Teh A

Racial background is a determinant factor in the maintenance dosage of Warfarin

Warfarin is a drug commonly used in the prevention of thromboembolic events. There have been reports suggesting that racial background may influence warfarin dose requirements. Malaysia is a multiracial country in which there are 3 major races, Malay, Chinese, and Indian.We examined 100 patients from our hospital on stable maintenance doses of warfarin, with international normalized ratio (INR) of 2.0 to 3.5.We found that the mean warfarin dose for Indian patients (n = 19) was 6.9 mg, for Chinese patients (n = 55) was 3.6 mg, and for Malay patients (n = 26) was 3.2 mg.The results showed that the Indian patients required a statistically significantly higher warfarin dose than did patients of the other 2 races (P >.0005). Age was also found to affect the daily warfarin maintenance dose.

Association of genotypes and haplotypes of multi-drug transporter genes ABCB1 and ABCG2 with clinical response to imatinib mesylate in chronic myeloid leukemia patients

The introduction and success of imatinib mesylate (IM) has become a paradigm shift in chronic myeloid leukemia (CML) treatment. However, the high efficacy of IM has been hampered by the issue of clinical resistance that might due to pharmacogenetic variability. In the current study, the contribution of three common single nucleotide polymorphisms (SNPs) of ABCB1 (T1236C, G2677T/A and C3435T) and two SNPs of ABCG2 (G34A and C421A) genes in mediating resistance and/or good response among 215 CML patients on IM therapy were investigated. Among these patients, the frequency distribution of ABCG2 421 CC, CA and AA genotypes were significantly different between IM good response and resistant groups (P=0.01). Resistance was significantly associated with patients who had homozygous ABCB1 1236 CC genotype with OR 2.79 (95%CI: 1.217-6.374, P=0.01). For ABCB1 G2677T/A polymorphism, a better complete cytogenetic remission was observed for patients with variant TT/AT/AA genotype, compared to other genotype groups (OR=0.48, 95%CI: 0.239-0.957, P=0.03). Haplotype analysis revealed that ABCB1 haplotypes (C1236G2677C3435) was statistically linked to higher risk to IM resistance (25.8% vs. 17.4%, P=0.04), while ABCG2 diplotype A34A421 was significantly correlated with IM good response (9.1% vs. 3.9%, P=0.03). In addition, genotypic variant in ABCG2 421C>A was associated with a major molecular response (MMR) (OR=2.20, 95%CI: 1.273-3.811, P=0.004), whereas ABCB1 2677G>T/A variant was associated with a significantly lower molecular response (OR=0.49, 95%CI: 0.248-0.974, P=0.04). However, there was no significant correlation of these SNPs with IM intolerance and IM induced hepatotoxicity. Our results suggest the usefulness of genotyping of these single nucleotide polymorphisms in predicting IM response among CML patients.

Bone marrow and stem cell transplantation: Malaysian experience

Malaysia conducted the first BMT in the country in 1987. Since then, there have been 1155 transplantations performed in a total of eight transplant centres. A majority of the transplantations were allogeneic, including myeloablative and nonmyeloablative. A vast majority of donors are HLA identical siblings. The mean age of transplanted patients was 26 years. The major reason for transplantation was hematological malignancies. The overall survival was 60% for allogeneic transplantation and 52% for autologous transplantation. The most common cause of death in transplanted patients was the underlying disease followed by infection-related complications. Currently, the government is expanding the existing public cord blood bank as well as the local donor registry.

A Case of T-Cell Acute Lymphoblastic Leukemia after Treatment of Acute Promyelocytic Leukemia

We diagnosed T-cell acute lymphoblastic leukemia (T-ALL) with multiple cytogenetic abnormalities in a 17-year-old girl a year after she had received a diagnosis of acute promyelocytic leukemia (APML). After the diagnosis of APML in June 2001, the patient was treated with idarubicin and all-trans-retinoic acid. In September 1999, her younger sister also received a diagnosis of APML and to date has remained well. T-ALL after remission of APML is very rare, and only 1 such case has been reported. Possible causes include therapy-related reasons, genetic susceptibility to leukemia, and environmental exposure.

Influence of genetic polymorphisms of cytokine genes in the outcome of HLA-matched allogeneic stem cell transplantation in a South East Asian population

Non-HLA gene polymorphisms have been shown to be associated with the risk of graft-versus-host disease (GVHD) and outcome of allogeneic haematopoietic stem cell transplantation (AHSCT). This study aims to investigate the role of IL6, TNFα, IL10, IL2 and IL12 gene polymorphisms in the outcome of AHSCT in a South East Asian population. A total of 67 patients and 59 donors who underwent HLA-identical matched sibling AHSCT were available for analysis. There was no significant association between the different cytokine genotypes of patients with the incidence and severity of acute GVHD. Patients with IL2 166∗T allele and patients who received donor stem cells who had IL2 166∗G allele appeared to have reduced incidence of cGVHD. Patients who received donor stem cells with IL12 1188∗C allele are found to be associated with better disease free survival. These results suggest a possible role of IL2 and IL12 gene polymorphisms in the outcome of AHSCT in a South East Asian population.

Advantage of induction therapy with all trans retinoic acid in acute promyelocytic leukaemia in a country with limited transfusion resources: A Malaysian experience

Induction of remission of acute promyelocytic leukaemia (APL) needs intensive blood support (16) to prevent bleeding attributed to disseminated intravascular coagulation. Between 1989 and 1991, at the University Hospital in Kuala Lumpur, Malaysia, the remission rate of APL was only 27% with conventional chemotherapy as a result of inadequate transfusion resources. The use of all trans retinoic acid in induction therapy followed by consolidation and maintenance chemotherapy has improved the situation dramatically. Twelve patients entered the study. Ten patients achieved remission (83%), indicating how ATRA had significantly improved the results (p = 0.003). Blood component transfusions were also significantly reduced (p = 0.003). Two ethnic Chinese patients developed pulmonary leucostasis. Published Chinese (2, 6) and Japanese (11) studies have not reported this serious adverse effect. We can now state that leucostasis is not a phenomenon limited to the Western population. ATRA has proved to be extremely beneficial for patients at this centre. Early analysis also suggests that consolidation and maintenance chemotherapy has prolonged remission duration. ATRA should be made available for the treatment of APL in all countries where there are inadequate transfusion services.

Acute organic brain syndrome due to drug-induced eosinophilia.

A 72 year old man developed acute organic brain syndrome associated with marked eosinophilia following self medication with a variety of drugs. Investigations revealed no other known causes of eosinophilia. Withdrawal of drugs resulted in dramatic drop in eosinophil count paralleled by clinical resolution of neurological problems. To our knowledge drug-induced eosinophilia has not previously been associated with acute organic brain syndrome.