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ABSTRACT: Patients who undergo human leukocyte antigen-matched unrelated donor (MUD) allogeneic hematopoietic stem cell transplantation (HSCT) with myeloablative conditioning for hematologic malignancies often develop acute graft-versus-host disease (GVHD) despite standard calcineurin inhibitor-based prophylaxis in combination with methotrexate. This trial evaluated a novel human CD24 fusion protein (CD24Fc/MK-7110) that selectively targets and mitigates inflammation due to damage-associated molecular patterns underlying acute GVHD while preserving protective immunity after myeloablative conditioning. This phase 2a, multicenter study evaluated the pharmacokinetics, safety, and efficacy of CD24Fc in combination with tacrolimus and methotrexate in preventing acute GVHD in adults undergoing MUD HSCT for hematologic malignancies. A double-blind, placebo-controlled, dose-escalation phase to identify a recommended dose was followed by an open-label expansion phase with matched controls to further evaluate the efficacy and safety of CD24Fc in preventing acute GVHD. A multidose regimen of CD24Fc produced sustained drug exposure with similar safety outcomes when compared with single-dose regimens. Grade 3 to 4 acute GVHD-free survival at day 180 was 96.2% (95% confidence interval [CI], 75.7-99.4) in the CD24Fc expansion cohort (CD24Fc multidose), compared with 73.6% (95% CI, 63.2-81.4) in matched controls (hazard ratio, 0.1 [95% CI, 0.0-0.6]; log-rank test, P = .03). No participants in the CD24Fc escalation or expansion phases experienced dose-limiting toxicities (DLTs). The multidose regimen of CD24Fc was well tolerated with no DLTs and was associated with high rates of severe acute GVHD-free survival after myeloablative MUD HSCT. This trial was registered at ClinicalTrials.gov as #NCT02663622.
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Enfermedad Injerto contra Huésped , Neoplasias Hematológicas , Trasplante de Células Madre Hematopoyéticas , Adulto , Humanos , Metotrexato/uso terapéutico , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Trasplante Homólogo , Recurrencia Local de Neoplasia/tratamiento farmacológico , Enfermedad Injerto contra Huésped/etiología , Enfermedad Injerto contra Huésped/prevención & control , Acondicionamiento Pretrasplante/efectos adversosRESUMEN
Older patients with acute myeloid leukemia (AML) have high relapse risk and poor survival after allogeneic hematopoietic cell transplantation (HCT). Younger patients may receive myeloablative conditioning to mitigate relapse risk associated with high-risk genetics or measurable residual disease (MRD), but older adults typically receive reduced-intensity conditioning (RIC) to limit toxicity. To identify factors that drive HCT outcomes in older patients, we performed targeted mutational analysis (variant allele fraction ≥2%) on diagnostic samples from 295 patients with AML aged ≥60 years who underwent HCT in first complete remission, 91% of whom received RIC, and targeted duplex sequencing at remission in a subset comprising 192 patients. In a multivariable model for leukemia-free survival (LFS) including baseline genetic and clinical variables, we defined patients with low (3-year LFS, 85%), intermediate (55%), high (35%), and very high (7%) risk. Before HCT, 79.7% of patients had persistent baseline mutations, including 18.3% with only DNMT3A or TET2 (DT) mutations and 61.4% with other mutations (MRD positive). In univariable analysis, MRD positivity was associated with increased relapse and inferior LFS, compared with DT and MRD-negative mutations. However, in a multivariable model accounting for baseline risk, MRD positivity had no independent impact on LFS, most likely because of its significant association with diagnostic genetic characteristics, including MDS-associated gene mutations, TP53 mutations, and high-risk karyotype. In summary, molecular associations with MRD positivity and transplant outcomes in older patients with AML are driven primarily by baseline genetics, not by mutations present in remission. In this group of patients, where high-intensity conditioning carries substantial risk of toxicity, alternative approaches to mitigating MRD-associated relapse risk are needed.
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Trasplante de Células Madre Hematopoyéticas , Leucemia Mieloide Aguda , Anciano , Humanos , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/terapia , Neoplasia Residual/diagnóstico , Neoplasia Residual/genética , Recurrencia , Estudios Retrospectivos , Acondicionamiento Pretrasplante , Trasplante HomólogoRESUMEN
Results of 2 parallel phase 2 trials of transplantation of unrelated umbilical cord blood (UCB) or bone marrow (BM) from HLA-haploidentical relatives provided equipoise for direct comparison of these donor sources. Between June 2012 and June 2018, 368 patients aged 18 to 70 years with chemotherapy-sensitive lymphoma or acute leukemia in remission were randomly assigned to undergo UCB (n = 186) or haploidentical (n = 182) transplant. Reduced-intensity conditioning comprised total-body irradiation with cyclophosphamide and fludarabine for both donor types. Graft-versus-host disease prophylaxis for UCB transplantation was cyclosporine and mycophenolate mofetil (MMF) and for haploidentical transplantation, posttransplant cyclophosphamide, tacrolimus, and MMF. The primary end point was 2-year progression-free survival (PFS). Treatment groups had similar age, sex, self-reported ethnic origin, performance status, disease, and disease status at randomization. Two-year PFS was 35% (95% confidence interval [CI], 28% to 42%) compared with 41% (95% CI, 34% to 48%) after UCB and haploidentical transplants, respectively (P = .41). Prespecified analysis of secondary end points recorded higher 2-year nonrelapse mortality after UCB, 18% (95% CI, 13% to 24%), compared with haploidentical transplantation, 11% (95% CI, 6% to 16%), P = .04. This led to lower 2-year overall survival (OS) after UCB compared with haploidentical transplantation, 46% (95% CI, 38-53) and 57% (95% CI 49% to 64%), respectively (P = .04). The trial did not demonstrate a statistically significant difference in the primary end point, 2-year PFS, between the donor sources. Although both donor sources extend access to reduced-intensity transplantation, analyses of secondary end points, including OS, favor haploidentical BM donors. This trial was registered at www.clinicaltrials.gov as #NCT01597778.
