Updated results in 51 adults with relapsed B-cell acute lymphoblastic leukemia (ALL) treated with chimeric antigen receptor (CAR) T cells at Memorial Sloan Kettering Cancer Center in New York showed high complete response rates regardless of pre–CAR T disease burden.1 That said, pretreatment disease burden had an impact on the durability of response as well as long-term survival, with improved outcomes in patients with minimal residual disease burden compared with those who had morphologic disease. Further, patients with minimal disease burden also had fewer serious side effects and a lower incidence of cytokine-release syndrome.
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An important finding of the study was that durable responses and long-term survivals are observed in a subset of patients who do not undergo subsequent allogeneic stem cell transplantation in both cohorts: patients with minimal disease burden and those with morphologic disease.
“These findings raise the question of whether using CAR T at the time of [minimal residual disease] after first-line chemotherapy can achieve CAR T-cell–mediated remissions and maximize survival, potentially sparing high-risk patients from transplant, rather than waiting until they relapse morphologically and then trying CAR T-cell therapy when it is less likely to achieve a durable long-term remission,” said lead author Jae H. Park, MD, Assistant Attending Physician at Memorial Sloan Kettering. “The benefit of transplant after CAR T-cell infusion is uncertain,” he added.
Adults with relapsed or refractory ALL have about an 8% 5-year survival rate. In an attempt to improve upon this dismal prognosis, several groups of investigators at different institutions have developed CAR T-cell therapy and achieved good results with high initial complete response rates.
“But relapses are common [after CAR T-cell therapy], even after achieving seemingly deep remission, and severe toxicities have been observed in some patients,” Dr. Park explained.
CAR T cells are created by genetically engineering the patient’s own T cells to express a chimeric antigen receptor—in this case, 19‑28z—to recognize the CD19-positive cancer cells. The T cells are put into a viral vector and replicated ex vivo and then are reinfused into the patient. Other centers in the United States have developed CAR T-cell therapy targeting different antigens with different vectors.
The investigators conducted a retrospective analysis of the experience with 51 adult B-cell ALL patients to identify factors associated with survival benefit from CAR T-cell therapy. Dr. Park presented the findings at the 2017 American Association for Cancer Research (AACR) Annual Meeting.
The phase I study included 51 patients with relapsed CD19-positive B-cell ALL treated with CAR T-cell therapy using autologous or patient-derived T cells (fresh or frozen). Patients were aged 18 or older. They were stratified into those with morphologic disease (≥ 5% blasts in bone marrow) or minimal residual disease (< 5% blasts in bone marrow); those with minimal residual disease got higher doses of CAR T. Four weeks after CAR T-cell infusion, bone marrow biopsies were performed to document response.
Patients with minimal residual disease were generally older (median age of 53 years at CAR T-cell infusion), whereas median age was 40 years in the morphologic disease group. Prior allogeneic transplant was conducted in 42% of the morphologic disease group and 25% of those with minimal residual disease.
The ongoing study was closed to accrual in November 2016. The first 41 patients received conditioning chemotherapy with cyclophosphamide, and the last 10 patients got cyclophosphamide plus fludarabine as conditioning chemotherapy, to test the effect of different conditioning chemotherapies on clinical outcome.
Complete response rates were 95% in those with minimal residual disease and 77% in those with morphologic disease, which was not a statistically significant difference. Minimal residual disease–negative complete response rates were 58% in the minimal residual disease group and 70% in the morphologic disease group. At a median of 18 months’ follow-up, median event-free survival and overall survival were not reached for patients in the minimal residual disease cohort and 6.3 months and 17 months, respectively, for the morphologic disease cohort (P = .0005 for the difference in event-free survival between disease-burden groups and P = .0189 for the difference in overall survival between disease-burden groups). Complete response rates did not correlate with subgroups or with peak CAR T-cell expansion.
Dr. Park and coauthors were also interested in the role of hematopoietic stem cell transplant. The study had small numbers of patients, but in this analysis, post–CAR T-cell transplant did not affect survival. Disease burden was the only factor that affected survival.
“The lack of benefit from transplant on survival appears to be related to transplant-related mortality, which ranges from 15% to 30%, and continued relapse even after transplant.... That is why we are always looking for better ways to treat patients without transplant, at least in a subset of patients,” he told the audience.
Disease burden also had an effect on adverse events. Cytokine-release syndrome and neurotoxicity are serious consequences of CAR T-cell therapy. In this series of patients, severe cytokine-release syndrome was reported in 42% of those with morphologic disease and 5% of the minimal residual disease cohort. Grade 3 or 4 neurotoxicity was reported in 58% and 15%, respectively, and grade 5 toxicity occurred in 13% and 0%. No grade 5 neurotoxicity and no cerebral edema were observed.
Both cytokine-release syndrome and neurotoxicity correlated with disease burden (P = .0019 and P = .013, respectively) and with peak T-cell expansion (P = .0326 and P = .0001). Use of tocilizumab (Actemra) and steroids to treat cytokine-release syndrome did not alter event-free and overall survival outcomes. ■
Disclosure: Dr. Park has an advisory relationship with Juno Therapeutics.
1. Park JH, Rivere I, Wang X, et al: Impact of disease burden and transplant on long-term survival after C19 CAR therapy in adults with relapsed B-cell acute lymphoblastic leukemia. 2017 AACR Annual Meeting. Abstract CT078. Presented April 3, 2017.
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