Administration Of All-trans Retinoic Acid Research Articles

A rare incidence of severe dermatological toxicities triggered by concomitant administration of all-trans retinoic acid and triazole antifungal in patients with acute promyelocytic leukemia: a case series and review of the literature

BackgroundAll-trans retinoic acid (ATRA) is an indispensable part of the treatment of acute promyelocytic leukemia (APL). Although, mild cutaneous toxicities like mucocutaneous xerosis, rash, and pruritus are well reported, ATRA associated severe dermatological toxicities are extremely rare. ATRA is primary metabolized by cytochrome P450 (CYP450) enzyme system, and triazole antifungals are notorious for their strong inhibitory effect on CYP450.Case presentationThree Asian APL patients experienced rare ATRA-induced severe dermatological toxicities: exfoliative dermatitis (ED) in cases 1 and 2, and necrotic scrotal ulceration in case 3. Both case 1 (33-year-old female), and case 2 (28-year-old male) landed in emergency department with dehydration, generalized skin erythema and xerosis during their induction chemotherapy. Both of these patients also developed invasive aspergillosis and required concomitant triazole antifungals during their chemotherapy. For ED, intravenous fluids and broad-spectrum antibiotics were started along with application of local emollients to prevent transdermal water loss. Although their general condition improved but skin exfoliation continued with complete desquamation of palms and soles. Dermatology was consulted, and clinical diagnosis of ED was established. Discontinuation of ATRA resulted in complete resolution of ED. Case 3 (15-year-old boy) reported two blackish mildly tender scrotal lesions during induction chemotherapy. He also had mucocutaneous candidiasis at presentation and was kept on triazole antifungal. Local bacterial & fungal cultures, and serological testing for herpes simplex virus were reported negative. Despite adequate local care and optimal antibiotic support, his lesions persisted, and improved only after temporary discontinuation of ATRA. After a thorough literature review and considering the temporal association of cutaneous toxicities with triazole antifungals, we speculate that the concomitant use of triazole antifungals inhibited the hepatic metabolism of ATRA, resulting in higher serum ATRA concentration, and markedly accentuated cutaneous toxicities in our patients.ConclusionBy highlighting this crucial pharmacokinetic interaction, we want to caution the fellow oncologists to be mindful of the inhibitory effect of triazole antifungals on CYP450. We propose using a non-myelosuppressive combination of ATRA and arsenic trioxide for management of APL hence, obliterating the need of prophylactic antifungals. However, in the event of invasive fungal infection (IFI), we suggest using alternative class of antifungals.

GSK-126 Enhances All-Trans-Retinoic Acid (ATRA) Response in Hepatocellular Carcinoma (HCC) by Upregulating RARG Expression.

Hepatocellular carcinoma (HCC) stands out as one of the most prevalent malignant tumors globally. The combination of all-trans-retinoic acid (ATRA) with FOLFOX chemotherapy has shown promise in enhancing the prognosis of HCC patients. ATRA, serving as a chemosensitizing agent, presents novel possibilities for therapeutic applications. Nevertheless, the responsiveness of HCC cells to ATRA varies. The epigenetic modifier-GSK-126 is currently under investigation as a potential antitumor drug. Our aim is to explore the molecular mechanisms underlying the diverse sensitivity of HCC patients to ATRA, and to propose a new combination regimen. This research aims to lay the groundwork for personalized medication approaches for individuals with HCC. A cell model with low expression of retinoic acid receptor Alfa (RARA), retinoic acid receptor belta (RARB), and retinoic acid receptor gamma (RARG) was established through siRNA interference. The impact of reduced expression of RARA, RARB, and RARG on the half maximal inhibitory concentration (IC50) of ATRA in Hep3B cells was assessed using the 3-(4,5-Dimethyl-2-Thiazolyl)-2,5-Diphenyl Tetrazolium Bromide (MTT) cytotoxicity assay. Flow cytometry revealed that RARG emerged as the key receptor influencing the combination's sensitivity. Conducting ChIP-qPCR analysis on genomic DNA from HCC cells through relevant websites demonstrated enrichment of the trimethylation modification of lysine 27 on histone H3 (H3K27me3) upstream of the RARG promoter. ChIP-PCR assay confirmed that GSK-126 could diminish H3K27me3 levels on the RARG promoter, subsequently elevating RARG expression. The synergistic efficacy of GSK-126 and ATRA was validated through MTT assay, flow cytometry apoptosis assay, cell cycle assay, and cell scratch assay. Our study unveiled that the insensitivity of HCC cells to ATRA could be linked to the low expression of RARG. ChIP-qPCR analysis illuminated that GSK-126 activated RARG expression by diminishing H3K27me3 enrichment in the RARG promoter region. Consequently, the concurrent administration of ATRA and GSK-126 to hepatoma cells exhibited a synergistic effect, inhibiting cell proliferation, inducing cell apoptosis, and reducing the proportion of cells in the S-phase. Our findings emphasize that the synergistic action of GSK-126 and ATRA enhances the sensitivity of HCC cells by upregulating the expression of RARG. This presents a potential foundation for personalized HCC treatment.

How to avoid early mortality in acute promyelocytic leukemia.

