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1.
Cytotherapy ; 26(4): 351-359, 2024 04.
Artículo en Inglés | MEDLINE | ID: mdl-38349310

RESUMEN

BACKGROUND AIMS: Traditional weight-based dosing of rabbit anti-thymocyte globulin (rATG) used in allogeneic hematopoietic cell transplantation (HCT) to prevent graft-versus-host disease (GVHD) and graft rejection leads to variable exposures. High exposures induce delayed CD4+immune reconstitution (CD4+IR) and greater mortality. We sought to determine the impact of rATG exposure in children and young adults receiving various types of EX-VIVO T-cell-depleted (EX-VIVO-TCD) HCT. METHODS: Patients receiving their first EX-VIVO-TCD HCT (CliniMACS CD34+, Isolex or soybean lectin agglutination), with removal of residual T cells by E-rosette depletion (E-) between 2008 and 2018 at Memorial Sloan Kettering Cancer Center were retrospectively analyzed. rATG exposure post-HCT was estimated (AU*d/L) using a validated population pharmacokinetic model. Previously defined rATG-exposures, <30, 30-55, ≥55 AU*d/L, were related with outcomes of interest. Cox proportional hazard and cause-specific models were used for analyses. RESULTS: In total, 180 patients (median age 11 years; range 0.1-44 years) were included, malignant 124 (69%) and nonmalignant 56 (31%). Median post-HCT rATG exposure was 32 (0-104) AU*d/L. Exposure <30 AU*d/L was associated with a 3-fold greater probability of CD4+IR (P < 0.001); 2- to 4-fold lower risk of death (P = 0.002); and 3- to 4-fold lower risk of non-relapse mortality (NRM) (P = 0.02). Cumulative incidence of NRM was 8-fold lower in patients who attained CD4+IR compared with those who did not (P < 0.0001). There was no relation between rATG exposure and aGVHD (P = 0.33) or relapse (P = 0.23). Effect of rATG exposure on outcomes was similar in three EX-VIVO-TCD methods. CONCLUSIONS: Individualizing rATG dosing to target a low rATG exposure post-HCT while maintaining total cumulative exposure may better predict CD4+IR, reduce NRM and increase overall survival, independent of the EX-VIVO-TCD method.


Asunto(s)
Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Humanos , Niño , Adulto Joven , Suero Antilinfocítico , Estudios Retrospectivos , Linfocitos T , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Acondicionamiento Pretrasplante
2.
Cytotherapy ; 26(5): 466-471, 2024 05.
Artículo en Inglés | MEDLINE | ID: mdl-38430078

RESUMEN

BACKGROUND AIMS: Daratumumab, a human IgG monoclonal antibody targeting CD38, is a promising treatment for pediatric patients with relapsed or refractory T-cell acute lymphoblastic leukemia (T-ALL). We describe a case of delayed engraftment following a mismatched, unrelated donor hematopoietic stem cell transplant (HSCT) in a 14-year-old female with relapsed T-ALL, treated with daratumumab and chemotherapy. By Day 28 post-HSCT, the patient had no neutrophil engraftment but full donor myeloid chimerism. METHODS: We developed two novel, semi-quantitative, antibody-based assays to measure the patient's bound and plasma daratumumab levels to determine if prolonged drug exposure may have contributed to her slow engraftment. RESULTS: Daratumumab levels were significantly elevated more than 30 days after the patient's final infusion, and levels inversely correlated with her white blood cell counts. To clear daratumumab, the patient underwent several rounds of plasmapheresis and subsequently engrafted. CONCLUSIONS: This is the first report of both delayed daratumumab clearance and delayed stem cell engraftment following daratumumab treatment in a pediatric patient. Further investigation is needed to elucidate the optimal dosing of daratumumab for treatment of acute leukemias in pediatric populations as well as daratumumab's potential effects on hematopoietic stem cells and stem cell engraftment following allogenic HSCT.


Asunto(s)
Anticuerpos Monoclonales , Trasplante de Células Madre Hematopoyéticas , Trasplante Homólogo , Humanos , Trasplante de Células Madre Hematopoyéticas/métodos , Femenino , Anticuerpos Monoclonales/uso terapéutico , Adolescente , Trasplante Homólogo/métodos , Leucemia-Linfoma Linfoblástico de Células T Precursoras/terapia , Leucemia-Linfoma Linfoblástico de Células T Precursoras/tratamiento farmacológico , Supervivencia de Injerto/efectos de los fármacos
3.
J Pediatr Hematol Oncol ; 46(2): e143-e146, 2024 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-38237014

RESUMEN

Isavuconazonium sulfate (ISA) is a triazole antifungal approved for the treatment of invasive aspergillosis and mucormycosis in adults. This single-center, retrospective review of pediatric oncology and stem cell transplant patients receiving ISA for prophylaxis (n=20) or treatment (n=6) of invasive fungal disease (IFD) aims to characterize real-world clinical efficacy and toxicity of ISA in patients <18 years of age. Of 20 patients receiving ISA for prophylaxis, three patients had presumed breakthrough IFD (1 proven, 2 probable/possible). No adverse effects were attributed to ISA use or led to the discontinuation of therapy.