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Sangre Fetal/fisiología , Enfermedad Aguda , Adulto , Anciano , Trasplante de Médula Ósea/efectos adversos , Causas de Muerte , Enfermedad Crónica , Femenino , Enfermedad Injerto contra Huésped/epidemiología , Enfermedad Injerto contra Huésped/etiología , Antígenos HLA/inmunología , Hematopoyesis , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Supervivencia sin Progresión , Trasplante Haploidéntico/efectos adversos , Resultado del Tratamiento , Donante no Emparentado , Adulto JovenRESUMEN
BACKGROUND: Optimizing CD34 recovery while minimizing harm to hematopoietic progenitor cell donors by apheresis (HPC(A) donors) is critical to the success of allogeneic hematopoietic cell transplantation. We examined the efficacy and safety of starting allogeneic HPC(A) donors at a collect pump rate (CPR) of 2 mL/min on the Spectra Optia regardless of the inlet flow rate and/or pre-apheresis white blood cell (WBC) count (high CPR group). STUDY DESIGN AND METHODS: A single-center retrospective study was performed on allogeneic adult donors from 10/2020 to 12/2022. From 10/2020 to 6/19/2022, all donors had CPR of ~1 mL/min (historical group). High CPR group started 6/20/2022. RESULTS: During the study period, 412 donors were in historical group versus 196 (32.2%) in high CPR group. Median CD34 collection efficiency (CE) was higher and more consistent in high CPR group (55.1% vs. 53% in historical group, p < .0001) and remained significant in multivariate analysis. Although product volume was higher in high CPR group, WBC, hematocrit, and platelet concentrations were significantly lower. No difference in engraftment outcomes in patients receiving products from two groups was observed. Moreover, no differences occurred in a significant peri-procedural adverse event or percent decrease in platelets (6.87% decrease in platelets per 100 × 106 CD34 cells collected versus 6.66% in historical group, p = .89). Furthermore, high CPR group had ~26 min less in collection time for every 100 × 106 CD34 cells collected, resulting in less positive fluid balances. CONCLUSIONS: Starting allogeneic HPC(A) donor collection at a CPR of 2 mL/min is safe and effective.
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Eliminación de Componentes Sanguíneos , Trasplante de Células Madre Hematopoyéticas , Humanos , Adulto , Movilización de Célula Madre Hematopoyética/métodos , Estudios Retrospectivos , Eliminación de Componentes Sanguíneos/métodos , Células Madre Hematopoyéticas , Antígenos CD34RESUMEN
Allogeneic hematopoietic cell transplantation (allo-HCT) is a potentially curative treatment for acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). While many factors influence the outcomes of allo-HCT, the independent impact of donor-recipient ABO mismatching remains unclear. Using the Center for International Blood and Marrow Transplant Research (CIBMTR) database, we identified patients aged ≥18 years with AML or ALL who underwent allo-HCT between 2008 and 2018. Our objectives were to analyze the outcomes of allo-HCT based on the donor-recipient ABO status (match, minor mismatch, major mismatch, bidirectional mismatch). Among 4946 eligible patients, 2741 patients (55.4%) were ABO matched, 1030 patients (20.8%) had a minor ABO mismatch, 899 patients (18.1%) had a major ABO mismatch, and 276 patients (5.6%) had a bidirectional ABO mismatch. In multivariable analyses, compared to ABO matched allo-HCT, the presence of a major ABO mismatch was associated with worse overall survival (HR 1.16, 95% CI 1.05-1.29; p = 0.005), inferior platelet engraftment (HR 0.83, 95% CI 0.77-0.90; p < 0.001), and higher primary graft failure (HR 1.60, 95% CI 1.12-2.30, p = 0.01). Relapse, acute graft versus host disease (GVHD) grades III-IV and chronic GVHD were not significantly associated with ABO status. While donor age was not significantly associated with outcomes, older recipient age was associated with worse survival and non-relapse mortality. Our study demonstrates that donor-recipient ABO status is independently associated with survival and other post-transplantation outcomes in acute leukemia. This underscores the importance of considering the ABO status in donor selection algorithms and its impact in acute leukemia.
