C1236T polymorphism in MDR1 gene correlates with therapeutic response to imatinib mesylate in Indian patients with chronic myeloid leukaemia.

Patients with chronic myeloid leukaemia show an excellent response to treatment with imatinib. However, in some patients, the disease is resistant to imatinib. This resistance may be related to the presence of genetic variations on the drug’s pharmacokinetics and metabolism. We therefore studied three polymorphisms (C1236T, G2677T and C3435T) in the human multidrug-resistance gene (MDR1) in 86 patients with chronic myeloid leukaemia treated with imatinib. Imatinib resistance was more frequent in patients with TT genotype at locus 1236 than in those with CT/CC genotypes (p=0.003). For the other two loci (G2677T and C3435T), resistance was seen to be higher for TT genotype when compared to GG/GT and CT/CC but it was not statistically significant (p=0.13 and p=0.099). In conclusion, determination of C1236T MDR1 genotype may help to predict response to imatinib therapy in patients with chronic myeloid leukaemia. Natl Med J India 2015;28:272–5

Cytogenetic profile of Indian patients with de novo myelodysplastic syndromes.

Background & objectives: Myelodysplastic syndrome (MDS) is a clonal haematopoietic stem cell disorder characterized by ineffective haematopoiesis and leukaemia progression. Cytogenetic analysis has proven to be a mandatory part of the diagnosis of MDS as well as a major indicator for predicting clinical course and outcome. Studies on cytogenetics of MDS are reported mostly from the West and only a few are available from Asian countries. We report herein cytogenetic studies on 40 Indian patients with primary MDS to find out the occurrence and type of chromosome abnormalities and recurring defects. Methods: Cytogenetic analysis was done using GTG banding and karyotyped according to the International System for Human Cytogenetic Nomenclature (ISCN). Results: Of the 40 patients, 19 patients (47.5%) showed clonal karyotypic abnormalities with distribution as follows: 3 of 15 (20%) of refractory anaemia (RA), 4 of 7 (57%) of refractory anaemia with excess blasts-1 (RAEB-1), 4 of 6 (67%) of refractory anaemia with excess blasts 2 (RAEB-2), 2 of 3 (67%) of refractory anaemia with ring sideroblasts (RARS), 2 of 4 (50%) of refractory cytopenia with multilineage dysplasia (RCMD), none (0%) RCMD-ringed sideroblasts (RCMD-RS) and 4 patients with 5q syndrome. The frequent abnormalities observed in our study were -7, 5q-and trisomy 8. Interpretation & conclusions: Two rare chromosomal abnormalities (6q-, 3q-) were found with unknown prognostic significance. Hence, cytogenetic analysis may be incorporated in the routine diagnosis of MDS since there are racial differences in clinical pictures and the molecular events.

Haematological & molecular profile of acute myelogenous leukaemia in India.

Background & objectives: Recurrent balanced translocations are generally recognized to be a major parameter for prognostication in acute myeloid leukaemia (AML). The chromosomal translocation t(15;17) results in PML/RARα fusion gene, t(8;21) results in AML1/ETO fusion gene and Inv 16 generates CBFβ/MYH11 fusion gene. Patients with these mutations have a good prognosis unlike abnormalities in chromosome 5 or 7 or FLT3 genes. Therefore, we screened the AmL patients for known specific genetic abnormalities that could lead to more definitive prognoses. Methods: A total of 113 AML patients were evaluated at diagnosis based on routine morphology and cytochemistry and classified according to the WHO criteria. The distribution of AML subtypes was M1(1), M2(32), M3(57), M4(14), M5(1), M6(1) and seven cases where morphological subtype could not be classified. RT-PCR was performed to identify PML/RARα, AML1/ETO, CBFβ/MYH11 and FLT3 internal tandem duplication (ITD). Results: Of the 57 patients with M3 subtype, 55 had the PML-RARα fusion transcript. The prevalence of bcr3 (short isoform) was higher (62%) than that of bcr1 (long isoform) (38%) and no correlation was found with age, sex or white blood cell count. FLT3 internal tandem duplication (ITD) mutations were more frequent in patients with APL than in other AML subtypes (17.5 vs. 8.9%), the frequency greater in patients with bcr3 isoform (70%) than in those with in bcr1 isoform (30%). Patients with FLT3/ITD mutations had a significantly higher median white cell count than those without these mutations (55 x 109/l vs. 6.3 x 109/l; P<0.001). More patients with FLT3/ITD mutations died early (53%) than those without these mutations (16%) (P<0.01). AML1-ETO fusion transcript was detected in 16 of 56 patients with no correlation with clinical or haematological parameters. Interpretation & conclusion: The results of the present study showed presence of bcr3 (short isoform) higher than bcr1 (long isoform). FLT3 internal tandem duplication (ITD) mutation was predominant in acute promyelocytic leukaemia patients with bcr3 isoform. Thus, patients with APL who have FLT3 mutation appear to have a poorer prognosis. Therefore, rapid identification of specific translocations at diagnosis is important for prognostic purposes and their detection should be incorporated into routine assessment.