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INTRODUCTION: Acute promyelocytic leukemia (APL) is a distinct form of acute myeloid leukemia characterized by the presence of t(15;17)(q24;21) and the PML:RARA gene fusion. Frontline use of intravenous arsenic trioxide (i.v.-ATO) and all-trans retinoic acid (ATRA) has vastly improved cure rates in APL. Researchers in Hong Kong invented the oral formulation of ATO (oral-ATO) and have confirmed a bioavailability comparable to i.v.-ATO. A plethora of studies have confirmed the safety and efficacy of oral-ATO-based regimens in the frontline and relapsed setting. AREAS COVERED: Aspects on the development of oral-ATO-based regimens for APL in the frontline and relapsed setting are discussed. The short-term and long-term safety and efficacy of oral-ATO-based regimens are discussed. The frontline use of oral-ATO in combination with ATRA and ascorbic acid (AAA) induction in a 'chemotherapy-free' is highlighted. EXPERT OPINION: Current and ongoing data on the use of oral-ATO-based regimens in APL support the use of oral-ATO as an alternative to i.v.-ATO allowing a more convenient and economical approach to the management of APL.
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Primary myelofibrosis (PMF) is the most aggressive of the myeloproliferative neoplasms and patients require greater attention and likely require earlier therapeutic intervention. Currently approved treatment options are limited in their selective suppression of clonal proliferation resulting from driver- and coexisting gene mutations. Janus kinase inhibitors are approved for symptomatic patients with higher-risk PMF. Additionally, most ongoing clinical studies focus on patients with higher-risk disease and/or high rates of transfusion dependency. Optimal treatment of early/lower-risk PMF remains to be identified and needs randomized clinical trial evaluations. Pegylated interferon alfa is recommended for symptomatic lower-risk PMF patients based on phase 2 non-randomized studies and expert opinion. Ropeginterferon alfa-2b (ropeg) is a new-generation pegylated interferon-based therapy with favorable pharmacokinetics and safety profiles, requiring less frequent injections than prior formulations. This randomized, double-blind, placebo-controlled phase 3 trial will assess its efficacy and safety in patients with "early/lower-risk PMF", defined as pre-fibrotic PMF or PMF at low or intermediate-1 risk according to Dynamic International Prognostic Scoring System-plus. Co-primary endpoints include clinically relevant complete hematologic response and symptom endpoint. Secondary endpoints include progression- or event-free survival, molecular response in driver or relevant coexisting gene mutations, bone marrow response, and safety. Disease progression and events are defined based on the International Working Group criteria and well-published reports. 150 eligible patients will be randomized in a 2:1 ratio to receive either ropeg or placebo. Blinded sample size re-estimation is designed. Ropeg will be administered subcutaneously with a tolerable, higher starting-dose regimen. The study will provide important data for the treatment of early/lower-risk PMF for which an anti-clonal, disease-modifying agent is highly needed.
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Defining mechanisms of resistance to hypomethylating agents (HMAs) and biomarkers predictive of treatment response remains challenging in myelodysplastic neoplasm (MDS). Currently available prognostic tools that predict overall survival and transformation to acute myeloid leukaemia have not been powered to predict responses to HMAs. Noguera-Castells et al. comprehensively characterized the epigenomic profile in patients with MDS treated with azacitidine and described a methylation signature-based prognostic tool in predicting responses to azacitidine. Commentary on: Noguera-Castells et al. DNA methylation profiling of myelodysplastic syndromes and clinical response to azacitidine: a multicentre retrospective study. Br J Haematol 2024;204:1838-1843.
