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Hematology, Transfusion and Cell Therapy May 2024Improvements in clinical assessment have occurred since the last published recommendations on the diagnosis and treatment of acute promyelocytic leukemia in 2013. Here,...
Diagnosis and management of acute promyelocytic leukemia: Brazilian consensus guidelines 2024 on behalf of the Brazilian Association of Hematology, Hemotherapy and Cellular Therapy.
Improvements in clinical assessment have occurred since the last published recommendations on the diagnosis and treatment of acute promyelocytic leukemia in 2013. Here, a committee of specialists of the Brazilian Association of Hematology, Hemotherapy and Cellular Therapy presents a comprehensive review on the current knowledge, focusing on the advances in diagnosis, risk assessment, and frontline and salvage therapy. The concept of urgent diagnosis is explored as well as the management of critical situations such as coagulopathy and differentiation syndrome. Recent adjustments in risk stratification based on white blood cell counts only are presented together with the incorporation of chemo-free regimens for non-high-risk patients. Special conditions such as acute promyelocytic leukemia in children, the elderly and pregnant women are discussed. Finally, acute promyelocytic leukemia is presented as a highly curable disease because of the real possibility of targeted therapy towards differentiation, and, paradoxically, as a serious and urgent condition that deserves prompt recognition and management to avoid early mortality.
PubMed: 38890097
DOI: 10.1016/j.htct.2024.05.002 -
Cureus May 2024The introduction of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) has transformed the outcome of acute promyelocytic leukemia (APL) from a uniformly fatal...
Acute Promyelocytic Leukemia With Long and Short Isoforms of PML::RARA Fusion Transcripts Complicated by Abdominal Distension and Acute Edematous Pancreatitis During Induction Treatment: A Case Report.
The introduction of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) has transformed the outcome of acute promyelocytic leukemia (APL) from a uniformly fatal disease to one of the most curable human malignancies in recent decades. However, early mortality caused by coagulopathy, infection, multi-organ failure, and differentiation syndrome (DS) during disease onset and induction treatment remains a major issue in APL, especially in elderly patients who may suffer from higher treatment-related mortality due to a higher vulnerability to treatment toxicities. Herein, we present a case of an elderly patient with APL with rare mixed long (L-) and short (S-) isoforms of PML::RARA fusion transcripts who had multiple complications at disease onset. In addition, the initiation of treatment with ATRA in combination with ATO led to the rapid onset of severe DS. In particular, this patient experienced a rare clinical feature of DS, acute edematous pancreatitis (AEP). Furthermore, due to the patient's refractory abdominal distension related to the dose of ATRA, ATO, and Realgar-Indigo Naturalis Formula (RIF), we have to repeatedly adjust the doses of these drugs that the patient can maximally tolerate. Nevertheless, the patient achieved complete remission (CR) even after receiving a substandard dose of these drugs. However, the patient relapsed, acquired the FLT3-ITD mutation nine months later, and experienced abdominal distension again while receiving the standard doses of ATRA and RIF. Therefore, these drugs were adjusted to the maximum tolerated dose based on the experience with the initial induction treatment, and the patient achieved CR after four weeks of reinduction treatment. We report that this case may provide some clinical information for the diagnosis and treatment of similar patients with APL.
PubMed: 38883104
DOI: 10.7759/cureus.60321 -
Cardiovascular & Hematological... Jun 2024The development of myeloid malignancies is a multi-step process starting from pre-malignant stages. Large-scale studies on clonal hematopoiesis of indeterminate...
The development of myeloid malignancies is a multi-step process starting from pre-malignant stages. Large-scale studies on clonal hematopoiesis of indeterminate potential (CHIP) identified this condition as a risk factor for developing hematologic malignancies, in particular myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). In parallel, CHIP was found to confer an enhanced thrombotic risk, in particular for cardiovascular diseases. In a similar fashion, in recent years, alongside their life-threatening features, increasing attention has been drawn toward thrombotic complications in myeloid malignancies. The purpose of this review is to gather growing body of evidence on incidence, pathogenesis and clinical impact of thrombosis in myeloid malignancies at every step of malignant progression, from CHIP to AML.
PubMed: 38879768
DOI: 10.2174/011871529X307253240530060107 -
Scientific Reports Jun 2024Acute promyelocytic leukemia (APL) is characterized by rearrangements of the retinoic acid receptor, RARα, which makes all-trans retinoic acid (ATRA) highly effective...
