Analysis benefits of a second Allo-HSCT after CAR-T cell therapy in patients with relapsed/refractory B-cell acute lymphoblastic leukemia who relapsed after transplant

The first edition of the European LeukemiaNet (ELN) recommendations for diagnosis and management of acute myeloid leukemia (AML) in adults, published in 2010, has found broad acceptance by physicians and investigators caring for patients with AML. Recent advances, for example, in the discovery of the genomic landscape of the disease, in the development of assays for genetic testing and for detecting minimal residual disease (MRD), as well as in the development of novel antileukemic agents, prompted an international panel to provide updated evidence- and expert opinion-based recommendations. The recommendations include a revised version of the ELN genetic categories, a proposal for a response category based on MRD status, and criteria for progressive disease.

Publisher's Note: There is an [Related article:] Inside Blood Commentary on this article in this issue. Defined-composition manufacturing platform of CD19 CAR T cells contributes to >90% intent-to-treat complete remission rate. Uniformity of durable persistence of CAR T cells and mitigation of antigen escape are key aspects for further optimization. Transitioning CD19-directed chimeric antigen receptor (CAR) T cells from early-phase trials in relapsed patients to a viable therapeutic approach with predictable efficacy and low toxicity for broad application among patients with high unmet need is currently complicated by product heterogeneity resulting from transduction of undefined T-cell mixtures, variability of transgene expression, and terminal differentiation of cells at the end of culture. A phase 1 trial of 45 children and young adults with relapsed or refractory B-lineage acute lymphoblastic leukemia was conducted using a CD19 CAR product of defined CD4/CD8 composition, uniform CAR expression, and limited effector differentiation. Products meeting all defined specifications occurred in 93% of enrolled patients. The maximum tolerated dose was 10 6 CAR T cells per kg, and there were no deaths or instances of cerebral edema attributable to product toxicity. The overall intent-to-treat minimal residual disease–negative (MRD − ) remission rate for this phase 1 study was 89%. The MRD − remission rate was 93% in patients who received a CAR T-cell product and 100% in the subset of patients who received fludarabine and cyclophosphamide lymphodepletion. Twenty-three percent of patients developed reversible severe cytokine release syndrome and/or reversible severe neurotoxicity. These data demonstrate that manufacturing a defined-composition CD19 CAR T cell identifies an optimal cell dose with highly potent antitumor activity and a tolerable adverse effect profile in a cohort of patients with an otherwise poor prognosis. This trial was registered at www.clinicaltrials.gov as #NCT02028455.

Grading acute graft-versus-host disease (GVHD) is usually based on quantification of rash, serum bilirubin and diarrhea. Standard criteria have been developed and used for > 20 years by most transplant centers. However, neither the standard GVHD grading system nor any of several revisions has been validated in the context of GVHD prophylaxis with cyclosporine. The 1994 Consensus Conference on Acute GVHD Grading held in Keystone in January 1994 provided an opportunity to: (1) review data regarding these standard criteria; (2) determine if there are sufficient data to revise these criteria; and (3) develop recommendations for reporting results of GVHD prevention trials. Data were provided for 8249 patients from 12 large transplant centers and 2 transplant registries. Standard GVHD grading criteria were found to distinguish different mortality risks and treatment response rates. Analysis of new data suggested that persistent nausea with histologic evidence of GVHD but no diarrhea be included as stage 1 gastrointestinal GVHD. Additional studies were recommended to evaluate heterogeneity of outcome within GVHD grades prior to making further revisions. To improve comparability between publications, reports of GVHD prevention trials should include an accurate description of the grading system used and should report actuarial rates of grades II-IV and III-IV GVHD corrected for graft failure and potential interventions for early relapse. Additional information should include indications for therapy of GVHD and response.