Late Effects in Hematopoietic Cell Transplant Recipients with Acquired Severe Aplastic Anemia: A Report from the Late Effects Working Committee of the Center for International Blood and Marrow Transplant Research

With improvements in hematopoietic cell transplant (HCT) outcomes for severe aplastic anemia (SAA), there is a growing population of SAA survivors after HCT. However, there is a paucity of information regarding late effects that occur after HCT in SAA survivors. This study describes the malignant and nonmalignant late effects in survivors with SAA after HCT. A descriptive analysis was conducted of 1718 patients post-HCT for acquired SAA between 1995 and 2006 reported to the Center for International Blood and Marrow Transplant Research (CIBMTR). the prevalence and cumulative incidence estimates of late effects are reported for 1-year HCT survivors with SAA. of the HCT recipients, 1176 (68.5%) and 542 (31.5%) patients underwent a matched sibling donor (MSD) or unrelated donor (URD) HCT, respectively. the median age at the time of HCT was 20 years. the median interval from diagnosis to transplantation was 3 months for MSD HCT and 14 months for URD HCT. the median follow-up was 70 months and 67 months for MSD and URD HCT survivors, respectively. Overall survival at I year, 2 years, and 5 years for the entire cohort was 76% (95% confidence interval [CI]: 74-78), 73% (95% CI: 71-75), and 70% (95% CI: 68-72). Among 1-year survivors of MSD HCT, 6% had 1 late effect and 1% had multiple late effects. for 1-year survivors of URD HCT, 13% had 1 late effect and 2% had multiple late effects. Among survivors of MSD HCT, the cumulative incidence estimates of developing late effects were all <3% and did not increase over time. in contrast, for recipients of URD HCT, the cumulative incidence of developing several late effects exceeded 3% by 5 years: gonadal dysfunction 10.5% (95% CI: 7.3-14.3), growth disturbance 7.2% (95% CI: 4.4-10.7), avascular necrosis 6.3% (95% CI: 3.6-9.7), hypothyroidism 5.5% (95% CI: 2.8-9.0), and cataracts 5.1% (95% CI: 2.9-8.0). Our results indicated that all patients undergoing HCT for SAA remain at risk for late effects, must be counseled about, and should be monitored for late effects for the remainder of their lives.Public Health Service Grant from the National Cancer InstituteNational Heart, Lung, and Blood InstituteNational Institute of Allergy and Infectious DiseasesNational Cancer InstituteHealth Resources and Services Administration/Department of Health and Human ServicesOffice of Naval ResearchAllosAmgenAngioblastChildrens Hosp Orange Cty, Dept Hematol, Orange, CA 92668 USACIBMTR Med Coll Wisconsin, Dept Biostat, Milwaukee, WI USAMed Coll Wisconsin, CIBMTR Stat Ctr, Milwaukee, WI 53226 USAKing Faisal Specialist Hosp & Res Ctr, Dept Oncol, Riyadh 11211, Saudi ArabiaNew York Med Coll, Dept Pediat Hematol Oncol & Stem Cell Transplanta, Valhalla, NY 10595 USAStemcyte, Covina, CA USADana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USAUniv Florida, Dept Hematol Oncol, Gainesville, FL USAPrincess Margaret Hosp, Dept Med, Toronto, ON M4X 1K9, CanadaUniv S Florida, All Childrens Hosp, Dept Pediat Hematol & Oncol, St Petersburg, FL 33701 USAUniv Basel Hosp, Dept Hematol, CH-4031 Basel, SwitzerlandOregon Hlth & Sci Univ, Dept Hematol & Oncol, Portland, OR 97201 USAChildrens Natl Med Ctr, Dept Blood & Marrow Transplantat, Washington, DC 20010 USABaylor Coll Med, Ctr Cell Therapy, Dept Hematol & Oncol, Houston, TX 77030 USAUniv N Carolina Hosp, Dept Pediat, Chapel Hill, NC USAUniv Hosp Case, Med Ctr, Dept Med, Cleveland, OH USAUniv Arkansas Med Sci, Dept Hematol & Oncol, Little Rock, AR 72205 USACincinnati Childrens Hosp Med Ctr, Dept Bone Marrow Transplantat & Immune Deficiency, Cincinnati, OH USATufts Med Ctr, Dept Med & Pediat, Boston, MA USAUniv S Florida, Coll Med, H Lee Moffitt Canc Ctr & Res Inst, Dept Hematol & Oncol, Tampa, FL 33612 USAFlorida Ctr Cellular Therapy, Dept Med, Orlando, FL USAUniv Fed Parana, Dept Bone Marrow Transplantat, BR-80060000 Curitiba, Parana, BrazilVanderbilt Univ, Med Ctr, Dept Med, Nashville, TN USAInst Oncol Pediat, Dept Pediat, São Paulo, BrazilFred Hutchinson Canc Res Ctr, Dept Clin Res & Transplantat, Seattle, WA 98104 USAMt Sinai Med Ctr, Dept Bone Marrow & Stem Cell Transplantat, New York, NY 10029 USAUniv N Carolina Hosp, Dept Hematol & Oncol, Chapel Hill, NC USAUniv Manitoba, CancerCare Manitoba, Dept Manitoba Blood & Marrow Transplant Program, Winnipeg, MB, CanadaKarolinska Univ Hosp, Ctr Allogene Stem Cell Transplantat, Dept Pediat, Stockholm, SwedenLouisiana State Univ, Hlth Sci Ctr, Childrens Hosp, Dept Pediat, New Orleans, LA USADept Natl Marrow Donor Program, Minneapolis, MN USAPublic Health Service Grant from the National Cancer Institute: U24-CA76518National Heart, Lung, and Blood Institute: 5U01HL069294Office of Naval Research: N00014-06-1-0704Office of Naval Research: N00014-08-1-0058HHSH234200637015CWeb of Scienc