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Azacitidina , Metilación de ADN , Síndromes Mielodisplásicos , Humanos , Síndromes Mielodisplásicos/genética , Síndromes Mielodisplásicos/tratamiento farmacológico , Pronóstico , Azacitidina/uso terapéutico , Azacitidina/farmacología , Epigenómica/métodos , Epigénesis Genética , Antimetabolitos Antineoplásicos/uso terapéutico , Antimetabolitos Antineoplásicos/farmacología , Biomarcadores de Tumor/genéticaRESUMEN
Developmental and epileptic encephalopathies (DEEs) are a heterogenous group of epilepsies in which altered brain development leads to developmental delay and seizures, with the epileptic activity further negatively impacting neurodevelopment. Identifying the underlying cause of DEEs is essential for progress toward precision therapies. Here we describe a group of individuals with biallelic variants in DENND5A and determine that variant type is correlated with disease severity. We demonstrate that DENND5A interacts with MUPP1 and PALS1, components of the Crumbs apical polarity complex, which is required for both neural progenitor cell identity and the ability of these stem cells to divide symmetrically. Induced pluripotent stem cells lacking DENND5A fail to undergo symmetric cell division during neural induction and have an inherent propensity to differentiate into neurons, and transgenic DENND5A mice, with phenotypes like the human syndrome, have an increased number of neurons in the adult subventricular zone. Disruption of symmetric cell division following loss of DENND5A results from misalignment of the mitotic spindle in apical neural progenitors. A subset of DENND5A is localized to centrosomes, which define the spindle poles during mitosis. Cells lacking DENND5A orient away from the proliferative apical domain surrounding the ventricles, biasing daughter cells towards a more fate-committed state and ultimately shortening the period of neurogenesis. This study provides a mechanism behind DENND5A-related DEE that may be generalizable to other developmental conditions and provides variant-specific clinical information for physicians and families.
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Myeloproliferative neoplasms (MPNs) are characterized by clonal myeloproliferation in 1 or more of the hematopoietic stem cell lineages. Primary myelofibrosis (MF), post-polycythemia vera MF, and post-essential thrombocythemia MF have the worst prognosis and are characterized by the presence of cytokine-mediated symptom complex, splenomegaly, progressive marrow failure, and clonal instability, leading to leukemic transformation. The key therapeutic aims encompass the management of symptoms, splenomegaly, and anemia and the improvement of survivals. These therapeutic aims have evolved with the availability of Jak inhibitors and novel agents, making disease modification potentially achievable. Novel agents may potentially target MPN stem cells, epigenetic alterations, signaling pathways, and apoptotic pathways. In this case-based review, we outline our approach to the management of MF and discuss the therapeutic landscape of MF, highlighting the utility of Jak inhibitors and novel Jak inhibitor-based combinations.
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Inhibidores de las Cinasas Janus , Trastornos Mieloproliferativos , Mielofibrosis Primaria , Trombocitemia Esencial , Humanos , Mielofibrosis Primaria/diagnóstico , Esplenomegalia/tratamiento farmacológico , Inhibidores de las Cinasas Janus/uso terapéutico , Trombocitemia Esencial/tratamiento farmacológico , Trastornos Mieloproliferativos/terapiaRESUMEN
INTRODUCTION: Myeloproliferative neoplasm (MPN) is a heterogeneous group of hematopoietic stem cell disorders characterized by clonal proliferation of one of more of the hematopoietic stem cell lineages. Clinical manifestations result from uncontrolled myeloproliferation, extramedullary hematopoiesis with splenomegaly and excessive inflammatory cytokine production. Currently available therapy improves hematologic parameters and symptoms but does not adequately address the underlying neoplastic biology. Bomedemstat has thus far demonstrated clinical efficacy and tolerability in the treatment of MPNs with recent evidence of impacting the malignant stem cell population. AREAS COVERED: This review summarizes the mechanisms of action, pharmacokinetics and pharmacodynamics, safety and efficacy of bomedemstat in MPN with specific emphasis on essential thrombocythemia (ET) and myelofibrosis (MF). EXPERT OPINION: In patients with MPNs, bomedemstat appears effective and well tolerated. The signs and symptoms of these diseases are managed as a reduction in the frequency of mutant cells was demonstrated in patients with ET and MF. Ongoing and planned studies of bomedemstat in MPN will establish the position of bomedemstat in MPNs and may help to redefine treatment endpoints of MPNs in the future.
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Trastornos Mieloproliferativos , Neoplasias , Mielofibrosis Primaria , Trombocitemia Esencial , Humanos , Trastornos Mieloproliferativos/tratamiento farmacológico , Trastornos Mieloproliferativos/epidemiología , Trastornos Mieloproliferativos/patología , Mielofibrosis Primaria/tratamiento farmacológico , Trombocitemia Esencial/tratamiento farmacológico , Trombocitemia Esencial/patología , Inhibidores EnzimáticosRESUMEN
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).
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Trastornos Mieloproliferativos , Policitemia Vera , Trombocitemia Esencial , Humanos , Cromosoma Filadelfia , Consenso , Trastornos Mieloproliferativos/diagnóstico , Trastornos Mieloproliferativos/genética , Trastornos Mieloproliferativos/terapia , Policitemia Vera/diagnóstico , Policitemia Vera/tratamiento farmacológico , Policitemia Vera/genética , Trombocitemia Esencial/tratamiento farmacológico , Trombocitemia Esencial/genética , Interferón-alfa/genética , Interferón-alfa/uso terapéuticoRESUMEN
This Viewpoint describes specific issues related to severe mental illnesses for palliative care.
