Fatih Azik

Successful bone marrow transplantation for DOCK8 deficient hyper IgE syndrome

Dear Editor, We report a girl with AR-DOCK8 deficiency treated successfully with allogeneic bone marrow transplantation (BMT). She was born to consanguineous parents (cousins) originating from and living in eastern Turkey. The first two children of the family were not diagnosed as immunodeficient despite hypereosinophilia and high IgE levels. They had neonatal onset pruritic eczematous dermatitis, food allergies, recurrent and severe pneumonias (LRTI) when they died at five and six yr old, respectively. Sibling 6 (the propositus) who was born after three healthy children, presented with severe neurological disease: beginning nearly 6–8 months ago with mild ataxia and gradual deterioration with restlessness, spasticity, progressive hearing, speech and vision loss, hyperactive deep tendon reflexes, Babinsky and clonus. Radiological diagnosis of progressive multifocal leukoencephalopathy (PML) with serial MRI was supported by high JCV-DNA in serum and cerebrospinal fluid (2200 copies/mL). He also was diagnosed with hyper IgE syndrome (HIES) caused by the dermatitis of neonatal onset, severe food allergies, LRTIs and high peripheral blood eosinophilia and serum IgE. There were no pneumatoceles despite recurrent pulmonary infections and cold abscesses nor joint hypermobility. We treated him with i.v. immunoglobulin (IVIG) 400 mg/kg/day for 15 days with no clinical response. As the response to rh-interferon-gamma (rhIFN-c) stimulation is shown in Tyk-2 deficient patient (1), we gave rhIFN-c to this patient with PML using 50 lg/m, ·3/wk, by sc route. He died at the age of seven yr with sepsis in our intensive care unit. The last child (DOB: 25 October 2006) of this family also presented with neonatal rash. She developed severe eczema with lichenification since the first months of life. She had multiple food, environmental and drug allergies, including lentil anaphylaxis. At the age of 18 months, she underwent further investigations after the diagnosis of her brother s JCV infection. She presented with severe disseminated ichthyosiform eczema, ectropion of the eyelids, recurrent LRTI, oral, cutaneous and ungual candidiasis. Fortunately, her brain CT was normal and the serum and CSF did not reveal JCV infection as her brother. High levels of IgE (>10 000 IU/mL) and hypereosinophilia (>5000/lL) were persistent. Serum immunoglobulin levels (G: 1580, M: 71 and A: 8.7 mg/dL) were normal except for low IgA for age while lymphocyte phenotyping revealed CD4+ T cell lymphopenia (absolute: 250/lL) with CD3+ T cell 28%, CD19+B cell 60%, CD16+56+ NK cell 5% in the peripheral blood. Her serum anti-HBs, antipolio, anti-HSV, anti-CMV, anti-EBV, anti-IgM and anti-IgG antibodies and isohemagglutinins were absent. The girl was also clinically diagnosed as autosomal recessive-HIES and treatment was initiated with IVIG, itraconazole, sulfamethoxazoletrimethoprim and rhIFN-c for prophylaxis and immune modulation. She was not responding to topical steroids, emollients and oral antihistamines. Genomic DNA of the patient, parents and her brother who died with JCV infection were evaluated for the DOCK8 gene as the possible cause for the phenotype at the Department of Immunology and Molecular Pathology of Royal Free Hospital (London, UK). Engelhardt et al. identified a homozygous large deletion up to and including exon 25 of the DOCK8 gene (c.?_3121?del), deleting the first half of the gene (JACI 2009;124:1289, patients with codes of ARH016.6, ARH016.7) (2). It could not be understood where the exact beginning of the deletion was; the first deleted exon they detected was exon 3, but as they did not analyze exon 1 and 2, it was concluded that the deletion began before or at the start of the DOCK8 gene. Because of recurrent sibling deaths, she was considered for hematopoietic stem cell Pediatr Transplantation 2012: 16: 398–399 2012 John Wiley & Sons A/S.

Related donor hematopoietic stem cell transplantation for Fanconi anemia without radiation: A single center experience in Turkey

Abstract:  Eight children with FA underwent allogeneic HSCT without using irradiation for the conditioning regimen. Patients received two different conditioning regimens: first two patients received BU 1.5 mg/kg/day for four days and CY 10 mg/kg/day for four days and the other regimen was: Flu 30 mg/m2/day for five days, CY 10 mg/kg/day for two days, and ATG‐Fresenius 9–10 mg/kg/day for four days. GVHD prophylaxis consisted of CsA + MTX for the first two patients and only CsA for the others. All patients received HLA‐identical stem cells from related donors. Primary engraftment was demonstrated in all patients. No patient developed acute GVHD and one patient had chronic GVHD. Only one patient who received BU based regimen died because of VOD. Overall, seven patients (87.5%) are alive with stable full donor chimerism at a median follow‐up time of 2.5 yr (range: 1.7–8.9 yr). None of the patients developed secondary malignancy. Based on our data, we conclude that Flu‐based, non‐irradiation conditioning regimen was safe with low organ toxicity and stable engraftment in FA patients undergoing HSCT from matched related donors.