Asunto(s)
Infecciones Fúngicas Invasoras , Neoplasias , Nitrilos , Piridinas , Adulto , Niño , Humanos , Estudios Retrospectivos , Antifúngicos , Infecciones Fúngicas Invasoras/tratamiento farmacológico , Triazoles , Trasplante de Células Madre , Neoplasias/tratamiento farmacológico
4.
Blood ; 137(6): 848-855, 2021 02 11.
Artículo en Inglés | MEDLINE | ID: mdl-33150379

RESUMEN

Acute graft-versus-host-Disease (aGVHD) is a major cause of morbidity and mortality after allogeneic hematopoietic cell transplantation (HCT). We previously showed that early CD4+ T-cell immune reconstitution (IR; CD4+ IR) predicts survival after HCT. Here, we studied the relation between CD4+ IR and survival in patients developing aGVHD. Pediatric patients undergoing first allogeneic HCT at University Medical Center Utrecht (UMC)/Princess Máxima Center (PMC) or Memorial Sloan Kettering Cancer Center (MSK) were included. Primary outcomes were nonrelapse mortality (NRM) and overall survival (OS), stratified for aGVHD and CD4+ IR, defined as ≥50 CD4+ T cells per µL within 100 days after HCT or before aGVHD onset. Multivariate and time-to-event Cox proportional hazards models were applied, and 591 patients (UMC/PMC, n = 276; MSK, n = 315) were included. NRM in patients with grade 3 to 4 aGVHD with or without CD4+ IR within 100 days after HCT was 30% vs 80% (P = .02) at UMC/PMC and 5% vs 67% (P = .02) at MSK. This was associated with lower OS without CD4+ IR (UMC/PMC, 61% vs 20%; P = .04; MSK, 75% vs 33%; P = .12). Inadequate CD4+ IR before aGVHD onset was associated with significantly higher NRM (74% vs 12%; P < .001) and inferior OS (24% vs 78%; P < .001). In this retrospective analysis, we demonstrate that early CD4+ IR, a simple and robust marker predictive of outcomes after HCT, is associated with survival after moderate to severe aGVHD. This association must be confirmed prospectively but suggests strategies to improve T-cell recovery after HCT may influence survival in patients developing aGVHD.


Asunto(s)
Recuento de Linfocito CD4 , Linfocitos T CD4-Positivos/inmunología , Enfermedad Injerto contra Huésped/inmunología , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Reconstitución Inmune , Enfermedad Aguda , Adolescente , Aloinjertos , Niño , Preescolar , Femenino , Estudios de Seguimiento , Enfermedad Injerto contra Huésped/mortalidad , Humanos , Lactante , Estimación de Kaplan-Meier , Masculino , Modelos de Riesgos Proporcionales , Estudios Retrospectivos , Índice de Severidad de la Enfermedad , Resultado del Tratamiento , Adulto Joven
5.
Pediatr Blood Cancer ; 70(1): e29921, 2023 01.
Artículo en Inglés | MEDLINE | ID: mdl-35934994

RESUMEN

BACKGROUND: Stage 4a metastatic retinoblastoma (RB) is curable with intensive multimodality therapy including myeloablative chemotherapy with autologous stem cell transplant (HDC-ASCT) and involved field radiation therapy (IFRT). To our knowledge, no data exist on the impact of (a) pre-ASCT disease status, and (b) IFRT to sites of metastatic disease post ASCT on survival. PROCEDURE: We retrospectively reviewed patients with stage 4a metastatic RB who underwent induction chemotherapy followed by HDC-ASCT, with or without IFRT, to residual tumor sites at Memorial Sloan Kettering Cancer Center (MSKCC) (n = 24). RESULTS: The degree of postinduction response prior to ASCT did not affect outcome, with 5-year overall survival (OS) of 68% and 86% in patients who achieved complete response (CR) and very good partial response (VGPR)/partial response (PR) prior to ASCT, respectively. IFRT administered post ASCT in patients with possible residual bony metastatic disease increases the likelihood of developing osteosarcoma in the radiation field. CONCLUSION: OS for patients with stage 4a metastatic RB treated with ASCT with VGPR or PR to pretransplant chemotherapy was not significantly different from patients with CR. In addition, IFRT does not seem to be required for bony disease control and increased the likelihood of developing osteosarcoma.


