RÉSUMÉ
Patients with hematologic malignancies (HMs) are at a significantly higher risk of contracting COVID-19 and experiencing severe outcomes compared to individuals without HMs. This heightened risk is influenced by various factors, including the underlying malignancy, immunosuppressive treatments, and patient-related factors. Notably, immunosuppressive regimens commonly used for HM treatment can lead to the depletion of B cells and T cells, which is associated with increased COVID-19-related complications and mortality in these patients. As the pandemic transitions into an endemic state, it remains crucial to acknowledge and address the ongoing risk for individuals with HMs. In this review, we aim to summarize the current evidence to enhance our understanding of the impact of HMs on COVID-19 risks and outcomes, identify particularly vulnerable individuals, and emphasize the need for specialized clinical attention and management. Furthermore, the impaired immune response to COVID-19 vaccination observed in these patients underscores the importance of implementing additional mitigation strategies. This may include targeted prophylaxis and treatment with antivirals and monoclonal antibodies as indicated. To provide practical guidance and considerations, we present two illustrative cases to highlight the real-life challenges faced by physicians caring for patients with HMs, emphasizing the need for individualized management based on disease severity, type, and the unique circumstances of each patient.
Sujet(s)
COVID-19 , Tumeurs hématologiques , Humains , COVID-19/complications , COVID-19/immunologie , Tumeurs hématologiques/complications , Tumeurs hématologiques/thérapie , SARS-CoV-2/immunologie , Mâle , Antiviraux/usage thérapeutique , Immunosuppresseurs/usage thérapeutique , Immunosuppresseurs/effets indésirables , Adulte d'âge moyen , FemelleRÉSUMÉ
Myeloproliferative neoplasms (MPN) are a heterogeneous group of clonal hematopoietic stem cell disorders characterized clinically by the proliferation of one or more hematopoietic lineage(s). The classical Philadelphia-chromosome (Ph)-negative MPNs include polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF). The Asian Myeloid Working Group (AMWG) comprises representatives from fifteen Asian centers experienced in the management of MPN. This consensus from the AMWG aims to review the current evidence in the risk stratification and treatment of Ph-negative MPN, to identify management gaps for future improvement, and to offer pragmatic approaches for treatment commensurate with different levels of resources, drug availabilities and reimbursement policies in its constituent regions. The management of MPN should be patient-specific and based on accurate diagnostic and prognostic tools. In patients with PV, ET and early/prefibrotic PMF, symptoms and risk stratification will guide the need for early cytoreduction. In younger patients requiring cytoreduction and in those experiencing resistance or intolerance to hydroxyurea, recombinant interferon-α preparations (pegylated interferon-α 2A or ropeginterferon-α 2b) should be considered. In myelofibrosis, continuous risk assessment and symptom burden assessment are essential in guiding treatment selection. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) in MF should always be based on accurate risk stratification for disease-risk and post-HSCT outcome. Management of classical Ph-negative MPN entails accurate diagnosis, cytogenetic and molecular evaluation, risk stratification, and treatment strategies that are outcome-oriented (curative, disease modification, improvement of quality-of-life).
Sujet(s)
Syndromes myéloprolifératifs , Polyglobulie primitive essentielle , Thrombocytémie essentielle , Humains , Chromosome Philadelphie , Consensus , Syndromes myéloprolifératifs/diagnostic , Syndromes myéloprolifératifs/génétique , Syndromes myéloprolifératifs/thérapie , Polyglobulie primitive essentielle/diagnostic , Polyglobulie primitive essentielle/traitement médicamenteux , Polyglobulie primitive essentielle/génétique , Thrombocytémie essentielle/traitement médicamenteux , Thrombocytémie essentielle/génétique , Interféron alpha/génétique , Interféron alpha/usage thérapeutiqueRÉSUMÉ
BACKGROUND: This is a pilot proof-of-concept study to evaluate the utility of a custom 15-gene circulating tumor DNA (ctDNA) panel as a potential companion molecular next-generation sequencing (NGS) assay for identifying somatic single nucleotide variants and indels in non-small-cell lung cancer (NSCLC) patients. The custom panel covers the hotspot mutations in EGFR, KRAS, NRAS, BRAF, PIK3CA, ERBB2, MET, KIT, PDGFRA, ALK, ROS1, RET, NTRK1, NTRK2 and NTRK3 genes which serve as biomarkers for guiding treatment decisions in NSCLC patients. METHOD: The custom 15-gene ctDNA NGS panel was designed using ArcherDX Assay Designer. A total of 20 ng or 50 ng input ctDNA was used to construct the libraries. The analytical performance was evaluated using reference standards at different allellic frequencies (0.1%, 1%, 5% and parental). The clinical performance was evaluated using plasma samples collected from 10 treatment naïve advanced stage III or IV NSCLC patients who were tested for tissue EGFR mutations. The bioinformatics analysis was performed using the proprietary Archer Analysis Software. RESULTS: For the analytical validation, we achieved 100% sensitivity and specificity for the detection of known mutations in the reference standards. The limit of detection was 1% allelic frequency. Clinical validation showed that the clinical sensitivity and specificity of the assay for detecting EGFR mutation were 83.3% and 100% respectively. In addition, the NGS panel also detected other mutations of uncertain significance in 6 out of 10 patients. CONCLUSION: This preliminary analysis showed that the custom 15-gene ctDNA NGS panel demonstrated good analytical and clinical performances for the EGFR mutation. Further studies incorporating the validation of other candidate gene mutations are warranted.
