Editor’s Note: The 50th Annual Meeting of the European Society for Blood and Marrow Transplantation (EBMT) was held from April 14th to 17th in Glasgow, United Kingdom, showcasing the latest advancements in stem cell transplantation and cell therapy. These advancements are driving better clinical outcomes for patients with hematological diseases and blood cancers. At this year’s conference, two studies conducted by Professor Xiaoyan Ke from Peking University Third Hospital/Beijing Chaoyang Hospital and Professor Kai Hu from Beijing Chaoyang Hospital were presented, highlighting how combined autologous hematopoietic stem cell transplantation and CAR-T cell therapy can improve survival rates for lymphoma and multiple myeloma patients.
Study One
Combining Autologous Hematopoietic Stem Cell Transplantation with CAR-T Cell Therapy Significantly Improves Progression-Free Survival in Relapsed/Refractory Central Nervous System Lymphoma
Presenter: Rui Liu
Background:
Treating relapsed/refractory central nervous system lymphoma (R/R CNSL) presents clinical challenges. CAR-T therapy has shown effectiveness in relapsed/refractory diffuse large B-cell lymphoma, and studies have indicated a high response rate in R/R CNSL treatment. However, the progression-free survival and long-term efficacy are not satisfactory. This study aims to explore the efficacy of CAR-T in R/R CNSL and factors influencing long-term survival. Additionally, the safety and efficacy of combining autologous hematopoietic stem cell transplantation (ASCT) with CAR-T therapy were analyzed.
Methods:
This single-center retrospective study analyzed patients with R/R CNSL who received CAR-T therapy at Beijing Chaoyang Hospital from March 2019 to August 2023. Baseline characteristics are shown in Table 1. 68% (47/69) had brain parenchymal involvement, 17% (12/69) had central nervous system (CNS) involvement, and 14% (10/69) had both. 65.2% (45/69) of patients achieved objective responses after bridging therapy, with 33 cases of complete response (CR) and 12 cases of partial response (PR). Based on the response to bridging therapy, patients were divided into two groups: Bridging Effective (BE), including CR/PR patients, and Bridging Ineffective (BI), including stable disease (SD)/disease progression (PD) patients. In the BE group, 53.3% (24/45) of patients underwent ASCT combined with CAR-T therapy.
Study Results:
The objective response rate (ORR) at 3 months was 70% (48/69), with a complete response rate (CRR) of 61% (42/69). The incidence of any grade cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) was 70% (48/69) and 12% (8/69), respectively, while the incidence of severe (≥ grade 3) CRS and ICANS was 12.5% (6/48) and 62.5% (5/8), respectively. Compared to the BI group, the BE group showed significantly higher 3-month ORR (84.4% vs. 41.6%) and CRR (82.2% vs. 20.8%).
The median follow-up time was 22.65 months. The median progression-free survival (PFS) in the BE group was 43.07 months, significantly longer than 6.08 months in the BI group (P<0.0001). The median overall survival (OS) was not reached in the BE group, while it was 12.79 months in the BI group (P<0.0001, Figure 1). The 1-year OS rates were 100% and 51.4% in the BE and BI groups, respectively (P<0.0001), and the 1-year PFS rates were 74.7% and 9.9%, respectively (P<0.0001).
Among the 45 patients in the BE group, there were more patients with ECOG PS score ≥2 in the ASCT combined with CAR-T treatment cohort, with more prior lines of therapy, and all were resistant to HD-MTX (Table 2). Compared to the CAR-T-only cohort, patients in the ASCT combined with CAR-T cohort had a significantly prolonged median PFS (not reached vs. 14.76 months, P=0.0008). The median OS in this cohort was not reached, while it was 27.48 months in the CAR-T-only cohort. However, the difference between the two cohorts was not statistically significant (Figure 2). There were also no statistically significant differences in CRS and ICANS between the two cohorts.
Study Conclusion:
Effective bridging therapy significantly improves the efficacy of CAR-T therapy in treating R/R CNSL. Following effective bridging therapy, the treatment modality of ASCT combined with CAR-T significantly improves progression-free survival.
Study Two
Allogeneic Hematopoietic Stem Cell Transplantation with Donor-Derived CAR-T Cells as a Preparative Regimen for Relapsed/Refractory B-Cell Lymphoma and Multiple Myeloma Following Prior CAR-T Therapy Failure
Presenter: Fan Yang
Background:
The prognosis for relapsed/refractory aggressive B-cell lymphoma (R/R B-NHL) and multiple myeloma (R/R MM) following failure of autologous chimeric antigen receptor T-cell (CAR-T) therapy is extremely poor.
