RESUMEN
OBJECTIVE: We analyzed events and therapies related to febrile neutropenia in patients receiving hematopoietic cell transplantation (HCT) for chronic granulomatous disease (CGD). METHODS: Three protocols for HCT were used to extract the relation between conditioning and infectious complications during transplantation for CGD, especially the relation of fever and neutropenia to microbiological events and antibiotic therapy. RESULTS: Sixty-nine recipients received either reduced intensity conditioning with matched related or unrelated donors or conditioning specific to haploidentical-related donors utilizing posttransplant cyclophosphamide. Fever prior to neutropenia was common (52) and in eight recipients, Gram negative bacterial infection occurred prior to neutropenia, and in nine during neutropenia. Alemtuzumab as conditioning was associated with preneutropenic infection. Empiric therapy (noncarbapenem) by institutional guideline was given in 40. Carbapenems were given before neutropenia (8) or as empiric therapy in neutropenia (18), or a switch to a carbapenem (n = 22) occurred in 48 cases. No deaths related to infection associated with neutropenia occurred. CONCLUSION: The management of febrile neutropenia in HCT for CGD led to no deaths related to infection associated with neutropenia. Bacteremias occurred both prior to neutropenia and during neutropenia. Bacteria isolated may have represented the recrudescence of prior infection, representing the population transplanted and the platform for HCT. The treatment of prior infections may have had an influence on the necessity of carbapenem use as either empiric or directed therapy for bacterial infections.
Asunto(s)
Neutropenia Febril , Infecciones por Bacterias Gramnegativas , Enfermedad Granulomatosa Crónica , Trasplante de Células Madre Hematopoyéticas , Antibacterianos/uso terapéutico , Neutropenia Febril/tratamiento farmacológico , Neutropenia Febril/etiología , Infecciones por Bacterias Gramnegativas/epidemiología , Enfermedad Granulomatosa Crónica/complicaciones , Enfermedad Granulomatosa Crónica/terapia , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Humanos , Acondicionamiento Pretrasplante/efectos adversosRESUMEN
PURPOSE: Haploidentical related donor (HRD) transplantation was performed in 7 recipients with chronic granulomatous disease (CGD) who had no matched-related or unrelated donor. METHODS: Peripheral blood cell (PBC) products were used with a conditioning regimen consisting of low-dose cyclophosphamide, fludarabine, total body irradiation, and busulfan. Graft-versus-host disease (GVHD) prophylaxis consisted of high-dose post-transplant cyclophosphamide and sirolimus. Recipients were ages 14-26 years, and 3 had severe infections active at transplant. RESULTS: All 7 recipients achieved full engraftment with complete donor chimerism early in the post-transplant period. Acute GVHD occurred in all cases and was grade 3 or steroid refractory in 3. Two patients with steroid-refractory GVHD died. Three patients with severe infectious complications active at transplant, 1 Nocardia pneumonia and 2 extensive invasive fungal infections), survived and were cured of their infection at last follow-up. Bacterial disease occurred post-transplant in all recipients, and viral infections/reactivation were common, including 4 cases of BK virus-associated hemorrhagic cystitis. CONCLUSIONS: Seven patients with CGD achieved rapid and full-donor engraftment from HRDs utilizing PBCs and a conditioning regimen with PTCy and sirolimus GVHD prophylaxis. However, the incidence of grade 3 and steroid-refractory GVHD was high and led to 2 deaths. Patients with active infections at transplant had successful transplant courses and were cured of their disease. Although there was an initial success with this regimen, the cumulative experience does not support its use in CGD due to an unacceptable rate of severe GVHD.
