ABSTRACT
BACKGROUND: P47phox (neutrophil cytosolic factor-1) deficiency is the most common cause of autosomal recessive chronic granulomatous disease (CGD) and is considered to be associated with a milder clinical phenotype. Allogeneic hematopoietic cell transplantation (HCT) for p47phox CGD is not well-described. OBJECTIVES: We sought to study HCT for p47phox CGD in North America. METHODS: Thirty patients with p47phox CGD who received allogeneic HCT at Primary Immune Deficiency Treatment Consortium centers since 1995 were included. RESULTS: Residual oxidative activity was present in 66.7% of patients. In the year before HCT, there were 0.38 CGD-related infections per person-years. Inflammatory diseases, predominantly of the lungs and bowel, occurred in 36.7% of the patients. The median age at HCT was 9.1 years (range 1.5-23.6 years). Most HCTs (90%) were performed after using reduced intensity/toxicity conditioning. HCT sources were HLA-matched (40%) and -mismatched (10%) related donors or HLA-matched (36.7%) and -mismatched (13.3%) unrelated donors. CGD-related infections after HCT decreased significantly to 0.06 per person-years (P = .038). The frequency of inflammatory bowel disease and the use of steroids also decreased. The cumulative incidence of graft failure and second HCT was 17.9%. The 2-year overall and event-free survival were 92.3% and 82.1%, respectively, while at 5 years they were 85.7% and 77.0%, respectively. In the surviving patients evaluated, ≥95% donor myeloid chimerism at 1 and 2 years after HCT was 93.8% and 87.5%, respectively. CONCLUSIONS: Patients with p47phox CGD suffer from a significant disease burden that can be effectively alleviated by HCT. Similar to other forms of CGD, HCT should be considered for patients with p47phox CGD.
Subject(s)
Granulomatous Disease, Chronic , Hematopoietic Stem Cell Transplantation , NADPH Oxidases , Humans , Granulomatous Disease, Chronic/therapy , Granulomatous Disease, Chronic/genetics , NADPH Oxidases/genetics , Male , Female , Child , Child, Preschool , Adolescent , Infant , Young Adult , Transplantation, Homologous , Transplantation Conditioning/methods , Graft vs Host Disease , Adult , Treatment OutcomeABSTRACT
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.
Subject(s)
Febrile Neutropenia , Gram-Negative Bacterial Infections , Granulomatous Disease, Chronic , Hematopoietic Stem Cell Transplantation , Anti-Bacterial Agents/therapeutic use , Febrile Neutropenia/drug therapy , Febrile Neutropenia/etiology , Gram-Negative Bacterial Infections/epidemiology , Granulomatous Disease, Chronic/complications , Granulomatous Disease, Chronic/therapy , Hematopoietic Stem Cell Transplantation/adverse effects , Humans , Transplantation Conditioning/adverse effectsABSTRACT
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.
Subject(s)
Cyclophosphamide/therapeutic use , GATA2 Deficiency/therapy , Hematopoietic Stem Cell Transplantation , Tissue Donors , Adolescent , Adult , Bone Marrow/pathology , Combined Modality Therapy , Comorbidity , Cyclophosphamide/administration & dosage , Cyclophosphamide/adverse effects , Female , GATA2 Deficiency/diagnosis , GATA2 Deficiency/mortality , Graft vs Host Disease/diagnosis , Graft vs Host Disease/etiology , Hematopoietic Stem Cell Transplantation/adverse effects , Hematopoietic Stem Cell Transplantation/methods , Humans , Immune Reconstitution , Leukocyte Count , Male , Middle Aged , Neutrophils , Postoperative Care , Prognosis , Transplantation Chimera , Transplantation Conditioning , Treatment Outcome , Young AdultABSTRACT
