High Response Rate of Moxetumomab Pasudotox in Relapsed/Refractory Hairy Cell Leukemia Includes Eradication of Minimal Residual Disease: Potential Importance for Outcome
Authors: Kreitman Robert J. , Arons Evgeny , Tallman Martin S , Tadeusz Robak , Coutre Steven , Wilson Wyndham H , Stetler-Stevenson Maryalice , Yuan Constance M. , Lanasa Mark , FitzGerald David JP , Pastan Ira 
Published: October 2019

Abstract
Background: In patients with hairy cell leukemia (HCL), the clinical importance of minimal residual disease is unknown; particularly by bone marrow aspirate (BMA) multicolor flow cytometry. It is often assumed that agents failing to eradicate MRD may prove equally effective as those that do. Moxetumomab pasudotox is a recombinant immunotoxin containing truncated Pseudomonas exotoxin fused to an anti-CD22 Fv. After the dose-escalation phase of a phase I trial in 28 patients with relapsed/refractory HCL treated with 5-50 ug/Kg every other day for 3 doses (QOD x3), a complete remission (CR) rate of 46% and overall response rate (ORR) of 86% were reported. Two cases of reversible grade-2 hemolytic uremic syndrome (HUS) were also reported, with transient grade I platelet and creatinine changes.
Methods: To determine response and toxicity at a fixed dose, Twenty-one additional patients were enrolled at the highest dose level, totaling 33 patients at 50 ug/Kg QOD x3 and 49 patients overall. Patients required at least 2 prior courses of purine analog, or 1 course each of purine analog and rituximab if response duration to the first purine analog was <2 years. CR criteria included absence of HCL cells by morphologic stains of bone marrow and blood. In CRs, multicolor flow cytometry was used to detect MRD in the BMA as well as blood.
Results: No dose limiting toxicity or additional HUS cases were observed in any of the 202 cycles administered to 49 patients. Of 33 patients receiving 143 cycles of 50 ug/Kg QOD x3, the overall response rate was 88% and 21 (64%) achieved CR. Of 20 CRs followed for response duration, the median duration of CR (disease-free survival, DFS) was 42 mo (range 5 - 72), with 12 (60%) of 20 remaining in CR at a median of 42 mo. In addition to the 21 CRs achieved at 50 ug/Kg, there were 2 CRs out of 4 patients treated at 40 ug/Kg, and 5 CRs out of 12 patients treated at lower dose levels. Of the 28 CRs, MRD by BMA flow cytometry was evaluated in all except in 1 patient each at 50 and 40 ug/Kg, and 2 patients at lower doses. By BMA flow cytometry, MRD-negative CR was achieved in 11 (34%) of 32 at 50 ug/Kg, 1 of 3 at 40 ug/Kg, and 0 of 10 at lower doses (Fisher's Exact comparison above vs below 40 ug/Kg, p=0.041). MRD+ CRs included 9 at 50 ug/Kg, 0 at 40 ug/Kg, and 3 at lower doses. For the 12 MRD-negative CRs at 40-50 ug/Kg, DFS has not been reached, compared to a DFS of 17 mo in the 9 remaining MRD+ CRs at 40-50 ug/Kg (p<0.0001). Of the 12 MRD-negative CRs, 11 (92%) remain in CR at 16-79 (median 42) mo of follow-up.
Conclusion: Moxetumomab pasudotox can eliminate HCL MRD, and MRD eradication significantly correlated with CR durability. In HCL, particularly after multiple relapses, CRs should optimally be achieved without MRD. To our knowledge, moxetumomab pasudotox is the only known agent capable of eliminating MRD in HCL in a high percentage of patients without causing myelosuppressive toxicities common to chemotherapy. Its activity and safety profile support multicenter pivotal phase III testing, which is currently ongoing.
This summary contains investigator reported data. This study was sponsored by MedImmune and supported by NCI's Intramural Research Program and the Hairy Cell Leukemia Research Foundation.

Disclosures
Lanasa: MedImmune: Employment. FitzGerald:NIH: Patents & Royalties: Coinventor on NIH Patent. Pastan:NIH: Patents & Royalties: Coinventor on NIH Patent.