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Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Leucemia Mieloide Aguda , Leucemia-Linfoma Linfoblástico de Células Precursoras , Humanos , Adolescente , Adulto , Leucemia Mieloide Aguda/terapia , Trasplante de Médula Ósea , Médula Ósea , Enfermedad Aguda , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Enfermedad Injerto contra Huésped/etiología , Estudios Retrospectivos , Acondicionamiento PretrasplanteRESUMEN
Early autologous hematopoietic cell transplantation (AHCT) with post-transplant maintenance therapy is standard of care in multiple myeloma (MM). While short-term quality of life (QOL) deterioration after AHCT is known, the long-term trajectories and symptom burden after transplantation are largely unknown. Toward this goal, a secondary analysis of QOL data of the BMT CTN 0702, a randomized controlled trial comparing outcomes of three treatment interventions after a single AHCT (N = 758), was conducted. FACT-BMT scores up to 4 years post-AHCT were analyzed. Symptom burden was studied using responses to 17 individual symptoms dichotomized as 'none/mild' for scores 0-2 and 'moderate/severe' for scores of 3 or 4. Patients with no moderate/severe symptom ratings were considered to have low symptom burden at 1-year. Mean age at enrollment was 55.5 years with 17% African Americans. Median follow-up was 6 years (range, 0.4-8.5 years). FACT-BMT scores improved between enrollment and 1-year and remained stable thereafter. Low symptom burden was reported by 27% of patients at baseline, 38% at 1-year, and 32% at 4 years post-AHCT. Predictors of low symptom burden at 1-year included low symptom burden at baseline: OR 2.7 (1.8-4.1), p < 0.0001; older age: OR 2.1 (1.3-3.2), p = 0.0007; and was related to being employed: OR 2.1 (1.4-3.2), p = 0.0004). We conclude that MM survivors who achieve disease control after AHCT have excellent recovery of FACT-BMT and subscale scores to population norms by 1-year post-transplant, though many patients continue to report moderate to severe severity in some symptoms at 1-year and beyond.
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Trasplante de Células Madre Hematopoyéticas , Mieloma Múltiple , Humanos , Persona de Mediana Edad , Mieloma Múltiple/terapia , Calidad de Vida , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Trasplante AutólogoRESUMEN
Importance: Preventing relapse for adults with acute myeloid leukemia (AML) in first remission is the most common indication for allogeneic hematopoietic cell transplant. The presence of AML measurable residual disease (MRD) has been associated with higher relapse rates, but testing is not standardized. Objective: To determine whether DNA sequencing to identify residual variants in the blood of adults with AML in first remission before allogeneic hematopoietic cell transplant identifies patients at increased risk of relapse and poorer overall survival compared with those without these DNA variants. Design, Setting, and Participants: In this retrospective observational study, DNA sequencing was performed on pretransplant blood from patients aged 18 years or older who had undergone their first allogeneic hematopoietic cell transplant during first remission for AML associated with variants in FLT3, NPM1, IDH1, IDH2, or KIT at 1 of 111 treatment sites from 2013 through 2019. Clinical data were collected, through May 2022, by the Center for International Blood and Marrow Transplant Research. Exposure: Centralized DNA sequencing of banked pretransplant remission blood samples. Main Outcomes and Measures: The primary outcomes were overall survival and relapse. Day of transplant was considered day 0. Hazard ratios were reported using Cox proportional hazards regression models. Results: Of 1075 patients tested, 822 had FLT3 internal tandem duplication (FLT3-ITD) and/or NPM1 mutated AML (median age, 57.1 years, 54% female). Among 371 patients in the discovery cohort, the persistence of NPM1 and/or FLT3-ITD variants in the blood of 64 patients (17.3%) in remission before undergoing transplant was associated with worse outcomes after transplant (2013-2017). Similarly, of the 451 patients in the validation cohort who had undergone transplant in 2018-2019, 78 patients (17.3%) with residual NPM1 and/or FLT3-ITD variants had higher rates of relapse at 3 years (68% vs 21%; difference, 47% [95% CI, 26% to 69%]; HR, 4.32 [95% CI, 2.98 to 6.26]; P < .001) and decreased survival at 3 years (39% vs 63%; difference, -24% [2-sided 95% CI, -39% to -9%]; HR, 2.43 [95% CI, 1.71 to 3.45]; P < .001). Conclusions and Relevance: Among patients with acute myeloid leukemia in first remission prior to allogeneic hematopoietic cell transplant, the persistence of FLT3 internal tandem duplication or NPM1 variants in the blood at an allele fraction of 0.01% or higher was associated with increased relapse and worse survival compared with those without these variants. Further study is needed to determine whether routine DNA-sequencing testing for residual variants can improve outcomes for patients with acute myeloid leukemia.