Acute promyelocytic leukemia (APL), a phenotypically and genotypically unique subtype of acute myeloid leukemia, has seen unprecedented advances in its management since the introduction of all-trans retinoic acid (ATRA) and arsenic trioxide. However, the phenomenal pharmacologic conversion of this once highly fatal disease to one with a long-term survival exceeding 90% among patients who survive induction remains impaired by the significant incidence of early death (ED) reaching 30% in some real-world studies. The key driver for ED in APL is catastrophic hemorrhage with a proclivity for cranial sites. Most EDs in APL are currently considered preventable. Here, we discuss the concept of early death in APL and its characteristics. Importantly, we outline implementable strategies to reduce the incidence of ED. Early recognition of APL underpins these preventive measures as significant delays in the diagnosis increase the likelihood of ED. While early administration of ATRA is often taught to all hematology trainees, this lifesaving intervention is only possible if providers, including those in emergency departments and urgent/immediate care settings, are trained to have a high index of suspicion and competence to recognize the morphologic and clinical characteristics of the disease. Other proposed strategies tackle the complications that can be present at diagnosis or arise during induction therapy and address the issues of expert consultation and protocol adherence in the management of these patients. While some of these measures appear intuitive and others aspirational, widespread adoption could bring about an era of cure for almost every patient with APL.

POU5F1 promotes the proliferation, migration, and invasion of gastric cancer cells by reducing the ubiquitination level of TRAF6

POU5F1 plays an important role in maintaining the cancer stem cell (CSC) -like properties of gastric cancer (GC) cells. The impact of POU5F1 on the proliferation and metastasis of GC was examined, along with the potential of ATRA as a specific therapeutic agent for GC. The dysregulation of POU5F1 expression in GC tissues was analyzed using public databases and bioinformatics techniques, and the disparity in POU5F1 expression between normal gastric tissues and GC tissues was further assessed through western blot, RT-qPCR, and immunohistochemistry. The present study aimed to investigate the impact of POU5F1 on the proliferation, migration, and invasion of GC cells through both in vivo and in vitro experiments. Additionally, the effects of ATRA on the proliferation, migration, and invasion of GC cells were examined using in vivo and in vitro approaches. Our findings revealed a significant upregulation of POU5F1 in GC tissues, which was found to be associated with a poorer prognosis in patients with GC. Moreover, POU5F1 was observed to enhance the proliferation, migration, and invasion of GC cells in vitro, as well as promote subcutaneous tumor growth and lung metastasis of GC cells in vivo. The overexpression of POU5F1 mechanistically triggers the process of Epithelial-mesenchymal transition (EMT) by down-regulating E-Cadherin and up-regulating N-Cadherin and VIM. POU5F1 hinders the ubiquitination of TRAF6 through negative regulation of TRIM59, thereby facilitating the activation of the NF-κB pathway. Furthermore, the administration of ATRA effectively impedes the proliferation, migration, and invasion of GC cells by suppressing the expression of POU5F1. The upregulation of POU5F1 elicits EMT, fosters the initiation of the NF-κB signaling pathway in GC cells, and stimulates the proliferation, invasion, and metastasis of GC cells. All-trans retinoic acid (ATRA) can impede these POU5F1-induced effects, thereby potentially serving as an adjunctive therapeutic approach for GC.

Time to Treatment for Patients with Suspected Acute Promyelocytic Leukemia (APL)

Introduction: Acute promyelocytic leukemia (APL) is a rare subtype of acute myeloid leukemia characterized by dysplastic promyelocytes which cause aberrations in coagulation, including hemorrhage and disseminated intravascular coagulation (DIC), leading to a rapidly fatal course if treatment is not initiated promptly. Early administration of all-trans retinoic acid (ATRA) in patients suspected of having APL is crucial for reducing morbidity and mortality. However, APL still exhibits a high early death rate in part due to failure to rapidly initiate ATRA. Therefore, we conducted a retrospective study to investigate the time it takes for ATRA to be ordered and administered to patients with suspected APL at our tertiary care University hospital. We also examined demographic and clinical variables to identify any opportunities for quality improvement. Methods: We queried our electronic medical record (EMR) for all adult patients without a prior diagnosis of APL from 2017-2021 who received at least one dose of ATRA at Thomas Jefferson University Hospital. Our analysis included 91 patients. We collected a wide range of demographic and clinical data (Table 1). The time of admission was defined as the time the admission order was placed in the EMR, and the time of administration was defined as the time the nurse marked the medication as administered. A simple general linear model was used to evaluate univariate association between each single covariate and each log transformed outcome. Model selection by Akaike information criterion (AIC) was conducted to identify the best model according to goodness of fit criteria. The smaller the AIC value, the better the model fit. The parsimonious models were obtained using backward elimination of non-significant predictors (p-values > 0.05) from the best models according to goodness of fit criteria (AIC). Results: The mean time for interval A (time from hospital admission to ordering ATRA) was 284 minutes, the mean time for interval B (time from ATRA order being placed to ATRA administration) was 104 minutes, and the mean time for interval C (time from admission to ATRA administration) was 388 minutes. Further analysis of the time intervals is presented in Table 2. The results of the demographic and clinical variables (Table 1) show that the majority of patients were transferred from an outside hospital (89%) and admitted overnight (87%). Consequently, ATRA was most often ordered (76%) and administered (70%) overnight. Only 26 (29%) patients were ultimately confirmed to have APL. During the index admission, patients required a mean of 6 units of packed red blood cells and 9 units of platelets. A quarter of patients were noted to have signs or symptoms of bleeding upon admission. The results of the multiple linear regression analysis are shown in Table 2. Only signs or symptoms of bleeding were associated with a statistically significant decrease in time to ATRA. Patients with signs of symptoms of bleeding experienced, on average, 39% less time from admission to ATRA being ordered (95% CI: 0.396-0.946, p=0.030) and 31% shorter time from admission to ATRA administration compared to those without signs or symptoms of bleeding (95% CI: 0.489-0.967, p=0.034). Conclusions: Our study highlights that, even at a large, resource-rich, academic medical center, the time to ATRA administration in patients with suspected APL is longer than optimal. The presence of bleeding was the only variable that significantly decreased the time to ATRA. Earlier identification of bleeding risk (including evolving DIC or thrombocytopenia), increased recognition of possible acute leukemia, and more rapid hematology/oncology consultation could help to decrease the time to ATRA and to avoid bleeding complications before they start. Additionally, we found that most patients (89%) were transferred from an outside hospital. Although we were not able to quantify the time from outside hospital admission to transfer, we suspect that the time was substantial and that there are even greater opportunities to improve the care of these patients by increasing ATRA availability at community hospitals, enhancing the education of all front-line providers regarding the prompt recognition of coagulopathy in the setting of suspected acute leukemia, and improving transfer center acceptance documentation that emphasizes the concern for APL and appropriate next steps in evaluation and treatment.

