Cerebral Infarction as an Initial Manifestation in Acute Promyelocytic Leukemia and Deterioration After All-Trans Retinoic Acid Treatment.

There are neither predictive tests nor preventive strategies/treatments for acute promyelocytic leukemia (APL)-associated bleeding/thrombosis incidence. We encountered the case of a woman in her 70s who was admitted due to sudden-onset right hemiparesis. The patient was diagnosed with acute cerebral infarction as the initial manifestation of APL. Intravenous recombinant human soluble thrombomodulin was initiated on admission, followed by oral all-trans retinoic acid two days later. However, the patient's condition deteriorated due to APL-associated diphasic cerebral infarction with left internal carotid artery occlusion, and she died 10 days after admission. Thus, the degree of main artery stenosis should be evaluated before treatment in patients with APL who have coagulopathy.

Acute Myeloid Leukemia Presenting as Extensive Arterial and Venous Thrombosis: A Case Report.

BACKGROUND: Thromboembolism with solid malignancies is a commonly associated feature, which is less common in hematological malignancies. Disseminated intravascular coagulation (DIC) causing thrombotic events is characteristically associated with certain hematological malignancies (e.g., acute promyelocytic leukemia (APL). Acute myeloid leukemia (AML) presenting as extensive thromboembolism is not a common clinical presentation. Anticoagulation in these subsets of patients remains a major challenge since patients often have thrombocytopenia and bleeding manifestations, requiring close monitoring. CASE PRESENTATION: A 54-year-old male with a known case of ischemic heart disease on regular anti- platelet therapy presented with acute onset progressive shortness of breath with mild anemia. On further evaluation, the patient was diagnosed with bilateral pulmonary artery and venous thrombosis along with left complete renal and partial inferior vena cava (IVC) thrombosis. The patient was started safely on anticoagulant therapy with normal platelet counts. Later, peripheral smear and immunophenotyping by flow cytometry revealed the diagnosis of acute myeloid leukemia, and the patient started its treatment. CONCLUSION: Extensive arterial and venous thrombosis at presentation of acute myeloid leukemia is an uncommon finding and needs anticoagulation therapy along with the treatment of the underlying disease. Close monitoring of bleeding and maintaining an adequate platelet count is required, especially in hematological malignancies.

Successfully treatment of PLZF-RARα positive acute promyelocytic leukemia by Venetoclax combining with decitabine: a case report and literature review.

INTRODUCTION: Acute promyelocytic leukemia (APL) is mainly due to the chromosome translocation t(15; 17) (q22; q12), leading to the formation of PML-RARα fusion protein. However, some patients carried rare translocation involving RARα gene, and they were referred to as variant APL caused by the RAR family (RARα, RARB, and RARG) and partner genes. PLZF-RARα was a rare type of molecular genetic abnormality with unfavorable prognosis that has been reported in few cases in variant APL. Knowledge of PLZF-RARα (+) APL treatment remains limited understood. CASE REPORT: We presented a case of variant APL in a 47-year-old female, who was PLZF-RARα positive detected by reverse transcription polymerase chain reaction (RT-PCR). The patient did not respond to all-trans retinoic acid (ATRA), idarubicin, and arsenic trioxide (As2O3) combined induction chemotherapy. Then, the patient was treated with Venetoclax combining with decitabine as the salvage therapy and achieved morphological remission and PLZF/RARα gene negative. CONCLUSION: Venetoclax combining with decitabine can be used as an effective therapy in the PLZF-RARα positive APL.

Therapy-related myeloid neoplasms following curative treatment of acute promyelocytic leukemia: incidence, correlation with therapeutic regimen, and future directions.

