Inequality in Drug Utilization among Chronic Myeloid Leukaemia Patients in Malaysia: A Cost-Utility Analysis.

BACKGROUND: The burden of chronic myeloid leukaemia (CML) is increasing due to longer patient survival, better life expectancy of the general population, and increasing drug prices. Funding is one of the main concerns in the choice of CML medication used worldwide; thus, patient assistance programmes were introduced to ensure accessibility to affordable treatment. In this study, we evaluated CML drug distribution inequality in Malaysia through patient assistance programmes, using pharmaco-economics methods to evaluate CML treatment from the care provider's perspective. METHODS: Patients with CML were recruited from outpatient haematological clinics at the national centre of intervention and referral for haematological conditions and a public teaching hospital. The health-related quality of life or utility scores were derived using the EuroQol EQ-5D-5L questionnaire. Costing data were obtained from the Ministry of Health Malaysia Casemix MalaysianDRG. Imatinib and nilotinib drug costs were obtained from the administration of the participating hospitals and pharmaceutical company. RESULTS: Of the 221 respondents in this study, 68.8% were imatinib users. The total care provider cost for CML treatment was USD23,014.40 for imatinib and USD43,442.69 for nilotinib. The governmental financial assistance programme reduced the total care provider cost to USD13,693.51 for imatinib and USD19,193.45 for nilotinib. The quality-adjusted life years (QALYs) were 17.87 and 20.91 per imatinib and nilotinib user, respectively. Nilotinib had a higher drug cost than imatinib, yet its users had better life expectancy, utility score, and QALYs. Imatinib yielded the lowest cost per QALYs at USD766.29. CONCLUSION: Overall, imatinib is more cost-effective than nilotinib for treating CML in Malaysia from the care provider's perspective. The findings demonstrate the importance of cancer drug funding assistance for ensuring that the appropriate treatments are accessible and affordable and that patients with cancer use and benefit from such patient assistance programmes. To establish effective health expenditure, drug distribution inequality should be addressed.

Clinical Epidemiology, Treatment Outcome and Mortality Rate of Newly Diagnosed Immune Thrombocytopenia in Adult Multicentre Study in Malaysia.

Background: Immune thrombocytopenia (ITP) is well characterized in Western, European and other Asia-Pacific countries. Nevertheless, the clinical epidemiology, treatment pattern and disease outcome of ITP in Malaysia are still limited and not well known. Objective: This study aimed to describe the clinical epidemiology, treatment outcome and mortality of ITP patients in haematology tertiary multicentre in Malaysia. Methods: Clinical and laboratory data of newly diagnosed adults with ITP by a platelet count <100 × 109/L from January 2010 to December 2020 were identified and analyzed. Results: Out of 500 incident ITP, 71.8% were females with a striking age preponderance of both genders among those aged 18-29 years. The median age was 36 years. The median platelet count was 17.5 × 109/L, 23.0% had a secondary ITP, 34.6% had a Charlson's score ≥1, 53.0% had bleeding symptoms including 2.2% intracranial bleedings (ICB). Helicobacter pylori screening was performed in <5% of cases. Persistency and chronicity rates were 13.6% and 41.8%, respectively. Most (80.6%) were treated at diagnosis onset and 31.2% needed second-line treatment. Throughout the course of ITP, 11.0% of patients died; 3.0% and 8.0% with bleeding and non-bleeding related ITP. Conclusion: This study confirms the epidemiology of ITP is comparable with worldwide studies. Our incidence is high in the female, Malay ethnicity, primary ITP and events of cutaneous bleeding at ITP onset with 18-29 years predominance age group for both genders. The frequency of persistent and chronic ITP is inconsistent with published literature. Corticosteroids and immunotherapies are the most prescribed first-line and second-line pharmacological treatments. Thrombopoietin receptor agonist medications (TPO-RAs) usage is restricted and splenectomy is uncommon. Our mortality rate is similar but ITP related bleeding death is fourth-fold lower than previous studies. Mortality risks of our ITP patients include age ≥60 years, male, severe bleeding at presentation, CCI≥1 and secondary ITP.

Clinical Management of Thrombotic Antiphospholipid Syndrome.