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Trasplante de Células Madre Hematopoyéticas , Leucemia Mieloide Aguda , Neoplasia Residual , Análisis de Secuencia de ADN , Femenino , Humanos , Masculino , Persona de Mediana Edad , Leucemia Mieloide Aguda/sangre , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/terapia , Neoplasia Residual/sangre , Neoplasia Residual/diagnóstico , Neoplasia Residual/genética , Proteínas Nucleares/genética , Cuidados Preoperatorios , Estudios Retrospectivos , Recurrencia , Análisis de SupervivenciaRESUMEN
In a systematic review and meta-analysis, we compared allogeneic transplant outcomes after myeloablative conditioning (MAC) versus reduced-intensity conditioning (RIC) in patients with myelodysplastic syndromes. Only 2 published randomized clinical trials were found, with a pooled sample size of 183 (RIC, 92; MAC, 91). Both studies suggested an overall survival advantage after RIC, with a pooled hazard ratio (HR) of .67 (95% confidence interval [CI], .41 to 1.09) for RIC versus MAC. Relapse results were also concordant, with a pooled HR of 1.55 (95% CI, .74 to 3.25) for RIC versus MAC. Neither result was statistically significant. Comparisons for other outcomes were unremarkable. In conclusion, the evidence for the optimal conditioning intensity in myelodysplastic syndromes is weak. Post-transplant maintenance strategies and incorporation of genomic information into decision-making may improve post-transplant outcomes.
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Trasplante de Células Madre Hematopoyéticas , Síndromes Mielodisplásicos , Humanos , Síndromes Mielodisplásicos/terapia , Recurrencia , Acondicionamiento PretrasplanteRESUMEN
Nonmalignant blood diseases such as bone marrow failure disorders, immune dysregulation disorders, and hemoglobinopathies often lead to shortened life spans and poor quality of life. Many of these diseases can be cured with allogeneic hematopoietic cell transplantation, but patients are often not offered the procedure because of perceived insufficient efficacy and/or excess toxicity. In 2018, the Blood and Marrow Transplant Clinical Trials Network convened a task force to identify the most urgently needed yet feasible clinical trials with potential to improve the outcomes for patients with nonmalignant diseases. This report summarizes the task force discussions and specifies the network plans for clinical trial development for nonmalignant blood diseases.
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Enfermedades Hematológicas , Trasplante de Células Madre Hematopoyéticas , Médula Ósea , Enfermedades Hematológicas/terapia , Humanos , Calidad de Vida , Acondicionamiento PretrasplanteRESUMEN
The COVID-19 pandemic has created significant barriers to timely donor evaluation, cell collection, and graft transport for allogeneic hematopoietic stem cell transplantation (allo-HCT). To ensure availability of donor cells on the scheduled date of infusion, many sites now collect cryopreserved grafts before the start of pretransplantation conditioning. Post-transplantation cyclophosphamide (ptCY) is an increasingly used approach for graft-versus-host disease (GVHD) prophylaxis, but the impact of graft cryopreservation on the outcomes of allo-HCT using ptCY is not known. Using the Center for International Blood and Marrow Transplant Research (CIBMTR) database, we compared the outcomes of HCT using cryopreserved versus fresh grafts in patients undergoing HCT for hematologic malignancy with ptCY. We analyzed 274 patients with hematologic malignancy undergoing allo-HCT between 2013 and 2018 with cryopreserved grafts and ptCY. Eighteen patients received bone marrow grafts and 256 received peripheral blood stem cell grafts. These patients were matched for age, graft type, disease risk index (DRI), and propensity score with 1080 patients who underwent allo-HCT with fresh grafts. The propensity score, which is an assessment of the likelihood of receiving a fresh graft versus a cryopreserved graft, was calculated using logistic regression to account for the following: disease histology, Karnofsky Performance Score (KPS), HCT Comorbidity Index, conditioning regimen intensity, donor type, and recipient race. The primary endpoint was overall survival (OS). Secondary endpoints included acute and chronic graft-versus-host disease (GVHD), non-relapse mortality (NRM), relapse/progression and disease-free survival (DFS). Because of multiple comparisons, only P values <.01 were considered statistically significant. The 2 cohorts (cryopreserved and fresh) were similar in terms of patient age, KPS, diagnosis, DRI, HCT-CI, donor/graft source, and conditioning intensity. One-year probabilities of OS were 71.1% (95% confidence interval [CI], 68.3% to 73.8%) with fresh grafts and 70.3% (95% CI, 64.6% to 75.7%) with cryopreserved grafts (P = .81). Corresponding probabilities of OS at 2 years were 60.6% (95% CI, 57.3% to 63.8%) and 58.7% (95% CI, 51.9% to 65.4%) (P = .62). In matched-pair regression analysis, graft cryopreservation was not associated with a significantly higher risk of mortality (hazard ratio [HR] for cryopreserved versus fresh, 1.05; 95% CI, .86 to 1.29; P = .60). Similarly, rates of neutrophil recovery (HR, .91; 95% CI, .80 to 1.02; P = .12), platelet recovery (HR, .88; 95% CI, .78 to 1.00; P = .05), grade III-IV acute GVHD (HR, .78; 95% CI, .50 to 1.22; P = .27), NRM (HR, 1.16; 95% CI, .86 to 1.55; P = .32) and relapse/progression (HR, 1.21; 95% CI, .97 to 1.50; P = .09) were similar with cryopreserved grafts versus fresh grafts. There were somewhat lower rates of chronic GVHD (HR, 78; 95% CI, .61 to .99; P = .04) and DFS (HR for treatment failure, 1.19; 95% CI, 1.01 to 1.29; P = .04) with graft cryopreservation that were of marginal statistical significance after adjusting for multiple comparisons. Overall, our data indicate that graft cryopreservation does not significantly delay hematopoietic recovery, increase the risk of acute GVHD or NRM, or decrease OS after allo-HCT using ptCY.
