Robert J. Kreitman, MD, discusses the role of minimal residual disease (MRD) status in hairy cell leukemia, how to effectively test for MRD, and how the combination of moxetumomab pasudotox and rituximab could alter the treatment landscape.
Robert J. Kreitman, MD
Following the September 2018 FDA approval of moxetumomab pasudotox-tdfk (Lumoxiti) in the hairy cell leukemia (HCL) paradigm, an ongoing trial combining the CD22-directed recombinant immunotoxin with rituximab (Rituxan) shows early promise, said Robert J. Kreitman, MD.
Additionally, it is providing insight to the role of minimal residual disease (MRD) in relapsed disease, he added.
“In at least a fraction of patients, MRD does cause relapse,” said Kreitman, chief of Clinical Immunotherapy Section in the Laboratory of Molecular Biology at the National Cancer Institute. “If we can prevent that either upfront or in the multiple-relapse setting, it would be a real step forward in treating HCL.”
The approval of moxetumomab pasudotox was specifically in patients with HCL who have previously received ≥2 lines of standard treatments, based on findings from a single-arm, open-label study that included 80 patients with HCL. Data showed that the agent elicited a durable complete response (CR) rate of 30% (95% CI, 20.3-41.3), and an objective response rate of 75%.
“We are going to need to see [these data mature] over many years,” explained Kreitman. “What are the long-term effects of being MRD-free? This is controversial in HCL. Some feel you don't need to be MRD-free. Patients with relapsed/refractory HCL have progressed after treatment and I believe this happened from MRD.”
In an interview with OncLive during the 2019 Hairy Cell Leukemia Foundation Annual Conference, Kreitman discussed the role of MRD status in HCL, how to effectively test for MRD, and how the combination of moxetumomab pasudotox and rituximab could alter the treatment landscape.
OncLive: Could you discuss the early data looking at the combination of moxetumomab pasudotox and rituximab in this space?
Kreitman: The moxetumomab pasudotox data combined phase I and phase III data looking at MRD. We found that if you can get rid of MRD, you can have a longer CR duration. We looked at the different tests of MRD, including immunohistochemistry, bone marrow aspirate flow cytometry, and blood flow cytometry. We found that the most sensitive is the bone marrow aspirate flow cytometry. That test can discriminate between patients who have a long CR duration and those who have a shorter CR duration. If you do not achieve MRD-negative disease, you have a shorter CR duration.
However, bone marrow biopsy is difficult to do often. It would be nice to determine MRD status with each cycle of moxetumomab pasudotox, but blood flow cytometry is not quite as sensitive. For example, of the 41 CRs we assessed using blood flow cytometry, only one was blood flow—positive. It doesn't discriminate patients who would have a longer or shorter CR duration.
High-sensitivity polymerase chain reaction (PCR) tests are more sensitive than blood-flow cytometry. We would like to use this test to determine how many cycles of moxetumomab pasudotox to administer.
Currently, we have a clinical trial at the National Institute of Health combining moxetumomab pasudotox with rituximab; perhaps this will lead to a more rapid CR duration. We would like to measure MRD with each cycle and determine when the appropriate time to stop is.
What makes PCR unique in determining MRD status?
We use a PCR assay that amplifies the immunoglobulin rearrangement, which is specific for each patient with HCL. It does not pick up normal B-cell immunoglobulin rearrangement. We published that it can detect 1 hairy cell out of 1 million normal cells. It is not quite as sensitive as bone marrow aspirate or quantitative PCR; however, it can be done at multiple time points because it is blood.
What types of patients appear to have a longer CR duration?
Patients who achieve MRD-negative disease have a longer CR duration, which could mean their bone marrow aspirate flow cytometry becomes negative or their blood or marrow PCR becomes negative. The blood flow cytometry becomes negative in almost all CRs, but it is not very helpful in determining which CR will last longer.
How does moxetumomab pasudotox best fit in the treatment landscape?
We know from the phase I and phase III trials that moxetumomab pasudotox by itself is highly effective in not only achieving CR, but eliminating MRD; additionally, CR eradication correlates with longer CR duration.
This is the only [available] non-chemotherapy drug associated with a fairly high elimination of MRD. It works out well for patients who want a break from chemotherapy, and it spares the T cells that chemotherapy kills.
What toxicities are associated with this agent?
It has a different toxicity from chemotherapy in terms of [systemic] capillary leak syndrome. Moxetumomab pasudotox goes through the blood vessels to get into the area surrounding the blood vessels where hairy cells often live. We hope that does happen; otherwise, the hairy cells outside the blood vessels will not be killed.
However, it does make the blood vessels leaky. As such, we have to make sure patients drink plenty of water otherwise kidney issues and dehydration can occur. We find that drinking water is a lot safer and easier than giving intravenous fluid as it is more adaptable to outpatient treatment.
Liver function abnormalities with alanine transaminase and aspartate aminotransferase can go up, but we don’t find that it correlates [beyond] low-level liver toxicity. Increased creatinine and decreased platelets can result as well, but we don’t see [the toxicities we see from] chemotherapy toxicities.
Mild headache, low-grade fever, and nausea can occur 6 to 12 hours after each of the 3 doses of moxetumomab pasudotox. This is not a severe toxicity, but it may [prevent patients from drinking water]. Giving a 4-mg oral dose of dexamethasone [appears to] knock out this toxicity quickly.
What else is important to note about moxetumomab pasudotox?
One problem that a minority of patients have is that [their immune system] recognizes the drug as foreign and makes antibodies. The drug is based on a bacteria toxin from pseudomonas.
In order to prevent that, and to potentate the efficacy of moxetumomab pasudotox, we are combining it with rituximab, which will hopefully increase the kill of the hairy cells and prevent antibody [production]. In turn, this may increase the rate of patients with MRD-negative disease.
We have patients who still have MRD-negative disease more than 8.5 years after moxetumomab pasudotox. It is tempting to say that those patients have permanent elimination of MRD, but it is still too early to say.
Kreitman RJ, Dearden C, Zinzani PL, et al. Moxetumomab pasudotox in relapsed/refractory hairy cell leukemia. Nature. 2018;32:1768-1777. doi: 10.1038/s41375-018-0210-1.