Thrombotic manifestations of antiphospholipid syndrome are often a therapeutic dilemma and challenge. Despite our increasing knowledge of this relatively new disease, many issues remain widely unknown and controversial. In this review, we summarise the latest literature and guidelines on the management of thrombotic antiphospholipid syndrome. These include the laboratory assays involved in antiphospholipid antibodies (aPL) testing, the use of direct oral anticoagulants in secondary prevention, management of recurrent thrombosis, individuals with isolated aPL, and catastrophic antiphospholipid syndrome. Treatment aims to prevent the potentially fatal and often disabling complications of APS with antithrombotic and cardiovascular risks prevention strategies. Some insights and updates on topical issues in APS are provided. We also include our current practice, which we believe is the pragmatic approach based on the currently available evidence.

Analysis of genetic variants in myeloproliferative neoplasms using a 22-gene next-generation sequencing panel.

BACKGROUND: The Philadelphia (Ph)-negative myeloproliferative neoplasms (MPNs), namely essential thrombocythaemia (ET), polycythaemia vera (PV) and primary myelofibrosis (PMF), are a group of chronic clonal haematopoietic disorders that have the propensity to advance into bone marrow failure or acute myeloid leukaemia; often resulting in fatality. Although driver mutations have been identified in these MPNs, subtype-specific markers of the disease have yet to be discovered. Next-generation sequencing (NGS) technology can potentially improve the clinical management of MPNs by allowing for the simultaneous screening of many disease-associated genes. METHODS: The performance of a custom, in-house designed 22-gene NGS panel was technically validated using reference standards across two independent replicate runs. The panel was subsequently used to screen a total of 10 clinical MPN samples (ET n = 3, PV n = 3, PMF n = 4). The resulting NGS data was then analysed via a bioinformatics pipeline. RESULTS: The custom NGS panel had a detection limit of 1% variant allele frequency (VAF). A total of 20 unique variants with VAFs above 5% (4 of which were putatively novel variants with potential biological significance) and one pathogenic variant with a VAF of between 1 and 5% were identified across all of the clinical MPN samples. All single nucleotide variants with VAFs ≥ 15% were confirmed via Sanger sequencing. CONCLUSIONS: The high fidelity of the NGS analysis and the identification of known and novel variants in this study cohort support its potential clinical utility in the management of MPNs. However, further optimisation is needed to avoid false negatives in regions with low sequencing coverage, especially for the detection of driver mutations in MPL.

Rare but Potentially Fatal Presentations of Diffuse Large B-cell Lymphoma: Leukemic Phase or Hemophagocytic Syndrome in Bone Marrow.

Diffuse large B-cell lymphoma (DLBCL) is a type of non-Hodgkin Lymphoma commonly presenting as a solid tumor either by nodal or extra-nodal manifestations. Here we describe two atypical presentations of lymphoma, finally resulting in the diagnosis of DLBCL. Case 1: A 53-year-old man with a previous history of nasopharyngeal carcinoma presented with a two-week history of B-symptoms and hyperleukocytosis. Peripheral blood film showed 78% abnormal mononuclear cells. Immunohistochemical stain showing Ki-67 of 90%, negative c-myc, BCL2 and BCL6, and negative c-MYC with fluorescence in-situ hybridization studies on the trephine biopsy, concluded the diagnosis of CD5+ DLBCL of ABC subtype. He received intravenous cyclophosphamide and oral prednisolone for cytoreduction, followed by 6 cycles of chemo-immunotherapy. However, he succumbed due to severe sepsis after the completion of therapy. Case 2: A 56-year-old lady who was initially investigated for pyrexia of unknown origin was noted to have hemophagocytosis upon bone marrow aspirate examination. The bone marrow trephine biopsy revealed some atypical clusters of B-cells positive for CD20 which was inconclusive. PET-CT scan noted an enlarged hypermetabolic spleen without lymphadenopathy. Splenic biopsy with immunohistochemical studies revealed DLBCL of ABC subtype. The diagnosis was consistent with primary splenic DLBCL. She became unwell post splenic biopsy and was admitted to the intensive care unit where she passed away 2 weeks later from Candida and Sternotrophomonas septicemia. These cases highlight the atypical presentations of a common subtype of NHL in our center. Arriving at the definitive diagnosis can be difficult especially when patients are acutely ill, hampering the necessary invasive procedures for diagnosis. The outcomes of both cases are briefly discussed hoping to spread awareness among clinicians on the rare and acutely critical presentations of DLBCL.

Health-related quality of life using EQ-5D among chronic myeloid leukaemia patients in health centres in Klang Valley, Malaysia.