Objective:
This study aims to evaluate the efficacy and safety of allogeneic hematopoietic stem cell transplantation (allo-HSCT) using donor-derived CAR-T cells (allo-CAR-T) as a preparative regimen for patients with R/R B-NHL and R/R MM who have failed prior CAR-T cell therapy.
Methods:
From September 2020 to November 2023, a total of 18 patients were enrolled, with a median age of 41 (range: 26-64) years. Diagnoses included diffuse large B-cell lymphoma (not otherwise specified) (DLBCL-NOS) (5 cases), high-grade B-cell lymphoma (6 cases), Burkitt lymphoma (3 cases), and multiple myeloma (4 cases). 11 patients carried TP53 mutations. Disease status included 4 patients with disease progression (PD), 7 with partial response (PR), and 7 with complete response (CR), all of whom had received multiple lines of treatment, including autologous hematopoietic stem cell transplantation (ASCT, 7 cases), local radiation (7 cases), and anti-PD-1 monoclonal antibody therapy (5 cases). Prior to the trial, pathology confirmed positive expression of CD19 and CD22 antigens in R/R B-NHL patients and positive expression of BCMA antigen in R/R MM patients. There were 4 matched sibling donors, 1 matched unrelated donor, and 13 haploidentical donors. A regimen based on busulfan and fludarabine was used in combination with allo-CAR-T as a preparative regimen. Calcium channel inhibitors, mycophenolate mofetil, short-term methotrexate, and/or anti-thymocyte globulin were used for the prevention of graft-versus-host disease (GVHD).
Results:
The median number of infused allo-CAR-T cells was 2 (range: 0.2-4.88) × 106/kg. CRS occurred in 16 patients, including 4 cases of grade III, with no occurrences of immune effector cell-associated neurotoxicity syndrome (ICANS). Peripheral blood stem cells mobilized with granulocyte colony-stimulating factor were infused 7 days after allo-CAR-T, with a median CD34+ cell count of 6 (range: 3-8.19) × 106/kg. The median time to neutrophil and platelet engraftment was 15 days (range: 11-24 days) and 16 days (range: 13-65 days) post-transplant, respectively. Bone marrow STR analysis at 28 days post-transplant showed donor chimerism in all 18 cases (100%). Two patients developed grade III acute GVHD. The median time to peak CAR-T cell expansion in vivo was 5 days (range: 1-20 days) post-infusion. The median peak level of CAR-T cells detected by PCR was 50.81% (range: 0.091-116). aGVHD was not directly associated with in vivo expansion of allogeneic CAR-T cells. Seven out of 18 (38.9%) patients had low levels of CAR-T cells within 2 months post-HSCT, which lasted for up to 5 months, with the longest duration being 239 days post-transplant. At a median follow-up time of 8.9 months (range: 0.69-133.8 months), 17 patients (17/18, 94.4%) achieved CR, with the longest duration of response (DoR) being 34.5 months. Six patients experienced disease relapse after achieving remission, and 4 of these (4/6, 66.6%) received treatment with donor-derived allo-CAR-T cells upon relapse, with 3 of them (3/4, 75%) achieving CR again.
The 2-year progression-free survival (PFS) rate and overall survival (OS) rate were 30.2% (95% CI: 9.5-54.3) and 40.4% (95% CI: 14.7-65.2), respectively. In comparison, the PFS and OS of the pre-transplant PR/CR cohort were significantly longer than those of the PD cohort, with median PFS of 10.2 months vs. 1.9 months (P=0.0006) and median OS of 14.8 months vs. 6.5 months (P=0.0178), respectively. Four out of 18 (22.2%) patients with pre-transplant PD died due to disease progression, and 4 patients (4/18, 22.2%) died due to infection.
Study Conclusion:
The use of allo-CAR-T cells as a preparative regimen for allo-HSCT is a safe and effective strategy for patients with R/R B-NHL and MM who have failed CAR-T cell therapy. CRS is manageable and does not affect hematopoietic reconstitution. Acute GVHD and viral reactivation are mild. Poor clinical outcomes are associated with higher tumor burden prior to transplantation.
