Minimal residual hairy cell leukemia eradication with moxetumomab pasudotox: phase 1 results and long-term follow-up

Abstract

Anti-CD22 moxetumomab pasudotox achieved 46% complete remissions (CRs) in previously reported phase 1 testing in relapsed/refractory hairy cell leukemia (HCL; n = 28). The importance of minimal residual disease (MRD) after CR in HCL is unknown. A 21-patient extension cohort received 50 µg/kg every other day for 3 doses in 4-week cycles. These patients plus 12 previously reported at this upper dose level received 143 cycles without dose-limiting toxicity. The combined 33-patient cohort achieved 64% CR and 88% overall response rates, with median CR duration of 42.4 months. Of 32 50-µg/kg patients evaluable for MRD by bone marrow aspirate flow cytometry (most stringent assessment), median CR duration was 13.5 (4.9-42.4) months in 9 MRD-positive CRs vs 42.1 (24.0-69.2) months in 11 MRD-negative CRs (P < .001). Among MRD-negative CRs, 10 patients had ongoing CR, 9 without MRD, at end of study. To our knowledge, moxetumomab pasudotox is the only nonchemotherapy regimen that can eliminate MRD in a significant percentage of HCL patients, to enhance CR duration. Repeated dosing, despite early neutralizing antibodies, increased active drug levels without detectable toxicity from immunogenicity. The activity and safety profiles of moxetumomab pasudotox support ongoing phase 3 testing in HCL. This trial was registered at www.clinicaltrials.gov as #NCT00586924.

Conflict of interest statement

Conflict-of-interest disclosure: I.P., D.J.F., and R.J.K. are coinventors on immunotoxin patents assigned to the government of the United States, as represented by the Secretary of the Department of Health and Human Services on behalf of the National Institutes of Health, which are licensed by Medimmune. L.S., G.G., and M.C.L. are employees of MedImmune. The remaining authors declare no competing financial interests.

Figures

Graphical abstract

Figure 1.

Duration of CR. CR duration is shown for patients at 50 μg/kg by consolidation cycles received (A) and by those evaluable for MRD (B). Durations of MRD-negative CR (C) and MRD negativity in blood for patients achieving CR or partial response are shown (D). MRD evaluation at the National Cancer Institute used multicolor flow cytometry (detection level of 0.002% to 0.006%) in blood and BMA (see supplemental Table 1 for details). MRD was also determined by immunohistochemistry of the bone marrow biopsy. Bone marrows were typically performed after cytopenias resolved consistent with CR, at end of treatment, annually at 0.5 to 2.5 years after best response, and every 2 years thereafter. Flow cytometry of blood was performed precycle, at end of treatment, every 6 months after best response until 2.5 years, and annually thereafter. Time to achieve and duration of response were calculated using Kaplan-Meier, with curves compared by log-rank. PR, partial response.

Figure 2.

Pharmacokinetic parameters, tumor burden, and immunogenicity. In patients receiving 50 µg/kg, clearance during cycle 1 day 5 was related to hairy cell count (A) and spleen size (B). At this dose level, peak levels (C), AUC (D), volumes of distribution (Vd; E), and clearance (F) on days 1 and 5 are shown for cycles given to 15 patients who had >50% neutralization (median, 93%) of 200 ng/mL documented from serum samples just before day 1. These patients were evaluated during cycles 2 (n = 3), 3 (n = 5), 4 (n = 4), 5 (n = 2), and 6 (n = 1) and received that cycle, because the result was known only after completion of the cycle, but were excluded from further retreatment. For the extension cohort enrolled at National Cancer Institute, immunogenicity was determined by in vitro cytotoxicity. Enrollment or retreatment for the extension cohort required ≤50% neutralization of 200 ng/mL of moxetumomab pasudotox. Approximately 17% of relapsed HCL/HCL variant patients have >50% neutralization of 200 ng/mL and would be ineligible for enrollment. Pharmacokinetic analyses were previously described.-