July-August 2019, Volume 16, Issue 4
On the Road to a Better CAR: Identifying the Variables Associated With a Durable Response to CAR T-Cell Therapy in Relapsed/Refractory B-ALL
Published on: June 05, 2019
Hay KA, Gauthier J, Hirayama AV, et al. Factors associated with durable EFS in adult B-cell ALL patients achieving MRD-negative CR after CD19 CAR T-cell therapy. Blood. 2019;133:1652-1663.
CD19-directed chimeric antigen receptor T-cell (CAR-T) therapy induces complete remission (CR) in approximately 80 percent of children and adults with relapsed or refractory B-cell acute lymphoblastic leukemia (B-ALL). In these responders, approximately 75 percent (range, 53-93%) have no detectable minimal residual disease (MRD) by multiparameter flow cytometry.1-9 Robust in vivo CAR T-cell expansion, followed by a rapid and targeted cytotoxic attack of the CD19 lymphoblasts, is the likely mechanism associated with high remission rates. However, only a subgroup of patients will maintain long-term remission, with relapse rates of approximately 35 percent (range, 21-50%) reported in phase I and II clinical trials.3,8,9 Although the clinical characteristics and laboratory biomarkers that determine the duration of the antitumor responses of CAR-T therapy have not been specifically defined, successful long-term responses have been linked to CAR T-cell persistence beyond the induction of CR3,8 and disease burden at the time of T-cell infusion.9 Also, whether additional consolidation therapy in the form of allogeneic hematopoietic stem cell transplantation (allo-HSCT) is required and/or beneficial for all relapsed B-ALL patients following CAR-T therapy has not been determined and remains an important unanswered clinical question. Thus, a better understanding of the clinical and laboratory variables that contribute to long-term remission will help define the optimal use of CAR-T immunotherapy for children and adults with B-ALL.
Dr. Kevin Hay and colleagues reported long-term follow-up data of 53 adult patients (age >18 years) with relapsed/refractory B-ALL who were treated at the Fred Hutchinson Cancer Research Center on a phase I-II clinical trial between August 2013 and April 2017, and provided an analysis of the factors associated with event-free survival (EFS). Patients on the trial received lymphodepleting chemotherapy (cyclophosphamide-based regimen with or without fludarabine) followed by infusion of autologous T cells engineered to express a CD19 CAR incorporating a 4-1BB costimulatory domain. Disease response assessment was performed three to four weeks after CAR-T infusion using flow cytometry–based MRD testing of the bone marrow aspirate and/or positron emission tomography–computed tomography and cerebral spinal fluid samples from patients with extramedullary disease. A subset of patients with an identified leukemia index clone by high-throughput sequence analysis (HTS) of the immunoglobulin heavy chain locus had HTS performed on the remission marrow to assess the depth of response of the clone.
The MRD-negative CR rate was 85 percent (n=45). Eight patients (15%) showed no response. At a median follow-up of 30.9 months, the median EFS among the 45 patients who had an MRD-negative CR was 7.6 months, and the median overall survival (OS) was 20 months. Among the eight patients with no response, the median EFS was 0.8 months, and the median OS was five months. In the subset of patients with an identified leukemia index clone by HTS prior to CAR-T therapy (n=28), who achieved an MRD-negative remission by flow cytometry and HTS (n=20), the EFS was superior compared to patients with an MRD-negative remission by flow cytometry, but with a persistent leukemia clone by HTS (n=8; 8.4 months vs. 3.6 months; p=0.036). Twenty-two (49%) of the 45 patients who achieved MRD-negative CR had a relapse (median time to relapse, 3.5 months). Fourteen (68%) of the 22 patients had a relapse with CD19+ blasts, and six patients (27%) had a relapse with CD19– blasts. The two-year cumulative incidence of relapse for patients with CD19+ blasts was 34 percent compared with 14 percent for CD19– blasts.
Of the 45 patients who had an MRD-negative CR, 18 (40%) proceeded to allo-HSCT. The median time from CAR-T infusion to transplantation was 70 days (range, 44-138 days). At a median follow-up of 28.4 months, the two-year estimated EFS and OS for the transplant cohort was 62 percent and 72 percent, respectively. The two-year cumulative incidence of relapse following transplantation was 17 percent, and the non-relapse mortality was 23 percent.
Univariable logistic regression analyses were used to evaluate baseline and treatment-related factors associated with achieving an induction response. These analyses showed that a robust CAR T-cell expansion was strongly associated with the high rates of MRD-negative CR, and central nervous system leukemia prior to lymphodepleting chemotherapy was associated with no response to treatment (odds ratio, 0.08; p=0.013). Next, the investigators developed a stepwise multivariable model to identify factors associated with superior EFS among the patients who achieved MRD-negative CR. Three factors associated with better EFS include normal pre-treatment LDH (HR, 1.39 per 100 U/L increment increase), higher pretreatment platelet count (HR, 0.65 per 50,000 cells/µL increment increase), and incorporation of fludarabine as part of lymphodepleting chemotherapy regimen (HR, 0.34). Patients with a normal serum LDH, with a platelet count higher than 100,000/µL, and who received fludarabine-containing lymphodepleting chemotherapy, had a predicted two-year EFS and OS of 78 percent and 86 percent, respectively, compared to an EFS of 13 percent and OS of 29 percent among patients without these three favorable characteristics. Allo-HCT was incorporated into the multivariable model as a time-dependent covariate to evaluate its independent effect on EFS for patients in MRD-negative CR after CAR-T therapy. Patients who proceeded to allo-HCT in MRD-negative CR had superior EFS compared to patients who did not proceed to HCT (HR, 0.39; 95% CI, 0.13-1.15; p=0.088).
In conclusion, Dr. Hay and colleagues have provided important long-term follow-up data on their cohort of adult patients with relapsed/refractory B-ALL and examined the variables associated with a durable CAR-T therapy response. The authors identified lower serum LDH concentration, higher platelet count prior to lymphodepleting chemotherapy, and the use of fludarabine in the lymphodepleting chemotherapy regimen to be associated with durable remissions. The relationship between a lower serum LDH and a higher platelet count as well as a higher frequency of durable remissions suggest that aggressive disease kinetics and tumor burden and the cumulative effects of prior salvage regiments on the marrow may limit CAR-T therapeutic effects. The use of fludarabine in lymphodepleting chemotherapy has been associated with CAR T-cell expansion and persistence,8 and these follow-up data support that association. Additionally, a multivariable analysis associated allo-HCT with better EFS in patients in MRD-negative CR following CAR-T therapy. Confirmation of the results of the multivariable model will require a larger cohort of patients. Determining whether allo-HCT is needed for consolidation treatment after CD19 CAR-T therapy in the relapsed patient will require randomized clinical trials.
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Conflict of Interests
Dr. Fries and Dr. O'Dwyer indicated no relevant conflicts of interest.
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