The European Society for Blood and Marrow Transplantation (EBMT) annual meeting is one of the most influential international academic conferences in the field of hematology. The 50th EBMT annual meeting (EBMT 2024) was held from April 14 to April 17 in Glasgow, UK, bringing together nearly 6,000 experts and scholars from around the world to discuss the latest research on hematopoietic stem cell transplantation and cell therapy. In this issue, “Oncology Frontier – Hematology Frontier” has specially invited Director Pan Jing from Beijing Gaobo Hospital to comment on two studies in the field of acute lymphoblastic leukemia (ALL).
Study 1 Long-term follow-up data of gene-edited “universal” CD19 CAR-T cells in treating relapsed/refractory pediatric B-ALL: A single-center study
Background
Gene-edited allogeneic chimeric antigen receptor (CAR) T cells provide a “universal” option compared to autologous CAR-T cells. Great Ormond Street Hospital (GOS) has developed an editing strategy that disrupts the expression of T-cell receptor (TCRαβ) and CD52. This editing aims to prevent graft-versus-host disease (GVHD) mediated by donor T cells mismatched for HLA, and allows the persistence of these cells in the presence of alemtuzumab. Following initial compassionate use of TALEN-edited CD19 CAR-T cells in two infants with B-ALL, six additional children were treated as part of the UCAR19 (NCT02808442) phase I clinical trial, and seven children received CRISPR/Cas9 gene-edited TT52CD19 CAR-T cells (NCT04557436). This study investigated the long-term follow-up of patients who achieved remission with these universal cell therapies and were subsequently bridged to allogeneic hematopoietic stem cell transplantation (allo-HSCT).
Methods
This study reviewed the outcomes of pediatric patients (ages 0.8-16 years) treated at GOS with UCART19 (1.1-4.6×10^6/kg) or TT52CAR19 (0.8-2.0×10^6/kg) CD19 CAR-T cells from 2015 to 2022. Collected data included overall survival (OS), disease-free survival (DFS), incidence of graft-versus-host disease (GVHD), chimerism, detected vector copy numbers, and immune reconstitution. The study used an enhanced lymphodepletion (ALD) regimen in 12 out of 15 children, including fludarabine (total dose 150 mg/m^2), cyclophosphamide (120 mg/kg), and alemtuzumab (1 mg/kg).
Results
Overall, 11 out of 15 patients (73%) achieved complete remission (CR/CRi) 28 days post-cell therapy as determined by bone marrow flow cytometry with no detectable disease, and 8 out of 15 (53%) were also confirmed to be minimal residual disease-negative (MRD<10^-4) by polymerase chain reaction (PCR). Allogeneic hematopoietic stem cell transplantation (allo-HSCT) was performed in the subsequent four weeks, with most patients (64%) undergoing a reduced-intensity conditioning (RIC) regimen that included anti-thymocyte globulin (ATG) and low-dose (2-4 Gy) total body irradiation (TBI). Seven out of the eleven transplant recipients were undergoing their second transplantation, with six of them using the previous donor.
Among the children who underwent transplantation with a PCR MRD<10^-4, 7 out of 8 (88%) achieved sustained molecular remission. Despite one patient dying from post-transplant complications while in remission, six patients maintained sustained remission, accounting for 40% (6/15) of overall survival. The overall survival (OS) and disease-free survival (DFS) are depicted in Figure 1. All surviving participants showed normal immune reconstitution (CD4-T cells > 300/mm^3) within 12 months post-stem cell transplantation (SCT), and patients receiving intravenous immunoglobulin (IVIG) discontinued replacement therapy. After the conditioning regimen and allogeneic stem cell transplantation (allo-SCT), no patients had persistent allo-CAR-T cells.