Asunto(s)
Trasplante de Células Madre Hematopoyéticas , Osteosarcoma , Neoplasias de la Retina , Retinoblastoma , Humanos , Supervivencia sin Enfermedad , Estudios Retrospectivos , Retinoblastoma/terapia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Trasplante Autólogo , Neoplasias de la Retina/terapia , Resultado del Tratamiento
6.
Nature ; 531(7595): 471-475, 2016 Mar 24.
Artículo en Inglés | MEDLINE | ID: mdl-26982726

RESUMEN

Mutations disabling the TP53 tumour suppressor gene represent the most frequent events in human cancer and typically occur through a two-hit mechanism involving a missense mutation in one allele and a 'loss of heterozygosity' deletion encompassing the other. While TP53 missense mutations can also contribute gain-of-function activities that impact tumour progression, it remains unclear whether the deletion event, which frequently includes many genes, impacts tumorigenesis beyond TP53 loss alone. Here we show that somatic heterozygous deletion of mouse chromosome 11B3, a 4-megabase region syntenic to human 17p13.1, produces a greater effect on lymphoma and leukaemia development than Trp53 deletion. Mechanistically, the effect of 11B3 loss on tumorigenesis involves co-deleted genes such as Eif5a and Alox15b (also known as Alox8), the suppression of which cooperates with Trp53 loss to produce more aggressive disease. Our results imply that the selective advantage produced by human chromosome 17p deletion reflects the combined impact of TP53 loss and the reduced dosage of linked tumour suppressor genes.


Asunto(s)
Genes p53/genética , Neoplasias/genética , Neoplasias/patología , Eliminación de Secuencia/genética , Proteína p53 Supresora de Tumor/deficiencia , Alelos , Animales , Transformación Celular Neoplásica/genética , Cromosomas Humanos Par 17/genética , Cromosomas de los Mamíferos/genética , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Femenino , Heterocigoto , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patología , Linfoma/genética , Linfoma/patología , Masculino , Ratones , Factores de Iniciación de Péptidos/genética , Factores de Iniciación de Péptidos/metabolismo , Proteínas de Unión al ARN/genética , Proteínas de Unión al ARN/metabolismo , Sintenía/genética , Factor 5A Eucariótico de Iniciación de Traducción
7.
Blood ; 134(26): 2361-2368, 2019 12 26.
Artículo en Inglés | MEDLINE | ID: mdl-31650176

RESUMEN

Chimeric antigen receptor (CAR) T cells have demonstrated clinical benefit in patients with relapsed/refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL). We undertook a multicenter clinical trial to determine toxicity, feasibility, and response for this therapy. A total of 25 pediatric/young adult patients (age, 1-22.5 years) with R/R B-ALL were treated with 19-28z CAR T cells. Conditioning chemotherapy included high-dose (3 g/m2) cyclophosphamide (HD-Cy) for 17 patients and low-dose (≤1.5 g/m2) cyclophosphamide (LD-Cy) for 8 patients. Fifteen patients had pretreatment minimal residual disease (MRD; <5% blasts in bone marrow), and 10 patients had pretreatment morphologic evidence of disease (≥5% blasts in bone marrow). All toxicities were reversible, including severe cytokine release syndrome in 16% (4 of 25) and severe neurotoxicity in 28% (7 of 25) of patients. Treated patients were assessed for response, and, among the evaluable patients (n = 24), response and peak CAR T-cell expansion were superior in the HD-Cy/MRD cohorts, as compared with the LD-Cy/morphologic cohorts without an increase in toxicity. Our data support the safety of CD19-specific CAR T-cell therapy for R/R B-ALL. Our data also suggest that dose intensity of conditioning chemotherapy and minimal pretreatment disease burden have a positive impact on response without a negative effect on toxicity. This trial was registered at www.clinicaltrials.gov as #NCT01860937.


Asunto(s)
Antígenos CD19/metabolismo , Resistencia a Antineoplásicos , Recurrencia Local de Neoplasia/terapia , Leucemia-Linfoma Linfoblástico de Células Precursoras B/terapia , Receptores de Antígenos de Linfocitos T/inmunología , Receptores Quiméricos de Antígenos/inmunología , Linfocitos T/trasplante , Adolescente , Adulto , Niño , Preescolar , Síndrome de Liberación de Citoquinas/etiología , Síndrome de Liberación de Citoquinas/patología , Síndrome de Liberación de Citoquinas/prevención & control , Femenino , Humanos , Lactante , Masculino , Recurrencia Local de Neoplasia/inmunología , Recurrencia Local de Neoplasia/metabolismo , Neoplasia Residual/etiología , Neoplasia Residual/patología , Neoplasia Residual/prevención & control , Síndromes de Neurotoxicidad/etiología , Síndromes de Neurotoxicidad/patología , Síndromes de Neurotoxicidad/prevención & control , Leucemia-Linfoma Linfoblástico de Células Precursoras B/inmunología , Leucemia-Linfoma Linfoblástico de Células Precursoras B/metabolismo , Terapia Recuperativa , Tasa de Supervivencia , Linfocitos T/inmunología , Resultado del Tratamiento , Adulto Joven
8.
Cytotherapy ; 22(9): 503-510, 2020 09.
Artículo en Inglés | MEDLINE | ID: mdl-32622752