Venous Thromboembolism after Allogeneic Pediatric Hematopoietic Stem Cell Transplantation: A Single-Center Study.

Objective: Venous thromboembolism (VTE) in children who undergo hematopoietic stem cell transplantation (HSCT) has high morbidity. The aim of this study is to assess the incidence of VTE in allogeneic pediatric HSCT recipients and the contribution of pretransplant prothrombotic risk factors to thrombosis. Materials and Methods: We retrospectively evaluated 92 patients between April 2010 and November 2012 undergoing allogeneic HSCT who had completed 100 days post-HSCT. Before HSCT, coagulation profiles; acquired and inherited prothrombotic risk factors including FV G1691A (factor V Leiden), prothrombin G20210A, methylenetetrahydrofolate reductase (MTHFR) C677T, and MTHFR A1298C mutations; and serum homocysteine and lipoprotein (a), plasma antithrombin III, protein C, and protein S levels were obtained from all patients. Results: In the screening of thrombophilia, 8 patients (9%) were heterozygous for factor V Leiden, 5 (6%) were homozygous for MTHFR 677TT, 12 (14%) were homozygous for MTHFR 1298CC, and 2 (2%) were heterozygous for prothrombin G20210A mutation. We observed VTE in 5 patients (5.4%); a prothrombotic risk factor was found in 3 out of these 5 patients, while 4 out of 5 patients had central venous catheters. It was determined there was no significant relationship between VTE and inherited prothrombotic risk factors. Conclusion: VTE after HSCT seems to be a low-frequency event that may be due to low-dose, low-molecular-weight heparin prophylaxis, and the role of inherited prothrombotic risk factors cannot be entirely excluded without a prospective study.

Neurological complications after allogeneic hematopoietic stem cell transplantation in children, a single center experience.

In this study, we retrospectively examined the data of children who underwent allo‐HSCT from HLA‐matched family donors. We analyzed the incidence, etiological factors, clinical characteristics, possible reasons, risk factors, and follow‐up of neurologic complications. BU‐based conditioning regimens were used in most of the cases (n = 62). The median duration of follow‐up for the 89 patients was 20 months (range 1–41 months). Eleven percent of transplanted children developed one or more neurological symptoms after HSCT with a median observation time of two months (range −6 days to 18 months). The median age of the four girls and six boys with neurological complication was 13 yr (range 5.3–17.6 yr). Cylosporine A neurotoxicity was diagnosed in five children, four of them were PRES. The rest of complications were BU and lorazepam toxicity, an intracranial hemorrhage, a sinovenous thrombosis, and a transient ischemic attack during extracorpereal photopheresis. No difference was found between groups of neurological complication according to age, gender, diagnosis, hospitalization time, neutrophil and platelet engraftment time, stem cell source, and conditioning regimen, acute and chronic GVHD or VOD. Neurological complication was the cause of death in one patient (1.1%).

Successful allogeneic hemopoietic stem cell transplantation in a case of Wiskott-Aldrich syndrome and non-Hodgkin lymphoma.

WAS is a severe X‐linked recessive disorder characterized by microthrombocytopenia, eczema, and immunodeficiency. A six‐yr‐old boy with WAS diagnosed as B‐cell NHL (Stage III) localized in the liver who underwent successful HSCT from HLA‐one antigen mismatch sibling donor has been presented here. His conditioning regimen included ATG, busulfan, and fludarabine. He received 2.3 × 106/kg CD 34(+) stem cells and 11 × 108/kg nucleated cells at day 0. Neutrophil engraftment was achieved at day +14 and platelet engraftment at day +20. He has been in CR for more than two yr after transplantation. Thus, HSCT is an effective treatment for children with WAS even after development of lymphoma.

