 4-18 years and weight ≥20 kg) receiving venetoclax (weight-adjusted equivalent of 400 mg daily) and navitoclax at three dose levels (25, 50, 100 mg) for patients weighing ≥45 kg and two dose levels (25, 50 mg) for patients weighing <45 kg. At investigator’s discretion, patients could receive chemotherapy (polyethylene glycosylated–asparaginase, vincristine, and dexamethasone). The primary outcomes were safety (including incidence of dose-limiting toxicities and adverse events) and pharmacokinetics. A safety expansion cohort assessed a 21-day dosing schedule of venetoclax at 400 mg followed by 7 days off plus navitoclax at 50 mg (patients ≥45 kg) or 25 mg (patients <45 kg).

Investigators enrolled 18 patients <18 years (median age, 10 years; range, 6-16; 56% male), with 12 in the dose-escalation cohort and 6 in the safety-expansion cohort. Three patients had prior chimeric antigen receptor (CAR) T treatment and four had received prior stem cell transplantation. In the overall cohort, B-cell ALL was most common (n = 13, 72%), with T-cell ALL (n = 3, 17%) and LL (n = 2, 11%) following. The median number of prior therapies was 2 (range 1-6). All patients received chemotherapy.
 

Grade 3-4 adverse events

Venetoclax-related grade 3-4 adverse events occurred in 56% of patients. Similarly, navitoclax-related grade 3-4 events were reported in 56% of patients. Navitoclax dose-limiting toxicities occurred in two patients (11%), delayed count recovery on 25 mg and sepsis on 50 mg. No grade 5 adverse events and tumor lysis syndrome were reported.

Among secondary endpoint efficacy parameters, complete responses, CRs with incomplete marrow recovery (CRi) and CRs without platelet recovery (CRp) combined occurred in 62% of B-ALL patients (8/13), 33% of T-cell ALL patients (1/3) and in 50% of LL patients (1/2). Separately, CRs/CRis/CRps occurred in 33%/22%/0% of all patients, respectively.

Subsequently, 5 of 18 (28%) of patients proceeded to stem cell transplantation and 3 (17%) to CAR T. Eight patients (44%) died from disease progression.
 

BH3 profiling

BH3 profiling revealed that at baseline, patients with B-cell ALL had more diversity in BCL-2 and BCL-XL dependency than did patients with T-cell ALL or early T-cell precursor ALL. The fact that responses were observed in patients who were BCL-2 or BCL-XL dependent, Dr. Rubnitz said, supports the use of venetoclax plus navitoclax in these patients. Analysis of these results led to a recommended phase 2 dose for pediatric patients of 400 mg venetoclax with 25 mg navitoclax (for patients weighing <45 kg) or 50 mg navitoclax (for patients weighing 45 kg or more).

Dr. Rubnitz concluded: “Venetoclax plus navitoclax plus chemotherapy was well tolerated in pediatric patients with relapsed/refractory ALL or LL, with promising response rates observed in a heavily pretreated pediatric population.”

Asked whether the combination might be used also before the refractory setting, in a minimal residual disease (MRD) setting, Dr. Rubnitz replied: “We have a lot of safety data on venetoclax but very little on navitoclax. The next trial, being developed by Seth Karol, MD, will include relapsed patients. MRD-positive patients will also be eligible for enrollment.” To a further question as to whether guiding titration via BH3 profiling would lead to improved outcomes, Dr. Rubnitz said, “I think BH3 profiling can be used to identify which patients will respond to these drugs, but we are still a long way from using it for titrating the doses and dose ratios for the two drugs.”

Dr. Rubnitz disclosed research funding from AbbVie.

SOURCE: Rubnitz JE et al. ASH 2020, Abstract 466.

In heavily pretreated pediatric patients with relapsed or refractory acute lymphoblastic leukemia (ALL) or lymphoblastic lymphoma (LL), venetoclax plus navitoclax with chemotherapy was well tolerated with promising responses, according to results of a phase 1 trial. Delayed count recovery, however, stated lead author Jeffrey E. Rubnitz, MD, PhD, St. Jude’s Children’s Research Hospital, Memphis, remained a key safety concern.
 

Unmet medical need

Despite intensive chemotherapy and novel therapeutics, Dr. Rubnitz said in a virtual oral presentation at the annual meeting of the American Society of Hematology, patients with relapsed or refractory ALL and LL have a poor prognosis and represent an unmet medical need. Venetoclax, a potent, highly selective oral B-cell lymphoma 2 inhibitor, and navitoclax, an oral BCL-2, BCL-XL, and BCL-W inhibitor, directly bind their BCL-2 family member targets to promote apoptosis. In ALL preclinical models, venetoclax and navitoclax have demonstrated antileukemic effects, which suggests dependence on BCL-2 family members. Venetoclax efficacy associated with BCL-2 family inhibition may be potentiated and dose-limiting thrombocytopenia associated with standard-dose navitoclax monotherapy may be avoided by adding venetoclax to low-dose navitoclax. Previous reports of an ongoing phase 1, multicenter, open-label, dose-escalation study in an adult and pediatric population (NCT03181126), Dr. Rubnitz noted, showed the venetoclax/navitoclax/chemotherapy combination to be well tolerated with promising response rates. In the current report, Dr. Rubnitz presented data on the safety, tolerability, pharmacokinetics, and antitumor activity of the triplet regimen in the subgroup of pediatric patients.

The study included pediatric patients (ages, 4-18 years and weight ≥20 kg) receiving venetoclax (weight-adjusted equivalent of 400 mg daily) and navitoclax at three dose levels (25, 50, 100 mg) for patients weighing ≥45 kg and two dose levels (25, 50 mg) for patients weighing <45 kg. At investigator’s discretion, patients could receive chemotherapy (polyethylene glycosylated–asparaginase, vincristine, and dexamethasone). The primary outcomes were safety (including incidence of dose-limiting toxicities and adverse events) and pharmacokinetics. A safety expansion cohort assessed a 21-day dosing schedule of venetoclax at 400 mg followed by 7 days off plus navitoclax at 50 mg (patients ≥45 kg) or 25 mg (patients <45 kg).

Investigators enrolled 18 patients <18 years (median age, 10 years; range, 6-16; 56% male), with 12 in the dose-escalation cohort and 6 in the safety-expansion cohort. Three patients had prior chimeric antigen receptor (CAR) T treatment and four had received prior stem cell transplantation. In the overall cohort, B-cell ALL was most common (n = 13, 72%), with T-cell ALL (n = 3, 17%) and LL (n = 2, 11%) following. The median number of prior therapies was 2 (range 1-6). All patients received chemotherapy.
 

Grade 3-4 adverse events

Venetoclax-related grade 3-4 adverse events occurred in 56% of patients. Similarly, navitoclax-related grade 3-4 events were reported in 56% of patients. Navitoclax dose-limiting toxicities occurred in two patients (11%), delayed count recovery on 25 mg and sepsis on 50 mg. No grade 5 adverse events and tumor lysis syndrome were reported.

Among secondary endpoint efficacy parameters, complete responses, CRs with incomplete marrow recovery (CRi) and CRs without platelet recovery (CRp) combined occurred in 62% of B-ALL patients (8/13), 33% of T-cell ALL patients (1/3) and in 50% of LL patients (1/2). Separately, CRs/CRis/CRps occurred in 33%/22%/0% of all patients, respectively.

Subsequently, 5 of 18 (28%) of patients proceeded to stem cell transplantation and 3 (17%) to CAR T. Eight patients (44%) died from disease progression.
 

BH3 profiling

BH3 profiling revealed that at baseline, patients with B-cell ALL had more diversity in BCL-2 and BCL-XL dependency than did patients with T-cell ALL or early T-cell precursor ALL. The fact that responses were observed in patients who were BCL-2 or BCL-XL dependent, Dr. Rubnitz said, supports the use of venetoclax plus navitoclax in these patients. Analysis of these results led to a recommended phase 2 dose for pediatric patients of 400 mg venetoclax with 25 mg navitoclax (for patients weighing <45 kg) or 50 mg navitoclax (for patients weighing 45 kg or more).

Dr. Rubnitz concluded: “Venetoclax plus navitoclax plus chemotherapy was well tolerated in pediatric patients with relapsed/refractory ALL or LL, with promising response rates observed in a heavily pretreated pediatric population.”

Asked whether the combination might be used also before the refractory setting, in a minimal residual disease (MRD) setting, Dr. Rubnitz replied: “We have a lot of safety data on venetoclax but very little on navitoclax. The next trial, being developed by Seth Karol, MD, will include relapsed patients. MRD-positive patients will also be eligible for enrollment.” To a further question as to whether guiding titration via BH3 profiling would lead to improved outcomes, Dr. Rubnitz said, “I think BH3 profiling can be used to identify which patients will respond to these drugs, but we are still a long way from using it for titrating the doses and dose ratios for the two drugs.”

Dr. Rubnitz disclosed research funding from AbbVie.

SOURCE: Rubnitz JE et al. ASH 2020, Abstract 466.

Hyper-CVAD (fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone) with sequential blinatumomab is highly effective as frontline therapy for Philadelphia Chromosome (Ph)–negative B-cell acute lymphoblastic leukemia (ALL), according to results of a phase 2 study reported at the annual meeting of the American Society of Hematology.

Favorable minimal residual disease (MRD) negativity and overall survival with low higher-grade toxicities suggest that reductions in chemotherapy in this setting are feasible, said Nicholas J. Short, MD, of the University of Texas MD Anderson Cancer Center, Houston.

While complete response rates with current ALL therapy are 80%-90%, long-term overall survival is only 40%-50%. Blinatumomab, a bispecific T-cell–engaging CD3-CD19 antibody, has been shown to be superior to chemotherapy in relapsed/refractory B-cell ALL, and to produce high rates of MRD eradication, the most important prognostic factor in ALL, Dr. Short said at the meeting, which was held virtually.

The hypothesis of the current study was that early incorporation of blinatumomab with hyper-CVAD in patients with newly diagnosed Ph-negative B-cell ALL would decrease the need for intensive chemotherapy and lead to higher efficacy and cure rates with less myelosuppression. Patients were required to have a performance status of 3 or less, total bilirubin 2 mg/dL or less and creatinine 2 mg/dL or less. Investigators enrolled 38 patients (mean age, 37 years,; range, 17-59) with most (79%) in performance status 0-1. The primary endpoint was relapse-free survival (RFS).
 

