Treatment Of Acute Promyelocytic Leukemia 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.

Diagnosis and management of acute promyelocytic leukemia: Brazilian consensus guidelines 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.

Inhibition of NRF2 signaling overcomes acquired resistance to arsenic trioxide in FLT3-mutated Acute Myeloid Leukemia.

De novo acute myeloid leukemia (AML) patients with FMS-like tyrosine kinase 3 internal tandem duplications (FLT3-ITD) have worse treatment outcomes. Arsenic trioxide (ATO) used in the treatment of acute promyelocytic leukemia (APL) has been reported to be effective in degrading the FLT3 protein in AML cell lines and sensitizing non-APL AML patient samples in-vitro. We have previously reported that primary cells from FLT3-ITD mutated AML patients were sensitive to ATO in-vitro compared to other non-M3 AML and molecular/pharmacological inhibition of NF-E2 related factor 2 (NRF2), a master regulator of antioxidant response improved the chemosensitivity to ATO and daunorubicin even in non FLT3-ITD mutated cell lines and primary samples.We examined the effects of molecular/pharmacological suppression of NRF2 on acquired ATO resistance in the FLT3-ITD mutant AML cell line (MV4-11-ATO-R). ATO-R cells showed increased NRF2expression, nuclear localization, and upregulation of bonafideNRF2 targets. Molecular inhibition of NRF2 in this resistant cell line improved ATO sensitivity in vitro. Digoxin treatment lowered p-AKT expression, abrogating nuclear NRF2 localization and sensitizing cells to ATO. However, digoxin and ATO did not sensitize non-ITD AML cell line THP1 with high NRF2 expression. Digoxin decreased leukemic burden and prolonged survival in MV4-11 ATO-R xenograft mice. We establish that altering NRF2 expression may reverse acquired ATO resistance in FLT3-ITD AML.

History of Developing Acute Promyelocytic Leukemia Treatment and Role of Promyelocytic Leukemia Bodies.

The story of acute promyelocytic leukemia (APL) discovery, physiopathology, and treatment is a unique journey, transforming the most aggressive form of leukemia to the most curable. It followed an empirical route fueled by clinical breakthroughs driving major advances in biochemistry and cell biology, including the discovery of PML nuclear bodies (PML NBs) and their central role in APL physiopathology. Beyond APL, PML NBs have emerged as key players in a wide variety of biological functions, including tumor-suppression and SUMO-initiated protein degradation, underscoring their broad importance. The APL story is an example of how clinical observations led to the incremental development of the first targeted leukemia therapy. The understanding of APL pathogenesis and the basis for cure now opens new insights in the treatment of other diseases, especially other acute myeloid leukemias.

Abstract 266: The effects of retinoid agents and retinoic acid receptor genotype on proliferation, differentiation, and stem cells in colorectal cancer

Abstract Understanding how to therapeutically target colonic stem cells (SCs) is important because SC overpopulation drives CRC growth and development. Our goal is to therapeutically sensitize cancer SCs (CSCs) to the differentiation-inducing effects of retinoid agents. We previously found that ALDH specifically marks normal and malignant colonic SCs. We also found that retinoic acid (RA) receptors and other RA signaling components are selectively expressed in ALDH+ SCs, indicating that RA signaling occurs through ALDH+ SCs. Because all-trans retinoic acid (ATRA) is a highly effective treatment for acute promyelocytic leukemia, which is caused by a genetic translocation involving retinoic acid receptor alpha (RARA), we conjecture that the response of RA agents may be effective against solid tumors depending on their pathway genotype. Our bioinformatics analysis on mutations and overexpression of RA signaling component genes in CRC showed that most of the RA pathway genes are altered in human CRCs. Therefore, we hypothesize that the ability of retinoid agents and retinoid metabolism blocking agents to induce differentiation of CSCs depends on the RA pathway genotype of CRC cells.Testing the effect of various retinoid drugs on cell proliferation shows that RA pathway genotype affects the response of RA agents in CRC cell lines. HCT116 and SW480 CRC cell lines, which have RA receptor mutations, displayed resistance to ATRA. In contrast, HT29 CRC cells that have wild-type RA receptors are sensitive to ATRA. All three cell lines however showed similar dose responses to the ATRA metabolizing enzyme, CYP26A1 inhibitor Liarozole. This finding indicates that regardless of RA receptor mutations, inhibition of ATRA metabolism can increase intracellular RA levels in a similar manner on all three cell lines to induce anti-proliferative effects. We used CRISPR-Cas9 gene editing to knock out the RARA gene in HT29 cells and evaluated its response to ATRA compared to HT29 cells. The RARA knockout derived lines showed reduced sensitivity to ATRA treatment and a slower rate of cell division compared to HT29 control cells. Additionally, Nanostring mRNA profiling analysis shows that ATRA treatment of HT29 cells increases expression of RARA, CYP26A1, and KRT20 (differentiation marker); and decreased decreases expression of CSC markers LGR5 and ALDH1A1. Altogether, these findings indicate that upregulated RA signaling can reduce cell proliferation, increase differentiation, and decrease CSC numbers in CRCs. Overall, our findings indicate that colon SCs are regulated by RA signaling mechanisms and dysregulation of RA signaling contributes to the SC overpopulation that drives CRC growth. Thus, therapeutically sensitizing CSCs to differentiation-inducing effects of retinoid agents should provide insight into designing new SC-targeted therapies for CRC. Citation Format: Victoria O. Hunsu, Caroline O. Facey, Bruce M. Boman. The effects of retinoid agents and retinoic acid receptor genotype on proliferation, differentiation, and stem cells in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 266.

