The phase 2 IMCL-2015 clinical trial aimed to propose a front-line tailored treatment for indolent clinical forms of mantle cell lymphoma (MCL). Investigators evaluated a chemotherapy-free regimen consisting of ibrutinib in combination with rituximab for these patients.

Eva Giné, MD, Hematology Department, Hospital Clínic of Barcelona, Spain, principal investigator of the study, spoke with Oncology Learning Network on behalf of GELTAMO group about the results of the trial and how these findings impact the future treatment and research of this disease.

What existing data led you and your co-investigators to conduct this research?

Different studies led to the recent recognition of a leukemic non-nodal variant (LNN) in MCL, which usually displays indolent behavior and is thought to have a different cell of origin arising in a germinal center experienced B-cell. However, the spectrum of indolent MCL may not be restricted just to this LNN variant—and what is more important is that we currently lack a reliable biomarker to identify cases that may deserve an individualized therapeutic approach.

This is a translational study with the aim to investigate a tailored treatment approach for indolent clinical forms of MCL to avoid an intensive treatment regimen and by using a “chemotherapy-free approach,” while also performing an extensive genomic study of these cases.

Please briefly describe your study and its findings.

We designed a phase 2 trial to evaluate the efficacy and safety of ibrutinib in combination with rituximab given upfront in patients with indolent clinical forms of MCL. The study plans to recruit up to 50 patients at 14 GELTAMO centers.

The primary end point of the study was the complete remission rate achieved at 12 months of treatment with ibrutinib plus rituximab. Lugano response criteria were applied, including central review of PET-CT. In addition, histologic review, sample collection for genomic studies, and minimal residual disease (MRD) studies were also centralized.

We gave ibrutinib at a dose of 560 mg daily for up to 2 years in cases of sustained MRD negativity, or until progression or unacceptable toxicity occurred. In addition, a total of 8 doses of rituximab were given during the first 9 months of therapy.

A total of 33 patients were evaluated for response at 12 months. The overall response rate was 83% and the complete response rate reached 77% of patients. The MRD data at 12 months was available in 31 cases, and showed that the responses were deep, with 74% of patients achieving MRD-negativity in peripheral blood and bone marrow. When restricting the results to only patients who achieved complete response, 84% were MRD-negative at 12 months with the ibrutinib plus rituximab combination.

We observed a predictable toxicity profile with this combination. In addition, preliminary results suggested that stopping ibrutinib at 24 months of sustained MRD-negativity is reasonable, because most patients maintained MRD negativity, with no clinical relapse having been observed so far.

What are the possible real-world applications of these findings in clinical practice?

The IMCL-2015 study can provide further evidence to help to identify patients with indolent clinical forms of MCL and give them an individualized therapeutic management by using a chemotherapy-free approach with a limited duration that is driven by MRD.

Genomic studies are ongoing to better characterize the indolent clinical forms of MCL included in the IMCL-2015 study, and to correlate biologic findings with quality of responses obtained and with relapses.