Study details

Patients received hyper-CVAD alternating with high-dose methotrexate and cytarabine for up to four cycles followed by four cycles of blinatumomab at standard doses. Those with CD20-positive disease (1% or greater percentage of the cells) received eight doses of ofatumumab or rituximab, and prophylactic intrathecal chemotherapy was given eight times in the first four cycles. Maintenance consisted of alternating blocks of POMP (6-mercaptopurine, vincristine, methotrexate, prednisone) and blinatumomab. When two patients with high-risk features experienced early relapse, investigators amended the protocol to allow blinatumomab after only two cycles of hyper-CVAD in those with high-risk features (e.g., CRLF2 positive by flow cytometry, complex karyotype, KMT2A rearranged, low hypodiploidy/near triploidy, TP53 mutation, or persistent MRD). Nineteen patients (56%) had at least one high-risk feature, and 82% received ofatumumab or rituximab. Six patients were in complete remission at the start of the study (four of them MRD negative).

Complete responses

After induction, complete responses were achieved in 81% (26/32), with all patients achieving a complete response at some point, according to Dr. Short. The MRD negativity rate was 71% (24/34) after induction and 97% (33/34) at any time. Among the 38 patients, all with complete response at median follow-up of 24 months (range, 2-45), relapses occurred only in those 5 patients with high-risk features. Twelve patients underwent transplant in the first remission. Two relapsed, both with high-risk features. The other 21 patients had ongoing complete responses.

RFS at 1- and 2-years was 80% and 71%, respectively. Five among seven relapses were without hematopoietic stem cell transplantation, and 2 were post HSCT. Two deaths occurred in patients with complete responses (one pulmonary embolism and one with post-HSCT complications). Overall survival at 1 and 2 years was 85% and 80%, respectively, with the 2-year rate comparable with prior reports for hyper-CVAD plus ofatumumab, Dr. Short said.

The most common nonhematologic grade 3-4 adverse events with hyper-CVAD plus blinatumomab were ALT/AST elevation (24%) and hyperglycemia (21%). The overall cytokine release syndrome rate was 13%, with 3% for higher-grade reactions. The rate for blinatumomab-related neurologic events was 45% overall and 13% for higher grades, with 1 discontinuation attributed to grade 2 encephalopathy and dysphasia.

“Overall, this study shows the potential benefit of incorporating frontline blinatumomab into the treatment of younger adults with newly diagnosed Philadelphia chromosome–negative B-cell lymphoma, and shows, as well, that reduction of chemotherapy in this context is feasible,” Dr. Short stated.

“Ultimately, often for any patients with acute leukemias and ALL, our only chance to cure them is in the frontline setting, so our approach is to include all of the most effective agents we have. So that means including blinatumomab in all of our frontline regimens in clinical trials – and now we’ve amended that to add inotuzumab ozogamicin with the goal of deepening responses and increasing cure rates,” he added.

Dr. Short reported consulting with Takeda Oncology and Astrazeneca, and receiving research funding and honoraria from Amgen, Astella, and Takeda Oncology.

SOURCE: Short NG et al. ASH 2020, Abstract 464.

Hyper-CVAD (fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone) with sequential blinatumomab is highly effective as frontline therapy for Philadelphia Chromosome (Ph)–negative B-cell acute lymphoblastic leukemia (ALL), according to results of a phase 2 study reported at the annual meeting of the American Society of Hematology.

Favorable minimal residual disease (MRD) negativity and overall survival with low higher-grade toxicities suggest that reductions in chemotherapy in this setting are feasible, said Nicholas J. Short, MD, of the University of Texas MD Anderson Cancer Center, Houston.

While complete response rates with current ALL therapy are 80%-90%, long-term overall survival is only 40%-50%. Blinatumomab, a bispecific T-cell–engaging CD3-CD19 antibody, has been shown to be superior to chemotherapy in relapsed/refractory B-cell ALL, and to produce high rates of MRD eradication, the most important prognostic factor in ALL, Dr. Short said at the meeting, which was held virtually.

The hypothesis of the current study was that early incorporation of blinatumomab with hyper-CVAD in patients with newly diagnosed Ph-negative B-cell ALL would decrease the need for intensive chemotherapy and lead to higher efficacy and cure rates with less myelosuppression. Patients were required to have a performance status of 3 or less, total bilirubin 2 mg/dL or less and creatinine 2 mg/dL or less. Investigators enrolled 38 patients (mean age, 37 years,; range, 17-59) with most (79%) in performance status 0-1. The primary endpoint was relapse-free survival (RFS).
 

Study details

Patients received hyper-CVAD alternating with high-dose methotrexate and cytarabine for up to four cycles followed by four cycles of blinatumomab at standard doses. Those with CD20-positive disease (1% or greater percentage of the cells) received eight doses of ofatumumab or rituximab, and prophylactic intrathecal chemotherapy was given eight times in the first four cycles. Maintenance consisted of alternating blocks of POMP (6-mercaptopurine, vincristine, methotrexate, prednisone) and blinatumomab. When two patients with high-risk features experienced early relapse, investigators amended the protocol to allow blinatumomab after only two cycles of hyper-CVAD in those with high-risk features (e.g., CRLF2 positive by flow cytometry, complex karyotype, KMT2A rearranged, low hypodiploidy/near triploidy, TP53 mutation, or persistent MRD). Nineteen patients (56%) had at least one high-risk feature, and 82% received ofatumumab or rituximab. Six patients were in complete remission at the start of the study (four of them MRD negative).

Complete responses

After induction, complete responses were achieved in 81% (26/32), with all patients achieving a complete response at some point, according to Dr. Short. The MRD negativity rate was 71% (24/34) after induction and 97% (33/34) at any time. Among the 38 patients, all with complete response at median follow-up of 24 months (range, 2-45), relapses occurred only in those 5 patients with high-risk features. Twelve patients underwent transplant in the first remission. Two relapsed, both with high-risk features. The other 21 patients had ongoing complete responses.

RFS at 1- and 2-years was 80% and 71%, respectively. Five among seven relapses were without hematopoietic stem cell transplantation, and 2 were post HSCT. Two deaths occurred in patients with complete responses (one pulmonary embolism and one with post-HSCT complications). Overall survival at 1 and 2 years was 85% and 80%, respectively, with the 2-year rate comparable with prior reports for hyper-CVAD plus ofatumumab, Dr. Short said.

The most common nonhematologic grade 3-4 adverse events with hyper-CVAD plus blinatumomab were ALT/AST elevation (24%) and hyperglycemia (21%). The overall cytokine release syndrome rate was 13%, with 3% for higher-grade reactions. The rate for blinatumomab-related neurologic events was 45% overall and 13% for higher grades, with 1 discontinuation attributed to grade 2 encephalopathy and dysphasia.

“Overall, this study shows the potential benefit of incorporating frontline blinatumomab into the treatment of younger adults with newly diagnosed Philadelphia chromosome–negative B-cell lymphoma, and shows, as well, that reduction of chemotherapy in this context is feasible,” Dr. Short stated.

“Ultimately, often for any patients with acute leukemias and ALL, our only chance to cure them is in the frontline setting, so our approach is to include all of the most effective agents we have. So that means including blinatumomab in all of our frontline regimens in clinical trials – and now we’ve amended that to add inotuzumab ozogamicin with the goal of deepening responses and increasing cure rates,” he added.

Dr. Short reported consulting with Takeda Oncology and Astrazeneca, and receiving research funding and honoraria from Amgen, Astella, and Takeda Oncology.

SOURCE: Short NG et al. ASH 2020, Abstract 464.

Hyper-CVAD (fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone) with sequential blinatumomab is highly effective as frontline therapy for Philadelphia Chromosome (Ph)–negative B-cell acute lymphoblastic leukemia (ALL), according to results of a phase 2 study reported at the annual meeting of the American Society of Hematology.

Favorable minimal residual disease (MRD) negativity and overall survival with low higher-grade toxicities suggest that reductions in chemotherapy in this setting are feasible, said Nicholas J. Short, MD, of the University of Texas MD Anderson Cancer Center, Houston.

While complete response rates with current ALL therapy are 80%-90%, long-term overall survival is only 40%-50%. Blinatumomab, a bispecific T-cell–engaging CD3-CD19 antibody, has been shown to be superior to chemotherapy in relapsed/refractory B-cell ALL, and to produce high rates of MRD eradication, the most important prognostic factor in ALL, Dr. Short said at the meeting, which was held virtually.

The hypothesis of the current study was that early incorporation of blinatumomab with hyper-CVAD in patients with newly diagnosed Ph-negative B-cell ALL would decrease the need for intensive chemotherapy and lead to higher efficacy and cure rates with less myelosuppression. Patients were required to have a performance status of 3 or less, total bilirubin 2 mg/dL or less and creatinine 2 mg/dL or less. Investigators enrolled 38 patients (mean age, 37 years,; range, 17-59) with most (79%) in performance status 0-1. The primary endpoint was relapse-free survival (RFS).
 

Study details

Patients received hyper-CVAD alternating with high-dose methotrexate and cytarabine for up to four cycles followed by four cycles of blinatumomab at standard doses. Those with CD20-positive disease (1% or greater percentage of the cells) received eight doses of ofatumumab or rituximab, and prophylactic intrathecal chemotherapy was given eight times in the first four cycles. Maintenance consisted of alternating blocks of POMP (6-mercaptopurine, vincristine, methotrexate, prednisone) and blinatumomab. When two patients with high-risk features experienced early relapse, investigators amended the protocol to allow blinatumomab after only two cycles of hyper-CVAD in those with high-risk features (e.g., CRLF2 positive by flow cytometry, complex karyotype, KMT2A rearranged, low hypodiploidy/near triploidy, TP53 mutation, or persistent MRD). Nineteen patients (56%) had at least one high-risk feature, and 82% received ofatumumab or rituximab. Six patients were in complete remission at the start of the study (four of them MRD negative).

Complete responses

After induction, complete responses were achieved in 81% (26/32), with all patients achieving a complete response at some point, according to Dr. Short. The MRD negativity rate was 71% (24/34) after induction and 97% (33/34) at any time. Among the 38 patients, all with complete response at median follow-up of 24 months (range, 2-45), relapses occurred only in those 5 patients with high-risk features. Twelve patients underwent transplant in the first remission. Two relapsed, both with high-risk features. The other 21 patients had ongoing complete responses.