Asunto(s)
Ciclofosfamida/uso terapéutico , Enfermedad Injerto contra Huésped/diagnóstico , Enfermedad Granulomatosa Crónica/terapia , Trasplante de Células Madre Hematopoyéticas , Inmunosupresores/uso terapéutico , Complicaciones Posoperatorias/diagnóstico , Acondicionamiento Pretrasplante/métodos , Adolescente , Adulto , Progresión de la Enfermedad , Femenino , Enfermedad Injerto contra Huésped/etiología , Enfermedad Granulomatosa Crónica/mortalidad , Humanos , Masculino , Análisis de Supervivencia , Trasplante Haploidéntico , Insuficiencia del Tratamiento , Adulto JovenRESUMEN
Patients with primary immunodeficiencies (PIDs) are potentially cured by allogeneic hematopoietic cell transplantation (HCT). The spectrum of PIDs has expanded greatly beyond those that present in infancy or are diagnosed on newborn screening and require urgent, preemptive HCT. Many PID diagnoses are now made later in life, and the role of HCT is only considered for severe disease manifestations; in these cases, the kinetics and goals of a donor search may be different than for severe combined immunodeficiency. Across all PIDs, related donor searches have the additional selection factor of the inherited disease, and such searches may yield more limited options than searches for patients with hematologic malignancies; thus, unrelated donor options often become more critical in these patients. We retrospectively evaluated the outcomes of donor searches among patents with PIDs referred for HCT at the National Institutes of Health, where the minimum patient age for evaluation is 3 years and where donor options include matched sibling donors or matched related donors, HLA-haploidentical (haplo), or 7-8/8 HLA matched unrelated donors (mMUDs/MUDs). Patient (nâ¯=â¯161) and donor demographics, MUD search results, HLA typing, pedigrees, mutation testing, and donor selection data were collected. The National Marrow Donor Program HapLogic 8/8 HLA match algorithm was used to predict the likelihood of a successful MUD search and categorized as very good, good, fair, poor, very poor, or futile per the Memorial Sloan Kettering Cancer Center (MSKCC) Search Prognosis method. There were significant differences by PID mode of inheritance in patient age, disposition (receipt of HCT or not), donor source, and donor relatedness. A related or unrelated donor option could be identified for 94% of patients. Of living first-degree relatives (median, 3; range, 0 to 12 per patient), a median of 1 donor remained for autosomal dominant and X-linked (XL) diseases after HLA typing, mutation testing, and other exclusions, and a median of 2 donors remained for autosomal recessive (AR) diseases. Among patients with a PID of known mode of inheritance (nâ¯=â¯142), the best related donor was haplo for 99 (70%) patients, with 56 (39%) haplos age 40 years or older and 5 (4%) second-degree haplos; 13 (9%) had no family donor options. The best related donor was a heterozygote/asymptomatic carrier of the PID mutation in 36 (49%) patients with AR or XL disease (nâ¯=â¯73). Among patients with MUD search performed (nâ¯=â¯139), 53 (38%) had very poor/futile 8/8 MUD searches, including 6 (32%) of those with unknown PID mutation and therefore no family donor options. The MSKCC Search Prognosis was less favorable for those of non-European ancestry compared with European ancestry (Pâ¯=â¯.002). Most patients of Hispanic or African ancestry had very poor/futile MUD searches, 71% and 63%, respectively. No HCT recipients with very poor/futile MUD searches (nâ¯=â¯38) received 8/8 MUD grafts. Alternative donor options, including haplo and unrelated donors, are critical to enable HCT for patients with PIDs. MUD search success remains low for those of non-European ancestry, and this is of particular concern for patients with PIDs caused by an unknown genetic defect. Among patients with PIDs, related donor options are reduced and haplos age 40 years and older and/or mutation carriers are often the best family option.
Asunto(s)
Algoritmos , Selección de Donante , Trasplante de Células Madre Hematopoyéticas , Enfermedades de Inmunodeficiencia Primaria/terapia , Donante no Emparentado , Adolescente , Adulto , Anciano , Aloinjertos , Niño , Preescolar , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios RetrospectivosRESUMEN
PURPOSE: The purpose of this study was to evaluate engraftment and adverse events with a conditioning and prophylactic regimen intended to achieve high rates of engraftment with minimal graft-versus-host disease (GVHD) in allogeneic transplantation for chronic granulomatous disease in a single center. METHODS: Forty patients, 37 male, with chronic granulomatous disease were transplanted. Transplant products were matched sibling peripheral blood stem cells (PBSCs) in four and matched unrelated donor (MUD) bone marrow in three, and one patient received mismatched unrelated PBSCs. Thirty-two patients received MUD PBSCs. All patients received a conditioning regimen of busulfan/alemtuzumab (with low-dose total body irradiation for MUD recipients) with sirolimus graft-versus-host disease prophylaxis. RESULTS: Engraftment occured in 38/40 recipients (95%). Acute or chronic GVHD occurred in 18 (45%) and 5 (12.5%), respectively, with 6 episodes of grades III-IV and/or steroid refractory GVHD. Overall survival was 33/40 (82.5%) and event-free survival was 30/40 (80%). Successful engraftment was associated with myeloid and NK cell, but not CD3+ chimerism. Myeloid engraftment was greater than 70% in 30/32 recipients at mean follow-up of 3.4 years. Evidence of persistent immunodeficiency was not seen in successful transplants. Attempts to rescue failed or poorly functioning grafts were associated with unacceptable morbidity and mortality. CONCLUSIONS: A reduced-intensity allogeneic transplant protocol based on alemtuzumab and busulfan with sirolimus GVHD prophylaxis produced high rates of successful engraftment and minimal regimen-related toxicity. Prolonged clinical follow-up has confirmed its efficacy in ameliorating CGD-related disease. Outcomes were not acceptable with donor cell infusion rescue of cause with poor graft function.
