Mmk Shing

Incidence, risk factors and outcome of varicella-zoster virus infection in children after haematopoietic stem cell transplantation.

We report a retrospective analysis of VZV infection after haematopoietic stem cell transplantation (HSCT) in children. Thirty-three (30%) of the total 109 children who were transplanted during a 7 year period developed post-transplant VZV infection. Twenty-four of these 33 (73%) children had VZV infection within 1 year following HSCT. The cumulative incidences of post-transplant VZV infection at 1 and 5 years were 26% and 45%, respectively. The positive and negative predictive values of pretransplant VZV serology in recipients on the development of HZ following HSCT were 39% and 88%, respectively. Pretransplant VZV seropositivity in recipients was the only risk factor for post-transplant herpes zoster (HZ) infection on multivariate analysis. All patients responded to acyclovir. The median duration of VZV infection was 5 days. Three (11%) and one (3%) children with HZ developed visceral dissemination and post-herpetic neuralgia, respectively. No mortality was directly attributed to VZV infection. VZV infection remains a major cause of morbidity in children after HSCT. Further studies are warranted to evaluate the potential use of VZV vaccine in these children. Bone Marrow Transplantation (2000) 25, 167–172.

Bone marrow transplantation for chronic granulomatous disease: long-term follow-up and review of literature.

Chronic granulomatous disease (CGD) is a heterogeneous group of disorders with defective respiratory burst activity in phagocytes which results in recurrent pyogenic infections. We report an 8-year-old boy with X-linked CGD who received an HLA-identical BMT from his sister. The nitroblue tetrazolium test returned to normal 3 months post transplant. Neutrophil engraftment has been stable for 7 years post BMT. Our patient was the eighth case of CGD successfully treated by BMT. Conditioning regimens in these patients have consisted mainly of BU and CY. We suggest that BMT is a safe and effective method of cure for patients with CGD. BMT should be considered for patients with HLA-identical siblings.

A fludarabine-based conditioning regimen for severe aplastic anemia.

Graft rejection is a common problem after alternative donor transplantation for patients with refractory severe aplastic anemia (SAA). Intensification of the conditioning regimen, with the inclusion of irradiation, has often been advocated to combat this problem. With this approach engraftment rate improved, but the incidence of transplant-related complications is also increased, resulting in little change in the overall outcome. We investigated the use of the combination of fludarabine, cyclophosphamide and anti-thymocyte globulin as the conditioning regimen in five multiply-transfused SAA patients. Three patients received an HLA one-antigen disparate related donor transplant, while two patients were given marrow from matched, unrelated donors. The regimen was well tolerated, with only grade I toxicity encountered. With a median follow-up of 9 months, all patients are alive with complete donor chimerism. We conclude that fludarabine may be used in place of irradiation to augment the conditioning regimen of cyclophosphamide and anti-thymocyte globulin for alternative donor transplantation in children with SAA. Bone Marrow Transplantation (2001) 27, 125–128.

Single vs twice daily G-CSF dose for peripheral blood stem cells harvest in normal donors and children with non-malignant diseases

The optimal dose and schedule of G-CSF for mobilization of peripheral blood stem cells (PBSC) is not well defined. G-CSF mobilization was performed in a group of healthy donors and paediatric patients for autologous back-up before receiving allogeneic stem cell transplant. Seventeen consecutive subjects who received G-CSF at 5 μg/kg/dose twice daily (group A) were compared with a historical control group of 25 subjects who received a single daily dose of 10 μg/kg/day G-CSF (group B). Double blood volume apheresis for PBSC collection was started on day 5. G-CSF was continued and apheresis repeated until the targeted CD34+ cell dose was achieved. Both groups were comparable for sex, age, body weight and reason for PBSC collection. Over two-thirds of the subjects in both groups were less than 16 years of age. The G-CSF priming and apheresis were well tolerated. When the first day apheresis products were analyzed, group A resulted in significantly higher yield of total nucleated cells (5.91 vs 3.92 × 108/kg, P = 0.013), mononuclear cells (5.73 vs 3.92 × 108/kg, P = 0.017), CD34+ cells (2.80 vs 1.69 × 106/kg, P = 0.049) and colony-forming units (107 vs 54 × 104/kg, P = 0.010) as compared with group B. We conclude that the two dose schedule is more efficient in mobilizing PBSC in normal donors and children with non-malignant diseases. This approach may reduce the number of aphereses required and thus reduce the transplant cost. Bone Marrow Transplantation (2000) 25, 931–935.

