Hathirat P

Frequency of thiopurine S-methyltransferase genetic variation in Thai children with acute leukemia

BACKGROUND Thiopurine S-methyltransferase (TPMT) catalyzes the S-methylation (inactivation) of mercaptopurine, azathioprine, and thioguanine, and exhibits genetic variation. About 11% of Caucasians have intermediate TPMT activity because of heterozygosity, and about 1 in 300 inherits TPMT deficiency as an autosomal codominant trait. If patients who have intermediate or deficient TPMT activity receive the standard dose of thiopurine medications, they can accumulate excessive thiopurine nucleotides in hematopoietic tissue, which could lead to severe and possibly fatal myelosuppression. There is very little information about TPMT genetic variation among Asian populations. We investigated the frequency of TPMT genetic variation among Thai children with acute leukemia. PROCEDURE Fresh whole blood was obtained from 75 Thai children with acute leukemia at the time of remission. Genomic DNA was isolated from total peripheral white blood cells. We performed polymerase chain reaction (PCR) to detect 3 types of variant of the human TPMT gene. RESULTS Among 75 patients, the frequency of heterozygotes for the TPMT gene among Thai children with acute leukemia was approximately 11%. However, the TPMT*3C was the only variant TPMT allele found among Thai children. This is different from the North American Caucasian populations, in which TPMT*3A is the predominant variant allele, and TPMT*3C is rare (approximately 5% of variant alleles). CONCLUSIONS There is no difference in the frequency of this genetic variation between Asian and North American Caucasian populations. Determination of the TPMT genotype by PCR method before antileukemic therapy is practical and may have clinical relevance. This knowledge could be applied towards organ transplant recipients who require these medications for immunosuppression.

Full chimerism in nonmyeloablative stem cell transplantation in a β-thalassemia major patient (class 3 Lucarelli)

Bone marrow transplantation is the only therapeutic option that can eliminate thalassemic disease. Early results indicated that children in class 3 Lucarelli had a much worse outcome because of high nonrejection mortality and high rejection rate. We therefore tried to investigate a nonmyeloablative stem cell transplantation (NST) approach for such a disease in order to reduce mortality and rejection. We report here the case of successful NST in a 10-year-old girl who had class 3 Lucarelli β-thalassemia major. The conditioning regimen consisted of busulfan, fludarabine, antilymphocyte globulin and total lymphoid irradiation. Her GVHD prophylaxis included mycophenolate mofetil and cyclosporin. The patient had full donor engraftment without acute and chronic GVHD. She is now alive and well and remains disease-free 1 year after transplant.

Survival analysis of patients with haemophilia at the International Haemophilia Training Centre, Bangkok, Thailand

Summary.  Haemophiliac treatment in less developed countries is limited to locally prepared fresh frozen plasma, cryoprecipitate, cryo‐removed plasma and lyophilized products as replacement therapy. Factor concentrate is seldom used because of the high price. The present study reports the survival analysis of 164 patients comprising 138 haemophilia A and 26 haemophilia B cases from 134 families registered at the International Haemophilia Training Centre‐Bangkok, Faculty of Medicine, Ramathibodi Hospital, Mahidol University from 1971 to 2000. The duration of follow‐up ranged from 1 to 27 years and 8 months with a median of 9 years and 1 month. They received treatment on demand of bleedings, and 85 patients received additional home treatment for early bleedings. The proportion of death was 15.2%. The Kaplan–Meier survival curves revealed the median (95% CI) survival time of patients with severe and moderate degrees of 35 years and 6 months (21.4–49.7), and 38 years and 1 month (28.8–47.3), respectively. To compare the progressive achievement of haemophilia care services, the treatment period was divided into three decades: 1971–1980, 1981–1990 and 1991–2000. The patients with unaided proper walking increased from 62.8% in the first decade to 84.5% in the third decade. However, one‐third of the patients developed one to four chronic haemarthrosis determined by clinical evaluation, especially patients with severe degree. Moreover, the estimated probability of a survival time beyond 13 years of age among patients with severe degree increased from 0.85 in the first decade to 0.94 and 1 in the second and third decades, respectively. Thus, established haemophilia care, even with limited resources, has significantly decreased the risk of death and increased the survival time among patients with haemophilia.

