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Moxetumomab Pasudotox-Tdfk for Hairy Cell Leukemia With Robert Kreitman, MD

Robert Kreitman, MD.

Hairy cell leukemia (HCL) comprises only 2% of all leukemias and has limited treatment options. In a phase 3 trial, a team of researchers led by Robert Kreitman, MD, a medical oncologist at the National Cancer Institute, found that moxetumomab pasudotox-tdfk, a recombinant CD22-directed cytotoxin, achieved a high rate of durable response in patients with relapsed/refractory HCL. Dr. Kreitman presented the long-term follow-up results of the trial at the American Society of Hematology (ASH) Annual Meeting on Sunday, December 8th. In this interview with i3 Health, he discusses the benefits of moxetumomab pasudotox-tdfk and the strategies that community oncologists and other members of the cancer care team can employ to optimize treatment in patients with HCL.

What are some of the most challenging aspects of treating patients with relapsed/refractory HCL?

Robert Kreitman, MD: One of the greatest challenges is that remissions become shorter with each cycle of chemotherapy. At the same time, toxicity accumulates so that patients can experience increasing neuropathy, stem cell damage, and bone marrow toxicity with each course of purine nucleoside analog (PNA) therapy. This often isn't noticeable after the first course of PNA, but it becomes a bigger issue as treatment continues. Another challenge has to do with targeted therapies like BRAF inhibitors, such as dabrafenib or vemurafenib, or Bruton's tyrosine kinase (BTK) inhibitors, such as ibrutinib. It doesn't appear that BRAF inhibitors eliminate minimal residual disease upon the discontinuation of therapy, at least to a point at which patients can do well without treatment for many years. Therefore, BRAF inhibitors are not often used as chronic treatments.

I think the most difficult issue, however, centers around patients with aggressive variants—a hairy cell variant or the IGHV4-34 variant, which can look like classic hairy cell. While the hairy cell variant can be differentiated because it's missing CD25, the IGHV4-34 variant is usually BRAF wild-type but otherwise looks like classic HCL. These can be very frustrating to treat because they don't respond to PNA chemotherapy, and because they are BRAF wild-type, they don't respond to BRAF inhibitors either.

Can you comment on the significance of your findings?

Dr. Kreitman: Moxetumomab pasudotox-tdfk targets CD22, and it kills cells by a different mechanism than the therapies that target BRAF or BTK. For example, rituximab, which targets CD20, requires a cell to kill itself to undergo apoptosis. However, in the case of many patients with HCL, the cell doesn't want to commit suicide and the immune system is not strong enough to help the rituximab work. The complete remission rate for rituximab as a single agent is therefore very low. Moxetumomab pasudotox-tdfk is a little different because it has a toxin on it that provides a lot of power for the molecule to kill the cells.

Moxetumomab pasudotox-tdfk works best in multiply relapsed patients who have low blood counts, because the treatment itself doesn't decrease the blood count. It is also effective for patients who don't have a very large tumor or large lymph nodes, because lymph nodes can interfere with the ability to bind to the cells, and the treatment won't reach all of the tumor cells. In the majority of patients who are multiply relapsed, however, we believe that moxetumomab pasudotox-tdfk is a good option to try.

How does moxetumomab pasudotox-tdfk compare with other treatments for HCL?

Dr. Kreitman: Ibrutinib, dabrafenib, vemurafenib, and trametinib are oral pills, while moxetumomab pasudotox-tdfk is a protein that is only given intravenously. In that sense, it's a lot less convenient for patients, but it's also not a chronic treatment. In most cases in which complete remission is achieved, we're able to eliminate the minimal residual disease that would otherwise cause relapse. In these cases, the complete remission lasts a lot longer, with the majority of patients staying in it for a long period of time. In fact, we have not yet seen half of them relapse. Moxetumomab pasudotox-tdfk is therefore much more effective in allowing patients to go off treatment.

Do you have any words of advice for community oncologists and hematologists as they treat patients with relapsed/refractory HCL with moxetumomab pasudotox-tdfk?

Dr. Kreitman: There are certain precautions that we have found to be very useful. Moxetumomab pasudotox-tdfk makes the blood vessels leaky, which is not a bad thing because it helps the drug get out of the blood vessels, but it's important that patients maintain a good fluid intake. Patients should drink about a cup of water an hour and not go more than three hours without drinking water during their treatment. In patients who get dehydrated, we can see kidney toxicity, which is called hemolytic uremic syndrome (HUS) if it is associated with low platelets. While HUS isn't a major problem to the health of the patient, it will get worse if the patient continues to receive moxetumomab pasudotox-tdfk. It's important to prevent it, and we believe that the way to do this is by ensuring that patients drink enough water. We don't want to overflow the intravascular compartment, but we do want to prevent dehydration. Because the leak is constant during the first eight days of treatment, that's the particular time to be most aware of this.

After day eight, kidney toxicity becomes less of an issue. Because the blood vessels may still be a little leaky, patients should still drink a couple of liters of water a day, just not the six liters that are required during the first week. Some patients will also experience nausea, headache, and mild fever during treatment with moxetumomab pasudotox-tdfk. This often happens the day after beginning treatment. While these are not very serious adverse events, they can be problematic if they prevent patients from drinking water. A low dose of dexamethasone can get rid of these side effects, allowing patients to maintain their fluid intake and optimize their treatment.

Additionally, we have found that our results are best when patients receive multiple cycles of moxetumomab pasudotox-tdfk after they achieve complete remission. If it only takes two cycles to get a complete remission, we recommend that the patient receive an additional four cycles for a total of six. We believe that those extra cycles are very important in order to eliminate minimal residual disease.

About Dr. Kreitman

Robert Kreitman, MD, is a medical oncologist at the National Cancer Institute at the National Institutes of Health (NIH) in Bethesda, Maryland. He serves as the Head of the Clinical Immunotherapy Section at NIH's Laboratory of Molecular Biology. Dr. Kreitman specializes in the treatment of hairy cell leukemia, and he has been the principal investigator in numerous clinical trials exploring novel therapeutic options for this disease. His research focuses on the development of targeted therapies using recombinant immunotoxins for the treatment of HCL and other hematologic malignancies.

For More Information

Kreitman RJ, Dearden CE, Zinzani PL, et al (2019). Moxetumomab pasudotox-tdfk in heavily pretreated patients with relapsed/refractory hairy cell leukemia (HCL): long-term follow-up from the pivotal phase 3 trial. 61st American Society of Hematology Annual Meeting & Exposition. Abstract 2808.

Transcript edited for clarity. Any views expressed above are the speaker's own and do not necessarily reflect those of i3 Health. 

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