Prompt Initiation of Conventional Chemotherapy to Avoid Early Death in Patients with Newly Diagnosed Acute Promyelocytic Leukemia.

Objective Compared to prospective trials, the early death rate of newly diagnosed acute promyelocytic leukemia (APL) in the real-world clinical setting is higher. However, the early death rate was heterogeneous according to the reported institutes. Thus, the therapeutic approach at each institute may be important for preventing early death. This study evaluated the management strategy for untreated APL in our institute to avoid early death. Methods and Patients We identified consecutive 21 patients with untreated APL who received induction therapy including all-trans retinoic acid (ATRA) between July 2007 and December 2021 at the University of Tokyo Hospital. Results As therapeutic approaches, 16 patients (76%) received ATRA administration on the day of admission, and the remaining 5 received ATRA within 4 days from admission. Notably, all patients received conventional chemotherapy added to ATRA at a median of 1 day from admission (range: 0-9 days). As clinical outcomes, no patient died during induction therapy for untreated APL, and all achieved complete molecular remission. Conclusions Compared to the previous nationwide survey, a higher proportion of patients at our institute received conventional chemotherapy in addition to ATRA, and it was initiated more promptly, which may have helped prevent early death.

Association between Hospital Volume and Early Mortality of Newly Diagnosed Acute Promyelocytic Leukemia: A Nationwide Database Study in Japan

Background: Compared to prospective studies from high-volume hospitals, real-world data have shown higher rates of early death in patients with newly-diagnosed acute promyelocytic leukemia (APL). Previous reports suggested that in-hospital mortality seemed to be lower in high-volume hospitals in urban areas. We therefore hypothesized that hospital volume was associated with in-hospital mortality of newly diagnosed APL. To examine this association, we performed a nationwide database study in Japan. Study Design and Methods: We retrospectively identified patients with newly diagnosed APL who received induction therapy including all-trans retinoic acid (ATRA) between July 2007 and March 2018 from the Diagnosis Procedure Combination database. A multivariable logistic regression model was used to examine factors affecting in-hospital mortality. Independent variables included patient backgrounds (age, sex, body mass index, comorbidity index, and activity of daily living) and institutional factors, including hospital volume (≥5 or <5 newly diagnosed APL patients hospitalized during the study period in each hospital), location of hospital (urban or rural), educational hospital, the number of beds in each hospital, and the number of hematologists in each prefecture (obtained from The Japanese Society of Hematology). We further evaluated the association between the institutional factors and treatment practices using univariate analyses by chi-square test. Regarding treatment practices, immediate initiation of ATRA was defined as ATRA administration within one day from admission, and prompt initiation of conventional chemotherapy was defined as the start within seven days from admission. Results: We identified a total of 1,138 patients who received induction therapy including ATRA. During hospitalization, 195 (17%) patients died at a median of 11 days (interquartile range, 5-25). In the multivariable model, treatment at high-volume hospitals was significantly associated with lower in-hospital mortality (odds ratio, 0.60; 95% confidence interval, 0.39-0.91). In-hospital mortality was not significantly associated with the number of beds in each hospital, location of hospital, educational hospital, or the number of hematologists in the prefecture. We found that patients treated in high-volume hospitals were significantly more likely to receive immediate initiation of ATRA than those in low-volume hospitals (83% vs. 76%, p=0.004). Similarly, higher hospital volume was associated with a higher proportion of prompt conventional chemotherapy in addition to ATRA (55% vs. 41%, p<0.001). Discussion and Conclusions: The present study using a nationwide database showed that treatment at high-volume hospitals was significantly associated with lower in-hospital mortality in patients with newly diagnosed APL. In such high-volume hospitals, treatments were performed more promptly. Our results from real-world data may suggest the benefits of centralizing APL patients to high-volume hospitals.