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Trasplante de Médula Ósea/métodos , Infecciones por Coronavirus/epidemiología , Criopreservación/métodos , Enfermedad Injerto contra Huésped/prevención & control , Trasplante de Células Madre Hematopoyéticas/métodos , Leucemia/terapia , Linfoma/terapia , Síndromes Mielodisplásicos/terapia , Neumonía Viral/epidemiología , Adulto , Anciano , Anciano de 80 o más Años , COVID-19 , Estudios de Cohortes , Ciclofosfamida/uso terapéutico , Femenino , Enfermedad Injerto contra Huésped/inmunología , Enfermedad Injerto contra Huésped/mortalidad , Enfermedad Injerto contra Huésped/patología , Prueba de Histocompatibilidad , Humanos , Leucemia/inmunología , Leucemia/mortalidad , Leucemia/patología , Linfoma/inmunología , Linfoma/mortalidad , Linfoma/patología , Masculino , Persona de Mediana Edad , Síndromes Mielodisplásicos/inmunología , Síndromes Mielodisplásicos/mortalidad , Síndromes Mielodisplásicos/patología , Pandemias , Hermanos , Análisis de Supervivencia , Acondicionamiento Pretrasplante/métodos , Trasplante Homólogo , Estados Unidos/epidemiología , Donante no Emparentado/provisión & distribuciónRESUMEN
Hematopoietic cell transplantation (HCT) is a well-established treatment to control and/or cure many malignant and nonmalignant diseases involving the hematopoietic system and some solid tumors. We report information about HCT procedures performed in the United States in 2018 and analyze trends and outcomes of HCT as reported to the Center for International Blood and Marrow Transplant Research (CIBMTR). Overall, compared with 2017, the number of allogeneic HCTs performed in the United States increased by 1%, and the number of autologous HCTs decreased by 5%. Key findings are fewer autologous HCTs performed for non-Hodgkin lymphoma and increasing numbers of haploidentical HCTs, nearly all of which use post-transplantation cyclophosphamide for graft-versus-host disease prophylaxis. There is a continuing increase in HCT in adults age >70 years, particularly for acute myelogenous leukemia and myelodysplastic syndromes. Survival rates by disease, disease stage, donor type, and age are presented. This report, prepared annually by the CIBMTR, provides a snapshot of current transplant activity in the United States.
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Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Leucemia Mieloide Aguda , Síndromes Mielodisplásicos , Adulto , Anciano , Ciclofosfamida , Enfermedad Injerto contra Huésped/prevención & control , Humanos , Leucemia Mieloide Aguda/terapia , Donantes de Tejidos , Acondicionamiento Pretrasplante , Estados UnidosRESUMEN
With the COVID-19 pandemic and the ensuing barriers to the collection and transport of donor cells, it is often necessary to collect and cryopreserve grafts before initiation of transplantation conditioning. The effect on transplantation outcomes in nonmalignant disease is unknown. This analysis examined the effect of cryopreservation of related and unrelated donor grafts for transplantation for severe aplastic anemia in the United States during 2013 to 2019. Included are 52 recipients of cryopreserved grafts who were matched for age, donor type, and graft type to 194 recipients who received noncryopreserved grafts. Marginal Cox regression models were built to study the effect of cryopreservation and other risk factors associated with outcomes. We recorded higher 1-year rates of graft failure (hazard ratio [HR], 2.26; 95% confidence interval, 1.17 to 4.35; P = .01) and of 1-year overall mortality (HR, 3.13; 95% CI, 1.60 to 6.11; P = .0008) after transplantation of cryopreserved compared with noncryopreserved grafts, with adjustment for sex, performance score, comorbidity, cytomegalovirus serostatus, and ABO blood group match. The incidence of acute and chronic graft-versus-host disease did not differ between the 2 groups. Adjusted probabilities of 1-year survival were 73% (95% CI, 60% to 84%) in the cryopreserved graft group and 91% (95% CI, 86% to 94%) in the noncryopreserved graft group. These data support the use of noncryopreserved grafts whenever possible in patients with severe aplastic anemia.