All-trans retinoic acid (ATRA) and arsenic trioxide (ATO) have revolutionized the treatment of acute promyelocytic leukemia (APL), offering a cure rate of > 80%. Along with improved survival, the long-term consequences of anti-APL therapy are becoming increasingly apparent, including potential therapy-related myeloid neoplasms (t-MNs). T-MNs are well known to arise after cytotoxic chemotherapy, but the leukemogenic potential of regimens utilizing only ATRA/ATO is not well established. The objective of this study is to examine the incidence, long-term risk, and clinicopathologic features of t-MNs arising after anti-APL therapy and how they correlates with the therapeutic regimen employed. We retrospectively collected treated APL patients between 01/2001 and 02/2021, categorized them into ATRA/ATO + chemo and ATRA/ATO groups based on the regimen used, and evaluated for the development of t-MN. A total of 110 APL patients were identified, including 67 (61%) treated with ATRA/ATO + chemo and 43 (39%) treated with ATRA/ATO only. Overall, 4/110 (3.6%) patients developed t-MNs, with all four emerging in the ATRA/ATO + chemo group. Ultimately, the incidence of t-MN in ATRA/ATO + chemo group was significantly higher compared with ATRA/ATO only group(5.97% vs. 0.0%, respectively; p = 0.0289). Our data spanning over two decades suggests that conventional chemotherapy for APL is associated with a small but significant risk of t-MN, whereas ATR/ATO does not carry this risk. This takes on new significance, considering several recent and ongoing trials have shown that a chemotherapy-free approach might become feasible for all risk APL types in the near future. Consequently, the omission of leukemogenic and arguably unnecessary chemotherapy from APL regimens may reduce the incidence of t-MNs in long-term survivors without sacrificing their cure rates.

ATPR induces acute promyelocytic leukemia cells differentiation and cycle arrest via the lncRNA CONCR/DDX11/PML-RARα signaling axis.

Acute promyelocytic leukemia (APL) is a type of acute myeloid leukemia (AML) with a high mortality rate, and the production of PML-RARα fusion protein is the cause of its pathogenesis. Our group has synthesized a novel compound, 4-amino-2-trifluoromethyl-phenyl retinate (ATPR), by structural modification of All-trans retinoic acid (ATRA), which has strong cell differentiation-inducing effects and inhibits the expression of PML-RARα. In this study, acute promyelocytic leukemia NB4 cells before and after ATPR induction were analyzed by whole transcriptome microarray, and the expression of lncRNA CONCR was found to be significantly downregulated. The role of CONCR in ATPR-induced cell differentiation and cycle arrest was explored through overexpression and silencing of CONCR. And then the database was used to predict that CONCR may bind to DEAD/H-Box Helicase 11 (DDX11) protein to further explore the role of CONCR binding to DDX11. The results showed that ATPR could reduce the expression of CONCR, and overexpression of CONCR could reverse the ATPR-induced cell differentiation and cycle blocking effect, and conversely silencing of CONCR could promote this effect. RNA immunoprecipitation (RIP) experiments showed that CONCR could bind to DDX11, the protein expression levels of DDX11 and PML-RARα were elevated after overexpression of CONCR. These results suggest that ATPR can regulate the expression of DDX11 through CONCR to affect the expression of PML-RARα fusion protein, which in turn induces the differentiation and maturation of APL cells.

Case report of pediatric TTMV-related acute promyelocytic leukemia with central nervous system infiltration and rapid accumulation of RARA-LBD mutations.

TTMV::RARA is a recently reported fusion gene associated with acute promyelocytic leukemia (APL), caused by the integration of torque teno mini virus (TTMV) genomic fragments into the second intron of the RARA gene. Currently, there have been only six documented cases, with clinical presentations showing significant variability. Although initial responses to all-trans retinoic acid (ATRA) treatment may be observed in patients with TTMV::RARA-APL, the overall prognosis remains unfavorable among infrequent reported cases. This article presents a pediatric case that manifested as PML::RARA-negative APL with central nervous system involvement at onset. The patient experienced both intramedullary and extramedullary relapse one year after undergoing allogeneic hematopoietic stem cell transplantation. Upon identification as TTMV::RARA-APL and subsequent administration of two rounds of ATRA-based treatment, the patient rapidly developed multiple RARA ligand-binding domain mutations and demonstrated extensive resistance to ATRA and various other therapeutic interventions. Additionally, the patient experienced ARID1A mutant clone expansion and progressed MYC-targeted gene activation. This case represents the first documentation of extramedullary involvement at both the initial diagnosis and relapse stages, emphasizing the intricate clinical features and challenges associated with the rapid accumulation of multiple ATRA-resistant mutations in TTMV::RARA-APL, characterizing it as a distinct and complex sub-entity of atypical APL.

No Association of AS3MT Gene Polymorphisms with Susceptibility to Hepatotoxicity in APL Patients Treated with AS2O3: A Single-Center Study.

