ASH Highlights for Saturday December 5, 2020

By Lynne Lederman

A Multi-Center Biologic Assignment Trial Comparing Reduced Intensity Allogeneic Hematopoietic Cell Transplantation to Hypomethylating Therapy or Best Supportive Care in Patients Aged 50-75 with Advanced Myelodysplastic Syndrome: Blood and Marrow Transplant Clinical Trials Network Study 1102 (Abstract 75)

Although allogeneic hematopoietic stem cell transplant (HCT) improves survival in MDS, it is not offered to many older individuals with high-risk myelodysplastic syndrome (MDS), and is not covered by Medicare. Corey Cutler, MD, MPH, City of Hope, Duarte, CA, presented the first analysis of an open-label, multicenter, biologic assignment trial (BMT CTN 1102, NCT02016781) in individuals age 50-75 years with higher risk de novo MDS who were candidates for reduced-intensity conditioning (RIC) allogeneic HCT. Patients (N=384) were assigned to the No Donor arm, and reassigned to the Donor arm when a suitable donor was identified from eligible family members and a 90-day search of unrelated donor registries.

Overall survival (OS) at 3 years from enrollment, the primary endpoint, in the Donor arm (n=260) was 47.9% versus 26.6% in the No Donor arm (n=124; P=.0001). Leukemia-free survival (LFS) a secondary endpoint, was greater in the Donor arm (35.8%) versus the No Donor arm (20.6%; P=.003). There were no differences in OS or LFS in subgroup analyses, including age >65 or ≤65 years. A sensitivity analysis excluding subjects assigned to the No Donor arm who died or withdrew prior to the end of the 90-day search window showed no effect on OS or LFS.

An as-treated analysis of HCT versus No HCT showed greater improvement in 3-year OS (47.4% vs. 16.0%, P<.0001) and LFS (39.3% vs. 10.9%, P<.0001) for subjects who underwent HCT. Of 25 subjects in the No Donor arm who subsequently underwent alternative donor RIC transplant, 3-year OS and LFS were both 58.5%, underscoring the potential value of alternative donor HCT. There were no clinically significant differences in quality of life (QoL) between Donor and No Donor arms.

Dr. Cutler concluded that HCT should be an integral part of MDS management, with early referral to a transplant center for evaluation and to begin a donor search. Pointing out a bias against referring older patients with MDS for HCT, he said, “We’d love to see these patients earlier in their disease course” because it takes longer to find donors for them. He also hoped that when CMS sees data showing HCT improves OS and LFS with no detriment to QoL, they would reconsider their decision ruling about not paying for this treatment.

Ruxolitinib (RUX) Vs Best Available Therapy (BAT) in Patients with Steroid-Refractory/Steroid-Dependent Chronic Graft-Vs-Host Disease (cGVHD): Primary Findings from the Phase 3, Randomized REACH3 Study (Abstract 77)

Robert Zeiser, PhD, University Medical Center, Freiburg Im Breisgau, Germany, presented the first successful randomized, open-label, phase 3 trial (REACH3 study; NCT03112603) of ruxolitinib, an oral JAK1/2 inhibitor, versus best available therapy (BAT) in steroid refractory/dependent (SR/D) cGVHD.

Patients age ≥12 years post-allogeneic HCT with moderate to severe SR/D cGVHD who had received ≥2 prior lines of systemic therapy in addition to corticosteroids were randomly assigned to ruxolitinib (n=165) or BAT (n=164). Cross-over was allowed on or after week 24.

The primary endpoint was overall response rate (ORR) at week 24; secondary endpoints included failure-free survival (FFS), and modified Lee Symptom Scale (mLSS). Baseline characteristics were balanced in both arms. More patients in the ruxolitinib arm (50.3% vs. 25.6% for BAT) remained on treatment at primary analysis. Lack of efficacy was the most common reason for discontinuation in the BAT arm (42.7%); 37.2% in the BAT arm crossed over to ruxolitinib.

The study met its primary endpoint. ORR with ruxolitinib was 49.5% versus 25.6% for BAT (P<.0001). Best ORR was 76.4% versus 60.4%, respectively. Duration of best ORR was not reached with ruxolitinib versus 6.24 months with BAT. FFS was significantly higher for ruxolitinib (not reached) than BAT (5.7 months; HR 0.370; P<.0001). Patients treated with ruxolitinib had greater improvements in symptoms than those treated with BAT by mLSS response (24% vs 11%; OR 2.62; P=.0011). The safety profile for ruxolitinib was as expected.

The Role of Structural Violence in Acute Myeloid Leukemia Outcomes (Abstract 217)

Irum Khan, MD, University of Illinois, Chicago, presented the first study to integrate clinical molecular data, neighborhood characteristics, and treatment patterns to examine race/ethnic disparities in adult AML survival.

The study included adults with AML (N=822) from 2012-2018 at 6 academic cancer centers in metropolitan Chicago, the third most segregated community in the US. Non-Hispanic whites (NHW; n=497) were less likely to be obese, and were twice as likely to have private insurance as non-Hispanic blacks (NHB; n=126; 51% vs. 25%, respectively). Hispanic patients (n=117) were younger, had a lower co-morbidity score, and were most likely to be uninsured.

Intensive induction was administered to 68% of patients. ICU admission during induction chemotherapy was more frequent for NHB (38%) and Hispanic (41%) than NHW (26%) patients. Allogeneic transplants were less common in NHB (22%) than NHW (47%) or Hispanic (42%) patients.

In a combined mediation analysis, tract socio-economic status (SES) variables accounted for 81% of the black/white disparity in leukemia deaths, with a hazard ratio of 1.58 to 1.11, adjusted for tract SES. Tract SES is a latent variable reflecting differences in environmental exposures, opportunities, and resources. Differences in induction treatment and transplant accounted for 41% of the black/white disparity. Co-morbidities and molecular disease differences did not mediate black/white or non-white disparities.

In a press briefing, Dr. Khan said they would like to understand the role of these proxy measures of structural violence prospectively, and how neighborhood SES and environmental exposure affect AML.

Outcomes of Patients with Hematologic Malignancies and COVID-19 Infection: A Report from the ASH Research Collaborative Data Hub (Abstract 215)

William A. Wood, MD, MPH, University of North Carolina, Chapel Hill, presented an updated analysis of outcomes for 656 patients with hematologic malignancies and COVID-19 infection from the ASH Research Collaborative COVID-19 Registry for Hematology. Malignancies included leukemia (57%), lymphoma (25%), and plasma cell neoplasms (18%).

The overall death rate was 20%; it was 33% in those requiring hospital care, and 65% in those requiring ICU-level care. In the prior year, 65% of patients with moderate or severe disease had been treated with cytotoxic chemotherapy, immunotherapy, targeted therapy, or other therapy. COVID-19 disease severity was higher in those with relapsed disease, who were older, or had a survival estimate of <12 months.

The death rate in those who declined ICU-level care was 73% versus 13% in those who did not. Those with a prognosis of <12 months (20% overall) were more likely to have moderate or severe disease and to have declined ICU-level care.

A key finding is that patients with hematologic malignancies are at increased risk for adverse COVID-19 outcomes and are a medically vulnerable population. The risks are greatest in those who are older, have advanced disease or a limited prognosis, or who forego intensive management of their COVID-19 infection. However, risks are not trivial for others.

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