Editor's Note: From April 14 to 17, 2024, the 50th European Society for Blood and Marrow Transplantation (EBMT) annual meeting was grandly held in Glasgow, UK. The conference focused on the latest advancements in stem cell transplantation and cellular therapy, pushing forward better clinical outcomes for patients with blood diseases and hematologic malignancies. In this issue, we are honored to have Professor Linhua Yang share selected advancements in the fields of allogeneic hematopoietic stem cell transplantation and cellular immunotherapy. We welcome our readers to engage and share their insights.Literature 1
Survival Analysis in Patients with Non-Familial HLA-Mismatched HCT in the Era of PTCy: A Comprehensive Study by the EBMT Cell Therapy and Immunobiology Working Group.
Main Author: Esteban Arrieta Bolaños (Germany)
Study Background
HLA matching is currently mainstream in allogeneic hematopoietic stem cell transplantation, with a preference now for matched unrelated donors (UD). Post-transplant cyclophosphamide (PTCy) is used to prevent GVHD, enhancing the accessibility of HCT with non-familial HLA mismatches, but its specific effects remain unclear.
Study Methods
This study analyzed the outcomes of 17,276 adult patients with malignant hematologic diseases registered with EBMT from 2016 to 2020 who underwent matched unrelated donor hematopoietic stem cell transplantation (UD-HCT). The primary diseases were AML, ALL, MDS, and MPN, accounting for 67.5%, with 66.2% of patients undergoing HCT and 56% receiving reduced intensity conditioning (RIC), 76% without ex-vivo T-cell depletion. High-resolution HLA mismatches were present in 23.5% of cases (9/10; N=3,561) or two mismatches (8/10; n=499). PTCy was used in 7% (n=924) of 10/10 matched patients and 15% (n=599) of less than 10/10 matched patients, while all other patients received standard calcineurin inhibitor-based GVHD prophylaxis. A multivariate model was constructed to analyze the impact of the number, type, location, resolution (allele vs antigen), and function [antigen recognition domain (ARD), peptide-binding motif (PBM)] of HLA mismatches on HCT outcomes.
Study Results
At 60 months follow-up, the overall survival (OS) was poorer for HLA mismatched transplants (45% for 8/10, 47% for 9/10, 52% for 10/10; P<0.001).
Multivariate analysis indicated that one (HR 1.24 [99% CI 1.15-1.34]; P<0.001) or two (HR 1.29 [1.09-1.54]; P<0.001) mismatched loci, compared to 10/10 matched transplants, were associated with a higher risk of death. Even excluding ARD mismatches, Class I HLA antigen mismatches significantly impacted OS negatively (HR 1.31 [1.20-1.42]; P<0.001), particularly HLA-A (HR 1.37 [1.21-1.54]; P<0.001) and HLA-B (HR 1.44 [1.23-1.69]; P<0.001) as opposed to HLA-C mismatches (HR 1.16 [1.01-1.33]; P=0.005). Antigen level mismatches were associated with worse OS than allele mismatches (HR 1.22 [1.01-1.46]; P=0.006). Class II HLA mismatches did not significantly affect OS (HR 1.07 [0.93-1.22]; P=0.23); similar results were observed for GRFS, RFS, NRM, and aGVHD, but no significant differences were noted in relapse or chronic GvHD.
Unacceptable HLA-DPB1 mismatches increased the risk of aGVHD in 9/10 and 10/10 transplants. Compared to standard prophylaxis, the use of PTCy significantly reduced the risk of GVHD and mortality, but did not mitigate the adverse effects of HLA mismatches. The presence of a single mismatch significantly increased the risk of death regardless of PTCy use (HR 1.38 [1.14-1.68]; P<0.001) and without PTCy (HR 1.23 [1.13-1.33]; P<0.001).
Compared to GvH-PBM mismatches, patients with GvH-PBM matches had a better OS whether or not PTCy was used for GVHD prevention (HR 1.2 [1.02-1.4]; P=0.004).
Study Conclusion
In current HCT practices, non-familial HLA incompatibility is associated with an increased risk of death, primarily driven by Class I HLA antigen mismatches. Even with the use of PTCy for GVHD prevention, this risk remains unmitigated. Choosing better-matched donors, such as those matching in PBM, may improve HCT outcomes.
Study Methods
This prospective Phase II study (NCT05385263) enrolled patients with diffuse large B-cell lymphoma (DLBCL) who progressed during lymphodepletion. Patients received navulimumab (3 mg/kg) 5-9 days after CAR-T infusion. Those with fewer than 100 CAR-T cells/μL on day +7 received an additional dose of navulimumab on day 19. Endpoints included safety, disease response assessment, and duration of remission.
Study Results
Twenty patients were enrolled, undergoing anti-CD19 CAR-T therapy (Axicabtagene ciloleucel, n=12; Tisagenlecleucel, n=8). The median age was 67 years (range 40-77), with six patients (30%) having an ECOG score of 1. The median LDH level before lymphocyte depletion was 528 U/L (range 367-1279).
Due to active CRS (n=6) and/or ICANS (n=3), eight patients (40%) were ineligible for navulimumab treatment (non-protocol group). Twelve patients entered the navulimumab group (protocol group, with seven receiving only one dose).
There were eight adverse events related to navulimumab, including fever in four cases, rash in two, diarrhea in one, and neutropenia in one; no severe adverse events related to the treatment were observed. One patient died from delayed and prolonged cytopenia and recurrent sepsis.
Flow cytometry in ten patients showed that 67% had re-expansion of CAR-T cells. Compared to the control group, PD-1 expression was significantly lower in the protocol group on mononuclear cells and CD3+ T cells [10.2% vs. 21% (P=0.0075) and 6.5% vs. 19.7% (P=0.0009), respectively], with no difference observed in PD-1 expression on CAR-T cells, activation markers, and T cell subtypes between the groups.
