Abstract
Findings from a phase I study suggest that the durability of patients' response to CAR T-cell therapy, and their long-term survival, are influenced by whether they have minimal residual or morphologic disease prior to treatment. The former fared better overall, and also experienced less-severe side effects from this form of immunotherapy.
Although chimeric antigen receptor (CAR) T-cell therapy often induces dramatic remissions, particularly among patients with hematologic malignancies, the key features associated with response durability—or lack thereof—remain undefined. Researchers at Memorial Sloan Kettering Cancer Center in New York, NY, have been investigating this important clinical question in a phase I study, and the findings were reported on April 3 by Jae Park, MD, during the American Association for Cancer Research Annual Meeting 2017 in Washington, DC.
Park and colleagues evaluated 19-28z CAR T cells in this trial, which are engineered to target CD19 and include a CD28 costimulatory domain for enhanced efficacy. Fifty-one adult patients with relapsed/refractory acute lymphoblastic leukemia were enrolled in the trial and received infusions of their own modified T cells. The investigators carried out a retrospective analysis to identify potential markers of response durability, sorting patients into two cohorts: 20 with minimal residual disease (MRD) and 31 with morphologic disease, respectively defined as bone marrow blast cell counts of less than or at least 5%. These cell counts had been measured in each patient prior to treatment.
The two groups had comparably high complete response rates to CAR T-cell therapy, Park said—95% for those with MRD, and 77% for those with morphologic disease. However, median event-free and overall survival, not reached in the MRD group, was 6.3 months and 17 months, respectively, for those with morphologic disease. In terms of side effects, patients with MRD fared better: Cytokine release syndrome and neurotoxicity—two common adverse events with this form of immunotherapy—occurred in 5% and 15% of patients, respectively, versus 42% and 58% of the morphologic disease cohort.
“The pretreatment disease burden appears to influence response durability and survival,” Park said. “Following first-line chemotherapy, incorporating CAR T cells at the time of MRD may be more effective than waiting until a patient relapses morphologically.”
Park also reported that long-term survival for patients in either group did not improve with a follow-up hematopoietic stem cell transplant (HSCT). “More patients and longer follow-up are needed to probe this finding's significance,” he said, “but it does raise the question of whether HSCT provides any benefit in this population.”
Carl June, MD, of the University of Pennsylvania in Philadelphia, observed that in his own evaluations of CD19-targeting CAR T cells, which have 4-1BB as the costimulatory domain and last much longer than 19-28z, “we haven't seen a similar correlation, so far, between disease burden and response durability. The caveat, of course, is that both therapies haven't been compared head to head, but a logical explanation would be differences in persistence.”
“All CARs are not identical,” agreed Terry Fry, MD, of the NCI in Bethesda, MD, so this study's “compelling information needs to be interpreted in the context of the specific CAR being used.” That HSCT may not improve long-term survival in these patients is “a very important observation; I'll be interested to see how the data mature,” he added, because this population could potentially be spared a risky procedure with appreciable mortality rates.
CAR T-cell persistence may well be a factor, Park acknowledged, but “we have several other hypotheses,” which the team plans to test in addition to validating their findings in a prospective trial. –Alissa Poh
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