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Trastornos Mentales , Psiquiatría , Humanos , Cuidados PaliativosRESUMEN
Relapse after allogeneic haematopoietic stem cell transplantation (HSCT) is one of the key determinants of outcome in myelofibrosis (MF) and remains an important unmet need. In this retrospective single-centre study, we evaluated 35 consecutive patients with MF receiving allogeneic HSCT. At 30 days post-HSCT, full donor chimerism was achieved in 31 patients (88.6%). The median time to neutrophil engraftment was 16.8 (10-42) days and the median time to platelet engraftment was 26 (12-245) days. Four patients (11.4%) experienced primary graft failure. With a median duration of follow-up of 33 (1-223) months, with the 5-year overall survival (OS) and progression-free survival (PFS) were 51.6% and 46.3%, respectively. Relapse after HSCT (P < 0.001), leucocyte count ≥ 18 × 109/L at HSCT (P = 0.003) and accelerated/blast phase disease at HSCT (P < 0.001) were significantly associated with worse OS. Age at HSCT ≥ 54 years (P = 0.01), mutated ETV6 (P = 0.03), leucocyte count ≥ 18 × 109/L (P = 0.02), accelerated/blast phase MF (P = 0.001), and grade 2-3 bone marrow reticulin fibrosis at 12 months post-HSCT (P = 0.002) were significantly associated with worse PFS. JAK2V617F MRD ≥ 0.047 [sensitivity 85.7%; positive predictive value (PPV) 100%; AUC 0.984; P = 0.001] at 6 months and JAK2V617F MRD ≥ 0.009 (sensitivity 100%; PPV 100%; AUC 1.0; P = 0.001) at 12 months were highly predictive of post-HSCT relapse. Inferior OS and PFS were significantly associated with detectable JAK2V617F MRD at 12 months (P = 0.003 and P = 0.0001, respectively).
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Trasplante de Células Madre Hematopoyéticas , Mielofibrosis Primaria , Humanos , Persona de Mediana Edad , Pronóstico , Mielofibrosis Primaria/diagnóstico , Mielofibrosis Primaria/genética , Mielofibrosis Primaria/terapia , Crisis Blástica , Estudios Retrospectivos , Trasplante Homólogo , Recurrencia Local de Neoplasia , Enfermedad Crónica , Neoplasia Residual , Reacción en Cadena de la PolimerasaRESUMEN
BACKGROUND: The epidemiology and treatment of acute promyelocytic leukaemia (APL) are changing. We have incorporated oral arsenic trioxide (oral-ATO) into induction/maintenance. METHODS: Newly-diagnosed APL from 1991 to 2021 divided into three 10-year periods were studied to define its epidemiology and how oral-ATO impacted on its outcome. Primary endpoints included APL incidence, early deaths (ED, first 30 days), and overall survival (OS). Secondary endpoints included post-30-day OS, relapse-free survival (RFS), and incidence of second cancers. RESULTS: APL occurred in 374 males and 387 females at a median age of 44 (1-97) years. Annual incidences increased progressively, averaging 0.32 per 100,000 people. All-trans retinoic acid (ATRA)-based and oral-ATO-based regimens were used in 469 and 282 patients. There were 144 EDs, occurring almost exclusively in ATRA-based inductions (N = 139), being more with males, age > 50 years, leucocyte > 10 × 109/L, diagnosis during 1991-2009 and fewer with oral-ATO-based regimens. After a median of 75 (interquartile range: 14-161) months, 5-year and 10-year OS were 68.1% and 63.3%, inferior with males, age > 50 years, leucocyte > 10 × 109/L, high-risk Sanz score and superior with oral-ATO-based regimens. Factoring out EDs, 5-year and 10-year post-30-day OS were 84.0% and 78.1%, inferior with males and superior with oral-ATO-based regimens. In 607 CR1 patients, the 5-year RFS was 83.8%, superior with diagnosis in 2010-2021 and oral-ATO-based regimens. Second cancers developed in 21 patients, unrelated to oral-ATO-based regimens. CONCLUSIONS: There was an increasing incidence of APL, and all survivals were superior with the use of oral-ATO-based regimens. This study formed part of the Acute Promyelocytic Leukaemia Asian Consortium Project (ClinicalTrials.gov identifier: NCT04251754).
