Expert Highlights Potential of Moxetumomab Pasudotox in Hairy Cell Leukemia

Robert J. Kreitman, MD

Moxetumomab pasudotox, a recombinant immunotoxin that targets CD22, demonstrated significant clinical activity in patients with relapsed/refractory hairy cell leukemia, according to findings from an international phase III trial presented at the 2018 ASCO Annual Meeting.

In the single-arm, multicenter, open-label trial (NCT01829711), moxetumomab pasudotox, induced a complete remission (CR) rate of 41% and a rate of CR with no minimal residual disease (MRD) of 34% among 80 patients with relapsed/refractory hairy cell leukemia.

The trial defined CR as hematologic remission for at least 4 weeks, clearing of hairy cells in the bone marrow by hematoxylin and eosin stain, and resolution of hepatomegaly and lymphadenopathy by imaging. Patients received 40 μg/kg of moxetumomab pasudotox intravenously on days 1, 3, and 5 of 28-day cycles. Disease response and MRD status were tracked by blinded independent central review.

Hairy cell leukemia is a rare B-cell malignancy distinguished by high CD22 expression. When moxetumomab, fused with a p38 toxin, binds to CD22 and internalizes, it inhibits protein synthesis and leads to cell death, explained lead author, Robert J. Kreitman, MD.

Based on findings from this trial, the FDA granted a priority review designation to moxetumomab pasudotox in April 2018 for the treatment of adult patients with hairy cell leukemia who have received at least 2 prior lines of therapy. The FDA is scheduled under the Prescription Drug User Fee Act to make a decision on the moxetumomab pasudotox application by the end of the third quarter of this year.

OncLive: Can you provide background on the hairy cell leukemia study presented at the 2018 ASCO Annual Meeting?

In an interview with OncLive^®, Kreitman, chief, Clinical Immunotherapy Section, Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, discussed the potential of moxetumomab pasudotox as a treatment for patients with hairy cell leukemia.Kreitman: The study that we did was a nonrandomized, single-arm trial of moxetumomab pasudotox. This is a recombinant protein made out of a fragment of an antibody that is genetically fused to a toxin called p38. It is a derivative of pseudomonas exotoxin. It is very powerful after it binds to cells; it internalizes and it gets into the cytosol. Once in the cytosol, it is believed that one molecule is sufficient to kill a cell. It does this catalytically by inhibiting protein synthesis.

With these findings, what will some of the next steps be for hairy cell leukemia treatment?

We previously found that we had activity in a phase I trial that we did at the National Institute of Health and a few other centers. Therefore, this phase III trial was done in 32 centers, in 14 countries, and there was a total of 80 patients who were treated with moxetumomab pasudotox. We would give patients as many as 6 cycles of the treatment and the cycles were 28 days apart. You could receive a lower number of cycles if you had a CR, which was negative for MRD. Our goal of the study was to achieve CR.We believe that this drug is potentially a new agent for patients with hairy cell leukemia. This is a first step. The future steps will be to consider whether this could be used for earlier-line treatment—for example, for frontline treatment.

What is the prognosis for patients with hairy cell leukemia?

There are 1200 new cases of hairy cell leukemia in the United States alone per year, so these patients are essentially all getting chemotherapy upfront. Some might be getting rituximab (Rituxan) with chemotherapy, but most of them are just getting chemotherapy. However, chemotherapy has side effects that moxetumomab pasudotox does not have. This is an avenue for future development, but it is not something that is ready right now.In the very beginning, back in the early 1970s, the life span of a patient with hairy cell leukemia averaged about 4 years after diagnosis. Therefore, we know that without effective treatment, a patient can last for about 4 years. This is not very good. With good treatment, we find that patients relapse to the point where their blood counts become low. This happens over a median period of about 15 years, so it is a long time.

What are some of the biggest challenges right now for hairy cell leukemia treatment?

Is there anything else you would like to add?

The efficacy is lower, and the toxicity levels are higher for chemotherapy the second time around. That is when nonchemotherapy treatment options come into play. Rituximab can be used, as well as BRAF inhibitors. The landscape has changed for patients with hairy cell leukemia. They can live a lot longer, but being able to get a treatment that puts them into CR is not something that these patients have a known option for right now.The biggest challenges, perhaps even in the patients who get moxetumomab pasudotox, are that some patients cannot get good responses because they make antibodies to the toxin. In this trial, we found that there is a trend of slower immunogenicity—meaning slower increase in antibody levels in those patients who got CR or partial response compared with those who did not respond. It is possible that antibodies against the toxin will be a problem.While they are not very common, the doctor treating these patients needs to be aware of the side effects. They can be prevented with good oral hydration and methods that are not really applicable to chemotherapy and preventing toxicity there.

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. J Clin Oncol. 2018;36 (suppl; abstr 7004).