Asunto(s)
Enfermedad Injerto contra Huésped/diagnóstico , Enfermedad Granulomatosa Crónica/terapia , Trasplante de Células Madre Hematopoyéticas , Inmunoglobulinas Intravenosas/uso terapéutico , Quimerismo , Femenino , Enfermedad Injerto contra Huésped/etiología , Enfermedad Injerto contra Huésped/mortalidad , Enfermedad Granulomatosa Crónica/diagnóstico , Enfermedad Granulomatosa Crónica/mortalidad , Histocompatibilidad , Humanos , Inmunosupresores/uso terapéutico , Masculino , Estudios Prospectivos , Hermanos , Donantes de Tejidos , Acondicionamiento Pretrasplante , Trasplante HomólogoRESUMEN
PURPOSE: We describe haploidentical hematopoietic cell transplantation (HCT) with high-dose post-transplant cyclophosphamide (PTCy) in a boy with x-linked chronic granulomatous disease (CGD). METHODS: A persistent and life-threatening fungal infection was the indication for HSCT. Non-myeloablative conditioning with PTCy (50 mg/kg days 3 and 4) was used in the absence of fully matched donors. RESULTS: Engraftment occurred on day 24. The patient experienced Grade 2 graft-versus-host disease of the skin and gastrointestinal tract and CMV infection, both of which were controlled. Chimerism was 100 % at days 30 and 6 months. Cessation of antifungal therapy was consistent with cure of the infection. CONCLUSIONS: Haploidentical HCT with high-dose PTCy for CGD is feasible and succeeded even in the context of active infection.
Asunto(s)
Transfusión de Sangre Autóloga , Ciclofosfamida/administración & dosificación , Enfermedad Injerto contra Huésped/prevención & control , Enfermedad Granulomatosa Crónica/terapia , Inmunosupresores/administración & dosificación , Micosis/terapia , Complicaciones Posoperatorias/prevención & control , Scedosporium , Quimerismo/efectos de los fármacos , Cálculo de Dosificación de Drogas , Enfermedad Injerto contra Huésped/etiología , Enfermedad Granulomatosa Crónica/complicaciones , Antígenos HLA/inmunología , Humanos , Lactante , Masculino , Micosis/etiología , National Institutes of Health (U.S.) , Acondicionamiento Pretrasplante , Estados UnidosRESUMEN
Caspase-8 deficiency (CED) was originally described in 2002 in two pediatric patients presenting with clinical manifestations resembling autoimmune lymphoproliferative syndrome (ALPS) accompanied by infections, and T, B and NK cell defects. Since then, no new CED patients were published. Here we report two adult siblings (Pt1 and Pt2) presenting in their late thirties with pulmonary hypertension leading to lung transplant (Pt1), and a complex neurological disease leading to multiple cranial nerves palsies (Pt2) as their main manifestations. A thorough clinical and immunological evaluation was performed at the Primary Immunodeficiency Clinic at NIH, followed by whole exome sequencing. The patients had multiorgan lymphocytic infiltration and granulomas, as well as clinical signs of immune deficiency/ immune dysregulation. Both siblings carried homozygous mutations in CASP8, c.1096C > T, p.248R > W. This was the same mutation described on the previously published CED patients, to whom these new patients were likely distantly related. We report two new CED patients presenting during adulthood with life-threatening end-organ lymphocyte infiltrates affecting the lungs, liver, spleen, bone marrow and central nervous system. This phenotype broadens the clinical spectrum of manifestations associated with this disease and warrants the search of CASP8 mutations in other cohorts of patients.
