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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 -
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 -
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 -
Discover Oncology Jun 2024Pediatric acute promyelocytic leukemia (APL) accounts for 5 to 15% of all myelocytic leukemia. A retrospective analysis of pediatric patients diagnosed and treated with...
BACKGROUND
Pediatric acute promyelocytic leukemia (APL) accounts for 5 to 15% of all myelocytic leukemia. A retrospective analysis of pediatric patients diagnosed and treated with APL was conducted at CCHE from July 2012 to the end of December 2019, to report the prevalence, clinical characteristics, results, and risk factors associated with induction failure and early death.
RESULT
Sixty-two patients were reported, with an age greater than ten, an initial poor coagulation profile, and a total leukocyte count (TLC) greater than 30 10/mm influencing 5-year overall (OS) and event-free survival (EFS), as well as a high promyelocyte count affecting 5-year EFS. Patients received a regimen based on the COG AAML0631 protocol. High-risk patients with an initial TLC > 10 × 10/mm and an initial promyelocytic count of 30% or more with a substantial P-value are prognostic markers for early death during induction. In females, wild FLT3 increases the risk of differentiation syndrome (DS). Receiving steroids with all-trans retinoic acid (ATRA) induction may reduce the occurrence of DS. Relapse alters the outcome. In the current study, 45 patients are alive in complete remission, with a 5-year OS of 72.5% and a 5-year EFS of 69.4%, respectively.
CONCLUSION
Pediatric APL outcomes are influenced by age above 10, an initial poor coagulation profile, and a promyelocyte count of more than 10%. An initial leukocyte count of more than 10 × 10/mm and an initial promyelocytic count of more than 30% increase the risk of early death. Receiving steroids with ATRA may reduce the occurrence of DS.
PubMed: 38861104
DOI: 10.1007/s12672-024-01037-6 -
Clinical and Experimental Reproductive... Jun 2024Some age-related testicular changes, such as Sertoli cell vacuolization and blood-testis barrier breakdown, reduce total sperm production and male fertility. Therefore,...
OBJECTIVE
Some age-related testicular changes, such as Sertoli cell vacuolization and blood-testis barrier breakdown, reduce total sperm production and male fertility. Therefore, this study investigated the effect of vitamin E on restoring testicular function in aged mice. Sperm cryo-resistance was also assessed.
METHODS
Twenty-eight 48-week-old male Naval Medical Research Institute mice were divided into four groups for a daily gavage of vitamin E: the control group received distilled water, while the three treatment groups were administered 100, 200, and 400 mg/kg, respectively, for 4 weeks. Subsequently, semen analyses, DNA fragmentation index (DFI), and protamine deficiency tests were conducted. Testicular histology, tissue antioxidant enzyme activity, and gene expression levels were also assessed.
RESULTS
The two higher dosages of vitamin E were associated with a higher sperm count, greater progressive motility, and improved sperm morphology (p<0.05). These benefits were also evident after sperm freezing (p<0.05). Although chromatin abnormalities increased following vitrification, the treatment groups showed better outcomes (p<0.05). The tubular diameter, epithelium height, and luminal diameters remained unchanged with age. The tissue antioxidant capacity was greater in the groups receiving the high doses of vitamin E. Additionally, significant increases in inhibitor of DNA binding protein-4 (Id4) and GDNF family receptor alpha-1 (Gfra1) expression were observed in the higher vitamin E dosage groups, and promyelocytic leukemia zinc finger protein (Plzf) expression was notably present in the 400 mg/kg treatment group compared to the control group (p<0.05).
CONCLUSION
Antioxidant supplementation might enhance reproductive outcomes in aging males. The observed effects included improved sperm cryo-resistance, which is advantageous for future applications such as sperm freezing or fertility preservation.
PubMed: 38853131
DOI: 10.5653/cerm.2023.06632 -
RSC Advances May 2024Twelve tricarbonyl rhenium(i) complexes in the '2 + 1' system with the anionic bidentate N,O-donor ligand (deprotonated 8-hydroxyquinoline (HQ) or its 2-methyl (MeHQ) or...
Twelve tricarbonyl rhenium(i) complexes in the '2 + 1' system with the anionic bidentate N,O-donor ligand (deprotonated 8-hydroxyquinoline (HQ) or its 2-methyl (MeHQ) or 5-chloro (ClHQ) derivative) and neutral N-donor diazoles (imidazole (Him), 2-methylimidazole (MeHim), 3,5-dimethylpyrazole (Hdmpz), and 3-phenylpyrazole (HPhpz)) were synthesized: [Re(CO)(L)L] (L = Q, MeQ, ClQ; L = Him, MeHim, Hdmpz, HPhpz). Their crystal structures were determined by the scXRD method, compared with the DFT-calculated ones, and characterized by analytical (EA) and spectroscopic techniques (FT-IR, NMR, and UV-Vis) interpreted with DFT and TD-DFT calculations. Most of the Re(i) complexes did not show relevant antibacterial activity against Gram-negative and Gram-positive bacterial strains. Only [Re(CO)(MeQ)Him] demonstrated significant action 4-fold better against Gram-negative than the free MeHQ ligand. The cytotoxicity of the compounds was estimated using human acute promyelocytic leukemia (HL-60), ovarian (SKOV-3), prostate (PC-3), and breast (MCF-7) cancer, and breast non-cancerous (MCF-10A) cell lines. Only HQ and ClHQ ligands and [Re(CO)(Q)Hdmpz] complex had good selectivity toward MCF-7 cell line. HL-60 cells were sensitive to all complexes (IC = 1.5-14 μM). Still, pure HQ and ClHQ ligands were slightly more active than the complexes.
