Minimal residual hairy cell leukemia eradication with moxetumomab pasudotox: phase 1 results and long-term follow-up

Abstract

Anti-CD22 moxetumomab pasudotox achieved 46% complete remissions (CRs) in previously reported phase 1 testing in relapsed/refractory hairy cell leukemia (HCL; n = 28). The importance of minimal residual disease (MRD) after CR in HCL is unknown. A 21-patient extension cohort received 50 µg/kg every other day for 3 doses in 4-week cycles. These patients plus 12 previously reported at this upper dose level received 143 cycles without dose-limiting toxicity. The combined 33-patient cohort achieved 64% CR and 88% overall response rates, with median CR duration of 42.4 months. Of 32 50-µg/kg patients evaluable for MRD by bone marrow aspirate flow cytometry (most stringent assessment), median CR duration was 13.5 (4.9-42.4) months in 9 MRD-positive CRs vs 42.1 (24.0-69.2) months in 11 MRD-negative CRs ( < .001). Among MRD-negative CRs, 10 patients had ongoing CR, 9 without MRD, at end of study. To our knowledge, moxetumomab pasudotox is the only nonchemotherapy regimen that can eliminate MRD in a significant percentage of HCL patients, to enhance CR duration. Repeated dosing, despite early neutralizing antibodies, increased active drug levels without detectable toxicity from immunogenicity. The activity and safety profiles of moxetumomab pasudotox support ongoing phase 3 testing in HCL. This trial was registered at www.clinicaltrials.gov as #NCT00586924.

Results from an international phase 2 study of the anti‐CD22 immunotoxin moxetumomab pasudotox in relapsed or refractory childhood B‐lineage acute lymphoblastic leukemia

“…However, the limited data with process 3 material in the phase I study did not reveal any obvious difference in activity or toxicity . Importantly, this manufacturing change also occurred during the development of moxetumomab pasudotox for HCL without any apparent difference in outcomes, and process 3 material was approved by the FDA for the treatment of adults with HCL …”

“…12 Importantly, this manufacturing change also occurred during the development of moxetumomab pasudotox for HCL without any apparent difference in outcomes, and process 3 material was approved by the FDA for the treatment of adults with HCL. 5,10 Pharmacokinetics, immunogenicity, and cytokine assays were performed as part of this study. No apparent correlation was observed between PK profiles and the development of CLS or HUS.…”

“…Targeting cell‐surface antigens in precursor B‐cell acute lymphoblastic leukemia (B‐ALL) represents a highly effective strategy, as evidenced by the great progress made over the last decade in the development of novel immunotherapeutic approaches to treat relapsed or refractory (r/r) ALL. Chimeric antigen receptor T‐cell therapies targeting CD19 have been shown to induce minimal residual disease (MRD)‐negative complete response (CR) rates that exceed 70% in early‐phase clinical trials, which has led to approval by the U.S. Food and Drug Administration (FDA) for children with r/r ALL . The bispecific CD19/CD3 antibody blinatumomab, also FDA approved for r/r ALL, has been shown to induce high CR rates and to eradicate MRD in a substantial proportion of patients .…”

“…Moxetumomab pasudotox was approved by the FDA for the treatment of hairy cell leukemia (HCL) based on results from a pivotal phase 3 study . Toxicities unique to moxetumomab pasudotox include capillary leak syndrome (CLS) and hemolytic uremic syndrome (HUS) …”

“…Chimeric antigen receptor T-cell therapies targeting CD19 have been shown to induce minimal residual disease (MRD)-negative complete response (CR) rates that exceed 70% in early-phase clinical trials, [1][2][3][4] which has led to approval by the U.S. Food and Drug Administration (FDA) for children with r/r ALL. 5 The bispecific CD19/CD3 antibody blinatumomab, also FDA approved for r/r ALL, has been shown to induce high CR rates and to eradicate MRD in a substantial proportion of patients. 6,7 Inotuzumab ozogamicin (IO), a CD22-targeted antibody-drug conjugate, has received FDA approval for the treatment of adults with r/r ALL.…”