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Fulltext Hypermethylation analysis of p16 and p15 promoters in chronic lymphocytic leukaemia patients and normal individuals.

Amira M, Sarina S, Azlan H, Muhammad Farid J, Chang KM

IIUM Medical Journal Malaysia, 2019;18(1):35-43.
MyJurnal

Chronic Lymphocytic Leukaemia (CLL) is a common type of leukaemia in persons of predominantly European descent but is rare in the Asian population. Disparities in CLL incidence among people of Asian and European descent may be related to the genetic make-up of the two different populations. Hypermethylation event might be one of the silencing mechanisms that inactivate the tumour suppressor genes in CLL. The aim of this study was to determine the hypermethylation status of p16INK4aand p15INK4bamong CLL patients and normal individuals. Materials & Methods: A total of 25 CLL patients and 25 normal individuals were recruited for this study and their genomic DNA were extracted from the peripheral blood. The hypermethylation status of p16INK4aand p15INK4bweredetermined using Methylation Specific-PCR (MS-PCR) whereas DNA sequencing method was applied to selected samples for validation of the MS-PCR results. We also evaluated the association between hypermethylation of these genes with the clinical and demographic characteristics of each group of subjects. Results: Among the CLL patients, p15INK4bpartial-methylation occurred in 6 (24%) subjects while methylation occurred in 1 (4%) subject. All the remaining patients were unmethylated at p15INK4b. All the samples showed unmethylation at p16INK4a. Statistically significant associations were found between p15INK4bhypermethylation with the presence of CLL (p=0.01) and with race (p=0.02). Conclusion: Further study using a larger sample size is warranted to explore the significance of DNA methylation incidenceamong the CLL patients of the Malaysian population. Hence, we suggest that hypermethylation at p15INK4bhas a huge influence that kick-starts CLL disease among Malaysians and MS-PCR technique is applicable to be used in methylation study.
Clinical impact of ABCC1 and ABCC2 genotypes and haplotypes in mediating imatinib resistance among chronic myeloid leukaemia patients

Au A, Baba AA, Azlan H, Norsa'adah B, Ankathil R

J Clin Pharm Ther, 2014 Dec;39(6):685-90.
PMID: 25060527 DOI: 10.1111/jcpt.12197

The introduction and success of imatinib mesylate (IM) has brought about a paradigm shift in chronic myeloid leukaemia (CML) treatment. However, despite the high efficacy of IM, clinical resistance develops due to a heterogeneous array of mechanisms. Pharmacogenetic variability as a result of genetic polymorphisms could be one of the most important factors influencing resistance to IM. The aim of this study was to investigate the association between genetic variations in drug efflux transporter ABCC1 (MRP1) and ABCC2 (MRP2) genes and response to IM in patients with CML.
Classifying DLBCL according cell of origin using Hans algorithm and its association with clinicopathological parameters: A single centre experience

Wn Najmiyah WAW, Azlan H, Faezahtul AH

Med J Malaysia, 2020 03;75(2):98-102.
PMID: 32281588

INTRODUCTION: In recent years, "double hit" and "double protein" involving gene rearrangement and protein expression of c-MYC and BCL2 and/or BCL6 are the most used terms to describe poor prognostic factors in diffuse large B-cell lymphoma (DLBCL). This study was to determine the frequency of double or triple protein expression by using immunohistochemistry (IHC) and comparing the result with clinicopathological features and cell of origin (COO) classification.
METHODS: We conducted a cross-sectional study by using 29 archived formalin-fixed paraffin embedded tissue blocks of DLBCL. All the samples were evaluated for the subgrouping of COO DLBCL was determined by expression of CD10, BCL6 and MUM1 based on Hans classification. In addition, expressions of c-MYC, BCL2 and BCL6 were detected by IHC.
RESULTS: Among the 29 cases, MYC, BCL2 and BCL6 proteins were detected in 72.4%, 62.1% and 62.1% of patients, respectively. Concurrent expression (c-MYC positive/BCL2 positive and/or BCL6 positive) was present in 58.6% of patients. 34.5% were categorised as germinal centre like (GCB) subgroup and 65.5% were categorised as nongerminal centre like (non-GCB) subgroup. Among the clinicopathological features, the double/triple protein expression lymphoma was significantly associated with elevated LDH level (p=0.018), IPI score (p=0.003), Ann Arbor stage (p=0.011) and complete response rate (p=0.011).
CONCLUSION: Double/triple protein lymphoma was strongly associated more adverse clinical risk factors. Thus, analyses of MYC, BCL2 and BCL6 expression by IHC represents a rapid and inexpensive approach to risk-stratify patients with DLBCL at diagnosis.
Survival and prognostic factors in Malaysian acute myeloid leukemia patients after allogeneic haematopoietic stem cell transplantation

