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Durable Responses With Moxetumomab Pasudotox in Pretreated Hairy Cell Leukemia


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Moxetumomab pasudotox produced deep and durable responses in a heavily pretreated population of patients with hairy cell leukemia, with the ability to eradicate minimal residual disease. The drug showed a favorable safety profile with less bone marrow suppression than with purine nucleoside analog treatment; however, it did cause “unique but manageable” adverse events, including hemolytic uremic syndrome and capillary leak syndrome. 

Robert Kreitman, MD

Robert Kreitman, MD

Leslie Ellis, MD

Leslie Ellis, MD

These findings come from a pivotal international trial, originally presented at the 2018 ASCO Annual Meeting by Robert Kreitman, MD, Senior Investigator, Clinical Immunotherapy Section, Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute.1 The study was later discussed at the Best of ASCO Chicago by Leslie Ellis, MD, along with other selected abstracts in leukemia.2

Hairy cell leukemia is a B-cell malignancy characterized by high levels of CD22 expression. “Although we certainly do get durable responses with front-line treatment with purine nucleoside analogs and CD20 monoclonal antibodies, there is this unmet need for patients with relapsed or refractory hairy cell leukemia,” explained Dr. Ellis, a hematologist-oncologist at Wake Forest Baptist Health in Winston-Salem, North Carolina. “So in keeping with that, this monoclonal antibody that binds to CD22 was developed.” 

Although we certainly do get durable responses with front-line treatment with purine nucleoside analogs and CD20 monoclonal antibodies, there is this unmet need for patients with relapsed or refractory hairy cell leukemia.
— Leslie Ellis, MD

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The single-arm, open-label, multicenter study evaluated moxetumomab pasudotox, a first-in-class anti-CD22 recombinant immunotoxin, in patients with relapsed or refractory hairy cell leukemia who had received at least two prior lines of therapy, including at least one purine nucleoside analog. 

Eighty patients (63 male; median age = 60 years) received the drug at 40 μg/kg intravenously on days 1, 3, and 5 of 28-day cycles, for up to 6 cycles. The median number of prior systemic therapies was three. The primary endpoint of the study was durable complete response, defined as complete response with hematologic remission for longer than 6 months.

“The outcome they were looking at was not just development of a complete response but of a durable complete response, which I think is important and reflects the extremely indolent nature of this disease,” she noted. 

Durable Complete Responses 

At a median follow-up of 16.7 months, the drug showed a 75% objective response rate, a 41% complete response rate, and a 30% durable complete response rate. Of the 33 patients who achieved a complete response, 73% (24/33) had a durable response and 82% (27/33) achieved negative minimal residual disease status. The median time to hematologic remission was 1 month. 

“Patients who were minimal residual disease–negative had a markedly improved duration of complete response compared to patients who were minimal residual disease–positive,” she noted. 

Only two patients lost their hematologic response and contributed to the nine-patient difference between complete response and durable complete response. According to the investigators, the other patients were not able to maintain their complete response for “logistical reasons.” 

In patients who developed stable disease or better, the investigators noticed an improvement in blood cell counts and a decrease in leukemic burden. They also noted that the hypocellularity of the bone marrow was not as severe as what is traditionally seen with nucleoside analog treatment, Dr. Ellis added. 

The median duration of overall survival and median progression-free survival were not reached, and 50% of patients are still participating in follow-up. 

Unique Adverse Events

Of the 80 patients, 50 completed 6 cycles of treatment: 15% of patients achieved a minimal residual disease–negative complete response before completing the 6 cycles, but the majority of patients who discontinued treatment did so because of an adverse event. 

The most frequent treatment-related adverse events were nausea (28%), peripheral edema (26%), headache (21%), and pyrexia (20%); 8% had infections, and 3% had neutropenia that was deemed to be treatment-related. Three patient deaths occurred, none of which were determined to be treatment-related. 

NOVEL AGENT IN HAIRY CELL LEUKEMIA

  • Moxetumomab pasudotox led to a 75% objective response rate, a 41% complete response rate, and a 30% durable complete response rate in a group of heavily pretreated patients with hairy cell leukemia. 
  • The trial met its primary endpoint of durable complete response. 
  • Of patients who achieved complete response, the vast majority had no remaining evidence of detectable cancer cells. 
  • The drug had a tolerable safety profile, with a caveat of two unique but manageable adverse events: hemolytic uremic syndrome and capillary leak syndrome.

Treatment-related adverse events leading to treatment discontinuation (grade 3/4) were hemolytic uremic syndrome in 4 patients and capillary leak syndrome in 2 patients, though 10 patients developed any-grade hemolytic uremic syndrome and/or capillary leak syndrome, including 4 patients who had both. Both of these adverse events were manageable and reversible. 

Although the investigators were unsure as to the exact mechanism causing these specific adverse events, they did note that patients who were better hydrated either prior to or on the days they received the drug appeared to have a lower incidence of either syndrome. 

According to Dr. Ellis, future directions will include consideration of moving this drug into the front-line setting.

On September 13, 2018, the U.S. Food and Drug Administration approved moxetumomab pasudotox-tdfk (Lumoxiti) injection for intravenous use in the treatment of adult patients with relapsed or refractory hairy cell leukemia who have received at least two prior systemic therapies, including a purine analog. ■

DISCLOSURE: Dr. Ellis has received honoraria from, is a consultant/advisor and on the speakers bureau for, and has received travel/accommodation or other expenses from Alexion Pharmaceuticals; and has received travel/accommodation or other expenses from the American Society of Hematology. 

REFERENCES 

1. Kreitman RJ, Dearden C, Zinzani PL, et al: Moxetumomab pasudotox in heavily pretreated patients with relapsed/refractory hairy cell leukemia: Results of a pivotal international study. 2018 ASCO Annual Meeting. Abstract 7010. Presented June 2, 2018.

2. Ellis LR: Hematologic malignancies—Leukemia. 2018 Best of ASCO Chicago. Presented August 10, 2018.


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