Conclusion
Long-term follow-up data from a single center on children treated with gene-edited allogeneic CD19 CAR-T cells show that patients who underwent transplantation while in molecular (PCR) MRD remission achieved sustained remission. Despite receiving multilayered treatments including CARs, Bi-specific T-cell Engagers (BiTEs), and previous transplants, the overall survival rate at our center is comparable to a broader setting of autologous CAR19 therapy. Notably, all surviving participants had undergone intensified lymphodepletion prior to CD19 CAR-T cell therapy, highlighting the importance of overcoming host-mediated barriers to allogeneic cells for deep and rapid leukemia clearance. The subsequent success of RIC transplantation aligns with donor source reconstitution rather than additional anti-leukemic chemotherapy effects.
Commentary
The content of the conference abstract pertains to a UK single-center study on the long-term follow-up of universal CD19 CAR-T treatment in children with refractory/relapsed B-ALL, incorporating retrospective data from 15 pediatric patients, involving clinical trials from 2015 to 2022. These trials focused on gene-edited universal CD19 CAR-T cells using TALEN and CRISPR/Cas9 technologies. The youngest leukemia patient was eight months old and the oldest was sixteen, with a lymphodepletion regimen consisting of fludarabine, cyclophosphamide, and alemtuzumab used in twelve patients. Approximately one month post-cell therapy, 73% of the patients achieved complete remission, with 53% testing MRD negative. This data aligns with early reports from the US on long-term universal CD19 CAR-T data. Four weeks later, patients underwent allogeneic transplantation with a reduced-intensity conditioning regimen including low-dose TBI, which is particularly relevant as TBI can reduce disease relapse in B-ALL patients. One patient died from transplant complications without disease relapse, while six maintained sustained remission, representing 40% of overall survival, with survival rates ranging between 30-40%. In terms of other quality of life indicators such as immune recovery and the necessity for continuous intravenous immunoglobulin, no patients were found to have persistent universal CAR-T cells post-transplant, and all showed immune reconstitution, including B and T cell recovery, within about 12 months post-transplant, thus eliminating the need for ongoing IVIG injections.
This study highlights the significance of universal CD19 CAR-T as a viable option for patients unable to undergo autologous CD19 CAR-T therapy. It includes two infant leukemia patients, who are also ideal candidates for universal CD19 CAR-T due to their young age and inability to collect adequate cells. While the remission rates for universal CD19 CAR-T are not as high as those for autologous treatments, subsequent transplantation is necessary to improve overall patient prognosis.
Study 2 Relapse of Pediatric Acute Lymphoblastic Leukemia Post CAR-T Cell Therapy: A Multi-Center Analysis by the Spanish Society for Bone Marrow Transplantation and Cell Therapy (GETH-TC) Pediatric Committee
Background
In patients with acute lymphoblastic leukemia (ALL), relapse following allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains a primary cause of transplant failure. Therapeutic approaches have evolved from palliative care and salvage chemotherapy to second transplants and now to current strategies based on immunotherapy and CAR-T cell therapy. This study analyzes the relapse of pediatric ALL patients post-HSCT across ten Spanish hospitals associated with the Spanish Society for Bone Marrow Transplantation (GETH) Pediatric Committee.
Methods
This retrospective study included 73 pediatric ALL patients (38 males, 35 females) who relapsed post-allo-HSCT from 2013 to 2021, with a median age of 7 years (range 1-21 years). B-cell ALL was present in 54 cases (74%), T-cell in 17 (23%), and mixed phenotype in 2 (3%). Disease status at the time of transplantation was first complete remission (CR) in 12 cases (16%), second CR in 53 (73%), and beyond second CR in 8 (11%). All patients were in hematological remission, but 21 (29%) were MRD positive at the time of their first allo-HSCT. Donors included matched sibling donors (MSD) for 24 patients (32%), mismatched unrelated donors (MUD) for 20 (27%), haploidentical donors for 27 (37%), and cord blood units (CBU) for 2 (4%). Sixty-two patients (85%) received myeloablative conditioning, and 17 (24%) underwent a conditioning regimen based on total body irradiation (TBI). Chronic graft-versus-host disease (GvHD) developed in 11 patients (15%).