RESUMEN

BACKGROUND: An association between early CD4+ T cell immune reconstitution (CD4+ IR) and survival after T-replete allogeneic hematopoietic cell transplantation (HCT) has been previously reported. Here we report validation of this relationship in a separate cohort that included recipients of ex vivo T-cell-depleted (TCD) HCT. We studied the relationship between CD4+ IR and clinical outcomes. METHODS: A retrospective analysis of children/young adults receiving their first allogeneic HCT for any indication between January 2008 and December 2017 was performed. We related early CD4+ IR (defined as achieving >50 CD4+ T cells/µL on two consecutive measures within 100 days of HCT) to overall survival (OS), relapse, non-relapse mortality (NRM), event-free survival (EFS) and acute graft-versus-host disease (aGVHD). Fine and Gray competing risk models and Cox proportional hazard models were used. RESULTS: In this analysis, 315 patients with a median age of 10.4 years (interquartile range 5.0-16.5 years) were included. The cumulative incidence of CD4+ IR at 100 days was 66.7% in the entire cohort, 54.7% in TCD (N = 208, hazard ratio [HR] 0.47, P < 0.001), 90.0% in uCB (N = 40) and 89.6% in T-replete (N = 47) HCT recipients. In multi-variate analyses, not achieving early CD4+ IR was a predictor of inferior OS (HR 2.35, 95% confidence interval [CI] 1.46-3.79, P < 0.001) and EFS (HR 1.80, 95% CI 1.20-2.69, P = 0.004) and increased NRM (HR 6.58, 95% CI 2.82-15.38, P < 0.001). No impact of CD4+ IR on relapse or aGVHD was found. Within the TCD group, similar associations were observed. CONCLUSION: In this HCT cohort, including recipients of TCD HCT, we confirmed that early CD4+ IR was an excellent predictor of outcomes. Finding strategies to predict or improve CD4+ IR may influence outcomes.


Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Trasplante de Células Madre Hematopoyéticas , Reconstitución Inmune , Adolescente , Niño , Preescolar , Estudios de Cohortes , Supervivencia sin Enfermedad , Femenino , Enfermedad Injerto contra Huésped/inmunología , Humanos , Masculino , Análisis Multivariante , Modelos de Riesgos Proporcionales , Estudios Retrospectivos , Trasplante Homólogo , Resultado del Tratamiento
11.
Biol Blood Marrow Transplant ; 23(12): 2088-2095, 2017 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-28711727

RESUMEN

We sought to develop a myeloablative chemotherapeutic regimen to secure consistent engraftment of T-cell depleted (TCD) hematopoietic stem cell transplantations (HSCT) without the need for total body irradiation, thereby reducing toxicity while maintaining low rates of graft-versus-host disease (GVHD) and without increasing relapse. We investigated the myeloablative combination of busulfan (Bu) and melphalan (Mel), with the immunosuppressive agents fludarabine (Flu) and rabbit antithymocyte globulin (r-ATG) as cytoreduction before a TCD HSCT. No post-transplantation immunosuppression was administered. Between April 2001 and May 2008, 102 patients (median age, 55 years) with a diagnosis of primary or secondary myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) underwent cytoreduction with Bu/Mel/Flu, followed by TCD grafts. TCD was accomplished by CD34+-selection followed by E-rosette depletion for peripheral blood stem cell grafts and, for bone marrow grafts, by soybean agglutination followed by E-rosette depletion. Donors included matched and mismatched, related and unrelated donors. Risk stratification was by American Society for Blood and Marrow Transplantation risk categorization for patients with primary disease. For patients with secondary/treatment-related MDS/AML, those in complete remission (CR) 1 or with refractory anemia were classified as intermediate risk, and all other patients were considered high risk. Neutrophil engraftment occurred at a median of 11 days in 100 of 101 evaluable patients. The cumulative incidences of grades II to IV acute and chronic GVHD at 1 year were 8.8% and 5.9%, respectively. Overall- and disease-free survival (DFS) rates at 5 years were 50.0% and 46.1%, respectively, and the cumulative incidences of relapse and treatment-related mortality were 23.5% and 28.4%, respectively. Stratification by risk group demonstrated superior DFS for low-risk patients (61.5% at 5 years) compared with intermediate- or high-risk (34.2% and 40.0%, respectively, P = .021). For patients with AML, those in CR1 had superior 5-year DFS compared with those in ≥CR2 (60% and 30.6%, respectively, P = .01), without a significant difference in incidence of relapse (17.1% and 30.6%, respectively, P = .209). There were no differences in DFS for other patient, donor, or disease characteristics. In summary, cytoreduction with Bu/Mel/Flu and r-ATG secured consistent engraftment of TCD transplantations. The incidences of acute/chronic GVHD and disease relapse were low, with favorable outcomes in this patient population with high-risk myeloid malignancies.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Trasplante de Células Madre Hematopoyéticas/métodos , Leucemia Mieloide Aguda/terapia , Depleción Linfocítica , Síndromes Mielodisplásicos/terapia , Adolescente , Adulto , Anciano , Animales , Suero Antilinfocítico/administración & dosificación , Busulfano/administración & dosificación , Niño , Preescolar , Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas/mortalidad , Humanos , Lactante , Leucemia Mieloide Aguda/mortalidad , Depleción Linfocítica/mortalidad , Melfalán/administración & dosificación , Persona de Mediana Edad , Síndromes Mielodisplásicos/mortalidad , Conejos , Medición de Riesgo , Análisis de Supervivencia , Trasplante Homólogo , Resultado del Tratamiento , Vidarabina/administración & dosificación , Vidarabina/análogos & derivados , Adulto Joven
12.
Biol Blood Marrow Transplant ; 22(8): 1449-1454, 2016 08.
Artículo en Inglés | MEDLINE | ID: mdl-27184623