Mangantig E, Naing NN, Norsa'adah B, Azlan H

Int J Hematol, 2013 Aug;98(2):197-205.
PMID: 23719676 DOI: 10.1007/s12185-013-1373-1

Studies of survival outcomes in acute myeloid leukemia (AML) patients treated with allogeneic haematopoietic stem cell transplantation (HSCT) are essential for planning patient care. The objectives of the present study were to determine overall survival (OS) and disease-free survival (DFS) in AML patients treated with allogeneic HSCT, and to identify prognostic factors associated with poor outcome. This study was conducted retrospectively, using data from the Blood and Bone Marrow Transplant, National Transplant Registry, Malaysia. All cases of AML treated with allogeneic HSCT registered at the registry between 1st January 1987 and 31st December 2010 were included in the study. A total of 300 patients were included for final analysis. The Kaplan-Meier method and Cox proportional hazard regression were used for statistical analysis. The overall 10-year OS and DFS for Malaysian AML patients after allogeneic HSCT were 63 and 67 %, respectively. Donor gender, marrow status, and conditioning intensity were identified as important prognostic factors for overall survival, whereas the significant prognostic factors for disease-free survival were ethnic group, donor gender, marrow status, and conditioning intensity. In conclusion, the survival outcomes for Malaysian AML patients treated with allogeneic HSCT were good, and this treatment should be considered the standard therapeutic approach for suitable candidates.
Fatal septicemic shock associated with Strongyloides stercoralis infection in a patient with angioimmunoblastic T-cell lymphoma: a case report and literature review

Abdelrahman MZ, Zeehaida M, Rahmah N, Norsyahida A, Madihah B, Azlan H, et al.

Parasitol Int, 2012 Sep;61(3):508-11.
PMID: 22575692 DOI: 10.1016/j.parint.2012.04.005

Strongyloides stercoralis infection can persist in the host for several decades, and patients with cancer and other clinical conditions who are exposed to immunosuppressive therapy are at risk of developing hyperinfection.
Fulltext Aberrant DNA methylation at HOXA4 and HOXA5 genes are associated with resistance to imatinib mesylate among chronic myeloid leukemia patients

Elias MH, Azlan H, Sulong S, Baba AA, Ankathil R

Cancer Rep (Hoboken), 2018 08;1(2):e1111.
PMID: 32721103 DOI: 10.1002/cnr2.1111

BACKGROUND: Imatinib mesylate is a molecularly targeted tyrosine kinase inhibitor drug. It is effectively used in the treatment of chronic myeloid leukemia (CML) patients. However, development of resistance to imatinib mesylate as a result of BCR-ABL dependent and BCR-ABL independent mechanisms has emerged as a daunting problem in the management of CML patients. Between these mechanisms, BCR-ABL independent mechanisms are still not robustly understood.
AIM: To investigate the correlation of HOXA4 and HOXA5 promoter DNA hypermethylation with imatinib resistance among CML patients.
METHODS AND RESULTS: Samples from 175 Philadelphia positive CML patients (83 good response and 92 BCR-ABL non-mutated imatinib resistant patients) were subjected to Methylation Specific High Resolution Melt Analysis for methylation levels quantification of the HOXA4 and HOXA5 promoter regions. Receiver operating characteristic curve analysis was done to elucidate the optimal methylation cut-off point followed by multiple logistic regression analysis. Log-Rank analysis was done to measure the overall survival difference between CML groups. The optimal methylation cut-off point was found to be at 62.5% for both HOXA4 and HOXA5. Chronic myeloid leukemia patients with ≥63% HOXA4 and HOXA5 methylation level were shown to have 3.78 and 3.95 times the odds, respectively, to acquire resistance to imatinib. However, overall survival of CML patients that have ≤62% and ≥ 63% methylation levels of HOXA4 and HOXA5 genes were found to be not significant (P-value = 0.126 for HOXA4; P-value = 0.217 for HOXA5).
CONCLUSION: Hypermethylation of the HOXA4 and HOXA5 promoter is correlated with imatinib resistance and with further investigation, it could be a potential epigenetic biomarker in supplement to the BCR-ABL gene mutation in predicting imatinib treatment response among CML patients but could not be considered as a prognostic marker.
Aberrant DNA Methylation of SOCS1 Gene is Not Associated with Resistance to Imatinib Mesylate among Chronic Myeloid Leukemia Patients

Elias MH, Azlan H, Baba AA, Ankathil R

Cardiovasc Hematol Disord Drug Targets, 2018;18(3):234-238.
PMID: 29669505 DOI: 10.2174/1871529X18666180419101416

