Results of the Astral Study: A Prospective Phase II Clinical Study of the German Lymphoma Alliance to Assess the Efficacy and Toxicity of High-Dose Chemotherapy Followed By Allogeneic Stem Cell Transplantation As Treatment of Primary Progressive and Relapsed Aggressive Non-Hodgkin Lymphoma

Abstract

Introduction Patients with relapsed and refractory (r/r) aggressive B- or T-cell lymphoma have a dismal prognosis. Registry analyses as well as one preceding prospective clinical study demonstrated durable disease control through graft-versus-lymphoma activity conferred by allogeneic stem cell transplantation (alloSCT) in this population and suggests this modality being a preferred treatment option after failing of less toxic approaches. Recently, allogeneic SCT has been shown to result in long term PFS in r/r large B-cell lymphoma (LBCL) with preceding CAR-T treatment. Despite the current achievements in treatment of r/r LBCL by introducing anti CD19 CAR-T as a treatment modality appproximately 60% need further approaches to achieve long term progression free survival (PFS). Here we represent the results of a prospective clinical trial of allogeneic SCT in r/r aggressive B- and T-cell lymphoma using a thiotepa based conditioning regimen. Methods ASTRAL is a national, multicenter, prospective phase II study of the German Lymphoma Alliance (GLA). Eligible were patients aged 18 or older with relapsed or primary progressive aggressive B- or T-cell lymphoma who had a fully matched (10/10) related or unrelated donor available. Patients underwent myeloablative conditioning regimen with Fludarabine 125 mg/m², Thiotepa 15 mg/kg and Cyclophosphamide 120 mg/kg (FTC). GVHD prophylaxis and posttransplant immunosuppression was done by local standards. The primary objective was to determine the efficacy and toxicity of the defined conditioning therapy followed by allogeneic stem cell transplantation. The primary endpoint was progression free survival at 1 year. Key secondary efficacy endpoints included rate of complete remissions (CR), rate of partial remissions (PR), overall response rate (OR), rate of progressive disease (PD), relapse rate, event free survival (EFS) and overall survival (OS) at 1 year and non-relapse mortality (NRM). Results From June 2019 until December 2021 in total 60 patients were enrolled. The demographic data are presented in table 1. The majority of patients (70%) had B-cell lymphomas. Patients had received a median of 3 prior lines (range 1-6), including autoSCT in 42% of all patients and CAR-T in 29% of the B-cell patients. The rate of primary progressive disease before salvage therapy was 27% (29% B-cell and 22% T-cell). 83% (50/60) still had measurable disease (no CR) prior to FTC, thereof 81% with B-cell (34/42) and 89% with T-cell lymphoma (16/18) and 13 (22%) had high intermediate and high IPI. After alloSCT, CR was achieved in 45% of patients with B-cell and in 67% with T-cell lymphoma, respectively. The overall response rate was 53%, 48% for B-cell lymphoma and 67% T-cell lymphoma. After a median observation time of 30 months, 1-year PFS was 40% [95%-CI: 28%-52%] (38% [23%-53%] (B-cell) vs. 44% [21%-67%] (T-cell) (figure 1). EFS was identical to PFS. After one year 15 patients (25%) had progressive disease or relapse, thereof 13 patients (29%) with B-cell lymphoma and two with T-cell lymphoma (11%). Thirty-seven patients died. Main cause of death was treatment related 19/37 (51%), including 8/19 deaths due to toxicity of the conditioning therapy (6 infections, 1 respiratory failure and 1 neurotoxicity). 12/37 (32%) patients died lymphoma related, 4/37 (11%) patients died of a SARS-Cov-2 infection, and two causes of death were unknown. 1-year OS was 43% [31%-56%] (40% [26%-55%] (B-cell) vs. 50% [27%-73%] (T-cell)). 1-year NRM was 35% [23%-47%] (31% [17%-45%] (B-cell) vs. 44% [20%-68%] (T-cell)). Most of the patients with grade 3-5 adverse events had infections 40/60 (67%), renal disorders 17/60 (28%) and oral mucositis 14/60 (23%). Conclusions This is the second prospective trial on alloSCT for r/r aggressive lymphoma ever performed, demonstrating that alloSCT can provide sustained disease control in heavily pretreated patients. Also in the modern era, including patients who failed CARTs the strong anti-lymphoma activity of allogeneic SCT is shown in the low relapse/progression rate and the long term PFS. FTC conditioning avoids the toxicities of busulfan-based regimens but fosters neuro- and other toxicities, especially when given at 15mg/kg. Still, NRM remains a challenge and warrants exploration of novel transplant strategies, such as modulation of conditioning intensity and GVHD prophylaxis, e. g. post-transplant cyclophosphamide.