Moxetumomab Pasudotox-Tdfk in Heavily Pretreated Patients with Relapsed/Refractory Hairy Cell Leukemia (HCL): Long-Term Follow-up from the Pivotal Phase 3 Trial
Authors: Kreitman Robert J. , Dearden Claire E. , Zinzani Pier Luigi Luigi , Delgado Julio , Robak Tadeusz , le Coutre Philipp D , Gjertsen Bjorn T. , Troussard Xavier , Roboz Gail J. , Karlin Lionel , Gladstone Douglas E , Kuptsova-Clarkson Nataliya , Liu Shiyao , Patel Priti , Wilson Wyndham , Pastan Ira , Giles Francis J. 
Published: November 2019

Moxetumomab pasudotox-tdfk is a first-in-class recombinant CD22-directed cytotoxin approved in the US for the treatment of adult patients with relapsed/refractory hairy cell leukemia (HCL). The pivotal, multicenter, open-label, single-arm trial (Study 1053; NCT01829711) evaluated the efficacy, safety, immunogenicity, and pharmacokinetics of moxetumomab pasudotox-tdfk monotherapy in patients with relapsed/refractory HCL. Here we present the final analysis, describing the long-term follow-up of patients in Study 1053, with a median follow-up of 24.6 months (range 1.2-71.7).
Eligible patients had received ≥ 2 prior systemic therapies, including ≥ 2 courses of a purine nucleoside analog (PNA) or 1 course of a PNA followed by ≥ 1 course of rituximab or a BRAF inhibitor. Patients received moxetumomab pasudotox-tdfk 40 µg/kg intravenously on days 1, 3, and 5 of each 28-day cycle for 6 cycles, or until minimal residual disease (MRD)-negative complete response (CR), disease progression, initiation of alternate therapy, or unacceptable toxicity. Disease response and immunohistochemistry MRD status were determined by blinded independent central review. The primary endpoint was durable CR (achieving CR and maintaining hematologic remission [HR] for > 180 days). Durable CR with HR ≥ 360 days was measured in this final analysis. HR was 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 4 preceding weeks of assessment.
Eighty patients (63 males; median age 60 years [range 34-84]) were enrolled and treated with moxetumomab pasudotox-tdfk. The median number of prior systemic therapies was 3 (range 2-11); 48.8% of patients were PNA-refractory and 37.5% were unfit for PNA retreatment. The median number of treatment cycles administered was 6 (range 1-7). The durable CR rate was 36.3% (29/80 patients; 95% confidence interval [CI]: 25.8-47.8%), durable CR rate with HR ≥ 360 days was 32.5% (26/80 patients; 95% CI: 22.4-43.9%), and the overall CR rate was 41.3% (33/80 patients; 95% CI: 30.4-52.8%) (Table). Overall, 27/33 (81.6%) patients who achieved a CR also achieved MRD-negative status (33.8% of all patients). HR was achieved by 64/80 patients (80.0%). The median duration of HR from CR was 62.8 months (Figure) and median progression-free survival was 41.5 months (range 0.0+ to 71.7).
Per the primary analysis, the most frequent treatment-related adverse events (AEs) were nausea (28%), peripheral edema (26%), headache (21%), and pyrexia (20%). Treatment-related Grade 3/4 AEs were reported in 24 patients (30.0%) and serious AEs in 28 (35.0%). Treatment-related AEs led to study drug discontinuation in 8 patients (10.0%): hemolytic uremic syndrome (HUS), n = 4 (5.0%); capillary leak syndrome (CLS), n = 2 (2.5%); and increased blood creatinine, n = 2 (2.5%). Grade ≥ 3 CLS events occurred in 2 patients (2.5%) and Grade ≥ 3 HUS occurred in 5 patients (6.3%). In general, CLS and HUS events were manageable and reversible with appropriate supportive care and monitoring. Based on primary and follow-up analyses of serum creatinine, there was no decline in renal function over time; 12 months post-treatment all mean (SD) serum creatinine laboratory values stayed within normal limits, which suggests current management strategies for HUS (oral hydration, i.v. fluid supplementation on the day of infusion, and the use of dexamethasone) are adequate. With 24.6 months of follow-up, 4 deaths were reported: 2 due to study disease progression and 2 due to an AE (1 each of pneumonia and septic shock).
Moxetumomab pasudotox-tdfk treatment was associated with a manageable safety profile. Moxetumomab pasudotox-tdfk achieved a high rate of durable responses, demonstrating the ability to achieve MRD negativity in heavily pretreated patients with HCL.

Disclosures
Kreitman: Genentech: Research Funding. Dearden:Abbvie: Honoraria; Genentech: Honoraria; Janssen: Honoraria; Sanofi: Honoraria. Zinzani:MSD: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; VERASTEM: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; CELLTRION: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; GILEAD: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; JANSSEN-CILAG: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; IMMUNE DESIGN: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; EUSAPHARMA: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ROCHE: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; SERVIER: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; SANDOZ: Membership on an entity's Board of Directors or advisory committees; KYOWA KIRIN: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; CELGENE: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; SANOFI: Consultancy; PORTOLA: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Robak:Amgen: Consultancy, Other: Travel grant; UCB: Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Other: Travel grant, Research Funding; Roche: Consultancy, Other: Travel grant, Research Funding; Abbvie: Consultancy, Honoraria, Other: Travel grant, Research Funding; Gilead: Consultancy, Research Funding; BeiGene: Consultancy, Research Funding; Acerta: Research Funding; Morphosys AG: Research Funding; Takeda: Consultancy, Research Funding. le Coutre:Novartis: Honoraria, Speakers Bureau; Bristol-Myers Squibb: Honoraria, Speakers Bureau; Incyte: Honoraria, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau. Gjertsen:Research Council of Norway: Research Funding; Daiichi Sankyo: Consultancy; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; BerGenBio: Consultancy; KinN Therapeutics AS: Equity Ownership; Seattle Genetics: Consultancy; ERA PerMed: Research Funding; Haukeland University Hospital / University of Bergen: Employment; ACTII AS: Equity Ownership; Astellas: Consultancy; BerGenBio AS: Membership on an entity's Board of Directors or advisory committees; The Norwegian Cancer Society: Research Funding; Helse Vest Health Trust: Research Funding; EU Horizon 2020: Research Funding. Troussard:Innate Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche: Other: Research Support; Sysmex: Other: Research Support. Roboz:Argenx: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Actinium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amphivena: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche/Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astex: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celltrion: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees; Eisai: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; MEI Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Orsenix: Consultancy, Membership on an entity's Board of Directors or advisory committees; Otsuka: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sandoz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Trovagene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees. Karlin:Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Support; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; AMGEN: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Support. Kuptsova-Clarkson:AstraZeneca: Employment, Equity Ownership. Liu:Acerta Pharma: Employment. Patel:Acerta Pharma: Employment, Equity Ownership; AstraZeneca: Equity Ownership.