T-cell/histiocyte-rich LBCL (THRLBCL) is an uncommon entity within the large B-cell lymphoma family, comprising less than 5% of all LBCL 1 . Compared to other LBCL, THRLBCL patients are younger, commonly male, present with higher International Prognostic Indexes (IPI), and advanced disease stages 2 . THRLBCL is named for its unique immunomodulating micro-milieu characterized by T-cell and histiocyte infiltration. Of note, THRLBCL overexpresses multiple immune checkpoint-molecules like PD-1, PD-L1 or LAG3. This mirrors Hodgkin lymphoma (HL) and a subfraction of patients with THRLBCL has a documented history of nodular lymphocyte-predominant Hodgkin lymphoma/ B-cell lymphoma (NLPHL/NLPBCL) 1 , 3 . The histologic similarities with HL and peripheral T-cell lymphomas lead to common misdiagnosis and likely underreporting of the disease. Despite the diagnostic uncertainties and the clinical and biological peculiarities described, the prognosis of THRLBCL appears to be similar to that of the most common form of LBCL, diffuse LBCL not otherwise specified (DLBCL, NOS) if treated with DLBCL-typical first-line chemoimmunotherapy 2 . Nevertheless, a considerable proportion of patients with THRLBCL fails first-line therapy and needs salvage treatment. Apart from high-dose therapy with autologous hematopoietic cell transplantation (auto-HCT), cellular immunotherapies, specifically allogeneic HCT (allo-HCT) and CD19-targeting chimeric antigen receptor-engineered T-cell (CAR-T) therapies, have proven efficacy in the LBCL salvage setting 4 , 5 , 6 , 7 . While a few case series on CAR-T therapies in THRLBCL with mostly disappointing results have been published, information on allo-HCT in patients with THRLBCL is extremely limited. Therefore, we studied real-world outcomes of allo-HCT in patients with r/r THRLBCL compared to DLBCL. Given the challenges associated with a correct histopathological diagnosis of THRLBCL, we primarily relied on cases with available pathology reports reviewed by an experienced hematopathologist and deemed consistent with THRLBCL. Outcome data was extracted from the EBMT registry database. Informed consent for transplantation and data collection was obtained locally according to regulations applicable at the time of therapy. Eligibility criteria for this study were: Diagnosis of THRLBCL or DLBCL, first allo-HCT between 2016 and 2020, and age ≥18 years at cellular therapy. All patients identified in the EBMT database fulfilling these criteria and having a minimum baseline data set available (age, sex, diagnosis, date of diagnosis, date of cellular therapy, number of pretreatment lines) represented the study cohort. For all patients registered as THRLBCL, diagnostic reports were requested from the centers and reviewed by an experienced hematopathologist (LdL). Patients with reports not consistent with THRLBCL were excluded. Cases without available report were considered separately. Primary endpoint was progression-free survival (PFS) 2 years after transplantation. Other endpoints analyzed were non-relapse mortality (NRM), relapse incidence (RI), and overall survival (OS). OS was defined as time from transplant to death from any cause, PFS as time from transplantation until disease relapse/progression or death from any cause. NRM included all causes of death without prior disease progression/relapse. Patient-, disease- and transplant-related variables were compared between cohorts using the Chi-square test or Fisher’s exact test for categorical variables and the Mann-Whitney test for continuous variables. The probabilities of OS and PFS were calculated using the Kaplan-Meier estimate. Cumulative incidences of RI and NRM were calculated accommodating for competing risks. Univariate analyses were performed on the matched dataset using log-rank comparisons for OS and PFS. The Gray test was used for cumulative incidence functions. Cox analysis was performed on the matched analysis to compare risk. All analyses were performed using R statistical software version 4.2.2 (available online at http://www.R-project.org ) and IBM SPSS version 26.0 (SPSS Inc., Chicago, IL). A total of 1476 patients with THRLBCL or DLBCL meeting the eligibility criteria were identified in the EBMT database. Of these, 64 had the diagnosis THRLBCL and 1,412 DLBCL. Diagnostic reports were received for 28 patients registered with THRLBCL from 19 centers. In 10 patients the reports were suggestive for lymphoma entities other than THRLBCL, or were not consistent with