Background: Arsenic three oxide (As2O3) is the treatment choice for acute promyelocytic leukemia (APL). Little is known about possible risk factors with predictive value for toxicity caused by As2O3. Biomethylation is considered to be a major pathway of detoxification for inorganic arsenics (iAs). Arsenic Methyltransferase (AS3MT) is one of the key enzymes involved in the transfer of a methyl group from S-adenosyl-L-methionine to trivalent arsenical and plays a critical role in arsenic detoxification. Polymorphisms in hAS3MT lead to a change in the catalytic activity of the enzyme and may increase the risk of arsenic-related toxicity. In this study, we investigated the association of the AS3MT polymorphisms (rs11191439, rs3740390, and rs3740393) genes with hepatotoxicity in APL patients treated with As2O3. Materials and Methods: Genotyping was performed in 140 adult patients with APL treated with As2O3 using PCR-RFLP for rs11191439 and tetra-primer ARMS-PCR for rs3740390 and rs3740393. The results of PCR-RFLP and ARMS-PCR were confirmed by direct sequencing of 10 % of DNA samples. The results were analyzed using SNPStats, SPSS, and FinchTV. Hepatotoxicity was graded according to the National Cancer Institute's Common Toxicity Criteria (CTC). Results : Hepatotoxicity was seen in 52 of the 140 patients (37.1%), with grades I and II hepatotoxicity in 40 (28.6%) and grades III and IV hepatotoxicity in 12 (8.5%) patients. The association between the three polymorphisms and hepatotoxicity was evaluated using five genetic models and none of the three studied polymorphisms were significantly associated with hepatotoxicity. Discussion : The results of our study showed that AS3MT rs11191439, rs3740390, and rs3740393 polymorphisms are not associated with hepatotoxicity in APL patients. Genetic polymorphisms in enzymes which are involved in arsenic metabolism have been shown to have ethnicity and race-related differences. To more precisely characterize the association between AS3MT gene polymorphism and hepatotoxicity, future large-scale studies in non-Asian populations and other ethnicities are needed.

A Review of Childhood Acute Myeloid Leukemia: Diagnosis and Novel Treatment.

Acute myeloid leukemia (AML) is the second most common hematologic malignancy in children. The incidence of childhood AML is much lower than acute lymphoblastic leukemia (ALL), which makes childhood AML a rare disease in children. The role of genetic abnormalities in AML classification, management, and prognosis prediction is much more important than before. Disease classifications and risk group classifications, such as the WHO classification, the international consensus classification (ICC), and the European LeukemiaNet (ELN) classification, were revised in 2022. The application of the new information in childhood AML will be upcoming in the next few years. The frequency of each genetic abnormality in adult and childhood AML is different; therefore, in this review, we emphasize well-known genetic subtypes in childhood AML, including core-binding factor AML (CBF AML), KMT2Ar (KMT2A/11q23 rearrangement) AML, normal karyotype AML with somatic mutations, unbalanced cytogenetic abnormalities AML, NUP98 11p15/NUP09 rearrangement AML, and acute promyelocytic leukemia (APL). Current risk group classification, the management algorithm in childhood AML, and novel treatment modalities such as targeted therapy, immune therapy, and chimeric antigen receptor (CAR) T-cell therapy are reviewed. Finally, the indications of hematopoietic stem cell transplantation (HSCT) in AML are discussed.

Treating low- and intermediate-risk acute promyelocytic leukemia with and without chemotherapy: A comparison in a tertiary care center.

Background: Acute promyelocytic leukemia (APL) comprises approximately 10% of acute myeloid leukemia (AML) cases. Material and Methods: Both options of treatment (ATRA-ATO and ATRA-chemotherapy) were discussed with patients with low- and intermediate-risk APL, pros and cons explained in details, and treatment regimen selected after getting informed written consent. Results: Total 71 patients were included in the study; among these patients, 3 were negative for both FISH for t (15,17) and RT-PCR for promyelocytic leukemia retinoic acid receptor alpha, and 36 patients with APL had white blood cell count at diagnosis >10 × 109/l. Total 30 patients with newly diagnosed as low- and intermediate-risk-APL fulfilled all inclusion criteria, treated and followed for a minimum period of 2 years up to June, 2016. Fifteen patients liked to be treated with all-trans retinoic acid (ATRA) and arsenic trioxide (ATO), while rest of the 15 patients preferred treatment with ATRA and chemotherapy. Conclusion: Combination of ATRA and ATO is equally effective, less toxic, and more feasible in comparison to ATRA and chemotherapy for patients with low- and intermediate-risk APL and is a viable option for this subset of patients, especially in countries with limited resources.