Chronic Myeloid Leukaemia (CML) responds well with the targeted therapy drugs, Tyrosine Kinase Inhibitors (TKI), that give potentially long-term disease control for the patients. The objective of this study was to determine the disease burden and factors influencing the health-related quality of life (HRQoL) and health status of CML patients in Klang Valley, Malaysia. CML patients were recruited from haematological outpatient clinics in health centres in Klang Valley, Malaysia. A semi-guided self-administered questionnaire was used. HRQoL was measured by EQ-5D utility value and health status was by visual analogue score (VAS). Logistic regression analysis was conducted to determine the factors influencing HRQoL and health status. A total of 221 respondents participated, where more than half were Malay (56.6%), male (53.4%), and an Imatinib user (68.8%). Majority were diagnosed at the chronic phase (89.5%). The mean age of diagnosis was 41 years old. Significant determinant associated with HRQoL was age of diagnosis. These factors had no significant effect on the HRQoL of these patients regardless of types of TKI used and initial phase of CML. The overall HRQoL of CML patients were comparable to, if not higher, than the general population. Any TKI that was good enough to eliminate disease symptoms and erase patient's worries, can possibly make CML patients have a better quality of life than typical cancer patients and even the general population.

Optic Nerve Infiltration in Systemic Metastatic Retinal Lymphoma (SMRL): Multimodal Imaging and Challenges in Diagnosis.

A 45-year-old man was diagnosed with diffuse large B-cell lymphoma stage IV which was confirmed by celiac lymph node biopsy. He subsequently completed six cycles of R-CHOP chemotherapy. Six months later, he presented with panuveitis OU with positive relative afferent pupillary defect OD. OCT revealed hyper-reflective lesions and irregularity of the retinal pigment epithelium OU. Fundus fluorescein angiogram shows hyper-auto fluorescence and granular changes on the retina. A month later, he developed swollen optic disc OD and hemorrhagic retinitis OU and treated as presumed CMV retinitis. Anti-TB was started after a positive Mantoux test. He finally consented for a vitreous biopsy which showed atypical lymphoid cells highly suggestive for vitreoretinal lymphoma and subsequently received intravitreal methotrexate OU.Conclusion: Optic nerve infiltration in systemic metastatic retinal lymphoma may have initial occult signs but with profound visual loss. Ocular infections like CMV retinitis and tuberculosis may mask and delay the diagnosis in immunocompromised patients.

Diffuse large B-cell lymphoma in Southeast Asian cohort: expression patterns of B-cell receptor (BCR) repertoire and its linkage with molecular subtypes and response to R-CHOP therapy.

AIMS: Heightened B-cell receptor (BCR) activity in diffuse large B-cell lymphoma (DLBCL) is well established, and a subset of patients with relapsed DLBCL can benefit from BCR-targeted therapies. Universal outreach of such emerging therapies mandates forming a global landscape of BCR molecular signalling in DLBCL, including Southeast Asia. METHODS: 79 patients with DLBCL (nodal, 59% and extranodal, 41%) treated with rituximab combined with cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) therapy were selected. Expression levels of BCR and linked signalling pathway molecules were inter-related with Lymph2Cx-based cell of origin (COO) types and overall survival (OS). RESULTS: Activated B-cell (ABC) type DLBCL constituted 49% (39/79) compared with germinal centre B-cell (GCB) type DLBCL (29/79; 37%) and revealed poor prognosis (p=0.013). In ABC-DLBCL, high BTK expression exerted poor response to R-CHOP, while OS in ABC-DLBCL with low BTK expression was similar to GCB-DLBCL subtype (p=0.004). High LYN expression coupled with a poor OS for ABC-DLBCL as well as GCB-DLBCL subtypes (p=0.001). Furthermore, high coexpression of BTK/LYN (BTK high/LYN high) showed poor OS (p=0.019), which linked with upregulation of several genes associated with BCR repertoire and nuclear factor-kappa B pathway (p<0.01). In multivariate analysis, high BTK and LYN expression retained prognostic significance against established clinical predictive factors such as age, International Prognostic Index and COO (p<0.05). CONCLUSIONS: Our data provide a clear association between high BCR activity in DLBCL and response to therapy in a distinct population. Molecular data provided here will pave the pathway for the provision of promising novel-targeted therapies to patients with DLBCL in Southeast Asia.

Pregnancy-related hemophagocytic lymphohistiocytosis associated with cytomegalovirus infection: A diagnostic and therapeutic challenge.