Reversible myelofibrosis associated with hemophagocytic lymphohistiocytosis

To theEditor:A 16-year-old femalewas referred to our center for fever, anemia, neutropenia, and thrombocytopenia. Her liver and spleen were not palpable. Biochemistry tests were significant for elevated lactate dehydrogenase and mildly elevated serum aspartate aminotransferase. Viral serologic studies were found to be negative. Tomography examination of the head, thorax, abdomen, and pelvis did not reveal any signs suggestive of infection. Treatment with broad-spectrum antibiotics was started. Bone marrow (BM) aspiration and biopsy were performed. Megakaryocyte, fat cell and dysplastic changing were not observed on the biopsy. Although she was on broad spectrum antibiotics, she had persistent fever, and hepatosplenomegaly 10 days after her hospitalization. Fifteen days after, her lung sounds were decreased at both lung bases and chest tomography examination showed that pericardial effusion and pneumonic infiltration at both lung bases. At this time, M. pneumonia specific PCR of blood was determined to be positive two times. On day 40, she developed hepatomegaly. Several BM biopsies did not showevidence for neoplasia. BMaspirations did not reveal sufficient material, and all BM biopsies showed reduced hematopoiesis and marked increased reticulin fibers (Fig. 1A). She was diagnosed with myelofibrosis on the basis of these biopsy results. Further laboratory analyses were performed but all of them failed to demonstrate the etiology of myelofibrosis. The fourth BM aspiration material was mildly hypocellular, and hemophagocytic histiocytes were present. She had persistant fever, pancytopenia, hepatosplenomegaly, hypertriglyceridemia, and hyperferritinemia. These findings indicated BM fibrosis associated with hemophagocytic lymphohistiocytosis (HLH). After treatment according to the HLH 94 chemotherapy protocol was initiated, the hepatosplenomegaly decreased and the blood cell counts improved. After the first positive PCR of M. pneumonia result, administration of clarithromycin was started, but no improvement was seen. Treatment with oral doxycycline was used concurrent with initiation of HLH 94 chemotherapy, resulting in a rapid and complete clinical improvement within 3 weeks. Six months after completion of chemotherapy, laboratory tests revealed normal hematological and biochemical parameters. The results of PCR of M. pneumonia were negative in blood and BM after recovery. BM aspirations were normocellular with no increased reticulin fibers and hemophagocytosis (Fig. 1B). Serum levels of immunoglobulin subclasses were normal. Two years after treatment completion, she remained healthy off therapy. HLH is characterized by a systemic activation of macrophages which are induced to phagocytose of hematopoietic elements [1,2]. Marrow fibrosis can be a polyclonal reaction to inflammatory mediators generated by the transformed clone [3,4]. In our case, the findings might have been induced by HLH because no predisposing factors were identified despite detailed inquiry. The lack of clinical evidence for extramedullary hemotopoiesis was striking; these findings suggest that reversiblemyelofibrosis can be associatedwith HLH. The relationship to the mycoplasma infection is unclear but may be associated well [5,6,7].

Comparison of prophylactic use of intravenous immunoglobulin versus Pentaglobin® in pediatric patients after hematopoietic stem cell transplantation

There are few studies evaluating the use of IgM‐enriched IVIG (Pentaglobin®) in HSCT recipients. This study aimed to compare the efficacy of prophylactic use of IVIG versus prophylactic use of Pentaglobin® within the first 100 days after allogeneic HSCT. We performed a prospective, randomized study of the use of prophylactic IVIG versus prophylactic use of Pentaglobin® in patients after allogeneic HSCT. The first dose of IVIG or Pentaglobin® was given before conditioning regimen and after transplant was given on day +1, +8, +15, and +22. And then, it was given if IgG level was below 400 mg/dL. Twenty‐seven patients in IVIG group and 32 patients in Pentaglobin® group were included in the study. There were no significant differences in the duration of neutropenia, hospitalization, fever, and in the number of pyrexial episode, septicemia, bacteremia, local infection, CMV infection, acute GVHD, VOD, and adverse events between the IVIG group and Pentaglobin® group. Randomized placebo‐controlled trials are needed to conclude that utilization of IVIG or Pentaglobin® has no beneficial effect in HSCT.

Clinical comparison of weight‐ and age‐based strategy of dose administration in children receiving intravenous busulfan for hematopoietic stem cell transplantation

Bu, combined with TDM‐guided dosing, is associated with fewer graft failures/relapses and lower toxicity in pediatric HSCT. We aimed this retrospective study for comparison of weight‐ and age‐based dosing in terms of clinical outcomes such as time to engraftment, early complications, EFS, OS, and toxicity profiles in children receiving iv Bu. Sixty‐one children who underwent HSCT from April 2010 to February 2013 by means of a Bu‐based conditioning regimen and completed 100 days after transplantation at Ankara Children?s Hematology and Oncology Hospital Bone Marrow Transplantation Unit were enrolled in this study. SOS and neutropenic fever occurred more frequently in the weight‐based dosing group. We found a statistically significant correlation between Bu dose and the incidence of SOS (r = 0.26, p = 0.04). Multivariate analysis showed only weight‐based dosing of Bu was a significant predictor of SOS (HR = 9.46; p = 0.009). However, no relationship was found between two groups in terms of hemorrhagic cystitis, engraftment syndrome, acute or chronic GvHD, time to engraftment, chimerism, TRM, OS, and EFS rates. Weight‐based dosing of Bu may cause higher incidence of SOS and early infectious complications at the places where TDM of Bu cannot be performed.