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Anemia Aplásica/terapia , Trasplante de Médula Ósea/métodos , Infecciones por Coronavirus/epidemiología , Criopreservación/métodos , Rechazo de Injerto/patología , Enfermedad Injerto contra Huésped/patología , Trasplante de Células Madre de Sangre Periférica/métodos , Neumonía Viral/epidemiología , Enfermedad Aguda , Adolescente , Adulto , Anciano , Anemia Aplásica/inmunología , Anemia Aplásica/mortalidad , Anemia Aplásica/patología , COVID-19 , Niño , Preescolar , Femenino , Rechazo de Injerto/inmunología , Rechazo de Injerto/mortalidad , Enfermedad Injerto contra Huésped/inmunología , Enfermedad Injerto contra Huésped/mortalidad , Prueba de Histocompatibilidad , Humanos , Masculino , Persona de Mediana Edad , Pandemias , Estudios Retrospectivos , Hermanos , Análisis de Supervivencia , Acondicionamiento Pretrasplante/métodos , Estados Unidos/epidemiología , Donante no EmparentadoRESUMEN
BACKGROUND: Both gemcitabine and bendamustine have been evaluated in patients with recurrent/refractory Hodgkin lymphoma but to the authors' knowledge not as a doublet. The authors completed a phase 1/2 trial to identify the optimal dose and frequency of administration and to assess the efficacy of this combination in patients with recurrent/refractory Hodgkin lymphoma. METHODS: Patients were treated up to a maximum dose of gemcitabine (1000 mg/m2 on day 1) and bendamustine (120 mg/m2 on days 1 and 2), which was determined to be the recommended phase 2 dose, administered every 21 days for up to 6 cycles. Patients could discontinue study therapy after 2 cycles to proceed with autologous or allogeneic stem cell transplantation. RESULTS: No dose-limiting toxicities were identified, but 4 patients experienced grade 3 to 5 pulmonary adverse events (toxicity was graded according to Common Terminology Criteria for Adverse Events [version 4]). A total of 26 patients were enrolled having completed a median of 4 prior lines of therapy (range, 1-7 lines), including 13 patients at the recommended phase 2 dose, in whom the overall response rate was 69% and the complete response rate was 46%. The median progression-free survival for the phase 2 patients was 11 months (95% CI, 3 months to not reached), and the median overall survival for this group had not been reached at the time of last follow-up (95% CI, 4 months to not reached). CONCLUSIONS: This doublet was found to be tolerable and effective, but patients must be monitored closely for pulmonary toxicity. The authors currently are evaluating this doublet in combination with nivolumab.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Clorhidrato de Bendamustina/administración & dosificación , Desoxicitidina/análogos & derivados , Enfermedad de Hodgkin/tratamiento farmacológico , Terapia Recuperativa/métodos , Adulto , Anciano , Antibióticos Antineoplásicos/administración & dosificación , Antibióticos Antineoplásicos/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Clorhidrato de Bendamustina/efectos adversos , Bleomicina/administración & dosificación , Bleomicina/efectos adversos , Desoxicitidina/administración & dosificación , Desoxicitidina/efectos adversos , Esquema de Medicación , Resistencia a Antineoplásicos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Supervivencia sin Progresión , Recurrencia , Adulto Joven , GemcitabinaRESUMEN
PD-1 blockade is an effective therapy in relapsed/refractory (R/R) classical Hodgkin Lymphoma (cHL) who have relapsed after or are ineligible for autologous hematopoietic cell transplantation (HCT). Although single-agent anti-PD-1 monoclonal antibodies (mAb's) are associated with high response rates and durable remissions, available results to date suggest that a large majority of patients will eventually progress on therapy. Many of these patients are potential candidates for allogeneic HCT (allo-HCT) after receiving anti-PD-1 mAb's, and allo-HCT remains for now the only treatment with demonstrated curative potential in this setting. However, initial reports suggested that allo-HCT in this setting may be associated with increased risk of early transplant-related toxicity, likely driven by lingering effects of PD-1 blockade. Furthermore, many patients with R/R cHL who undergo allo-HCT will relapse after transplantation, most often with limited treatment options. Here again, PD-1 blockade appears to yield high response rates, but with an increased risk of attendant immune toxicity. Many questions remain regarding the use of PD-1 blockade before or after allo-HCT, especially in relation to the feasibility, outcome, optimal timing, and method of allo-HCT after PD-1 blockade. Despite the scarcity of prospective data, these questions are unavoidable and must be tackled by clinicians in the routine care of patients with advanced cHL. We provide consensus recommendations of a working group based on available data and experience, in an effort to help guide treatment decisions until more definitive data are obtained.
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Antineoplásicos Inmunológicos/uso terapéutico , Enfermedad de Hodgkin/terapia , Proteínas de Neoplasias/antagonistas & inhibidores , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Acondicionamiento Pretrasplante , Aloinjertos , Trasplante de Células Madre Hematopoyéticas , Humanos , Guías de Práctica Clínica como Asunto , RecurrenciaRESUMEN
MicroRNA-155 (miR-155) is a small noncoding RNA critical for the regulation of inflammation as well as innate and adaptive immune responses. MiR-155 has been shown to be dysregulated in both donor and recipient immune cells during acute graft-versus-host disease (aGVHD). We previously reported that miR-155 is upregulated in donor T cells of mice and humans with aGVHD and that mice receiving miR-155-deficient (miR155-/-) splenocytes had markedly reduced aGVHD. However, molecular mechanisms by which miR-155 modulates T cell function in aGVHD have not been fully investigated. We identify that miR-155 expression in both donor CD8+ T cells and conventional CD4+ CD25- T cells is pivotal for aGVHD pathogenesis. Using murine aGVHD transplant experiments, we show that miR-155 strongly impacts alloreactive T cell expansion through multiple distinct mechanisms, modulating proliferation in CD8+ donor T cells and promoting exhaustion in donor CD4+ T cells in both the spleen and colon. Additionally, miR-155 drives a proinflammatory Th1 phenotype in donor T cells in these two sites, and miR-155-/- donor T cells are polarized toward an IL-4-producing Th2 phenotype. We further demonstrate that miR-155 expression in donor T cells regulates CCR5 and CXCR4 chemokine-dependent migration. Notably, we show that miR-155 expression is crucial for donor T cell infiltration into multiple target organs. These findings provide further understanding of the role of miR-155 in modulating aGVHD through T cell expansion, effector cytokine production, and migration.
