Rituximab Reduces Immunogenicity and Increases Complete Remissions without Minimal Residual Disease in Relapsed/Refractory Hairy Cell Leukemia Patients Receiving Moxetumomab Pasudotox

Background: Moxetumomab pasudotox (Moxe) is an anti-CD22 recombinant immunotoxin which was FDA-approved as a single-agent in 2018 for relapsed/refractory hairy cell leukemia (HCL). Moxe contains a CD22 Fv fragment connected to a 38 kDa truncated form of Pseudomonas exotoxin called PE38. In phase 1-3 testing, complete remissions (CRs) were more frequent in patients with lower tumor burden and lower titers of antidrug antibodies (ADA). Eradication of minimal residual disease (MRD) was associated with longer CR duration. HCL and the poorer-prognosis disease counterpart HCLv both strongly express CD20 and CD22, but CD20 Mab Rituximab monotherapy achieved only 13% CRs in those with relapsed disease. A clinical trial was initiated to determine if rituximab could decrease immunogenicity in HCL patients receiving Moxe. In addition to preventing or delaying ADA by eradicating normal B-cells, rituximab was combined with Moxe to more quickly reduce HCL disease burden and hasten MRD-free CR before ADA might develop.

Methods: Moxe was delivered by 30-minute infusion on days 1, 3 and 5 of 28-day cycles. Three patients received 30 mcg/Kg/dose and the next 15 patients received the FDA-approved 40 mcg/dose. To allow enough time to reduce both ADA and tumor burden, rituximab was administered 3 days before day 1 of cycle 1 at 375 mg/m², and on day 1 of subsequent cycles. Patients 14-18 received the biosimilar Ruxience instead of rituximab. Patients received up to 4 cycles after achieving MRD-free CR, up to 8 cycles if MRD-free CR was achieved after cycle 4, or fewer cycles if disease progression or significant toxicity occurred. MRD was tested by blood and bone marrow aspirate (BMA) flow cytometry and bone marrow biopsy immunohistochemistry (IHC). BMA flow cytometry was the most sensitive MRD test, able to detect 0.002% HCL cells. To confirm durability of MRD-free CR, bone marrow studies were performed yearly until 2.5 years after end of treatment, and then every 2 years. The ADA assay, an FDA-validated test for anti-CD22 recombinant immunotoxin BL22, was used to determine the percent neutralization by serum of the cytotoxicity of Moxe on a CD22+ cell line.

Results: All 18 patients were evaluable for toxicity and response, none had dose-limiting toxicity. Patients received 1-8 (median 6) cycles each. One patient had laboratory evidence of transient grade 3 hemolytic uremic syndrome during cycle 3 without significant symptoms or need for therapy. Of the 18 patients, 15 (83%) responded, 14 (78%) achieved CR and 13 (72%) achieved MRD-free CR by all MRD tests. The 1 patient with HCLv achieved MRD-free CR. The Moxe license was returned to NIH preventing enrollment of the planned 26 patients needed to achieve a 1-sided p-value <0.025. Nevertheless, compared to Moxe alone where 30 (47%) of 64 phase 1-3 patients achieved MRD-free CR, the 53% relative improvement with MoxeR achieved a 1-sided p-value of 0.05. Compared to 29 (48%) of 61 evaluable phase 1-3 HCL patients who received Moxe alone with high ADA levels, only 4 (29%) of 18 patients had high ADA levels to MoxeR (p=0.048). At a median 36.7 months of follow-up, 11 of 13 MRD-free CRs continue to be followed, with MRD relapse-free survival at 19-56 (median 37.3) months. One multiply relapsed patient with rituximab allergy was treated off-protocol with 8 cycles of Moxe plus Obinutuzumab and achieved an MRD-free CR.

Conclusions: MoxeR is a safe regimen for relapsed-refractory HCL/HCLv, with the highest MRD-free CR rate reported yet for this disease. Despite enrolling slightly fewer patients than planned, MoxeR was more effective than Moxe alone at achieving MRD-free CR, probably due to both lower immunogenicity and more rapid reduction of HCL/HCLv disease burden. Non-Hodgkin's lymphomas (NHL), such as diffuse large B-cell, mantle cell, marginal zone, follicular, and lymphoplasmacytic lymphoma, express significant levels of CD22, and lymphoma cells from these patients have sensitivity to Moxe similar to HCL. We believe this trial supports the testing of Moxe plus anti-CD20 Mab in patients with early HCL/HCLv, and in patients with NHL to convert MRD-positive to MRD-negative CRs.

No relevant conflicts of interest to declare.