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Safety of allogeneic hematopoietic cell transplant in adults after CD19-targeted CAR T-cell therapy.

ABSTRACT: Allogeneic hematopoietic cell transplantation (allo-HCT) is offered to selected patients after chimeric antigen receptor-modified T-cell (CAR-T) therapy. Lymphodepleting chemotherapy and CAR-T therapy have immunosuppressive and immunomodulatory effects that could alter the safety profile of subsequent allo-HCT. We reviewed our experience with 32 adults (acute lymphoblastic leukemia [ALL], n = 19; B-cell non-Hodgkin lymphoma [NHL]/chronic lymphocytic leukemia [CLL], n = 13) who received an allo-HCT after CAR-T therapy, with a focus on posttransplant toxicities. Myeloablative conditioning (MAC) was used in 74% of ALL patients and 39% of NHL/CLL patients. The median time from CAR-T therapy to allo-HCT was 72 days in ALL patients and 122 days in NHL/CLL patients. Cumulative incidences of grade 3-4 acute graft-versus-host disease (GVHD) and chronic GVHD were 25% and 10%, respectively. All patients had neutrophil recovery (median, 18.5 days) and all but 3 had platelet recovery (median, 12 days). Twenty-two percent had viral or systemic fungal infection within 100 days after allo-HCT. The 100-day and 1-year cumulative incidences of NRM were 16% and 21%, respectively, for ALL patients and 15% and 33%, respectively, for NHL/CLL patients. In ALL patients, later utilization of allo-HCT after CAR-T therapy was associated with higher mortality. In NHL/CLL patients, MAC was associated with higher mortality. Toxicities did not exceed the expected incidences in this high-risk population.

SUBMITTER: Shadman M

PROVIDER: S-EPMC6849954 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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Safety of allogeneic hematopoietic cell transplant in adults after CD19-targeted CAR T-cell therapy.

Shadman Mazyar M Gauthier Jordan J Hay Kevin A KA Voutsinas Jenna M JM Milano Filippo F Li Ang A Hirayama Alexandre V AV Sorror Mohamed L ML Cherian Sindhu S Chen Xueyan X Cassaday Ryan D RD Till Brian G BG Gopal Ajay K AK Sandmaier Brenda M BM Maloney David G DG Turtle Cameron J CJ

Blood advances 20191001 20

Allogeneic hematopoietic cell transplantation (allo-HCT) is offered to selected patients after chimeric antigen receptor-modified T-cell (CAR-T) therapy. Lymphodepleting chemotherapy and CAR-T therapy have immunosuppressive and immunomodulatory effects that could alter the safety profile of subsequent allo-HCT. We reviewed our experience with 32 adults (acute lymphoblastic leukemia [ALL], n = 19; B-cell non-Hodgkin lymphoma [NHL]/chronic lymphocytic leukemia [CLL], n = 13) who received an allo-H ...[more]

PMID: 31648329

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Project description:Objective: This study aimed to evaluate the maintenance therapy following an anti-CD19-CAR T-cell therapy for a B-cell acute lymphoblastic leukemia (ALL) patient who relapsed after allogeneic hematopoietic cell transplantation (allo-HSCT) and investigate the effect of donor stem cells and donor T lymphocyte infusion on the amplification of CD19 CAR-T cells. Methods: One refractory B-ALL patient relapsed after murine CD19 CAR-T cell therapy followed by a sibling allo-HSCT. He underwent a humanized CD19 CAR-T cell therapy followed by donor stem cell and donor T lymphocytes infusions as maintenance therapy in our hospital. The level of cytokines, the proportion of CD19 CAR-T cell, the level of CAR19 DNA expression in the peripheral blood, and the proportion of leukemia cells and donor chimerism in the bone marrow were detected. Correspondingly, T lymphocytes from the C57 spleen were separated to modify the CD19 CAR lentivirus and refused into C57 mice, and after 14 days, the B lymphocytes from C57 mice were separated and refused into the same C57 mice. The CD19 CAR T cells, B cells, and CD19 CAR gene counts in the peripheral blood were evaluated at different time points. Results: ?The patient achieved a complete response (CR) 14 days after a humanized CD19 CAR-T therapy with grade 1 cytokine release syndrome (CRS) and restored a donor chimerism to 99.76%. ? Following the remission from humanized CD19 CAR-T therapy, the patient received a maintenance therapy of donor stem cell infusion. Mild graft-versus-host disease (GVHD) manifested 24 days after infusion with an increased proportion of CD19 CAR-T cells and an increased level of CAR19 DNA expression in the peripheral blood. It fell with the remission of GVHD. The patient maintained CR and 99.69% donor chimerism during this period. ? Throughout the subsequent donor T lymphocytes maintenance therapy, mild GVHD surfaced12 days after infusion without an increased proportion of CD19 CAR-T cells and an increased level of CAR19 DNA expression in the peripheral blood. The patient maintained CR and 99.87% donor chimerism during this period. ? In vivo experiments on C57 mice confirmed that the proportion of CD19 CAR-T cells and the level of CAR19 DNA expression were upregulated in mice following CAR-T cell infusion, accompanied by depletion of CD19(+) B lymphocyte. After infusion of CD19(+) B lymphocyte cells, an increased proportion of CD19 CAR-T cells and an increased level of CAR19 DNA expression in the peripheral blood were observed again. Conclusions: The infusion of donor stem cells and donor T lymphocytes could be used as a maintenance treatment after CD19 CAR-T cell therapy for B-ALL patients who relapsed after allo-HSCT. Infusion of donor stem cells induced an increased proportion of CD19 CAR-T cells and an increased level of CAR19 DNA expression with the occurrence of GVHD. It might lead to further elimination of minimal residual disease.

