RESUMEN
Inherited or de novo germ line heterozygous mutations in the gene encoding the transcription factor GATA2 lead to its deficiency. This results in a constellation of clinical features including nontuberculous mycobacterial, bacterial, fungal, and human papillomavirus infections, lymphedema, pulmonary alveolar proteinosis, and myelodysplasia. The onset, or even the presence, of disease is highly variable, even in kindreds with the identical mutation in GATA2. The clinical manifestations result from the loss of a multilineage progenitor that gives rise to B lymphocytes, monocytes, natural killer cells, and dendritic cells, leading to cytopenias of these lineages and subsequent infections. The bone marrow failure is typically characterized by hypocellularity. Dysplasia may either be absent or subtle but typically evolves into multilineage dysplasia with prominent dysmegakaryopoiesis, followed in some instances by progression to myeloid malignancies, specifically myelodysplastic syndrome, acute myelogenous leukemia, and chronic myelomonocytic leukemia. The latter 3 malignancies often occur in the setting of monosomy 7, trisomy 8, and acquired mutations in ASXL1 or in STAG2. Importantly, myeloid malignancy may represent the primary presentation of disease without recognition of other syndromic features. Allogeneic hematopoietic stem cell transplantation (HSCT) results in reversal of the phenotype. There remain important unanswered questions in GATA2 deficiency, including the following: (1) Why do some family members remain asymptomatic despite harboring deleterious mutations in GATA2? (2) What are the genetic changes that lead to myeloid progression? (3) What causes the apparent genetic anticipation? (4) What is the role of preemptive HSCT?
Asunto(s)
Deficiencia GATA2 , Síndromes Mielodisplásicos , Trastornos Mieloproliferativos , Humanos , Deficiencia GATA2/complicaciones , Deficiencia GATA2/genética , Deficiencia GATA2/terapia , Síndromes Mielodisplásicos/genética , Síndromes Mielodisplásicos/terapia , Síndromes Mielodisplásicos/patología , Mutación , Mutación de Línea Germinal , Factor de Transcripción GATA2/genéticaRESUMEN
The choice to postpone treatment while awaiting genetic testing can result in significant delay in definitive therapies in patients with severe pancytopenia. Conversely, the misdiagnosis of inherited bone marrow failure (BMF) can expose patients to ineffectual and expensive therapies, toxic transplant conditioning regimens, and inappropriate use of an affected family member as a stem cell donor. To predict the likelihood of patients having acquired or inherited BMF, we developed a 2-step data-driven machine-learning model using 25 clinical and laboratory variables typically recorded at the initial clinical encounter. For model development, patients were labeled as having acquired or inherited BMF depending on their genomic data. Data sets were unbiasedly clustered, and an ensemble model was trained with cases from the largest cluster of a training cohort (n = 359) and validated with an independent cohort (n = 127). Cluster A, the largest group, was mostly immune or inherited aplastic anemia, whereas cluster B comprised underrepresented BMF phenotypes and was not included in the next step of data modeling because of a small sample size. The ensemble cluster A-specific model was accurate (89%) to predict BMF etiology, correctly predicting inherited and likely immune BMF in 79% and 92% of cases, respectively. Our model represents a practical guide for BMF diagnosis and highlights the importance of clinical and laboratory variables in the initial evaluation, particularly telomere length. Our tool can be potentially used by general hematologists and health care providers not specialized in BMF, and in under-resourced centers, to prioritize patients for genetic testing or for expeditious treatment.
Asunto(s)
Anemia Aplásica , Enfermedades de la Médula Ósea , Pancitopenia , Humanos , Enfermedades de la Médula Ósea/diagnóstico , Enfermedades de la Médula Ósea/genética , Enfermedades de la Médula Ósea/terapia , Diagnóstico Diferencial , Anemia Aplásica/diagnóstico , Anemia Aplásica/genética , Anemia Aplásica/terapia , Trastornos de Fallo de la Médula Ósea/diagnóstico , Pancitopenia/diagnósticoRESUMEN
GATA2 deficiency was described in 2011, and shortly thereafter allogeneic hematopoietic stem cell transplantation (HSCT) was shown to reverse the hematologic disease phenotype. However, there remain major unanswered questions regarding the type of conditioning regimen, type of donors, and graft-versus-host disease (GVHD) prophylaxis. We report 59 patients with GATA2 mutations undergoing HSCT at National Institutes of Health between 2013 and 2020. Primary endpoints were engraftment, reverse of the clinical phenotype, secondary endpoints were overall survival (OS), event-free survival (EFS), and the incidence of acute and chronic GVHD. The OS and EFS at 4 years were 85·1% and 82·1% respectively. Ninety-six percent of surviving patients had reversal of the hematologic disease phenotype by one-year post-transplant. Incidence of grade III-IV aGVHD in matched related donor (MRD) and matched unrelated donor recipients (URD) patients receiving Tacrolimus/Methotrexate for GVHD prophylaxis was 32%. In contrast, in the MRD and URD who received post-transplant cyclophosphamide (PT/Cy), no patient developed grade III-IV aGVHD. Six percent of haploidentical related donor (HRD) recipients developed grade III-IV aGVHD. In summary, a busulfan-based HSCT regimen in GATA2 deficiency reverses the hematologic disease phenotype, and the use of PT/Cy reduced the risk of both aGVHD and cGVHD.