RESUMEN

Relapse after allogeneic hematopoietic stem cell transplantation (alloHSCT) remains one of the leading causes of mortality in patients with leukemia. Treatment options in this population remain limited, with concern for both increased toxicity and further relapse. We treated 18 patients with acute leukemia for marrow ± extramedullary relapse after a previous alloHSCT with a myeloablative cytoreductive regimen including clofarabine, melphalan, and thiotepa followed by a second or third transplantation from the same or a different donor. All patients were in remission at the time of the second or third transplantation. All evaluable patients engrafted. The most common toxicity was reversible transaminitis associated with clofarabine. Two patients died from transplantation-related causes. Seven patients relapsed after their second or third transplanation and died of disease. Nine of 18 patients are alive and disease free, with a 3-year 49% probability of overall survival (OS). Patients whose remission duration after initial alloHSCT was >6 months achieved superior outcomes (3-year OS, 74%, 95% confidence interval, 53% to 100%), compared with those relapsing within 6 months (0%) (P < .001). This new cytoreductive regimen has yielded promising results with acceptable toxicity for second or third transplantations in patients with high-risk acute leukemia who relapsed after a prior transplantation, using various graft and donor options. This approach merits further evaluation in collaborative group studies.


Asunto(s)
Trasplante de Células Madre Hematopoyéticas/métodos , Leucemia/terapia , Inducción de Remisión/métodos , Terapia Recuperativa/métodos , Enfermedad Aguda , Nucleótidos de Adenina/administración & dosificación , Nucleótidos de Adenina/toxicidad , Adolescente , Adulto , Arabinonucleósidos/administración & dosificación , Arabinonucleósidos/toxicidad , Niño , Preescolar , Clofarabina , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Trasplante de Células Madre Hematopoyéticas/mortalidad , Humanos , Leucemia/complicaciones , Leucemia/mortalidad , Melfalán/administración & dosificación , Agonistas Mieloablativos/uso terapéutico , Terapia Recuperativa/mortalidad , Análisis de Supervivencia , Tiotepa/administración & dosificación , Trasplante Homólogo , Adulto Joven
13.
Blood ; 124(11): 1790-8, 2014 Sep 11.
Artículo en Inglés | MEDLINE | ID: mdl-25006131

RESUMEN

Somatic cohesin mutations have been reported in myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). To account for the morphologic and cytogenetic diversity of these neoplasms, a well-annotated cohort of 1060 patients with myeloid malignancies including MDS (n = 386), myeloproliferative neoplasms (MPNs) (n = 55), MDS/MPNs (n = 169), and AML (n = 450) were analyzed for cohesin gene mutational status, gene expression, and therapeutic and survival outcomes. Somatic cohesin defects were detected in 12% of patients with myeloid malignancies, whereas low expression of these genes was present in an additional 15% of patients. Mutations of cohesin genes were mutually exclusive and mostly resulted in predicted loss of function. Patients with low cohesin gene expression showed similar expression signatures as those with somatic cohesin mutations. Cross-sectional deep-sequencing analysis for clonal hierarchy demonstrated STAG2, SMC3, and RAD21 mutations to be ancestral in 18%, 18%, and 47% of cases, respectively, and each expanded to clonal dominance concordant with disease transformation. Cohesin mutations were significantly associated with RUNX1, Ras-family oncogenes, and BCOR and ASXL1 mutations and were most prevalent in high-risk MDS and secondary AML. Cohesin defects were associated with poor overall survival (27.2 vs 40 months; P = .023), especially in STAG2 mutant MDS patients surviving >12 months (median survival 35 vs 50 months; P = .017).


