Rituximab Maintenance Failure in Mantle Cell Lymphoma Is Associated with High Risk of Death: Analysis of the Czech Lymphoma Study Group (CLSG)

Background: Mantle cell lymphoma (MCL) is an incurable B-cell malignancy comprising 5-10% of all non-Hodgkin lymphomas. Induction strategy is based on an intensive immunochemotherapy (Ara-C containing regimens) with autologous stem cell transplant (ASCT) consolidation in younger or on R-CHOP / R-Bendamustine in the elderly patients. The response rate to the induction therapy is high but majority of the patients relapse and their outcome remains unsatisfactory. Indeed, there is a need to control and/or eradicate residual lymphoma population. Several maintenance strategies using bortezomib, ibrutinib, lenalidomide or rituximab have been evaluated. Maintenance with rituximab (RM) was found to improve survival in patients treated both inside the clinical trials after intensive induction (LeGouill; ASH 2016 #145) or R-CHOP (Kluin-Nelemans et al., NEJM 2012) and also in a population-based setting (Obr et al., Klener et al. ICML 2017, #209, #210). Predictors of the RM failure remains unclear.

Aim: (1)To describe an outcome of MCL patients who were treated with RM, (2) to identify predictors of the RM therapy failure

Methods: The study is part of observational NiHiL project (GovTrial No NCT03199066). Patients (pts) with therapy naïve MCL who were treated with rituximab-containing induction regimen, achieved complete (CR) a or partial response (PR) and subsequently received rituximab maintenance therapy were included. Survival was calculated both from diagnosis and from the RM application start. RM failure was defined as a progression/relapse or death within 24 months from the first maintenance dose.

We have identified 279 MCL pts with centrally reviewed diagnosis who met the inclusion criteria above and were diagnosed since DEC-2002 for JUN-2015. Median age at diagnosis was 66 (range 40-87) years; male-to-female ratio 2:1. Ann Arbor clinical stages (I-II) were observed in 5.7% and advanced (III-IV) in 84.3% of the patients. MIPI score was: low in 22.2%, intermediate in 34.1% and high in 43.7% patients, respectively. Induction immuno-chemotherapy consisted of R-CHOP or R-CHOP like regimen in 149 (53.4%), intensive chemotherapy with high cytarabine (Nordic protocol, Hyper-CVAD) in 89 (31.9%) and non-anthracycline regimen (fludarabine, bendamustine-based) in 41 (13.7%) of the patients, respectively. ASCT with BEAM conditioning was applied in 92 (33.0%) of the cases. Median time from the post-induction response assessment to RM delivery was 71 days (2.3 months). Median number of RM doses given was 8, median time span of the RM therapy was 20.5 months.

Results: Treatment response was known in all patients: 203 (72.8%) pts achieved CR/CRu and 76 (27.2%) of the pts PR. After median follow up of 3.8 years 87 (31.2%) pts relapsed or progressed and 56 (20.1%) of the pts died. Five-year overall survival (5-y OS) was 75% (95% CI 0.69-0.81) and five-year progression-free survival (5-y PFS) reached 56% (95% CI 0.49-0.63). Fifty-eight (66.6%) of progressions/relapses and 23 (41.1%) deaths have occurred within first 24 months after RM therapy initiation. Two-year PFS calculated from the RM start (2-y RM-PFS) was 71.6% and a 2-y RM-OS achieved 88.0%. Patients who relapsed/progressed on RM experienced significantly inferior OS: 2-y RM-OS 70.3% vs 91.7%, (p<0.001, HR=15.0) [Fig. 1].

Selected laboratory and clinical variables were analyzed, and following predictors were significantly associated with a RM failure: elevated beta-2-microglobuline (p=0.003), systemic symptoms (p=0.0024), ECOG>0 (p=0.0033), age (p=0.014) and MIPI (p<0.001). Patients who failed to achieve CR1 have had two-fold higher risk of RM failure (HR = 2.23, p<0.001). ASCT application lowers RM failure risk by 69% (HR=0.31, p<0.001). Multivariate logistic regression identified a MIPI index along with a beta-2-microglobulin level to be independent predictors of RM failure.

Conclusions: Rituximab maintenance failure in MCL patients is extremely unfavorable event associated with high risk of death. On the other hand, pts without relapse or progression on RM therapy have very good prognosis with 91.7% probability to be alive at 2 years. In patients who are at risk of RM failure, an alternative maintenance strategy should be considered.

Acknowledgment: Supported by IGA_LF_2017_007 and the Czech Ministry of Health AZV 16-31092A grants.

Figure 1

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Figure 1

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