RFS at 1- and 2-years was 80% and 71%, respectively. Five among seven relapses were without hematopoietic stem cell transplantation, and 2 were post HSCT. Two deaths occurred in patients with complete responses (one pulmonary embolism and one with post-HSCT complications). Overall survival at 1 and 2 years was 85% and 80%, respectively, with the 2-year rate comparable with prior reports for hyper-CVAD plus ofatumumab, Dr. Short said.

The most common nonhematologic grade 3-4 adverse events with hyper-CVAD plus blinatumomab were ALT/AST elevation (24%) and hyperglycemia (21%). The overall cytokine release syndrome rate was 13%, with 3% for higher-grade reactions. The rate for blinatumomab-related neurologic events was 45% overall and 13% for higher grades, with 1 discontinuation attributed to grade 2 encephalopathy and dysphasia.

“Overall, this study shows the potential benefit of incorporating frontline blinatumomab into the treatment of younger adults with newly diagnosed Philadelphia chromosome–negative B-cell lymphoma, and shows, as well, that reduction of chemotherapy in this context is feasible,” Dr. Short stated.

“Ultimately, often for any patients with acute leukemias and ALL, our only chance to cure them is in the frontline setting, so our approach is to include all of the most effective agents we have. So that means including blinatumomab in all of our frontline regimens in clinical trials – and now we’ve amended that to add inotuzumab ozogamicin with the goal of deepening responses and increasing cure rates,” he added.

Dr. Short reported consulting with Takeda Oncology and Astrazeneca, and receiving research funding and honoraria from Amgen, Astella, and Takeda Oncology.

SOURCE: Short NG et al. ASH 2020, Abstract 464.

Patients with hematologic disease who develop COVID-19 may experience substantial morbidity and mortality related to SARS-CoV-2 infection, according to recent registry data reported at the all-virtual annual meeting of the American Society of Hematology.

Overall mortality was 28% for the first 250 patients entered into the ASH Research Collaborative COVID-19 Registry for Hematology, researchers reported in an abstract of their study findings.

However, the burden of death and moderate-to-severe COVID-19 outcomes was highest in patients with poorer prognosis and those with relapsed/refractory hematological disease, they added.

The most commonly represented malignancies were acute leukemia, non-Hodgkin lymphoma, and myeloma or amyloidosis, according to the report.

Taken together, the findings do support an “emerging consensus” that COVID-19 related morbidity and mortality is significant in these patients, authors said – however, the current findings may not be reason enough to support a change in treatment course for the underlying disease.

“We see no reason, based on our data, to withhold intensive therapies from patients with underlying hematologic malignancies and favorable prognoses, if aggressive supportive care is consistent with patient preferences,” wrote the researchers.

ASH President Stephanie Lee, MD, MPH, said these registry findings are important to better understand how SARS-CoV-2 is affecting not only patients with hematologic diseases, but also individuals who experience COVID-19-related hematologic complications.

However, the findings are limited due to the heterogeneity of diseases, symptoms, and treatments represented in the registry, said Dr. Lee, associate director of the clinical research division at Fred Hutchinson Cancer Center in Seattle.

“More data will be coming in, but I think this is an example of trying to harness real-world information to try to learn things until we get more controlled studies,” Dr. Lee said in a media briefing held in advance of the ASH meeting.
 

Comorbidities and more

Patients with blood cancers are often older and may have comorbidities such as diabetes or hypertension that have been linked to poor COVID-19 outcomes, according to the authors of the report, led by William A. Wood, MD, MPH, associate professor of medicine with the UNC Lineberger Comprehensive Cancer Center in Chapel Hill, N.C.

Moreover, these patients may have underlying immune dysfunction and may receive chemotherapy or immunotherapy that is “profoundly immunosuppressive,” Dr. Wood and coauthors said in their report.

To date, however, risks of morbidity and mortality related to SARS-CoV-2 infection have not been well defined in this patient population, authors said.

More data is emerging now from the ASH Research Collaborative COVID-19 Registry for Hematology, which includes data on patients positive for COVID-19 who have a past or present hematologic condition or have experienced a hematologic complication related to COVID-19.

All data from the registry is being made available through a dashboard on the ASH Research Collaborative website, which as of Dec. 1, 2020, included 693 complete cases.

The data cut in the ASH abstract includes the first 250 patients enrolled at 74 sites around the world, the authors said. The most common malignancies included acute leukemia in 33%, non-Hodgkin lymphoma in 27%, and myeloma or amyloidosis in 16%.

The most frequently reported symptoms included fever in 73%, cough in 67%, dyspnea in 50%, and fatigue in 40%, according to that report.

At the time of this data snapshot, treatment with COVID-19-directed therapies including hydroxychloroquine or azithromycin were common, reported in 76 and 59 patients, respectively, in the cohort.

Batch submissions from sites with high incidence of COVID-19 infection are ongoing. The registry has been expanded to include nonmalignant hematologic diseases, and the registry will continue to accumulate data as a resource for the hematology community.

Overall mortality was 28% at the time, according to the abstract, with nearly all of the deaths occurring in patients classified as having COVID-19 that was moderate (i.e., requiring hospitalization) or severe (i.e., requiring ICU admission).

“In some instances, death occurred after a decision was made to forgo ICU admission in favor of a palliative approach,” said Dr. Wood and coauthors in their report.

Dr. Wood reported research funding from Pfizer, consultancy with Teladoc/Best Doctors, and honoraria from the ASH Research Collaborative. Coauthors provided disclosures related to Celgene, Madrigal Pharmaceuticals, Pharmacyclics, and Amgen, among others.

SOURCE: Wood WA et al. ASH 2020, Abstract 215.

Patients with hematologic disease who develop COVID-19 may experience substantial morbidity and mortality related to SARS-CoV-2 infection, according to recent registry data reported at the all-virtual annual meeting of the American Society of Hematology.

Overall mortality was 28% for the first 250 patients entered into the ASH Research Collaborative COVID-19 Registry for Hematology, researchers reported in an abstract of their study findings.

However, the burden of death and moderate-to-severe COVID-19 outcomes was highest in patients with poorer prognosis and those with relapsed/refractory hematological disease, they added.

The most commonly represented malignancies were acute leukemia, non-Hodgkin lymphoma, and myeloma or amyloidosis, according to the report.

Taken together, the findings do support an “emerging consensus” that COVID-19 related morbidity and mortality is significant in these patients, authors said – however, the current findings may not be reason enough to support a change in treatment course for the underlying disease.

“We see no reason, based on our data, to withhold intensive therapies from patients with underlying hematologic malignancies and favorable prognoses, if aggressive supportive care is consistent with patient preferences,” wrote the researchers.

ASH President Stephanie Lee, MD, MPH, said these registry findings are important to better understand how SARS-CoV-2 is affecting not only patients with hematologic diseases, but also individuals who experience COVID-19-related hematologic complications.

However, the findings are limited due to the heterogeneity of diseases, symptoms, and treatments represented in the registry, said Dr. Lee, associate director of the clinical research division at Fred Hutchinson Cancer Center in Seattle.

“More data will be coming in, but I think this is an example of trying to harness real-world information to try to learn things until we get more controlled studies,” Dr. Lee said in a media briefing held in advance of the ASH meeting.
 

Comorbidities and more

Patients with blood cancers are often older and may have comorbidities such as diabetes or hypertension that have been linked to poor COVID-19 outcomes, according to the authors of the report, led by William A. Wood, MD, MPH, associate professor of medicine with the UNC Lineberger Comprehensive Cancer Center in Chapel Hill, N.C.

Moreover, these patients may have underlying immune dysfunction and may receive chemotherapy or immunotherapy that is “profoundly immunosuppressive,” Dr. Wood and coauthors said in their report.

To date, however, risks of morbidity and mortality related to SARS-CoV-2 infection have not been well defined in this patient population, authors said.

More data is emerging now from the ASH Research Collaborative COVID-19 Registry for Hematology, which includes data on patients positive for COVID-19 who have a past or present hematologic condition or have experienced a hematologic complication related to COVID-19.

All data from the registry is being made available through a dashboard on the ASH Research Collaborative website, which as of Dec. 1, 2020, included 693 complete cases.

The data cut in the ASH abstract includes the first 250 patients enrolled at 74 sites around the world, the authors said. The most common malignancies included acute leukemia in 33%, non-Hodgkin lymphoma in 27%, and myeloma or amyloidosis in 16%.

The most frequently reported symptoms included fever in 73%, cough in 67%, dyspnea in 50%, and fatigue in 40%, according to that report.

At the time of this data snapshot, treatment with COVID-19-directed therapies including hydroxychloroquine or azithromycin were common, reported in 76 and 59 patients, respectively, in the cohort.

Batch submissions from sites with high incidence of COVID-19 infection are ongoing. The registry has been expanded to include nonmalignant hematologic diseases, and the registry will continue to accumulate data as a resource for the hematology community.

Overall mortality was 28% at the time, according to the abstract, with nearly all of the deaths occurring in patients classified as having COVID-19 that was moderate (i.e., requiring hospitalization) or severe (i.e., requiring ICU admission).

“In some instances, death occurred after a decision was made to forgo ICU admission in favor of a palliative approach,” said Dr. Wood and coauthors in their report.

Dr. Wood reported research funding from Pfizer, consultancy with Teladoc/Best Doctors, and honoraria from the ASH Research Collaborative. Coauthors provided disclosures related to Celgene, Madrigal Pharmaceuticals, Pharmacyclics, and Amgen, among others.

SOURCE: Wood WA et al. ASH 2020, Abstract 215.

Patients with hematologic disease who develop COVID-19 may experience substantial morbidity and mortality related to SARS-CoV-2 infection, according to recent registry data reported at the all-virtual annual meeting of the American Society of Hematology.

Overall mortality was 28% for the first 250 patients entered into the ASH Research Collaborative COVID-19 Registry for Hematology, researchers reported in an abstract of their study findings.

However, the burden of death and moderate-to-severe COVID-19 outcomes was highest in patients with poorer prognosis and those with relapsed/refractory hematological disease, they added.

The most commonly represented malignancies were acute leukemia, non-Hodgkin lymphoma, and myeloma or amyloidosis, according to the report.

Taken together, the findings do support an “emerging consensus” that COVID-19 related morbidity and mortality is significant in these patients, authors said – however, the current findings may not be reason enough to support a change in treatment course for the underlying disease.

“We see no reason, based on our data, to withhold intensive therapies from patients with underlying hematologic malignancies and favorable prognoses, if aggressive supportive care is consistent with patient preferences,” wrote the researchers.