Asunto(s)
Ciclofosfamida/uso terapéutico , Deficiencia GATA2/terapia , Trasplante de Células Madre Hematopoyéticas , Donantes de Tejidos , Adolescente , Adulto , Médula Ósea/patología , Terapia Combinada , Comorbilidad , Ciclofosfamida/administración & dosificación , Ciclofosfamida/efectos adversos , Femenino , Deficiencia GATA2/diagnóstico , Deficiencia GATA2/mortalidad , Enfermedad Injerto contra Huésped/diagnóstico , Enfermedad Injerto contra Huésped/etiología , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Trasplante de Células Madre Hematopoyéticas/métodos , Humanos , Reconstitución Inmune , Recuento de Leucocitos , Masculino , Persona de Mediana Edad , Neutrófilos , Cuidados Posoperatorios , Pronóstico , Quimera por Trasplante , Acondicionamiento Pretrasplante , Resultado del Tratamiento , Adulto JovenRESUMEN
PURPOSE: Deficiency of adenosine deaminase 2 (DADA2) is an inherited inborn error of immunity, characterized by autoinflammation (recurrent fever), vasculopathy (livedo racemosa, polyarteritis nodosa, lacunar ischemic strokes, and intracranial hemorrhages), immunodeficiency, lymphoproliferation, immune cytopenias, and bone marrow failure (BMF). Tumor necrosis factor (TNF-α) blockade is the treatment of choice for the vasculopathy, but often fails to reverse refractory cytopenia. We aimed to study the outcome of hematopoietic cell transplantation (HCT) in patients with DADA2. METHODS: We conducted a retrospective study on the outcome of HCT in patients with DADA2. The primary outcome was overall survival (OS). RESULTS: Thirty DADA2 patients from 12 countries received a total of 38 HCTs. The indications for HCT were BMF, immune cytopenia, malignancy, or immunodeficiency. Median age at HCT was 9 years (range: 2-28 years). The conditioning regimens for the final transplants were myeloablative (n = 20), reduced intensity (n = 8), or non-myeloablative (n = 2). Donors were HLA-matched related (n = 4), HLA-matched unrelated (n = 16), HLA-haploidentical (n = 2), or HLA-mismatched unrelated (n = 8). After a median follow-up of 2 years (range: 0.5-16 years), 2-year OS was 97%, and 2-year GvHD-free relapse-free survival was 73%. The hematological and immunological phenotypes resolved, and there were no new vascular events. Plasma ADA2 enzyme activity normalized in 16/17 patients tested. Six patients required more than one HCT. CONCLUSION: HCT was an effective treatment for DADA2, successfully reversing the refractory cytopenia, as well as the vasculopathy and immunodeficiency. CLINICAL IMPLICATIONS: HCT is a definitive cure for DADA2 with > 95% survival.
