Orlando, Florida—Study findings being presented at the 2019 ASH Annual Meeting posit that interim minimal residual disease (MRD) testing at cycle 3 can help identify high-risk patients with mantle cell lymphoma (MCL) who may benefit from alternative therapies.

“Initial therapy for MCL is effective, but most patients eventually relapse. Validated intermediate biomarkers for MCL are important to provide early assessment of treatment efficacy, prognostic information and potentially guide consolidation,” explained Mitchell Smith, MD, PhD, George Washington University Cancer Center, Washington, DC, and colleagues.

Thus, Dr Smith et al conducted the US-Canadian Intergroup trial E1411. Between May 2012 and September 2016, 373 patients with untreated MCL were randomized to receive bendamustine–rituximab induction for 6 cycles followed by rituximab for 2 years; bendamustine, bortezomib, and rituximab (BVR) followed by rituximab; bendamustine–rituximab followed by lenalidomide–rituximab; or BVR followed by lenalidomide–rituximab.

MRD was assessed after cycle 3 (I3), at the end of induction (EOI), and after 4 cycles of consolidation (C4) as a planned correlative through the use of 2 methods.

“[These methods included] a research version of clonoSEQ a next-generation sequencing (NGS) MRD assay, that leverages multiplex PCR followed by NGS to identify and track rearrangements of IgH, V-J, D-J and IgK/L loci as well as translocations in Bcl1/2-IgH, and flow cytometry (FC) (I3 and EOI only) at a central laboratory,” Dr Smith and co-investigators reported.

Although treatment outcomes by arm are blinded, the investigators are able to share the results of the MRD tests conducted by each method, as well as the associated progression free survival (PFS) rates.

Ultimately, 296 (79%) of the 373 patients consented to correlatives; 255 (86%) had baseline NGS samples, and 214 were analyzable. A further 6 patients were excluded due to protocol ineligibility, as were 20 for lack of clinical follow-up; only 7 (2.7%) patients were deemed ineligible because of an inability to identify a dominant clone necessary for MRD tracking via NGS.

At baseline (before therapy was initiated), 92% of patients were found to have a dominant clone in bone marrow or peripheral blood via NGS, with only 17 (8%) needing biopsy tissue exams. Among the 296 patients who consented to correlatives, only 240 had baseline FC data, and 9 of these patients were excluded from protocol, leaving 231 analyzable cases.

A non-MCL monoclonal B-cell lymphocytosis clone was detected via FC in a small proportion of patients.

“While NGS may have higher sensitivity, as FC sensitivity is 10-4, for this analysis we used that cutoff for both NGS and FC. Cohen’s Kappa statistic compares concordance between MRD pairs, and p-value is from exact McNemar’s test,” the researchers said.

A higher number of patients achieved early MRD-negativity with initial bendamustine–rituximab-based therapy.

Furthermore, the results of the study showed that MRD status correlated with progression-free survival (PFS). According to the investigators, they focused on MRD status at I3 (10-4 cutoff for both NGS and FC), and used a landmark analysis of 4 months on study because of the low MRD-positivity rate at EOI and C4.

At I3 mid-induction, NGS and FC revealed that the median PFS for patients with MRD-negativity was 58.9 months, whereas among those with MRD-positivity, the median PFS was 26.9 months via NGS versus 29.9 months via FC.

“Both NGS and FC were feasible to assess MRD status in this multi-center trial….NGS can be more sensitive when adequate material is available, and analysis of this subgroup is ongoing. The high MRD- rate (≥ 90%) at EOI in this BR [bendamustine–rituximab]-based trial and MRD correlation with PFS supports its use as a platform for MCL trials, although consolidation may confound PFS. Early interim MRD testing at cycle 3 identifies a high-risk population who may benefit from alternative treatment strategies,” Dr Smith and colleagues said.

“Analysis by treatment arm with longer follow-up, as well as comparison with centrally reviewed PET/CTs included in this study, will help define the most informative method(s), cutoff values, and timing for assessing degree of response in MCL,” they concluded.—Hina Porcelli

Smith M, Jegede O, Parekh S, et al. Minimal Residual Disease (MRD) Assessment in the ECOG1411 Randomized Phase 2 Trial of Front-Line Bendamustine-Rituximab (BR)-Based Induction Followed By Rituximab (R) with or without Lenalidomide (L) Consolidation for Mantle Cell Lymphoma (MCL). Presented at: the 2019 ASH Annual Meeting & Exposition; December 7-10, 2019; Orlando, FL. Abstract 751.