Results
Median time to post-transplant relapse was 7 months (range 1-59 months). Thirty patients received CAR-T cell therapy (10 post-chemotherapy, 3 post-monoclonal antibody treatment). Among those treated with CAR-T cells, 27 (90%) achieved MRD-negative complete remission (CR), two died from cytokine release syndrome, and one did not achieve CR. Among the 27 who reached CR, 11 relapsed after CAR-T cell therapy (relapse CI: 39±11%). Eighteen out of thirty remained alive and in CR (disease-free survival [DFS]: 52±13%). For patients relapsing before 6 months post-transplant, the DFS was significantly lower compared to those relapsing after 6 months (15±6% vs. 48±6%, P=0.0001).
Nineteen patients underwent a second allo-HSCT (17 with different donors than the first transplant). Two patients underwent HSCT post-CAR-T cell therapy. Donor types were MUD for 8 (42%), haploidentical for 10 (53%), and CBU for 1 (5%). Three patients died from transplant-related mortality (TRM CI: 25±14%). Twelve patients relapsed (relapse CI: 65±11%), of which two were salvaged by CAR-T cell therapy. Eight out of nineteen patients survived and were in CR post-second transplant (DFS: 38±12%) (as shown in Figure B). No patients who relapsed within six months of the first transplant survived a second transplant.
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Fifteen patients received chemotherapy but experienced disease progression before consolidation treatment could be administered. Nine patients received only palliative care. The median follow-up time was 4 years (range 1-8 years). Of the 73 patients, 28 survived, with 24 in complete remission (CR), implying a disease-free survival (DFS) rate of 21±6%.
Conclusion
Currently, patients who relapse more than 6 months after transplantation have a real opportunity to be salvaged through immunotherapy or a second transplant. The results also indicate a shift in the treatment of post-transplant relapsed ALL patients towards cellular therapies and immunotherapies rather than a second allo-HSCT.
Commentary
This abstract from the conference covers a multicenter, retrospective study conducted from 2013 to 2021 across ten Spanish hospitals. It explores subsequent treatment options and outcomes for pediatric and adolescent patients with acute lymphoblastic leukemia (ALL) who relapsed after their first transplant. Among these 73 pediatric relapse cases, the median age was 7 years, with the oldest being 21 and the youngest 1. This data retrospectively indicates whether survival has improved in the new era of immune therapies, showing a median relapse time of about 7 months, ranging from 1 to 59 months post-transplant. Thirty of these patients chose CAR-T cell therapy. After receiving CAR-T cell therapy, 90% achieved MRD-negative complete remission. Some patients opted for a second transplant, while others did not. Among the 27 patients who did not undergo a second transplant, 11 experienced a relapse after CAR-T therapy, with a relapse rate of approximately 39%, and 52% remained MRD-negative. The survival curves suggest that the long-term survival data for post-transplant relapse in B-cell ALL patients are significantly better than before. The disease-free survival rate for the 19 patients who chose a second transplant was about 38%, with outcomes not as favorable as those who received CAR-T therapy.
Combining this abstract with our own clinical experience, a clear statistical difference is evident, particularly among patients who are more likely to relapse after post-transplant or after receiving CAR-T therapy or a second transplant, potentially leading to worse survival rates. Therefore, the remission rate for patients who relapse post-transplant is likely very high, making CAR-T cell therapy an excellent option for these patients. Currently in China, especially at our center (Gaobo Medical [Hematology] Beijing Research Center, Beijing Gaobo BoRen Hospital), CAR-T cell therapy is the preferred treatment for relapsed B-cell ALL due to its high remission rates. Our center’s several five-year phase I and II studies have shown that while there is indeed a 40%-50% relapse rate among patients treated with a single target, combining CAR-T therapy with (or other centers’) multi-target vascular reintroduction of CD19 and CD22 can significantly improve the long-term disease-free survival of post-transplant patients. Retrospective data shows that for post-transplant relapsed patients who achieve remission with CAR-T, especially in children and adolescents, it is necessary to consider whether a second transplant is essential. Our center is currently conducting a prospective cohort study to hopefully provide answers in the coming years.