Among all patients, the overall response rate (ORR) was 80% (CR, n=12, 60%; PR, n=4, 20%) and progressive disease (PD, n=3, 15%). One patient died without relapse, and efficacy was not evaluated. This outcome was better than historical controls (CR, n=16, 39%; PR, n=10, 24%; PD, n=15, 37%). At six months, 48% of patients were progression-free, and 85% were alive. Compared to baseline, the 3-month EORTC QLQ-C30 questionnaire indicated improved perceptions of overall health (P=0.025) and overall quality of life (P=0.059), with no difference between the protocol and non-protocol groups.
Study Conclusion
Navulimumab adjusted according to CAR-T expansion is safe for patients with PD during lymphodepletion and is associated with excellent remission rates. However, the duration of remission remains insufficient, and future studies need to address this issue to further improve survival.
Literature 3
Effective Treatment of Post-Transplant Recurrence in Young ALL Patients: A Real-World Study Post-Approval of Tisagenlecleucel
Author: Laura M. Moser (Germany)
Study Background
Relapse of high-risk acute lymphoblastic leukemia (ALL) post-hematopoietic stem cell transplantation (HSCT) poses a significant challenge due to scarce treatment options. Tisagenlecleucel (Tisa-cel), a CD19-targeted CAR-T cell therapy, has previously shown promising results in patients under 25 years of age with post-transplant recurrence.
Study Methods
The study included 210 patients from 28 European centers who received Tisa-cel treatment for post-transplant recurrence between September 2018 and September 2023. The median age of the patients was 10 years (range 0.9-25.3).
Study Results
The pre-HSCT conditioning regimens included TBI for 93 patients (55%), a thiotepa-based regimen for 39 (23%), and a busulfan-based regimen for 35 (21%) (1 other, 42 unspecified). Early post-transplant relapses (within 6 months of HSCT) occurred in 55 patients (26%), and late relapses in 154 (74%). Before lymphodepletion, 62% of patients had ＜5% leukemic cells in the bone marrow (23% MRD-; 39% MRD+), while 38% had ≥5%. By day 28 post-CAR-T treatment, 196 patients (93%) achieved complete remission (CR), with 2 deaths (1%) related to CAR-T cell toxicity. Cytokine release syndrome (CRS) occurred in 124 patients
(59%), with 16 (8%) experiencing grade ≥3 CRS. Neurotoxicity associated with immune effector cells (ICANS) occurred in 25 patients (12%), with 10 (5%) experiencing grade ≥3 ICANS.
The median follow-up was 30.0 months (range 0.6-59.9), with a 2-year event-free survival (EFS) of 42.1% (±3.9%) and a 2-year overall survival (OS) of 66.5% (±3.7%). The non-relapse mortality rate was 1.1% (±0.7%). Both the leukemia burden before LDC and the timing of post-HSCT relapse significantly influenced prognosis; MRD- patients at LDC had significantly higher 2-year EFS (56.8%±8.7%) and OS (80.7%±6.8%) compared to MRD+ patients (EFS 48.1%±6.1%; OS 68.8%±5.8%) or non-remission (NR) patients (EFS 27.3%±5.8%; OS 54.4%±6.3%). EFS (21.5%±7.2%) and OS (45.9%±7.8%) for early relapse patients were lower than for late relapse patients (2-year EFS 48.7%±4.6%; OS 73.6%±4.0%, P<0.001). Late relapse patients had a lower cumulative incidence of relapse (CIR) (47.4%±4.6% vs. 68.1%±8.2%, P=0.019).
Two years post-CAR-T infusion, 37.3% (±4.5%) of patients continued to exhibit B-cell aplasia. Relapses after two years were mostly CD19+ (2-year CIR 33.3% ±3.8% vs. 15.5% ±2.7%), with CD19- relapses occurring earlier and having worse prognosis: 2-year OS for CD19+ relapse was 39.9% (±7.4%), compared to 23.3% (±8.3%) for CD19- relapse (P=0.007).
Study Conclusion
Real-world data from Europe indicates that Tisa-cel treatment is promising for children and young adults relapsing more than six months post-HSCT. Notably, leukemia burden at lymphodepletion and early post-HSCT relapse are considered adverse factors for EFS and OS. The results emphasize the need for more effective alternative treatment strategies for these high-risk groups.
Expert Profile
Linhua Yang
Second-Level Professor, PhD Supervisor, Recipient of the State Council Special Allowance
Head of the Department of Hematology at the Second Hospital of Shanxi Medical University, Director of the Institute of Hematology at Shanxi Medical University
Standing Committee Member of the Chinese Society of Hematology, Chinese Medical Association
Vice Chair of the Hematology Committee of the Chinese Medical Education Association
Vice Chair of the Hematology Precision Diagnosis and Treatment Committee of the Chinese Research Hospital Association
Council Member of the Chinese Geriatrics Society
Standing Committee Member of CSCO for Leukemia and Lymphoma in China
Standing Committee Member of the Hematologic Oncology Committee, Chinese Women’s Physician Association
Standing Committee Member of the Hemato-Immunology Branch, Chinese Society of Pathophysiology
President of the Hematology Physicians Branch of the Shanxi Medical Association
Chairman of the Leukemia and Lymphoma Committee, Shanxi Anti-Cancer Association
Leading Talent in Emerging Industries of Shanxi Province
High-end Leading Talent of Sanjin Talent in Shanxi Province
Editorial Board Member of the Chinese editions of “Hemophilia” and “Blood,” and editor for journals such as “Chinese Journal of Hematology,” “Chinese Journal of Internal Medicine,” and “Chinese General Practice.”