BACKGROUND: GATA2 deficiency is a genetic disorder of hematopoiesis, lymphatics, and immunity caused by autosomal dominant or sporadic mutations in GATA2. The disease has a broad phenotype encompassing immunodeficiency, myelodysplasia, leukemia, and vascular or lymphatic dysfunction as well as prominent pulmonary manifestations. RESEARCH QUESTION: What are the pulmonary manifestations of GATA2 deficiency? STUDY DESIGN AND METHODS: A retrospective review was conducted of clinical medical records, diagnostic imaging, pulmonary pathologic specimens, and tests of pulmonary function. RESULTS: Of 124 patients (95 probands and 29 ascertained), the lung was affected in 56%. In addition to chronic infections, pulmonary alveolar proteinosis (11 probands) and pulmonary arterial hypertension (nine probands) were present. Thoracic CT imaging found small nodules in 54% (54 probands and 12 relatives), reticular infiltrates in 40% (45 probands and four relatives), paraseptal emphysema in 25% (30 probands and one relative), ground-glass opacities in 35% (41 probands and two relatives), consolidation in 21% (23 probands and two relatives), and a typical crazy-paving pattern in 7% (eight probands and no relatives). Nontuberculous mycobacteria were the most frequent organisms associated with chronic infection. Allogeneic hematopoietic stem cell transplantation successfully reversed myelodysplasia and immune deficiency and also improved pulmonary hypertension and pulmonary alveolar proteinosis in most patients. INTERPRETATION: GATA2 deficiency has prominent pulmonary manifestations. These clinical observations confirm the essential role of hematopoietic cells in many aspects of pulmonary function, including infections, alveolar proteinosis, and pulmonary hypertension, many of which precede the formal diagnosis, and many of which respond to stem cell transplantation.
Subject(s)
GATA2 Deficiency/physiopathology , Multiple Pulmonary Nodules/physiopathology , Pulmonary Alveolar Proteinosis/physiopathology , Pulmonary Arterial Hypertension/physiopathology , Pulmonary Emphysema/physiopathology , Respiratory Tract Infections/physiopathology , Adolescent , Adult , Aged , Aged, 80 and over , Child , Female , GATA2 Deficiency/diagnostic imaging , GATA2 Deficiency/therapy , Hematopoietic Stem Cell Transplantation , Humans , Lung/diagnostic imaging , Lung/physiopathology , Male , Middle Aged , Multiple Pulmonary Nodules/diagnostic imaging , Mycobacterium Infections, Nontuberculous/physiopathology , Pulmonary Emphysema/diagnostic imaging , Retrospective Studies , Tomography, X-Ray Computed , Young AdultABSTRACT
GATA2 deficiency is a bone marrow failure syndrome effectively treated with hematopoietic cell transplantation (HCT), which also addresses the predisposition to many infections (prominently mycobacterial). However, many GATA2-deficient persons who come to HCT also have prevalent and refractory human papilloma virus disease (HPVD), which can be a precursor to cancer. We analyzed 75 HCT recipients for the presence of HPVD to identify patient characteristics and transplantation results that influence HPVD outcomes. We assessed the impact of cellular recovery and iatrogenic post-transplantation immunosuppression, as per protocol (PP) or intensified/prolonged (IP) graft-versus-host disease (GVHD) prophylaxis or treatment, on the persistence or resolution of HPVD. Our experience with 75 HCT recipients showed a prevalence of 49% with anogenital HPVD, which was either a contributing or primary factor in the decision to proceed to HCT. Of 24 recipients with sufficient follow-up, 13 had resolution of HPVD, including 8 with IP and 5 with PP. Eleven recipients had persistent HPVD, including 5 with IP and 6 with PP immunosuppression. No plausible cellular recovery group (natural killer cells or T cells) showed a significant difference in HPV outcomes. One recipient died of metastatic squamous cell carcinoma, presumably of anogenital origin, at 33 months post-transplantation after prolonged immunosuppression for chronic GVHD. Individual cases demonstrate the need for continued aggressive monitoring, especially in the context of disease prevalent at transplantation or prior malignancy. HCT proved curative in many cases in which HPVD was refractory and recurrent prior to transplantation, supporting a recommendation that HPVD should be considered an indication rather than contraindication to HCT, but post-transplantation monitoring should be prolonged with a high level of vigilance for new or recurrent HPVD.
Subject(s)
Alphapapillomavirus , GATA2 Deficiency , Hematopoietic Stem Cell Transplantation , Papillomavirus Infections , GATA2 Transcription Factor/genetics , Humans , Papillomaviridae/geneticsABSTRACT
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.