Acute promyelocytic leukemia (APL) is characterized by rearrangements of the retinoic acid receptor, RARα, which makes all-trans retinoic acid (ATRA) highly effective in the treatment of this disease, inducing promyelocytes differentiation. Current therapy, based on ATRA in combination with arsenic trioxide, with or without chemotherapy, provides high rates of event-free survival and overall survival. However, a decline in the drug activity, due to increased ATRA metabolism and RARα mutations, is often observed over long-term treatments. Furthermore, dedifferentiation can occur providing relapse of the disease. In this study we evaluated fenretinide, a semisynthetic ATRA derivative, encapsulated in nanomicelles (nano-fenretinide) as an alternative treatment to ATRA in APL. Nano-fenretinide was prepared by fenretinide encapsulation in a self-assembling phospholipid mixture. Physico-chemical characterization was carried out by dinamic light scattering and spectrophotometry. The biological activity was evaluated by MTT assay, flow cytometry and confocal laser-scanning fluorescence microscopy. Nano-fenretinide induced apoptosis in acute promyelocytic leukemia cells (HL60) by an early increase of reactive oxygen species and a mitochondrial potential decrease. The fenretinide concentration that induced 90-100% decrease in cell viability was about 2.0 µM at 24 h, a concentration easily achievable in vivo when nano-fenretinide is administered by oral or intravenous route, as demonstrated in previous studies. Nano-fenretinide was effective, albeit at slightly higher concentrations, also in doxorubicin-resistant HL60 cells, while a comparison with TK6 lymphoblasts indicated a lack of toxicity on normal cells. The results indicate that nano-fenretinide can be considered an alternative therapy to ATRA in acute promyelocytic leukemia when decreased efficacy, resistance or recurrence of disease emerge after protracted treatments with ATRA.
Topics: Humans; Fenretinide; Leukemia, Promyelocytic, Acute; HL-60 Cells; Apoptosis; Reactive Oxygen Species; Antineoplastic Agents; Nanoparticles; Cell Survival; Micelles; Membrane Potential, Mitochondrial
PubMed: 38877119
DOI: 10.1038/s41598-024-64629-w -
American Journal of Physiology. Heart... Jun 2024Glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter-2 (SGLT2) inhibitors are guideline-recommended therapies for the management of type...
Glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter-2 (SGLT2) inhibitors are guideline-recommended therapies for the management of type 2 diabetes (T2D), atherosclerotic cardiovascular disease, heart failure and chronic kidney disease. We previously observed in people living with T2D and coronary artery disease that circulating vascular regenerative (VR) progenitor cell content increased following 6-month use of the SGLT2 inhibitor empagliflozin. In this post hoc sub-analysis of the ORIGINS-RCE CardioLink-13 study, we analyzed the circulating VR progenitor cell content of 92 individuals living with T2D, among whom 20 were on a GLP-1RA, 42 were on an SGLT2 inhibitor but not a GLP-1RA, and 30 were on neither of these vascular protective therapies. In the GLP-1RA group, the mean absolute count of circulating VR progenitor cells defined by high aldehyde dehydrogenase (ALDH) activity (ALDHSSC) and VR progenitor cells further characterized by surface expression of the pro-angiogenic marker CD133 (ALDHSSCCD133) was higher than the group receiving neither a GLP-1RA nor an SGLT2 inhibitor (P=0.02), and comparable to that in the SGLT2 inhibitor group (P=0.25). The absolute count of pro-inflammatory, granulocyte-restricted precursor cells (ALDHSSC) was significantly lower in the GLP-1RA group compared to the group on neither therapy (P=0.031). Augmented vessel repair initiated by VRcells with previously documented pro-angiogenic activity, alongside a reduction in systemic, granulocyte precursor-driven inflammation, may represent novel mechanisms responsible for the cardiovascular-metabolic benefits of GLP-1RA therapy. Prospective, randomized clinical trials are now warranted to establish the value of recovering circulating VR progenitor cell content with blood vessel regenerative functions.
PubMed: 38874618
DOI: 10.1152/ajpheart.00257.2024 -
International Journal of Laboratory... Jun 2024In recent years, the correlation between CD117 antigen and the prognosis of hematological malignancies has been demonstrated. However, there is limited literature on the...
