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Blinatumomab triggers complete MRD response in ALL

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Compelling evidence of benefit

The study by Dr. Gökbuget and her colleagues provides “strong evidence” that blinatumomab immunotherapy eliminates residual B-cell acute lymphoblastic leukemia (ALL) cells, thereby preventing relapse and improving survival, according to Patrick Brown, MD.

“This addresses the most important unsolved clinical problem in adults with B-ALL: the development of chemotherapy-resistant relapsed disease,” Dr. Brown wrote in an editorial.

Persistence of minimal residual disease (MRD) is the strongest independent predictor of outcomes in B-cell ALL, and is seen in up to 50% of adult patients after chemotherapy, according to Dr. Brown.

The “well-designed and well-executed” multicenter phase 2 study demonstrated an MRD clearance rate of 78% after one cycle of blinatumomab with modest adverse effects, according to Dr. Brown. Moreover, the results show a doubling of overall survival and tripling of relapse-free survival in MRD responders versus nonresponders, he said.

“An important caveat, however, is that, although the MRD clearance rate was no lower in the 35% of patients who had already relapsed once before enrolling, these patients had a substantially inferior RFS [relapse-free survival] and OS [overall survival], compared with those treated in first remission,” he added. “The clear lesson is that the impact of immunotherapeutic clearance of MRD on survival is greatest when applied early in the disease course.

The “most pressing question” not answered by this study is the impact of hematopoietic stem cell transplantation after complete MRD response, since the study allowed optional HSCT.

Patrick A. Brown, MD, is with Johns Hopkins University, Baltimore. These comments are adapted from his editorial in Blood (2018;131:1497-8). Dr. Brown reported having no competing financial interests related to his editorial.



After treatment with blinatumomab, most patients with minimal residual disease–positive acute lymphoblastic leukemia (ALL) achieved complete MRD response, according to results of a single-arm phase 2 study.

Achieving complete MRD response was associated with significantly longer relapse-free and overall survival in the patients, who were already in hematologic complete remission, researchers reported in the journal Blood.

“Our results suggest that targeted treatment in early stages of MRD is a viable therapeutic strategy for patients with B-cell precursor ALL and that it should also be evaluated in other hematologic malignancies,” Nicola Gökbuget, MD, University Hospital, Frankfurt, Germany, and her coauthors wrote.

This is the first international multicenter study to specifically enroll MRD-positive ALL patients and evaluate them for an MRD-based primary outcome in a cohort of MRD-positive ALL patients, according to the authors.

Preemptively treating low but measurable disease in ALL in remission, instead of waiting for overt relapse, is a strategy that may prolong overall survival, Dr. Gökbuget and her colleagues said in describing the rationale for their study. While there is no standard therapy yet for ALL patients with detectable MRD after intensive chemotherapy, hematopoietic stem cell transplantation (HSCT) is recommended, based on data that it may improve outcomes in patients with persistent MRD. However, other studies suggest detectable MRD before HSCT is associated with higher relapse rates, and many patients relapse while waiting for HSCT, the researchers noted.

To test an MRD-directed treatment strategy, Dr. Gökbuget and colleagues at 46 centers in Europe and Russia conducted an open-label, single-arm, phase 2 study including 116 patients with B-cell precursor ALL in hematologic complete remission. Patients in the study received up to four cycles of blinatumomab, a bispecific, T cell–engager antibody construct that enables T cells to recognize and eliminate CD19-positive cells.

Of 113 evaluable patients, 88 (78%) achieved complete MRD response after one cycle, the primary end point of the study. Relapse-free survival at 18 months was estimated at 54% and median overall survival was 36.5 months in the subset of 110 patients with Philadelphia chromosome–negative ALL in hematologic remission.

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