Gin Gin Gan

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.

A man with concomitant polycythaemia vera and chronic myeloid leukemia: the dynamics of the two disorders

The co-occurrence of JAK2 V617F mutation with BCR-ABL reciprocal translocation is uncommon. We report a 60-year-old man who initially presented with phenotype of polycythemia vera (PV), which evolved into chronic myeloid leukemia and back to PV once treatment with imatinib was commenced. JAK2 V617F mutation and BCR-ABL fusion transcripts were detected in the initial sample. However, JAK2 V617F alleles diminished when BCR-ABL mRNA burden increased and reappeared once the patient was commenced on imatinib. The dynamic interaction between JAK2 V617F and BCR-ABL implies that two independent clones exist with the JAK2 V617F clone only achieving clonal dominance when BCR-ABL positive clones are suppressed by imatinib.

Effect of polymorphisms within methotrexate pathway genes on methotrexate toxicity and plasma levels in adults with hematological malignancies

AIM Pharmacogenetics of methotrexate (MTX) contributes to interindividual differences in toxicity. We aimed to evaluate the impact of SNPs within the MTX pathway genes on MTX-induced toxicity and MTX plasma levels at 48 h following treatment in Asian adults with acute lymphoblastic leukemia or non-Hodgkin lymphoma. PATIENTS & METHODS Patients (n = 71) were genotyped for MTHFR C677T, MTHFR A1298C, SLC19A1 G80A, ABCG2 C421A and ABCB1 C3435T using the Sequenom MassARRAY platform. Plasma MTX concentrations at 48 h were measured by fluorescence polarization immunoassay. RESULTS Forty-eight patients had hematopoietic toxicity, 51 had hepatic toxicity and 36 had mucositis. Patients homozygous for MTHFR 677TT were associated with increased risk of both hematopoietic (odds ratio [OR]: 9.03; 95% CI: 2.28-36.16; p = 0.002) and hepatic (OR: 3.92; 95% CI: 1.01-15.11; p = 0.036) toxicities. Hepatic toxicity was associated with SLC19A1 G80A (OR: 5.27, 95% CI: 1.21-22.72; p = 0.032) and ABCB1 C3435T (OR: 8.62; 95% CI: 1.96-37.57; p = 0.004). However, polymorphisms in MTHFR A1298C and ABCG2 C421A were not associated with any of the toxicities, and mucositis was not associated with any polymorphisms of the MTX pathway genes. Patients with MTHFR C677T and ABCB1 C3435T polymorphisms appear to have significantly higher MTX plasma concentrations (p < 0.05). CONCLUSION Our results in Asian adults provides evidence for the contribution pharmacogenetics to the toxicity of high-dose MTX and plasma MTX concentrations at 48 h following treatment in patients with acute lymphoblastic leukemia or non-Hodgkin lymphoma. These results will contribute towards the effort of MTX therapy individualization.

Anaerobiospirillum succiniciproducens bacteraemia in a patient with acute lymphoblastic leukaemia.

A 17-year-old man with acute lymphoblastic leukaemia had fever and diarrhoea during a febrile neutropenic episode. A spiral-shaped, Gram-negative anaerobic bacterium was isolated from blood, and confirmed as Anaerobiospirillum succiniciproducens by 16S rRNA sequencing. The patient responded to imipenem.

Clinical relevance of CD10, BCL-6 and multiple myeloma-1 expression in diffuse large B-cell lymphomas in Malaysia.

Diffuse large B‐cell lymphoma (DLBCL) is the most common subtype of non‐Hodgkin lymphoma, and it is recognized to constitute a heterogenous group of neoplasms. It can be divided into germinal center B‐cell‐like (GCB) and non‐GCB subgroups. The aim of the present study was to evaluate the utility of immunophenotype subgrouping of DLBCL in a cohort of multi‐ethnic Asian patients. A total of 84 reconfirmed de novo DLBCL were immunostained for the expression of CD10, BCL‐2, BCL‐6 and multiple myeloma‐1. Thirty‐three (39.3%) had the GCB phenotype, and the remainder (60.7%), the non‐GCB phenotype. The results concur with most reports using a similar method of stratification. Forty‐five patients had complete demographic and phenotype studies and 42 patients did not have rituximab treatment and had sufficient data for survival rate analysis. Similar to other studies, patients with combined low and low–intermediate International Prognostic Index score had better overall survival (P = 0.006). But patients with GCB phenotype did not have better prognosis, and BCL‐2 expression was not associated with better prognosis. The expression of BCL‐6 was associated with lower overall survival rate (P = 0.038). No apparent difference in overall and disease‐free survival was noted between patients with GCB and non‐GCB disease. BCL‐6 expression by tumor cells appears to be associated with poorer prognosis.

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.