Asunto(s)
Agammaglobulinemia/terapia , Trastornos de Fallo de la Médula Ósea/terapia , Trasplante de Células Madre Hematopoyéticas , Inmunodeficiencia Combinada Grave/terapia , Adenosina Desaminasa/deficiencia , Adolescente , Adulto , Agammaglobulinemia/enzimología , Agammaglobulinemia/genética , Agammaglobulinemia/mortalidad , Trastornos de Fallo de la Médula Ósea/enzimología , Trastornos de Fallo de la Médula Ósea/genética , Trastornos de Fallo de la Médula Ósea/mortalidad , Niño , Preescolar , Femenino , Enfermedad Injerto contra Huésped/etiología , Enfermedad Injerto contra Huésped/mortalidad , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Humanos , Péptidos y Proteínas de Señalización Intercelular/deficiencia , Estimación de Kaplan-Meier , Masculino , Estudios Retrospectivos , Inmunodeficiencia Combinada Grave/enzimología , Inmunodeficiencia Combinada Grave/genética , Inmunodeficiencia Combinada Grave/mortalidad , Resultado del Tratamiento , Adulto JovenRESUMEN
BACKGROUND: Recent case reports have described the efficacy of daratumumab to treat refractory pure red cell aplasia (PRCA) following major ABO mismatched allogeneic hematopoietic stem cell transplantation (HSCT). In this report, we describe the use of daratumumab as a first-line agent for treatment of delayed red blood cell (RBC) engraftment following a major ABO mismatched pediatric HSCT and provide a review of the literature. STUDY DESIGN AND MATERIALS: We report on a 14-year-old with DOCK8 deficiency who underwent a myeloablative, haploidentical bone marrow transplant from her major ABO mismatched sister (recipient O+, donor A+) for treatment of her primary immunodeficiency. Despite achieving full donor chimerism, she had delayed RBC engraftment requiring ongoing transfusions. Due to iron deposition, symptomatic anemia, and persistence of anti-A iso-hemagglutinins despite discontinuation of immunosuppression, treatment for delayed RBC engraftment with the CD38-targeted monoclonal antibody daratumumab was selected as a less immunosuppressive agent that could more selectively target iso-hemagglutinin producing plasma cells without causing broad B-cell aplasia. RESULTS: Clinical effect with daratumumab was demonstrated by reduced iso-hemagglutinin titer, increased reticulocytosis, normalization of her hemoglobin, and transfusion independence. In the 11-month follow-up period to date, no additional transfusions or immunosuppression have been necessary, despite persistence of low-level anti-A iso-hemagglutinin. CONCLUSION: Our experience suggests that daratumumab was an effective first-line therapy for delayed RBC engraftment and that earlier consideration for daratumumab in treatment of delayed RBC engraftment may be warranted.
Asunto(s)
Sistema del Grupo Sanguíneo ABO/inmunología , Anticuerpos Monoclonales/farmacología , Trasplante de Médula Ósea/métodos , Funcionamiento Retardado del Injerto/tratamiento farmacológico , Factores de Intercambio de Guanina Nucleótido/deficiencia , Enfermedades de Inmunodeficiencia Primaria/terapia , Adolescente , Cuidados Posteriores , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales/uso terapéutico , Quimerismo , Eritrocitos/inmunología , Femenino , Hemaglutininas/sangre , Hemaglutininas/efectos de los fármacos , Humanos , Enfermedades de Inmunodeficiencia Primaria/diagnóstico , Enfermedades de Inmunodeficiencia Primaria/genética , Aplasia Pura de Células Rojas/tratamiento farmacológico , Trasplante Haploidéntico/efectos adversos , Resultado del TratamientoRESUMEN
Deficiency of adenosine deaminase 2 (DADA2) is caused by biallelic deleterious mutations in CECR1 DADA2 results in variable autoinflammation and vasculopathy (recurrent fevers, livedo reticularis, polyarteritis nodosa, lacunar ischemic strokes, and intracranial hemorrhages), immunodeficiency and bone marrow failure. Tumor necrosis factor-α blockade is the treatment of choice for the autoinflammation and vascular manifestations. Hematopoietic stem cell transplantation (HSCT) represents a potential definitive treatment. We present a cohort of 14 patients from 6 countries who received HSCT for DADA2. Indication for HSCT was bone marrow dysfunction or immunodeficiency. Six of 14 patients had vasculitis pre-HSCT. The median age at HSCT was 7.5 years. Conditioning regimens were myeloablative (9) and reduced intensity (5). Donors were HLA-matched sibling (n = 1), HLA-matched unrelated (n = 9), HLA-mismatched unrelated (n = 3), and HLA haploidentical sibling (n = 1). All patients are alive and well with no new vascular events and resolution of hematological and immunological phenotype at a median follow-up of 18 months (range, 5 months to 13 years). Plasma ADA2 enzyme activity normalized in those tested post-HSCT (7/7), as early as day +14 (myeloid engraftment). Post-HSCT hematological autoimmunity (cytopenias) was reported in 4 patients, acute graft-versus-host disease grade 1 in 2, grade 2 in 3, and grade 3-4 in 1, and moderate chronic graft-versus-host disease in 1 patient. In conclusion, in 14 patients, HSCT was an effective and definitive treatment of DADA2.