Subject(s)
Cyclophosphamide/therapeutic use , Graft vs Host Disease/diagnosis , Granulomatous Disease, Chronic/therapy , Hematopoietic Stem Cell Transplantation , Immunosuppressive Agents/therapeutic use , Postoperative Complications/diagnosis , Transplantation Conditioning/methods , Adolescent , Adult , Disease Progression , Female , Graft vs Host Disease/etiology , Granulomatous Disease, Chronic/mortality , Humans , Male , Survival Analysis , Transplantation, Haploidentical , Treatment Failure , Young AdultABSTRACT
Allogeneic blood or marrow transplantation (BMT) is a potentially curative therapy for patients with primary immunodeficiency (PID). Safe and effective reduced-intensity conditioning (RIC) approaches that are associated with low toxicity, use alternative donors, and afford good immune reconstitution are needed to advance the field. Twenty PID patients, ranging in age from 4 to 58 years, were treated on a prospective clinical trial of a novel, radiation-free and serotherapy-free RIC, T-cell-replete BMT approach using pentostatin, low-dose cyclophosphamide, and busulfan for conditioning with post-transplantation cyclophosphamide-based graft-versus-host-disease (GVHD) prophylaxis. This was a high-risk cohort with a median hematopoietic cell transplantation comorbidity index of 3. With median follow-up of survivors of 1.9 years, 1-year overall survival was 90% and grade III to IV acute GVHD-free, graft-failure-free survival was 80% at day +180. Graft failure incidence was 10%. Split chimerism was frequently observed at early post-BMT timepoints, with a lower percentage of donor T cells, which gradually increased by day +60. The cumulative incidences of grade II to IV and grade III to IV acute GVHD (aGVHD) were 15% and 5%, respectively. All aGVHD was steroid responsive. No patients developed chronic GVHD. Few significant organ toxicities were observed. Evidence of phenotype reversal was observed for all engrafted patients, even those with significantly mixed chimerism (nâ¯=â¯2) or with unknown underlying genetic defect (nâ¯=â¯3). All 6 patients with pre-BMT malignancies or lymphoproliferative disorders remain in remission. Most patients have discontinued immunoglobulin replacement. All survivors are off immunosuppression for GVHD prophylaxis or treatment. This novel RIC BMT approach for patients with PID has yielded promising results, even for high-risk patients.
Subject(s)
Bone Marrow Transplantation , Busulfan/administration & dosage , Cyclophosphamide/administration & dosage , Graft vs Host Disease , Pentostatin/administration & dosage , Transplantation Conditioning , Adolescent , Adult , Busulfan/adverse effects , Child , Child, Preschool , Cyclophosphamide/adverse effects , Disease-Free Survival , Female , Follow-Up Studies , Graft vs Host Disease/mortality , Graft vs Host Disease/prevention & control , Humans , Lymphocyte Transfusion , Male , Middle Aged , Pentostatin/adverse effects , Primary Immunodeficiency Diseases/mortality , Primary Immunodeficiency Diseases/therapy , Prospective Studies , Survival RateABSTRACT
Strains of Pseudomonas aeruginosa with deficiencies in DNA mismatch repair have been studied in the context of chronic infection, where elevated mutational rates ("hypermutation") may facilitate the acquisition of antimicrobial resistance. Whether P. aeruginosa hypermutation can also play an adaptive role in the more dynamic context of acute infection remains unclear. In this work, we demonstrate that evolved mismatch repair deficiencies may be exploited by P. aeruginosa to facilitate rapid acquisition of antimicrobial resistance in acute infection, and we directly document rapid clonal succession by such a hypermutating lineage in a patient. Whole-genome sequencing (WGS) was performed on nine serially cultured blood and respiratory isolates from a patient in whom ceftazidime-avibactam (CZA) resistance emerged in vivo over the course of days. The CZA-resistant clone was differentiated by 14 mutations, including a gain-of-function G183D substitution in the PDC-5 chromosomal AmpC cephalosporinase conferring CZA