ASH President Stephanie Lee, MD, MPH, said these registry findings are important to better understand how SARS-CoV-2 is affecting not only patients with hematologic diseases, but also individuals who experience COVID-19-related hematologic complications.

However, the findings are limited due to the heterogeneity of diseases, symptoms, and treatments represented in the registry, said Dr. Lee, associate director of the clinical research division at Fred Hutchinson Cancer Center in Seattle.

“More data will be coming in, but I think this is an example of trying to harness real-world information to try to learn things until we get more controlled studies,” Dr. Lee said in a media briefing held in advance of the ASH meeting.
 

Comorbidities and more

Patients with blood cancers are often older and may have comorbidities such as diabetes or hypertension that have been linked to poor COVID-19 outcomes, according to the authors of the report, led by William A. Wood, MD, MPH, associate professor of medicine with the UNC Lineberger Comprehensive Cancer Center in Chapel Hill, N.C.

Moreover, these patients may have underlying immune dysfunction and may receive chemotherapy or immunotherapy that is “profoundly immunosuppressive,” Dr. Wood and coauthors said in their report.

To date, however, risks of morbidity and mortality related to SARS-CoV-2 infection have not been well defined in this patient population, authors said.

More data is emerging now from the ASH Research Collaborative COVID-19 Registry for Hematology, which includes data on patients positive for COVID-19 who have a past or present hematologic condition or have experienced a hematologic complication related to COVID-19.

All data from the registry is being made available through a dashboard on the ASH Research Collaborative website, which as of Dec. 1, 2020, included 693 complete cases.

The data cut in the ASH abstract includes the first 250 patients enrolled at 74 sites around the world, the authors said. The most common malignancies included acute leukemia in 33%, non-Hodgkin lymphoma in 27%, and myeloma or amyloidosis in 16%.

The most frequently reported symptoms included fever in 73%, cough in 67%, dyspnea in 50%, and fatigue in 40%, according to that report.

At the time of this data snapshot, treatment with COVID-19-directed therapies including hydroxychloroquine or azithromycin were common, reported in 76 and 59 patients, respectively, in the cohort.

Batch submissions from sites with high incidence of COVID-19 infection are ongoing. The registry has been expanded to include nonmalignant hematologic diseases, and the registry will continue to accumulate data as a resource for the hematology community.

Overall mortality was 28% at the time, according to the abstract, with nearly all of the deaths occurring in patients classified as having COVID-19 that was moderate (i.e., requiring hospitalization) or severe (i.e., requiring ICU admission).

“In some instances, death occurred after a decision was made to forgo ICU admission in favor of a palliative approach,” said Dr. Wood and coauthors in their report.

Dr. Wood reported research funding from Pfizer, consultancy with Teladoc/Best Doctors, and honoraria from the ASH Research Collaborative. Coauthors provided disclosures related to Celgene, Madrigal Pharmaceuticals, Pharmacyclics, and Amgen, among others.

SOURCE: Wood WA et al. ASH 2020, Abstract 215.

The days of using chemotherapy to treat Philadelphia chromosome–positive acute lymphoblastic leukemia (Ph+ ALL) may be numbered.

In a phase 2 trial, upfront chemotherapy-free induction/consolidation with the tyrosine kinase inhibitor dasatinib (Sprycel) and the bispecific T-cell engager antibody blinatumomab (Blincyto) yielded high rates of molecular response, “impressive” survival at 18 months, and few toxic effects of grade 3 or higher, say researchers.

With this approach, “60% of adult Ph+ ALL patients, of all ages, can obtain a molecular response, and this percent can increase further with more cycles of blinatumomab,” lead researcher Robin Foà, MD, from Sapienza University of Rome, said in an interview.

“The rates of disease-free survival and overall survival at 18 months are highly favorable, and the protocol is associated with limited toxicity,” Dr. Foà added.

“I see this chemo-free approach becoming a realistic approach for a substantial proportion of adult Ph+ ALL patients, particularly for the older patients, keeping in mind that the incidence of Ph+ ALL increases with age,” Dr. Foà said.

The results of the study were published Oct. 22 in the New England Journal of Medicine.
 

‘Innovative’ and ‘highly successful’

This “innovative” chemotherapy-free approach proved “highly successful” with “surprisingly” few toxic effects, Dieter Hoelzer, MD, PhD, University of Frankfurt (Germany), wrote in a linked editorial.

The Italian GIMEMA LAL2116 D-ALBA trial enrolled 63 adults (median age, 54 years; range, 24-82 years) with newly diagnosed Ph+ ALL. All patients received a glucocorticoid for 31 days beginning 7 days before starting treatment with dasatinib.

Dasatinib (140 mg once daily) induction therapy lasted 85 days. All patients who completed the induction phase received blinatumomab (28 mcg/d) consolidation therapy. Dexamethasone (20 mg) was administered before each blinatumomab cycle. To prevent central nervous system adverse events, levetiracetam (500 mg twice daily) was administered.

All but two patients completed dasatinib induction. One was a 73-year-old woman who withdrew from the trial because of toxic effects after 10 days of dasatinib treatment. She later died of pneumonia. The other was an 82-year-old woman who had a complete hematologic response but left the trial because of pneumonia and pneumonitis.

At the end of the induction phase, 98% of the patients (62 of 63) had a complete hematologic response, including the patient with a complete hematologic response who withdrew; 29% (17 of 59 patients) had a molecular response.

Of the 61 patients who completed the induction phase, 58 received one cycle of blinatumomab, 56 received two cycles, 45 received three cycles, 37 received four cycles, and 29 received five cycles. At the end of the second blinatumomab cycle, 60% of the patients (33 of 55 patients) had a molecular response.

The percentage of patients with a molecular response increased further after receiving additional cycles of blinatumomab – to 70% (28 of 40 patients) after the third cycle, 81% (29 of 36 patients) after the fourth cycle, and 72% (21 of 29 patients) after the fifth cycle.

At a median follow-up of 18 months, overall survival was 95%, and disease-free survival was 88%.

There were no significant differences in DFS between patients with p190-kd fusion protein (85%) and those with p210-kd fusion protein (95%). However, DFS was lower in patients with IKZF1 deletion plus additional genetic aberrations (CDKN2A or CDKN2B, PAX5, or both).

ABL1 mutations were present in six patients who had increased minimal residual disease during induction therapy. All these mutations were cleared by blinatumomab.

There were six relapses, of which three were hematologic. One occurred in a patient with a major protocol violation (a delay of more than 2 months in receiving blinatumomab), one occurred after 12 months in the patient who discontinued the trial after receiving dasatinib for 12 days, and one occurred in a patient after the second cycle of blinatumomab.

A total of 21 adverse events of grade 3 or higher were noted. They included cytomegalovirus reactivation or infection in six patients; neutropenia in four patients; persistent fever in two patients; and pleural effusion, pulmonary hypertension, and a neurologic disorder in one patient each.

Of the 24 patients who received a stem-cell allograft, two died, but only one death was related to transplant (4%).

The very low nonrelapse mortality among patients who underwent transplant during remission is “remarkable,” Dr. Hoelzer wrote. It suggests that toxicity from induction chemotherapy puts the patient at risk for toxic effects and death from subsequent stem-cell transplant – “a consequence that is avoided with targeted therapy.”
 

Unanswered questions

“Will the excellent outcomes be preserved with longer follow-up? The answer is probably yes, given that the majority of relapses in ALL occur within the first 1.5 to 2.0 years after the initiation of treatment,” Dr. Hoelzer wrote.

He said other outstanding questions include whether long-term outcomes will differ between patients who undergo transplant and those who do not; whether ABL1 mutations emerge; whether minimal residual disease recurs with longer follow-up; and whether this treatment approach can be used for patients with other subtypes of ALL, such as Ph-negative, B-lineage ALL, or even T-cell ALL.

“If these promising trial results hold, chemotherapy-free induction without the immediate and long-term toxic effects of intensive chemotherapy regimens could also be used in adolescents and, finally, in children. These questions will need to be addressed with longer follow-up and large, prospective trials,” Dr. Hoelzer concluded.

The study was supported by grants from the Italian Association for Cancer Research and Sapienza University of Rome.

A version of this article originally appeared on Medscape.com

The days of using chemotherapy to treat Philadelphia chromosome–positive acute lymphoblastic leukemia (Ph+ ALL) may be numbered.

In a phase 2 trial, upfront chemotherapy-free induction/consolidation with the tyrosine kinase inhibitor dasatinib (Sprycel) and the bispecific T-cell engager antibody blinatumomab (Blincyto) yielded high rates of molecular response, “impressive” survival at 18 months, and few toxic effects of grade 3 or higher, say researchers.

With this approach, “60% of adult Ph+ ALL patients, of all ages, can obtain a molecular response, and this percent can increase further with more cycles of blinatumomab,” lead researcher Robin Foà, MD, from Sapienza University of Rome, said in an interview.

“The rates of disease-free survival and overall survival at 18 months are highly favorable, and the protocol is associated with limited toxicity,” Dr. Foà added.

“I see this chemo-free approach becoming a realistic approach for a substantial proportion of adult Ph+ ALL patients, particularly for the older patients, keeping in mind that the incidence of Ph+ ALL increases with age,” Dr. Foà said.

The results of the study were published Oct. 22 in the New England Journal of Medicine.
 

‘Innovative’ and ‘highly successful’

This “innovative” chemotherapy-free approach proved “highly successful” with “surprisingly” few toxic effects, Dieter Hoelzer, MD, PhD, University of Frankfurt (Germany), wrote in a linked editorial.

The Italian GIMEMA LAL2116 D-ALBA trial enrolled 63 adults (median age, 54 years; range, 24-82 years) with newly diagnosed Ph+ ALL. All patients received a glucocorticoid for 31 days beginning 7 days before starting treatment with dasatinib.

Dasatinib (140 mg once daily) induction therapy lasted 85 days. All patients who completed the induction phase received blinatumomab (28 mcg/d) consolidation therapy. Dexamethasone (20 mg) was administered before each blinatumomab cycle. To prevent central nervous system adverse events, levetiracetam (500 mg twice daily) was administered.

All but two patients completed dasatinib induction. One was a 73-year-old woman who withdrew from the trial because of toxic effects after 10 days of dasatinib treatment. She later died of pneumonia. The other was an 82-year-old woman who had a complete hematologic response but left the trial because of pneumonia and pneumonitis.

At the end of the induction phase, 98% of the patients (62 of 63) had a complete hematologic response, including the patient with a complete hematologic response who withdrew; 29% (17 of 59 patients) had a molecular response.