Asunto(s)
Adenosina Desaminasa/genética , Trasplante de Células Madre Hematopoyéticas/métodos , Síndromes de Inmunodeficiencia/genética , Síndromes de Inmunodeficiencia/terapia , Péptidos y Proteínas de Señalización Intercelular/genética , Mutación , Adenosina Desaminasa/sangre , Adenosina Desaminasa/metabolismo , Adolescente , Niño , Preescolar , Estudios de Cohortes , Femenino , Enfermedad Injerto contra Huésped/diagnóstico , Enfermedad Injerto contra Huésped/etiología , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Humanos , Síndromes de Inmunodeficiencia/enzimología , Lactante , Recién Nacido , Péptidos y Proteínas de Señalización Intercelular/sangre , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Masculino , Fenotipo , Acondicionamiento Pretrasplante/métodosRESUMEN
Allogeneic hematopoietic stem cell transplantation (HSCT) reverses the bone marrow failure syndrome due to GATA2 deficiency. The intensity of conditioning required to achieve reliable engraftment and prevent relapse remains unclear. Here, we describe the results of a prospective study of HSCT in 22 patients with GATA2 deficiency using a busulfan-based conditioning regimen. The study included 2 matched related donor (MRD) recipients, 13 matched unrelated donor (URD) recipients, and 7 haploidentical related donor (HRD) recipients. MRD and URD recipients received 4 days of busulfan and 4 days of fludarabine. HRD recipients received low-dose cyclophosphamide for 2 days, fludarabine for 5 days, 2 to 3 days of busulfan depending on cytogenetics, and 200 cGy total body irradiation. MRD and URD recipients received tacrolimus and short-course methotrexate for graft-versus-host disease (GVHD) prophylaxis. HRD recipients received high-dose post-transplant cyclophosphamide (PTCy) followed by tacrolimus and mycophenolate mofetil. At a median follow-up of 24 months (range, 9 to 50), 19 of 22 patients were alive with reversal of the disease phenotype and correction of the myelodysplastic syndrome, including eradication of cytogenetic abnormalities. Three patients died: 1 from refractory acute myelogenous leukemia, 1 from GVHD, and 1 from sepsis. There was a 26% incidence of grades III to IV acute GVHD in the MRD and URD groups and no grades III to IV acute GVHD in the HRD cohort. Similarly, there was a 46% incidence of chronic GVHD in the MRD and URD cohorts, whereas only 28% of HRD recipients developed chronic GVHD. Despite excellent overall disease-free survival (86%), GVHD remains a limitation using standard prophylaxis for GVHD. We are currently extending the use of PTCy to the MRD and URD cohorts to reduce GVHD.
Asunto(s)
Busulfano/uso terapéutico , Deficiencia GATA2/terapia , Trasplante de Células Madre Hematopoyéticas/métodos , Acondicionamiento Pretrasplante/métodos , Adulto , Anciano , Supervivencia sin Enfermedad , Femenino , Deficiencia GATA2/mortalidad , Enfermedad Injerto contra Huésped/etiología , Enfermedad Injerto contra Huésped/prevención & control , Trasplante de Células Madre Hematopoyéticas/mortalidad , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Donantes de Tejidos , Trasplante Homólogo , Adulto JovenRESUMEN
PURPOSE: To describe controlled ovarian stimulation (COS) in a population of women with GATA2 deficiency, a genetic bone marrow failure syndrome, prior to allogeneic hematopoietic stem cell transplant METHODS: This is a retrospective case series of nine women with GATA2 deficiency who underwent oocyte preservation at a research institution. Main outcomes measured include baseline fertility characteristics ((antimullerian hormone (AMH) and day 3 follicle-stimulating hormone (FSH) and estradiol (E2)) and total doses of FSH and human menopausal gonadotropins (HMG), E2 on day of trigger, and total number of metaphase II oocytes retrieved. RESULTS: The mean age was 24 years [16-32], mean AMH was 5.2 ng/mL [0.7-10], and day 3 mean FSH was 5.1 U/L [0.7-8.1], and E2 was 31.5 pg/mL [< 5-45]. The mean dose of FSH was 1774 IU [675-4035], and HMG was 1412 IU [375-2925] with a mean E2 of 2267 pg/mL [60.7-4030] on day of trigger. The mean total of metaphase II oocytes was 7.7 [0-15]. One patient was diagnosed with a deep vein thrombosis (DVT) with pulmonary embolism (PE) during COS. CONCLUSION: This study is the first to analyze the outcomes of COS in women with GATA2 deficiency. The response to ovarian stimulation suggests that oocyte cryopreservation should be considered prior to gonadotoxic therapy. However, due to the risk of potentially life-threatening complications, it is prudent that patients are properly counseled of the risks and are evaluated by a multi-disciplinary medical team prior to COS.