Haematopoietic stem cell transplantation for thalassaemia major in Hong Kong: prognostic factors and outcome.

From August 1992 to August 1999, 44 patients received allogeneic haematopoietic stem cell transplantation in a single institution. The donors were HLA-identical siblings except for one who was a phenotypically matched father. Thirty-eight patients received bone marrow stem cells and the others received peripheral blood stem cells or umbilical cord blood (UCB). The mean age at transplant was 10.7 ± 5.1 years, ranging from 1.8 to 21 years. Patients received busulphan (16 mg/kg) and cyclophosphamide (150 to 200 mg/kg) as conditioning, and antithymocyte globulin was given to 42 patients to prevent graft rejection. All had engraftment except a patient who received a UCB transplant. Four patients died from early treatment-related mortality, and one died from interstitial pneumonitis 3 months after transplant. Two patients developed secondary graft rejection and both received a second transplant. Thirty-eight patients survived and all except one were transfusion independent. The 5-year overall and event-free survival rates were 86% and 82%, respectively. By multivariate stepwise Cox proportional hazard analyses, severe veno-occlusive disease (VOD) of liver and Pesaro class 3 features were the significant factors associated with survival. Patients aged more than 11 years were more inclined to develop VOD. In conclusion, haematopoietic stem cell transplantation should be performed early if an HLA identical sibling is available.Bone Marrow Transplantation (2002) 29, 101–105. doi:10.1038/sj.bmt.1703340

Early iron reduction programme for thalassaemia patients after bone marrow transplantation

Thirty thalassaemia patients received iron reduction starting at around 3 months post transplant. Sixteen received desferrioxamine and nine had phlebotomy, five patients had desferrioxamine followed by phlebotomy. The desferrioxamine group had higher serum ferritin levels at the start of iron reduction as compared to the phlebotomy group (5292 vs 2453 μg/l, P EQ 0.001). After 444 and 407 days of iron reduction, serum ferritins at cessation of iron reduction in both groups was similar (665 vs 588 μg/l). The rate of decline of serum ferritin in both groups was similar. There was no graft rejection during the programme. Early institution of iron reduction in ex-thalassaemia is safe. Bone Marrow Transplantation (2000) 25, 653–656.

Human herpesvirus-6 encephalitis after unrelated umbilical cord blood transplant in children.

Three children developed human herpesvirus-6 (HHV-6), variant B encephalitis after unrelated umbilical cord blood transplant, in a single center. They developed clinical manifestations of encephalitis around day 17 post transplant. Impairment of consciousness, incoherent speech, episodic focal pruritis, motor weakness, convulsions and severe hyponatremia were features at presentation. Radiological investigation of brain ranged from unremarkable to extensive white matter and meningeal lesions. Diagnosis was established by the presence of HHV-6 DNA in cerebrospinal fluid (CSF). Retrospective analyses of plasma revealed the presence of viral DNAemia prior to the onset of disease in two subjects. Treatment with ganciclovir or foscarnet was given. Two subjects did not achieve engraftment and died of other transplant-related complications on day 38 and 56 post-transplant, respectively. One subject achieved disease-free survival for more than 1 year with a satisfactory neurological outcome. In conclusion, HHV-6 encephalitis is not uncommon among patients undergoing umbilical cord blood transplantation. It is worth conducting further studies on early diagnosis and optimal management of this potentially fatal disease.

