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Mantle Cell Lymphoma: Evaluating the Treatment Landscape

Friday, July 28, 2017

This story first appeared in Cancer Therapy Advisor. Read the original here.

Photo of Peter Martin, M.D.Peter Martin, M.D. Mantle cell lymphoma (MCL) is a rare, biologically and clinically heterogeneous mature B cell lymphoma, representing 5 to 10 percent of non-Hodgkin lymphomas (NHLs) in the United States.

MCL is more than twice as common among men and tends to be diagnosed in late adulthood, with a median age at diagnosis of 68 years. Rates are highest among non-Hispanic Caucasian males.

Optimal treatment is “highly individualized,” according to Peter Martin, M.D., of the division of hematology and medical oncology at Weill Cornell Medicine and co-author of a recent review of the standards of care for MCL.

“The treating physician must consider patient and disease-related factors, balancing the goals of therapy with expected therapy-related toxicities,” they reported. “[I]t demands constant attention; clinicians must continually integrate new data while researchers are constantly pushed to develop new options. Fortunately, these efforts appear to be paying off with significant improvements in overall survival over the past decade.”

Despite those advances, prognosis remains poor and the goal of treatment is rarely curative, though risk stratification is used to identify patients with low-risk and aggressive disease.

Deferred treatment is sometimes an option for newly diagnosed, asymptomatic patients with low-risk disease. Approximately 1 in 4 patients with MCL has indolent disease at diagnosis, for which active surveillance is the preferred approach.

Once a patient becomes symptomatic, develops cytopenias, or develops symptomatic, rapidly-growing lymphadenopathy, or splenomegaly, systemic treatment is initiated.

Most newly diagnosed patients have more aggressive MCL and must undergo induction therapy. Comorbidities and patient preference preclude intensive therapy for approximately 75 percent of newly diagnosed patients with MCL.

Intensive induction regimens that include high-dose cytarabine are considered for more fit and younger patients in the hope of achieving durable remission, according to Dr. Martin and his co-authors.

“High-dose cytarabine has a proven benefit as part of induction therapy in younger, fitter patients,” they noted. “Interestingly, high-dose cytarabine alone does not appear to be sufficient therapy for newly diagnosed MCL, which led to the early closure of the Nordic Lymphoma Group MCL-5 study.”

Compared with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) alone, R-CHOP administered in alternating cycles with a high-dose cytarabine regimen (rituximab, dexamethasone, high-dose cytarabine, and cisplatin [R-DHAP]) followed by autologous stem cell transplantation (ASCT) yielded higher complete-response rates (55% vs 39%; = 0.0005) and no-minimal residual disease rates (79% vs 47%; = 0.0001) in a phase 3 clinical trial — and a time-to-treatment-failure (TTF) of 9.1 years vs 4 years for R-CHOP alone.

For patients who are not candidates for intensive induction therapy, there are several alternative immunochemotherapy regimens.

Bendamustine plus rituximab (BR) appears to also be non-inferior to R-CHOP, and possibly better tolerated.1,7 Replacing vincristine with bortezomib in R-CHOP (VR-CAP) was associated with a longer PFS but greater hematologic toxicity than R-CHOP (PFS: 24 vs 14 months; < 0.001).1,8

“Several recent and ongoing trials are building on the BR backbone, so hopefully we will have more options in the near future,” Dr. Martin said.

Younger and fitter patients may be eligible for high-dose consolidation chemotherapy and ASCT. Based on data from a single phase 3 trial, it is “reasonable to consider ASCT as a standard of care for younger, fitter patients,” Dr. Martin's team reported.

“It should be noted, however, that these data were generated prior to the widespread use of rituximab and incorporation of high-dose cytarabine into induction regimes,” Dr. Martin told Cancer Therapy Advisor.

Post-consolidation maintenance therapy is administered with the goal of delaying MCL relapse among patients who have achieved remission. Rituximab is the “only standard of care maintenance drug” for MCL.

The emerging roles for the angiogenesis inhibitor, lenalidomide, and the irreversible Bruton's tyrosine kinase inhibitor, ibrutinib, in maintenance therapy are not yet clear, Dr Martin told Cancer Therapy Advisor.

“In all honesty, I'm not sure what to expect,” Dr Martin said. “Both drugs are active in MCL but neither has resulted in improved overall survival in phase 3 trials in the relapsed/refractory setting. Maybe they will get there in the maintenance setting but I admit I'm a little skeptical.

“I think it's easy enough to predict that both drugs can improve PFS [progression-free survival] and both drugs are associated with side effects. Whether the PFS benefit is sufficient to warrant the side effects is the big question.”

Dr Martin is studying whether treatment-pause “drug holidays” reduce toxicity rates and improve patients' quality of life — though it's too soon for clinicians to consider this practice an option for patients with MCL.

“At Weill Cornell we are in the process of exploring this concept. I think it has to be done carefully.”

Relapsed/Refractory MCL

Eventual relapse is inevitable and universal among patients with MCL, necessitating second- and third-line therapies. Ibrutinib exhibits a high overall response rate (68%) in and is considered a standard of care for previously treated patients.

Bendamustine, usually in combination with rituximab is “the first choice of chemotherapy-based second-line therapy in patients that did not receive bendamustine previously,” according to Dr Martin and colleagues.

“There are 3 drugs approved by the FDA (bortezomib, ibrutinib, and lenalidomide) and multiple other chemotherapy regimens that have demonstrated activity and safety in this setting,” Dr Martin told Cancer Therapy Advisor.

“As many options as there are, there are infinitely more scenarios defined by human diversity and tumor biology. Our job is to consider all of the options and propose those that make the most sense. I always look at all of the options and almost always I find myself believing that the clinical trial is the standard of care.”

Innovations involving chimeric antigen receptor (CAR)-T cell therapy might improve remission rates and are undergoing research in relapsed/refractory MCL.

Adding Ki67 to the MIPI improved its prognostic power, though other prognostic and treatment-predictive biomarkers are in development.

“Ki67 significantly improves the prognostic ability of the MIPI, which is great,” Dr Martin said. “My impression is that assays of proliferation generally fall into the ‘prognostic' category. Right now, I think that TP53 mutational analysis probably does as well.”

Dr. Martin also expects the development of biomarkers that predict outcomes for different treatments.

“I think that the new generation of studies with targeted molecules will help us to better understand this relationship,” he noted. “For example, TP53 mutation analysis may be very predictive of poor outcome with chemotherapy but not with certain small molecules.”

“Given the multitude of promising drugs being evaluated in MCL, we should expect to see new potential biomarkers described this year,” Dr. Martin said. “But the process of evaluating the functional implications of those biomarkers, validating them in larger studies, and trying to overcome them with alternate therapies is where we need to move faster.”

There are multiple approaches to evaluating MRD in research settings, each with its own advantages and disadvantages.

“I'm sure new options will pop up in the future,” Dr. Martin said. “I'm more interested in how this kind of assay could be moved into the clinic in a way that would actually benefit patients, not just predict outcome.”