Asunto(s)
Proteínas de Ciclo Celular , Proteínas Cromosómicas no Histona , Genes Relacionados con las Neoplasias , Leucemia Mieloide Aguda , Mutación , Trastornos Mieloproliferativos , Anciano , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Proteínas Cromosómicas no Histona/genética , Proteínas Cromosómicas no Histona/metabolismo , Subunidad alfa 2 del Factor de Unión al Sitio Principal/genética , Subunidad alfa 2 del Factor de Unión al Sitio Principal/metabolismo , Estudios Transversales , Supervivencia sin Enfermedad , Femenino , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/mortalidad , Masculino , Trastornos Mieloproliferativos/genética , Trastornos Mieloproliferativos/metabolismo , Trastornos Mieloproliferativos/mortalidad , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Represoras/genética , Proteínas Represoras/metabolismo , Tasa de Supervivencia , Cohesinas
14.
Transplant Cell Ther ; 30(7): 692.e1-692.e12, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-38643958

RESUMEN

The clinical value of serial routine bone marrow aspirates (rBMAs) in the first year after allogeneic hematopoietic cell transplantation (alloHCT) to detect or predict relapse of acute leukemia (AL) and myelodysplastic syndrome (MDS) in pediatric and young adult patients is unclear. The purpose of this analysis was to determine if assessment of minimal residual disease (MRD) by multiparameter flow cytometry (MFC, MFC-MRD) or donor chimerism (DC) in rBMAs or serial complete blood counts (CBCs) done in the year after alloHCT predicted relapse of AL or MDS in pediatric and young adult patients. We completed a retrospective analysis of patients with AL or MDS who had rBMAs performed after alloHCT between January 2012 and June 2018. Bone marrow (BM) was evaluated at approximately 3, 6, and 12 months for disease recurrence by morphology, MFC-MRD, and percent DC by short tandem repeat molecular testing. CBCs were performed at every clinic visit. The main outcome of interest was an assessment of whether MFC-MRD or DC in rBMAs or serial CBCs done in the year after alloHCT predicted relapse in AL or MDS pediatric and young adult patients. A total of 121 recipients with a median age of 13 years (range 1 to 32) were included: 108 with AL and, 13 with MDS. A total of 423 rBMAs (median 3; 0 to 13) were performed. Relapse at 2 years was 23% (95% CI: 16% to 31%) and at 5 years 25% (95% CI: 18% to 33%). One hundred fifty-four of 157 (98%) rBMAs evaluated for MRD by MFC were negative and did not preclude subsequent relapse. Additionally, low DC (<95%) did not predict relapse and high DC (≥95%) did not preclude relapse. For patients alive without relapse at 1 year, BM DC (P = .74) and peripheral T-cell DC (P = .93) did not predict relapse. Six patients with low-level T-cell and/or BM DC had a total of 8 to 20 BM evaluations, none of these patients relapsed. However, CBC results were informative for relapse; 28 of 31 (90%) relapse patients presented with an abnormal CBC with peripheral blood (PB) blasts (16 patients), cytopenias (9 patients), or extramedullary disease (EMD, 3 patients). Two patients with BM blasts >5% on rBMA had circulating blasts within 5 weeks of rBMA. Neutropenia (ANC <1.5 K/mcl) at 1 year was predictive of relapse (P = .01). Neutropenia and thrombocytopenia (<160 K/mcl) were predictive of disease-free survival (DFS) with inferior DFS for ANC <1.5 K/mcl, P = .001, or platelet count <160 K/mcl (P = .04). These results demonstrate rBMAs after alloHCT assessed for MRD by MFC and/or for level of DC are poor predictors for relapse in pediatric and young adult patients with AL or MDS. Relapse in these patients presents with PB blasts, cytopenias, or EMD. ANC and platelet count at 1-year were highly predictive for DFS.


Asunto(s)
Trasplante de Células Madre Hematopoyéticas , Síndromes Mielodisplásicos , Recurrencia , Humanos , Síndromes Mielodisplásicos/terapia , Niño , Masculino , Adolescente , Femenino , Adulto Joven , Adulto , Preescolar , Estudios Retrospectivos , Médula Ósea/patología , Neoplasia Residual , Leucemia/terapia , Lactante , Enfermedad Aguda , Citopenia
15.
Blood Adv ; 8(3): 686-698, 2024 02 13.
Artículo en Inglés | MEDLINE | ID: mdl-37991991

RESUMEN

ABSTRACT: Serial prognostic evaluation after allogeneic hematopoietic cell transplantation (allo-HCT) might help identify patients at high risk of lethal organ dysfunction. Current prediction algorithms based on models that do not incorporate changes to patients' clinical condition after allo-HCT have limited predictive ability. We developed and validated a robust risk-prediction algorithm to predict short- and long-term survival after allo-HCT in pediatric patients that includes baseline biological variables and changes in the patients' clinical status after allo-HCT. The model was developed using clinical data from children and young adults treated at a single academic quaternary-care referral center. The model was created using a randomly split training data set (70% of the cohort), internally validated (remaining 30% of the cohort) and then externally validated on patient data from another tertiary-care referral center. Repeated clinical measurements performed from 30 days before allo-HCT to 30 days afterwards were extracted from the electronic medical record and incorporated into the model to predict survival at 100 days, 1 year, and 2 years after allo-HCT. Naïve-Bayes machine learning models incorporating longitudinal data were significantly better than models constructed from baseline variables alone at predicting whether patients would be alive or deceased at the given time points. This proof-of-concept study demonstrates that unlike traditional prognostic tools that use fixed variables for risk assessment, incorporating dynamic variability using clinical and laboratory data improves the prediction of mortality in patients undergoing allo-HCT.