Project description:Early response could be obtained in most patients with relapsed or refractory B cell lymphoblastic leukemia (R/R B-ALL) treated with chimeric antigen receptor T-cell (CAR-T) therapy, but relapse occurs in some patients. There is no consensus on treatment strategy post CAR-T cell therapy. In this retrospective study of humanized CD19-targeted CAR-T cell (hCART19s) therapy for R/R B-ALL, we analyzed the patients treated with allogeneic hematopoietic stem cell transplantation (allo-HSCT) or received a second hCART19s infusion, and summarized their efficacy and safety. We retrospectively studied 28 R/R B-ALL patients treated with hCART19s in the Affiliated Hospital of Xuzhou Medical University from 2016 to 2020. After the first hCART19s infusion, 10 patients received allo-HSCT (CART+HSCT group), 7 patients received a second hCART19s infusion (CART2 group), and 11 patients did not receive HSCT or a second hCART19s infusion (CART1 group). The safety, efficacy, and long-term survival were analyzed. Of the 28 patients who received hCART19s treatment, 1 patient could not be evaluated for efficacy, and 25 (92.6%) achieved complete remission (CR) with 20 (74.7%) achieving minimal residual disease (MRD) negativity. Seven (25%) patients experienced grade 3-4 CRS, and one died from grade 5 CRS. No patient experienced ≥3 grade ICANS. The incidence of second CR is higher in the CART+HSCT group compared to the CART2 group (100% vs. 42.9%, p=0.015). The median follow-up time was 1,240 days (range: 709–1,770). Significantly longer overall survival (OS) and leukemia-free survival (LFS) were achieved in the CART+HSCT group (median OS and LFS: not reached, p=0.006 and 0.001, respectively) compared to the CART2 group (median OS: 482; median LFS: 189) and the CART1 group (median OS: 236; median LFS: 35). In the CART+HSCT group, the incidence of acute graft-versus-host disease (aGVHD) was 30% (3/10), and transplantation-related mortality was 30% (3/10). No chronic GVHD occurred. Multivariate analysis results showed that blasts ≥ 20% in the bone marrow and MRD ≥ 65.6% are independent factors for inferior OS and LFS, respectively, while receiving allo-HSCT is an independent factor associated with both longer OS and LFS. In conclusion, early allo-HSCT after CAR-T therapy can achieve long-term efficacy, and the adverse events are controllable.

Project description:Importance:Studies demonstrating improved survival after allogeneic hematopoietic cell transplant generally exclude infants. Objective:To analyze overall survival trends and other outcomes among infants who undergo allogeneic hematopoietic cell transplant. Design, Setting, and Participants:In this cohort study, we used time-trend analysis to evaluate 3 periods: 2000 through 2004, 2005 through 2009, and 2010 through 2014. The study was conducted in a multicenter setting through the Center for International Blood and Marrow Transplant Research, which is made up of a voluntary working group of more than 450 transplant centers worldwide. Two groups of infants aged 1 year or younger in 2 cohorts were included: those with malignant conditions, such as leukemia, and those with nonmalignant disorders, including immunodeficiencies. Data analysis was conducted from July 2017 to December 2018. Exposures:Allogeneic hematopoietic cell transplant. Main Outcomes and Measures:Survival trends, disease relapse, and toxicity. Results:A total of 2498 infants with a median age of 7 months (range, <1-12 months) were included. In the nonmalignant cohort (n = 472), survival rates improved from the first to the second period (hazard ratio, 0.77 [95% CI, 0.63-0.93]; P = .007) but did not change after 2004. Compared with infants with nonmalignant diseases (n = 2026; 3-year overall survival: 2000-2004, 375/577 [65.0%]; 2005-2009, 503/699 [72.0%]; and 2010-2014, 555/750 [74.0%]), those with malignant conditions had poorer survival rates, without improvement over time (3-year overall survival: 2000-2004, 109/199 [54.8%]; 2005-2009, 104/161 [64.6%]; and 2010-2014, 66/112 [58.9%]). From 2000 through 2014, relapse rates increased in infants with malignant conditions (3-year relapse rate: 2000-2004, 19% [95% CI, 14%-25%]; 2005-2009, 23% [95% CI, 17%-30%]; 2010-2014, 36% [95% CI, 27%-46%]; P = .01). Sinusoidal obstruction syndrome was frequent, occurring with a cumulative incidence of 13% (95% CI, 11%-16%) of infants with nonmalignant diseases and 32% (95% CI, 22%-42%) of those with malignant diseases. Generally, recipients of human leukocyte antigen-identical sibling bone marrow grafts had the best outcomes. Conclusions and Relevance:Survival rates have not improved for infants with malignant diseases over the 15-year study period. Infants with nonmalignant diseases had improved survival rates in the earlier but not the later study period. Higher relapses for the malignant cohort and toxicities for all infants remain significant challenges. Strategies to reduce relapse and toxicity and optimize donor and graft selection may improve outcomes in the future.

Dataset Information

Safety of allogeneic hematopoietic cell transplant in adults after CD19-targeted CAR T-cell therapy.

Publications

Safety of allogeneic hematopoietic cell transplant in adults after CD19-targeted CAR T-cell therapy.

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