ASH Highlights for Monday, December 3, 2018

By Lynne Lederman, PhD

As the 2018 American Society of Hematology (ASH) Annual Meeting continues, we focus on two studies that have the potential to be practice-changing for the treatment of older patients with AML and younger patients with favorable-prognosis diffuse large B-cell lymphoma (DLBCL), the development of a personalized risk stratification model for patients with myelodysplastic syndromes (MDS), and the finding that pre-hematopoietic cell transplant (HCT) microbiota injury is associated with poorer overall survival (OS).

Initial Report of the Beat AML Umbrella Study for Previously Untreated AML: Evidence of Feasibility and Early Success in Molecularly Driven Phase 1 and 2 Studies (559)

Results from the Beat AML umbrella study demonstrated that it was feasible to implement a rapid treatment assignment within 7 days or less for 95.8% of elderly patients with AML, reported Amy Burd, PhD, Leukemia and Lymphoma Society.

This precision medicine trial tested the hypothesis that outcomes for patients could be improved by matching them to the increasing number of available targeted therapies. The primary objectives were to determine (1) the feasibility of completing molecular, immunophenotypic, and/or biochemical studies in ≤7 calendar days, (2) the feasibility of assigning patients to sub-studies in the master protocol based on the test results, and (3) the clinical efficacy of novel treatment strategies in each of the sub-studies.

The trial enrolled patients age ≥60 years with previously untreated AML. Treatment was assigned based on the best curative option using molecular profiling results. Median age was 72 years, and 37.9% of patients were age ≥75 years.

So far 365 patients have been enrolled, of whom 285 were assigned treatment; 146 patients received the assigned treatment. Most of the patients who were not treated received other therapies, including standard of care, alternative treatment prior to assignment, or enrollment in an alternative trial after assignment; 7 died during the 7-day period, and 23 opted to enter palliative care.

The trial began with 3 sub-studies, which has since increased to 11 sub-studies, providing more options. Promising efficacy has been seen in several treatment arms, and early death and disease progression prior to treatment assignment is uncommon outside of MLL rearranged AML which progresses rapidly and requires early treatment initiation. Two sub-study updates are being presented at the meeting (abstracts 4053 and 287).

Excellent Outcome of Young Patients (18-60 years) with Favourable-Prognosis Diffuse Large B-Cell Lymphoma (DLBCL) Treated with 4 Cycles CHOP Plus 6 Applications of Rituximab: Results of the 592 Patients of the Flyer Trial of the Dshnhl/GLA (781)

Results of the FLYER trial showed that reducing cycles of CHOP-like chemotherapy from the standard 6 cycles of rituximab (R)-CHOP to 4 cycles of CHOP plus 6 doses of R maintained efficacy and reduced toxicity for younger patients with good prognosis DLBCL.

Viola Poeschel, MD, Department of Hematology, Oncology and Rheumatology, Saarland University Medical School, Homburg/Saar, Germany, presented the results. FLYER enrolled previously untreated patients age 18 to 60 years with stage I/II aggressive B-cell lymphoma, with age-adjusted International Prognostic Index of zero and no bulky disease. Patients were randomly assigned to treatment with 6 cycles or R-CHOP or 4 cycles R-CHOP plus 2 additional cycles of R in 21-day cycles.

The primary endpoint was progression-free survival (PFS). The 36 month PFS was 94% (95% CI 91%-97%) for the 6 x R-CHOP-21 group (n=295), and 96% (95% CI 94%-99%) for the 4 x R-CHOP-21 + 2 x R group (n=293) at a median follow-up of 66 months.

Likewise, the 36-month overall survival (OS) was similar between the treatment groups: 98% (95% CI 96%-99%) in the standard therapy group and 99% (95% CI 98%-100%) in the reduced chemotherapy group at a median follow-up of 67 months.

Fewer hematologic adverse events (AE) were reported in the reduced chemotherapy group, as well as an overall reduction of non-hematologic AEs by approximately one third.

A Personalized Prediction Model to Risk Stratify Patients with Myelodysplastic Syndromes (793)

Current treatment guidelines for MDS are based on risk stratification for progression to AML, and although HCT is potentially curative in high-risk disease, associated toxicities make it inappropriate for low-risk disease. Aziz Nazha, MD, Cleveland Clinic, Cleveland, OH, described the development of a prediction model that uses a machine learning approach to provide a personalized, patient-specific estimate of risk.

Dr. Nazha’s group show that when looking at survival of patients with MDS by Revised International Prognostic Scoring System (IPSS-R) for MDS risk category, outcomes are heterogeneous.

The model was developed using clinical and mutational data from patients with MDS in a combined cohort from the Cleveland Clinic and Munich Leukemia Laboratory (training cohort, n=1471) and validated in a separate cohort (validation cohort, n=831) from the Moffitt Cancer Center. Forty gene mutations commonly occurring in myeloid malignancies were sequenced. Patients undergoing HCT were censored at the time of transplant. An algorithm was used to build the model that randomly selected clinical and molecular variables to determine survival. Variables were ranked from the most to the least important for OS.

A clinic-friendly web application tool has been built from the final model, allowing input of important risk factors to calculate predicted OS for individual patients. Dr. Nazha said that this new model has a better predictability index for OS and leukemia-free survival than the IPSS.

Multicenter Microbiota Analysis Indicates that Pre-HCT Microbiota Injury Is Prevalent across Geography and Predicts Poor Overall Survival (811)

The intestinal microbiota composition is associated with important outcomes after allogeneic (allo) HCT including OS, organ toxicity, relapse, graft-versus-host disease (GvHD), and infection. Most studies have looked at the microbiota after transplantation. Jonathan U. Peled, MD, PhD, Adult Bone Marrow Transplant Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, described this study looking at the intestinal microbiota composition in 1922 stool samples from patients both before and after allo-HCT in three geographic regions.

Dr. Peled said it was striking that no matter where in the world these patients lived, their intestinal microbiota composition and diversity were comparable at baseline. Higher diversity pre-HCT microbiota is associated with better OS than low diversity (HR 0.69; P=.002), as well as with peri-neutrophil engraftment. After transplant, a decrease in diversity and domination of single species are correlated with poorer outcomes.

Approaches that could manipulate microbiota-host interactions to prevent damage include antibiotics, prebiotics, probiotics, and postbiotics.

 

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