TMIC-72. ALL-TRANS RETINOIC ACID INDUCES DURABLE TUMOR IMMUNITY IN IDH MUTANT GLIOMAS AND CIRCUMVENTS REPRESSION OF CRBP1-RETINOIC ACID AXIS

Abstract Diffuse gliomas are fatal, immunologically cold tumors characterized by mutations in isocitrate dehydrogenase 1 or 2 (IDH1/2) genes. IDH mutations have been shown to result in global genomic hypermethylation and drastically altered transcriptomic landscape. We and others have shown that IDH mutation is direct responsible for the immunological cold landscape observed in IDH mutated glioma. Using a combination of animal models and patient-derived glioma stem cells (GSCs), we identify retinoic acid signaling as a primary regulator of innate and adaptive immune activation in IDHm gliomas. Using the Sleeping Beauty (SB) orthotopic murine model of IDH glioma, which faithfully recapitulates the TME seen in patients, we show that intracellular accumulation of oncometabolite 2-HG leads to hypermethylation and transcriptional repression of Retinol Binding Protein-1 (RBP1), which encode CRBP1, a key chaperone protein required for intracellular all-trans-retinoic-acid biosynthesis in glial cells. Restoration retinoic acid signaling through the addition of all-trans retinoic acid (ATRA) resulted in spontaneous tumor regression and prolonged survival. ATRA administration is further correlated with increased CD8, NK, M1 macrophages and decreased Treg and MDSC populations within the TME. Single-cell sequencing of the TME shows increased type I interferon signaling, myeloid cell polarization, T cell activation, and TCR diversity. Using knockdown and overexpression techniques in patient-derived GSCs, we show that CRBP1 activity is critical for NK mediated immune surveillance and cytotoxicity through regulation of NKG2D ligand expression and immune cell migration through differential regulation of CXCL12 and CCL2. In summary, epigenetic silencing of RBP1 by 2-HG induced hypermethylation leads to a global immune dysregulation resulting in an immunologically cold landscape. Restoration of retinoic acid signaling is a promising immunotherapeutic approach for the treatment of IDHm gliomas.

Treatment for relapsed acute promyelocytic leukemia.

The advent of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) has significantly improved the outcomes of acute promyelocytic leukemia (APL); nevertheless, a small fraction of patients still experience relapse. Due to the infrequency of APL relapse coupled with the rapid change in the therapeutic landscape, there are limited available data regarding the treatment of relapsed APL. In this situation, however, ATO-based therapy has been shown to result in high rates of hematological and molecular complete remission (CR). Autologous hematopoietic cell transplantation (HCT) is considered the postremission therapy of choice when patients achieve molecular CR, whereas recent studies have suggested that molecular CR is not prerequisite for the success of autologous HCT. Allogeneic HCT can be reserved for selected patients, i.e., those who cannot achieve CR and those who relapse after autologous HCT, because of high toxicities and the expectation of highly favorable outcomes with autologous HCT during CR. For patients who are ineligible for HCT, prolonged administration of ATRA + ATO would be a viable option. To further refine the therapy for patients with relapsed APL, it is imperative to aggregate clinical data of patients who relapse after the ATRA + ATO frontline therapy within the framework of national and international collaboration.

All-trans Retinoic Acid has Limited Therapeutic Effects on Cognition and Hippocampal Protein Expression After Controlled Cortical Impact

Traumatic brain injury (TBI) is known to impair synaptic function, and subsequently contribute to observed cognitive deficits. Retinoic Acid (RA) signaling modulates expression of synaptic plasticity proteins and is involved in hippocampal learning and memory. All trans-retinoic acid (ATRA), a metabolite of Vitamin A, has been identified as a potential pharmacotherapeutic for other neurological disorders due to this role. This study conducted an ATRA dose response to determine its therapeutic effects on cognitive behaviors and expression of hippocampal markers of synaptic plasticity and RA signaling proteins after experimental TBI. Under isoflurane anesthesia, adult male Sprague Dawley rats received either controlled cortical impact (CCI, 2.5 mm deformation, 4 m/s) or control surgery. Animals received daily intraperitoneal injection of 0.5, 1, 5, or 10 mg/kg of ATRA or vehicle for 2 weeks. Animals underwent motor and spatial learning and memory testing. Hippocampal expression of synaptic plasticity proteins neurogranin (Ng), and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor GluA1 sub-unit, as well as RA signaling proteins STRA6, ADLH1a1, CYP26A1 and CYP26B1 were evaluated by western blot at 2-weeks post-injury. ATRA treatment significantly recovered Ng synaptic protein expression, while having no effect on motor performance, spatial learning, and memory, and GluA1 expression after TBI. RA signaling protein expression is unchanged 2 weeks after TBI.Overall, ATRA administration after TBI showed limited therapeutic benefits compared to the vehicle.