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Linfocitos T CD4-Positivos/metabolismo , Linfocitos T CD8-positivos/metabolismo , Movimiento Celular/genética , Enfermedad Injerto contra Huésped/genética , MicroARNs/genética , Enfermedad Aguda , Animales , Proliferación Celular/genética , Colon/metabolismo , Subunidad alfa del Receptor de Interleucina-2/genética , Activación de Linfocitos/genética , Ratones , Ratones Endogámicos C57BL , Receptores CCR5/genética , Receptores CXCR4/genética , Bazo/metabolismo , Regulación hacia Arriba/genéticaRESUMEN
Blood and marrow transplant (BMT) programs worldwide frequently employ a quality management professional who is charged with securing quality and maintaining regulatory requirements. Although many BMT programs employ an individual to oversee quality management, there are no standard definitions of the education, training, and core competencies needed to successfully perform this role. The goal of this article is to propose the required qualifications and responsibilities of the BMT professional who oversees quality management and to elicit discussion to standardize such a role in BMT and cellular immunotherapy programs. Our results could serve as a model for quality managers in other complex healthcare environments. The recommendation and findings are primarily limited to cell therapy centers in North America.
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Médula Ósea , Personal de Salud/educación , Inmunoterapia , Femenino , Humanos , Masculino , América del NorteRESUMEN
A higher number of donor plasmacytoid dendritic cells (pDCs) is associated with increased survival and reduced graft-versus-host disease (GVHD) in human recipients of unrelated donor bone marrow (BM) grafts, but not granulocyte colony-stimulating factor (G-CSF)-mobilized peripheral blood grafts. We show that in murine models, donor BM pDCs are associated with increased survival and decreased GVHD compared with G-CSF-mobilized pDCs. To increase the content of pDCs in BM grafts, we studied the effect of FMS-like tyrosine kinase 3 ligand (Flt3L) treatment of murine BM donors on transplantation outcomes. Flt3L treatment (300 µg/kg/day) resulted in a schedule-dependent increase in the content of pDCs in the BM. Mice treated on days -4 and -1 had a >5-fold increase in pDC content without significant changes in numbers of HSCs, T cells, B cells, and natural killer cells in the BM graft. In an MHC-mismatched murine transplant model, recipients of Flt3L-treated T cell-depleted (TCD) BM (TCD F-BM) and cytokine-untreated T cells had increased survival and decreased GVHD scores with fewer Th1 and Th17 polarized T cells post-transplantation compared with recipients of equivalent numbers of untreated donor TCD BM and T cells. Gene array analyses of pDCs from Flt3L-treated human and murine donors showed up-regulation of adaptive immune pathways and immunoregulatory checkpoints compared with pDCs from untreated BM donors. Transplantation of TCD F-BM plus T cells resulted in no loss of the graft-versus-leukemia (GVL) effect compared with grafts from untreated donors in 2 murine GVL models. Thus, Flt3L treatment of BM donors is a novel method for increasing the pDC content in allografts, improving survival, and decreasing GVHD without diminishing the GVL effect.
Asunto(s)
Adyuvantes Inmunológicos/uso terapéutico , Trasplante de Médula Ósea/métodos , Células Dendríticas/inmunología , Proteínas de la Membrana/uso terapéutico , Trasplante Homólogo/métodos , Adyuvantes Inmunológicos/farmacología , Animales , Humanos , Masculino , Proteínas de la Membrana/farmacología , Ratones , Donantes de TejidosRESUMEN
The appropriate dose of antithymocyte globulin (ATG) to be used in reduced-intensity conditioning (RIC) allogeneic hematopoietic stem cell transplantation (allo-HSCT) is yet to be determined. We retrospectively analyzed the outcomes of patients who underwent unrelated or mismatch related RIC allo-HSCT for hematologic malignancies and received r-ATG (4.5 mg/kg, 141 patients) versus R-ATG (6 mg/kg, 216 patients). There was a higher incidence of cytomegalovirus (P < .001) and Epstein-Barr virus viremia (P =.03) in the R-ATG group than in the r-ATG group. The cumulative incidences of acute graft-versus-host disease (aGVHD) grades II to IV at day 180 in the r-ATG and R-ATG groups were 59% and 44% (Pâ¯=â¯.006) and grades III to IV 20% and 12% (Pâ¯=â¯.029), respectively. In multivariable models adjusting for disease diagnosis, the risk of aGVHD grades III to IV did not reach statistical significance (Pâ¯=â¯.087). The respective cumulative incidences of chronic GVHD in the r-ATG and R-ATG groups were 26% and 15% (Pâ¯=â¯.10), respectively. There were no significant differences in relapse rate (Pâ¯=â¯.24), nonrelapse mortality (Pâ¯=â¯.96), progression-free survival (Pâ¯=â¯.24), overall survival (Pâ¯=â¯.70), and GVHD-free relapse-free survival (Pâ¯=â¯.24). In this retrospective analysis, aGVHD incidence was higher in those treated with r-ATG compared with R-ATG, but this did not translate into significant differences of clinical outcome. Given the increasing use of RIC allo-HSCT for treating malignant hematologic conditions, the correct dose and schedule of ATG administration should be defined by prospective randomized controlled trials.
