Objectives: The complement component 5 (C5) inhibitor ravulizumab demonstrated non-inferiority to eculizumab following 26 weeks of treatment in complement inhibitor-naïve and complement inhibitor-experienced patients with paroxysmal nocturnal hemoglobinuria (PNH; studies 301 and 302, respectively). This study aims to describe the results of both studies from 27 weeks to 2 years.Methods: Patients (N = 441) continued to receive ravulizumab throughout the extension period. Efficacy endpoints included lactate dehydrogenase (LDH) normalization, transfusion avoidance and fatigue score (FACIT-F). Safety analyses were also performed.Results: From 27 weeks to 2 years, improvements in LDH levels were maintained in both study populations. Transfusion avoidance was maintained in 81.9% (study 301) and 85.6% (study 302) of patients, and FACIT-F scores remained stable. Ravulizumab was well tolerated, and the incidence of adverse events (AEs) were similar between patients of both studies. Incidence of serious AEs deemed related to ravulizumab treatment was low (<3%).Conclusions: This study reports, to date, the longest period of follow-up in over 400 patients with PNH treated with ravulizumab (662 patient-years). Long-term, ravulizumab demonstrated durable efficacy and was well tolerated, highlighting the importance of C5 inhibitors as the mainstay of PNH treatment.
MYH9-related disorders (MYH9-RDs) caused by mutation of the MYH9 gene which encodes non-muscle myosin heavy-chain-IIA (NMMHC-IIA), an important motor protein in hemopoietic cells, are the most commonly encountered cause of inherited macrothrombocytopenia. Despite distinguishing features including an autosomal dominant mode of inheritance, giant platelets on the peripheral blood film accompanied by leucocytes with cytoplasmic inclusion bodies (döhle-like bodies), these disorders remain generally under-recognized and often misdiagnosed as immune thrombocytopenia (ITP). This may result in inappropriate treatment with corticosteroids, immunosupressants and in some cases, splenectomy. We explored the efficacy of next generation sequencing (NGS) with a candidate gene panel to establish the aetiology of thrombocytopenia for individuals who had been referred to our center from hematologists in the Australasian region in whom the cause of thrombocytopenia was suspected to be secondary to an inherited condition but which remained uncharacterized despite phenotypic investigations. Pathogenic MYH9 variants were detected in 15 (15/121, 12.4%) individuals and the pathogenecity of a novel variant of uncertain significance was confirmed in a further two related individuals following immunofluorescence (IF) staining performed in our laboratory. Concerningly, only one (1/17) individual diagnosed with MYH9-RD had been referred with this as a presumptive diagnosis, in all other cases (16/17, 94.1%), a diagnosis was not suspected by referring clinicians, indicating a lack of awareness or a failing of our diagnostic approach to these conditions. We examined the mean platelet diameter (MPD) measurements as a means to better identify and quantify platelet size. MPDs in cases with MYH9-RDs were significantly larger than controls (p < 0.001) and in 91% were greater than a previously suggested threshold for platelets in cases of ITP. In addition, we undertook IF staining in a proportion of cases and confirm that this test and/or NGS are satisfactory diagnostic tests. We propose that fewer cases of MYH9-RDs would be missed if diagnostic algorithms prioritized IF and/or NGS in cases of thrombocytopenia associated with giant platelets, even if döhle-like bodies are not appreciated on the peripheral blood film. Finally, our report describes the long-term use of a thrombopoietin agonist in a case of MYH9-RD that had previously been diagnosed as ITP, and demonstrates that treatment with these agents may be possible, and is well tolerated, in this group of patients.
BackgroundThe evolution of molecular studies in myeloproliferative neoplasms (MPN) has enlightened us the understanding of this complex disease consisting of polycythaemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF). The epidemiology is well described in the western world but not in Asian countries like Malaysia.Materials and methodsThis retrospective national registry of MPN was conducted from year 2009 to 2015 in Malaysia.ResultsA total of 1010 patients were registered over a period of 5 years. The mean age was 54 years with male predominance. The ethnic distribution revealed that Chinese had a relatively high weighted incidence proportion (43.2%), followed by Indian (23.8%), Malay (15.8%) and other ethnic groups (17.2%). The types of MPN reported were 40.4% of ET (n = 408), 38.1% of PV (n = 385), 9.2% of PMF (n = 93), 3.1% of hypereosinophilic syndrome (HES) (n = 31) and 7.9% of unclassifiable MPN (MPN-U) (n = 80). Splenomegaly was only palpable clinically in 32.2% of patients. The positive JAK2 V617F mutation was present in 644 patients with 46.6% in PV, 36.0% in ET, 9.0% in PMF, and 7.4% in MPN-U, and had significantly lower haemoglobin (p < 0.001), haematocrit (p < 0.001) and white blood cells (WBC) (p < 0.001) than those with negative mutation. Significant differences in platelet and WBC count were detected in ethnic groups and MPN sub-types. There were more arterial thrombosis events seen in those with JAK2 V617F mutation as compared to venous thrombosis events (23.1% vs 4.4%). The bleeding rate was only 6.6%. Among the risk factors, previous thrombosis, old age (≥ 60 years) and hypertension were significantly correlated to positive JAK2 V617F mutation. The arterial thrombosis event is associated with higher presenting HB, HCT and PLT while the bleeding event is associated with lower presenting HB, HCT but higher PLT. The presence of JAK2 V617F mutation is associated with higher risk of arterial thrombosis.ConclusionChinese ethnicity is associated with higher rates of MPN. The history of thrombosis, age ≥ 60 years and hypertension are risk factors that can be correlated to JAK2 V617F mutation. This study is instrumental for policy makers to ensure preventive strategies can be implemented in future.
Coronavirus disease (COVID-19) has a wide spectrum of clinical manifestations. In this case report, we describe our first case of COVID-19 pneumonia that was complicated by cerebral venous thrombosis and bleeding in a patient with polycythemia vera. Madam A, a 72-year-old lady with polycythemia vera, ischemic stroke, hemorrhoids, diabetes mellitus, hypertension, and dyslipidemia was admitted to the hospital for COVID-19 pneumonia. She was treated with hydroxychloroquine and lopinavir/ ritonavir as per hospital protocol. She continued taking hydroxyurea and aspirin for her treatment of polycythemia vera. Subsequently, she developed rectal bleeding when her platelet count was 1247 × 10 3 /μl, even though she was not on an anticoagulant. Her aspirin was withheld. One week later, she was readmitted to the hospital for cerebral venous thrombosis and her D-dimer was 2.02 μg/ml. She was commenced on a therapeutic dose of low molecular weight heparin. Following that, her D-dimer level showed a decreasing trend and normalized upon her discharge. Patients with polycythemia vera are prone to develop thrombotic and bleeding complications. Management of this group of patients has become more complex with COVID-19 infection. It is crucial for us to decide when to start an anticoagulant especially when there is a history of recent bleeding. We need to balance the risks of further bleeding versus potentially fatal thrombotic events. Studies have shown that D-dimer can be used as a clinical marker to predict thrombotic events in COVID-19 infection. Patients with COVID-19 infection and polycythemia vera will benefit from both pharmacological thromboprophylaxis and close monitoring for bleeding.
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