Acute promyelocytic leukemia: A single institution's experience.

e19001 Background: Acute Promyelocytic Leukemia (APL) is highly curable but carries high risk of early morbidity and mortality, including hemostatic abnormalities, differentiation syndrome and infection. Induction regimens include all-trans-retinoic acid (ATRA) to promote promyelocyte differentiation and arsenic trioxide (ATO), with chemotherapy added for high-risk patients. Our objective was to characterize clinical characteristics and complications during APL induction. Methods: Electronic medical records were screened for ATRA, ATO, or idarubicin from 2011-2021. APL induction hospitalization records were reviewed for: demographics, white blood cell (WBC) and platelet count at presentation, fibrinogen at presentation, time to ATRA administration, time to complete remission (CR), infection, thrombohemorrhagic complications, ATO related QT interval prolongation, incidence of and time to differentiation syndrome. Results: 56 patients (pts) (median age 50) were analyzed. Mean time from initial presentation at our institution to ATRA administration was 1.5 days (range 0-6 days). Findings upon arrival: median WBC 1.7 K/UL (range 0.3-134.9), median platelets 32 K/UL (range 7-373), hypofibrinogenemia in 39.2% (N = 22) (median 161 MG/DL, range 35-473). 80.3% had documented thrombohemorrhagic complications during induction hospitalization: DIC (N = 24), venous thromboembolism (N = 12), gastrointestinal bleed (N = 6), oral mucosal bleeding (N = 5), vaginal bleeding (N = 3), gross hematuria (N = 3), intracranial hemorrhage (N = 3), epistaxis (N = 2), intraocular hemorrhage (N = 1), cerebral vascular accident (CVA) (N = 1). 21% (N = 12) developed differentiation syndrome with mean time of onset of 8.8 days (range 1-23 days). 55% (N = 31) had clinically significant infections most commonly neutropenic fever (N = 13), bacterial pneumonia (N = 10), skin (N = 5) and bacteremia (N = 5). 48 pts were given ATO during induction and 31% (N = 15) developed QT interval prolongation with no arrhythmias in the cohort. Among 8 pts who did not receive ATO, one died prior to therapy initiation and 7 were treated prior to ATO as standard of care. Among evaluable patients (N = 51): 98% (N = 50) achieved complete remission (CR) or complete remission with incomplete count recovery (CRi). Median time to CR was 35 days (range 27-50). 6 pts did not achieve CR or had unknown status: 1 patient died during induction (CVA) and 5 had post-induction bone marrow evaluations at outside facilities. Conclusions: Thrombohemorrhagic complications, infection and differentiation syndrome are critical to be mindful of during the early phase of treatment in APL. Our data adds to the landscape of knowledge regarding the incidence and timeline of complications. Although we observed prolonged QTc in pts on ATO, there were no arrhythmias detected and all pts were able to quickly resume therapy.

The treatment with all-trans retinoic acid causes apoptosis without chromosomal instability in adipose-derived stem cells and might act starting the browning process

Introduction: The knowledge about the biology of obesity and apoptosis induction of adipose-derived stem cells (ADSCs) may support in the development of new therapies. Objective: The present research aimed to investigate the toxicogenic effect of all-trans retinoic acid (ATRA) as well as its influence in the adipogenic differentiation and expression of genes related to DNA damage, cell cycle and thermogenesis. Methodology: Cell cultures of human adipose-derived stem cells were treated for 12 hours with ATRA (20.75 μM) and were performed the adipogenic differentiation, comet assay, micronucleous, cell death, cell cycle and qPCR. Results: The ATRA treatment decreased the capacity of adipogenic differentiation of ADSCs. The comet assay demonstrated increase in nucleoid frequency with genomic damage and scoring. However, these damages were not fixed at the chromosome level, since the tail moment was not significant. The treatment with ATRA increased cytotoxicity and increased cell death by apoptosis. The relative expression of CHEK-1, CHEK-2, CDC25A, CDC25C, ATM and ATR decreased and only UCP1 increased significantly. Conclusion: The results of the present study demonstrate that the use of ATRA induces genomic damage in ADSCs, although it was eliminated in the apoptosis process. Therefore, administration of ATRA in ADSCs did not cause chromosomal instability, which suggests toxicogenic safety. Also it was considered that ATRA might active the browning effect. Thus, this compound is considered a promising candidate for the development of novel therapies for the treatment of obesity and / or localized fat by the use of mesotherapy.

Effect of Therapeutically Related Drugs on Coagulation-Anticoagulation Balance in Acute Promyelocytic Leukemia.

Acute promyelocytic leukemia (APL) usually presents with a series of coagulation-anticoagulation disturbance. Early administration of All-trans retinoic acid (ATRA) can reduce the risk of bleeding, but the potential for thrombosis needs to be addressed in some cases. The role of arsenic agent in correcting coagulation disorder remains to be studied, but oral arsenic agent shows potential advantages in coagulation recovery compared with intravenous agent, and chemotherapy can aggravate the progress of coagulation disease. In addition to early application of ATRA, avoiding invasive procedures and transfusion support can reduce the risk of bleeding. Whether the administration of heparin, thrombomodulin, recombinant factor VIIa or antifibrinolytics reduces the risk of bleeding and thrombosis associated with APL remains to be further explored, and their routine use outside of clinical trials is not recommended. This article reviews the effects of related drugs on coagulation-anticoagulation balance in APL patients.

