Intensified Immunochemotherapy with Autologous Stem Cell Transplantation for Mantle Cell Lymphoma - Could It Still be Considered the Standard of Care?

Background:

Therapy of younger patients (pts) with mantle cell lymphoma (MCL) has been established as the alternation of R(ituximab)-CHOP, and high-dose cytarabine (HDA) +/- platinum-based regimen, consolidation with autologous stem cell transplantation (ASCT) and rituximab maintenance (RM). The role of ASCT was questioned by the recently published TRIANGLE trial (Dreyling et al., 2024), but ASCT is still considered as standard of care for younger pts where ibrutinib in 1^st line is not available. We have decided to analyze pts treated in a single center [real-world (RW) data] to assess the long-term results of this regimen.

Method:

We retrospectively analyzed the outcome of 114 consecutive newly diagnosed transplant-eligible pts who started the therapy at the Charles University General Hospital in Prague between Jan-1 2009 and Dec-31 2022 (14 years). The treatment regimen comprised the induction (R-Maxi-CHOP + R- HDA / DHAOx [+oxaliplatin] / DHAP [+cisplatin])), 3+3 cycles, ASCT, and RM for 2-3 years. All pts received at least one cycle of induction therapy in the intent-to-treat analysis. Lugano classification was used for staging as well as response assessment.

Results:

The median age at diagnosis was 59 years (37 to 68 years). The cohort comprised 75% men and 25% women. MIPI was available in 112 pts: 42%, 32%, and 26% for low, intermediate, and high risk MIPI, resp. Proliferation index Ki-67 (≥30%) was present in 53% pts of 81 available. Stage III-IV disease comprised 96% pts - bone marrow involvement (inv.), and other extranodal inv. was present in 86% and 53% pts, resp. Central nervous system inv. was documented in 7 (6%) pts at diagnosis (leptomeningeal infiltration only), these pts received adjuvant intrathecal therapy, and 3 of them progressed or died. After the induction therapy, 48% pts reached CT-based complete remission and 84% metabolic complete remission. ASCT was performed in 92 pts (81%), 22 (20%) pts did not receive ASCT due to toxicity, therapy failure, stem cell collection failure, and patient’s decision. RM was initiated in 76 (83%) pts who underwent ASCT, and 14 (64% of 22 pts) pts that did not undergo ASCT. The main reasons RM was not initiated in 24 (21%) pts were disease progression (n=14), toxicity/infections after ASCT (n=4), the remaining 6 cases were due to pts´ or physicians´ decision, death, or unknown. Total 67% of pts completed the intended therapy with at least 1 administration of RM.

With the median follow-up of 8.8 years (alive pts), 42 (37%) pts relapsed/progressed, and 34 (30%) pts died. For the whole cohort, median PFS and OS were 9.7 years and not reached, resp (with 8-year PFS and OS 56% and 72%, resp.).

Pretreatment factors that significantly correlated with shorter PFS included high risk MIPI, TP53 deletion, male sex and diagnosis to treatment interval < 15 days. Of those, only MIPI and TP53 deletion showed independent contribution in multivariate analysis for PFS (p < 0.05 and < 0.01, resp.), only MIPI for OS (p < 0.05). Interim PET-CT positivity significantly correlated with shorter PFS but not OS. Final PET-CT positivity after induction correlated with both shorter PFS and OS. The conversion to PET-CT negativity after ASCT occurred in 57% cases. The progression of disease < 2 years was the strongest negative post-treatment prognostic factor, with median OS 2 years. There was no PFS plateau observed, with relapses occurring as late as 10 years after the induction. We have found no outcome improvement between pts treated in 2009-2012 versus 2019-2022.

Discussion:

Our RW data are comparable to the results of large prospective trials including Nordic MCL2 (Eskelund et al., 2016, median PFS 8.5 years), MCL2004-2 (NCT00209222) (Hermine et al., 2016, median PFS in R-CHOP/R-DHAP arm 8.4 years), LyMA Trial ([Tessoulin et al., 2021; Sarkozy et al., 2023], 7-year PFS 55.5% versus 59.1% in our study), and control arm (A) in TRIANGLE trial (3-year PFS 75% versus 73.5% in our study). Immunochemotherapy induction followed by ASCT and RM is going to be standard until ibrutinib approval in 1^st line. There is however an urgent need to improve the outcome of pts with high-risk MIPI and/or TP53deletion who do not profit from intensified immunochemotherapy and ASCT. Beyond the ibrutinib incorporation there is a CAR T-cell approach currently tested in high-risk pts (CARMAN study NCT06482684).

This work was supported by the Charles University Hematology-Oncology Cooperatio Program.