Rituximab maintenance significantly prolongs progression‐free survival of patients with newly diagnosed mantle cell lymphoma treated with the Nordic MCL2 protocol and autologous stem cell transplantation
Authors: Pavel Klener, David Salek, Robert Pytlik, Heidi Mocikova, Kristina Forsterova, Petra Blahovcova, Vit Campr, Vit Prochazka, Ales Obr, Radek Jaksa, Jana Kuntscherova, Ludmila Boudová, Roman Kodet, Andrea Janikova, Marek Trneny
Journal: American Journal of Hematology (2018)

Mantle cell lymphoma (MCL) is still considered to be an incurable subtype of B-NHL, but the outcome is improving and the implementation of anti-CD20 rituximab and high-dose cytarabine (HDAC) into induction therapy, consolidation with high-dose therapy and autologous stem cell transplant (ASCT), and rituximab maintenance (RM) are currently considered standard approaches for all transplant-eligible patients. Recently, progression free survival (PFS) and overall survival (OS) benefit of RM were confirmed in patients (pts) with MCL treated with R-DHAP and ASCT.1 Whether RM improves outcomes in patients treated with other induction regimens is unknown. As part of the NiHiL observational study in patients with malignant lymphomas (GovTrial No. NCT03199066), we analyzed outcome of 143 consecutive patients with newly diagnosed MCL treated with the Nordic MCL2 protocol followed by ASCT and RM or observation.2, 3 The study was approved by the Ethics Committee of the Charles University General Hospital in Prague under number 1816/15S-IV. Further details are described in the Supplemental Methods. Baseline characteristics of the 143 analyzed patients are summarized in Supporting Information Table S1. Briefly, median age was 56 (26-68) with male to female ratio 1.9. Patients with high, intermediate and low risk according to MIPI comprised 20.6%, 38.3% and 41.1%, respectively. Splenomegaly ≥13 cm, and extra-nodal (extramedullary) involvement was observed in 53.2% and 49.7% pts, respectively. Flowchart of therapy delivery including reasons for no ASCT is displayed in Supporting Information Figure S1. Altogether 141 and 138 pts were evaluated during and after the induction, respectively. According to International Working Group (IWG) 1999 response criteria, 133 of the 143 analyzed patients (93%) achieved a response including 96 CRs (67.1%) and 37 PRs (25.9%). Three pts (2.1%) had stable disease according to the interim restaging and were treated with salvage therapy. Two of these three pts were allotransplanted, while the third died due to lymphoma progression. No progressive disease (PD) was observed after the R-maxiCHOP/HD-AraC induction. In five pts (3.5%), restaging procedures were not implemented during or after the induction (but only after ASCT). Two pts (1.4%) died during the induction as a complication of therapy (Supporting Information Table S2). Out of 138 patients, who completed the induction, 119 were transplanted. After ASCT, 110 pts (92.4%) achieved response including 97 CRs (81.5%) and 13 PRs (10.9%). Five patients (4.2%) had PD, and one patient (0.8%) was not evaluated. Two pts (1.7%) died from complications associated with ASCT (Supporting Information Table S3 and Figure S2). Out of 19 pts who were not transplanted, CR was achieved 17 patients (89.5%) and PR in two patients (10.5%). From 136 pts, who completed the induction with or without ASCT, 6 pts experienced early progression within 120 days from the last therapy delivery, that is, either from the stem cell reinfusion or from the last cycle of the induction therapy (in the not transplanted pts). Out of 130 pts evaluable for maintenance, 66 pts initiated RM and 64 pts were observed only. From the 112 transplanted pts, who did not experience early progression within 120 days from the last therapy delivery, 53 started RM, while 59 were observed only. The reasons for RM (or observation) were largely logistical and depended on the center practice and RM reimbursement. Baseline characteristics of the pts assessable to RM or observation arms are shown in Supporting Information Table S4. With the median follow-up of the living pts 4.1 years, 34 deaths were observed, in 25 pts because of lymphoma progression and four patients died because of treatment-associated toxicity. Altogether 39 relapses or progressions were recorded, in 6 and 33 pts within and after 120 days from the final therapy delivery, respectively. By the day of database lock, median progression-free survival (PFS) for the whole cohort of 143 pts reached 9.8 years and median OS was not reached (Figure 1A). Five year (5-y) PFS and OS was 66.2% and 74.4%. Five-year PFS and OS in the RM arm (n = 66) compared to the observation arm (n = 64) was 82.9% vs 63.3% (P = 0.004, HR = 0.36, 95% CI = 0.21-0.74), and 83% vs 78.6% (P = 0.163, HR = 0.52, 95% CI = 0.23-1.26), respectively (Figure 1B). Five-year PFS and OS in the subcohort of the transplanted patients, who initiated RM (n = 53) compared to observation (n = 59) was 77.8% vs 67.5% (P = 0.017, HR = 0.36, 95% CI = 0.20-0.84), and 77.5% vs 78% (P = 0.505, HR = 0.7158, 95% CI = 0.28-1.86), respectively (Figure 1C). Univariate analysis of pre-treatment and post-treatment factors is displayed in Supporting Information Figure S3. Pre-treatment factors that independently correlated with shorter PFS included MIPI (high vs intermediate vs low risk, P < 0.001, hazard ratio [HR] = 2.12, 95% confidence interval [CI] = 1.36-3.3), EN involvement ≥7.5 cm (P = 0.003, HR = 2.62, 95% CI = 1.38-4.95) and splenomegaly ≥13 cm (P = 0.044, HR = 2.18, 95% CI = 1.02-4.64). Pre-treatment factors that independently correlated with shorter OS included MIPI (P = 0.028, HR = 1.79, 95% CI = 1.07-3.0) and splenomegaly (P = 0.046, HR = 2.95, 95% CI = 1.02-8.53). Post-treatment factors that independently correlated with PFS included response after ASCT (CR vs PR), P = 0.004, HR = 0.28, 95% CI = 0.12-0.67) and RM (yes vs no, P = 0.026, HR = 0.36, 95% CI = 0.14-0.88). Study by Kluin-Nelemans et al. demonstrated survival benefit of RM in elderly MCL pts.4 Another landmark trial by Le Gouill et al. demonstrated benefit of RM in pts treated with four cycles of R-DHAP and ASCT.1 Pts randomized to RM received rituximab every 2 months for 3 years (ie, for the maximum of 18 doses). The 4-year PFS in the RM vs observation arm was 83% and 64% (P < 0.001). In our study, RM given every 3 months for 2 years (ie, for the maximum of 8 doses) was associated with 64% reduction of death or progression risk. It represents a comparable prolongation of 4-year PFS compared to observation despite the fact that the percentage of low-risk MIPI patients was lower (41%) compared to the LYMA trial (61%). Four-year PFS in our study was 90.7% compared to 67.6% in the cohort of all patients assessable to RM or observation (n = 130, P = 0.004), and 89.9% compared to 69.8% in the cohort of the transplanted pts assessable to RM or observation (n = 112, P = 0.017). The data thus suggest that both induction regimens (ie, 4 cycles of R-DHAP and the Nordic MCL2 protocol) appear comparably efficacious. It must be recalled that the total dose of cytarabine in the HDAC regimen (2-3 g/m2 for the total of 4 doses) is significantly higher than in the DHAP regimen (2 g/m2 for the total of 2 doses), which might compensate for the lack of cisplatin in the Nordic MCL2 protocol. MIPI once again proved to be an excellent predictor of outcome including PFS and OS. Besides MIPI, splenomegaly also independently correlated with shorter survival. Splenomegaly was adversely prognostic for failure-free survival and OS in elderly pts treated according to the MD Anderson Cancer Center protocol.5, 6 In conclusion, Nordic MCL2 protocol followed by ASCT and RM represents a safe and very effective treatment approach for transplant-eligible MCL patients. RM reduces by 64% death or progression risk compared to observation, but we have failed to confirm OS benefit. The length and density of RM administration, as well as the precise role of ASCT in the era of RM need to be answered in future studies. This work was supported by the Ministry of Health of the Czech Republic grant AZV 17-28980A, Charles University Center of Excellence grant UNCE/MED/016, Ministry of Education, Youth and Sports Institutional Support for Long-term Development of Research Organizations PROGRES Q26/LF1, PROGRES Q28/LF1. The authors have declared no conflicts of interest. Table S1: Baseline characteristics of the analyzed patients Table S2: Intent to treat analysis of response after the induction (before ASCT) Table S3: Response after autologous stem cell transplantation Table S4 Figure S1: Study flow-chart Figure S2: Overall response rate in the transplanted patients before and after high-dose therapy and autologous stem cell transplantation Figure S3: Univariate analysis of selected pretreatment and posttreatment factors Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.