Asunto(s)
Trasplante de Células Madre Hematopoyéticas , Adulto Joven , Humanos , Niño , Trasplante Homólogo/efectos adversos , Teorema de Bayes , Estudios Retrospectivos , Pronóstico , Trasplante de Células Madre Hematopoyéticas/efectos adversos
16.
Bone Marrow Transplant ; 59(1): 23-33, 2024 01.
Artículo en Inglés | MEDLINE | ID: mdl-37773270

RESUMEN

The only curative approach for myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) arising in patients with Fanconi anemia (FA) is allogeneic hematopoietic stem cell transplantation (HCT); however, HCT approaches are inconsistent and limited data on outcomes exist. We retrospectively evaluated outcomes of thirty patients with FA and MDS/AML who underwent first allogeneic HCT with a T-cell depleted (TCD) graft at our institution. Patients were transplanted on successive protocols with stepwise changes in cytoreduction and GVHD prophylaxis. All but two patients (93%) experienced durable hematopoietic engraftment. With median follow-up of 8.7 years, 5-year OS was 66.8% and DFS 53.8%. No significant differences in survival were found in patients with high-risk prognostic features (age ≥20 years, AML diagnosis, alternative donor graft) or when stratified by conditioning regimen. The 5-year cumulative incidences of relapse and NRM were 24.3% and 21.9%, respectively. NRM was higher in patients ≥20 years at HCT but did not otherwise differ. We herein demonstrate promising outcomes following allogeneic HCT for patients with FA and MDS/AML using TCD grafts, particularly in a cohort of high-risk patients with 50% ≥20 years and a majority receiving mismatched grafts. Future prospective studies are needed to compare this approach with other HCT platforms.


Asunto(s)
Anemia de Fanconi , Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Leucemia Mieloide Aguda , Humanos , Adulto Joven , Adulto , Anemia de Fanconi/terapia , Anemia de Fanconi/complicaciones , Estudios Retrospectivos , Trasplante Homólogo/efectos adversos , Acondicionamiento Pretrasplante/métodos , Linfocitos T , Trasplante de Células Madre Hematopoyéticas/métodos , Enfermedad Injerto contra Huésped/etiología
17.
Blood Adv ; 8(4): 846-856, 2024 Feb 27.
Artículo en Inglés | MEDLINE | ID: mdl-38147626

RESUMEN

ABSTRACT: Clonal hematopoiesis (CH) identified by somatic gene variants with variant allele fraction (VAF) ≥ 2% is associated with an increased risk of hematologic malignancy. However, CH defined by a broader set of genotypes and lower VAFs is ubiquitous in older individuals. To improve our understanding of the relationship between CH genotype and risk of hematologic malignancy, we analyzed data from 42 714 patients who underwent blood sequencing as a normal comparator for nonhematologic tumor testing using a large cancer-related gene panel. We cataloged hematologic malignancies in this cohort using natural language processing and manual curation of medical records. We found that some CH genotypes including JAK2, RUNX1, and XPO1 variants were associated with high hematologic malignancy risk. Chronic disease was predicted better than acute disease suggesting the influence of length bias. To better understand the implications of hematopoietic clonality independent of mutational function, we evaluated a set of silent synonymous and noncoding mutations. We found that silent CH, particularly when multiple variants were present or VAF was high, was associated with increased risk of hematologic malignancy. We tracked expansion of CH mutations in 26 hematologic malignancies sequenced with the same platform. JAK2 and TP53 VAF consistently expanded at disease onset, whereas DNMT3A and silent CH VAFs mostly decreased. These data inform the clinical and biological interpretation of CH in the context of nonhematologic cancer.