Relapse Analysis and Resistance Mutations of PML-Rara Fusion Gene in Acute Promyelocytic Leukemia Patients Treated with All-Trans Retinoic Acid and Arsenic

The clinical manifestations, management, and prognosis of acute promyelocytic leukemia (APL) are distinctive in acute myeloid leukemia (AML). Administration of all-trans retinoic acid (ATRA) and arsenic agents have greatly improved the outcome of APL from the most lethal to the most curable subtype AML. Unfortunately, relapse is still observed. And in the case of combined medication with ATRA and arsenic, the resistance mutation spectrum of PML-RARA is far from being revealed. We retrospectively analyzed 40 APL patients that admitted to our hospital from Jan. 2013 to Jul. 2020. There were 21 males and 19 females, aged 6-65 years (median age 31.5), and follow-up time was 3-210 months (median time 58.85 months).There were 3 cases that developed secondary tumors, although APL remission has been achieved. One developed refractory AML with KMT2A-MLLT3 fusion during the consolidation treatment one year after the diagnosis of APL. One case relapsed with APL 5 years after the initial diagnosis, and she developed refractory AML with RUNX1-MECOM fusion 3.5 years more after enduring multiple relapses and treatment courses. Another case developed AML-M2 3.5 years after the initial diagnosis of APL, and achieved sustained remission again through allogeneic hematopoietic stem cell transplantation (allo-HSCT).A total of 8 cases came to our hospital at the initial onset of APL, and 1 came during remission. All these cases got sustained remission through combined triple therapy (ATRA, arsenic, and chemotherapy), with the follow-up time of 3 to 37 months (median 20.5 months). No PML-RARA resistant mutation was detected in these 9 cases.A total of 28 cases came to our hospital after APL relapse. The time from APL onset to the first relapse was 9-189 months (median 34 months). PML-RARA resistance mutations were detected in 9 cases, including 8 cases that carry single RARA mutations each, and 1 case that relapsed with multiple extramedullary infiltrations carry quadruple mutations (PML S214L-A216T and RARA R276W-H298N) (Figure 1a and b). A total of 4 cases underwent allo-HSCT after APL relapse. One of them relapsed 6 months after allo-HSCT, and the other 3 got sustained remission with the follow-up time of 47, 39, and 52 months, respectively.There were 2 cases relapsed after maintaining sustained remission for more than 5 years. One was a 58-year-old male who achieved sustained remission after 2.5 years of combined triple therapy. However, APL recurred 16 years after the primary diagnosis. He achieved remission again and now underwent the consolidation course of combined triple therapy. Another was a 23-year-old male who achieved sustained remission after combined arsenic and chemotherapy, but APL relapsed 75 months after the primary diagnosis. He was resistant to combined triple therapy and achieved remission through allo-HSCT. We failed to retrieve archived specimens at the first onset of APL for genomic variation comparison with the second onset. Therefore, we could not determine whether these two cases were relapsed from the original APL or developed another APL.Although we have achieved a high remission rate and long-term survival for APL through combined triple therapy, relapse and secondary tumors still occur in some cases. Especially for cases that endure heavy treatment, genomic toxicity may promote the oncogenesis of secondary tumors. Also, APL may recur over 5 years after the primary diagnosis and sustained remission. Whether there were inherited predisposing factors in these cases is worthy of further investigation.The incidence of PML and RARA resistant mutations in cases resistance for ATRA and arsenic is not very high. This may be related to the combination use of chemotherapeutic drugs and suggests underlying resistance mechanisms. Although both ATRA and arsenic were used in most cases, the incidence of ATRA resistance mutations is significantly higher than that of arsenic, which might attribute to the sparse interaction sites of arsenic and PML.A better combination strategy of arsenic, ATRA, with or without chemotherapy is worthy of further investigation to reduce the incidence of secondary tumors and relapse. Adhering to a systematically planed treatment course is essential for acquiring rapid remission and reduction of relapse. Treatment compliance should be paid attention to guaranteed, especially during the oral administration courses outside the hospital. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Administration of All-Trans Retinoic Acid to Pregnant Sows Alters Gut Bacterial Community of Neonatal Piglets With Different Hoxa1 Genotypes.