Of the 61 patients who completed the induction phase, 58 received one cycle of blinatumomab, 56 received two cycles, 45 received three cycles, 37 received four cycles, and 29 received five cycles. At the end of the second blinatumomab cycle, 60% of the patients (33 of 55 patients) had a molecular response.

The percentage of patients with a molecular response increased further after receiving additional cycles of blinatumomab – to 70% (28 of 40 patients) after the third cycle, 81% (29 of 36 patients) after the fourth cycle, and 72% (21 of 29 patients) after the fifth cycle.

At a median follow-up of 18 months, overall survival was 95%, and disease-free survival was 88%.

There were no significant differences in DFS between patients with p190-kd fusion protein (85%) and those with p210-kd fusion protein (95%). However, DFS was lower in patients with IKZF1 deletion plus additional genetic aberrations (CDKN2A or CDKN2B, PAX5, or both).

ABL1 mutations were present in six patients who had increased minimal residual disease during induction therapy. All these mutations were cleared by blinatumomab.

There were six relapses, of which three were hematologic. One occurred in a patient with a major protocol violation (a delay of more than 2 months in receiving blinatumomab), one occurred after 12 months in the patient who discontinued the trial after receiving dasatinib for 12 days, and one occurred in a patient after the second cycle of blinatumomab.

A total of 21 adverse events of grade 3 or higher were noted. They included cytomegalovirus reactivation or infection in six patients; neutropenia in four patients; persistent fever in two patients; and pleural effusion, pulmonary hypertension, and a neurologic disorder in one patient each.

Of the 24 patients who received a stem-cell allograft, two died, but only one death was related to transplant (4%).

The very low nonrelapse mortality among patients who underwent transplant during remission is “remarkable,” Dr. Hoelzer wrote. It suggests that toxicity from induction chemotherapy puts the patient at risk for toxic effects and death from subsequent stem-cell transplant – “a consequence that is avoided with targeted therapy.”
 

Unanswered questions

“Will the excellent outcomes be preserved with longer follow-up? The answer is probably yes, given that the majority of relapses in ALL occur within the first 1.5 to 2.0 years after the initiation of treatment,” Dr. Hoelzer wrote.

He said other outstanding questions include whether long-term outcomes will differ between patients who undergo transplant and those who do not; whether ABL1 mutations emerge; whether minimal residual disease recurs with longer follow-up; and whether this treatment approach can be used for patients with other subtypes of ALL, such as Ph-negative, B-lineage ALL, or even T-cell ALL.

“If these promising trial results hold, chemotherapy-free induction without the immediate and long-term toxic effects of intensive chemotherapy regimens could also be used in adolescents and, finally, in children. These questions will need to be addressed with longer follow-up and large, prospective trials,” Dr. Hoelzer concluded.

The study was supported by grants from the Italian Association for Cancer Research and Sapienza University of Rome.

A version of this article originally appeared on Medscape.com

The days of using chemotherapy to treat Philadelphia chromosome–positive acute lymphoblastic leukemia (Ph+ ALL) may be numbered.

In a phase 2 trial, upfront chemotherapy-free induction/consolidation with the tyrosine kinase inhibitor dasatinib (Sprycel) and the bispecific T-cell engager antibody blinatumomab (Blincyto) yielded high rates of molecular response, “impressive” survival at 18 months, and few toxic effects of grade 3 or higher, say researchers.

With this approach, “60% of adult Ph+ ALL patients, of all ages, can obtain a molecular response, and this percent can increase further with more cycles of blinatumomab,” lead researcher Robin Foà, MD, from Sapienza University of Rome, said in an interview.

“The rates of disease-free survival and overall survival at 18 months are highly favorable, and the protocol is associated with limited toxicity,” Dr. Foà added.

“I see this chemo-free approach becoming a realistic approach for a substantial proportion of adult Ph+ ALL patients, particularly for the older patients, keeping in mind that the incidence of Ph+ ALL increases with age,” Dr. Foà said.

The results of the study were published Oct. 22 in the New England Journal of Medicine.
 

‘Innovative’ and ‘highly successful’

This “innovative” chemotherapy-free approach proved “highly successful” with “surprisingly” few toxic effects, Dieter Hoelzer, MD, PhD, University of Frankfurt (Germany), wrote in a linked editorial.

The Italian GIMEMA LAL2116 D-ALBA trial enrolled 63 adults (median age, 54 years; range, 24-82 years) with newly diagnosed Ph+ ALL. All patients received a glucocorticoid for 31 days beginning 7 days before starting treatment with dasatinib.

Dasatinib (140 mg once daily) induction therapy lasted 85 days. All patients who completed the induction phase received blinatumomab (28 mcg/d) consolidation therapy. Dexamethasone (20 mg) was administered before each blinatumomab cycle. To prevent central nervous system adverse events, levetiracetam (500 mg twice daily) was administered.

All but two patients completed dasatinib induction. One was a 73-year-old woman who withdrew from the trial because of toxic effects after 10 days of dasatinib treatment. She later died of pneumonia. The other was an 82-year-old woman who had a complete hematologic response but left the trial because of pneumonia and pneumonitis.

At the end of the induction phase, 98% of the patients (62 of 63) had a complete hematologic response, including the patient with a complete hematologic response who withdrew; 29% (17 of 59 patients) had a molecular response.

Of the 61 patients who completed the induction phase, 58 received one cycle of blinatumomab, 56 received two cycles, 45 received three cycles, 37 received four cycles, and 29 received five cycles. At the end of the second blinatumomab cycle, 60% of the patients (33 of 55 patients) had a molecular response.

The percentage of patients with a molecular response increased further after receiving additional cycles of blinatumomab – to 70% (28 of 40 patients) after the third cycle, 81% (29 of 36 patients) after the fourth cycle, and 72% (21 of 29 patients) after the fifth cycle.

At a median follow-up of 18 months, overall survival was 95%, and disease-free survival was 88%.

There were no significant differences in DFS between patients with p190-kd fusion protein (85%) and those with p210-kd fusion protein (95%). However, DFS was lower in patients with IKZF1 deletion plus additional genetic aberrations (CDKN2A or CDKN2B, PAX5, or both).

ABL1 mutations were present in six patients who had increased minimal residual disease during induction therapy. All these mutations were cleared by blinatumomab.

There were six relapses, of which three were hematologic. One occurred in a patient with a major protocol violation (a delay of more than 2 months in receiving blinatumomab), one occurred after 12 months in the patient who discontinued the trial after receiving dasatinib for 12 days, and one occurred in a patient after the second cycle of blinatumomab.

A total of 21 adverse events of grade 3 or higher were noted. They included cytomegalovirus reactivation or infection in six patients; neutropenia in four patients; persistent fever in two patients; and pleural effusion, pulmonary hypertension, and a neurologic disorder in one patient each.

Of the 24 patients who received a stem-cell allograft, two died, but only one death was related to transplant (4%).

The very low nonrelapse mortality among patients who underwent transplant during remission is “remarkable,” Dr. Hoelzer wrote. It suggests that toxicity from induction chemotherapy puts the patient at risk for toxic effects and death from subsequent stem-cell transplant – “a consequence that is avoided with targeted therapy.”
 

Unanswered questions

“Will the excellent outcomes be preserved with longer follow-up? The answer is probably yes, given that the majority of relapses in ALL occur within the first 1.5 to 2.0 years after the initiation of treatment,” Dr. Hoelzer wrote.

He said other outstanding questions include whether long-term outcomes will differ between patients who undergo transplant and those who do not; whether ABL1 mutations emerge; whether minimal residual disease recurs with longer follow-up; and whether this treatment approach can be used for patients with other subtypes of ALL, such as Ph-negative, B-lineage ALL, or even T-cell ALL.

“If these promising trial results hold, chemotherapy-free induction without the immediate and long-term toxic effects of intensive chemotherapy regimens could also be used in adolescents and, finally, in children. These questions will need to be addressed with longer follow-up and large, prospective trials,” Dr. Hoelzer concluded.

The study was supported by grants from the Italian Association for Cancer Research and Sapienza University of Rome.

A version of this article originally appeared on Medscape.com

Immunotherapy is a rising star among emerging therapies for acute lymphoblastic leukemia (ALL), according to Patrick A. Brown, MD.

“Most of the emerging therapies in ALL are immunotherapies that have really made an impact in the relapsed and refractory setting,” he said during a presentation at the National Comprehensive Cancer Network Hematologic Malignancies Annual Congress. “Another very exciting development is that these immunotherapies are now demonstrating efficacy and increased tolerability over chemotherapy in the minimal residual disease (MRD)-positive setting up front.”

Dr. Brown, director of the pediatric leukemia program at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, focused on blinatumomab, inotuzumab, and chimeric antigen receptor (CAR) T-cell therapy for ALL, and explained the rationale for their use.
 

Why immunotherapy?

“It turns out that in normal B cell development there are a number of proteins that are expressed on the surface of B cells and these same proteins are expressed on the surface of many B-cell malignancies,” he said, noting that ALL is “probably the least differentiated of the B-lineage malignancies,” but the vast majority of ALL cases will express CD19 and CD22, and – in adults more often than pediatric patients – CD20.

These antigens make good targets for ALL therapy because they aren’t expressed on bone marrow stem cells or other tissues in the body.

“They really are specific for B cells,” he said, explaining that inotuzumab, a CD22 antibody drug conjugate (ADC), and blinatumomab, a bi-specific T cell-engaging antibody (BiTE) that targets CD19, are antibody-based immunotherapies, whereas CAR T-cell therapies are a separate category that can be single- or multi-antigen targeted.
 

Inotuzumab, blinatumomab, and CAR T cells

Inotuzumab targets the CD22 immunotoxin antigen via a T-cell independent process and is delivered as a once-weekly 1-hour infusion. It is approved for adult relapsed/refractory B-ALL. Blinatumomab binds CD19 on the surface of the tumor cells and CD3 on the surface of any T cell in the vicinity of the tumor cell.

“The recognition that blinatumomab allows between the tumor cell and the T cell is independent of the specificity of the T-cell receptor. It also does not require [major histocompatibility complex] class 1 or peptide antigens on the surface of the T cell,” he said, adding that it does, however, rely on a functional endogenous cytotoxic T-cell response, unlike inotuzumab. “It’s also very difficult technically to give because it’s given as a 28-day continuous IV infusion with bag changes required every 4-7 days.”