Asunto(s)
Hematopoyesis Clonal , Neoplasias Hematológicas , Humanos , Anciano , Hematopoyesis/genética , Mutación , Neoplasias Hematológicas/epidemiología , Neoplasias Hematológicas/genética , Neoplasias Hematológicas/patología , Genotipo
18.
Transplant Cell Ther ; 29(1): 46.e1-46.e6, 2023 01.
Artículo en Inglés | MEDLINE | ID: mdl-36210027

RESUMEN

Poor graft function (PGF) is a life-threatening complication after allogeneic stem cell transplantation (alloSCT). Historically, outcomes of patients with PGF have been very poor, and there are no standardized approaches to treatment. Furthermore, few outcomes after CD34-selected stem cell boost (CD34+SCB) for PGF in pediatric alloSCT recipients have been reported. Here we report on a single center experience with CD34+SCB for PGF after alloSCT in patients treated on the Pediatric Transplant and Cellular Therapy Service at MSK Kids, Memorial Sloan Kettering Cancer Center. A retrospective analysis of patients transplanted for malignant and nonmalignant disorders who received a CD34+SCB between 2008 to 2020 for treatment of PGF defined as the need for granulocyte colony-stimulating factor (G-CSF) and/or packed red blood cell or platelet transfusion support with bone marrow donor chimerism ≥85%. Peripheral blood stem cells from the original donor were the source for CD34+SCB. Durable complete recovery (durable CR) was defined as recovery of peripheral blood counts without recurrent need for G-CSF or transfusion support. The main outcomes of interest were recovery of hematopoiesis and overall survival. Development of graft versus host disease (GVHD) was an additional outcome of interest. Fourteen patients with PGF received a boost. Six patients had no known infection, while 8 patients had PGF associated with an infection. The probability of CR at 60 days was 79% (95% confidence interval [CI], 57%-100%). The overall survival at both 2 and 5 years was 78% (95% CI, 56%-100%). One patient developed GVHD, which was fatal. No other CD34+SCB-related toxicities were observed. While including patients with PGF as recently defined by the American Society for Transplantation and Cellular Therapy, as well as PGF in patients with concomitant infections, we demonstrate that CD34+SCB is safe and can provide for durable trilineage hematopoietic recovery and long-term survival in pediatric patients after alloSCT.


Asunto(s)
Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Células Madre de Sangre Periférica , Humanos , Niño , Estudios Retrospectivos , Trasplante Homólogo/efectos adversos , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Antígenos CD34/análisis , Enfermedad Injerto contra Huésped/etiología , Factor Estimulante de Colonias de Granulocitos/uso terapéutico
19.
Blood Adv ; 7(17): 5069-5081, 2023 09 12.
Artículo en Inglés | MEDLINE | ID: mdl-37327118

RESUMEN

Although allogeneic hematopoietic cell transplant (allo-HCT) is curative for high-risk pediatric acute myeloid leukemia (AML), disease relapse remains the primary cause of posttransplant mortality. To identify pressures imposed by allo-HCT on AML cells that escape the graft-versus-leukemia effect, we evaluated immune signatures at diagnosis and posttransplant relapse in bone marrow samples from 4 pediatric patients using a multimodal single-cell proteogenomic approach. Downregulation of major histocompatibility complex class II expression was most profound in progenitor-like blasts and accompanied by correlative changes in transcriptional regulation. Dysfunction of activated natural killer cells and CD8+ T-cell subsets at relapse was evidenced by the loss of response to interferon gamma, tumor necrosis factor α signaling via NF-κB, and interleukin-2/STAT5 signaling. Clonotype analysis of posttransplant relapse samples revealed an expansion of dysfunctional T cells and enrichment of T-regulatory and T-helper cells. Using novel computational methods, our results illustrate a diverse immune-related transcriptional signature in posttransplant relapses not previously reported in pediatric AML.


Asunto(s)
Trasplante de Células Madre Hematopoyéticas , Leucemia Mieloide Aguda , Humanos , Niño , Trasplante de Células Madre Hematopoyéticas/métodos , Trasplante Homólogo , Antígenos de Histocompatibilidad Clase II , Recurrencia
20.
Nat Genet ; 55(6): 1022-1033, 2023 06.
Artículo en Inglés | MEDLINE | ID: mdl-37169874

RESUMEN

Patients with high-risk neuroblastoma generally present with widely metastatic disease and often relapse despite intensive therapy. As most studies to date focused on diagnosis-relapse pairs, our understanding of the genetic and clonal dynamics of metastatic spread and disease progression remain limited. Here, using genomic profiling of 470 sequential and spatially separated samples from 283 patients, we characterize subtype-specific genetic evolutionary trajectories from diagnosis through progression and end-stage metastatic disease. Clonal tracing timed disease initiation to embryogenesis. Continuous acquisition of structural variants at disease-defining loci (MYCN, TERT, MDM2-CDK4) followed by convergent evolution of mutations targeting shared pathways emerged as the predominant feature of progression. At diagnosis metastatic clones were already established at distant sites where they could stay dormant, only to cause relapses years later and spread via metastasis-to-metastasis and polyclonal seeding after therapy.


Asunto(s)
Recurrencia Local de Neoplasia , Neuroblastoma , Humanos , Recurrencia Local de Neoplasia/genética , Neuroblastoma/genética , Evolución Clonal , Mutación , Metástasis de la Neoplasia
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