Therapy-Related Acute Promyelocytic Leukemia: A Case Report and a Review of Literature.

Acute promyelocytic leukemia (APL) is a subgroup of acute myeloid leukemia (AML), and while not a common form of cancer, it does make up a modest portion of acute leukemia. The genetic hallmark of APL is the t(15;17)(q24.1;q21.2) promyelocytic leukemia/retinoic acid receptor alpha (PML/RARA) protein. We present the case of a patient who had undergone prior therapy for stage IIIC squamous cell carcinoma of the anorectal region with 5-fluorouracil, mitomycin C, and radiation and developed therapy-related acute promyelocytic leukemia about 18 months later. We also review the clinical features and management of APL while also highlighting that therapy-related APL, although uncommon, can develop from chemoradiation. The specific diagnosis of therapy-related APL is its own distinct diagnosis, but its treatment remains the same as primary APL.

Fatal intracranial haemorrhage in acute promyelocytic leukemia patients with short isoform of PML-RARα: Review of molecular and radiological data.

Three major PML-RARα fusion gene transcripts (long [bcr1], variant [bcr2], and short [bcr3]) are currently used in clinical laboratories for the diagnosis and treatment monitoring of APL patients. Despite highly improved outcome, relapse and intracranial haemorrhage that may lead to early death is still an unsolved complication in APL. We reviewed APL patients confirmed by qPCR for the presence of PML-RARα transcripts (n = 27) and studied their outcome in relation to the isoform expression at diagnosis and follow-up in King Fahad Medical City. Eight in twenty-seven patients showed bcr3 and nineteen patients with bcr1 as major isoforms at diagnosis. Half of the bcr3 patients (n = 4/8) showed early mortality, prolonged qPCR positivity, 4-fold higher neutrophil/lymphocyte ratio, higher creatinine levels, and significantly reduced relapse free and overall survival time compared with bcr1 patients. Radiological findings in bcr3 patients revealed CNS involvement in the form of intracranial haemorrhage and periventricular microangiopathy and no CNS involvement in bcr1 patients. In conclusion, PML-RARα isoform expression at diagnosis in selective patients influences disease course over time and may even lead to early mortality due to haemorrhage. Thus, timely reporting of the specific PML-RARα isoform by clinical laboratories and CNS assessment by radiology can prevent complications leading to death in some APL patients.

Dissection of scientific compatibility of Chinese medicinal formula Realgar-Indigo naturalis as an effective treatment for promyelocytic leukemia from the perspective of toxicology.

ETHNOPHARMACOLOGICAL RELEVANCE: Realgar-Indigo naturalis formula (RIF), a first-line drug for the treatment of acute promyelocytic leukemia (APL),is also a TCM formula entirely designed based on TCM theories. There have been studies that explain the scientific connotation of the compatibility of RIF from the perspective of pharmacodynamics. However, as one of the arsenic-containing preparations, the safety of realgar is widely concerned, and there has not been systematic studies to explain the scientific connotation of RIF from the perspective of toxicology. AIM OF THIS STUDY: Dissection of scientific compatibility of Chinese medicinal formula Realgar-Indigo naturalis as an effective treatment for promyelocytic leukemia from the perspective of toxicology. MATERIALS AND METHODS: We used normal mice and an APL model to explore (i) the effects of different components on intestinal permeability, (ii) the changes in intestinal flora, and (iii) toxic effects. At the same time, a bionic extraction method was used to study the effects of different components on the dissolution of soluble arsenic in realgar under the acidic environment in the stomach and the alkaline environment in the intestinal tract. RESULTS: Salvia miltiorrhiza Bunge can repair the intestinal mucosal barrier, maintain the homeostasis of intestinal flora, intervene in the dissolution process of realgar, reverse the increase in intestinal permeability and the disturbance of intestinal flora caused by realgar, and reduce toxicity. CONCLUSION: From the perspective of toxicology, we propose new insights into the definition of the roles of each component in the RIF formula, namely realgar is the monarch, Indigo naturalis is the minister, Salvia miltiorrhiza Bungeis the assistant.

