Autologous Stem Cell Transplant in 2^nd Line DLBCL in 2022, Still the Standard of Care ? a Monocentric Experience

Introduction: Patients with relapsed or refractory (R/R) diffuse large B cell lymphoma (DLBCL) after frontline chemotherapy have a dismal prognosis. Salvage chemotherapy followed by high dose consolidation chemotherapy supported with autologous stem cell transplantation (ASCT) can achieve cure in about 50%, and remains the standard of care for fit patients under 70 yo. Nevertheless, this approach is less effective for patients with primo-refractory disease (refractory to 1^st line CT or experiencing relapse during the 12 months after completion of 1^st line treatment). With the advent of autologous CAR T cells targeting CD19 in second line of treatment, the place of ASCT must be redefined based on robust clinical data to offer candidate patients their best available treatment. As part of this "choose wisely" approach, we report the outcomes of patients receiving ASCT as consolidation therapy at our center.

Methods: we report the retrospective experience of a monocentric transplantation program. Inclusion criteria were: 1) R/R DLBCL 2) In response to salvage therapy according to Deauville score criteria. Complete response (CR) was defined as Deauville scores 1-2-3, partial response (PR) as Deauville 4 or 5. 3) ASCT between 2010 and 2020 at IPC, Marseille 4) Conditioning regimen with BEAM or Bendamustine-Eam.

The patients were stratified according to the NCCN-IPI in 2 groups: low risk (NCCN-IPI≤3) and high risk (NCCN-IPI>3). Univariate analyses included age, aaIPI, NCCN IPI and disease status pre ASCT. Multivariate analyse included disease status pre ASCT and NCCN-IPI

Results: Ninety eight patients with a median age of 57 yo (26-71) were included. Most of them were primary refractory (52 patients, 53%). Patients received a median number of 2 lines of chemotherapy (2-4) before ASCT. At time of reinjection, all were in response (78% were in CR and 22% in PR). With a median follow up of 42 months (33-60), 3 year progression free survival (PFS) and overall survival (OS) were 68% and 82% respectively, and 3 year cumulative incidence of relapse (CIR) was 27%.

In the whole group, 12 month NRM was 2%.Age was not associated with an increased risk of NRM (SHR 2.3 CI95 [0.44-12.24], p:0.3) .

Three year PFS and OS were significantly higher in patients who underwent ASCT in CR: 3 years PFS 74% CR vs. 43% PR (HR 3.04 95CI [1.5-6.17], p: 0.001.), 3 year OS 88% CR vs 61% PR (HR 4.53 95CI [1.74-11.81 ], p< 0.001.). This was confirmed by multivariate analyse (HR 3.08 95CI [1.50,6.29] , p=0.0021 for PFS and HR 5.4 95CI [1.99-14.65 ], p=0.0009 for OS).

Disease status at the time of ASCT and NCCN IPI >3 were strongly associated with PFS and OS (3 year PFS 71% CR and NCCN IPI ≤3 vs. 17% PR and NCCNIPI >3 (HR 5.62 95CI [2.03-15.54], p<.001 ) . Three year OS for CR and NCCN IPI ≤3 vs. PR and NCCNIPI >3 were: 86% vs. 17% (HR 16.15 95CI [4.87-53.57], p<.001).

In the primary refractory group, 3 year PFS, OS and CIR were 70%, 75% and 22% respectively. No differences were observed with non primary refractory group (3 years PFS 66% vs. 70%, p=0.56 , 3 years OS 90% vs 75%, p= 0.077)

Conclusion : We confirm that ASCT provides good disease control with few toxicity and remains a valid option in 2^nd line DLBCL until 70 years of age. However, our results appear to be superior to previously published reports, even more in the group of primary refractory diseases, possibly due to a strict selection of patients achieving complete response after salvage therapy. Disease status before ASCT remains the most relevant parameter to predict survival, and should be incorporated in treatment decision algorithms to elect the optimal treatment sequence. Questions remain about the best strategy for patients in PR before ASCT, and we await long term results of randomized phase 3 CART cells studies (ZUMA7, TRANSFORM). According to our results, given the unfavorable prognosis of the group of patients in PR and NCCN IPI ≥ 3 could be the subgroup of patients that would most certainly benefit from CART cells.

In conclusion, the best 2^nd line strategy between ASCT and CAR T cells should be decided according to response quality, the access to CAR T cells program and economic impact. Moreover, the combination of pre treatment prognostic factors ( NCCN IPI) and pre-ASCT response to treatment could be even more halpful to choose the best consolidation treatment.

Brisou:Gilead: Honoraria; BMS: Honoraria; Novartis: Honoraria; Incyte: Honoraria. Schiano de Collela:Takeda: Honoraria; Abbvie: Honoraria; Janssen: Honoraria. Inchiappa:ASTRAZENECA: Honoraria; JANSSEN: Honoraria; ABBVIE: Honoraria; Gilead: Honoraria. Vey:Roche: Honoraria; Novartis: Honoraria, Research Funding; BMS: Honoraria; Janssen: Honoraria; Jazz Pharmaceuticals: Honoraria; Amgen: Honoraria. Chabannon:BELLICUM PHARMACEUTICALS: Membership on an entity's Board of Directors or advisory committees; NOVARTIS: Speakers Bureau; SANOFI SA: Honoraria, Research Funding, Speakers Bureau; BMS/CELGENE: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; TERUMO BCT: Speakers Bureau; MILTENYI BIOTECH: Research Funding; EBMT: Membership on an entity's Board of Directors or advisory committees; GILEAD: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; FRESENIUS KABI: Research Funding; JANSSEN PHARMACEUTICALS: Membership on an entity's Board of Directors or advisory committees.