OBJECTIVE: Hemophagocytic lymphohistiocytosis (HLH) is a disorder characterized by uncontrolled mature histiocyte proliferation, hemophagocytosis, and hypercytokinemia. We describe a previously healthy pregnant patient who presented in the third trimester of pregnancy with HLH. CASE REPORT: A 35-year-old woman presented at 38 weeks' gestation with pyrexia, jaundice, severe anemia, elevated liver enzymes, and lactate dehydrogenase suggestive of HELLP (hemolysis, elevated liver enzyme, low platelet) syndrome. Unfortunately, her condition deteriorated and she was ventilated in the intensive care unit despite delivery of the baby and administration of dexamethasone. She developed microangiopathic hemolytic anemia, thrombocytopenia, and renal impairment suggestive of thrombotic thrombocytopenic purpura/hemolytic uremic syndrome. However, she was refractory to plasma exchange, intravenous immunoglobulin, and broad-spectrum antibiotics. HLH was eventually diagnosed from biochemical and bone marrow findings. An extensive search for possible causes yielded negative results. She improved significantly with intravenous dexamethasone and cyclosporine A and was transferred out of the intensive care unit. Unfortunately, she developed cytomegalovirus disease 2 weeks later, which improved transiently with intravenous ganciclovir; later, however, she succumbed to multidrug-resistant nosocomial infections, rapidly progressive cytomegalovirus disease, and multiorgan failure. CONCLUSION: This case highlights the challenges and difficulties involved in the diagnosis and management of pregnancy-related HLH. Immunosuppressive treatment for HLH can precipitate life-threatening opportunistic infections, which need to be promptly diagnosed and treated.

α-thalassemia-associated hydrops fetalis: A rare cause of thyrotoxic cardiomyopathy.

α°-thalassemia is a well-known cause of hydrops fetalis in South-East Asia and can be detected in utero. We report a very rare case of thyrotoxic cardiomyopathy associated with hyperplacentosis secondary to α°-thalassemia-associated hydrops fetalis. A 22-year-old primigravida with microcytic anemia presented at 27 weeks' gestation with pre-eclampsia, hyperthyroidism and cardiac failure. Serum ß-human chorionic gonadotrophin was markedly elevated and abdominal ultrasound revealed severe hydropic features and enlarged placenta. Serum ß-human chorionic gonadotrophin, cardiac function and thyroid function tests normalized after she delivered a macerated stillbirth. Histopathology of the placenta showed hyperplacentosis. Blood DNA analysis revealed that both patient and husband have the α°-thalassemia trait. This case illustrates a very atypical presentation of α°-thalassemia-associated hydrops fetalis and the importance of early prenatal diagnosis of α-thalassemia in women of relevant ethnic origin with microcytic anemia so that appropriate genetic counseling can be provided to reduce maternal morbidity and the incidence of hydrops fetalis.

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 Langhan's 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.

Effects of preeclampsia on the yield of hematopoietic stem cells obtained from umbilical cord blood at delivery.

AIM: To compare the numbers of cord blood CD34(+) hematopoietic stem cells (HSC) between preeclampsia (PE) and control (non-PE) subjects and to determine the factors that may influence this observation. METHODS: Umbilical cord blood was collected from 28 PE and 19 non-PE subjects. Nucleated and CD34(+) cell counts were derived using the Trucount tube-based stem cell enumeration kit on BD FACSCalibur. RESULTS: The cord blood volume, nucleated and CD34(+) cell counts were significantly reduced in PE subjects compared to non-PE subjects. Among the PE subjects, systolic and diastolic blood pressure demonstrated a negative correlation with total nucleated and CD34(+) cell counts. Gestational age at delivery influenced cord blood volume and nucleated cell counts, but not CD34(+) cell counts. Birth weight and placental weight correlated strongly with cord blood volume, and nucleated and CD34(+) cell counts. There were no correlations observed between cord blood parameters and maternal age, maternal white cell count, gravidity, route of delivery or neonatal gender among PE subjects. CONCLUSION: Preeclampsia has a negative impact on the yield of HSC obtained from cord blood at delivery. Maternal blood pressure, neonatal birth weight and placental weight are important factors influencing the numbers of cord blood HSC. These findings should be taken into consideration when selecting cord blood units from mothers with PE for banking. Selecting the heaviest term neonate might improve the yield of cord blood HSC obtained from PE mothers.