Blinatumomab is approved for adult and pediatric Philadelphia chromosome-negative relapsed/refractory B-cell precursor ALL and MRD-positive B-cell precursor ALL.

CAR T-cell therapy, an autologous immunotherapy, is “really kind of the pinnacle of technological advances in immunotherapy in that it combine three different modalities into one: cellular therapy, gene therapy, and immunotherapy,” he said, noting that the process of genetically engineering T cells to express a CAR is complex and costly and access is limited, but expanding with about 90 centers in the U.S. now providing CAR T-cell therapy.

Response rates with each of these therapies represent a paradigm shift in the relapsed/refractory ALL setting, Dr. Brown said.

Studies have shown complete remission (CR) and minimum residual disease (MRD)-negative CR rates of 81% and 78%, respectively, with inotuzumab, and 43% and 33%, respectively, with blinatumomab.

“This depth of remission was really not seen with prior salvage therapies,” he noted, but added that neither has shown significant durable improvement in overall survival (OS) rates.

CAR T-cell therapy, however, has the highest response rates, with tisagenlecleucel – which targets CD19 and was the first CAR T-cell therapy approved for refractory or second or greater relapse in patients up to age 26 years – showing 81% CR and MRD-negative CR rates and providing a durable survival advantage without subsequent therapy in 40-50% of patients.

“So CAR T cells can represent definitive therapy in a subset of patients,” Dr. Brown said. “One thing we’re struggling with is to be able to predict which patients those are, and there are some emerging biomarkers that may help us with that, but as of now it’s very difficult to predict which patients, when you’re treating them, are going to be in [that group].”

Toxicities and limitations

Cytokine release syndrome and neurotoxicity are the primary toxicities associated with both blinatumomab and tisagenlecleucel. Hepatotoxicity is a major concern with inotuzumab.

“This is particularly important because that hepatotoxicity appears to be primarily a problem in patients who receive inotuzumab either after or prior to hematopoietic stem cell transplant, and since this therapy does not represent definitive therapy and often is really a bridge to transplant, this ... can be a significant limitation to this product,” Dr. Brown said.

A limitation of CAR T cells is failure to manufacture the product, which occurs most often in very young and heavily pretreated patients in whom it can be difficult to obtain enough functional T cells to create the product. Failure to engraft or lack of persistence of the CAR T cells can also occur.

Endogenous or CAR T-cell exhaustion is another potential limitation with blinatumomab and CAR T-cell therapy, and antigen escape can occur with both therapies, as well.

Strategies are being investigated to overcome treatment challenges, Dr. Brown noted.

Examples include efforts to develop universal “off-the-shelf” allogeneic CAR T-cell products to address failure to manufacture, working on more co-stimulatory domains that may be more effective to promote engraftment and persistence, adding immune checkpoint inhibitors to therapy to combat endogenous or CAR T-cell exhaustion, and developing multi-antigen targeted approaches to overcome antigen escape, he said.
 

NCCN Treatment Guidelines

Based on the currently available data, the NCCN has included these immunotherapies in guidelines for both adolescent and young adult (AYA)/adult ALL and for pediatric ALL.

Each of the treatments is listed as an option to consider in both Philadelphia chromosome-positive and -negative AYA and adult patients under age 65 years. Additionally, blinatumomab is listed as an option for up-front treatment of MRD-positive Philadelphia chromosome-negative AYA patients and older patients.

Pediatric guidelines include blinatumomab and tisagenlecleucel as options for patients with MRD-positive disease after induction and for first relapse, and they include all three therapies as options in patients with multiple relapses or refractory disease, said Dr. Brown who chairs the NCCN Clinical Practice Guidelines panel for adult and pediatric ALL.
 

Treatment decision making

Asked by session moderator Ranjana H. Advani, MD, how to decide between the available immunotherapies, Dr. Brown said there is no one-size-fits-all answer.

“Is it availability, insurance coverage, the patient fits better with one therapy,” asked Dr. Advani, the Saul Rosenberg Professor of Lymphoma and the Physician Leader of the Lymphoma Clinical Care Program of Stanford Cancer Institute, Palo Alto, Calif.

“All of the above,” Dr. Brown said. “In 2020 with all these options available, we are a little bit spoiled for choice ... but every patient is an individual case and the risk -benefit ratios of all these therapies differ.”

An exception is that CAR T-cell therapy is a clear stand-out for the patient who isn’t transplant eligible, he noted, adding that CAR T cells “probably give that patient the best chance of survival.”

In a patient who could potentially go to transplant, selection is a bit more challenging, but given the risks associated with inotuzumab, blinatumomab is generally the preferred non-CAR T option, he said.

“It’s a complicated question, and the answer ... is [that it is] an individualized patient-by-patient decision,” he added.

Dr. Brown reported consulting, advisory board, or expert witness activity for Novartis Pharmaceuticals Corporation and Takeda Pharmaceuticals North America Inc.

[email protected]

Immunotherapy is a rising star among emerging therapies for acute lymphoblastic leukemia (ALL), according to Patrick A. Brown, MD.

“Most of the emerging therapies in ALL are immunotherapies that have really made an impact in the relapsed and refractory setting,” he said during a presentation at the National Comprehensive Cancer Network Hematologic Malignancies Annual Congress. “Another very exciting development is that these immunotherapies are now demonstrating efficacy and increased tolerability over chemotherapy in the minimal residual disease (MRD)-positive setting up front.”

Dr. Brown, director of the pediatric leukemia program at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, focused on blinatumomab, inotuzumab, and chimeric antigen receptor (CAR) T-cell therapy for ALL, and explained the rationale for their use.
 

Why immunotherapy?

“It turns out that in normal B cell development there are a number of proteins that are expressed on the surface of B cells and these same proteins are expressed on the surface of many B-cell malignancies,” he said, noting that ALL is “probably the least differentiated of the B-lineage malignancies,” but the vast majority of ALL cases will express CD19 and CD22, and – in adults more often than pediatric patients – CD20.

These antigens make good targets for ALL therapy because they aren’t expressed on bone marrow stem cells or other tissues in the body.

“They really are specific for B cells,” he said, explaining that inotuzumab, a CD22 antibody drug conjugate (ADC), and blinatumomab, a bi-specific T cell-engaging antibody (BiTE) that targets CD19, are antibody-based immunotherapies, whereas CAR T-cell therapies are a separate category that can be single- or multi-antigen targeted.
 

Inotuzumab, blinatumomab, and CAR T cells

Inotuzumab targets the CD22 immunotoxin antigen via a T-cell independent process and is delivered as a once-weekly 1-hour infusion. It is approved for adult relapsed/refractory B-ALL. Blinatumomab binds CD19 on the surface of the tumor cells and CD3 on the surface of any T cell in the vicinity of the tumor cell.

“The recognition that blinatumomab allows between the tumor cell and the T cell is independent of the specificity of the T-cell receptor. It also does not require [major histocompatibility complex] class 1 or peptide antigens on the surface of the T cell,” he said, adding that it does, however, rely on a functional endogenous cytotoxic T-cell response, unlike inotuzumab. “It’s also very difficult technically to give because it’s given as a 28-day continuous IV infusion with bag changes required every 4-7 days.”

Blinatumomab is approved for adult and pediatric Philadelphia chromosome-negative relapsed/refractory B-cell precursor ALL and MRD-positive B-cell precursor ALL.

CAR T-cell therapy, an autologous immunotherapy, is “really kind of the pinnacle of technological advances in immunotherapy in that it combine three different modalities into one: cellular therapy, gene therapy, and immunotherapy,” he said, noting that the process of genetically engineering T cells to express a CAR is complex and costly and access is limited, but expanding with about 90 centers in the U.S. now providing CAR T-cell therapy.

Response rates with each of these therapies represent a paradigm shift in the relapsed/refractory ALL setting, Dr. Brown said.

Studies have shown complete remission (CR) and minimum residual disease (MRD)-negative CR rates of 81% and 78%, respectively, with inotuzumab, and 43% and 33%, respectively, with blinatumomab.

“This depth of remission was really not seen with prior salvage therapies,” he noted, but added that neither has shown significant durable improvement in overall survival (OS) rates.

CAR T-cell therapy, however, has the highest response rates, with tisagenlecleucel – which targets CD19 and was the first CAR T-cell therapy approved for refractory or second or greater relapse in patients up to age 26 years – showing 81% CR and MRD-negative CR rates and providing a durable survival advantage without subsequent therapy in 40-50% of patients.

“So CAR T cells can represent definitive therapy in a subset of patients,” Dr. Brown said. “One thing we’re struggling with is to be able to predict which patients those are, and there are some emerging biomarkers that may help us with that, but as of now it’s very difficult to predict which patients, when you’re treating them, are going to be in [that group].”

Toxicities and limitations

Cytokine release syndrome and neurotoxicity are the primary toxicities associated with both blinatumomab and tisagenlecleucel. Hepatotoxicity is a major concern with inotuzumab.

“This is particularly important because that hepatotoxicity appears to be primarily a problem in patients who receive inotuzumab either after or prior to hematopoietic stem cell transplant, and since this therapy does not represent definitive therapy and often is really a bridge to transplant, this ... can be a significant limitation to this product,” Dr. Brown said.

A limitation of CAR T cells is failure to manufacture the product, which occurs most often in very young and heavily pretreated patients in whom it can be difficult to obtain enough functional T cells to create the product. Failure to engraft or lack of persistence of the CAR T cells can also occur.

Endogenous or CAR T-cell exhaustion is another potential limitation with blinatumomab and CAR T-cell therapy, and antigen escape can occur with both therapies, as well.

Strategies are being investigated to overcome treatment challenges, Dr. Brown noted.

Examples include efforts to develop universal “off-the-shelf” allogeneic CAR T-cell products to address failure to manufacture, working on more co-stimulatory domains that may be more effective to promote engraftment and persistence, adding immune checkpoint inhibitors to therapy to combat endogenous or CAR T-cell exhaustion, and developing multi-antigen targeted approaches to overcome antigen escape, he said.
 

NCCN Treatment Guidelines

Based on the currently available data, the NCCN has included these immunotherapies in guidelines for both adolescent and young adult (AYA)/adult ALL and for pediatric ALL.

Each of the treatments is listed as an option to consider in both Philadelphia chromosome-positive and -negative AYA and adult patients under age 65 years. Additionally, blinatumomab is listed as an option for up-front treatment of MRD-positive Philadelphia chromosome-negative AYA patients and older patients.