PubMed: 38841398
DOI: 10.1039/d4ra03141e -
Archives of Pathology & Laboratory... Jun 2024Acute promyelocytic leukemia (APL) is a subtype of acute myeloid leukemia distinguished by its rapidly progressive and fatal clinical course. Measurable/minimal residual...
Measurable Residual Disease Analysis by Flow Cytometry and Correlation With Molecular Measurable Residual Disease in Acute Promyelocytic Leukemia: A Real-World Prospective Study.
CONTEXT.—
Acute promyelocytic leukemia (APL) is a subtype of acute myeloid leukemia distinguished by its rapidly progressive and fatal clinical course. Measurable/minimal residual disease (MRD) monitoring is vital for the prognosis and clinical management of acute myeloid leukemia.
OBJECTIVE.—
To examine the immunophenotypes of the residual leukemic cells, evaluate the performance of multiparametric flow cytometry (FCM) measuring MRD, and compare it with molecular monitoring in patients diagnosed with APL.
DESIGN.—
Two hundred seventy-seven patients with APL were enrolled. Immunophenotypes were prospectively analyzed by a 1-tube-10-color antibody panel via FCM. MRD of APL with PML::RARα was detected by real-time quantitative polymerase chain reaction (RQ-PCR). The clinical value of MRD as an indicator of survival was also examined.
RESULTS.—
APL showed 5 distinct patterns of residual leukemic cells, based on CD45 and side-scatter scattergram, all with CD9 positivity and a previously unrealized loss of CD117. FCM-based MRD evaluation showed a concordance rate of 87.7% with PCR. At the end of the consolidation therapy, MRD measured by both PCR and FCM could differentiate patients with longer and shorter overall survival (OS) (P = .04 and P = .03, respectively). Patients with APL variant had a shorter OS than patients with APL who harbored PML::RARα (P < .001).
CONCLUSIONS.—
CD9 is a reliable marker to differentiate residual leukemic cells from normally differentiating myeloid cells. FCM demonstrated a high comparability to PCR-MRD and an excellent performance in predicting OS, and thus could potentially be used as a routine indicator in the clinical management of patients with APL.
PubMed: 38838353
DOI: 10.5858/arpa.2023-0460-OA -
Frontiers in Oncology 2024Acute promyelocytic leukemia (APL) is rarely caused by the fusion gene. While APL patients with fusion commonly exhibit diverse hematologic symptoms, the presentation...
BACKGROUND
Acute promyelocytic leukemia (APL) is rarely caused by the fusion gene. While APL patients with fusion commonly exhibit diverse hematologic symptoms, the presentation of myeloid sarcoma (MS) as an initial manifestation is infrequent.
CASE PRESENTATION
A 61-year-old patient was referred to our hospital with 6-month history of low back pain and difficulty walking. Before this admission, spine magnetic resonance imaging (MRI) conducted at another hospital revealed multiple abnormal signals in the left iliac bone and vertebral bodies spanning the thoracic (T11-T12), lumbar (L1-L4), and sacral (S1/S3) regions. This led to a provisional diagnosis of bone tumors with an unknown cause. On admission, complete blood count (CBC) test and peripheral blood smear revealed a slightly increased counts of monocytes. Immunohistochemical staining of both spinal and bone marrow (BM) biopsy revealed positive expression for CD117, myeloperoxidase (MPO), and lysozyme. BM aspirate showed a significant elevation in the percentage of promyelocytes (21%), which were morphologically characterized by round nuclei and hypergranular cytoplasm. Multiparameter flow cytometry of BM aspirate revealed that blasts were positive for CD13, CD33, CD117, and MPO. Through the integrated application of chromosome analysis, fluorescence hybridization (FISH), reverse transcriptase polymerase chain reaction (RT-PCR), and Sanger sequencing, it was determined that the patient possessed a normal karyotype and a rare cryptic fusion gene, confirming the diagnosis of APL.
CONCLUSION
In the present study, we report the clinical features and outcome of a rare APL patient characterized by a cryptic fusion and spinal myeloid sarcoma (MS) as the initial presenting symptom. Our study not only offers valuable insights into the heterogeneity of APL clinical manifestations but also emphasizes the crucial need to promptly consider the potential link between APL and MS for ensuring a timely diagnosis and personalized treatments.
PubMed: 38835381
DOI: 10.3389/fonc.2024.1375737