Late effects in hematopoietic cell transplant recipients with acquired severe aplastic anemia: a report from the late effects working committee of the center for international blood and marrow transplant research (CIBMTR)

CHOC Children’s Hospital - UC Irvine, Orange, CAMedical College of Wisconsin, Milwaukee, WIMedical College of Wisconsin, Milwaukee, WIKing Faisal Specialist Hospital and Research Center, Riyadh, TX, Saudi ArabiaNew York Medical College, Valhalla, NYStemcyte, Covina, CADana Farber Cancer Institute, Boston, MAUniversity of Florida, Gainesville, FLPrincess Margaret Hospital, Toronto, ON, CanadaAll Children’s Hospital, St. Petersburg, FLUniversity Hospital Basel, Basel, SwitzerlandOregon Health and Science University, Portland, ORChildren’s National Medical Center, Washington, DCBaylor College of Medicine Center for Cell Therapy, Houston, TXUniversity of North Carolina Hospitals, Chapel Hill, NCUniversity Hospitals Case Medical Center, Cleveland, OHUniversity of Arkansas for Medical Sciences, Little Rock, ARCincinnati Children’s Hospital Medical Center, Cincinnati, OHTufts Medical Center, Boston, MAH Lee Moffitt Cancer Center and Research Institute, Tampa, FLFlorida Center for Cellular Therapy, Orlando, FLUniversidade Federal de Parana, Curitiba, BrazilVanderbilt University Medical Center, Nashville, TNInstituto de Oncologia Pediatrica, Sao Paulo, BrazilFred Hutchinson Cancer Research Center, Seattle, WAMount Sinai Medical Center, New York, NYUniversity of North Carolina, Chapel Hill, NCCancerCare Manitoba, University of Manitoba, Winnipeg, CanadaKarolinska University Hospital, Center for Allogeneic Stem Cell Transplantation, Stockholm, SwedenChildrens Hospital LSU Health Sciences Center, New Orleans, LANational Marrow Donor Program, Minneapolis, MNWeb of Scienc

ASBMT Consensus Grading for Cytokine Release Syndrome and Neurologic Toxicity Associated with Immune Effector Cells