the diagnosis of THRLBCL for other reasons, leaving 18 patients with confirmed THRLBCL (Fig. 1a ). Within the limits of heterogeneous available information contained in the reports, some of the cases appeared to correspond to THRLBCL-like evolution or transformation of NLPHL/BCL. Fig. 1: Outcome of pathology-reviewed and verified THRLBCL patients with allo-HCT. The alternative text for this image may have been generated using AI. Full size image a Overview of cases selected for survival analysis after histological report review, Kaplan-Meier curves depicting b Kaplan-Meier curves depicting PFS, c OS, d RI and e NRM for verified THRLBCL and DLBCL patients after allo-HCT. The baseline characteristics of the 18 allo-HCT recipients are summarized in Table 1 . Of note, the vast majority proceeded to transplant with chemo-sensitive disease. With a median follow-up of 4.3 years, 6 relapse/progression and 2 NRM events were observed, all within the first the first 7 months after allo-HCT, resulting in 2-year PFS and OS rates of 53% (95%CI 28–73%) and 56% (95%CI 31–75%), respectively (Fig. 1b, c ). Compared to 1412 DLBCL patients with similar baseline characteristics, except younger age and fewer previous lines of therapy in THRLBCL, no significant differences were detected in terms of PFS, OS, RI, and NRM (Table 1 , Fig. 1b–e ). Of note, in contrast to THRLBCL, relapse events continued to occur beyond the 6 months landmark in the DLBCL cohort (Fig. 1b,d ). Table 1 Baseline characteristics of pathology-reviewed and verified THRLBCL and DLBCL patients treated with allo-HCT. Full size table Characteristics and outcome of the patients with non-reviewed THRLBCL undergoing allo-HCT were not significantly different from those with verified pathology reports. However, a trend towards higher age was observed in the not-reviewed group. As young age is a feature of THRLBCL, this suggests a contamination of non THRLBCL cases also within the non-reviewed cases (Fig. 1b–e , Supplemental Table 1 ). While there is abundant published experience with allo-HCT in DLBCL, even from the CAR-T era 5 , 6 , 7 , 8 , specific information on the safety and efficacy of allo-HCT in patients with relapsed/refractory THRLBCL is virtually absent. This is particularly important as preliminary data including the evidence provided in this study suggest that cellular immunotherapy through CAR-T therapies is mostly associated with a remarkably poor efficacy 3 , 9 , 10 , 11 , 12 . Here we show for the first time that allo-HCT is effective and feasible in patients with THRLBCL. With more than half of the patients living progression-free at the 2-year landmark, the efficacy of allo-HCT in THRLBCL appears to be at least as good as in DLBCL, where published outcomes are in line with those observed in this study, i.e. 2-year PFS rates in chemosensitive patients between 40% and 50% 5 , 6 , 7 , 8 . In contrast to our experience with auto-HCT 4 , all THRLBCL relapse/progression events occurred early after allo-HCT, suggesting at least some contribution of graft-versus-lymphoma activity to long-term disease control. The second major finding in this study is that high quality reporting on THRLBCL requires central expert review. In the absence of diagnostic tumor samples, review of pathology reports resulted in the exclusion of more than one third of cases registered. Similar drop-out rates have been reported previously for other rare lymphoma entities and to some extent reflect the difficulties encountered when interpreting results from registry studies on orphan or difficult-to-diagnose entities also beyond the lymphoma cosmos 13 . With the continuous advent of novel therapies for LBCL, the arsenal of options to induce responses before transplantation are increasing rapidly. Since the curative potential of antibody drug conjugates, e.g. Loncastuximab tesirine, or bispecific antibodies alone or in combinations remains uncertain 14 , 15 , the role of allo-HCT for consolidating targeted treatment responses of relapsed/refractory LBCL having failed or being ineligible for CAR T-cell therapy may undergo a renaissance. In conclusion, allo-HCT appears to be a curative therapeutic option for a substantial proportion of patients with r/r THRLBCL responding to salvage therapy. In the absence of individual biopsies, central review of diagnostic reports appears to be strongly advisable in registry studies involving orphan diseases and those difficult to diagnose.
Renders et al. (Mon,) studied this question.