Effectiveness of Ropeginterferon Alfa-2B in High-Risk Patients with Philadelphia Chromosome Negative Myeloproliferative Neoplasms- Evaluation of Clinicohaematologic Response, and Safety Profile: Single Centre Experience.

Background: Treatment of Philadelphia chromosome negative myeloproliferative neoplasms (Ph - MPNs) requires individualized approach depending on multiple factors. Novel pegylated Interferon (IFN) formulations have become an attractive therapeutic option in young Ph- MPN patients associated with better patient compliance. Methods: In this retrospective observational study a total of 16 high-risk Ph- MPN patients treated off-label with ropeginterferon alfa-2b given twice monthly, were included. Median follow-up was 24 months. High-risk patients were defined using the IPSET score. Response to treatment was evaluated using ELN, IWG-MET EUMNET standardized criteria and occurrence of side effects was documented. Results: 11 patients were female (68.8%) and 5 male (31.2%); average age at diagnosis was 36 years (17-51); 12 patients (75%) had ET, one (6.2%) PV and three (18.8%) hypercellular phase of PMF. JAK2V617F mutation was detected in 10 patients (62.5%), CALR in three (18.8%), and three (18.7%) were triple-negative cases. In 7 patients (43.7%), ropeginterferon alfa-2b was used in first-line, and 9 (56.3%) were previously treated with HU and/or standard IFN. Among initially ropeginterferon alfa-2b treated patients, complete haematological response was observed in 4/7 (57.1%), partial in 2/7 (28.6%) and suboptimal in one (14.3%). Complete haematological response was observed in 8/9 (88.9%) among previously treated patients. Average time to blood count normalization was 8 weeks, at a dose ranging between 100mcg and 300mcg. Side effects were observed in one patient (6.2%). Conclusion: Our experience is in support of previous studies regarding ropeginterferon alfa-2b efficacy and safety profile in the treatment of young patients with Ph- MPNs.

Early-Onset Colorectal Cancer in a Young Woman with Type 1 Gaucher Disease.

Introduction: Gaucher disease (GD) is a rare inherited lysosomal storage disease characterized by multi-system impairment. One of its main features is the over-expressed chronic stimulation and activation of the immune system, which may play a crucial role in the development of some malignancies associated with GD. Case description: We describe a young woman diagnosed with GD type 1 in early adulthood who developed early-onset colorectal cancer shortly after GD diagnosis and the initiation of enzyme replacement therapy. She underwent radical surgical resection of the colon and adjuvant chemotherapy due to metastatic disease in the liver. She failed first-line therapy with capecitabine and is currently being treated with irinotecan plus the monoclonal antibody cetuximab. Discussion: Although there is no evidence of an association between GD and colorectal cancer, this presentation in a young woman without a family history or risk factors may indicate a link. During anticancer treatment, only grade 3 anaemia was documented and no other haematological toxicities were observed. Enzyme replacement therapy at the recommended dose is regularly administered at scheduled intervals. The dosage may be increased in future if necessary to alleviate profound cytopenia. Conclusion: Anticancer treatment in patients with GD can be challenging due to the accompanying cytopenia. Optimal treatment of these patients with cancer requires greater understanding of the pathophysiology of GD and its impact on haematopoiesis. LEARNING POINTS: There may be a correlation between the hyperinflammatory background of untreated Gaucher disease and the development of neoplasia.Gaucher disease has rarely been described in association with colorectal cancer.Gaucher disease can be further worsened by chemotherapeutic agents.

Gaucher disease in North Macedonia: Unexpected prevalence of the N370S GBA1 allele with attenuated disease expression.

The majority of Gaucher Disease (GD) cases result from pathologic mutations in the GBA1 gene. A rich mutational spectrum of about 500 identified variants has been recognized. The disease is characterized by phenotypic diversity. Data regarding the genotype-phenotype correlation are scanty and inconclusive. Here, we summarize the genetic and phenotypic "portraits" of 14 patients with GD type 1 in the Republic of North Macedonia, 4 of Macedonian and 10 of Albanian origin. Altogether, 6 variants were detected, compounding 6 different genotypes. All genotypes contained the N370S variant, which was detected with an overall prevalence of 60.7%. Other frequent variants included the 1263del55 deletion and the double mutant allele D409H;H255Q, each with a prevalence of 14.2%. We detected two rare mutations: W92* - a pathogenic nonsense mutation and D399N - a single nucleotide variant of uncertain pathogenicity. The most common genotypes were N370S/1263del55 and H255Q;D409H/N370S, both present in 4/14 patients, followed by N370S homozygosity (3/14). Splenomegaly was the most common clinical manifestation, identified in all patients. Hepatomegaly was less frequent and was present in 50% of cases. Thrombocytopenia was present in 9/14, while half of the patients had anemia. Bone pathology was demonstrated in 8 patients. Patients with different genotypes displayed a high degree of phenotypic heterogeneity, suggesting that the other allele determines the onset and severity of the disease in patients with the N370S mutation. Longer follow-up, bigger cohorts of patients and multicentric studies should be conducted to further define the association between the genotypic and phenotypic expression in GD.

