Browsing by Author "Scheid, Christof"

The purpose of this prospective multicenter phase 2 trial was to investigate the long-term outcome of reduced-intensity conditioning allogeneic stem cell transplantation (alloSCT) in patients with poor-risk chronic lymphocytic leukemia. Conditioning was fludarabine/cyclophosphamide-based. Longitudinal quantitative monitoring of minimal residual disease (MRD) was performed centrally by MRD-flow or real-time quantitative polymerase chain reaction. One hundred eligible patients were enrolled, and 90 patients proceeded to alloSCT. With a median follow-up of 46 months (7-102 months), 4-year nonrelapse mortality, event-free survival (EFS) and overall survival (OS) were 23%, 42%, and 65%, respectively. Of 52 patients with MRD monitoring available, 27 (52%) were alive and MRD negative at 12 months after transplant. Four-year EFS of this subset was 89% with all event-free patients except for 2 being MRD negative at the most recent assessment. EFS was similar for all genetic subsets, including 17p deletion (17p-). In multivariate analyses, uncontrolled disease at alloSCT and in vivo T-cell depletion with alemtuzumab, but not 17p-, previous purine analogue refractoriness, or donor source (human leukocyte antigen-identical siblings or unrelated donors) had an adverse impact on EFS and OS. In conclusion, alloSCT for poor-risk chronic lymphocytic leukemia can result in long-term MRD-negative survival in up to one-half of the patients independent of the underlying genomic risk profile. This trial is registered at http://clinicaltrials.gov as NCT00281983. (Blood. 2010;116(14):2438-2447)

Introduction: Obesity is a major health care burden and has been linked to numerous adverse outcomes including alterations of antitumor immunologic responses. Patients with high body mass index (BMI) undergoing autologous or allogeneic hematopoietic stem cell transplantation (HSCT) for hematological malignancies were repeatedly shown to have higher rates of non-relapse mortality (NRM) and relapse, translating into a reduced overall survival (OS). However, the impact of obesity on outcomes after CAR T-cell therapy has not been studied at large scale. The present study aims to investigate whether high BMI is associated with outcomes in patients receiving anti-CD19 CAR T-cell therapy. Methods: This is a retrospective analysis using EBMT registry data of adult patients after first therapy with commercial CD19 CAR T-cell products for relapsed/refractory B-Non-Hodgkin lymphoma (B-NHL) between 1/1/2016 and 30/6/2022. Only patients with available information on height and weight at CAR T-cell therapy were included. Patients with a history of allogeneic stem cell transplantation were excluded. As we exclusively focused on the impact of increased BMI we excluded all patients with a BMI below 18.5 from the analysis. The primary outcome was the impact of BMI on OS. Multivariate analyses were performed with cause-specific Cox models, employing as risk factors patient age, sex, ECOG status and year of CAR T-cell therapy besides BMI categories (18.5-25, 25-30, >30). Results: A total of 4576 CAR T-cell therapy patients were registered during the study period, with 3125 patients meeting inclusion criteria. Selection of patients with available height and weight including BMI of 18.5 and above resulted in a final study cohort of 1653 patients. Median follow-up was 21.2 months [95% CI: 19.6-22.6]. Patients' characteristics are summarized in Table 1. Half of the cohort had a normal range BMI, while one third was overweight (BMI 25-30) and about 18% met criteria for obesity. A significant interaction was found between age and BMI. Therefore, we divided the cohort in two groups by the median age of 62.5 years. OS was significantly reduced in younger patients with normal range BMI compared to higher BMI patients. However, this effect was not significant in the older patients (Figure 1). Upon multivariate analysis, younger patients with BMI 25-30 had a survival advantage with a hazard ratio (HR) of 0.74 (0.57-0.95, P=0.02) and patients with BMI >30 a HR of 0.68 (0.51-0.91, P=0.01) compared to normal range BMI. Progression free survival was significantly improved for younger BMI 25-30 (HR 0.79, 0.64-0.99, P=0.04) but not BMI >30 (HR 0.82, 0.64-1.05, P=0.11), and NRM was reduced only in the younger BMI 25-30 subgroup (HR 0.52, 0.31-0.9, P=0.02) but not in the obese patients (HR 0.7, 0.42-1.18, P=0.19). Multivariate analysis of BMI subgroups in patients above the age of 62.5 years did not show significant differences with regard to OS (BMI 25-30 HR 0.94, 0.74-1.18; BMI >30 HR 1.04, 0.77-1.41), PFS (BMI 25-30 HR 1.06, 0.86-1.31; BMI >30 HR 1.1, 0.83-1.47), or NRM (BMI 25-30 HR 1.35, 0.89-2.06; BMI >30 HR 1.11, 0.6-2.06). Conclusion: Our European real world data on the impact of increased BMI on anti-CD19 CAR T-cell therapy for relapsed/refractory B-NHL shows that half of these patients are overweight or obese and that this seems to confer a survival benefit to younger (<62.5 years) patients. As this finding is rather surprising, future studies are required to fine tune the risk analysis, including in-depth analysis of patients' characteristics to identify protective factors linked to an elevated BMI as well as a possible selection bias. Our findings could in part be explained by the body weight-dependent dose of infused CAR T-cells for B-cell lymphoma. Therefore, for the same tumor burden, obese patients might receive more CAR T-cells than normal weight ones. A future study should test this hypothesis also in B-ALL or multiple myeloma patients, as they typically receive a fixed dose of CAR T-cells regardless of their body weight. Ultimately, our study might contribute to identify underlying mechanisms for improved outcome of CAR T-cell patients.

Tyrosine kinase inhibitors represent today's treatment of choice in chronic myeloid leukemia (CML). Allogeneic hematopoietic stem cell transplantation (HSCT) is regarded as salvage therapy. This prospective randomized CML-study IIIA recruited 669 patients with newly diagnosed CML between July 1997 and January 2004 from 143 centers. Of these, 427 patients were considered eligible for HSCT and were randomized by availability of a matched family donor between primary HSCT (group A; N = 166 patients) and best available drug treatment (group B; N = 261). Primary end point was long-term survival. Survival probabilities were not different between groups A and B (10-year survival: 0.76 (95% confidence interval (CI): 0.69-0.82) vs 0.69 (95% CI: 0.61-0.76)), but influenced by disease and transplant risk. Patients with a low transplant risk showed superior survival compared with patients with high( P < 0.001) and non-high-risk disease (P = 0.047) in group B; after entering blast crisis, survival was not different with or without HSCT. Significantly more patients in group A were in molecular remission (56% vs 39%; P = 0.005) and free of drug treatment (56% vs 6%; P < 0.001). Differences in symptoms and Karnofsky score were not significant. In the era of tyrosine kinase inhibitors, HSCT remains a valid option when both disease and transplant risk are considered.