The Role of High-Dose Regimens Followed By Autologous Stem Cell Transplantation for Salvage Chemotherapy-Sensitive DLBCL Patients

INTRODUCTION：

It has been reported that lisocabtagene maraleucel improved event-free survival and complete response rate compared with standard care as second -line therapy for early relapsed/refractory diffuse large B-cell lymphoma (rrDLBCL) patients(pts). However, CAR T-cell therapy could not be available for some candidates with rrDLBCL due to socioeconomical issues and manufacturing limitations. High-dose chemotherapy followed by autologous stem cell transplantation (auto-SCT) is a conventional curative treatment for salvage chemotherapy-sensitive DLBCL. We have devised AECC regimen (Usui, Clin Lymph; 2005, and Yano, Clin Lymph and Myeloma; 2007) for auto-SCT. Further, we have also used ranimustine (MCNU) based MEAM regimen due to not availability for carmustine in Japan. In this retrospective study, we compared the efficacy and safety of AECC with MEAM.

METHODS：

We retrospectively analyzed 68 pts with DLBCL who received AECC or MEAM followed by auto-SCT from January 2006 to December 2021 at the Jikei University Hospital and the Jikei University Kashiwa Hospital. AECC regimen consists of nimustine 200mg/m ² on day -7 to day -6, etoposide (ETP) 30mg/kg on day -5 to day -4, cyclophosphamide 60mg/kg on day -3 to day -2, carboplatin 700mg/m ² on day -3 to day -2. MEAM regimen consists of MCNU 300 mg/m ² on day -7, ETP 200 mg/m ² on day -6 to day -3, cytarabine 200 mg/m ² q12 hrs on day -6 to day -3, and melphalan 140 mg/m ² on day -2. In this study, early relapsed DLBCL (erDLBCL) was defined as DLBCL pts relapsed within 2 years from diagnosis. We retrospectively analyzed overall survival (OS), progression-free survival (PFS) and adverse events (AE).

Thirty-five pts received AECC and 33 pts MEAM in DLBCL, respectively. AECC was mainly used from 2006 to 2013, and MEAM was used from 2014 to 2021. The patient characteristics between AECC and MEAM were as bellows; the median follow-up time for survival was 109 (0-193) vs 35(1-83) months ( P <0.01), the median age at auto-SCT was 54(25-65) vs 58 (40-68) years ( P = 0.01), 66% vs 61% were male ( P = 0.80), the median years from diagnosis to auto-SCT was 1.43(0.39-12.79) vs 1.67(0.39-22.40) years ( P = 0.41), the number of pts who receive 2 lines of therapy before auto-SCT were 18 vs 23 ( P = 0.144). Disease status at auto-SCT in the AECC and MEAM groups were 16 vs 12 pts in complete response (CR), 15 vs 21 pts in partial response (PR), and 4 vs 0 pts in stable disease or progressive disease (SD/PD) ( P = 0.06). The 2-year OS and PFS rates in the AECC and MEAM groups were 76.9% vs 68.3% ( P =0.323), and 68.2% vs 59.4% ( P =0.137), respectively.

In addition, we focused er DLBCL pts whose disease status at auto-SCT was CR or PR, named as “chemotherapy-sensitive er DLBCL”. Twenty-one pts were treated with AECC and 19 pts were received MEAM. The patient characteristics between AECC and MEAM were as bellows; the median age at auto-SCT in the AECC group was younger than those in the MEAM group (53(25-65) vs 60 (47-68) years, P = 0.01), the number of pts with CR in the AECC group was higher than those in the MEAM group. (10 vs 3, P = 0.046). The OS and PFS in the AECC group were significantly higher than those in the MEAM group (2-year OS 85.4% vs 48.5% ( P = 0.019), and 2-year PFS 75.6% vs 39.0% ( P <0.01), respectively). Additionally, AECC achieved long-term survival with 8-year OS and PFS of 80.4% and 75.6% in the chemotherapy-sensitive er DLBCL, respectively.

At the time of data analysis, deaths had been reported in 12 of 35 pts in the AECC and 12 of 33 in the MEAM. The most common cause of death was disease progression (10 pts in the AECC and 8 in the MEAM). Non-relapse mortality (NRM) was observed in 2 pts of the AECC (drug-induced cardiomyopathy (n = 2)), and 4 of the MEAM (liver failure (n = 2), pneumonia (n = 1), and suicide (n = 1)). It should be mentioned that grade 3 or higher heart failure was observed in the AECC group (n = 8) compared to in the MEAM group (n = 0). Treatment related mortality (TRM) within 100 days was 2 pts in the AECC group due to cardiomyopathy and 0 in the MEAM group.

AECC followed by auto-SCT achieved both long-term OS and PFS compared to MEAM in chemotherapy-sensitive er DLBCL pts. Further validation for efficacy is needed due to the differences in patient's background and follow-up period in the study. However, AECC was associated with a higher incidence of cardiac toxicity and TRM within 100 days. It was suggested that auto-SCT with AECC may be a treatment option when CAR T-cell therapy was not available.

Kawashima:The Uehara Memorial Foundation: Research Funding. Suzuki:Janssen Pharmaceutical K.K.: Honoraria; Takeda Pharmaceuticals: Honoraria; Sanofi: Honoraria; Bristol-Myers Squibb: Honoraria. Nishiwaki:Alexion Pharmaceuticals: Research Funding; Alexion Pharmaceuticals: Honoraria. Yano:Astra Zeneca: Honoraria; Otsuka Pharmaceutical: Research Funding.