Mismatched related cord blood transplantation in a severe thalassemia patient

In Southeast Asia, b-thalassemia, and hemoglobin (Hb) E are common. The frequencies of the traits can be as high as 3–9% forb thalassemia, and up to 54% or higher for Hb E. Patients withb-thalassemia/Hb E can be as severely affected as those with homozygous b-thalassemia or Cooley’s anemia. At present, allogeneic hematopoietic stem cell transplantation is the only curative therapy for thalassemia. Issaragrisilet al were the first to report successful use of matched related cord blood transplantation (CBT) in a child with b-thalassemia/Hb E disease. In the published literature review, all thalassemic patients treated with CBT received fully matched cord blood (CB). 3–6 We report our experience of utilizing mismatched CBT in a child with severeb-thalassemia/Hb E disease. A 3-year-old female was diagnosed withbthalassemia/Hb E at 4 months of age when she presented with anemia. Her steady-state hemoglobin level was 7 gm/dl. The result of hemoglobin typing was: Hb F 58.2%, Hb E 41.8%. The patient required packed red blood cell transfusion on three occasions. Her father had b-thalassemia trait and her mother had Hb E trait. Analysis of b globin gene mutation demonstrated a nonsense mutation at codon 17. The patient’s HLA typing was: A 2,10; B 62,46; Cw 1,6; Bw 6,−; DR B1* 1502,1401; DR 51,52; DQ A1* 0101,0104; DQ B1* 0501,0502. During a subsequent maternal pregnancy, cord blood was collected at the time of delivery. The male fetus was homozygous for wild-typeb-thalassemia gene. The volume of collected cord blood was 150 ml. The total numbers of nucleated cells and CD34 + cells were 6.1× 10 cells/kg and 1.58× 10 cells/kg, respectively. Cord blood typing was: A 10,11; B 62,48; Cw 6,8; Bw 6, -; DR B1* 1502,1401; DR 51,52; DQ A1* 0101,0104; DQ B1* 0501,0503 (HLA class I by serology, and class II by high resolution sequencespecific primer DNA typing). The patient shared one haplotype with his brother. However, no mismatch in HLA-DR B1* and HLA-DQ A1* was noted. Due to inability to access international bone marrow donor registries from Thailand, we decided to perform CBT instead of a matched unrelated BMT in this patient. from a single institution.Bone Marrow Transplant1995; 15: 293–298. 2 Flowers MED, Zanis J, Pasquini R et al. Marrow transplantation for Fanconi anemia: conditioning with reduced doses of cyclophosphamide without irradiation. Br J Haematol1996;92: 699–706. 3 Medeiros CR, Zanis-Neto J, Pasquini R. Bone marrow transplantation for patients with Fanconi anemia: reduced doses of cyclophosphamide without irradiation as conditioning. Bone Marrow Transplant1999;24: 849–852. 4 Auerbach DA, Bitencourt MA, Magdalena N et al. Phenotypic consequences of mutations in the Fanconi anemia gene FANCA in patients in Brazil.Blood 1999; 94 (Suppl. 1): 410a (Abstr. 1816).

Disarticulation of a knee joint in a haemophiliac with high inhibitor titre

Summary. Disarticulation of a knee joint in an 8‐year‐old haemophilia A patient with high inhibitor of 3450 Bethesda units (BU) is described. He had an infected compound fracture of the tibia and fibula. Surgery was successfully performed after extensive plasma exchange; administration of immunosuppressive agents such as cyclophosphamide, methylprednisolone, intravenous immunoglobulin and cyclosporine were combined with a loading dose of 100 units kg‐1 of factor VIII concentrate, followed by continuous infusion of 16 units kg‐1 h‐1 of factor VIII in the form of factor VIII concentrate and cryoprecipitate for 7 days and decreased to 8 units kg‐1 h‐1 in the form of cryoprecipitate for 19 more days. During the 1st to 7th post‐operative days, the lowest factor VIII inhibitor was 18 BU and the factor VIII level ranged from < 1–2.1 IU dL‐1. On the 9th and 13th post‐operative day, although the inhibitor rose to 330 and 2700 BU, respectively, there was no serious bleeding. The suture was removed on the 21st post‐operative day. The inhibitor spontaneously decreased to 550, 232 and 14 BU at 1, 7 and 10 months, respectively.

Allogeneic peripheral blood stem cell transplantation in a Wiskott-Aldrich syndrome patient.

Allogeneic peripheral blood stem cell transplantation in a Wiskott-Aldrich syndrome patient