Umbilical cord blood transplantation for Maroteaux–Lamy syndrome (mucopolysaccharidosis type VI)

Severe Maroteaux–Lamy syndrome (mucopoly- saccharidosis type VI) is usually fatal by early adulthood. Bone marrow transplantation is the only form of definitive enzyme replacement therapy available. A 5-year-old boy with Maroteaux–Lamy syndrome has successful recovery of bone marrow and enzymatic functions after umbilical cord blood transplant from his unaffected HLA-identical brother. Busulphan (16 mg/kg) and cyclophosphamide (200 mg/kg) were used as preparative chemotherapy with short methotrexate and long cyclosporin as prophylaxis against graft-versus-host disease (GVHD). A total of 6.08 × 107/kg nucleated cells and 2.92 × 105/kg CD34+cells were transplanted with neutrophil engraftment achieved on day 26. There was no evidence of acute and chronic GVHD. Fifteen months after transplant, a normal level of N-acetylgalactosamine-4-sulphatase activity was achieved despite mixed chimerism. There was clinical improvement of hepatosplenomegaly, facial and skin features, joint mobility and resolution of suppurative middle ear effusion. He returned to school and continued to perform well in academic studies. We report here the first successful umbilical cord blood transplant as treatment of Maroteaux–Lamy syndrome. Bone Marrow Transplantation (2000) 26, 455–458.

Busulphan level and early mortality in thalassaemia patients after BMT

The aim of the study was to correlate busulphan (BU) levels of thalassaemia patients with outcome of allogeneic transplant. BU levels were measured by gas chromatography mass fragmentography. All patients received a standardised dose of BU 16 mg/kg, and cyclophosphamide 150 or 200 mg/kg. For area-under-the-curve analysis (AUC), blood samples were obtained at 0, 1, 2, 3, 4 and 6 h after the first and fifth dose for all patients, and additional levels were measured after ninth and/or 13th dose in most patients. Outcome parameters examined included veno-occlusive disease of liver (VOD), idiopathic interstitial pneumonitis, chimerism, and day 90 survival. Twenty consecutive thalassaemia patients who underwent haematopoietic stem cell transplantation were studied. The median age at transplant was 11.2 years (range 3–21 years). Mean BU AUC levels were correlated with age at transplant (r = 0.58, P = 0.007). Nine patients developed VOD and six had mixed chimerism, but these did not correlate with mean BU AUC level. Four patients died before day 50 from VOD and interstitial pneumonitis. Patients with BU AUC levels greater than the median (908 μmol × min/l) had significantly lower probability of survival at day 90 (60%), whereas patients with BU AUC level less than the median all survived beyond day 90. No patient had graft rejection. In conclusion, a high BU AUC level was associated with a higher treatment-related mortality in thalassaemia patients after transplant.

Bone mineral density in children with thalassaemia major: determining factors and effects of bone marrow transplantation

Summary:Osteoporosis and osteopenia affect up to half of patients with thalassaemia major (TM). We investigate the effects of acquired factors and BMT on bone mineral density (BMD) in these patients. In all, 53 patients on regular transfusion (BT group) and 33 patients at 5.7±1.9 years post transplant (BMT group) were recruited. BMD was measured by dual energy X-ray absorptiometry. Serum concentrations of osteocalcin, bone-specific alkaline phosphatase (ALP), beta-crossLap and urinary cross-linking deoxypyridinoline (DPD) were measured by chemiluminescence and enzyme immunoassay, respectively. Severe BMD deficit (Z-score <−2.5) at spine and hip were noted in 62 and 35% of BT group. Serum osteocalcin (β=−0.463; P=0.006) was predictive of spine BMD, whereas age (β=−0.843; P=0.007) and urine DPD (β=−0.439; P=0.037) were associated with hip BMD in BT group. Among BMT patients, post transplant duration (β=0.450; P=0.009) and serum bone-specific ALP (β=−0.495; P=0.013) were associated with spine BMD. Severe BMD deficit was less common among BMT than BT patients (6 vs 35%; P=0.036). The mean (s.d.) osteocalcin levels in BMT and BT groups were 96.4 (72.7) μg/l and 68.9 (40.3) μg/l, respectively (P=0.037). In conclusion, severe BMD deficit is common in Chinese TM patients and BMT may reverse BMD deficit in these patients.