Successful treatment of hemorrhagic cystitis after hematopoietic stem cell transplantation with intravesical hyaluronic acid

Dear Editor, Hemorrhagic cystitis (HC) may cause severe morbidity and mortality in patients who had hematopoietic stem cell transplantation (HSCT) (1). Early onset HC begins within 48–72 h, and late onset begins more than 72 h after conditioning. Alkylating agents or radiotherapy used in conditioning is usually responsible for early onset cases. However, the late form of HC usually has a more severe clinical course that is usually caused by infection, including reactivation, with certain microorganisms such as BK polyomavirus, cytomegalovirus (CMV), and adenovirus (2). The incidence of HC has been reported to be 10–70%. Grade III–IV HC may result in urinary obstruction, acute renal failure, and finally death (1). We herein present a pediatric patient with late/severe HC, successfully treated with intravesical hyaluronic acid. A 13-yr-old male patient with thalassemia major (Pesaro Class 3) had been transplanted from a full-matched sibling. As conditioning, Pesaro Protocol 26 (3) had been given. At day +3, he developed macroscopic hematuria and lower urinary tract symptoms; severe dysuria and suprapubic tenderness. He was diagnosed with late/Grade II hemorrhagic cystitis according to Droller’s classification (4). During that time, he was thrombocytopenic; however, prothrombin time and partial thromboplastin time values were within normal limits. The patient received hyperhydration and mesna. His urine examination revealed negative results for BK-virus, CMV, and adenovirus PCR studies, and also his serum CMV PCR study was negative. In addition, his urine examination did not reveal CMV inclusion bodies on microscopic examination. His urine cultures for bacterial and fungal infections disclosed negative results. He received intensive platelet and red blood cell support during that period. At day +33, he started to urinate at first small, then subsequently big clots (Grade III HC). Repeated PCR examinations of urine for BK-virus, CMV, and adenovirus were again negative. He developed urinary tract obstruction and vesical globe at day +37. A urinary catheter was inserted, and irrigation with saline was performed. Intravesical prostaglandin E1 (500 lg in 50 mL saline, twice a day) was administered three times without resolution. His catheter was replaced several times due to obstruction by clots. At this point, we decided to use intravesical hyaluronic acid treatment. At day +43, 40 mg hyaluronic acid was administered through the urinary catheter and locked up intravesically for 20 min. The following day, gross clots in urine disappeared; however, macroscopic hematuria continued. At day +50, one wk after the initial treatment, the same treatment was repeated. After the second dose, his hematuria turned microscopic. Within a few days, microscopic hematuria also resolved. No local or systemic complication due to hyaluronic acid treatment has been observed. He is still well with 100% donor chimerism at one yr after HSCT. Conventional therapeutic approaches of HC include forced hydration, analgesic and spasmolytic drugs, and irrigation of the bladder regardless of its etiology. In patients who do not respond to these treatments, several other treatment approaches have been reported such as intravenous or intravesical antiviral drugs, intravesicular prostaglandin treatment, corticosteroids, conjugated estrogens, hyperbaric oxygen treatment, factor 7 infusion, and surgical treatments (5, 6). Sodium hyaluronate is a glycosaminoglycan that is protective against damage to the normal vesical mucosa. Intravesical administration is an effective treatment in patients with

Defective UNC13D gene-associated familial hemophagocytic lymphohistiocytosis triggered by visceral leishmaniasis: a diagnostic challenge.

Background: Visceral leishmaniasis (VL) triggered genetic hemophagocytic lymphohistiocytosis (HLH) is clinically challenging. Observations: One-year-old VL-HLH patient improved after liposomal-amphotericin-B therapy, but subsequently deteriorated, although bone marrow amastigotes disappeared. Symptoms resolved after 8 weeks of HLH-2004 therapy but recurred upon cessation. Homozygous UNC13D gene 627delT mutation was identified however stem cell donor was unavailable. The patient died at age 4 years after central nervous system attacks and HLH recurrences. Conclusions: VL in HLH patients does not exclude a genetic etiology and requires structured clinical management. VL should be excluded in all HLH patients in endemic regions before immunochemotherapy, which is recommended for VL-HLH patients unresponsive to VL treatment and/or reactivated.