Moxetumomab pasudotox in heavily pre-treated patients with relapsed/refractory hairy cell leukemia (HCL): long-term follow-up from the pivotal trial

Abstract

Background: Moxetumomab pasudotox is a recombinant CD22-targeting immunotoxin. Here, we present the long-term follow-up analysis of the pivotal, multicenter, open-label trial (NCT01829711) of moxetumomab pasudotox in patients with relapsed/refractory (R/R) hairy cell leukemia (HCL).

Methods: Eligible patients had received ≥ 2 prior systemic therapies, including ≥ 2 purine nucleoside analogs (PNAs), or ≥ 1 PNA followed by rituximab or a BRAF inhibitor. Patients received 40 µg/kg moxetumomab pasudotox intravenously on Days 1, 3, and 5 of each 28-day cycle for up to six cycles. Disease response and minimal residual disease (MRD) status were determined by blinded independent central review. The primary endpoint was durable complete response (CR), defined as achieving CR with hematologic remission (HR, blood counts for CR) lasting > 180 days.

Results: Eighty adult patients were treated with moxetumomab pasudotox and 63% completed six cycles. Patients had received a median of three lines of prior systemic therapy; 49% were PNA-refractory, and 38% were unfit for PNA retreatment. At a median follow-up of 24.6 months, the durable CR rate (CR with HR > 180 days) was 36% (29 patients; 95% confidence interval: 26-48%); CR with HR ≥ 360 days was 33%, and overall CR was 41%. Twenty-seven complete responders (82%) were MRD-negative (34% of all patients). CR lasting ≥ 60 months was 61%, and the median progression-free survival without the loss of HR was 71.7 months. Hemolytic uremic and capillary leak syndromes were each reported in ≤ 10% of patients, and ≤ 5% had grade 3-4 events; these events were generally reversible. No treatment-related deaths were reported.

Conclusions: Moxetumomab pasudotox resulted in a high rate of durable responses and MRD negativity in heavily pre-treated patients with HCL, with a manageable safety profile. Thus, it represents a new and viable treatment option for patients with R/R HCL, who currently lack adequate therapy.

Trial registration: ClinicalTrials.gov identifier: NCT01829711; first submitted: April 9, 2013. https://ichgcp.net/clinical-trials-registry/NCT01829711.

Keywords: B cell malignancy; CD22; Hairy cell leukemia (HCL); Immunotoxin; Minimal residual disease (MRD); Moxetumomab pasudotox; Relapsed/refractory.

Conflict of interest statement

RJK is listed as a co-inventor on the National Institutes of Health (NIH) patent for moxetumomab; he has received grants and non-financial support from AstraZeneca, Innate Pharma, and Novartis, and non-financial support from Genentech and Teva. CD is on the advisory board for MedImmune and Innate Pharma. PLZ has received personal fees from Celltrion, MSD, Verastem, Gilead, Astellas, and Kirin Kyowa. TR has received a research grant from AstraZeneca. XT is a consultant for Innate Pharma. GJR is a consultant and on the advisory board or data/safety monitoring committee for AbbVie, Actinium, Agios, Amphivena, Argenx, Array Biopharma, Astex, Astellas, AstraZeneca, Bayer, Celgene, Celltrion, Daiichi Sankyo, Eisai, Epizyme, Helsinn, Janssen, Jasper Therapeutics, Jazz, MEI Pharma, Novartis, Orsenix, Otsuka, Pfizer, Roche/Genentech, Sandoz, Takeda, and Trovagene, with research support from Celgene. LK has received personal fees from Amgen, Celgene, Janssen, and Takeda. FR and EM are employees and stakeholders of Innate Pharma. NKC and PP are employees of AstraZeneca. SL was an employee of Acerta Pharma, now Arcus Biosciences. JD, PlC, BTG, DEG, IP, and FG have no conflicts of interest to declare.

Figures

Fig. 1

Moxetumomab pasudotox provided durable responses in heavily pre-treated patients. As assessed by BICR in the ITT population, Kaplan–Meier plots of a duration of CR and b duration of HR, in patients with CR, c duration of HR in all patients with HR, and d PFS. HR is defined as hemoglobin ≥ 11.0 g/dL, absolute neutrophil count ≥ 1.5 × 103/µL, and platelet count ≥ 100 × 103/µL, without receiving transfusions or growth factors within the preceding 4 weeks of assessment. BICR blinded independent central review, CI confidence interval, CR complete response, HR hematologic remission, ITT intent-to-treat population, LR landmark rate, NE not evaluable, NR not reported, OR objective response, PFS progression-free survival

Fig. 1

Moxetumomab pasudotox provided durable responses in heavily pre-treated patients. As assessed by BICR in the ITT population, Kaplan–Meier plots of a duration of CR and b duration of HR, in patients with CR, c duration of HR in all patients with HR, and d PFS. HR is defined as hemoglobin ≥ 11.0 g/dL, absolute neutrophil count ≥ 1.5 × 103/µL, and platelet count ≥ 100 × 103/µL, without receiving transfusions or growth factors within the preceding 4 weeks of assessment. BICR blinded independent central review, CI confidence interval, CR complete response, HR hematologic remission, ITT intent-to-treat population, LR landmark rate, NE not evaluable, NR not reported, OR objective response, PFS progression-free survival

Fig. 2

MRD negativity was associated with durable CR. Kaplan–Meier plot for the patients with a complete response in the ITT population, as assessed by BICR (n = 33). The starting point of the observation was from the onset of CR and MRD testing. BICR blinded independent central review, CI confidence interval, CR complete response, ITT intent-to-treat, MRD minimal residual disease, NE not evaluable