Asunto(s)
Síndrome Linfoproliferativo Autoinmune/diagnóstico , Síndrome Linfoproliferativo Autoinmune/genética , Caspasa 8/genética , Granuloma/patología , Mutación , Hermanos , Adulto , Síndrome Linfoproliferativo Autoinmune/complicaciones , Biopsia , Citocinas/biosíntesis , Exoma , Femenino , Hepatomegalia/diagnóstico , Secuenciación de Nucleótidos de Alto Rendimiento , Homocigoto , Humanos , Inmunofenotipificación , Pulmón/patología , Linfocitos/inmunología , Linfocitos/metabolismo , Masculino , Esplenomegalia/diagnóstico , Tomografía Computarizada por Rayos XRESUMEN
BACKGROUND: Chronic granulomatous disease (CGD) is due to defective nicotinamide adenine dinucleotide phosphate oxidase activity and characterized by recurrent infections with a limited spectrum of bacteria and fungi as well as inflammatory complications. To understand the impact of common severe infections in CGD, we examined the records of 268 patients followed at a single center over 4 decades. METHODS: All patients had confirmed diagnoses of CGD, and genotype was determined where possible. Medical records were excerpted into a standard format. Microbiologic analyses were restricted to Staphylococcus, Burkholderia, Serratia, Nocardia, and Aspergillus. RESULTS: Aspergillus incidence was estimated at 2.6 cases per 100 patient-years; Burkholderia, 1.06 per 100 patient-years; Nocardia, 0.81 per 100 patient-years; Serratia, 0.98 per 100 patient-years, and severe Staphylococcus infection, 1.44 per 100 patient-years. Lung infection occurred in 87% of patients, whereas liver abscess occurred in 32%. Aspergillus incidence was 55% in the lower superoxide-producing quartiles (quartiles 1 and 2) but only 41% in the higher quartiles (rate ratio, <0.0001). Aspergillus and Serratia were somewhat more common in lower superoxide producing gp91phox deficiency. The median age at death has increased from 15.53 years before 1990 to 28.12 years in the last decade. Fungal infection carried a higher risk of mortality than bacterial infection and was the most common cause of death (55%). Gastrointestinal complications were not associated with either infection or mortality. CONCLUSIONS: Fungal infections remain a major determinant of survival in CGD. X-linked patients generally had more severe disease, and this was generally in those with lower residual superoxide production. Survival in CGD has increased over the years, but infections are still major causes of morbidity and mortality.
Asunto(s)
Aspergilosis/epidemiología , Infecciones Bacterianas/epidemiología , Enfermedad Granulomatosa Crónica/complicaciones , Adolescente , Adulto , Niño , Preescolar , Estudios de Cohortes , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Análisis de Supervivencia , Adulto JovenRESUMEN
WHIM syndrome is a rare, autosomal dominant, immunodeficiency disorder so-named because it is characterized by warts, hypogammaglobulinemia, infections, and myelokathexis (defective neutrophil egress from the BM). Gain-of-function mutations that truncate the C-terminus of the chemokine receptor CXCR4 by 10-19 amino acids cause WHIM syndrome. We have identified a family with autosomal dominant inheritance of WHIM syndrome that is caused by a missense mutation in CXCR4, E343K (1027G â A). This mutation is also located in the C-terminal domain, a region responsible for negative regulation of the receptor. Accordingly, like CXCR4(R334X), the most common truncation mutation in WHIM syndrome, CXCR4(E343K) mediated approximately 2-fold increased signaling in calcium flux and chemotaxis assays relative to wild-type CXCR4; however, CXCR4(E343K) had a reduced effect on blocking normal receptor down-regulation from the cell surface. Therefore, in addition to truncating mutations in the C-terminal domain of CXCR4, WHIM syndrome may be caused by a single charge-changing amino acid substitution in this domain, E343K, that results in increased receptor signaling.