Insight in the Current Progress in the Largest Clinical Trials for Covid-19 Drug Management (As of January 2021).

The outbreak of the COVID-19 pandemic has generated the largest global health crisis of the 21st century, evolving into accelerating socioeconomic disruption. In spite of all rapidly and widely emerging scientific data on epidemiology, diagnosis, prevention and treatment of the COVID-19 disease, severe acute respiratory coronavirus 2 (SARS-CoV-2) is continuing to propagate in lack of definitive and specific therapeutic agents. Current therapeutic strategies are mainly focused on viral inhibition by antiviral drugs and hampering the exuberant immune response of the host by immunomodulatory drugs. In this review, we have studied the reports of the largest clinical trials intended to COVID-19 treatment published during the first year of the pandemics. In general, these results concentrate on seven therapeutic options: remdesivir, chloroguine/hydroxychloroquine, lopinavir-ritonavir combination, corticosteroids, tocilizumab, convalescent plasma and monoclonal antibodies. In line with the reviewed data, as of January 2021, most of the evidence support the use of remdesivir in hospitalized patients with moderate and severe forms of the disease and provide reliable data on the substantial beneficial effect of corticosteroids in patients requiring supplemental oxygen. Moreover, preliminary RECOVERY trial results have demonstrated the efficacy of tociluzumab in the treatment of critically ill patients. The reports presenting the outcomes of the other immune-based therapies under investigation are enthusiastically awaited.

The use of remdesivir outside of clinical trials during the COVID-19 pandemic.

With a scientific background from filoviruses, paramyxoviruses, SARS-CoV, and MERS-CoV, remdesivir entered into the COVID-19 battle to become one of the favorable therapeutic candidates with potential antiviral activity in the treatment of this disease. Globally, remdesivir was accessed and investigated through clinical research (clinical trials) and clinical practice (compassionate use, expanded access, early access scheme, and emergency use). Currently, remdesivir approval status differs between states. This paper aims to review and analyze regulatory approaches for accessing and investigating remdesivir, by communicating regulatory variability between countries in terms of terminology, modalities, and protocols.

Molecular Monitoring in Acute Myeloid Leukemia Patients Undergoing Matched Unrelated Donor - Hematopoietic Stem Cell Transplantation: Single Center Experience.

INTRODUCTION: Minimal residual disease (MRD) assessment in acute myeloid leukemia (AML) cases is a complex, multi-modality process and, though much of its clinical implications at different points are extensively studied, it remains even now a challenging area. It is a disease the biology of which governs the modality of MRD assessment; in patients harboring specific molecular targets, high sensitivity techniques can be applied. On the other hand, relapse is considered as the leading cause of treatment failure in AML patients undergoing allogeneic hematopoietic stem cell transplantation (alloHSCT). MATERIALS AND METHODS: Since November 2018 until June 2020, 10 AML patients underwent matched unrelated donor (MUD) HSCT at the University Clinic of Hematology-Skopje, Republic of North Macedonia. Molecular markers were identified in a total of 4 patients; 3 patients expressed chimeric fusion transcripts; two RUNX-RUNX1T1 and one for CBFB-MYH11. One patient harbored mutation in the transcription factor CCAAT/enhancer binding protein α (CEBPA). Post-transplant MRD kinetics was evaluated by using quantitative polymerase chain reaction (RT-qPCR) or multiplex fluorescent-PCR every three months during the first two years after the transplantation. RESULTS: MRD negativity was achieved in three pre-transplant MRD positive patients by the sixth month of HSCT. They sustained hematological and molecular remission for 19, 9 and 7 months, respectively. The fourth patient died due to transplant-related complications. CONCLUSION: According to our experience, when molecularly-defined AML patients undergo HSCT, regular MRD monitoring helps predict impending relapse and direct future treatment strategies.