Clinical and genomic characterization of an ATRA-insensitive acute promyelocytic leukemia variant with a FNDC3B::RARB fusion.

The promyelocytic leukemia-retinoic acid receptor-α (PML::RARA) fusion is the hallmark of acute promyelocytic leukemia (APL) and is observed in over 95% of APL cases. RARA and homologous receptors RARB and RARG are occasionally fused to other gene partners, which differentially affect sensitivity to targeted therapies. Most APLs without RARA fusions have rearrangements involving RARG or RARB, both of which frequently show resistance to all-trans-retinoic acid (ATRA) and/or multiagent chemotherapy for acute myeloid leukemia (AML). We present a 13-year-old male diagnosed with variant APL with a novel FNDC3B::RARB in-frame fusion that showed no response to ATRA but responded well to conventional AML therapy. While FNDC3B has been identified as a rare RARA translocation partner in ATRA-sensitive variant APL, it has never been reported as a fusion partner with RARB and it is only the second known fusion partner with RARB in variant APL. We also show that this novel fusion confers an RNA expression signature that is similar to APL, despite clinical resistance to ATRA monotherapy.

Influence of cytokines on early death and coagulopathy in newly diagnosed patients with acute promyelocytic leukemia.

Introduction: Acute promyelocytic leukemia (APL) is a subtype of acute myeloid leukemia (AML) with a better prognosis. But early death (ED) rate remains high. APL patients are simultaneously accompanied by coagulopathy and hyperinflammation at the onset. It is not known what effects cytokines have on ED and coagulopathy in these patients. Therefore, the purposes of this study are to explore the clinical differences between APL and other types of AML, the link between cytokines and coagulopathy in newly diagnosed APL, and their roles in the ED for APL. Methods: This study retrospectively collected the information of 496 adult patients with AML (age ≥14 years at admission) newly diagnosed in the First People's Hospital of Yunnan Province between January 2017 to February 2022, including 115 APL patients. The difference of clinical manifestations between two groups [APL and AML (non-APL)] was statistically analyzed. Then, the factors affecting ED in APL patients were screened, and the possible pathways of their influence on ED were further analyzed. Results: The results indicate APL at the onset have a younger age and higher incidence of ED and DIC than other types of AML. Intracranial hemorrhage (ICH), age, and PLT count are found to be independent factors for ED in newly APL, among which ICH is the main cause of ED, accounting for 61.54% (8/13). The levels of cytokines in newly APL are generally higher than that in AML (non-APL), and those in the group of ED for APL were widely more than the control group. IL-17A and TNF-ß are directly related to the ED in newly APL, especially IL-17A, which also affects ICH in these patients. Moreover, the increase of IL-17A and TNF-ß cause the prolongation of PT in APL patients, which reflected the exogenous coagulation pathway. However, they have no effect on APTT prolongation and FIB reduction. Thus, it is speculated that IL-17A leads to early cerebral hemorrhage death in newly APL by inducing tissue factor (TF) overexpression to initiate exogenous coagulation and further leading to excessive depletion of clotting factors and prolongation of PT. Conclusions: In conclusion, compared with other types of AML, APL patients have a younger age of onset and high inflammatory state, and are more likely to develop into DIC and die early. Age, and PLT count at diagnosis are independent factors for ED of APL, especially ICH. IL-17A is confirmed to be an independent risk factor for ED and ICH of newly APL. Hence, IL-17A may serve as a predictor of ED in newly diagnosed APL patients, and controlling its expression probably reduce ED in these patients.

Epidemiology and early mortality patterns of acute promyelocytic leukemia in the United States.

