Factors associated with durable EFS in adult B-cell ALL patients achieving MRD-negative CR after CD19 CAR T-cell therapy

Abstract

Autologous T cells engineered to express a CD19-specific chimeric antigen receptor (CAR) have produced impressive minimal residual disease–negative (MRD-negative) complete remission (CR) rates in patients with relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL). However, the factors associated with durable remissions after CAR T-cell therapy have not been fully elucidated. We studied patients with relapsed/refractory B-ALL enrolled in a phase 1/2 clinical trial evaluating lymphodepletion chemotherapy followed by CD19 CAR T-cell therapy at our institution. Forty-five (85%) of 53 patients who received CD19 CAR T-cell therapy and were evaluable for response achieved MRD-negative CR by high-resolution flow cytometry. With a median follow-up of 30.9 months, event-free survival (EFS) and overall survival (OS) were significantly better in the patients who achieved MRD-negative CR compared with those who did not (median EFS, 7.6 vs 0.8 months; P < .0001; median OS, 20.0 vs 5.0 months; P = .014). In patients who achieved MRD-negative CR by flow cytometry, absence of the index malignant clone by IGH deep sequencing was associated with better EFS (P = .034). Stepwise multivariable modeling in patients achieving MRD-negative CR showed that lower prelymphodepletion lactate dehydrogenase concentration (hazard ratio [HR], 1.38 per 100 U/L increment increase), higher prelymphodepletion platelet count (HR, 0.74 per 50 000/μL increment increase), incorporation of fludarabine into the lymphodepletion regimen (HR, 0.25), and allogeneic hematopoietic cell transplantation (HCT) after CAR T-cell therapy (HR, 0.39) were associated with better EFS. These data allow identification of patients at higher risk of relapse after CAR T-cell immunotherapy who might benefit from consolidation strategies such as allogeneic HCT. This trial was registered at www.clinicaltrials.gov as #NCT01865617.

Immunobiology of chimeric antigen receptor T cells and novel designs

“…This has most notably been observed in the treatment of ALL in pediatric and young adult patients with CAR T cells targeting the CD22 antigen, in which the majority of patients who initially achieved remission relapsed with decreased CD22 expression despite persistence of the CAR T cells . Recently, Hay et al described five adult patients with pre‐B ALL who relapsed with CD19 dim ALL after CD19 CAR T cell therapy . While these relapses occurred in the setting of loss of CAR T cells, they suggest that antigen downregulation in response to CAR pressure may not be unique to CD22‐targeted therapy.…”

“…CAR T cells have also demonstrated such abilities and have been found to persist for several years in a subset of patients. This persistence, however, is not universal and premature loss of CAR T cells occurs in a significant number of patients despite an initial clearance of their disease . This has been best described in the use of CD19‐directed CAR T cells for the treatment of ALL, in which various clinical trials have demonstrated that 15%‐25% of patients who achieve initial remission will experience a relapse of leukemia which retains expression of the CD19 antigen .…”

“…While remission rates in clinical trials of CD19 directed CAR T cell therapy for ALL established the promise of CAR T cell therapy, relapsed disease remains a major obstacle for the field. Loss of the targeted antigen is one of the most frequent mechanisms underlying post‐CAR T cell relapse in the CD19 CAR experience and has been seen following a variety of CAR T cell products across several different institutions . Multiple mechanisms have been reported in the loss of CD19, including alternative splicing of the CD19 transcript, mutations in the CD19 gene, and aberrant trafficking of the CD19 molecule .…”

“…As the clinical experience with CAR T cells has matured, it has become apparent that a significant number of patients who initially achieve remission will experience a relapse of their primary cancer after CAR T cell therapy. This has been most evident in the treatment of ALL where despite the induction of remission in ~ 90% of patients, only ~ 50% of patients remained leukemia‐free 1 year after receiving CAR T cells across multiple trials . Relapses post‐CAR T cell therapy have been observed following three main patterns.…”

Updates on CAR T‐cell therapy in B‐cell malignancies

“…Ten patients received more than one infusion, eight for loss of CAR T‐cell engraftment with two subsequently re‐engrafting, and two for low levels of engraftment who had continued CAR T‐cell persistence, but without substantial re‐expansion or antileukemic effect. Among the many notable outcomes from this study, particularly salient features of their study included the first utilization of EGFRt in a clinically tested CAR construct, successful apheresis and treatment of those with infant ALL, initial experiences of relapses with myeloid phenotype in MLLr patients, and incorporation of early intervention strategies to prevent high‐grade CRS. Fred Hutchinson Cancer Center Phase I : The adult counterpart to the Seattle Children's trial simultaneously conducted a Phase I/II clinical trial out of the Fred Hutchison Cancer Center with a different manufacturing strategy . They also selected their PMBCs prior to activation, isolating CD4+ and central memory‐enriched CD8+ T cells, which they later infused the CD4 and CD8 products in a 1:1 ratio.…”