Asunto(s)
Factor de Transcripción GATA2/deficiencia , Oocitos/metabolismo , Oocitos/fisiología , Adolescente , Adulto , Hormona Antimülleriana/metabolismo , Criopreservación/métodos , Estradiol/metabolismo , Femenino , Fertilidad/fisiología , Preservación de la Fertilidad/métodos , Fertilización In Vitro/métodos , Hormona Folículo Estimulante/metabolismo , Humanos , Recuperación del Oocito/métodos , Inducción de la Ovulación/métodos , Estudios Retrospectivos , Adulto JovenRESUMEN
Dedicator-of-cytokinesis 8 (DOCK8) deficiency, a primary immunodeficiency disease, can be reversed by allogeneic hematopoietic stem cell transplantation (HSCT); however, there are few reports describing the use of alternative donor sources for HSCT in DOCK8 deficiency. We describe HSCT for patients with DOCK8 deficiency who lack a matched related or unrelated donor using bone marrow from haploidentical related donors and post-transplantation cyclophosphamide (PT/Cy) for graft-versus-host disease (GVHD) prophylaxis. Seven patients with DOCK8 deficiency (median age, 20 years; range, 7 to 25 years) received a haploidentical related donor HSCT. The conditioning regimen included 2 days of low-dose cyclophosphamide, 5 days of fludarabine, 3 days of busulfan, and 200 cGy total body irradiation. GVHD prophylaxis consisted of PT/Cy 50 mg/kg/day on days +3 and +4 and tacrolimus and mycophenolate mofetil starting at day +5. The median times to neutrophil and platelet engraftment were 15 and 19 days, respectively. All patients attained >90% donor engraftment by day +30. Four subjects developed acute GVHD (1 with maximum grade 3). No patient developed chronic GVHD. With a median follow-up time of 20.6 months (range, 9.5 to 31.7 months), 6 of 7 patients are alive and disease free. Haploidentical related donor HSCT with PT/Cy represents an effective therapeutic approach for patients with DOCK8 deficiency who lack a matched related or unrelated donor.
Asunto(s)
Factores de Intercambio de Guanina Nucleótido/deficiencia , Trasplante de Células Madre Hematopoyéticas/métodos , Síndromes de Inmunodeficiencia/terapia , Ciclofosfamida/uso terapéutico , Enfermedad Injerto contra Huésped/prevención & control , Trasplante de Células Madre Hematopoyéticas/mortalidad , Humanos , Síndromes de Inmunodeficiencia/mortalidad , Tasa de Supervivencia , Acondicionamiento Pretrasplante/métodos , Trasplante Haploidéntico/métodos , Trasplante Haploidéntico/mortalidad , Resultado del TratamientoRESUMEN
We performed allogeneic hematopoietic stem cell transplantation in a patient with GATA2 deficiency and an Epstein-Barr virus (EBV)-related spindle cell tumor involving the liver and possibly bone. He received a matched-related donor transplant with donor peripheral blood stem cells following a myeloablative conditioning regimen. He achieved rapid and high levels of donor engraftment and had complete reversal of the clinical and immunologic phenotype of MonoMAC/GATA2 deficiency and eradication of the EBV tumors after 3 years of follow-up. Thus, allogeneic hematopoietic stem cell transplant results in reconstitution of immunologic function and cure of EBV-associated malignancy in MonoMAC/GATA2 deficiency.