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Arsenicales , Leucemia Promielocítica Aguda , Neoplasias Primarias Secundarias , Masculino , Femenino , Humanos , Adulto , Persona de Mediana Edad , Anciano , Anciano de 80 o más Años , Trióxido de Arsénico/efectos adversos , Leucemia Promielocítica Aguda/tratamiento farmacológico , Leucemia Promielocítica Aguda/epidemiología , Leucemia Promielocítica Aguda/diagnóstico , Recurrencia Local de Neoplasia , Tretinoina/efectos adversos , Resultado del Tratamiento , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , ÓxidosRESUMEN
Palliative care (PC) has expanded to medical conditions beyond its conventional scope of terminal malignancy and end-stage organ failure. This editorial showed our opinion in care model for the integration of PC into rheumatology and the growing needs of both rheumatology and PC services in view of increasing comorbidities and novel therapies. We anticipate an escalating demand for PC in this special group of patients who have concomitant long-standing systemic rheumatic diseases and age-related comorbidities. In addition, patients with advanced malignancy who develop rheumatological problems and require PC is also an emerging area of service need.
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Enfermería de Cuidados Paliativos al Final de la Vida , Neoplasias , Reumatología , Humanos , Cuidados Paliativos , Neoplasias/terapiaRESUMEN
Mutations in NPM1, also known as nucleophosmin-1, B23, NO38, or numatrin, are seen in approximately one-third of patients with acute myeloid leukaemia (AML). A plethora of treatment strategies have been studied to determine the best possible approach to curing NPM1-mutated AML. Here, we introduce the structure and function of NPM1 and describe the application of minimal residual disease (MRD) monitoring using molecular methods by means of quantitative polymerase chain reaction (qPCR), droplet digital PCR (ddPCR), next-generation sequencing (NGS), and cytometry by time of flight (CyTOF) to target NPM1-mutated AML. Current drugs, now regarded as the standard of care for AML, as well as potential drugs still under development, will also be explored. This review will focus on the role of targeting aberrant NPM1 pathways such as BCL-2 and SYK; as well as epigenetic regulators (RNA polymerase), DNA intercalators (topoisomerase II), menin inhibitors, and hypomethylating agents. Aside from medication, the effects of stress on AML presentation have been reported, and some possible mechanisms outlined. Moreover, targeted strategies will be briefly discussed, not only for the prevention of abnormal trafficking and localisation of cytoplasmic NPM1 but also for the elimination of mutant NPM1 proteins. Lastly, the advancement of immunotherapy such as targeting CD33, CD123, and PD-1 will be mentioned.
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Leucemia Mieloide Aguda , Nucleofosmina , Humanos , Leucemia Mieloide Aguda/genética , Mutación , Proteínas Nucleares/genética , Reacción en Cadena de la PolimerasaRESUMEN
The authors would like to make the following corrections to the published paper [...].
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This account describes how orally administered Arsenic-trioxide (ATO) therapy influences the epidemiology of acute promyelocytic leukaemia (APL), and how the experience that ensued may expand the indications for oral ATO as a treatment for diseases/disorders other than APL. Over the last two decades, experience with APL patients in Hong Kong treated with an oral regimen comprising ATO, all-trans retinoic acid (ATRA), and ascorbic acid (also known as "AAA") has confirmed a dramatic improvement in overall survival. Over that period, there has been an estimated 60-fold increase in the prevalence of APL (proportion of surviving APL patients in the population on December 31 including those deemed to be 'cured'). In contrast to regimens entailing intravenous (IV) ATO, the consequential therapeutic benefits of using oral ATO have been achieved with much less patient inconvenience and quality of life disruption, reduced burdens on health care facilities (hospitalisations and staff involvement), and much enhanced affordability (retail drug & other cost reductions). Numerous experimental and a few clinical studies suggest that ATO may also have a therapeutic role in many other diseases/disorders. Several such diseases (e.g. autoimmune disorders & idiopathic pulmonary fibrosis) are far more prevalent than APL, which means that very large numbers of patients may potentially benefit from ATO treatment, even if its efficacy is limited to selected populations with these diseases. The known safety of oral ATO and its advantages over repeated long-term IV delivery suggests that this route be used in future clinical studies of its possible role in treating such patients. If the clinical utility of oral ATO treatment is validated for patients enduring any such non-APL diseases, very large numbers of patients may stand to benefit.
