Phase 2 study of pembrolizumab for measurable residual disease in adults with acute lymphoblastic leukemia
Ryan D Cassaday1,2,3, Kelsey-Leigh A Garcia1, Jonathan R Fromm4
1Division of Hematology, Department of Medicine, University of Washington, Seattle, WA.
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.
Insights
Pembrolizumab showed minimal effectiveness in eliminating measurable residual disease (MRD) in acute lymphoblastic leukemia (ALL). While generally well-tolerated, this PD-1 inhibitor did not meet primary efficacy endpoints in this patient population.
Area of Science:
- Oncology
- Immunotherapy
- Hematology
Background:
- Measurable residual disease (MRD) in acute lymphoblastic leukemia (ALL) indicates a poor prognosis.
- CD19-targeted immunotherapy is effective for MRD but has limitations, including lineage restriction and logistical challenges.
- PD-1 inhibition with pembrolizumab was hypothesized as a potential alternative for MRD, irrespective of leukemia cell type.
Purpose of the Study:
- To evaluate the efficacy of pembrolizumab in adult patients with B- or T-cell ALL and detectable MRD.
- To assess the complete MRD response rate as the primary endpoint.
Main Methods:
- A phase 2 study administered pembrolizumab 200 mg intravenously every 3 weeks to adult ALL patients with detectable MRD.
- Eligibility included MRD detection via multiparameter flow cytometry or qPCR in bone marrow aspirate (BMA), despite prior chemotherapy.
- Response was assessed by BMA using the same methods that detected MRD.
Main Results:
- Enrollment was stopped early; only 1 out of 12 patients (8%) achieved a complete MRD response, which was transient (3 weeks).
- The single responder had prior hematopoietic cell transplantation and CAR-T therapy and experienced a grade 3 immune-related adverse event (Stevens-Johnson syndrome).
- Median overall survival from enrollment was 12.7 months, and pembrolizumab was generally well-tolerated.
Conclusions:
- Pembrolizumab demonstrated minimal activity against MRD in ALL patients in this study.
- The findings suggest that PD-1 inhibition alone has limited efficacy for MRD in ALL.
- Further research is warranted, particularly in combination with other therapies, and highlights the need for dedicated trials for MRD-positive patients.
