Prognostic impact of Mantle Cell Lymphoma frontline induction response assessments in the ECOG-ACRIN E1411 study of bendamustine-rituximab +/- bortezomib and maintenance with rituximab +/- lenalidomide

Abstract Background The prognostic utility of positron emission tomography/computer tomography (PET/CT) scan and bone marrow biopsy (BMB) as response assessments in mantle cell lymphoma (MCL) is incompletely explored. We sought to: 1) interrogate the prognostic impact of a mid-induction PET/CT scan, and 2) investigate whether end-of-induction (EOI) BMB results add prognostic significance to EOI PET/CT scan results in patients with MCL receiving frontline chemoimmunotherapy (CIT) in the context of the E1411 clinical trial. Methods Briefly, the E1411 randomized phase 2 study (NCT01415752) investigated whether addition of bortezomib to bendamustine/rituximab (BR) induction and/or addition of lenalidomide to rituximab maintenance improved progression-free-survival (PFS) in treatment-naïve MCL. Patient characteristics and results are as previously published (Smith et al., 2024). Neither addition of bortezomib to BR nor addition of lenalidomide to rituximab maintenance following BR-based induction impacted PFS. PET/CT scans, read locally, were completed at initial staging, after cycle 3, and at EOI. BMB was part of initial staging and was required at EOI for any patient with baseline BM involvement who otherwise met complete remission (CR) criteria. Response criteria were per International Working Group 2007. Survival distributions were estimated by Kaplan-Meier method. Univariable Cox proportional hazards models were used to evaluate the association between PET/CT or BMB and PFS or overall survival (OS). Results 37% (132/358) of patients who initiated induction therapy had interim PET/CT results available, with 42% (56/132) remaining PET-positive after 3 cycles of treatment. With median survival follow-up of 7.5 years (yrs), median PFS for interim PET-positive vs. negative patients was 4.9 vs. 7.4 yrs (HR 1.49; 95% CI: 0.89-2.49; p=0.13). Median OS for interim PET-positive vs. negative patients was 9.2 vs. 10.2 yrs (HR 1.40; 95% CI: 0.76-2.57; p=0.28). All patients who initiated induction therapy underwent baseline BMB, 82% of whom (293/358) had confirmed lymphoma involvement. 237/304 patients who completed 6 cycles of induction had EOI BMB results available, 96% (227/237) of which were negative for lymphoma. Rates of EOI BM involvement by PET response were as follows: 1/181 patients with CR, 6/50 with partial response (PR), 1/1 with stable disease, 0/1 with progressive disease, 2/3 with response unevaluable. Median PFS and OS of patients with CR and negative EOI BM was 6.8 yrs and 10.1 yrs, respectively (95% CI: 5.9-NR). Within patients who achieved PR and had EOI BM results available, the median PFS for EOI BM-positive vs. negative was 3.1 vs. 5.4 yrs (HR 2.38; 95% CI: 0.95-5.99; p=0.06). The median OS for EOI BM-positive vs. negative patients was 6.3 vs. 9.4 yrs (HR 2.39; 95% CI: 0.67-8.50; p=0.18). Conclusion Our results generate 3 key either conclusions or hypotheses for future studies. First, the trend to inferior PFS with PET-positive disease after 3 cycles of induction therapy provides foundation to evaluate whether patients may benefit from early adjustment of therapeutic strategy. Second, the extremely low rate of 0.6% of patients in a CR with EOI BM involvement suggests EOI BMB is not needed for patients achieving metabolic CR after frontline CIT. These results align with a recent study demonstrating baseline BMB adds little value to response assessment in follicular lymphoma, leading to recommendation for deferral in most cases (Rutherford et al., 2023). Patients with MCL could therefore similarly be spared a procedure that does not provide clear clinical utility. Third, the trend toward difference in PFS by EOI BMB status even in patients with a PR additionally identifies a group for whom escalated treatment, such as intensified maintenance treatment, may be beneficial to investigate. Limitations of our analyses include the unavailable interim PET/CT results for 63% of patients who initiated induction therapy. Additionally, none received frontline BTK inhibition. Future directions include combining minimal residual disease with interim and EOI PET/CT results. EOI BMB analyses should be performed in trials investigating frontline BTK inhibitors and particularly those without chemotherapy, to determine if a BMB is of similarly low clinical utility across treatment types. Such analyses will shed further light on the assessments with highest prognostic utility for MCL.

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