Phase 2 study of pembrolizumab for measurable residual disease in adults with acute lymphoblastic leukemia

Abstract

The presence of measurable residual disease (MRD) in acute lymphoblastic leukemia (ALL) confers a poor prognosis. CD19-targeted immunotherapy is effective against MRD but is logistically challenging, potentially toxic, and not applicable to T-cell ALL. We thus hypothesized that inhibition of PD-1 with pembrolizumab could also be effective for MRD, but without lineage restriction. The primary objective of this phase 2 study was to evaluate the efficacy of pembrolizumab in patients with ALL and MRD. Key eligibility criteria included adults with B- or T-cell ALL and MRD detectable by multiparameter flow cytometry or quantitative polymerase chain reaction from bone marrow aspirate (BMA) despite chemotherapy (plus ABL kinase inhibitor if Philadelphia chromosome positive). Pembrolizumab 200 mg IV was given every 3 weeks. Response was assessed by BMA using methods that previously detected MRD. The primary end point was complete MRD response rate. We stopped enrollment early; only 1 of 12 (8%) experienced a complete MRD response, which lasted 3 weeks. Interestingly, this patient had previously received hematopoietic cell transplantation and CD19-targeted chimeric antigen receptor-modified T-cell therapy and was the only patient to experience an immune-related adverse event from pembrolizumab (grade 3 Stevens-Johnson syndrome). Median overall survival from enrollment was 12.7 months. In summary, pembrolizumab had minimal activity against MRD but was generally well tolerated. These data can be compared with ongoing anti-PD-1 combination studies in ALL, and they further establish the role of trials specifically for patients with MRD. This trial was registered at www.clinicaltrials.gov as #NCT02767934.

Conflict of interest statement

Conflict-of-interest disclosure: R.D.C. has received research funding from Amgen, Kite/Gilead, Merck, Pfizer, and Vanda Pharmaceuticals and honoraria/consulting from Amgen and Pfizer, and his spouse is employed by and owns stock in Seattle Genetics. J.R.F. has received research funding from Merck. M.-E.M.P. has received research funding from Pfizer, Biosight, Nohla, Trillium, and FLX Bio as well as honoraria from Genentech. C.J.T. receives research funding from Juno Therapeutics, Nektar Therapeutics, TCR2 Therapeutics, and AstraZeneca; is a member of scientific advisory boards and has options in Precision Biosciences, Eureka Therapeutics, Caribou Biosciences, Myeloid Therapeutics, and ArsenalBio; serves on scientific advisory boards for T-CURX and Century Therapeutics; has served on advisory boards for Nektar Therapeutics, Allogene, Kite/Gilead, Novartis, Humanigen, PACT Pharma, and AstraZeneca; and has patents licensed to Juno Therapeutics. P.T.N. has served on advisory boards for Pfizer and EMD Serono, and his institution receives research support from Bristol-Myers Squibb and EMD Serono. The remaining authors declare no competing financial interests.

© 2020 by The American Society of Hematology.

Figures

Graphical abstract

Figure 1.

Changes in burden of ALL as determined by MFC of BMAs collected before and after each cycle of pembrolizumab. To better discriminate changes at the lower range of detection, blast percentage is plotted with a base-8 logarithmic scale. This graph depicts outcomes for the 11 patients who had disease detectable by MFC during study treatment. The course for the 1 patient who experienced a complete MRD response is depicted as a hashed line.

Figure 2.

Time-to-event analyses following treatment with pembrolizumab. Kaplan-Meier curves depicting overall survival (A) and morphologic relapse-free survival (B) after administration of pembrolizumab in adults with ALL and MRD. Tick mark represent censored events.