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Suero Antilinfocítico/uso terapéutico , Trasplante de Células Madre Hematopoyéticas/métodos , Acondicionamiento Pretrasplante/métodos , Trasplante Homólogo/métodos , Adulto , Anciano , Femenino , Humanos , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Estudios Retrospectivos , Adulto JovenRESUMEN
We previously reported that acute myelogenous leukemia (AML) transplants using killer cell immunoglobulin-type receptor (KIR) B haplotype better or best (≥2 B activating gene loci ± Cen B/B) unrelated donors (URDs) yield less relapse and better survival. In this prospective trial we evaluated 535 AML searches from 14 participating centers with centralized donor KIR genotyping for donor selection. This represented 3% to 48% of all AML searches (median 20%) per center, totaling 3 to 172 patients (median 22) per center. Donor KIR genotype was reported at a median of 14 days after request (≤26 days for 76% of searches). In 535 searches, 2080 donors were requested for KIR genotyping (mean 4.3 per search); and a median of 1.8 (range, 0 to 4.5) per search were KIR typed. Choosing more donors for confirmatory HLA and KIR haplotype identification enriched the likelihood of finding KIR better or best donors. The search process identified a mean of 30% KIR better or best donors; the success ranged from 24% to 38% in the 11 centers enrolling ≥8 patients. More donors requested for KIR genotyping increased the likelihood of identifying KIR better or best haplotype donors. Of the 247 transplants, 9.3% used KIR best, 19% used KIR better, and 48% used KIR neutral donors while 24% used a non-KIR-tested donor. KIR genotyping did not delay transplantation. The time from search to transplant was identical for transplants using a KIR-genotyped versus a non-KIR-genotyped donor. Prospective evaluation can rapidly identify KIR favorable genotype donors, but choosing more donors per search would substantially increase the likelihood of having a KIR best or better donor available for transplantation. Transplant centers and donor registries must both commit extra effort to incorporate new characteristics (beyond HLA, age, and parity) into improved donor selection. Deliberate efforts to present additional genetic factors for donor selection will require novel procedures.
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Selección de Donante , Haplotipos , Trasplante de Células Madre Hematopoyéticas , Leucemia Mieloide Aguda/terapia , Receptores KIR/genética , Donante no Emparentado , Adolescente , Adulto , Estudios de Factibilidad , Femenino , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patología , Masculino , Persona de Mediana Edad , Estudios ProspectivosRESUMEN
Relapse remains the major cause of death in older patients transplanted for acute myeloid leukemia (AML) in first complete remission or for patients with advanced myelodysplastic syndrome (MDS) at any age. Conventional myeloablative conditioning followed by allogeneic blood or marrow transplantation is associated with significantly less relapse compared with reduced-intensity conditioning when performed in younger patients with AML or MDS, but the toxicity of this approach in older patients is prohibitive. We hypothesized that pharmacokinetic targeting to optimize busulfan (BU) exposure, combined with the administration of azacitidine (AZA) post-transplant would mitigate the risk of relapse while reducing nonrelapse mortality and ultimately improve progression-free survival (PFS). On this phase II multicenter study, 63 patients (40 unrelated donors and 23 matched related donors) received a uniform conditioning regimen consisting of fludarabine i.v. (days -7 to -3), BU targeted to a daily area under the curve (AUC) of 4000 µM/min (days -6 to -3) after the administration of a 25-mg/m2 i.v. test dose on 1 day between days -14 to -9, and antithymocyte globulin (days -6, -5, and -4 (2 doses for matched related donors and 3 for matched unrelated donors only). Beginning on days +42 to +90, all patients were planned to receive up to 6 monthly cycles of AZA at 32â¯mg/m2 subcutaneously for 5 days. The median age was 62 years (range, 44 to 74); 13 had AML and 50 had MDS; 87% of patients were within 20% of the target AUC based on a validation sample. Forty-one patients (65%) started AZA at a median of 61 days (range, 43 to 91) post-transplant, and 17 patients (41%) completed all 6 cycles of AZA. The cumulative incidence of nonrelapse mortality at 2 years was 33.4% (95% confidence interval [CI], 22%-45%). The cumulative incidence of relapse was 25% (95% CI, 15%-37%) at 2 years. With a median follow-up of 58.9 months, the estimated PFS probability at 2 years and 5 years after transplantation was 41.2% (80% CI, 33.9%-49.9%) and 26.9% (80% CI, 20.4%-35.5%), respectively, for the entire group with a median PFS of 15.8 months (95% CI, 6.7 to 28.3). The probability of overall survival at 2 and 5 years was 45.7% (95% CI, 34.9%-59.9%) and 31.2% (95% CI, 21.3% to 45.8%), respectively, for the entire group with a median overall survival of 19.2 months (95% CI, 8.7 to 37.5). In summary, we demonstrated the feasibility of a novel reduced-intensity conditioning regimen with test dose BU targeted to an AUC of 4000 µM/min. The feasibility of AZA in this setting appears to be limited if applied to an unselected population of older hematopoietic stem cell transplantation recipients. (ClinicalTrials.gov Identifier: NCT01168219.).