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Three-year outcomes in recipients of mismatched unrelated bone marrow donor transplants using post-transplant cyclophosphamide: follow-up from a National Marrow Donor Program-sponsored prospective clinical trial
Shaw, B. E., Jimenez-Jimenez, A. M., Burns, L. J., Logan, B. R., Khimani, F., Shaffer, B. C., Shah, N. N., Mussetter, A., Tang, X. Y., McCarty, J. M., et al
Transplantation and cellular therapy. 2022
Abstract
The use of Post-Transplant Cyclophosphamide (PTCy) as Graft Versus Host Disease (GVHD) prophylaxis has resulted in reductions in GVHD and improved outcomes in allogeneic hematopoietic cell transplant (HCT) using HLA-mismatched related donors. We report the 3-year outcomes of the first multi-center prospective clinical trial using PTCy in the setting of mismatched unrelated donor (MMUD) bone marrow HCT. The study enrolled 80 patients (Either myeloablative (MAC) (N=40) or reduced intensity conditioning (RIC) (N=40)) with the primary endpoint of 1-year overall survival (OS). The median follow-up for this report is 34 months (range 12-46) in RIC and 36 months (range 18-49) in MAC. Three-year OS and non-relapse mortality (NRM) were 70% and 15%, and 62% and 10% in the RIC and MAC strata, respectively. No GVHD was reported after 1 year. Relapse incidence was 29% and 51% in RIC and MAC strata. OS did not differ based on HLA match grade (63% in the 7/8 strata and 71% in the 4-6/8 strata). These encouraging outcomes, sustained 3 years post-HCT, support the continued exploration of MMUD HCT using a PTCy platform. Important future areas to address include relapse reduction and furthering our understanding of optimal donor selection based on HLA and non-HLA factors.
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Geriatric syndromes in 2-year, progression-free survivors among older recipients of allogeneic hematopoietic cell transplantation
Lin, R. J., Baser, R. E., Elko, T. A., Korc-Grodzicki, B., Shahrokni, A., Maloy, M. A., Young, J. W., Tamari, R., Shah, G. L., Shaffer, B. C., et al
Bone marrow transplantation. 2020
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3.
Off-the-shelf EBV-specific T cell immunotherapy for rituximab-refractory EBV-associated lymphoma following transplant
Prockop, S., Doubrovina, E., Suser, S., Heller, G., Barker, J., Dahi, P., Perales, M. A., Papadopoulos, E., Sauter, C., Castro-Malaspina, H., et al
The Journal of clinical investigation. 2019
Abstract
BACKGROUND Adoptive transfer of donor-derived EBV-specific T-cells (EBV-CTLs) can eradicate EBV associated lymphomas post hematopoietic cell (HCT) or solid organ (SOT) transplants but is not available for most patients. METHODS We developed a 3rd-party, allogeneic, off-the-shelf bank of 330 GMP grade EBV-CTL lines from specifically consented healthy HCT donors. We treated 46 recipients of HCT (N=33) or SOT (N=13) with established EBV associated lymphomas, who failed rituximab therapy, with 3rd-party EBV-CTLs. Treatment cycles consisted of 3 weekly infusions of EBV-CTLs and 3 weeks of observation. RESULTS The EBV-CTLs did not induce significant toxicities or graft injury. One patient developed grade I skin GVHD requiring topical therapy. Complete and sustained partial remissions were achieved in 68% of HCT recipients and 54% of SOT recipients. For patients who achieved CR/PR or stable disease after cycle 1, overall survival was 88.9% and 81.8% respectively at 1 year. Although only 1/11 patients (9.1%) with progression of disease (POD) after cycle 1 who received additional EBV-CTLs from the same donor survived, 3 of 5 with POD subsequently treated with EBV-CTLs from a different donor achieved CR or durable PR (60%) and survive > 1 year. Maximal responses were achieved after a median of 2 cycles. CONCLUSIONS Third party EBV-CTLs of defined HLA restriction provide safe, immediately accessible treatment for EBV PTLD. Secondary treatment with EBV-CTLs restricted by a different HLA allele (switch therapy) can also induce remissions if initial EBV-CTLs are ineffective. These results suggest a promising potential therapy for patients with rituximab refractory EBV-associated lymphoma post transplant.Phase II protocols (NCT01498484 and NCT00002663) were approved by the Institutional Review Board at Memorial Sloan Kettering Cancer Center, Food and Drug Administration and National Marrow Donor Program.This work was supported through NIH grants CA23766, NIH R21CA162002, Aubrey Fund, The Claire Tow Foundation, Major Family Foundation, Max Cure Foundation, Richard "Rick" J. EIsemann Pediatric Research Fund, Banbury Foundation, Edith Robertson Foundation, Larry Smead Foundation. In June 2015 Atara Biotherapeutics licensed the EBV-CTL bank and is developing this as ATA-129.