Pediatric guidelines include blinatumomab and tisagenlecleucel as options for patients with MRD-positive disease after induction and for first relapse, and they include all three therapies as options in patients with multiple relapses or refractory disease, said Dr. Brown who chairs the NCCN Clinical Practice Guidelines panel for adult and pediatric ALL.
 

Treatment decision making

Asked by session moderator Ranjana H. Advani, MD, how to decide between the available immunotherapies, Dr. Brown said there is no one-size-fits-all answer.

“Is it availability, insurance coverage, the patient fits better with one therapy,” asked Dr. Advani, the Saul Rosenberg Professor of Lymphoma and the Physician Leader of the Lymphoma Clinical Care Program of Stanford Cancer Institute, Palo Alto, Calif.

“All of the above,” Dr. Brown said. “In 2020 with all these options available, we are a little bit spoiled for choice ... but every patient is an individual case and the risk -benefit ratios of all these therapies differ.”

An exception is that CAR T-cell therapy is a clear stand-out for the patient who isn’t transplant eligible, he noted, adding that CAR T cells “probably give that patient the best chance of survival.”

In a patient who could potentially go to transplant, selection is a bit more challenging, but given the risks associated with inotuzumab, blinatumomab is generally the preferred non-CAR T option, he said.

“It’s a complicated question, and the answer ... is [that it is] an individualized patient-by-patient decision,” he added.

Dr. Brown reported consulting, advisory board, or expert witness activity for Novartis Pharmaceuticals Corporation and Takeda Pharmaceuticals North America Inc.

[email protected]

Immunotherapy is a rising star among emerging therapies for acute lymphoblastic leukemia (ALL), according to Patrick A. Brown, MD.

“Most of the emerging therapies in ALL are immunotherapies that have really made an impact in the relapsed and refractory setting,” he said during a presentation at the National Comprehensive Cancer Network Hematologic Malignancies Annual Congress. “Another very exciting development is that these immunotherapies are now demonstrating efficacy and increased tolerability over chemotherapy in the minimal residual disease (MRD)-positive setting up front.”

Dr. Brown, director of the pediatric leukemia program at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, focused on blinatumomab, inotuzumab, and chimeric antigen receptor (CAR) T-cell therapy for ALL, and explained the rationale for their use.
 

Why immunotherapy?

“It turns out that in normal B cell development there are a number of proteins that are expressed on the surface of B cells and these same proteins are expressed on the surface of many B-cell malignancies,” he said, noting that ALL is “probably the least differentiated of the B-lineage malignancies,” but the vast majority of ALL cases will express CD19 and CD22, and – in adults more often than pediatric patients – CD20.

These antigens make good targets for ALL therapy because they aren’t expressed on bone marrow stem cells or other tissues in the body.

“They really are specific for B cells,” he said, explaining that inotuzumab, a CD22 antibody drug conjugate (ADC), and blinatumomab, a bi-specific T cell-engaging antibody (BiTE) that targets CD19, are antibody-based immunotherapies, whereas CAR T-cell therapies are a separate category that can be single- or multi-antigen targeted.
 

Inotuzumab, blinatumomab, and CAR T cells

Inotuzumab targets the CD22 immunotoxin antigen via a T-cell independent process and is delivered as a once-weekly 1-hour infusion. It is approved for adult relapsed/refractory B-ALL. Blinatumomab binds CD19 on the surface of the tumor cells and CD3 on the surface of any T cell in the vicinity of the tumor cell.

“The recognition that blinatumomab allows between the tumor cell and the T cell is independent of the specificity of the T-cell receptor. It also does not require [major histocompatibility complex] class 1 or peptide antigens on the surface of the T cell,” he said, adding that it does, however, rely on a functional endogenous cytotoxic T-cell response, unlike inotuzumab. “It’s also very difficult technically to give because it’s given as a 28-day continuous IV infusion with bag changes required every 4-7 days.”

Blinatumomab is approved for adult and pediatric Philadelphia chromosome-negative relapsed/refractory B-cell precursor ALL and MRD-positive B-cell precursor ALL.

CAR T-cell therapy, an autologous immunotherapy, is “really kind of the pinnacle of technological advances in immunotherapy in that it combine three different modalities into one: cellular therapy, gene therapy, and immunotherapy,” he said, noting that the process of genetically engineering T cells to express a CAR is complex and costly and access is limited, but expanding with about 90 centers in the U.S. now providing CAR T-cell therapy.

Response rates with each of these therapies represent a paradigm shift in the relapsed/refractory ALL setting, Dr. Brown said.

Studies have shown complete remission (CR) and minimum residual disease (MRD)-negative CR rates of 81% and 78%, respectively, with inotuzumab, and 43% and 33%, respectively, with blinatumomab.

“This depth of remission was really not seen with prior salvage therapies,” he noted, but added that neither has shown significant durable improvement in overall survival (OS) rates.

CAR T-cell therapy, however, has the highest response rates, with tisagenlecleucel – which targets CD19 and was the first CAR T-cell therapy approved for refractory or second or greater relapse in patients up to age 26 years – showing 81% CR and MRD-negative CR rates and providing a durable survival advantage without subsequent therapy in 40-50% of patients.

“So CAR T cells can represent definitive therapy in a subset of patients,” Dr. Brown said. “One thing we’re struggling with is to be able to predict which patients those are, and there are some emerging biomarkers that may help us with that, but as of now it’s very difficult to predict which patients, when you’re treating them, are going to be in [that group].”

Toxicities and limitations

Cytokine release syndrome and neurotoxicity are the primary toxicities associated with both blinatumomab and tisagenlecleucel. Hepatotoxicity is a major concern with inotuzumab.

“This is particularly important because that hepatotoxicity appears to be primarily a problem in patients who receive inotuzumab either after or prior to hematopoietic stem cell transplant, and since this therapy does not represent definitive therapy and often is really a bridge to transplant, this ... can be a significant limitation to this product,” Dr. Brown said.

A limitation of CAR T cells is failure to manufacture the product, which occurs most often in very young and heavily pretreated patients in whom it can be difficult to obtain enough functional T cells to create the product. Failure to engraft or lack of persistence of the CAR T cells can also occur.

Endogenous or CAR T-cell exhaustion is another potential limitation with blinatumomab and CAR T-cell therapy, and antigen escape can occur with both therapies, as well.

Strategies are being investigated to overcome treatment challenges, Dr. Brown noted.

Examples include efforts to develop universal “off-the-shelf” allogeneic CAR T-cell products to address failure to manufacture, working on more co-stimulatory domains that may be more effective to promote engraftment and persistence, adding immune checkpoint inhibitors to therapy to combat endogenous or CAR T-cell exhaustion, and developing multi-antigen targeted approaches to overcome antigen escape, he said.
 

NCCN Treatment Guidelines

Based on the currently available data, the NCCN has included these immunotherapies in guidelines for both adolescent and young adult (AYA)/adult ALL and for pediatric ALL.

Each of the treatments is listed as an option to consider in both Philadelphia chromosome-positive and -negative AYA and adult patients under age 65 years. Additionally, blinatumomab is listed as an option for up-front treatment of MRD-positive Philadelphia chromosome-negative AYA patients and older patients.

Pediatric guidelines include blinatumomab and tisagenlecleucel as options for patients with MRD-positive disease after induction and for first relapse, and they include all three therapies as options in patients with multiple relapses or refractory disease, said Dr. Brown who chairs the NCCN Clinical Practice Guidelines panel for adult and pediatric ALL.
 

Treatment decision making

Asked by session moderator Ranjana H. Advani, MD, how to decide between the available immunotherapies, Dr. Brown said there is no one-size-fits-all answer.

“Is it availability, insurance coverage, the patient fits better with one therapy,” asked Dr. Advani, the Saul Rosenberg Professor of Lymphoma and the Physician Leader of the Lymphoma Clinical Care Program of Stanford Cancer Institute, Palo Alto, Calif.

“All of the above,” Dr. Brown said. “In 2020 with all these options available, we are a little bit spoiled for choice ... but every patient is an individual case and the risk -benefit ratios of all these therapies differ.”

An exception is that CAR T-cell therapy is a clear stand-out for the patient who isn’t transplant eligible, he noted, adding that CAR T cells “probably give that patient the best chance of survival.”

In a patient who could potentially go to transplant, selection is a bit more challenging, but given the risks associated with inotuzumab, blinatumomab is generally the preferred non-CAR T option, he said.

“It’s a complicated question, and the answer ... is [that it is] an individualized patient-by-patient decision,” he added.

Dr. Brown reported consulting, advisory board, or expert witness activity for Novartis Pharmaceuticals Corporation and Takeda Pharmaceuticals North America Inc.

[email protected]

Hematopoietic stem cell transplantation (HCT) is one of the most important treatment options for acute leukemias. However, posttransplant cancer recurrence remains a continuing issue. And while there are reasons to think that hypomethylating agents (HMAS) could be helpful as maintenance tools to prevent cancer recurrence after HCT in leukemia, a hematologist/oncologist told colleagues that the treatment isn’t yet ready for prime time.

“I don’t think you can prefer hypomethylating agents over anything right now. Unfortunately, there’s no data that we can hang our hat on that says they are of benefit in the posttransplant setting,” said Frederick Appelbaum, MD, executive vice president and deputy director of the Fred Hutchinson Cancer Research Center, Seattle, in a presentation at the virtual Acute Leukemia Forum of Hemedicus.

However, there’s still plenty of room for improvement for patients following HCT, he said, pointing to the findings of a 2020 study. The report, which he cowrote, found that 200-day mortality after HCT fell by a third from 2003-2007 to 2013-20017, but also noted that “relapse of cancer remains the largest obstacle to better survival outcomes.”

Dr. Appelbaum described the findings this way: “Without a doubt, the major limitation to transplants for hematologic malignancies today is disease recurrence,” he said. “In fact, if you look at patients after day 100, over 60% of the reason for failure is tumor regrowth. Thus, people are very anxious to look at any method that we can to prevent posttransplant relapse, including the use of hypomethylating agents.”

In regard to strategy, “we don’t have to get rid of every last leukemic cell. Just delaying recurrence might be enough,” he said. “If you can keep the patient from relapsing for the first 3 months, and then take the brakes off the immune suppression and allow immunity to regrow, that may be enough to allow increased numbers of patients to be cured of their disease.”
 

A potential role

Why might HMAS be a possible option after transplant? They do appear to play a role after chemotherapy, he said, pointing to four 2019 studies: One that examined decitabine and three that examined azacytidine: Here, here, and here.

