Timothy S. Fenske, MD, MS, is a medical oncologist and professor of medicine at the Froedtert & Medical College of Wisconsin.

Timothy S. Fenske, MD, MS, details the rationale of a phase 3 trial assessing rituximab with or without ASCT in mantle cell lymphoma. 

Dr Fenske on the Rationale of Assessing Rituximab With or Without ASCT in MRD-Negative MCL

“Patients [with mantle cell lymphoma (MCL)] were treated with whatever induction regimen their physician chose to use. We designed the study that way, acknowledging that there are [several] different [induction] regimens that are in use in the United States for MCL, we just required that they receive a [rituximab (Rituxan)] plus chemotherapy combination.”

Timothy S. Fenske, MD, MS, medical oncologist, professor of medicine, the Froedtert & Medical College of Wisconsin, details the rationale of the phase 3 ECOG-ACRIN EA4151 trial (NCT03267433) investigating the use of consolidative autologous stem cell transplant (ASCT) followed by rituximab or rituximab alone in patients with MCL who achieved a minimal residual disease (MRD)–negative complete remission following frontline induction therapy.

Data from the study were presented at the 

 included those with MCL who were undergoing first-line therapy and achieved CR, Fenske begins. The design of the study permitted patients to be treated with a physician’s choice induction regimen to represent different induction regimens used in the United States for MCL, he says. However, he explains that patients were required to be treated with a rituximab plus chemotherapy combination. Acceptable induction regimens included BTK inhibitors, although 7.2% of patients were treated with BTK inhibitors following the completion of induction therapy, he notes.

The primary end point of the study was overall survival (OS) between ASCT plus maintenance rituximab vs maintenance rituximab alone. At a median follow-up of 2.7 years, the futility boundary for OS was crossed for ASCT/rituximab vs rituximab alone in all patients randomly assigned (n = 375; HR, 1.11; 95% CI, 0.71-1.74) and those treated as assigned (n = 375; HR, 1.00; 95% CI, 0.58-1.74; 

 = .99) Of note, the 3-year OS rate in all randomly assigned patients was 82.1% in the ASCT/rituximab arm vs 82.7% in the rituximab monotherapy arm.

Patients were then assessed with a PET/CT scan, bone marrow biopsy, and a highly sensitive next-generation MRD assay called the clonoSEQ assay, Fenske continues. He explains that the assay is more sensitive, as it can detect 1 in 1 million lymphoma cells. Following these assessments, patients in CR with undetectable MRD were eligible for randomization, Fenske concludes.

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Timothy S. Fenske, MD, MS, details the rationale of a phase 3 trial assessing rituximab with or without ASCT in mantle cell lymphoma.

Timothy S. Fenske, MD, MS, discusses implications for data on the omission of auto-HCT in MCL after first CR and with undetectable MRD. 

Dr Fenske on the Omission of ASCT in Mantle Cell Lymphoma After First CR and uMRD

“Considering that the median age for patients with mantle cell lymphoma is somewhere in the range of 60 to 70 [years, for] a lot of these patients, ASCT is a very difficult procedure for them to get through. It has a significant amount of toxicity.”

Timothy S. Fenske, MD, MS, medical oncologist, professor of medicine, the Medical College of Wisconsin, discusses implications for the mantle cell lymphoma (MCL) treatment landscape following the readout of data regarding the omission of consolidative autologous stem cell transplant (ASCT) from the phase 3 ECOG-ACRIN EA4151 trial (NCT03267433).

, Fenske presented initial data of an analysis from ECOG-ACRIN EA4151, which investigated rituximab (Rituxan) with or without consolidative ASCT in patients with MCL in their first complete remission (CR) with undetectable minimal residual disease (uMRD).

—along with data from the phase 3 TRIANGLE trial (NCT02858258) from Europe evaluating ibrutinib (Imbruvica) plus immunochemotherapy with or without ASCT— showed that ASCT could be omitted in first-line therapy in patients with MCL who achieve uMRD, Fenske says. Data from ECOG-ACRIN EA4151s showed that at a median follow-up of 2.7 years, the futility boundary for overall survival (OS) was crossed for ASCT plus rituximab vs rituximab alone in all randomly assigned patients (n = 516; HR, 1.11; 95% CI, 0.71-1.74; P = .66) and in all patients treated as assigned (n = 375; HR, 1.00; 95% CI, 0.58-1.74; 

However, Fenske notes that offering ASCT may still be appropriate for patients who have detectable MRD after first CR, which was determined by the 3-year OS and progression-free survival rates from other arms in the ECOG-ACRIN EA4151 trial.

The findings regarding the omission of ASCT in patients with uMRD in first CR are significant, especially because patients with MCL are generally older, Fenske emphasizes, explaining that ASCT can be a difficult procedure for those in this age group because of the level of toxicity. The outcomes from the ECOG-ACRIN EA4151 and TRIANGLE trials have established that safely omitting ASCT in patients with undetectable MRD is a notable advancement, he concludes.

Timothy S. Fenske, MD, MS,

Timothy S. Fenske, MD, MS, professor of Medicine, the Medical College of Wisconsin, shares an initial report of the randomized, phase 3 ECOG-ACRIN EA4151 trial (NCT03267433), evaluating the use of autologous stem cell transplant in patients with mantle cell lymphoma with undetectable minimal residual disease following first complete remission. Fenske and colleagues shared these results in a presentation at the 

Timothy S. Fenske, MD, MS, shares outcomes from the phase 3 ECOG-ACRIN EA4151 trial of patients with mantle cell lymphoma after first MRD-negative CR.

Dr Fenske on ASCT Outcomes in MCL After First MRD-Negative CR

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.

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

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