S. Fadilah Abdul Wahid

Comparison of reduced-intensity and myeloablative conditioning regimens for allogeneic hematopoietic stem cell transplantation in patients with acute myeloid leukemia and acute lymphoblastic leukemia: a meta-analysis.

Currently, the indications to perform reduced-intensity conditioning allogeneic hematopoietic stem cell transplant (RIC-HCT) are based on data derived mainly from large registry and single-centre retrospective studies. Thus, at the present time, there is limited direct evidence supporting the current practice in selecting patients with acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) for RIC versus myeloablative conditioning (MAC) transplants. To determine the relationship between dose intensity of conditioning regimen and survival outcomes after allografting in AML/ALL patients, we performed a meta-analysis of 23 clinical trials reported between 1990 and 2013 involving 15,258 adult patients that compare survival outcomes after RIC-HCT versus MAC-HCT. RIC-HCT resulted in comparable <2-year and 2-6 year overall survival (OS) rates post-transplantation even though the RIC-HCT recipients were older and had more active disease than MAC-HCT recipients. The 2-6 year progression-free survival (PFS), nonrelapse mortality, acute graft-versus-host disease (GvHD) and chronic GvHD rates were reduced after RIC-HCT, but relapse rate was increased. Similar outcomes were observed regardless of disease type and status at transplantation. Odds ratio for all outcomes remained comparable with or without performing separate analyses for the year of HCT and for retrospective versus prospective studies. Among RIC-HCT recipients, survival rates were superior if patients were in CR at transplantation. Significant inter-study heterogeneity for aGvHD data and publication bias for PFS data were observed. This meta-analysis showed no OS benefit of MAC-HCT over RIC-HCT across the entire cohort of patients suggesting that RIC-HCT could be an effective therapeutic option for AML/ALL patients who are ineligible for MAC-HCT and CR status is preferred before RIC-HCT.

HOXA4 Gene Promoter Hypermethylation as an Epigenetic Mechanism Mediating Resistance to Imatinib Mesylate in Chronic Myeloid Leukemia Patients

Development of resistance to imatinib mesylate (IM) in chronic myeloid leukemia (CML) patients has emerged as a significant clinical problem. The observation that increased epigenetic silencing of potential tumor suppressor genes correlates with disease progression in some CML patients treated with IM suggests a relationship between epigenetic silencing and resistance development. We hypothesize that promoter hypermethylation of HOXA4 could be an epigenetic mechanism mediating IM resistance in CML patients. Thus a study was undertaken to investigate the promoter hypermethylation status of HOXA4 in CML patients on IM treatment and to determine its role in mediating resistance to IM. Genomic DNA was extracted from peripheral blood samples of 95 CML patients (38 good responders and 57 resistant) and 12 normal controls. All samples were bisulfite treated and analysed by methylation-specific high-resolution melt analysis. Compared to the good responders, the HOXA4 hypermethylation level was significantly higher (P = 0.002) in IM-resistant CML patients. On comparing the risk, HOXA4 hypermethylation was associated with a higher risk for IM resistance (OR 4.658; 95% CI, 1.673–12.971; P = 0.003). Thus, it is reasonable to suggest that promoter hypermethylation of HOXA4 gene could be an epigenetic mechanism mediating IM resistance in CML patients.

Indications and outcomes of reduced-toxicity hematopoietic stem cell transplantation in adult patients with hematological malignancies

Hematopoietic stem cell transplantation (HCT) utilizing non-myeloablative (NMA) and reduced-intensity conditioning (RIC) regimens (collectively referred to as reduced-toxicity HCT, RT-HCT) has become a viable therapeutic option for patients with hematological malignancies who are ineligible for standard myeloablative conditioning transplantation (MA-HCT). RT-HCT has been shown to induce stable engraftment with low toxicity, and to produce similar overall and progression-free survival (PFS) when compared to MA-HCT in acute myeloid leukemia and myelodysplastic syndrome. The best results for RT-HCT have been reported for patients with disease that is in remission, indolent and chemosensitive, and with a strong graft-versus-malignancy effect. Chronic graft-versus-host disease seems to correlate with a lower relapse rate and better PFS. RT-HCT is inferior when performed in poor risk or advanced disease, due to high relapse rates. A search for novel strategies that includes the most appropriate conditioning regimens and post-transplant immunomodulation protocols with more intensive anti-malignancy activity but limited toxicity is in progress. This review provides an update on the results of clinical studies of RT-HCT, and discusses possible indications and investigative strategies for improving the clinical outcomes of RT-HCT for the major hematological malignancies.