Asunto(s)
Sustitución de Aminoácidos/genética , Síndromes de Inmunodeficiencia/genética , Receptores CXCR4/química , Receptores CXCR4/genética , Verrugas/genética , Secuencia de Aminoácidos , Niño , Preescolar , Salud de la Familia , Femenino , Humanos , Células K562 , Leucopenia/genética , Masculino , Datos de Secuencia Molecular , Linaje , Fenotipo , Enfermedades de Inmunodeficiencia Primaria , Estructura Terciaria de Proteína/genéticaRESUMEN
WHIM syndrome is a rare congenital immunodeficiency disorder characterized by warts, hypogammaglobulinemia, infections, and myelokathexis (neutropenia because of impaired egress from the BM); most patients also have severe panleukopenia. Because WHIM syndrome is caused by mutations in the chemokine receptor CXCR4 that result in increased agonist-dependent signaling, we hypothesized that the CXCR4 antagonist plerixafor (Mozobil [Genyzme Corporation], AMD3100), might be an effective treatment. To test this, we enrolled 3 unrelated adult patients with the most common WHIM mutation, CXCR4(R334X), in a phase 1 dose-escalation study. Plerixafor increased absolute lymphocyte, monocyte, and neutrophil counts in blood to normal without significant side effects in all 3 patients. Peak responses occurred at 3-12 hours after injection and waned by 24 hours after injection which tracked the drug's pharmacokinetics. All 3 cell types increased in a dose-dependent manner with the rank order of responsiveness absolute lymphocyte > monocyte > neutrophil. These data provide the first pharmacologic evidence that panleukopenia in WHIM syndrome is caused by CXCL12-CXCR4 signaling-dependent leukocyte sequestration, and support continued study of plerixafor as mechanism-based therapy in this disease. This study is registered at http://www.clinicaltrials.gov as NCT00967785.
Asunto(s)
Compuestos Heterocíclicos/uso terapéutico , Síndromes de Inmunodeficiencia/tratamiento farmacológico , Linfopenia/tratamiento farmacológico , Verrugas/tratamiento farmacológico , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Fármacos Anti-VIH/administración & dosificación , Fármacos Anti-VIH/farmacocinética , Fármacos Anti-VIH/farmacología , Fármacos Anti-VIH/uso terapéutico , Bencilaminas , Recuento de Células Sanguíneas , Ciclamas , Relación Dosis-Respuesta a Droga , Femenino , Compuestos Heterocíclicos/administración & dosificación , Compuestos Heterocíclicos/farmacocinética , Compuestos Heterocíclicos/farmacología , Humanos , Síndromes de Inmunodeficiencia/sangre , Síndromes de Inmunodeficiencia/complicaciones , Síndromes de Inmunodeficiencia/genética , Leucocitos/efectos de los fármacos , Leucocitos/patología , Linfopenia/complicaciones , Linfopenia/patología , Masculino , Persona de Mediana Edad , Enfermedades de Inmunodeficiencia Primaria , Receptores CXCR4/antagonistas & inhibidores , Receptores CXCR4/genética , Resultado del Tratamiento , Verrugas/sangre , Verrugas/complicaciones , Verrugas/genética , Adulto JovenRESUMEN
WHIM is an acronym for a rare immunodeficiency syndrome (OMIM #193670) caused by autosomal dominant mutations truncating the C-terminus of the chemokine receptor CXC chemokine receptor 4 (CXCR4). WHIM mutations may potentiate CXCR4 signalling, suggesting that the United States Food and Drug Administration (FDA)-approved CXCR4 antagonist AnorMED3100 (AMD3100) (also known as Plerixafor) may be beneficial in WHIM syndrome. We have tested this at the preclinical level by comparing Chinese hamster ovary (CHO) and K562 cell lines matched for expression of recombinant wild-type CXCR4 (CXCR4(WT)) and the most common WHIM variant of CXCR4 (CXCR4(R334X)), as well as leucocytes from a WHIM patient with the CXCR4(R334X) mutation versus healthy controls. We found that CXCR4(R334X) mediated modestly increased signalling (~2-fold) in all functional assays tested, but strongly resisted ligand-dependent down-regulation. AMD3100 was equipotent and equieffective as an antagonist at CXCR4(R334X) and CXCR4(WT) . Together, our data provide further evidence that CXCR4(R334X) is a gain-of-function mutation, and support clinical evaluation of AMD3100 as mechanism-based treatment in patients with WHIM syndrome.