resistance. This lineage also contained a substitution (R656H) at a conserved position in the ATPase domain of the MutS mismatch repair (MMR) protein, and elevated mutational rates were confirmed by mutational accumulation experiments with WGS of evolved lineages in conjunction with rifampin resistance assays. To test whether MMR-deficient hypermutation could facilitate rapid acquisition of CZA resistance, in vitro adaptive evolution experiments were performed with a mutS-deficient strain. These experiments demonstrated rapid hypermutation-facilitated acquisition of CZA resistance compared with the isogenic wild-type strain. Our results suggest a possibly underappreciated role for evolved MMR deficiency in facilitating rapid adaptive evolution of P. aeruginosa in the context of acute infection.IMPORTANCE Antimicrobial resistance in bacteria represents one of the most consequential problems in modern medicine, and its emergence and spread threaten to compromise central advances in the treatment of infectious diseases. Ceftazidime-avibactam (CZA) belongs to a new class of broad-spectrum beta-lactam/beta-lactamase inhibitor combinations designed to treat infections caused by multidrug-resistant bacteria. Understanding the emergence of resistance to this important new drug class is of critical importance. In this work, we demonstrate that evolved mismatch repair deficiency in P. aeruginosa, an important pathogen responsible for significant morbidity and mortality among hospitalized patients, may facilitate rapid acquisition of resistance to CZA in the context of acute infection. These findings are relevant for both diagnosis and treatment of antimicrobial resistance emerging in acute infection in the hypermutator background and additionally have implications for the emergence of more virulent phenotypes.
Subject(s)
Azabicyclo Compounds/pharmacology , Ceftazidime/pharmacology , DNA Mismatch Repair , Drug Resistance, Multiple, Bacterial/genetics , Pseudomonas aeruginosa/drug effects , Pseudomonas aeruginosa/genetics , Acute Disease , Anti-Bacterial Agents/pharmacology , Directed Molecular Evolution , Drug Combinations , Fatal Outcome , Humans , Microbial Sensitivity Tests , Mutation , Pseudomonas Infections/blood , Pseudomonas Infections/microbiology , Respiratory System/microbiology , Whole Genome SequencingABSTRACT
A patient with WHIM syndrome immunodeficiency presented with sudden painless right eye blindness associated with advanced retinal and optic nerve damage. Toxoplasma gondii was detected by PCR in vitreous fluid but not serum. The patient was treated with pyrimethamine/sulfadiazine for 6 weeks due to evidence of active ocular inflammation and then received prophylaxis with trimethoprim-sulfamethoxazole due to his immunosuppression. Vision did not return; however, the infection did not spread to involve other sites. Toxoplasmosis is rare in primary immunodeficiency disorders and is the first protozoan infection reported in WHIM syndrome.
Subject(s)
Primary Immunodeficiency Diseases , Toxoplasmosis, Ocular , Warts , Humans , Toxoplasma , Trimethoprim, Sulfamethoxazole Drug CombinationABSTRACT
BACKGROUND: Patients with GATA2 deficiency present with nontuberculous mycobacterial infections, severe viral infections (particularly refractory human papillomavirus disease), lymphedema, myelodysplastic syndrome (MDS), and acute myeloid leukemia. Patients with GATA2 deficiency who undergo allogeneic hematopoietic stem cell transplantation prior to the development of life-threatening infections or cytogenetic abnormalities may have optimal clinical outcomes. OBJECTIVES: The aim of this article is to determine ways in which oncology nurses can identify GATA2 deficiency in patients early and optimize treatment decisions. METHODS: A case study is presented of a 33-year-old man with recurrent infections and MDS and his two sons, all of whom were found to have the same GATA2 mutation. FINDINGS: Oncology nurses play an important role in early detection and identification by interviewing patients and obtaining a complete and thorough family history.
