Allogeneic Hematopoietic Cell Transplantation for Patients with Relapsed or Refractory Diffuse Large B Cell Lymphoma with Stable or Progressive Disease

Background

Allogeneic hematopoietic cell transplantation (HCT) is a curative treatment option for relapsed/refractory diffuse large B-cell lymphoma (r/rDLBCL). Despite the advent of chimeric antigen receptor T-cell (CAR-T) therapy, several barriers to it exist and prevent its widespread use, ruling out CAR-T therapy as an option for every patient with r/rDLBCL. In addition, up to approximately 60% of patients experience relapse after CAR-T cell therapy, and several studies have demonstrated the efficacy of allogeneic HCT in these patients. Therefore, allogeneic HCT still plays an important role even in the CAR-T era. However, limited data are available on allogeneic HCT in patients with r/rDLBCL who have stable disease (SD) or progressive disease (PD) at transplant. Therefore, this study investigated the outcomes and prognostic factors in patients with r/rDLBCL with SD or PD who underwent allogeneic HCT.

Methods

This study included 662 adult patients with r/rDLBCL who underwent their first allogeneic HCT with SD or PD between January 2001 and December 2018. Missing data were imputed considering the missing at random assumption. The primary endpoint was 5-year progression-free survival (PFS), and secondary endpoints were 5-year overall survival (OS), 5-year cumulative incidence of relapse/progression, and 5-year cumulative incidence of non-relapse mortality. The OS and PFS were evaluated using the log-rank test. The other endpoints were evaluated using Gray's method. Prognostic factors for the primary endpoint were evaluated using the multivariable Cox proportional hazards model, considering age, sex, performance status (PS), HCT-specific comorbidity index, disease status (primary induction failure, early relapse, and late relapse), conditioning regimen, donor type (related vs. unrelated donor), donor source (bone marrow [BM], peripheral blood [PB], and cord blood), the recipient and donor sex (male recipient with female donor vs. others), graft-versus-host disease prophylaxis, previous history of autologous HCT and the interval between autologous and allogeneic HCT (no previous autologous HCT, relapse over 12 months after autologous HCT, and relapse within 12 months after autologous HCT), allogeneic HCT performed within 24 months after diagnosis, four or more lines of chemotherapy before allogeneic HCT, and years of allogeneic HCT. The impacts of the candidate factors are shown as hazard ratios (HRs) with 95% confidence intervals (CIs).

Results

The median age was 53 years (interquartile range, 45-59 years), and 369 (56%) patients were male. A total of 201 (31%) patients had PS of 2 or higher and 82 (12%) patients had HCT-specific comorbidity index of 3 or higher. There were 225 (34%) patients with PIF, 73 (11%) with early relapse, and 364 (55%) with late relapse. Reduced-intensity conditioning was administered to 462 (70%) patients. Regarding the donor type, 303 (46%) patients received related BM or PB, 120 (18%) received unrelated BM or PB, and 239 (36%) patients received unrelated cord blood. Regarding the primary endpoint, the 5-year PFS was 11.4% (95% CI, 9.1-14.0). In multivariable analysis, age 50 and above (HR, 1.19; 95% CI, 1.00-1.42; p = 0.047), male (HR, 1.26; 95% CI, 1.04-1.53; p = 0.020), and PS of 2 or higher (HR, 1.67; 95% CI, 1.39-2.00; p < 0.001) were identified as significantly negative prognostic factors for 5-year PFS, while relapsed over 12 months after autologous HCT (HR, 0.55; 95% CI, 0.42-0.73; p < 0.001) and male recipient with female donor (HR, 0.74; 95% CI, 0.60-0.93; p = 0.008) were identified as significantly positive prognostic factors for 5-year PFS. For the secondary endpoints, the 5-year OS, 5-year cumulative incidence of relapse/progression, and 5-year cumulative incidence of non-relapse mortality were 16.0% (95% CI, 13.3-19.0), 62.5% (95% CI, 58.7-66.1), 28.0% (95% CI, 24.5-31.6), respectively.

Conclusion

We demonstrated poor survival outcomes in patients with r/r DLBCL who underwent allogeneic HCT with SD or PD, with a 5-year PFS of 11.4%. Despite this, a subgroup of patients achieved a durable response after allogeneic HCT, potentially leading to a cure. We explored prognostic factors that may guide patients to benefit from allogeneic HCT.

Uchida:Astellas Pharma Inc.: Consultancy; Chugai Pharmaceutical Co.: Research Funding; Fuji Pharma Co.: Research Funding; Sumitomo Pharma Co.: Research Funding; Nippon Boehringer Ingelheim Co.: Research Funding; JCR Pharmaceuticals Co.: Research Funding; CSL Behring: Honoraria; MSD (Merck & Co. Inc.): Honoraria; Asahi Kasei Pharma Co.: Honoraria; Astellas Pharma Inc.: Honoraria; AstraZeneca: Honoraria; AbbVie GK: Honoraria; Otsuka Pharmaceutical Co.: Honoraria; Kyowa Kirin Co.: Honoraria; SymBio Pharmaceuticals: Honoraria; Daiichi Sankyo Co.: Honoraria; Takeda Pharmaceutical Co.: Honoraria; Chugai Pharmaceutical Co.: Honoraria; Nippon Shinyaku Co.: Honoraria; Takeda Pharmaceutical Co.: Consultancy; Novartis Pharma Co.: Honoraria. Yoshihara:Novartis Pharma K.K.: Honoraria; Janssen Pharmaceutical K.K.: Honoraria; Bristol-Myers Squibb Co: Honoraria; CHUGAI PHARMACEUTICAL Co., Ltd.: Research Funding. Serizawa:Sanofi K.K.: Honoraria; Janssen Pharmaceutical K.K.: Honoraria; Takeda Pharmaceutical Company Limited: Honoraria. Yoshimitsu:Sanofi: Honoraria; Takeda: Honoraria; Genmab: Honoraria; Daiichi Sankyo: Honoraria; Kissei: Honoraria; Bristol-Myers Squibb Company: Honoraria; Ono Pharmaceutical: Honoraria; Asteras: Honoraria; Meiji Seika Pharma Co., Ltd: Honoraria; Novartis: Honoraria; Chugai Pharmaceutical: Honoraria; Nippon Kayaku Co., Ltd.: Honoraria; PharmaEssentia Corp.: Honoraria. Kanda:Ono Pharma Inc.: Honoraria; Novartis Pharma K.K.: Consultancy, Honoraria; Janssen Pharmaceutical K.K.: Consultancy, Honoraria; Astellas Pharma Inc.: Consultancy, Honoraria; CSL Behring K.K.: Honoraria; Takeda Pharmaceutical Company Limited: Honoraria; CHUGAI PHARMACEUTICAL Co., Ltd.: Honoraria; Amgen Pharma Inc.: Honoraria; Otsuka Pharmaceutical Co., Ltd.: Honoraria; Bristol-Myers Squibb Co: Honoraria; ASAHI KASEI PHARMA CORPORATION: Honoraria; Sanofi K.K.: Honoraria; asclepia: Honoraria; Kyowa Kirin Co., Ltd: Honoraria; NIPPON KAYAKU CO．，LTD．: Honoraria; MSD K.K.: Honoraria; DAIICHI SANKYO Co., Ltd.: Consultancy, Honoraria; Nippon Shinyaku Co., Ltd.: Honoraria; Sumitomo Dainippon Pharma Co., Ltd.: Honoraria; SymBio Pharmaceuticals, Ltd.: Consultancy; Megakaryon Co: Consultancy; AbbVie Inc.: Consultancy, Honoraria; Eisai: Research Funding.