The Effect of Moxetumomab Pasudotox on Minimal Residual Disease in Hairy Cell Leukemia

Nearly two-thirds of patients with relapsed/refractory hairy cell leukemia (HCL) who were treated with the anti-CD22 recombinant immunotoxin moxetumomab pasudotox achieved complete remission (CR), according to research published in Blood. More than half of these patients also experienced minimal residual disease (MRD)-negativity, reported Robert J. Kreitman, MD, of the National Cancer Institute’s Center for Cancer Research, and co-authors.

This study expands on a previously reported phase I study of 28 patients with relapsed/refractory HCL, in which moxetumomab pasudotox produced overall response and CR rates during a median 16 weeks of follow-up that were similar to the present study. The updated results include 12 patients from the original study who received the upper dose level of moxetumomab (50 μg/kg every other day for 3 doses in 4-week cycles), plus 21 additional patients enrolled in an expanded 50 μg/kg cohort.

All 33 participants (age range = 40-77 years) had a confirmed diagnosis of classic or variant HCL with measurable disease and had received two or more prior systemic therapies, including two courses of a purine analog, unless response to the first course lasted less than two years. Patients were excluded if they had poor hepatic, renal, or pulmonary function; received therapy within three weeks of enrollment; or previously received immunotoxin.

The previously reported cohort received 143 treatment cycles without experiencing dose-limiting toxicity (DLT), while those in the extension cohort received 88 cycles without DLT, for an average treatment duration of 116 cycles in the entire study group.

Four patients died from disease progression after relapsing and going off study. They died a median of 17 months (range = 2-29 months) after the last study dose. One of these patients had a best response of MRD-positive CR and developed grade 2 hemolytic uremic syndrome after five cycles of treatment.

In the combined 33-patient cohort, 29 (88%) responded to moxetumomab treatment and 21 (64%) achieved CR. The median duration of CR was 42.4 months (range not provided). No patients relapsed after receiving consolidation therapy, while nine of 14 participants who did not receive consolidation relapsed a median of 13.5 months (range = 4.9-42.4 months; p=0.004) after finishing moxetumomab treatment.

CR appeared to be unrelated to the number of prior purine analog courses, prior rituximab, or baseline spleen size. However, none of the four patients who achieved CR had prior splenectomy, compared with 72 percent in the other 29 patients (p=0.012).

Median time to CR was 17 weeks (range = 4-110 weeks). “For six patients with longest time to CR (range = 11-25 months), positive bone marrow (BM) at end of treatment became negative during follow-up, despite no intervening therapy,” the investigators reported. “Thus, in the absence of the myelotoxicity expected from chemotherapy, patients responded quickly and achieved CR, usually at the first response assessment … performed after resolution of cytopenias.”

Among the complete responders, nine (45%) had detectable MRD (via BM aspirate [BMA] and/or blood flow cytometry), and 11 (55%) did not (one patient was not evaluable for MRD). Ten of the MRD-negative patients remained in CR at the end of the study, for a median CR duration of 42.2 months (range = 16.3-72.1 months). These results suggest that “elimination of MRD was significantly associated with prolonged CR duration (p<0.0001),” the authors observed.

The authors assessed nine patients for lymphocyte subsets before and after treatment: Circulating HCL cells cleared in all patients, but normal B cells decreased by <50 percent in three patients and increased in all others. T cells and their subsets increased in all but one patient, “thus, [the anti-CD22 drug] spared T cells and, with its short half-life, avoided prolonged B-cell depletion,” they noted.

“Moxetumomab pasudotox 50 µg/kg, particularly with consolidation cycles, cleared MRD in more than half of [patients who experienced] CR,” the authors wrote, noting that MRD clearance was associated with improved CR duration. Of the 29 patients who received the 50 µg/kg dose, 22 (76%) clearing MRD in the blood had higher CR (n=19/22 vs. n=1/7; p=0.001) and higher overall response rates (n=22/22 vs. n=4/7; p=0.01), compared with those who never achieved MRD-negativity.

Pharmacokinetics analysis in 29 evaluable patients revealed that plasma concentrations of moxetumomab increased 213 percent during cycle one (p<0.001) and increased 121 percent during cycle two from days one to five (p=0.002). The volumes of distribution and clearances decreased, while soluble CD22 levels and HCL burden decreased, per enzyme-linked immunosorbent assays assays. These findings, the authors noted, suggest “moxetumomab pasudotox at 50 μg/kg achieved cytotoxic plasma levels that increased with rapid resolution of tumor burden and were not completely blocked when neutralizing antibodies were first detectable.”

An ongoing multicenter, pivotal study is assessing moxetumomab pasudotox in patients with relapsed/refractory HCL.

This early-phase study is limited by its small patient population and lack of a comparator arm.

MedImmune provided support for the study.

Some of the authors are co-inventors of immunotoxin patents assigned to the government of the U.S., 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.


Kreitman RJ, Tallman MS, Robak T, et al. Minimal residual hairy cell leukemia eradication with moxetumomab pasudotox: phase I results and long-term follow-up. Blood. 2018 February 27. [Epub ahead of print]