α-Haemoglobin stabilising protein expression is influenced by mean cell haemoglobin and HbF levels in HbE/β-thalassaemia individuals

The alpha haemoglobin stabilising protein (AHSP) acts as a molecular chaperone for α-globin by stabilising nascent α-globin before transferring it to waiting free β-globin chains. Binding of AHSP to α-globin renders α-globin chemically inert whereby preventing it from precipitating and forming reactive oxygen species byproducts. The AHSP has been actively studied in the recent years, particularly in its relation to β-thalassaemia. Studies have shown that AHSP is a modifier in β-thalassaemia mice models. However, this relationship is less established in humans. Studies by some groups showed no correlation between the AHSP haplotypes and the severity of β-thalassaemia, whereas others have shown that certain AHSP haplotype could modify the phenotype of β-thalassaemia intermedia patients. We investigated the expression of AHSP in relation to selected demographic data, full blood count, HPLC results, HbE/β-thalassaemia genotype, Xmn-1 Gγ polymorphism, α-globin, β-globin and γ-globin expression. We found that AHSP expression was significantly correlated to mean cell haemoglobin level, HbF %, α-globin, β-globin and excess α-globin expression. We concluded that AHSP could be a secondary compensatory mechanism in red blood cells to counterbalance the excess α-globin chains in HbE/β-thalassaemia individuals.

Identification of copy number alterations by array comparative genomic hybridization in patients with late chronic or accelerated phase chronic myeloid leukemia treated with imatinib mesylate

The outcome of treating chronic myeloid leukemia (CML) with imatinib mesylate (IM) is inferior when therapy is commenced in late chronic or accelerated phase as compared to early chronic phase. This may be attributed to additional genomic alterations that accumulate during disease progression. We sought to identify such lesions in patients showing suboptimal response to IM by performing array-CGH analysis on 39 sequential samples from 15 CML patients. Seventy-four cumulative copy number alterations (CNAs) consisting of 35 losses and 39 gains were identified. Alterations flanking the ABL1 and BCR genes on chromosomes 9 and 22, respectively, were the most common identified lesions with 5 patients losing variable portions of 9q34.11 proximal to ABL1. Losses involving 1p36, 5q31, 17q25, Y and gains of 3q21, 8q24, 22q11, Xp11 were among other recurrent lesions identified. Aberrations were also observed in individual patients, involving regions containing known leukemia-associated genes; CDKN2A/2B, IKZF1, RB1, TLX1, AFF4. CML patients in late stages of their disease, harbor pre-existing and evolving sub-microscopic CNAs that may influence disease progression and IM response.

High frequency of germinal centre derivation in diffuse large B cell lymphoma from Asian patients

Background: Recent reports have divided diffuse large B cell lymphoma (DLBCL) into germinal centre B cell-like and activated B cell-like subgroups with implicated differences in prognosis. Aims: To delineate the germinal centre B cell derivation group from an Asian series of DLBCLs. Methods: Fifty four cases were analysed by polymerase chain reaction to detect the t(14;18) translocation and immunohistochemistry for BCL2, CD10, BCL6, and E2F1 expression. Results: Eighteen of 54 cases had bcl2 gene rearrangement, 36 of 52 expressed BCL2, 29 of 52 expressed BCL6, 20 of 53 expressed CD10, and 18 of 53 expressed E2F1. There was a significant association between bcl2 gene rearrangement and the expression of both BCL2 and CD10. Using the minimally acceptable criteria of t(14;18) rearrangement and/or CD10 expression, 26 of 54 cases were probably germinal centre derived, in agreement with other reports. A higher proportion of cases had t(14;18) translocation, suggesting that they may be derived from transformed follicular lymphomas. E2F1 positivity did not correlate with the known germinal centre markers, even though it has recently been suggested that it may be a new GC marker. Conclusions: It may be possible to stratify patients for treatment using markers for specific lineages of B cell differentiation.

Analysis of interleukin-10 promoter single nucleotide polymorphisms and risk of non-Hodgkin lymphoma in a Malaysian population.

Abstract We evaluated the association of two IL10 single nucleotide polymorphisms (SNPs) (rs1800896 and rs1800871) with non-Hodgkin lymphoma (NHL) risk in the three major races of the Malaysian population (Malay, Chinese and Indian; 317 cases and 330 controls). Our initial screening demonstrated that rs1800871 but not rs1800896 was significantly associated with increased NHL risk in Malays (pMalay-Rec = 0.007) and Chinese only (pChinese-Rec = 0.039). Subsequent combined analysis of the Malay and Chinese revealed significant association of rs1800871 with all (ALL) NHL subtypes (pMeta-ALL-NHL-Rec = 0.001), ALL B-cell subtypes (pMeta-ALL-B-cell-Rec = 0.003), diffuse large B-cell lymphoma (DLBCL) subtype (pMeta-DLBCL-Rec = 0.002) and ALL T-cell subtypes (pMeta-ALL-T-cell-Rec = 0.031). SNP rs1800896 showed increased risk only in follicular lymphoma (FL) (pMeta-FL-Dom = 0.0004). We also detected a male-specific association of rs1800871 with increased NHL risk (pMeta-Male-ALL-NHL-Rec = 0.006) in the combined analysis. To our knowledge, this is the first report on the association of IL10 promoter SNPs with NHL susceptibility in the three major races of Malaysia.