Sujet(s)
Carcinome pulmonaire non à petites cellules , ADN tumoral circulant , Tumeurs du poumon , Humains , Carcinome pulmonaire non à petites cellules/anatomopathologie , ADN tumoral circulant/génétique , Protéines proto-oncogènes B-raf/génétique , Tumeurs du poumon/anatomopathologie , Protéines proto-oncogènes p21(ras)/génétique , Protéines proto-oncogènes/génétique , Séquençage nucléotidique à haut débit , Mutation , Phosphatidylinositol 3-kinases de classe I/génétique , Nucléotides , Marqueurs biologiques tumoraux/génétiqueRÉSUMÉ
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.
Sujet(s)
Syndromes myéloprolifératifs , Polyglobulie primitive essentielle , Séquençage nucléotidique à haut débit , Humains , Kinase Janus-2/génétique , Mutation , Syndromes myéloprolifératifs/diagnostic , Syndromes myéloprolifératifs/génétique , Polyglobulie primitive essentielle/diagnostic , Polyglobulie primitive essentielle/génétiqueRÉSUMÉ
Introduction: Individuals who are exposed to cytotoxic agents are at risk of developing therapyrelated myeloid neoplasms (t-MN). Cytogenetic findings of a neoplasm play an important role in stratifying patients into different risk groups and thus predict the response to treatment and overall survival. Case report: A 59-year-old man was diagnosed with acute promyelocytic leukaemia. Following this, he underwent all-trans retinoic acid (ATRA) based chemotherapy and achieved remission. Four years later, the disease relapsed and he was given idarubicin, mitoxantrone and ATRA followed by maintenance chemotherapy (ATRA, mercaptopurine and methotrexate). He achieved a second remission for the next 11 years. During a follow-up later, his full blood picture showed leucocytosis, anaemia and leucoerythroblastic picture. Bone marrow examination showed hypercellular marrow with trilineage dysplasia, 3% blasts but no abnormal promyelocyte. Fluorescence in-situ hybridisation (FISH) study of the PML/RARA gene was negative. Karyotyping result revealed complex abnormalities and monosomal karyotype (MK). A diagnosis of therapy-related myelodysplastic syndrome/myeloproliferative neoplasm with unfavourable karyotypes and MK was made. The disease progressed rapidly and transformed into therapy-related acute myeloid leukaemia in less than four months, complicated with severe pneumonia. Despite aggressive treatment with antibiotics and chemotherapy, the patient succumbed to the illness two weeks after the diagnosis. Discussion and Conclusion: Diagnosis of t-MN should be suspected in patients with a history of receiving cytotoxic agents. Karyotyping analysis is crucial for risk stratification as MK in addition to complex aberrant karyotypes predicts unfavourable outcome. Further studies are required to address the optimal management for patients with t-MN.
RÉSUMÉ
A rare case of double Philadelphia chromosome-positive B Acute lymphoblastic Leukaemia (B-ALL) is reported here. A 60-year-old lady presented with one month history of fever, submandibular lymphadenopathy, loss of appetite and weight loss. Physical examination revealed multiple palpable cervical lymph nodes. Blood film showed leucocytosis with 72% blasts. Bone marrow assessment confirmed a diagnosis of B-ALL with presence of double Philadelphia (Ph) chromosomes. As she was very ill, she was initially treated with an attenuated regimen of induction chemotherapy consisting of rituximab, cyclophosphamide, vincristine and prednisolone (R-CVP) along with intrathecal chemotherapy comprising methotrexate, cytarabine and hydrocortisone. Bone marrow examination post-induction chemotherapy showed >5% blasts. She was subsequently re-induced with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone (R-CHOP) along with intrathecal chemotherapy, following which she went into complete remission. Consolidation chemotherapy consisting of methotrexate, methylprednisolone, cytarabine, intrathecal chemotherapy and imatinib was subsequently administered followed by maintenance chemotherapy consisting of vincristine, prednisolone and imatinib (IDEAMOP). She developed spontaneous bruises and relapsed four months into her maintenance chemotherapy with 90% blasts in the bone marrow which was treated with fludarabine, cytarabine and granulocyte colony stimulating factor (FLAG). Unfortunately she developed neutropenic sepsis which was complicated by invasive lung aspergillosis. Bone marrow examination post-FLAG showed 80% blasts. Despite aggressive antifungal therapy, her lung infection worsened and she finally succumbed to her illness 13 months after the initial diagnosis. We highlight a rare case of elderly B-ALL with double Ph chromosomes which carries a poor prognosis despite aggressive treatment for the disease and its complications.
Sujet(s)
Chromosome Philadelphie , Leucémie-lymphome lymphoblastique à précurseurs B et T/génétique , Caryotype anormal , Protocoles de polychimiothérapie antinéoplasique/usage thérapeutique , Issue fatale , Femelle , Humains , Adulte d'âge moyen , Leucémie-lymphome lymphoblastique à précurseurs B et T/traitement médicamenteuxRÉSUMÉ
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.
Sujet(s)
Infections à cytomégalovirus/diagnostic , Infections à cytomégalovirus/thérapie , Lymphohistiocytose hémophagocytaire/diagnostic , Lymphohistiocytose hémophagocytaire/thérapie , Complications infectieuses de la grossesse/diagnostic , Complications infectieuses de la grossesse/thérapie , Adulte , Césarienne/méthodes , Association thérapeutique , Ciclosporine/administration et posologie , Infections à cytomégalovirus/complications , Dexaméthasone/administration et posologie , Évolution de la maladie , Multirésistance aux médicaments , Association de médicaments , Issue fatale , Femelle , Humains , Perfusions veineuses , Lymphohistiocytose hémophagocytaire/complications , Défaillance multiviscérale , Échange plasmatique/méthodes , Grossesse , Troisième trimestre de grossesse , Indice de gravité de la maladieRÉSUMÉ
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.