December 2020 Edition Vol.12, Issue 12

ASH 2020: Immunotherapy Advances; Spotlight on Health Disparities

By Mary Ellen Schneider

This year’s annual meeting of the American Society of Hematology (ASH) featured new research on chimeric antigen receptor (CAR) T-cell therapy and bispecific T-cell engager (BiTE) molecules, along with trends toward treating cancer patients with immunotherapies earlier in the course of their disease.

The meeting, which was held virtually for the first time, also highlighted studies evaluating the extent and impact of racial and ethnic health disparities in hematology and oncology.

Latest Data in CAR T-Cell Therapy, BiTEs

The ASH annual meeting included a variety of studies on CAR T-cell therapy, from clinical trials to real-world data.

Among the noteworthy research, Catherine Bollard, MD, director of the Center for Cancer and Immunology Research at Children’s National Hospital in Washington, D.C., and a professor of pediatrics and immunology at George Washington University, pointed to a real-world study that investigated the tumor-specific factors driving inherent or acquired resistance to CAR T cells in large B-cell lymphoma (Abstract 556). The study, led by researchers at Stanford University, identified CD58 status as an important biomarker for durable response to CAR T cells in large B-cell lymphoma.

“What strikes me now is that in the CD19 CAR T-cell space, you’re getting much more robust real-world data,” Dr. Bollard told OBR.

This type of real-world data will be even more important as CAR T-cell therapy moves earlier in the treatment of disease, said Dr. Bollard.

“As we continue to expand the reach of new targeted therapies, it is imperative that we deeply study our patients to determine the mechanisms that underscore success, and perhaps even more importantly, failure,” Leslie S. Kean, MD, PhD, of Boston Children’s Hospital and Dana-Farber Cancer Institute and one of the ASH scientific program co-chairs, said during her “Best of ASH” presentation, in which she highlighted Abstract 556.

Dr. Kean also highlighted findings from the primary analysis of the phase 2, Zuma-5 trial, which evaluated axicabtagene ciloleucel (axi-cel) in patients with relapsed/refractory follicular and marginal zone lymphoma (Abstract 700), noting that one of the themes of the ASH meeting was an expansion of cellular therapies beyond their initial indications.

At a median follow-up of 17.5 months, the objective response rate in Zuma-5 was 92% among 104 efficacy-evaluable patients. Overall, the complete response rate was 76%. Among patients with follicular lymphoma, the objective response rate was 94%, with a complete response rate of 80%. Among marginal zone lymphoma patients, the objective response rate was 85% and the complete response rate was 60%.

“The maturation of the field is evidenced by multiple commercial CARs now being investigated in these more indolent lymphoma patients,” said Dr. Kean.

Sattva Neelapu, MD, shares highlights in the development of CAR T-cell therapies in lymphoma:

Dr. Kean also pointed to an early study looking at the combination of the CAR T product lisocabtagene maraleucel (liso-cel) with the BTK inhibitor ibrutinib for the treatment of patients with relapsed/refractory chronic lymphocytic leukemia (CLL). In the phase 1 TRANSCEND CLL 004 study, researchers found promising efficacy and a manageable safety profile with the combination (Abstract 544).

At 10 months of follow up, the researchers reported a 95% overall response rate and a 63% complete response rate among 19 patients. The study had no dose-limiting toxicities and there were no grade 5 adverse events or grade 4 events of cytokine release syndrome or neurological events.

Other immunotherapy studies presented at ASH focused on the use of I-O treatments earlier in the course of therapy.

Dr. Kean discussed a phase 3 trial in children with high-risk first relapse B-cell precursor acute lymphoblastic leukemia (ALL) that assessed the BiTE molecule blinatumomab, compared with high-risk consolidation chemotherapy before allogeneic hematopoietic stem cell transplant in 108 patients. Blinatumomab monotherapy achieved significantly better event-free survival, causing the trial’s data monitoring committee to recommend early termination of enrollment due to benefit (Abstract 268).

The median event-free survival was not reached in the blinatumomab arm and was 7.4 months in the chemotherapy arm. Events were reported for 32% of patients receiving blinatumomab and 57% of patients receiving chemotherapy (Hazard Ratio [HR] 0.33; 95% CI 0.18-0.61).