Administration of all-trans retinoic acid (ATRA) to pregnant sows improves developmental defects of Hoxa1–/– fetal pigs, and this study aimed to explore the influence of maternal ATRA administration during pregnancy on gut microbiota of neonatal piglets. Samples of jejunal and ileal meconium of neonatal piglets before suckling were collected including 5 Hoxa1–/– and 20 non-Hoxa1–/– (Hoxa1+/+ and Hoxa1+/−) neonatal piglets from the control group and 5 Hoxa1–/– and 7 non-Hoxa1–/– neonatal piglets from the experimental group. Results indicated that Hoxa1 mutation shaped the bacterial composition of the jejunum and ileum of neonatal piglets and Hoxa1–/– neonatal piglets had significantly higher diversity and species richness, higher relative abundance of phylum Bacteroidetes, lower relative abundances of phylum Firmicutes and genus Lactobacillus, and lower ratio of Firmicutes to Bacteroidetes than non-Hoxa1–/– neonatal piglets. After maternal ATRA administration, Hoxa1–/– neonatal piglets had significantly higher diversity and species richness, higher relative abundances of two bacterial phyla (Bacteroidetes and Proteobacteria), and lower relative abundances of phylum Firmicutes and genus Lactobacillus in the jejunum than non-Hoxa1–/– neonatal piglets. Hoxa1–/– neonatal piglets delivered by sows with maternal ATRA administration had lower diversity and species richness and higher relative abundance of phylum Firmicutes in the jejunum than Hoxa1–/– neonatal piglets born by sows with no maternal ATRA administration. Non-Hoxa1–/– neonatal piglets delivered by sows with maternal ATRA administration had higher diversity and species richness and significantly lower relative abundances of phyla Firmicutes and Actinobacteria and genus Lactobacillus in the ileum than non-Hoxa1–/– neonatal piglets born by sows with no maternal ATRA administration. Hoxa1 mutation decreased the expression of bacterial genes involved in ABC transporters, purine metabolism, and aminoacyl-tRNA biosynthesis and increased the expression of bacterial genes involved in two-component system, starch and sucrose metabolism, and arginine and proline metabolism. Maternal ATRA administration decreased the expression of bacterial genes involved in arginine and proline metabolism, peptidoglycan biosynthesis, and fatty acid biosynthesis. Hoxa1 mutation resulted in bacterial dysbiosis of the small intestine of Hoaxa1–/– neonatal piglets, and maternal ATRA administration restored the bacterial dysbiosis of Hoxa1–/– neonatal piglets and altered the bacterial composition of the small intestine of non-Hoxa1–/– neonatal piglets.

Risk factors for early in-hospital death in patients who developed coagulopathy during induction therapy for acute promyelocytic leukemia: a nationwide analysis in Japan.

To prevent early death, management of coagulopathy is important in patients with untreated acute promyelocytic leukemia (APL). This study aimed to clarify factors associated with in-hospital death in patients with coagulopathy during induction therapy for APL. We retrospectively identified patients with newly diagnosed APL who received induction therapy including all-trans retinoic acid (ATRA) and developed coagulopathy, using a nationwide inpatient database in Japan. Of 1115 eligible patients, 175 (15%) died at a median of 13days (interquartile range, 7-30) after admission. In the multivariable analysis, compared with younger patients (aged < 40years), the occurrence of in-hospital death was significantly more common among older patients (aged ≥ 40 and < 60years: odds ratio = 2.58 [95% confidence interval: 1.29-5.19]; aged ≥ 60 and < 80years: 7.66 [3.89-15.10]; aged ≥ 80years: 16.83 [7.41-38.21]). Delayed initiation of ATRA and no conventional chemotherapy were significantly associated with in-hospital death (1.79 [1.16-2.76] and 2.40 [1.47-3.92], respectively). A total of 699 patients (63%) received anticoagulant therapies, but none of these was significantly associated with lower mortality. Although the present study was constrained by a lack of laboratory findings because of database limitations, the results showed that untreated patients with APL, especially the elderly, had a poor prognosis. Immediate administration of ATRA may reduce in-hospital mortality.

Characteristics and predictors of early hospital deaths in newly diagnosed APL: a 13-year population-wide study

Despite therapeutic advances, early death (ED) remains a major factor curtailing survival of acute promyelocytic leukemia (APL). Studies examining factors that cause early death (ED; within 30 days of admission) and the correlation of survival with the timing of administration of all-trans retinoic acid (ATRA) and hemostatic parameters are scarce. We performed a cohort analysis of nonselect patients with newly diagnosed APL who presented to the health care system in Hong Kong, where oral arsenic trioxide was used. From 1 January 2007 to 30 April 2020, 358 patients (median age, 47 [1-97] years) with newly diagnosed APL were identified. ED occurred in 56 patients (16%): 11 (3%) died in the first 2 days after admission (intracranial hemorrhage [ICH], n = 6; APL-differentiation syndrome [APL-DS], n = 4; infection, n = 1); 22 (6%) died within 3 to 7 days (ICH, n = 12; APL-DS, n = 8; infections, n = 2), and 23 (6%) died within 8 to 30 days (ICH, n = 7; APL-DS, n = 11; infection, n = 5). Factors significantly associated with ED by multivariate analysis included male sex (P = .01); presenting leukocyte count ≥10 × 109/L (P = .03); fibrinogen <1.5 g/L (P = .02); and ATRA administration >24 hours after hospital admission (P < .001). After a median follow-up of 47 (0-166) months, the 5- and 10-year overall survival (OS) was 68.6% and 61.2%, respectively. Excluding EDs, the 5- and 10-year post–30-day OS improved to 81.3% and 72.5%. Early administration of ATRA (<24 hours) and vigorous correction of hemostatic abnormalities, including hypofibrinogenemia, are key to reducing ED.