Asunto(s)
Infecciones por Virus de Epstein-Barr/complicaciones , Factor de Transcripción GATA2/deficiencia , Trasplante de Células Madre Hematopoyéticas , Herpesvirus Humano 4 , Tumor de Músculo Liso/diagnóstico , Tumor de Músculo Liso/etiología , Biomarcadores , Infecciones por Virus de Epstein-Barr/virología , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Trasplante de Células Madre Hematopoyéticas/métodos , Herpesvirus Humano 4/genética , Humanos , Inmunofenotipificación , Imagen por Resonancia Magnética , Masculino , Tomografía Computarizada por Tomografía de Emisión de Positrones , Factores de Tiempo , Quimera por Trasplante , Trasplante Homólogo , Adulto JovenRESUMEN
Germ-line GATA2 gene mutations, leading to haploinsufficiency, have been identified in patients with familial myelodysplastic syndrome/acute myeloid leukemia, monocytopenia and mycobacterial infections, Emberger syndrome, and dendritic cell, monocyte, B-, and NK-cell deficiency. GATA2 mutations have also been reported in a minority of patients with congenital neutropenia and aplastic anemia (AA). The bone marrow (BM) from patients with GATA2 deficiency is typically hypocellular, with varying degrees of dysplasia. Distinguishing GATA2 patients from those with AA is critical for selecting appropriate therapy. We compared the BM flow cytometric, morphologic, and cytogenetic features of 28 GATA2 patients with those of 32 patients being evaluated for idiopathic AA. The marrow of GATA2 patients had severely reduced monocytes, B cells, and NK cells; absent hematogones; and inverted CD4:CD8 ratios. Atypical megakaryocytes and abnormal cytogenetics were more common in GATA2 marrows. CD34(+) cells were comparably reduced in GATA2 and AA. Using these criteria, we prospectively identified 4 of 32 patients with suspected AA who had features suspicious for GATA2 mutations, later confirmed by DNA sequencing. Our results show that routine BM flow cytometry, morphology, and cytogenetics in patients who present with cytopenia(s) can identify patients for whom GATA2 sequencing is indicated.
Asunto(s)
Anemia Aplásica/diagnóstico , Enfermedades de la Médula Ósea/diagnóstico , Factor de Transcripción GATA2/deficiencia , Adulto , Anemia Aplásica/genética , Anemia Aplásica/metabolismo , Antígenos CD34/metabolismo , Médula Ósea/patología , Enfermedades de la Médula Ósea/genética , Estudios de Cohortes , Citogenética , Femenino , Citometría de Flujo , Humanos , Inmunohistoquímica , Masculino , Persona de Mediana Edad , Mutación , Análisis de Secuencia de ADN , Adulto JovenRESUMEN
Haploinsufficiency of the hematopoietic transcription factor GATA2 underlies monocytopenia and mycobacterial infections; dendritic cell, monocyte, B, and natural killer (NK) lymphoid deficiency; familial myelodysplastic syndromes (MDS)/acute myeloid leukemia (AML); and Emberger syndrome (primary lymphedema with MDS). A comprehensive examination of the clinical features of GATA2 deficiency is currently lacking. We reviewed the medical records of 57 patients with GATA2 deficiency evaluated at the National Institutes of Health from January 1, 1992, to March 1, 2013, and categorized mutations as missense, null, or regulatory to identify genotype-phenotype associations. We identified a broad spectrum of disease: hematologic (MDS 84%, AML 14%, chronic myelomonocytic leukemia 8%), infectious (severe viral 70%, disseminated mycobacterial 53%, and invasive fungal infections 16%), pulmonary (diffusion 79% and ventilatory defects 63%, pulmonary alveolar proteinosis 18%, pulmonary arterial hypertension 9%), dermatologic (warts 53%, panniculitis 30%), neoplastic (human papillomavirus+ tumors 35%, Epstein-Barr virus+ tumors 4%), vascular/lymphatic (venous thrombosis 25%, lymphedema 11%), sensorineural hearing loss 76%, miscarriage 33%, and hypothyroidism 14%. Viral infections and lymphedema were more common in individuals with null mutations (P = .038 and P = .006, respectively). Monocytopenia, B, NK, and CD4 lymphocytopenia correlated with the presence of disease (P < .001). GATA2 deficiency unites susceptibility to MDS/AML, immunodeficiency, pulmonary disease, and vascular/lymphatic dysfunction. Early genetic diagnosis is critical to direct clinical management, preventive care, and family screening.