Subject(s)
GATA2 Transcription Factor/deficiency , Myelodysplastic Syndromes/therapy , Treatment Outcome , Adult , Female , Hematopoietic Stem Cell Transplantation , Humans , Male , Myelodysplastic Syndromes/nursing , Oncology NursingABSTRACT
BACKGROUND: An 11-year-old girl with dedicator of cytokinesis 8 (DOCK8) deficiency was proposed for potentially curative hematopoietic stem cell transplantation (HSCT), the donor being her haploidentical mother. However, end-stage liver disease caused by chronic Cryptosporidium infection required liver transplantation before HSCT. METHODS: Consequently, a staged approach of a sequential liver transplant followed by a HSCT was planned with her mother as the donor for both liver and HSCT. RESULTS: The patient successfully underwent a left-lobe orthotopic liver transplant; however, she developed a biliary leak delaying the HSCT. Notably, the recipient demonstrated 3% donor lymphocyte chimerism in her peripheral blood immediately before HSCT. Haploidentical-related donor HSCT performed 2 months after liver transplantation was complicated by the development of acyclovir-resistant herpes simplex virus viremia, primary graft failure, and sinusoidal obstruction syndrome. The patient died from sinusoidal obstruction syndrome-associated multiorgan failure with Candida sepsis on day +40 following HSCT. CONCLUSIONS: We discuss the many considerations inherent to planning for HSCT preceded by liver transplant in patients with primary immunodeficiencies, including the role of prolonged immunosuppression and the risk of infection before immune reconstitution. We also discuss the implications of potential recipient sensitization against donor stem cells precipitated by exposure of the recipient to the donor lymphocytes from the transplanted organ.
Subject(s)
Cryptosporidiosis/surgery , Guanine Nucleotide Exchange Factors/deficiency , Hematopoietic Stem Cell Transplantation/methods , Liver Transplantation/methods , Severe Combined Immunodeficiency/surgery , Adult , Calcineurin Inhibitors/administration & dosage , Child , Cryptosporidiosis/immunology , Cryptosporidiosis/microbiology , Cryptosporidium/immunology , Cryptosporidium/isolation & purification , Female , Humans , Living Donors , Mothers , Myeloablative Agonists/administration & dosage , Severe Combined Immunodeficiency/genetics , Severe Combined Immunodeficiency/immunology , Transplantation Conditioning/methods , Transplantation, Haploidentical/methods , Treatment OutcomeSubject(s)
GATA2 Transcription Factor/genetics , Germ-Line Mutation , Hematopoietic Stem Cell Transplantation , Leukemia, Myeloid, Acute/genetics , Myelodysplastic Syndromes/genetics , Adolescent , Adult , Female , Humans , Leukemia, Myeloid, Acute/pathology , Leukemia, Myeloid, Acute/therapy , Male , Myelodysplastic Syndromes/pathology , Myelodysplastic Syndromes/therapy , Pedigree , Tissue Donors , Treatment Outcome , Young AdultABSTRACT
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.
Subject(s)
Busulfan/therapeutic use , GATA2 Deficiency/therapy , Hematopoietic Stem Cell Transplantation/methods , Transplantation Conditioning/methods , Adult , Aged , Disease-Free Survival , Female , GATA2 Deficiency/mortality , Graft vs Host Disease/etiology , Graft vs Host Disease/prevention & control , Hematopoietic Stem Cell Transplantation/mortality , Humans , Male , Middle Aged , Prospective Studies , Tissue Donors , Transplantation, Homologous , Young AdultABSTRACT
Disseminated Fusarium infection is associated with high mortality in immunocompromised patients. Patients with acute myeloid leukemia (AML) often have an extended duration of neutropenia during intensive induction chemotherapy, consolidation chemotherapy, and hematopoietic stem cell transplantation (SCT). There is no consensus regarding management of invasive disseminated Fusarium infections in the setting of prolonged neutropenia (Tortorano et al., 2014) [1]. We report a case of disseminated Fusarium in a patient with relapsed AML who underwent successful chemotherapy and haplo-identical allogeneic SCT with administration of granulocyte colony stimulating factor (G-CSF) and granulocyte infusions.
ABSTRACT
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.
Subject(s)
Graft vs Host Disease/diagnosis , Granulomatous Disease, Chronic/therapy , Hematopoietic Stem Cell Transplantation , Immunoglobulins, Intravenous/therapeutic use , Chimerism , Female , Graft vs Host Disease/etiology , Graft vs Host Disease/mortality , Granulomatous Disease, Chronic/diagnosis , Granulomatous Disease, Chronic/mortality , Histocompatibility , Humans , Immunosuppressive Agents/therapeutic use , Male , Prospective Studies , Siblings , Tissue Donors , Transplantation Conditioning , Transplantation, HomologousABSTRACT
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.