BACKGROUND: In exploring the cause of Imatinib Mesylate (IM) resistance among Chronic Myeloid Leukemia (CML) patients who do not harbor BCR-ABL dependent mechanism, BCR-ABL independent pathways are the most probable pathways that should be explored. In BCR-ABL independent pathway, SOCS1 plays an important role as it helps in regulating optimal JAK/STAT activity.
OBJECTIVE: To identify the association of SOCS1 gene hypermethylation in mediating IM Resistance.
METHOD: The SOCS1 promoter methylation level of 92 BCR-ABL non mutated IM resistant CML patients, 83 IM good response CML patients and 5 normal samples from healthy individuals were measured using Methylation Specific-High Resolution Melt (MS-HRM) analysis.
RESULTS: Both primers used to amplify promoter region from -333 to -223 and from -332 to -188 showed less than 10% methylation in all CML and normal samples. Consequently, there was no significant difference in SOCS1 promoter methylation level between IM resistant and IM good response patients.
CONCLUSION: SOCS1 promoter methylation level is not suitable to be used as one of the biomarkers for predicting the possibility of acquiring resistance among CML patients treated with IM.
Pharmacogenetics and the treatment of chronic myeloid leukemia: how relevant clinically? An update

Ankathil R, Azlan H, Dzarr AA, Baba AA

Pharmacogenomics, 2018 04;19(5):475-393.
PMID: 29569526 DOI: 10.2217/pgs-2017-0193

Despite the excellent efficacy and improved clinical responses obtained with imatinib mesylate (IM), development of resistance in a significant proportion of chronic myeloid leukemia (CML) patients on IM therapy have emerged as a challenging problem in clinical practice. Resistance to imatinib can be due to heterogeneous array of factors involving BCR/ABL-dependent and BCR/ABL-independent pathways. Although BCR/ABL mutation is the major contributory factor for IM resistance, reduced bio-availability of IM in leukemic cells is also an important pharmacokinetic factor that contributes to development of resistance to IM in CML patients. The contribution of polymorphisms of the pharmacogenes in relation to IM disposition and treatment outcomes have been studied by various research groups in numerous population cohorts. However, the conclusions arising from these studies have been highly inconsistent. This review encompasses an updated insight into the impact of pharmacogenetic variability on treatment response of IM in CML patients.
Fulltext A retrospective prevalence study of malaria in an aborigine hospital in Gombak, Selangor, Malaysia

Jamaiah I, Rohela M, Nissapatorn V, Mohamad Azlan H, Nor Adli AR, Shahrul Rizan I, et al.

Southeast Asian J. Trop. Med. Public Health, 2006;37 Suppl 3:1-4.
PMID: 17547040

This was a five-year retrospective study (1999-2004) on the prevalence of malaria at the Aborigine Hospital, Gombak, Malaysia. A total of 94 malaria cases was analysed. The highest case reports were for the year 2000, with 32 cases (34%), and the lowest was in 2004, with only 1 (1%). The majority of cases reported were among the Semai tribe (44%), followed by the Temiar tribe (34%) and the unspecified tribe (s) (20%). Females (53%) were more commonly affected than males (47%). The majority of cases were within the age group 1-5 years (51%). Plasmodium falciparum was the most common species reported in this study, at 57%, followed by Plasmodium vivax (38%) and 5% mixed infection of P. falciparum and P. vivax. Most patients (27%) stayed for more than one month in hospital. Most patients came from Kuala Lipis, Pahang, (78%). The most common complication was anemia (38%) followed by splenomegaly (18%); only 2% had cerebral malaria. All patients were treated with the standard anti-malarial drugs. No deaths were reported in this study.
Fulltext Rare post-operative complications in a previously undiagnosed Congenital Factor X deficiency patient

Mohd Nazri H, Suhair AA, Wan Suriana WA, Zefarina Z, Azlan H, Wan Zaidah A

Malays J Pathol, 2016 Dec;38(3):327-331.
PMID: 28028305 MyJurnal

Factor X (FX) deficiency is a rare autosomal recessive congenital bleeding disorder. The clinical presentation is among the most severe among the rare coagulation defects. Thus, majority of diagnosed patients will receive factor replacement therapy before surgical manipulation. However, the diagnosis of FX deficiency may be overlooked because it is a rare entity. This is a case report of a 15-year-old male patient who was diagnosed with FX deficiency after developing post-operative complications. With regular fresh frozen plasma infusion given, the patient responded well and recovered. However, had he been diagnosed earlier pre-operatively, the post-operative complication could have been prevented. Therefore, pre-operative coagulation screening should be performed in patients with significant bleeding history in both emergency and elective situations to prevent surgical morbidity related to post-operative bleeding.
Fulltext Hyperdiploid Multiple Myeloma with Novel Complex Structural Chromosome Abnormalities Associated with Poor Prognosis : A Rare Case Report

Ankathil R, Foong E, Siti-Mariam I, Norhidayah R, Nazihah MY, Sangeetha V, et al.