There is a lack of contemporary population-based data on the epidemiology of acute promyelocytic leukemia (APL) in the United States. In this study, we aim to elucidate the demographics and early mortality patterns of APL hospitalizations utilizing the National Inpatient Sample database from 2016-2019. APL's annual age-adjusted incidence rate was 0.28/100,000, and the incidence increased with age, with the peak incidence in the 75-79 age group at 0.62/100,000. Whites constituted the majority of admissions at 67.7%, followed by Hispanics at 15.3%, the youngest racial group with a median age of 40 years. The median length of stay was 31 days for patients age < 60 years and 25 days for age ≥ 60 years (p < 0.001). After adjusting for confounders, the mean length of stay was 7 days higher in teaching hospitals compared to non-teaching hospitals (p 0.001). Overall mortality was 12.1% (22.2% for age ≥ 60 and 6.4% for < 60 years {p < 0.001}), and 56.5% of deaths happened before 7 days, with the median time to death being 6 days. The proportion of early deaths (< 7 days) in non-teaching hospitals was higher than late deaths (≥ 7 days) (19.2% vs. 5%; p 0.03), and admission to a teaching hospital was associated with lower mortality (adjusted odds ratio 0.27; p 0.01). Therefore, optimal treatment strategies need to be explored to mitigate this significant early mortality, especially in non-teaching hospitals.

Caspase-9-mediated cleavage of vimentin attenuates the aggressiveness of leukemic NB4 cells.

Vimentin is a main type 3 intermediate filament protein. It seems that abnormal expression of vimentin is contributed to the appearance of the aggressive feature of cancer cells. So that it has been reported that malignancy and epithelial-mesenchymal transition in solid tumors, and poor clinical outcomes in patients with lymphocytic leukemia and acute myelocytic leukemia have been associated with the high expression of vimentin. Vimentin is a non-caspase substrate of caspase-9 although its cleavage by caspase-9 in biological processes has not been reported. In the present study, we sought to understand whether vimentin cleavage mediated by caspase-9 could reverse the malignancy in leukemic cells. Herein, to address the issue, we investigated vimentin changes in differentiation and took advantage of the inducible caspase-9 (iC9)/AP1903 system in human leukemic NB4 cells. Following the transfection and treatment of the cells using the iC9/AP1903 system, vimentin expression, cleavage, and subsequently, the cell invasion and the relevant markers such as CD44 and MMP-9 were evaluated. Our results revealed the downregulation and cleavage of vimentin which attenuates the malignant phenotype of the NB4 cells. Considering the favorable effect of this strategy in keeping down the malignant features of the leukemic cells, the effect of the iC9/AP1903 system in combination with all-trans-retinoic acid (ATRA) treatment was evaluated. The obtained data prove that iC9/AP1903 significantly makes the leukemic cells more sensitive to ATRA.

A Pathogenic NRAS c.38G>A (p.G13D) Mutation in RARA Translocation-negative Acute Promyelocytic-like Leukemia with Concomitant Myelodysplastic Syndrome.

An acute promyelocytic leukemia (APL) patient not demonstrating the retinoic acid receptor α (RARA) translocation is rare. A 76-year-old man was diagnosed with myelodysplastic syndrome (MDS). After a year, abnormal promyelocytes were detected with pancytopenia and disseminated intravascular coagulopathy. Morphologically, the patient was diagnosed with APL; however, a genetic examination failed to detect RARA translocation. Thereafter, whole-genome sequencing revealed an NRAS missense mutation [c.38G>A (p.G13D)]. This mutation was not detected in posttreatment bone marrow aspirate, despite residual MDS. Few reports are available on similar cases. Furthermore, the NRAS c.38G>A mutation may be a novel pathogenic variant exacerbating RARA translocation-negative acute promyelocytic-like leukemia.

A Race Against Time: Early-Onset Differentiation Syndrome Following All-Trans-Retinoic-Acid (ATRA) Therapy in Acute Promyelocytic Leukemia (AML-M3).

This study reports a case of differentiation syndrome, a rare complication of ATRA (all-trans-retinoic-acid) therapy, observed in a 20-year-old male with acute promyelocytic leukemia (APML). Following the initiation of ATRA therapy for APML, the patient presented with fever, bleeding gums, bloody stool, and mouth ulcers. After 36 hours, he developed respiratory distress, hypotension, tachycardia, and hypoxemia, leading to the diagnosis of differentiation syndrome. ATRA therapy was promptly discontinued, and the patient, exhibiting type 1 respiratory failure, necessitated intubation. The management included hydroxyurea, dexamethasone, vasopressors, intravenous fluids, and furosemide. After seven days, significant improvement was observed, underscoring the importance of recognizing and promptly addressing differentiation syndrome in APML patients undergoing ATRA therapy. This case emphasizes the necessity of ATRA discontinuation, coupled with the judicious use of steroids and hydroxyurea, in the effective management of differentiation syndrome.