“These four studies provide convincing evidence that hypomethylating-agent therapy after conventional chemotherapy may either prevent or delay relapse when given as maintenance,” Dr. Appelbaum said.

If HMAS work after standard chemotherapy, why might they fail to work after transplantation? “For one, by the time the disease has been able to go through chemotherapy and transplant, you’re left with highly resistant cells,” he said. “Therefore, hypomethylating agents may not be enough to get rid of the disease. Secondly, any of you who have tried to give a maintenance therapy after transplantation know how difficult it can be with CMV [cytomegalovirus] reactivation, count suppression with ganciclovir, graft-versus-host disease [GVHD] causing nausea and vomiting, diarrhea and renal dysfunction caused by calcineurin inhibitors. These are daily events during the first 3 months after transplantation, making drug administration difficult.”

In addition, he said, “even if you can give the drug, the clinical and disease variability may make it very difficult to detect an effect.”

In another study, researchers “did make a valiant attempt to study azacitidine in the posttransplant setting by randomizing 181 patients to either azacitidine or observation,” Dr. Appelbaum said. “Unfortunately, as they reported in 2018, they could not detect a difference in either disease-free or overall survival.”

The researchers reported that nearly 75% of patients in the azacitidine arm failed to complete the planned 12 cycles of treatment, he said. “The reasons for stopping the drug were pretty profound. Half of the patients stopped because they relapsed. Others had stopped because of grades three or four toxicity, death, or severe GVHD or significant infections. It is very difficult to give the drug.”

In the future, “if we truly want to optimize the benefit of using hypomethylating agents after transplantation, it’s going to be very important for us to understand how they work,” he said. “Understanding that would then help us to select which drug we should use, what the dosing and schedule might be, and also to select patients that might benefit from it. Unfortunately, right now, it’s pretty much of a black box. We don’t really understand the effects of hypomethylating agents in the posttransplant period.”

Still, he added, “without question, the results that we have seen with the use of hypomethylating agents after conventional chemotherapy – prolonging disease-free and, probably, overall survival – are going to provide a very, very strong stimulus to study hypomethylating agents after transplantation as well.”

Dr. Appelbaum reports no disclosures.

The Acute Leukemia Forum is held by Hemedicus, which is owned by the same company as this news organization.

Hematopoietic stem cell transplantation (HCT) is one of the most important treatment options for acute leukemias. However, posttransplant cancer recurrence remains a continuing issue. And while there are reasons to think that hypomethylating agents (HMAS) could be helpful as maintenance tools to prevent cancer recurrence after HCT in leukemia, a hematologist/oncologist told colleagues that the treatment isn’t yet ready for prime time.

“I don’t think you can prefer hypomethylating agents over anything right now. Unfortunately, there’s no data that we can hang our hat on that says they are of benefit in the posttransplant setting,” said Frederick Appelbaum, MD, executive vice president and deputy director of the Fred Hutchinson Cancer Research Center, Seattle, in a presentation at the virtual Acute Leukemia Forum of Hemedicus.

However, there’s still plenty of room for improvement for patients following HCT, he said, pointing to the findings of a 2020 study. The report, which he cowrote, found that 200-day mortality after HCT fell by a third from 2003-2007 to 2013-20017, but also noted that “relapse of cancer remains the largest obstacle to better survival outcomes.”

Dr. Appelbaum described the findings this way: “Without a doubt, the major limitation to transplants for hematologic malignancies today is disease recurrence,” he said. “In fact, if you look at patients after day 100, over 60% of the reason for failure is tumor regrowth. Thus, people are very anxious to look at any method that we can to prevent posttransplant relapse, including the use of hypomethylating agents.”

In regard to strategy, “we don’t have to get rid of every last leukemic cell. Just delaying recurrence might be enough,” he said. “If you can keep the patient from relapsing for the first 3 months, and then take the brakes off the immune suppression and allow immunity to regrow, that may be enough to allow increased numbers of patients to be cured of their disease.”
 

A potential role

Why might HMAS be a possible option after transplant? They do appear to play a role after chemotherapy, he said, pointing to four 2019 studies: One that examined decitabine and three that examined azacytidine: Here, here, and here.

“These four studies provide convincing evidence that hypomethylating-agent therapy after conventional chemotherapy may either prevent or delay relapse when given as maintenance,” Dr. Appelbaum said.

If HMAS work after standard chemotherapy, why might they fail to work after transplantation? “For one, by the time the disease has been able to go through chemotherapy and transplant, you’re left with highly resistant cells,” he said. “Therefore, hypomethylating agents may not be enough to get rid of the disease. Secondly, any of you who have tried to give a maintenance therapy after transplantation know how difficult it can be with CMV [cytomegalovirus] reactivation, count suppression with ganciclovir, graft-versus-host disease [GVHD] causing nausea and vomiting, diarrhea and renal dysfunction caused by calcineurin inhibitors. These are daily events during the first 3 months after transplantation, making drug administration difficult.”

In addition, he said, “even if you can give the drug, the clinical and disease variability may make it very difficult to detect an effect.”

In another study, researchers “did make a valiant attempt to study azacitidine in the posttransplant setting by randomizing 181 patients to either azacitidine or observation,” Dr. Appelbaum said. “Unfortunately, as they reported in 2018, they could not detect a difference in either disease-free or overall survival.”

The researchers reported that nearly 75% of patients in the azacitidine arm failed to complete the planned 12 cycles of treatment, he said. “The reasons for stopping the drug were pretty profound. Half of the patients stopped because they relapsed. Others had stopped because of grades three or four toxicity, death, or severe GVHD or significant infections. It is very difficult to give the drug.”

In the future, “if we truly want to optimize the benefit of using hypomethylating agents after transplantation, it’s going to be very important for us to understand how they work,” he said. “Understanding that would then help us to select which drug we should use, what the dosing and schedule might be, and also to select patients that might benefit from it. Unfortunately, right now, it’s pretty much of a black box. We don’t really understand the effects of hypomethylating agents in the posttransplant period.”

Still, he added, “without question, the results that we have seen with the use of hypomethylating agents after conventional chemotherapy – prolonging disease-free and, probably, overall survival – are going to provide a very, very strong stimulus to study hypomethylating agents after transplantation as well.”

Dr. Appelbaum reports no disclosures.

The Acute Leukemia Forum is held by Hemedicus, which is owned by the same company as this news organization.

Hematopoietic stem cell transplantation (HCT) is one of the most important treatment options for acute leukemias. However, posttransplant cancer recurrence remains a continuing issue. And while there are reasons to think that hypomethylating agents (HMAS) could be helpful as maintenance tools to prevent cancer recurrence after HCT in leukemia, a hematologist/oncologist told colleagues that the treatment isn’t yet ready for prime time.

“I don’t think you can prefer hypomethylating agents over anything right now. Unfortunately, there’s no data that we can hang our hat on that says they are of benefit in the posttransplant setting,” said Frederick Appelbaum, MD, executive vice president and deputy director of the Fred Hutchinson Cancer Research Center, Seattle, in a presentation at the virtual Acute Leukemia Forum of Hemedicus.

However, there’s still plenty of room for improvement for patients following HCT, he said, pointing to the findings of a 2020 study. The report, which he cowrote, found that 200-day mortality after HCT fell by a third from 2003-2007 to 2013-20017, but also noted that “relapse of cancer remains the largest obstacle to better survival outcomes.”

Dr. Appelbaum described the findings this way: “Without a doubt, the major limitation to transplants for hematologic malignancies today is disease recurrence,” he said. “In fact, if you look at patients after day 100, over 60% of the reason for failure is tumor regrowth. Thus, people are very anxious to look at any method that we can to prevent posttransplant relapse, including the use of hypomethylating agents.”

In regard to strategy, “we don’t have to get rid of every last leukemic cell. Just delaying recurrence might be enough,” he said. “If you can keep the patient from relapsing for the first 3 months, and then take the brakes off the immune suppression and allow immunity to regrow, that may be enough to allow increased numbers of patients to be cured of their disease.”
 

A potential role

Why might HMAS be a possible option after transplant? They do appear to play a role after chemotherapy, he said, pointing to four 2019 studies: One that examined decitabine and three that examined azacytidine: Here, here, and here.

“These four studies provide convincing evidence that hypomethylating-agent therapy after conventional chemotherapy may either prevent or delay relapse when given as maintenance,” Dr. Appelbaum said.

If HMAS work after standard chemotherapy, why might they fail to work after transplantation? “For one, by the time the disease has been able to go through chemotherapy and transplant, you’re left with highly resistant cells,” he said. “Therefore, hypomethylating agents may not be enough to get rid of the disease. Secondly, any of you who have tried to give a maintenance therapy after transplantation know how difficult it can be with CMV [cytomegalovirus] reactivation, count suppression with ganciclovir, graft-versus-host disease [GVHD] causing nausea and vomiting, diarrhea and renal dysfunction caused by calcineurin inhibitors. These are daily events during the first 3 months after transplantation, making drug administration difficult.”

In addition, he said, “even if you can give the drug, the clinical and disease variability may make it very difficult to detect an effect.”

In another study, researchers “did make a valiant attempt to study azacitidine in the posttransplant setting by randomizing 181 patients to either azacitidine or observation,” Dr. Appelbaum said. “Unfortunately, as they reported in 2018, they could not detect a difference in either disease-free or overall survival.”

The researchers reported that nearly 75% of patients in the azacitidine arm failed to complete the planned 12 cycles of treatment, he said. “The reasons for stopping the drug were pretty profound. Half of the patients stopped because they relapsed. Others had stopped because of grades three or four toxicity, death, or severe GVHD or significant infections. It is very difficult to give the drug.”

In the future, “if we truly want to optimize the benefit of using hypomethylating agents after transplantation, it’s going to be very important for us to understand how they work,” he said. “Understanding that would then help us to select which drug we should use, what the dosing and schedule might be, and also to select patients that might benefit from it. Unfortunately, right now, it’s pretty much of a black box. We don’t really understand the effects of hypomethylating agents in the posttransplant period.”

Still, he added, “without question, the results that we have seen with the use of hypomethylating agents after conventional chemotherapy – prolonging disease-free and, probably, overall survival – are going to provide a very, very strong stimulus to study hypomethylating agents after transplantation as well.”

Dr. Appelbaum reports no disclosures.

The Acute Leukemia Forum is held by Hemedicus, which is owned by the same company as this news organization.