Not all younger patients with mantle cell lymphoma (MCL) are ideal candidates for conventional high-intensity upfront treatment, according to a recent review published in Best Practice & Research Clinical Haematology.

Use of high-dose cytarabine plus rituximab as frontline treatment is well established, with median overall survival now exceeding 10 years, said Rory McCulloch, MD, and Simon Rule, MD, of the department of Haematology, Derriford Hospital, Plymouth, England. However, there is no proven benefit to conventional therapy in patients with asymptomatic, non-bulky disease, making a watch-and-wait strategy appropriate for these patients, the authors said.

On the opposite end of the spectrum there is a subgroup of patients characterized by TP53 mutations and poor prognostic index scores that have poor outcomes in spite of conventional therapy.

These patients might have improved outcomes either with early allogeneic haematopoietic cell transplantation (allo-HCT), or, especially, clinical trials of novel agents in the upfront setting, the authors noted.

“There are a host of exciting novel agents, most prominently the BTK inhibitors, that are game changing with respect to their activity,” wrote Dr. McCulloch and Dr. Rule. “Based on the long-term results seen with conventional therapy, it is premature to be considering such new drugs in the frontline setting outside the context of a clinical trial, but it is hard to believe they will not become incorporated into treatment protocols in the future.”

Watch-and-wait treatment strategies for lower-risk patients are supported by the results of two single-center, retrospective studies published in 2009 that suggest the practice has no adverse impact on overall survival. More recent registry studies, published in 2016 and 2017, have shown that a significant proportion of patients can be managed according to the watch-and-wait strategy.

Although it’s been challenging to precisely define the group of patients for whom watch-and-wait is appropriate, enrollment criteria for studies have generally specified that patients be asymptomatic with non-bulky disease and non-blastoid morphology, they said.

For the minority of patients presenting with high-risk disease, allo-HCT may improve outcomes, according to Dr. McCulloch and Dr. Rule. One prospective study evaluating allogeneic transplants in frontline therapy showed favorable outcomes in younger patients, although few high-risk patients were enrolled.

However, a second prospective study of allo-HCT, involving 25 patients with untreated MCL in the United Kingdom, demonstrated a 2-year overall survival of 80%. “Although immature, the results are encouraging and provide data to support frontline allogeneic transplant for some patients,” Dr. McCulloch and Dr. Rule said in a comment on that study.

Novel agent studies have produced mixed results in treatment settings relevant to younger, high-risk MCL patients, though key trials are ongoing that could change practice.

One phase 2 study is evaluating obinituzumab, the fully humanized anti-CD20, as part of MCL induction and maintenance. Results of that study could challenge the role of rituximab in maintenance, the review authors noted. Likewise, the immune modulator lenalidomide has been evaluated as maintenance in an Italian phase 3 trial that recently closed to recruitment.

BTK inhibitors represent a “step change” in the management of MCL, according to the authors of this review.

“It has become clear that earlier use of ibrutinib leads to an improved outcome [in MCL] and it is logical to extend this into frontline treatment,” they wrote.

A randomized phase 3, multinational trial known as TRIANGLE, now open to recruitment, is designed to evaluate use of ibrutinib in both induction and maintenance. Investigators plan to enroll 870 patients into the three-arm study, which will also evaluate the use of ibrutinib as part of induction, but with no autologous stem cell transplant.

“The trial is the first to randomize to a non-ASCT arm since the introduction of rituximab and cytarabine to the induction regimen and the results have the potential to significantly reduce chemotherapy intensity and toxicity,” the authors said.

Dr. Rule reported consulting for Pharmacyclics, Napp, Sunesis, Acerta Pharma, Kite, AstraZeneca, Roche, Janssen, and Celgene, and research funding from Janssen, Celgene, and GSK. Dr. McCulloch reported having no financial disclosures.

SOURCE: McCulloch R et al. Best Pract Res Clin Haematol. 2018 Mar;31(1):90-8.

In young MCL patients, optimal treatment may vary