Rate of Differentiation Syndrome in Patients Based on Timing of Initial All-Trans Retinoic Acid Administration

Rate of Differentiation Syndrome in Patients Based on Timing of Initial All-Trans Retinoic Acid Administration

RARB Translocations in Acute Promyelocytic Leukemia without Rara translocation

Introduction: Acute promyelocytic leukemia (APL) is defined by unique morphological features, typically abnormal promyelocytes containing azurophilic granules. Genomic basis of APL is characterized by the translocation t(15;17)(q22;q21), inducing fusions between promyelocytic leukemia (PML) and retinoic acid receptor-a (RARA). APL cells with PML-RARA respond to all-trans retinoic acid (ATRA) and arsenic trioxide (ATO), and recent clinical trials have achieved excellent outcome for typical APL with PML-RARA . Although a certain fraction of APL cases lacks PMR-RARA, most of them had translocation including RARA and other genes, namely, PLZF, NPM, and TBL1XR1 . Eventually, all known APL-associated translocations involve RARA, accounting for 99% of APL. However, RARA rearrangement is unable to be detected in the rest of APL cases, and molecular mechanisms underlying this small subset is still unclear. We here analyzed APL cases without RARA translocation, and identified a novel RARB fusion in the majority of patients with RARA -negative APL.Materials and methods: We first performed whole-genome sequencing to identify potential genomic alterations in a case with RARA -negative APL, and successfully identified an in-frame fusion between TBL1XR1 and RARB . As RARB, encodes retinoic acid receptor-b, and RARA are both members of the nuclear receptor superfamily, we further searched for RARB alterations in additional 4 cases diagnosed APL morphologically lacking RARA translocation, using whole-transcriptome sequencing, RT-PCR, and FISH, according to sample availability. The five RARA -negative APL cases consist of one male and four females, and the median age of the cases were 3 years (range, 2-4 years of age). All cases were refractory to ATRA, and multiagent chemotherapy was given as acute myeloblastic leukemia but four cases suffered relapse or failed to achieve remission. To investigate functional effect of this novel fusion on leukemogenesis, we then transduced cell lines, bone marrow cells of mice, and human cord blood with TBL1XR1-RARB, RARB, and PML-RARA . Influence of all-trans retinoic acid (ATRA), arsenic trioxide (ATO) was also assessed.Results: Four of the five (80%) cases had RARB translocations (three had the TBL1XR1-RARB fusion (Figure), and one had RARB rearrangement detected by FISH although partner gene of the case could not be determined). The novel fusion protein, TBL1XR1-RARB, could homodimerize, and diminished transcriptional activity with a dominant negative effect on both RARA and RARB. Transduced U937 cell lines with TBL1XR1-RARB showed cell differentiation with increased expression of CD11b when treated with ATRA, and neutrophil differentiation was confirmed by morphology. These effect of TBL1XR1-RARB were cancelled by administration of ATRA, although the impact was partial compared to that of PML-RARA. ATO, leading PML-RARA degradation by biding PML, could not affect TBL1XR1-RARB transduced cell lines. Colony replating assay demonstrated that this TBL1XR1-RARB could enhance replating ability of murine bone marrow. Differentiation of human cord blood was blocked by TBL1XR1-RARB, as well as PML-RAR, which was also confirmed by morphological features.Conclusion: We found that the majority of RARA-negative APL had RARB translocation, defining a novel genetic subgroup in APL. Unlike wild type RARB, the TBL1XR1-RARB proteins homodimerize, suppress retinoic acid pathway, and are confirmed as having oncogenic potency, as well as PML-RARA. Our study confirmed that dysregulation in retinoic acid pathway was a hallmark of APL, however, response to ATRA was partial, which is concordant to clinical resistance to ATRA of RARA -negative APL. Thus, in the context of precision medicine, RARB alteration should be screened for RARA -negative APL cases. [Display omitted] DisclosuresKitamura:Daiichi Sankyo: Research Funding.

All-trans-retinoic acid restores CD4+ T cell response after sepsis by inhibiting the expansion and activation of myeloid-derived suppressor cells

BackgroundPatients are susceptible to immunosuppression in late-stage of sepsis, in which myeloid-derived suppressor cells (MDSCs) is an important contributor. This study aims to investigate whether all-trans-retinoic acid (ATRA), which has been proved to inhibit MDSCs generation in cancer, will ameliorate sepsis-induced immuno-suppression through modulating MDSCs. MethodsA clinically relevant “two-hit’’ model of sepsis, the cecal ligation and puncture (CLP) model and secondary pneumonia model, were established in mice. The effects of ATRA on the mortality, the bacterial burden, the expansion and activity of CLP-induced MDSCs, as well as the function of CD4+ T cells were evaluated. ResultsIn CLP model, ATRA was found to reduce frequency of MDSCs in spleen of mice and inhibit activity of MDSCs by regulating the generation and activity of arginase-1 and iNOS, and the secretion of immune-supressive cytokines. ATRA administration eventually reduced mortality of secondary infection by Legionella pneumophila in CLP-surviving mice, which might be associated with the restoration of CD4+ T cells proliferating and secreting activity. ConclusionATRA can restore CD4+ T cells dysfunction in sepsis by modulating the expansion and function of MDSCs and therefore provides a potential therapy that targets the immunosuppressive state of sepsis.