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Impact of T-cell dose on the outcome of T-cell replete HLA matched allogeneic peripheral blood stem cell transplantation
Saad, A., Lamb, L., Wang, T., Hemmer, M. T., Spellman, S., Couriel, D., Alousi, A., Pidala, J., Abdel-Azim, H., Agrawal, V., et al
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2019
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Editor's Choice
Abstract
BACKGROUND Data on whether T-cell dose of allogeneic peripheral blood stem cell (PBSC) product influences transplant outcome are conflicting. METHODS Using CIBMTR database, we identified 2,736 adult patients who underwent first allogeneic peripheral blood stem cell (PBSC) transplant for acute leukemia (AML, ALL) or myelodysplastic syndrome (MDS) between 2008-2014 using an HLA-matched sibling donor (MSD) or 8/8-matched unrelated donor (MUD). We excluded ex-vivo and in-vivo T-cell depleted transplants. Correlative analysis was performed between CD3+ T-cell dose and risk of graft-versus-host-disease (GVHD), relapse, non-relapse mortality (NRM), disease free survival (DFS) and overall survival (OS). RESULTS Using maximum likelihood estimation method, we identified CD3+ T-cell cell dose cutoff that separated risk of acute GVHD (aGVHD) grade II-IV in both MSD and MUD groups. A CD3+ T-cell dose cutoff of 14x10(7) cells/kg identified MSD/low CD3+ (n=223) and MSD/high CD3+ (n=1214), and a dose of 15x10(7) cells/kg identified MUD/low CD3+ (n=197) and MUD/high CD3+ (n=1102). With univariate analysis, MSD/high CD3+ group had higher cumulative incidence of day 100 aGVHD grade II-IV of 33% vs 25% when compared to MSD/low CD3+ group (P value =0.009). There was no other difference between both groups in engraftment rate, risk of aGVHD grade III-IV or chronic GVHD (cGVHD), NRM, relapse, DFS, or OS. MUD/high CD3+ group had higher cumulative incidence of day 100 aGVHD grade II-IV of 49% vs 41% when compared to MUD/low CD3+ group (P value =0.04). There was no other difference between both groups in engraftment rate, risk of severe aGVHD or cGVHD, NRM, relapse, DFS, or OS. Multivariate analysis of MSD and MUD groups failed to show an association between CD3+ T-cell dose and risk of either aGVHD grade II-IV (p value =0.1 and 0.07 respectively) or cGVHD (p value=0.8 and 0.3 respectively). Sub-analysis of CD4, CD8 and CD4/CD8 ratio failed to identify cutoff values predictive of transplant outcome. Using log-rank test, the sample size was, however, suboptimal to identify difference at these cutoff cell dose. CONCLUSION In this registry study, CD3+ T-cell dose of PBSCT product did not influence risk of aGVHD or cGVHD or other transplant outcomes when using HLA-matched sibling or 8/8 unrelated donors. Subset analysis of CD4+ and CD8+ T-cell dose was not possible for small sample size.
PICO Summary
Population
Patients reported to CIBMTR database with acute leukaemia (ALL or AML) or myelodysplastic syndrome between 2008-2014 (n=2736)
Intervention
First allogeneic peripheral blood stem cell using an HLA-matched sibling donor (MSD)
Comparison
8/8-matched unrelated donor (MUD)
Outcome
Using maximum likelihood estimation method, we identified CD3+ T-cell cell dose cutoff that separated risk of acute GVHD (aGVHD) grade II-IV in both MSD and MUD groups. A CD3+ T-cell dose cutoff of 14x10(7) cells/kg identified MSD/low CD3+ (n=223) and MSD/high CD3+ (n=1214), and a dose of 15x10(7) cells/kg identified MUD/low CD3+ (n=197) and MUD/high CD3+ (n=1102). With univariate analysis, MSD/high CD3+ group had higher cumulative incidence of day 100 aGVHD grade II-IV of 33% vs 25% when compared to MSD/low CD3+ group. MUD/high CD3+ group had higher cumulative incidence of day 100 aGVHD grade II-IV of 49% vs 41% when compared to MUD/low CD3+ group. Multivariate analysis of MSD and MUD groups failed to show an association between CD3+ T-cell dose and risk of either aGVHD grade II-IV or cGVHD. Sub-analysis of CD4, CD8 and CD4/CD8 ratio failed to identify cutoff values predictive of transplant outcome.
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Clinical utilization of Chimeric Antigen Receptor T-cells (CAR-T) in B-cell acute lymphoblastic leukemia (ALL)-an expert opinion from the European Society for Blood and Marrow Transplantation (EBMT) and the American Society for Blood and Marrow Transplantation (ASBMT)
Kansagra, A. J., Frey, N. V., Bar, M., Laetsch, T. W., Carpenter, P. A., Savani, B. N., Heslop, H. E., Bollard, C. M., Komanduri, K. V., Gastineau, D. A., et al
Bone marrow transplantation. 2019
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Editor's Choice
Abstract
On August 30, 2017, the U.S. Food and Drug Administration (US-FDA) approved tisagenlecleucel (KYMRIAH, Novartis, Basel, Switzerland), a synthetic bioimmune product of anti-CD19 chimeric antigen receptor-T cells (CAR-T), for the treatment of children and young adults with relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL). With this new era of personalized cancer immunotherapy, multiple challenges are present ranging from implementation of a CAR-T program to safe delivery of the drug, long-term toxicity monitoring and disease assessments. To address these issues, experts representing the American Society for Blood and Marrow Transplant (ASBMT), the European Group for Blood and Marrow Transplantation (EBMT), the International Society of Cell and Gene Therapy (ISCT), and the Foundation for the Accreditation of Cellular Therapy (FACT), formed a global CAR-T task force to identify and address key questions pertinent for hematologists and transplant physicians regarding the clinical use of anti CD19 CAR-T therapy in patients with B-ALL. This article presents an initial roadmap for navigating common clinical practice scenarios that will become more prevalent now that the first commercially available CAR-T product for B-ALL has been approved.
PICO Summary
Population
Children and young adults with relapsed/refractory B-cell acute lymphoblastic leukemia
Intervention
Expert opinion on clinical utilization of Chimeric Antigen Receptor T-cells (CAR-T) in B-cell acute lymphoblastic leukemia
Comparison
None
Outcome
An initial roadmap for navigating common clinical practice scenarios since the approval of the first commercially available CAR-T product for B-ALL.