Subject(s)
Guanine Nucleotide Exchange Factors/deficiency , Hematopoietic Stem Cell Transplantation/methods , Immunologic Deficiency Syndromes/therapy , Cyclophosphamide/therapeutic use , Graft vs Host Disease/prevention & control , Hematopoietic Stem Cell Transplantation/mortality , Humans , Immunologic Deficiency Syndromes/mortality , Survival Rate , Transplantation Conditioning/methods , Transplantation, Haploidentical/methods , Transplantation, Haploidentical/mortality , Treatment OutcomeABSTRACT
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.
Subject(s)
Epstein-Barr Virus Infections/complications , GATA2 Transcription Factor/deficiency , Hematopoietic Stem Cell Transplantation , Herpesvirus 4, Human , Smooth Muscle Tumor/diagnosis , Smooth Muscle Tumor/etiology , Biomarkers , Epstein-Barr Virus Infections/virology , Hematopoietic Stem Cell Transplantation/adverse effects , Hematopoietic Stem Cell Transplantation/methods , Herpesvirus 4, Human/genetics , Humans , Immunophenotyping , Magnetic Resonance Imaging , Male , Positron Emission Tomography Computed Tomography , Time Factors , Transplantation Chimera , Transplantation, Homologous , Young AdultSubject(s)
Cyclophosphamide/therapeutic use , Guanine Nucleotide Exchange Factors/deficiency , Hematopoietic Stem Cell Transplantation , Immunologic Deficiency Syndromes/therapy , Immunosuppressive Agents/therapeutic use , Transplantation, Haploidentical , Female , Guanine Nucleotide Exchange Factors/genetics , Histocompatibility/genetics , Histocompatibility/immunology , Humans , Immunologic Deficiency Syndromes/genetics , Immunologic Deficiency Syndromes/immunology , Transplantation Conditioning , Young AdultSubject(s)
Adenosine Deaminase/deficiency , Agammaglobulinemia/diagnosis , Agammaglobulinemia/therapy , GATA2 Transcription Factor/deficiency , Hematopoietic Stem Cell Transplantation , Intercellular Signaling Peptides and Proteins/deficiency , Severe Combined Immunodeficiency/diagnosis , Severe Combined Immunodeficiency/therapy , Adenosine Deaminase/genetics , Adolescent , Adult , Agammaglobulinemia/genetics , Child , Child, Preschool , Codon, Nonsense , Diagnostic Errors , Female , Humans , Intercellular Signaling Peptides and Proteins/genetics , Male , Severe Combined Immunodeficiency/genetics , Transplantation, Haploidentical , Exome Sequencing , Young AdultABSTRACT
Background. Successful treatment of infections caused by multidrug-resistant (MDR) Pseudomonas aeruginosa is thwarted by the emergence of antibiotic resistance and biofilm formation on prosthetic devices. Our aims were to decipher the molecular basis of resistance in a unique case of prosthetic valve endocarditis (PVE) caused by MDR P. aeruginosa. Methods. Five sequential MDR P. aeruginosa blood isolates collected during a 7-month period were recovered from a patient suffering from PVE previously exposed to ß-lactam antibiotics. Minimum inhibitory concentrations (MICs) of several classes of antibiotics were used to indicate clinical resistance characteristics; relatedness of the isolates was determined using multilocus sequence typing and repetitive sequence-based polymerase chain reaction. Amplification and sequencing of regulatory and resistance genes was performed. Results. All isolates belonged to ST 298, possessed blaPDC-16, and were resistant to fluoroquinolones and carbapenems. In the course of therapy, we observed a >2-fold increase in cephalosporin resistance (4 µg/mL to >16 µg/mL). Sequencing of the AmpC regulator, ampR, revealed a D135N point mutation in cephalosporin-resistant isolates. Common carbapenemase genes were not identified. All isolates demonstrated a premature stop codon at amino acid 79 of the outer membrane protein OprD and mutations in the quinolone resistance-determining regions of gyrA and parC. Point mutations in nalC, an efflux pump regulator, were also observed. Conclusions. In this analysis, we chart the molecular evolution of ß-lactam resistance in a case of PVE. We show that mutations in regulatory genes controlling efflux and cephalosporinase production contributed to the MDR phenotype.