Timothy Fenske, MD, MS, associate professor at the Medical College of Wisconsin, discusses the utility of next-generation BTK inhibitors in mantle cell lymphoma (MCL).

Quite a few next-generation inhibitors are in development, says Fenske. Two classes of BTK inhibitors exist in MCL: covalent inhibitors and noncovalent inhibitors. Acalabrutinib (Calquence) and ibrutinib (Imbruvica) covalently bind to the BTK enzyme and when there is a mutation where the drug resides, then it cannot bind anymore; this leads to the development of resistance,explains Fenske. A new category of BTK inhibitors are noncovalent binders that still appear to block the enzyme in vitro, even when that mutation is present.

The field can envision a day, hopefully not too far down the road, when a patient with MCL who shows resistance to ibrutinib or acalabrutinib could have a BTK mutation analysis performed and that would inform which BTK inhibitor they should be switched to, concludes Fenske.

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Timothy Fenske, MD, MS, discusses the utility of next-generation BTK inhibitors in mantle cell lymphoma.

Dr. Fenske on the Utility of Next-Generation BTK Inhibitors in MCL

Timothy Fenske, MD, MS, associate professor at the Medical College of Wisconsin, discusses an ongoing study in the frontline treatment of mantle cell lymphoma (MCL).

Researchers from the Medical College of Wisconsin are participating in an ECOG-led study using a next-generation sequencing (NGS) minimal residual disease (MRD) assay that measures levels of circulating tumor DNA. The hypothesis, Fenske says, is that not all patients with MCL will benefit from an autologous stem cell transplant (ASCT) in first response.

In the study, patients are treated with physician’s choice of induction therapy, and then they are assessed by PET scan, bone marrow, and the NGS test. Only the patients in complete remission and an MRD-negative state will then be randomized to undergo either immediate ASCT followed by maintenance rituximab (Rituxan) or deferral of ASCT and just rituximab. Researchers are evaluating if being MRD-negative means patients can forego an ASCT.

Timothy Fenske, MD, MS, an associate professor at the Medical College of Wisconsin, discusses an ongoing study in the frontline treatment of mantle cell lymphoma.

Dr. Fenske Discusses Ongoing Study in Frontline MCL

Timothy Fenske, MD, MS, an associate professor at the Medical College of Wisconsin, discusses targets under investigation in mantle cell lymphoma (MCL).

The proteasome has long been a target, and bortezomib (Velcade) was one of the first novel agents to be FDA approved in MCL, Fenske says. Other proteasome inhibitors are being tested. An ECOG trial involving the Medical College of Wisconsin is studying the combination of ibrutinib and ixazomib (Ninlaro) in patients with relapsed/refractory MCL.

There are several other intriguing targets under investigation, Fenske adds. PI3K inhibitors, which have made the most headway in chronic lymphocytic leukemia, have been of interest in MCL. Although there has been some activity with these inhibitors in this space, no dramatic single-agent activity has been observed. None of these agents have an FDA approval in MCL, but combination approaches with PI3K inhibitors might serve as a more effective strategy.

Timothy Fenske, MD, MS, an associate professor at the Medical College of Wisconsin, discusses targets under evaluation in mantle cell lymphoma.

Dr. Fenske Discusses Targets Under Evaluation in MCL

Timothy Fenske, MD, MS, associate professor, Medical College of Wisconsin, discusses the future of daratumumab (Darzalex) in mantle cell lymphoma (MCL).

Daratumumab has not shown as much promise in lymphoma as it has in other malignancies, explains Fenske. In T-cell lymphomas, some anecdotal activity has been observed with daratumumab. In most B-cell lymphomas, however, there hasn't been a lot of activity seen with this agent, even though some of these lymphomas express CD38. It is unclear why daratumumab has shown greater success in plasma cell disorders rather than in B-cell malignancies, says Fenske.

In MCL, patients tend to have a high proportion of genomic instability, chromosome complex karyotypes, 

 mutations, and other factors that promote drug resistance. However, over the years, there has been an undoubtable improvement in survival in MCL with slow but sure successes, more so in the frontline setting than anywhere else, adds Fenske.

With some of the more aggressive induction strategies, physicians are seeing 8- to 10-year first remissions. Once a patient relapses, the disease becomes increasingly difficult to manage, after which remissions range from 1- to 2-years. Notably, long-term follow-up with acalabrutinib (Calquence) has shown remissions in the range of 2 years, further attesting to the slow but sure progress in the paradigm, concludes Fenske.

Dr. Fenske on the Future of Daratumumab in MCL

Timothy Fenske, MD, MS, an associate professor at the Medical College of Wisconsin, discusses his recommendations for oncologists treating patients with mantle cell lymphoma (MCL) who are progressing on ibrutinib (Imbruvica).

If patients appear to be progressing on ibrutinib, it is necessary to establish whether they are truly progressing on the BTK inhibitor or whether they are intolerant to the medication, says Fenske.

Sometimes, the drug will be stopped due to adverse events. For example, if a patient is experiencing atrial fibrillation, renal insufficiency, diarrhea, rash, or some of the more musculoskeletal complaints to ibrutinib, but they are still responding to it, then a switch to the other FDA-approved BTK inhibitor acalabrutinib (Calquence) should be considered.

However, if the patient’s lymphoma is progressing even though they’ve been compliant, there is no evidence to suggest that acalabrutinib would be effective in that setting, explains Fenske. Some of the data regarding newer-generation BTK inhibitors may have the potential to overcome resistance. For now, off-protocol, the recommended approach is to switch to a different class of drug, such as lenalidomide (Revlimid), or a proteasome inhibitor. Otherwise, patients may be able to receive venetoclax (Venclexta) off-label or enroll in a clinical trial, concludes Fenske.

Timothy Fenske, MD, MS

Articles

Dr. Fenske on the Utility of Next-Generation BTK Inhibitors in MCL

Dr. Fenske Discusses Ongoing Study in Frontline MCL

Dr. Fenske Discusses Targets Under Evaluation in MCL

Dr. Fenske on the Future of Daratumumab in MCL

Dr. Fenske Discusses Disease Progression on Ibrutinib in MCL