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4.
Burden and impact of multifactorial geriatric syndromes in allogeneic hematopoietic cell transplantation for older adults
Lin, R. J., Hilden, P. D., Elko, T. A., Dahi, P. B., Shahrokni, A., Jakubowski, A. A., Perales, M. A., Sauter, C. S., Castro-Malaspina, H. R., Barker, J. N., et al
Blood advances. 2019;3(1):12-20
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Abstract
Multifactorial geriatric syndromes are highly prevalent in older patients with cancer. Because an increasing number of older patients undergo allogeneic hematopoietic stem cell transplantation (allo-HCT), we examined the incidence and impact of transplant-related geriatric syndromes using our institutional database and electronic medical records. We identified 527 patients age 60 years or older who had undergone first allo-HCT from 2001 to 2016 for hematologic malignancies. From the initiation of conditioning to 100 days posttransplant, new geriatric syndromes were predominantly delirium with a cumulative incidence of 21% (95% confidence interval [CI], 18%-25%) at day 100 followed by fall at 7% (95% CI, 5%-9%). In multivariable analyses of available pretransplant variables, fall within the last year, potentially inappropriate use of medication, thrombocytopenia, and reduced creatinine clearance were significantly associated with delirium; age older than 70 years and impaired activities of daily living were significantly associated with fall. In the 100-day landmark analysis, both delirium (hazard ratio [HR], 1.66; 95% CI, 1.09-2.52; P = .023) and fall (HR, 2.14; 95% CI, 1.16-3.95; P = .026) were significantly associated with increased nonrelapse mortality; moreover, fall (HR, 1.93; 95% CI, 1.18-3.14; P = .016), but not delirium, was significantly associated with reduced overall survival. Here, we establish baseline incidences and risk factors of common transplant-related geriatric syndromes. Importantly, we demonstrate significant associations of delirium and fall with inferior transplant outcomes. The burden and impact of transplant-related geriatric syndromes warrant the institution of patient-centered, preemptive, longitudinal, and multidisciplinary interventions to improve outcomes for older allo-HCT patients.
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Long-term prognosis for 1-year relapse-free survivors of CD34+ cell-selected allogeneic hematopoietic stem cell transplantation: a landmark analysis
Cho, C., Hsu, M., Barba, P., Maloy, M. A., Avecilla, S. T., Barker, J. N., Castro-Malaspina, H., Giralt, S. A., Jakubowski, A. A., Koehne, G., et al
Bone Marrow Transplantation. 2017;52(12):1629-1636
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Abstract
CD34+ cell selection significantly improves GvHD-free survival in allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, specific information regarding long-term prognosis and risk factors for late mortality after CD34+ cell-selected allo-HSCT is lacking. We conducted a single-center landmark analysis in 276 patients alive without relapse 1 year after CD34+ cell-selected allo-HSCT for AML (n=164), ALL (n=33) or myelodysplastic syndrome (n=79). At 5 years' follow-up after the 1-year landmark (range 0.03-13 years), estimated relapse-free survival (RFS) was 73% and overall survival (OS) 76%. The 5-year cumulative incidence of relapse and non-relapse mortality (NRM) were 11% and 16%, respectively. In multivariate analysis, Hematopoietic Cell Transplantation Comorbidity Index score3 correlated with marginally worse RFS (hazard ratio (HR) 1.78, 95% confidence interval (CI) 0.97-3.28, P=0.06) and significantly worse OS (HR 2.53, 95% CI 1.26-5.08, P=0.004). Despite only 24% of patients with acute GvHD within 1 year, this also significantly correlated with worse RFS and OS, with increasing grades of acute GvHD associating with increasingly poorer survival on multivariate analysis (P<0.0001). Of 63 deaths after the landmark, GvHD accounted for 27% of deaths and was the most common cause of late mortality, followed by relapse and infection. Although prognosis is excellent for patients alive without relapse 1 year after CD34+ cell-selected allo-HSCT, risks of late relapse and NRM persist, particularly due to GvHD.
