Moxetumomab pasudotox in relapsed/refractory hairy cell leukemia

Abstract

This is a pivotal, multicenter, open-label study of moxetumomab pasudotox, a recombinant CD22-targeting immunotoxin, in hairy cell leukemia (HCL), a rare B cell malignancy with high CD22 expression. The study enrolled patients with relapsed/refractory HCL who had ≥2 prior systemic therapies, including ≥1 purine nucleoside analog. Patients received moxetumomab pasudotox 40 µg/kg intravenously on days 1, 3, and 5 every 28 days for ≤6 cycles. Blinded independent central review determined disease response and minimal residual disease (MRD) status. Among 80 patients (79% males; median age, 60.0 years), durable complete response (CR) rate was 30%, CR rate was 41%, and objective response rate (CR and partial response) was 75%; 64 patients (80%) achieved hematologic remission. Among complete responders, 27 (85%) achieved MRD negativity by immunohistochemistry. The most frequent adverse events (AEs) were peripheral edema (39%), nausea (35%), fatigue (34%), and headache (33%). Treatment-related serious AEs of hemolytic uremic syndrome (7.5%) and capillary leak syndrome (5%) were reversible and generally manageable with supportive care and treatment discontinuation (6 patients; 7.5%). Moxetumomab pasudotox treatment achieved a high rate of independently assessed durable response and MRD eradication in heavily pretreated patients with HCL, with acceptable tolerability.

Conflict of interest statement

This study was sponsored by MedImmune. RJK received a research grant from MedImmune and is co-inventor of moxetumomab pasudotox, with the NIH holding the patent. CD has received personal fees from Gilead, Infinity, Janssen/Pharacyclics, MedImmune, Roche, and Sanofi Aventis, and has received clinical trial support from MedImmune. PLZ has served as an advisor for Bristol-Myers Squibb, Celgene, Gilead, Janssen, Merck, Roche, Servier, and Takeda. JD served on a data monitoring board for MedImmune, has received research grants from Janssen and Roche, and has received personal fees from Abbvie, Gilead, Janssen, and Roche. LK, DEG, M Gotic, LL, FO, RS, GS, SD, LB, CAY, AH, KB, MB, MG, AC, MD, SD, SL, MR, PR, TT, GS, GJR, XT, and WW have no conflicts to report. TR has received research grants from AstraZeneca. PLC has served as a speaker for Bristol-Myers Squibb, Incyte, Novartis, and Pfizer. DAB has received personal fees from Amgen, Novartis, and Teva, and his institution has received reimbursement for clinical trials from Ablynx, Amgen, Astellas, Astex, Cyclacel, Genzyme, Janssen, MedImmune, Merus, Menarini, Novella Clinical, Pfizer, and Seattle Genetics. BTG has received personal fees from BerGenBio AS, Novartis AS, Pfizer, and Seattle Genetics, received non-financial support from Merck Sharpe & Dohme and Roche, and owns shares in Alden Cancer Therapeutics 2 AS and Kinn Therapeutics AS. FM has received research grants from Amgen and Sandoz, received travel accommodations from Octapharma and Roche, and served on advisory boards for Pfizer, Roche, and Sandoz. FR has received research grants from MedImmune. TS has served on speakers’ bureaus for Pharmacyclics and Seattle Genetics, and on a steering committee for Juno. KB, NS, PH, SM, and NSY are employees of MedImmune and may own stock/options in AstraZeneca. IP is co-inventor of moxetumomab pasudotox, with the NIH holding the patent. FG has received a research grant from MedImmune.

Figures

Fig. 1

Evaluation of primary end point (blinded independent central review). a Hemoglobin (top), neutrophil counts (middle), and platelet counts (bottom) over time, as a function of best objective response. Median and interquartile range are shown at each displayed time point and the threshold for hematologic remission is indicated as a dotted line. b HCL involvement in bone marrow, assessed by hematoxylin and eosin stain, as a function of best objective response; median and interquartile range are shown (top), and as representative pretreatment and posttreatment images (×100) of a patient who obtained a minimal residual disease-negative complete response (bottom). Yellow arrows indicate hairy cells. c Spleen size by imaging, as a function of best objective response. Median and interquartile range are shown. Splenectomy patients (n = 5) not included. d Kaplan–Meier plot of duration of hematologic remission from complete response

Fig. 2

Assessment of minimal residual disease by immunohistochemistry (blinded independent central review). a Representative immunohistochemistry images from pretreatment and posttreatment bone marrow biopsy specimens of the same patient shown in Fig. 1b: CD20 (left) and PAX5/TRAP (right). b Kaplan–Meier plot of duration of complete response, by minimal residual disease status