INTRODUCTION
In recent years, the correlation between CD117 antigen and the prognosis of hematological malignancies has been demonstrated. However, there is limited literature on the clinical significance of CD117 antigen in acute promyelocytic leukemia (APL). The aim of this study was to retrospectively analyze the clinical features and prognostic significance of CD117 in APL.
METHODS
In this study, we retrospectively investigated the clinicopathological characteristics, outcome, and prognostic impact of negative CD117 expression (CD117) in 169 APL patients treated with all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) containing regimen.
RESULTS
The median follow-up period was 63.0 months. CD117 was detected in 13 APL patients (7.7%). No significant differences were found in baseline characteristics between CD117+ and CD117 subgroups. However, compared to CD117+ APL, the incidence of early death (ED) was significantly higher in CD117 APL (p = 0.023). By multivariate analysis, CD117- was an independent adverse prognostic factor for overall survival (OS) and progression-free survival (PFS) (p = 0.022 and p = 0.014, respectively).
CONCLUSIONS
To sum up, CD117 is associated with greater risk of ED and has the statistical power to predict inferior OS and PFS, this marker may be considered to build prognostic scores for risk-adapted therapeutic strategies in APL management.
PubMed: 38874282
DOI: 10.1111/ijlh.14326 -
Translational Oncology Aug 2024New treatments are urgently required for triple-negative breast cancer (TNBC). As TP53 is mutated in approximately 80% of TNBC, it is theoretically an attractive target...
New treatments are urgently required for triple-negative breast cancer (TNBC). As TP53 is mutated in approximately 80% of TNBC, it is theoretically an attractive target for new drugs for this disease. Arsenic trioxide (ATO), which is used to treat promyelocytic leukaemia, was recently shown to reactivate mutant p53 and restore wild-type functionality. The aim of this study was to evaluate ATO as a potential new treatment for TNBC. Using a panel of 20 cell lines, we found that TNBC cell lines were more sensitive to ATO than non-TNBC cell lines (P = 0.045). Consistent with its ability to reactivate mutant p53, ATO was a more potent inhibitor of proliferation in cell lines with mutant TP53 than the wildtype TP53 (P = 0.027). Direct evidence of mutant p53 reactivation was the induction of multiple wild-type p53 canonical target genes such as CDKN1A, SLC7A11, BBC3, PMAIP1, SESN2, SRXN1 and TXNRD1. Our findings support the activation of mutant p53 by ATO and, furthermore, the possible repurposing of ATO to treat TP53-mutated TNBC.
PubMed: 38870678
DOI: 10.1016/j.tranon.2024.102025 -
Clinical Laboratory Jun 2024Acute promyelocytic leukemia (APL) is a specific type of acute myeloid leukemia [1,2], the onset of the disease is insidious and the disease progresses rapidly, and...
BACKGROUND
Acute promyelocytic leukemia (APL) is a specific type of acute myeloid leukemia [1,2], the onset of the disease is insidious and the disease progresses rapidly, and failure to detect it in time or missing the best time to seek medical treatment is likely to cause secondary cerebral hemorrhage and lead to early death (ED: deaths occur in the first 30 days post diagnosis) [3-5].
METHODS
A patient with APL was rapidly identified by peripheral blood image, fibrinogen (FIB), and D-dimer within 24 hours. Finally, APL was confirmed by bone marrow cell morphology, molecular biology, and cytogenetics.
RESULTS
The presence of faggot cells with Auer rods in the peripheral blood image and the coagulation function changes abnormally at the same time. Once the above abnormal results are found, APL should be highly suspected and timely reported to the clinic for corresponding treatment.
CONCLUSIONS
APL is a critical disease, the time limit for definitive diagnosis should be calculated in hours rather than days. Peripheral blood smear microscopic examination can effectively screen out rare promyelocytes and combine with abnormal FIB and D-dimer results that are highly suspicious of APL. These methods have important clinical significance in the initial screening, early diagnosis, and reduction of early mortality due to APL.
Topics: Humans; Leukemia, Promyelocytic, Acute; Fibrin Fibrinogen Degradation Products; Male; Fibrinogen; Time Factors
PubMed: 38868893
DOI: 10.7754/Clin.Lab.2024.240116 -
A HNRNPC::RARB variant of acute promyelocytic leukemia with concurrent myeloid sarcoma of the spine.Annals of Hematology Jun 2024
PubMed: 38864905
DOI: 10.1007/s00277-024-05833-6