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Effects of Late Toxicities on Outcomes in Long-Term Survivors of Ex-Vivo CD34<sup>+</sup>-Selected Allogeneic Hematopoietic Cell Transplantation
Scordo, M., Shah, G. L., Kosuri, S., Herrera, D. A., Cho, C., Devlin, S. M., Maloy, M. A., Nieves, J., Borrill, T., Avecilla, S. T., et al
Biology of Blood & Marrow Transplantation. 2017
Abstract
The late adverse events in long-term survivors after myeloablative-conditioned allogeneic hematopoietic cell transplantation (HCT) with ex vivo CD34+ cell selection are not well characterized. Using the National Cancer Institute's Common Terminology Criteria for Adverse Events, version 4.0, we assessed all grade>=3 toxicities from the start of conditioning to the date of death, relapse, or last contact in 131 patients who survived>1 year post-HCT, identifying 285 individual toxicities among 17 organ-based toxicity groups. Pretransplantation absolute lymphocyte count>.5K/micro L and serum albumin>4.0g/dL were associated with a reduced risk of toxicities, death, and nonrelapse mortality (NRM), whereas serum ferritin>1000ng/mL was associated with an increased risk of toxicities and NRM after 1 year. An HCT Comorbidity Index (HCT-CI)score >=3 was associated with an increased risk of all-cause death and NRM, but was not associated with a specific increased toxicity risk after 1 year. Patients who incurred more than the median number of toxicities (n=7) among all patients within the first year subsequently had an increased risk of hematologic, infectious, and metabolic toxicities, as well as an increased risk of NRM and inferior 4-year overall survival (OS) (67% versus 86%; P=.003) after the 1-year landmark. The development of grade II-IV acute graft-versus-host disease (GVHD) within the first year was associated with incurring>7 toxicities within the first year (P=.016), and also with an increased risk of all-cause death and NRM after 1 year. In multivariate models, cardiovascular, hematologic, hepatic, infectious, metabolic, neurologic, and pulmonary toxicities incurred after 1 year were independently associated with increased risk of death and NRM when adjusting for both HCT-CI and grade II-IV acute GVHD within the first year. One-year survivors of ex vivo CD34+ selection had a favorable 4-year OS of 77%, although the development of grade>=3 toxicities after the first year was associated with poorer outcomes, emphasizing the fundamental importance of improving survivorship efforts that may improve long-term toxicity burden and outcome. Copyright © 2017 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.
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Autoimmune hemolysis and immune thrombocytopenic purpura after cord blood transplantation may be life-threatening and warrants early therapy with rituximab
Bhatt, V., Shune, L., Lauer, E., Lubin, M., Devlin, S. M., Scaradavou, A., Parameswaran, R., Perales, M. A., Ponce, D. M., Mantha, S., et al
Bone Marrow Transplantation. 2016;51(12):1579-1583
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Abstract
Autoimmune hemolysis (AH) and immune thrombocytopenic purpura (ITP) are recognized complications after cord blood transplantation (CBT). We evaluated the incidence and characteristics of AH/ITP after double-unit CBT in a day 100 landmark analysis of 152 patients (median age 36 years, range 0.9-70 years) transplanted for hematologic malignancies with myeloablative or nonmyeloablative conditioning and calcineurin inhibitor (CNI)/mycophenolate mofetil. With a median 5.2-year (range 1.6-9.7 years) survivor follow-up, 10 patients developed autoimmune cytopenias (8 AH, 1 ITP, 1 both) at a median of 10.4 months (range 5.8-24.5) post CBT for a 7% cumulative incidence 3 years after the day 100 landmark. Six patients presented with severe disease (hemoglobin 6g/dL and/or platelets <20 x 109/L). All AH patients were direct antiglobulin test positive. All 10 cases developed during immunosuppression taper with 8 having prior acute GVHD. All 10 patients received rituximab 2-18 days after diagnosis, and corticosteroids combined with rituximab within <7 days was the most effective. No patient died of AH/ITP. AH/ITP occurs infrequently after CBT but may be life-threatening requiring emergency therapy. Rituximab combined with corticosteroids at diagnosis is warranted in patients with severe disease.