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Cancer-associated thrombosis (CAT) poses a significant disease burden and the incidence in Asian populations is increasing. Anticoagulation is the cornerstone of treatment, but can be challenging due to the high bleeding risk in some cancers and the high risk of recurrent venous thromboembolism (VTE) in patients with malignancies. Direct oral anticoagulants (DOACs) are well established as first-choice treatments for VTE in non-cancer patients, offering a more convenient and less invasive treatment option than low-molecular-weight heparin (LMWH). Asian patients have exhibited comparable efficacy and safety outcomes with other races in trials of DOACs for VTE in the general population. Although no specific data are available in Asian patients with CAT, results from randomized controlled trials of apixaban, edoxaban, or rivaroxaban versus the LMWH, dalteparin, indicate that DOACs are a reasonable alternative to LMWH for anticoagulation in Asian patients with CAT. This is further supported by analyses of real-world data in Asian populations demonstrating the efficacy and safety of DOACs in Asian patients with CAT. Apixaban, edoxaban, or rivaroxaban are recommended in the most recently updated international guidelines as first-line therapy for CAT in patients without gastrointestinal or genitourinary cancers and at low risk of bleeding. An increased risk of major gastrointestinal bleeding was evident with edoxaban or rivaroxaban, but not apixaban, versus dalteparin in the clinical trials, suggesting that apixaban could be a safe alternative to LMWH in patients with gastrointestinal malignancies. Determining the optimal anticoagulant therapy for patients with CAT requires careful consideration of bleeding risk, tumor type, renal function, drug-drug interactions, financial costs, and patients' needs and preferences.
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BACKGROUND AND OBJECTIVE: Recent advances have led to cure or long-term disease control for patients with hematological malignancy (HM). Unfortunately, some of them still have poor prognoses and are often associated with significant symptom burden and poor quality of life for patients and families. These patients usually require supportive care including red blood cell and platelet transfusion, due to disease itself and the oncological treatment, apart from their symptom management. However, there is currently lack of the literatures review in these aspects. The objective of this review is to summarize practical supportive care recommendations for physicians or nurses practicing in palliative care (PC)/hematology-oncology unit, starting with core approaches in use of blood products for anemia and thrombocytopenia, management of tumor lysis syndrome, PC and oncology nursing care. METHODS: Evidence for this review was obtained from a search of the Cochrane database, PubMed, guidelines of European Society of Medical Oncology, British society of Hematology, American Society of Clinical Oncology, National Comprehensive Cancer Network and peer-reviewed journal articles. KEY CONTENT AND FINDINGS: For asymptomatic cancer patients who are anaemic, a threshold of haemoglobin level of 7 g/dL is considered to be safe and generally favored for blood transfusion. 'Single-unit' red cell transfusion is safer and at least as effective as 'double-unit' transfusion. Prophylactic platelet transfusion should be given to stable patients without bleeding and with platelet count less than 10×109/L. In febrile patients, the threshold is lifted to 20×109/L. There are also recommendations for the use of blood products during COVID-19 pandemic. In general, HM patients were more prone to painful infections when compared with solid cancer patients. Thus, antibiotics to treat underlying infections should be applied whenever possible and as required to control pain. CONCLUSIONS: This narrative review showed the recent literatures in the supportive care and symptom management of advanced HM patients. However, it is limited by some of the 'evidence-based' recommendations for interventions (including symptom management) based on early phase of HM populations rather than those receiving end-of-life care.
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COVID-19 , Neoplasias Hematológicas , Neoplasias , Humanos , Cuidados Paliativos , Calidad de Vida , Pandemias , COVID-19/terapia , Neoplasias Hematológicas/tratamiento farmacológicoRESUMEN
Appreciation of the properties of arsenic trioxide (ATO) has redefined the treatment landscape for acute promyelocytic leukaemia (APL) and offers promise as a treatment for numerous other diseases. The benefits of ATO in patients with APL is related to its ability to counteract the effects of PML::RARA, an oncoprotein that is invariably detected in the blood or bone marrow of affected individuals. The PML::RARA oncoprotein is degraded specifically by binding to ATO. Thus ATO, in combination with all-trans retinoic acid, has become the curative treatment for ATO. The multiple mechanisms of action of ATO has also paved the way for application in various condition encompassing autoimmune or inflammatory disorders, solid organ tumours, lymphomas and other subtypes of AML. The development of oral formulation of ATO (oral ATO) has reduced costs of treatment and improved treatment convenience allowing widespread applicability. In this review, we discuss the mechanisms of action of ATO, the development of oral ATO, and the applications of oral ATO in APL and other diseases.