Page 206 - Haematologica May 2022

Letters to the Editor
Autologous hematopoietic cell transplantation in dif- fuse large B-cell lymphoma after three or more lines of prior therapy: evidence of durable benefit
While most patients with diffuse large B-cell lym- phoma (DLBCL) are cured with initial chemoim- munotherapy, one-third of patients will have relapsed and/or refractory (r/r) disease after frontline treatment. Salvage combination chemoimmunotherapy followed by autologous hematopoietic cell transplantation (autoHCT), in patients achieving an objective response to cures less than half of such patients.1,2 Most patients who undergo autoHCT do so after second line (2L) ther- apy, but some do so after having received three or more lines (3L+) of prior therapy. Data are lacking on the out- comes after autoHCT in patients with DLBCL in the 3L+ setting. Although CD19-directed chimeric antigen recep- tor T-cell (CAR-T) therapy is being increasingly used in the 3L+ setting with curative intent,3-5 this topic remains relevant given issues with access to CAR-T both in the US6 and worldwide, particularly in low and middle income countries.7 Here we report outcomes after autoHCT in the subset of patients with DLBCL who received 3L+ of systemic therapy in a Center for International Blood and Marrow Transplant Research (CIBMTR) registry analysis.
The CIBMTR is a collaborative research program man- aged by the Medical College of Wisconsin and the National Marrow Donor Program that collects data from more than 380 transplant centers worldwide. Participating sites are required to report detailed data on both autologous and allogeneic HCT with frequent updates gathered during the longitudinal follow-up of transplant patients, and the compliance is monitored by on-site audits. Computerized checks for discrepancies, physicians’ review of submitted data, and on-site audits of participating centers ensure data quality. Observational studies conducted by the CIBMTR are performed in compliance with all applicable federal reg- ulations pertaining to the protection of human research participants. The Medical College of Wisconsin and National Marrow Donor Program Institutional Review Boards approved this study.
Patients with DLBCL (aged ≥18 years) who received autoHCT between 2003 and 2017 with a preparative regimen of either BEAM (carmustine, etoposide, cytara- bine, melphalan) or R-BEAM (rituximab with BEAM) conditioning after 3L+ therapy were included in this analysis. All patients received rituximab-containing, anthracycline-based frontline therapy. Patients who received a bone marrow graft, with chemorefractory dis- ease after salvage therapy, and with active central nerv- ous system involvement prior to autoHCT were exclud- ed. Patients with transformed DLBCL evolving from prior indolent lymphoma were also excluded. Chemosensitive disease was defined as achieving either a complete remission (CR) or partial remission (PR) to salvage treatment. Response to frontline chemoim- munotherapy and disease status at autoHCT were deter- mined by each center using the International Working Group criteria.8,9 Early chemoimmunotherapy failure was defined as not achieving a CR after frontline chemoim- munotherapy or relapse/progression within 1 year of ini- tial diagnosis.10
The primary endpoint was OS. Death from any cause was considered an event and surviving patients were censored at last follow-up. Secondary outcomes includ- ed non-relapse mortality (NRM), relapse/progression,
and progression-free survival (PFS). NRM was defined as death without preceding evidence of lymphoma progres- sion/relapse; relapse was considered a competing risk. Relapse/progression was defined as progressive lym- phoma after autoHCT or lymphoma recurrence after a CR; NRM was considered a competing risk. For PFS, a patient was considered a treatment failure at the time of progression/relapse or death from any cause. Patients alive without evidence of disease relapse or progression were censored at last follow-up. All outcomes were cal- culated relative to the autoHCT date.
The study cohort was divided according to remission status at the time of autoHCT (CR vs. PR). Patient-, dis- ease- and transplant-related variables were compared between the two cohorts using the Chi-square test for categorical variables and the Wilcoxon two-sample test for continuous variables. The distribution of OS and PFS were estimated using the Kaplan-Meier method. Cumulative incidence method was used to estimate NRM, relapse/progression while accounting for compet- ing events. The Cox proportional hazards model for PFS and OS and the cause-specific hazards model for relapse and NRM were used to identify prognostic factors using forward stepwise variable selection. No covariates vio- lated the proportional hazards assumption. No signifi- cant interactions between the main effect and significant covariates were found. No center effects were found based on the score test of homogeneity.11 Results were reported as hazard ratio (HR), 95% confidence interval (CI) for HR and P-value. The adjusted probabilities for each outcome were calculated based on the final regres- sion model. Covariates with a P-value <0.05 were con- sidered statistically significant. All statistical analyses were performed using SAS version 9.4 (SAS Institute, Cary, NC).
A total of 285 patients met the inclusion criteria; over the same interval, 577 patients in the dataset who other- wise met the inclusion criteria had undergo autoHCT after receiving two or fewer lines of prior therapy. Median age was 60 years (range, 19-80 years), 60% were male, 80% were Caucasian, and 63% had early chemoimmunotherapy failure. Eighty percent received BEAM conditioning and 20% received R-BEAM. Details regarding the 3L treatment regimen are included in the Online Supplementary Table S3. Baseline characteristics are shown in Table 1. 5-year OS and PFS were 51% (95% CI: 44-57) and 38% (95% CI: 32-55), respectively. Adjusted 1-year, 3-year, and 5-year PFS and OS are shown in Table 2. Patients in CR at autoHCT had a high- er 1-year OS (84% vs. 63%, P<0.001) and PFS (69% vs. 48%, P<0.001) in contrast to patients in PR, with the dif- ference in OS persisting at 3 years (OS 64% vs. 50%, P=0.02). There was a trend towards improved 5-year OS for patients in CR (56% vs. 45%, P=0.06), whereas 5- year PFS did not differ significantly between the two cohorts (42% vs. 34%, P=0.18).
The 1- and 5-year incidence of relapse/progression for all patients was 36% (95% CI: 31-42) and 50% (95% CI: 43-56), respectively. Patients in CR had a significantly lower 1-year incidence of relapse/progression (26% vs. 47%, P<0.001); however, there was no difference found in relapse/progression at 5 years between the two cohorts (45% vs. 54%, P=0.14). The 1-year and 5-year NRM were 5% (95% CI: 3-8) and 12% (95% CI: 9-17), respectively with no difference identified between patients in CR and those in PR. A graph of outcomes stratified by disease status at autoHCT is provided in Figure 1.
A multivariable regression model was constructed to
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haematologica | 2022; 107(5)