At the 60th Annual Meeting of ASH, more than 25,000 attendees from all over the world will gather In San Diego, December 4-8 to hear the latest and greatest news in the field of hematology. Reporters got a sneak preview of what to expect at an official ASH pre-meeting webinar on November 20, 2018. Below are highlights from the webinar on hematologic cancers organized around key themes.
CAR-T Cell Therapies: New Research and Updates from Pivotal Trials
Key abstracts to watch for in the CAR-T space include two small feasibility studies and two larger trials showing durability of response to CAR-T cell therapies.
Abstract 299 describes a small phase 1/2 study designed to compare CD19-specific CAR-T cells alone or in combination with ibrutinib in patients with relapsed and/or refractory chronic lymphocytic leukemia (CLL). Patients treated with fludarabine/cyclophosphamide lymphodepletion followed by CAR-T were compared with a cohort of patients treated the same way with the addition of ibrutinib given at least 2 weeks prior to leukapheresis until at least 3 months after CAR-T infusion.
“In this small study, ibrutinib was well tolerated and preliminary results suggest that ibrutinib can reduce the incidence of cytokine release syndrome and may actually improve outcomes,” said ASH Secretary, Robert A. Brodsky, MD.
A second small study (Abstract 556) looked at the addition of a checkpoint inhibitor to augment response to CD19-directed CAR-T in 14 children with relapsed B-cell acute lymphoblastic leukemia (ALL).
“The idea is that after patients relapse, pembrolizumab will take the brakes off the immune system and re-initiate an immune attack on the cancer. In this study, it appears that pembrolizumab is safe to combine with CAR-T, and this approach may turn out to be efficacious,” Dr. Brodsky commented.
Long-term follow-up of two large trials of CAR-T provides reassurance that CAR-T-achieved remissions can be deep and durable. Abstract 895 describes longer follow-up of the phase 2 ELIANA trial of 79 pediatric and young adults with relapsed/refractory ALL treated with CAR-T infusion. Response rate was 81% and two thirds of responders remain in remission at 18 months.
Abstract 1684 follows patients enrolled in the phase 2 JULIET trial that enrolled 167 patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL)—115 patients underwent a single infusion of CAR-T. Many of these patients had received multiple therapies including transplant. At a median follow-up of 18 months, the probability of sustained remission and survival was 43%.
A fifth study (Abstract 967) showed that late recurrences were reduced and survival improved in patients who received bone marrow transplant (BMT) as consolidation after CAR-T cell-induced remission. The study compared outcomes in patients who did and didn’t undergo BMT after CAR-T. Almost all the patients had ALL.
Observing the 17 patients who did not get BMT prior to CAR-T, at remission 14 of them received BMT; and of those, two relapsed. For the other three patients who did not get BMT, two relapsed.
Of the 33 patients who had BMT before CAR-T and were offered a second transplant, 10 received the transplant and five remained in remission. Of the remaining 23 patients who did not undergo a second BMT, 15 remained in remission.
“This small retrospective study suggests that BMT can be used for consolidation of remission after CAR-T. The role of second BMT is less clear,” noted Dr. Brodsky.
Four Key Abstracts for the Treatment of Blood Diseases and Disorders
Abstract 781 shows that treatment can be de-escalated in younger (age 18-60 years), favorable-prognosis patients with DLBCL. Prior to this study, the standard of care was 6 cycles of rituximab-CHOP chemotherapy (R-CHOP).
The FLYER study was a large, international, randomized, phase 3 trial in 592 younger, favorable-prognosis DLBCL patients showed that 4 cycles of R-CHOP can achieve comparable outcomes as standard of care. These findings suggest that 2 cycles of CHOP can be avoided in these younger patients, potentially reducing toxicity.
“This study is almost certainly practice-changing,” said Dr. Brodsky.
Another practice-changing, randomized, phase 3 study (Abstract 6) compared ibrutinib alone and ibrutinib/rituximab (IR) versus bendamustine/rituximab (BR) in 547 older untreated CLL patients.
Ibrutinib is approved for untreated CLL, but this study was based on comparison with chlorambucil, an older drug. Until now, ibrutinib has not been compared with modern chemo-immunotherapy. Progression-free survival (PFS) was 41 months in the BR arm and not yet reached in both ibrutinib-containing arms.
“In this study, both ibrutinib alone and IR improved progression-free survival at 32 months versus BR,” noted Dr. Brodsky. “These results showing superiority to standard chemotherapy in older patients are likely to be practice-changing.”
Patients with low- to intermediate-risk myelodysplastic syndrome (MDS) have new hope, according to results of the Medalist trial—a phase 3 randomized, double-blind, placebo-controlled study.
In this study, 229 patients with low- to intermediate-risk MDS and anemia requiring transfusions who were refractory or intolerant to erythropoiesis-stimulating agents were randomized 2:1 to luspatercept versus placebo. Luspatercept—a first-in-class experimental red blood cell maturation agent—reduced the likelihood of the need for transfusion and was generally well tolerated.
“Luspatercept is moving through the pipeline, and this is potentially a practice-changing study [once the drug is approved],” commented Dr. Brodsky.
Abstract 793 discusses a new personalized prediction model for MDS that incorporates traditional criteria (age, hemoglobin, cell counts, cytogenetics, number of blasts in bone marrow, etc.) as well as genomics. Next generation sequencing (NGS) of 40 gene mutations commonly found in MDS and other myeloid malignancies was performed. The training cohort for the new model included 1,471 patients and the validation cohort had 831 patients.
The new model outperformed both standard models (IPSS and IPSS-R) in predicting overall survival and transformation to acute myeloid leukemia (AML).
“This could be very exciting and can inform the design of clinical trials,” said Dr. Brodsky.
A multicenter analysis of 1922 stool samples from 991 patients on three different continents undergoing allogeneic BMT for a variety of underlying cancers showed that the pre-transplant microbiome can predict outcome (Abstract 811). A decrease in pre-BMT intestinal flora predicted for poorer survival following BMT.
“These findings will lead to studies exploring whether interventions that change the microbiome can improve outcomes from allogeneic BMT,” said Dr. Brodsky.
The Beat UMBRELLA trial of patients with previously untreated AML utilized rapid NGS to identify personalized treatments early in the course of disease (Abstract 559). “Most of those patients were over age 60 and tended to be poor risk,” said ASH President Alexis A. Thompson, MD.
This ongoing study now has 11 treatment arms using seven novel agents based on AML subtype according to genetic mutations. At ASH, data will be presented on 268 patients with a median age of 72 years.
“The study shows that it’s feasible to use precision medicine approaches in older AML patients using treatment tailored to mutations. This will impact how we design our clinical trials. We need to see if this approach impacts outcomes,” said Dr. Thompson.
By John McCleery, Content Director, OBR