Dengue infection associated hemophagocytic syndrome: Therapeutic interventions and outcome

Infection associated hemophagocytic syndrome is increasingly recognized as a potentially fatal complication of dengue fever. It should be suspected with prolonged fever beyond seven days associated with hepatosplenomegaly, hyperferritinemia, worsening cytopenias and development of multiorgan dysfunction. Surge of similar pro-inflammatory cytokines observed in dengue associated hemophagocytic syndrome and multiorgan dysfunction may indicate they are part of related inflammatory spectrum. A proportion of patients recovered with supportive therapy, however most required interventions with corticosteroids, intravenous immunoglobulin or chemotherapy. We report three cases of dengue associated IAHS with good outcome following early recognition and treatment with dexamethasone and intravenous immunoglobulin.

Contribution of BCR-ABL kinase domain mutations to imatinib mesylate resistance in philadelphia chromosome positive malaysian chronic myeloid leukemia patients

Development of resistance to imatinib mesylate (IM) in chronic myeloid leukemia (CML) patients is mediated by different mechanisms that can be classified as BCR-ABL dependent or BCR-ABL independent pathways. BCR-ABL dependent mechanisms are most frequently associated with point mutations in tyrosine kinase domain (TKD) of BCR-ABL1 and also with BCR-ABL gene amplification. Many different types and frequencies of mutations have been reported in different studies, probably due to the different composition of study cohorts. Since no reports are available from Malaysia, this study was undertaken to investigate the frequency and pattern of BCR-ABL kinase domain mutations using dHPLC followed by sequencing, and also status of BCR-ABL gene amplification using fluorescence in situ hybridization (FISH) on 40 IM resistant Malaysian CML patients. Mutations were detected in 13 patients (32.5%). Five different types of mutations (T315I, E255K, Y253H, M351T, V289F) were identified in these patients. In the remaining 27 IM resistant CML patients, we investigated the contribution made by BCR-ABL gene amplification, but none of these patients showed amplification. It is presumed that the mechanisms of resistance in these 27 patients might be due to BCR-ABL independent pathways. Different mutations confer different levels of resistance and, therefore, detection and characterization of TKD mutations is highly important in order to guide therapy in CML patients.

Low Level of TERC Gene Amplification between Chronic Myeloid Leukaemia Patients Resistant and Respond to Imatinib Mesylate Treatment

The amplification of telomerase component (TERC) gene could play an important role in generation and treatment of haematological malignancies. This present study was aimed to investigate copy number amplification status of TERC gene in chronic myeloid leukaemia (CML) patients who were being treated with imatinib mesylate (IM). Genomic DNA was extracted from peripheral blood of CML-IM Resistant (n=63), CML-IM Respond (n=63) and healthy individuals (n=30). TERC gene copy number predicted (CNP) and copy number calculated (CNC) were determined based on Taqman® Copy Number Assay. Fluorescence in situ hybridization (FISH) analysis was performed to confirm the normal signal pattern in C4 (calibrator) for TERC gene. Nine of CML patients showed TERC gene amplification (CNP=3), others had 2 CNP. A total of 17 CML patients expressed CNC>2.31 and the rest had 2.31>CNC>1.5. TERC gene CNP value in healthy individuals was 2 and their CNC value showed in range 1.59-2.31. The average CNC TERC gene copy number was 2.07, 1.99 and 1.94 in CML- IM Resistant patients, CML-IM Respond and healthy groups, respectively. No significant difference of TERC gene amplification observed between CML-IM Resistant and CML-IM Respond patients. Low levels of TERC gene amplification might not have a huge impact in haematological disorders especially in terms of resistance towards IM treatment.

