Use of Post-Induction Treatment in Mantle Cell Lymphoma (MCL) in Spain. Do All Young Fit Patients Need Autologous Stem Cell Transplantation (ASCT) in the Era of High-Dose Ara-C (HiDAC) and Rituximab Maintenance?

INTRODUCTION:

Consolidation with ASCT after induction immunochemotherapy (ICT) is the standard strategy in MCL to prolong progression-free survival (PFS) in young fit eligible patients since 2005. HiDAC-based ICT further improved these results and, years later, Rituximab Maintenance (RM) prolongued PFS and overall survival (OS) not only in young patients responding to HiDAC+ASCT but also in those older or non-eligible for such intensive approach, challenging the current role of ASCT consolidation in the era of HiDAC and Rituximab Maintenance.

We described the post-induction management of patients with MCL in Spain and its impact on their survival, with special focus on the results of SCT and RM.

PATIENTS AND METHODS:

We retrospectively analyzed the clinical-biologic data, post-induction management and their impact on PFS and OS in the GELTAMO-MCL-2022 study, excluding indolent cases treated or not after observation. Post-induction treatment (PIT) was individually indicated as per clinical practice and physicians’ criteria and included autologous (ASCT) or allogeneic stem cell transplant (allo-SCT) and/or Maintenance with rituximab (RM) alone or with other agent. ICT regimens were grouped as HiDAC (HD-AraC-based) or non-HiDAC. Kaplan-Meier was used to analyze survival and the COX model for HR (CI95%) and p value of factors associated with PFS and OS.

RESULTS:

Out of 1105 patients diagnosed from 2000-2023 in 32 Spanish centers in the GELTAMO-MCL-2022 study, 757 were in Complete or Partial Response (CR, PC) after upfront ICT and were eligible for PIT and for this analysis: 241 (32%) received RM, 150 (20%) SCT, 127 (17%) sequential SCT-RM and 239 (31.6%) received none.

In the total 277 patients receiving SCT (only 6 allo-SCT), ICT was HiDAC in 85% and non-HiDAC in 15% and age was ≤65yrs in 65% vs. >65 in 10%. In 368 RM (23(6%) +BTKi or lenalidomide), ICT was HiDAC in 45% vs. 55% non-HiDAC, age was ≤65 in 47% vs. 50.6% >65 yrs, median time on RM= 24m(2-160).

SCT patients (vs. non-SCT) were younger (M age 57yr [29-78]) vs. 71 yr [34-91]), more frequently men (78% vs. 29%), had died of infection (11% vs. 4%) and toxicity (28% vs. 21%) rather than progression (44% vs. 50%), had lower MIPI (LR-MIPI 39% vs. 23%), showed higher CRR after ICT (90% vs. 81%) and more L-POD (84% vs. 68%).

With mFU= 89 m, mPFS in SCT vs. Non-SCT patients was 73m vs. 45m (HR=0.57, p<.001) and mOS 152m vs. 86m (HR= 0.61, p<.001). However, when analizing survival by PIT groups, SCT showed no benefit on mPFS over RM (HR=0.98, p=.09) and only ASCT-MR had mPFS and mOS advantage (HR=0.37, p<.001 and HR=0.46, p=.002), while receiving no PIT reduced only mPFS (HR=1.62 p<.001). In multivariate analysis, age at diagnosis, morphologic variant and Ki67 were independently associated with shorter PFS and OS (MIPI also with OS) and both RM and SCT consolidation were associated with longer PFS, but only RM retained its independent impact on OS.

We explored the effect of PIT on PFS/OS in specific subgroups: age, type of ICT, CR vs. PR to 1L, Ki67, TP53 and morphology. When analyzing SCT vs. non-SCT, only patients in CR, classic MCL and Ki67≥30% showed PFS and OS advantage with SCT while no survival advantage was observed in TP53 mutated MCL or according to age (>65 or ≤65). When analyzing the different PIT modalities taking RM alone as reference, SCT alone only showed OS benefit in CR after ICT, while ASCT+RM showed better PFS and OS than RM in both classic MCL and patients in CR after ICT. No PFS or OS advantage of ASCT+RM over RM was observed in the remaining subgroups: >65 or ≤65 (even ≤65 receiving HiDAC), Ki67<30%, patients in PR after ICT and blastoid or TP53 mutated MCL.

CONCLUSIONS:

In our cohort, the highest benefit from SCT is seen in patients achieving CR after 1L, classic MCL and Ki67≥30%, with advantage of ASCT+RM vs. RM, while no survival benefit is observed in patients with blastoid or TP53 mutated MCL and older>65, where RM alone is not inferior to ASCT+RM. In PR after ICT, SCT shows only PFS benefit over no-SCT, and neither SCT or ASCT+RM showed PFS or OS advantage vs. RM.

Regarding HiDAC or non-HiDAC, ASCT+MR showed only longer PFS vs. RM, but not OS. In fact, even in younger patients receiving HiDAC, neither SCT nor ASCT+RM were associated with better PFS or OS vs. RM.

These retrospective data should be taken cautiously, but they might suggest that some of the patients currently eligible for intensive treatment might benefit from the omission of ASCT in the era of rituximab maintenance.