Asunto(s)
Factor de Transcripción GATA2/genética , Síndromes de Inmunodeficiencia/mortalidad , Leucemia Mieloide Aguda/mortalidad , Síndromes Mielodisplásicos/mortalidad , Adolescente , Adulto , Anciano , Niño , Femenino , Factor de Transcripción GATA2/deficiencia , Estudios de Asociación Genética , Haploinsuficiencia , Hematopoyesis , Humanos , Síndromes de Inmunodeficiencia/genética , Síndromes de Inmunodeficiencia/patología , Lactante , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patología , Sistema Linfático , Masculino , Persona de Mediana Edad , Síndromes Mielodisplásicos/genética , Síndromes Mielodisplásicos/patología , Pronóstico , Estudios Prospectivos , Tasa de Supervivencia , Adulto JovenRESUMEN
We performed allogeneic hematopoietic stem cell transplantation in 6 patients with mutations in the dedicator-of-cytokinesis-8 (DOCK8) gene using a myeloablative conditioning regimen consisting of busulfan 3.2 mg/kg/day i.v. for 4 days and fludarabine 40 mg/m(2)/day for 4 days. Three patients received allografts from matched related donors and 3 patients from matched unrelated donors. Two patients received peripheral blood stem cells and 4 patients bone marrow hematopoietic stem cells. Tacrolimus and short-course methotrexate on days 1, 3, 6, and 11 were used for graft-versus-host-disease (GVHD) prophylaxis. All 6 patients are alive at a median follow-up of 22.5 months (range, 14 to 35). All patients achieved rapid and high levels of donor engraftment and complete reversal of the clinical and immunologic phenotype. Adverse events consisted of acute skin GVHD in 2 patients and post-transplant pulmonary infiltrates in a patient with extensive bronchiectasis pretransplant. Thus, a uniform myeloablative conditioning regimen followed by allogeneic hematopoietic stem cell transplantation in DOCK8 deficiency results in reconstitution of immunologic function and reversal of the clinical phenotype with a low incidence of regimen-related toxicity.
Asunto(s)
Enfermedad Injerto contra Huésped/prevención & control , Factores de Intercambio de Guanina Nucleótido/deficiencia , Trasplante de Células Madre Hematopoyéticas , Inmunosupresores/uso terapéutico , Agonistas Mieloablativos/uso terapéutico , Inmunodeficiencia Combinada Grave/terapia , Adolescente , Adulto , Busulfano/uso terapéutico , Niño , Femenino , Supervivencia de Injerto , Enfermedad Injerto contra Huésped/genética , Enfermedad Injerto contra Huésped/inmunología , Enfermedad Injerto contra Huésped/patología , Factores de Intercambio de Guanina Nucleótido/genética , Factores de Intercambio de Guanina Nucleótido/inmunología , Prueba de Histocompatibilidad , Humanos , Inmunofenotipificación , Masculino , Metotrexato/uso terapéutico , Mutación , Proyectos Piloto , Inmunodeficiencia Combinada Grave/genética , Inmunodeficiencia Combinada Grave/inmunología , Inmunodeficiencia Combinada Grave/patología , Hermanos , Tacrolimus/uso terapéutico , Acondicionamiento Pretrasplante/métodos , Trasplante Homólogo , Donante no Emparentado , Vidarabina/análogos & derivados , Vidarabina/uso terapéuticoAsunto(s)
Factor de Transcripción GATA2/genética , Mutación de Línea Germinal , Trasplante de Células Madre Hematopoyéticas , Leucemia Mieloide Aguda/genética , Síndromes Mielodisplásicos/genética , Adolescente , Adulto , Femenino , Humanos , Leucemia Mieloide Aguda/patología , Leucemia Mieloide Aguda/terapia , Masculino , Síndromes Mielodisplásicos/patología , Síndromes Mielodisplásicos/terapia , Linaje , Donantes de Tejidos , Resultado del Tratamiento , Adulto JovenRESUMEN
Previous reports of GATA2 mutations have focused on the coding region of the gene or full gene deletions. We recently identified 2 patients with novel insertion/deletion mutations predicted to result in mRNA nonsense-mediated decay, suggesting haploinsufficiency as the mechanism of GATA2 deficient disease. We therefore screened patients without identified exonic lesions for mutations within conserved noncoding and intronic regions. We discovered 1 patient with an intronic deletion mutation, 4 patients with point mutations within a conserved intronic element, and 3 patients with reduced or absent transcription from 1 allele. All mutations affected GATA2 transcription. Full-length cDNA analysis provided evidence for decreased expression of the mutant alleles. The intronic deletion and point mutations considerably reduced the enhancer activity of the intron 5 enhancer. Analysis of 512 immune system genes revealed similar expression profiles in all clinically affected patients and reduced GATA2 transcript levels. These mutations strongly support the haploinsufficient nature of GATA2 deficiency and identify transcriptional mechanisms and targets that lead to MonoMAC syndrome.