Retroperitoneal hemorrhage associated with bone marrow trephine biopsy

Patient: Male, 19 Final Diagnosis: Hyperleukocytosis • thrombocytosis Symptoms: Hyperleukocytosis • retroperitoneal hemorrhage • thrombocytosis Medication: — Clinical Procedure: Bone marrow trephine biopsy Specialty: Hematology • Radiology Objective: Diagnostic/therapeutic accidents Background: Bone marrow (BM) trephine biopsy is generally a safe procedure, but adverse events such as retroperitoneal hemorrhage (RPH) may occur. We report 3 cases of this complication. Case Report: A 19-year-old male with thrombocytopenia and coagulopathy underwent BM trephine biopsy to confirm relapse of acute lymphoblastic leukemia. Two hours later, he developed severe hypotension and a CT scan revealed a massive RPH, and was treated conservatively. The RPH recurred 2 weeks after chemotherapy and was successfully treated with gel foam embolization. A 55-year-old male with coagulopathy underwent BM trephine biopsy for hyperleukocytosis and thrombocytosis. He developed a large RPH preceded by left lumbar dermatome sensory neuropathy. He was treated conservatively. A 56-year-old overweight woman on aspirin underwent BM trephine biopsy for polycythemia. Twelve hours later she developed severe abdominal pain with hypotension. A CT scan showed a massive RPH and secondary hemothorax. She was treated conservatively and the RPH resolved after several months. Conclusions: We and others showed that myeloproliferative neoplasm, quantitative or qualitative platelet abnormalities, aspirin, coagulopathy, and obesity are associated with development of RPH following BM trephine biopsy. Early diagnosis and intervention are crucial. Correction of coagulopathy and cessation of anti-platelet treatment prior to biopsy can prevent this serious complication.PATIENT Male, 19 FINAL DIAGNOSIS: Hyperleukocytosis • thrombocytosis SYMPTOMS Hyperleukocytosis • retroperitoneal hemorrhage • thrombocytosis MEDICATION - Clinical Procedure: Bone marrow trephine biopsy Specialty: Hematology • Radiology. OBJECTIVE Diagnostic/therapeutic accidents. BACKGROUND Bone marrow (BM) trephine biopsy is generally a safe procedure, but adverse events such as retroperitoneal hemorrhage (RPH) may occur. We report 3 cases of this complication. CASE REPORT A 19-year-old male with thrombocytopenia and coagulopathy underwent BM trephine biopsy to confirm relapse of acute lymphoblastic leukemia. Two hours later, he developed severe hypotension and a CT scan revealed a massive RPH, and was treated conservatively. The RPH recurred 2 weeks after chemotherapy and was successfully treated with gel foam embolization. A 55-year-old male with coagulopathy underwent BM trephine biopsy for hyperleukocytosis and thrombocytosis. He developed a large RPH preceded by left lumbar dermatome sensory neuropathy. He was treated conservatively. A 56-year-old overweight woman on aspirin underwent BM trephine biopsy for polycythemia. Twelve hours later she developed severe abdominal pain with hypotension. A CT scan showed a massive RPH and secondary hemothorax. She was treated conservatively and the RPH resolved after several months. CONCLUSIONS We and others showed that myeloproliferative neoplasm, quantitative or qualitative platelet abnormalities, aspirin, coagulopathy, and obesity are associated with development of RPH following BM trephine biopsy. Early diagnosis and intervention are crucial. Correction of coagulopathy and cessation of anti-platelet treatment prior to biopsy can prevent this serious complication.

Consolidation radiotherapy for advanced-stage aggressive B-cell non-hodgkin lymphoma: A systematic review and meta-analysis

Patients with advanced aggressive B-cell non-Hodgkin lymphomas (NHL) are usually treated with rituximab in combination with chemotherapy. However, disease relapse rates are high. Radiotherapy (RT) has been shown to be efficacious in treating early-stage NHL but its role in advanced stage diseases is unclear. We performed a systematic review of randomized controlled trials (RCTs) comparing chemotherapy with RT to chemotherapy alone in patients with newly diagnosed advanced aggressive NHL. We searched online databases and pooled similar outcome estimates. For time-to-event outcomes, we estimated hazard ratios (HR) for overall survival (OS) and event-free survival (EFS) using the fixed-effect model. Two RCTs involving 254 patients met inclusion criteria. The trials were single-centre RCTs with follow-up period of five and ten years. Both trials were conducted in the pre-rituximab era. Patients treated with consolidation RT had better OS (HR for mortality 0.61; 95 % CI 0.38 to 0.97) and EFS (HR for mortality 0.67; 95 % CI 0.46 to 0.98) compared to those who received no RT. There was an apparent benefit of RT on local control (OR 0.09; 95 % CI 0.04 to 0.20); although this was estimated as a dichotomous rather than time-to-event outcome. Limited evidence shows benefits of consolidation RT in advanced aggressive NHL. However, we were not able to estimate the effect size with confidence due to small number of trials and sample size. We cannot recommend routine consolidation RT in advanced aggressive NHL. More RCTs with the inclusion of rituximab and PET-CT monitoring are needed.

Radiotherapy for advanced-stage aggressive non-Hodgkin lymphoma

This is the protocol for a review and there is no abstract. The objectives are as follows: To assess the benefits (overall survival, progression-free survival, event-free survival and quality of life) and harms (toxicities) of radiotherapy for people with advanced aggressive non-Hodgkin lymphoma (NHL).

Disseminated tuberculosis masquerading primary myelodysplastic syndrome

Tuberculosis is notoriously known to be a great mimicker of other diseases and may cause various haematologic abnormalities, especially with marrow involvement. A 61-year-old man who presented with right empyema and pancytopenia was diagnosed to have disseminated tuberculosis supported by the presence of caseating granuloma with Langhans giant cells in the marrow and demonstration of acid-fast bacilli in the pleural fluid. Trilineage dysplasia from marrow aspirate was initially attributed to be reactive to the infection. A cytogenetic study was repeated after he showed poor response to a year of anti-tuberculosis treatment. The underlying primary myelodysplastic syndrome was unmasked when his cytogenetics showed trisomy 8. This case report has demonstrated the various haematological manifestations of tuberculosis and highlighted the importance of cytogenetic study in differentiating between primary and secondary myelodysplastic marrow changes.