Chimeric antigen receptor (CAR) T cell therapy is rapidly emerging as one of the most promising therapies for hematologic malignancies. Two CAR T products were recently approved in the United States and Europe for the treatment of patients up to age 25 years with relapsed or refractory B cell acute lymphoblastic leukemia years "?>and/or adults with large B cell lymphoma. Many more CAR T products, as well as other immunotherapies, including various immune cell- and bi-specific antibody-based approaches that function by activation of immune effector cells, are in clinical development for both hematologic and solid tumor malignancies. These therapies are associated with unique toxicities of cytokine release syndrome (CRS) and neurologic toxicity. The assessment and grading of these toxicities vary considerably across clinical trials and across institutions, making it difficult to compare the safety of different products and hindering the ability to develop optimal strategies for management of these toxicities. Moreover, some aspects of these grading systems can be challenging to implement across centers. Therefore, in an effort to harmonize the definitions and grading systems for CRS and neurotoxicity, experts from all aspects of the field met on June 20 and 21, 2018, at a meeting supported by the American Society for Blood and Marrow Transplantation (ASBMT) in Arlington, VA. Here we report the consensus recommendations of that group and propose new definitions and grading for CRS and neurotoxicity that are objective, easy to apply, and ultimately more accurately categorize the severity of these toxicities. The goal is to provide a uniform consensus grading system for CRS and neurotoxicity associated with immune effector cell therapies, for use across clinical trials and in the postapproval clinical setting

ASTCT Consensus Grading for Cytokine Release Syndrome and Neurologic Toxicity Associated with Immune Effector Cells

•Cytokine release syndrome (CRS) and neurotoxicity are common after immune effector cell (IEC) therapy.•Neurotoxicity is now termed IEC-associated neurotoxicity syndrome (ICANS).•A consensus grading system for CRS and ICANS has been developed by experts in the field.•The grading system is designed for IEC therapies in clinical trials and commercial use.•Standardized reporting through the Center for International Blood and Marrow Transplant Research will meet commercial Risk Evaluation and Mitigation Strategies requirements. Chimeric antigen receptor (CAR) T cell therapy is rapidly emerging as one of the most promising therapies for hematologic malignancies. Two CAR T products were recently approved in the United States and Europe for the treatment ofpatients up to age 25years with relapsed or refractory B cell acute lymphoblastic leukemia and/or adults with large B cell lymphoma. Many more CAR T products, as well as other immunotherapies, including various immune cell- and bi-specific antibody-based approaches that function by activation of immune effector cells, are in clinical development for both hematologic and solid tumor malignancies. These therapies are associated with unique toxicities of cytokine release syndrome (CRS) and neurologic toxicity. The assessment and grading of these toxicities vary considerably across clinical trials and across institutions, making it difficult to compare the safety of different products and hindering the ability to develop optimal strategies for management of these toxicities. Moreover, some aspects of these grading systems can be challenging to implement across centers. Therefore, in an effort to harmonize the definitions and grading systems for CRS and neurotoxicity, experts from all aspects of the field met on June 20 and 21, 2018, at a meeting supported by the American Society for Transplantation and Cellular Therapy (ASTCT; formerly American Society for Blood and Marrow Transplantation, ASBMT) in Arlington, VA. Here we report the consensus recommendations of that group and propose new definitions and grading for CRS and neurotoxicity that are objective, easy to apply, and ultimately more accurately categorize the severity of these toxicities. The goal is to provide a uniform consensus grading system for CRS and neurotoxicity associated with immune effector cell therapies, for use across clinical trials and in the postapproval clinical setting

Pooled safety analysis of tisagenlecleucel in children and young adults with B cell acute lymphoblastic leukemia

Background Tisagenlecleucel, an anti-CD19 chimeric antigen receptor T cell therapy, has demonstrated efficacy in children and young adults with relapsed/refractory B cell acute lymphoblastic leukemia (B-ALL) in two multicenter phase 2 trials (ClinicalTrials.gov, NCT02435849 (ELIANA) and NCT02228096 (ENSIGN)), leading to commercialization of tisagenlecleucel for the treatment of patients up to age 25 years with B-ALL that is refractory or in second or greater relapse. Methods A pooled analysis of 137 patients from these trials (ELIANA: n=79; ENSIGN: n=58) was performed to provide a comprehensive safety profile for tisagenlecleucel. Results Grade 3/4 tisagenlecleucel-related adverse events (AEs) were reported in 77% of patients. Specific AEs of interest that occurred 1 year postinfusion. Conclusions This pooled analysis provides a detailed safety profile for tisagenlecleucel during the course of clinical trials, and AE management guidance, with a longer follow-up duration compared with previous reports