Asunto(s)
Factor de Transcripción GATA2/genética , Haploinsuficiencia/genética , Leucopenia/genética , Mutación/fisiología , Infección por Mycobacterium avium-intracellulare/genética , Adolescente , Adulto , Anciano , Secuencia de Bases , Niño , Preescolar , Secuencia Conservada/genética , Femenino , Humanos , Lactante , Intrones/genética , Células K562 , Leucopenia/sangre , Masculino , Persona de Mediana Edad , Datos de Secuencia Molecular , Monocitos/patología , Infección por Mycobacterium avium-intracellulare/sangre , Degradación de ARNm Mediada por Codón sin Sentido/genética , Síndrome , Adulto JovenRESUMEN
In experimental models, ex vivo induced T-cell rapamycin resistance occurred independent of T helper 1 (Th1)/T helper 2 (Th2) differentiation and yielded allogeneic CD4(+) T cells of increased in vivo efficacy that facilitated engraftment and permitted graft-versus-tumor effects while minimizing graft-versus-host disease (GVHD). To translate these findings, we performed a phase 2 multicenter clinical trial of rapamycin-resistant donor CD4(+) Th2/Th1 (T-Rapa) cells after allogeneic-matched sibling donor hematopoietic cell transplantation (HCT) for therapy of refractory hematologic malignancy. T-Rapa cell products, which expressed a balanced Th2/Th1 phenotype, were administered as a preemptive donor lymphocyte infusion at day 14 post-HCT. After T-Rapa cell infusion, mixed donor/host chimerism rapidly converted, and there was preferential immune reconstitution with donor CD4(+) Th2 and Th1 cells relative to regulatory T cells and CD8(+) T cells. The cumulative incidence probability of acute GVHD was 20% and 40% at days 100 and 180 post-HCT, respectively. There was no transplant-related mortality. Eighteen of 40 patients (45%) remain in sustained complete remission (range of follow-up: 42-84 months). These results demonstrate the safety of this low-intensity transplant approach and the feasibility of subsequent randomized studies to compare T-Rapa cell-based therapy with standard transplantation regimens.
Asunto(s)
Linfocitos T CD4-Positivos/trasplante , Neoplasias Hematológicas/terapia , Trasplante de Células Madre Hematopoyéticas/métodos , Transfusión de Linfocitos/métodos , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/metabolismo , Citocinas/inmunología , Citocinas/metabolismo , Resistencia a Medicamentos/inmunología , Femenino , Perfilación de la Expresión Génica , Enfermedad Injerto contra Huésped/etiología , Enfermedad Injerto contra Huésped/inmunología , Neoplasias Hematológicas/inmunología , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Humanos , Inmunosupresores/administración & dosificación , Inmunosupresores/farmacología , Masculino , Persona de Mediana Edad , Análisis de Secuencia por Matrices de Oligonucleótidos , Inducción de Remisión , Sirolimus/administración & dosificación , Sirolimus/farmacología , Células TH1/inmunología , Células TH1/metabolismo , Células TH1/trasplante , Células Th2/inmunología , Células Th2/metabolismo , Células Th2/trasplante , Factores de Tiempo , Trasplante Homólogo , Resultado del Tratamiento , Adulto JovenRESUMEN
New treatments are needed for B-cell malignancies persisting after allogeneic hematopoietic stem cell transplantation (alloHSCT). We conducted a clinical trial of allogeneic T cells genetically modified to express a chimeric antigen receptor (CAR) targeting the B-cell antigen CD19. T cells for genetic modification were obtained from each patient's alloHSCT donor. All patients had malignancy that persisted after alloHSCT and standard donor lymphocyte infusions (DLIs). Patients did not receive chemotherapy prior to the CAR T-cell infusions and were not lymphocyte depleted at the time of the infusions. The 10 treated patients received a single infusion of allogeneic anti-CD19-CAR T cells. Three patients had regressions of their malignancies. One patient with chronic lymphocytic leukemia (CLL) obtained an ongoing complete remission after treatment with allogeneic anti-CD19-CAR T cells, another CLL patient had tumor lysis syndrome as his leukemia dramatically regressed, and a patient with mantle cell lymphoma obtained an ongoing partial remission. None of the 10 patients developed graft-versus-host disease (GVHD). Toxicities included transient hypotension and fever. We detected cells containing the anti-CD19-CAR gene in the blood of 8 of 10 patients. These results show for the first time that donor-derived allogeneic anti-CD19-CAR T cells can cause regression of B-cell malignancies resistant to standard DLIs without causing GVHD.