Int J Hematol Oncol Stem Cell Res, 2021 Jul 01;15(3):199-205.
PMID: 35083001 DOI: 10.18502/ijhoscr.v15i3.6852

Hyperdiploid multiple myeloma (MM) is associated with better prognosis and non-hyperdiploid subtype is associated with variable to adverse prognosis based on the nature of karyotype abnormality. Rarely exceptions to this hyperdiploid and non-hyperdiploid divisions do exist in a minority. We report an adult male MM patient who showed hyperdiploid karyotype with few novel complex abnormalities and who showed poor clinical outcome. Conventional cytogenetic analysis carried out in 22 GTG banded metaphases showed 53,Y,der(X)t(X;22)(q27;q11.2),+3,+5,+6,+9,+11,+15,der(17)ins(17;1;3)(q11.2;?;?),der(17)ins(17;1;3)(q11.2;?;?),+19,-22,+mar karyotype pattern in 15 metaphases whereas 7 metaphases showed 46,XY karyotype pattern. Interphase FISH revealed biallelic del(13q14) and del(17p13) but no translocations involving the 14q32 region. Through Spectral karyotyping FISH, the origin of complex abnormalities involving der(17) chromosome, translocation t(X;22), and marker chromosome could be clearly delineated. Although the present case showed hyperdiploid karyotype, he showed an adverse prognosis probably due to the co-existence of high risk and complex abnormalities and expired 5 months after initial diagnosis despite standard treatment given.
BCR-ABL kinase domain mutations, including 2 novel mutations in imatinib resistant Malaysian chronic myeloid leukemia patients-Frequency and clinical outcome

Elias MH, Baba AA, Azlan H, Rosline H, Sim GA, Padmini M, et al.

Leuk. Res., 2014 Apr;38(4):454-9.
PMID: 24456693 DOI: 10.1016/j.leukres.2013.12.025

Discovery of imatinib mesylate (IM) as the targeted BCR-ABL protein tyrosine kinase inhibitor (TKI) has resulted in its use as the frontline therapy for chronic myeloid leukemia (CML) across the world. Although high response rates are observed in CML patients who receive IM treatment, a significant number of patients develop resistance to IM. Resistance to IM in patients has been associated with a heterogeneous array of mechanisms of which point mutations within the ABL tyrosine kinase domain (TKD) are the frequently documented. The types and frequencies of mutations reported in different population studies have shown wide variability. We screened 125 Malaysian CML patients on IM therapy who showed either TKI refractory or resistance to IM to investigate the frequency and pattern of BCR-ABL kinase domain mutations among Malaysian CML patients undergoing IM therapy and to determine the clinical significance. Mutational screening using denaturing high performance liquid chromatography (dHPLC) followed by DNA sequencing was performed on 125 IM resistant Malaysian CML patients. Mutations were detected in 28 patients (22.4%). Fifteen different types of mutations (T315I, E255K, G250E, M351T, F359C, G251E, Y253H, V289F, E355G, N368S, L387M, H369R, A397P, E355A, D276G), including 2 novel mutations were identified, with T315I as the predominant type of mutation. The data generated from clinical and molecular parameters studied were correlated with the survival of CML patients. Patients with Y253H, M351T and E355G TKD mutations showed poorer prognosis compared to those without mutation. Interestingly, when the prognostic impact of the observed mutations was compared inter-individually, E355G and Y253H mutations were associated with more adverse prognosis and shorter survival (P=0.025 and 0.005 respectively) than T315I mutation. Results suggest that apart from those mutations occurring in the three crucial regions (catalytic domain, P-loop and activation-loop), other rare mutations also may have high impact in the development of resistance and adverse prognosis. Presence of mutations in different regions of BCR-ABL TKD leads to different levels of resistance and early detection of emerging mutant clones may help in decision making for alternative treatment. Serial monitoring of BCR-ABL1 transcripts in CML patients allows appropriate selection of CML patients for BCR-ABL1 KD mutation analysis associated with acquired TKI resistance. Identification of these KD mutations is essential in order to direct alternative treatments in such CML patients.
Fulltext Deterioration of left ventricular systolic function in extended Pacing to Avoid Cardiac Enlargement (PACE) trial: the predictive value of early systolic dyssynchrony

Fang F, Luo XX, Zhang Q, Azlan H, Razali O, Ma Z, et al.

Europace, 2015 Oct;17 Suppl 2:ii47-53.
PMID: 26842115 DOI: 10.1093/europace/euv130

Biventricular (BiV) pacing was superior to right ventricular apical (RVA) pacing at extended follow-up in the Pacing to Avoid Cardiac Enlargement (PACE) trial. Early pacing-induced systolic dyssynchrony (DYS) might be related to mid-term result. However, it remains unknown whether early pacing-induced DYS can predict long-term reduction of left ventricular (LV) systolic function.

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