A phase 2 study focused on treatment with a BiTE molecule earlier in the course of therapy. The trial examined the use of a hyper-CVAD chemotherapy regimen with sequential blinatumomab in adults with newly diagnosed Philadelphia chromosome-negative B-cell ALL (Abstract 464). The researchers found that the combination was effective in front-line treatment, with a 2-year relapse-free survival rate of 71% and a measurable residual disease negativity rate of 97%. Just 3% of patients had grade 3 or 4 cytokine release syndrome (CRS) and 13% had blinatumomab-related neurologic events.

Potential New Treatments in Multiple Myeloma

Dr. Kean also highlighted two clinical studies of antibody-based and CAR T-cell therapies for the treatment of multiple myeloma.

The phase 1b/2 CARTITUDE-1 study examined ciltacabtagene autoleucel (cilta-cel), a B-cell maturation antigen-directed CAR T-cell therapy, in the treatment of relapsed/refractory multiple myeloma (Abstract 177). Researchers reported an overall response rate of 96.9% and a stringent complete response rate of 67%. CRS was mostly grade 1 or 2, and CAR T-related neurotoxicities occurred in 20% of patients, with 10% at grade 3 or higher.

The safety and efficacy data indicate that larger studies of this agent are warranted, Dr. Kean said.

Along with CAR T-cell advances, Dr. Kean pointed to a new antibody-based therapy with potential in relapsed/refractory multiple myeloma. A phase 1, first-in-human study, evaluated talquetamab, a first-in-class bispecific antibody that binds to the G Protein-Coupled Receptor Family C Group 5 Member D (GPRC5D) and CD3 (Abstract 290).

The most common grade 3 or 4 adverse events were lymphopenia (36%), neutropenia (31%), and anemia (27%). CRS of all grades occurred in more than half of patients and 3% had grade 3 CRS. In terms of efficacy, talquetamab had an overall response rate of 69% (9 of 13 patients) at the recommended phase 2 dose.

“This study suggests that there continue to be ‘new kids on the block’ for these otherwise difficult-to-treat patients,” said Dr. Kean.

David Siegel, MD, PhD, regarding bispecific antibodies in the management of relapsed/refractory MM:

Health Disparities Highlighted

The ASH plenary session placed a spotlight on poor treatment outcomes for African American patients younger than 60 years of age with acute myeloid leukemia (AML). In a study that analyzed data from the Surveillance Epidemiology End Results (SEER) Program and characterized molecular features by race, researchers found that younger African American patients had a higher likelihood of death than white patients, with a 3-year overall survival rate of 34% for younger African American patients and 43% for white patients (P <.001). They also discovered that African American patients had a lower frequency of prognostically favorable NPM1 mutations, compared with white patients (25% vs 38%, P=.04) (Abstract 6).

Bhavana Bhatnagar, DO, regarding data on racial disparities in the treatment of AML:

Risk factors for cancer-associated thrombosis were also identified as an area of health disparity in patients by race/ethnicity. Relying on a database of 942,109 cancer patients in California, researchers found that African American cancer patients had the highest 12-month cumulative incidence of cancer-associated thrombosis, compared with other racial groups, for all cancers except multiple myeloma. Similarly, African American cancer patients had the highest 12-month cumulative incidence of isolated pulmonary embolism for all cancer except brain cancer, compared with other racial groups (Abstract 203).

What is driving the disparities in cancer-associated thrombosis? The researchers acknowledged possible contributions from underlying biological traits. But they also pointed to the contribution of systemic racism, access to care, and the severity of underlying comorbidities.

“Since current risk prediction models for cancer-associated thrombosis do not include race and ethnicity as parameters, future studies should examine if incorporating these factors can improve predictive value,” Alisa S. Wolberg, of the University of North Carolina at Chapel Hill and one of the ASH scientific program co-chairs, said during her “Best of ASH” presentation.

Bringing attention to disparities in outcomes and access to cancer care offers the potential for “immediate improvement in outcomes for those persons without a new diagnostic test, or without a new drug,” Chancellor Donald, MD, an assistant professor of clinical medicine at Tulane University in New Orleans, told OBR.

“As part of caring for patients and our citizens, ASH chose to have a significant light shine upon disparities in health care, or differences in outcomes between different groups of our patients,” said Dr. Donald.

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