Hematology Xagena

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Relapsed B-cell acute lymphoblastic leukemia: durability of CAR T-cell therapy response may depend on pretreatment disease burden

Although most patients with relapsed B-cell acute lymphoblastic leukemia ( B-ALL ) experienced complete response after treatment with a type of CAR T-cell immunotherapy, pretreatment disease burden impacted the durability of the responses and long-term survival.

Adult patients with relapsed or refractory acute lymphoblastic leukemia have extremely poor outcomes, with the five-year survival rate being less than 10%. Therefore, there is a clear need to develop effective therapy for these patients.

Researchers at Memorial Sloan Kettering Cancer Center ( MSKCC ) in New York ( United States ) have developed and tested CD19-specific CAR T-cell therapy [ 19-28z CAR T-cell therapy ] and have reported encouraging results, with high initial complete response rates in patients with B-cell acute lymphoblastic leukemia.
However, relapses are common, even after achieving seemingly deep remission, and severe toxicities have been observed in some patients.

Investigators retrospectively analyzed data from a prospective clinical trial that tested 19-28z CAR T-cell therapy to identify patients who benefited the most from this therapy.
All of the 51 adult patients in this trial had relapsed or refractory B-ALL after one or more conventional multiagent chemotherapy.

The researchers measured disease burden prior to CAR T-cell infusion in all patients and divided them into two cohorts, those who had minimal residual disease ( MRD ) with less than 5% blast cells in bone marrow ( 20 patients ), and those who had morphologic disease, with 5% or more blast cells in bone marrow ( 31 patients ).

Complete response rates in the MRD cohort and morphologic disease cohort were 95% and 77%, respectively, which was not statistically different. After a median of 18 months of follow-up, median event-free survival and overall survival could not be computed for those in the MRD cohort ( because most patients were still disease-free and alive ), but they were 6.3 months and 17 months, respectively, for those in the morphologic disease cohort.
The study also found that long-term survival did not improve for patients in either cohort by having a hematopoietic stem cell transplant ( HSCT ) after CAR T-cell therapy.

While more patients and longer follow-up will be needed to adequately address the significance of HSTC, the result of this analysis raises a question as to whether 19-28z CAR therapy can be considered as a definitive, curative therapy rather than a bridge to stem cell transplant, at least in a subset of patients,

The data suggest that incorporation of 19-28z CAR T cells at the time of minimal residual disease following first-line chemotherapy will maximize the durability of CAR T-cell mediated remissions and survival and can potentially spare these high-risk patients from HSCT, 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 outcome.

Patients from the MRD cohort fared well in terms of side effects as well, compared with those in the morphologic disease cohort. Two of the major side effects associated with CAR T cells, cytokine release syndrome ( CRS ) and neurotoxicity, occurred in 42% and 58% of the patients, respectively, in the morphologic disease cohort, compared with 5% and 15%, respectively, in those from the MRD cohort.
No case of cerebral edema was observed in either cohort of this study.

A limitation of the study is that this is a retrospective analysis and the findings will need to be validated prospectively. Further, the analysis on the impact of post-CAR allogeneic HSCT was limited by a relatively small sample size in each cohort as the study was not designed to specifically answer or address that question. ( Xagena )

Source: AACR ( American Association for Cancer Research ) Annual Meeting, 2017