Research progress on arsenic, arsenic-containing medicinal materials, and arsenic-containing preparations: clinical application, pharmacological effects, and toxicity.

Introduction: The toxicity of arsenic is widely recognized globally, mainly harming human health by polluting water, soil, and food. However, its formulations can also be used for the clinical treatment of diseases such as leukemia and tumors. Arsenic has been used as a drug in China for over 2,400 years, with examples such as the arsenic-containing drug realgar mentioned in Shennong's Herbal Classic. We have reviewed references on arsenic over the past thirty years and found that research has mainly focused on clinical, pharmacological, and toxicological aspects. Results and Discussion: The finding showed that in clinical practice, arsenic trioxide is mainly used in combination with all-trans retinoic acid (ATRA) at a dose of 10mg/d for the treatment of acute promyelocytic leukemia (APL); realgar can be used to treat acute promyelocytic leukemia, myelodysplastic syndrome, and lymphoma. In terms of pharmacology, arsenic mainly exerts anti-tumor effects. The dosage range of the action is 0.01-80μmol/L, and the concentration of arsenic in most studies does not exceed 20μmol/L. The pharmacological effects of realgar include antiviral activity, inhibition of overactivated lactate dehydrogenase, and resistance to malaria parasites. In terms of toxicity, arsenic is toxic to multiple systems in a dose-dependent manner. For example, 5μmol/L sodium arsenite can induce liver oxidative damage and promote the expression of pro-inflammatory factors, and 15μmol/L sodium arsenite induces myocardial injury; when the concentration is higher, it is more likely to cause toxic damage.

Risk factors and remaining challenges in the treatment of acute promyelocytic leukemia.

The treatment of acute promyelocytic leukemia (APL) has evolved with the introduction of all-trans retinoic acid (ATRA) and subsequent arsenic trioxide (ATO), particularly in standard-risk APL with an initial white blood cell count (WBC) < 10,000/μL, where a high cure rate can now be achieved. However, for some patients with risk factors, early death or relapse remains a concern. Insights from the analysis of patients treated with ATRA and chemotherapy have identified risk factors such as WBC, surface antigens, complex karyotypes, FLT3 and other genetic mutations, p73 isoforms, variant rearrangements, and drug resistance mutations. However, in the ATRA + ATO era, the significance of these risk factors is changing. This article provides a comprehensive review of APL risk factors, taking into account the treatment approach, and explores the challenges associated with APL treatments.

Evolution in treatment of acute promyelocytic leukemia: a major victory.

Evolution in treatment of acute promyelocytic leukemia: a major victory.

Identification of a novel fusion gene, RARA::ANKRD34C, in acute promyelocytic leukemia.

Acute promyelocytic leukemia (APL) is a specific subtype of acute myeloid leukemia that is distinguished by the chromosomal translocation t(15;17)(q24;q21), which leads to the fusion of the promyelocytic leukemia (PML) gene with the retinoic acid receptor alpha (RARA). Recently, we identified a novel fusion gene in APL, RARA::ankyrin repeat domain 34C (ANKRD34C), identified its functions by morphological, cytogenetic, molecular biological and multiplex fluorescence in situ hybridization analyses, and demonstrated the potential therapeutic effect clinically and experimentally of all-trans retinoic acid (ATRA); the findings have important implications for the diagnosis and treatment of atypical APL.

Arsenic treatment of acute promyelocytic leukemia affects neutrophil function in a compensatory manner

BackgroundArsenic (ATO) and retinoic acid (ATRA) are successfully used as chemotherapy-free regimens to treat acute APL. Compared to traditional chemotherapy approaches, this therapy evokes fewer haematological side effects, such as severe neutropenia and thrombocytopenia, but little is known about the impact of the treatment on neutrophil function.MethodsWe included three patients undergoing consolidation treatment for APL. To evaluate the functionality of neutrophils, we assessed chemotaxis, ROS production, and neutrophil extracellular trap (NET) release during different time points of the treatment and compared them with neutrophils from healthy donors.ResultsWe revealed that the chemotactic ability of neutrophils isolated from APL patients was decreased before starting each cycle of treatment. However, there was an increase in chemotactic ability in the first week of treatment compared to other time points. Additionally, we observed increased ROS production at the start of the treatment cycle. In vitro exposure of isolated neutrophils from healthy donors to ATO led to decreased chemotaxis at high ATO concentrations exceeding those achieved in vivo, while ROS production was not affected. Chemotaxis and ROS production were not altered by exposure to ATRA in vitro and neither ATO nor ATRA had an effect on neutrophils’ ability to release NETs.ConclusionsOur study suggests that ATO and ATRA therapy alter neutrophil function by increasing chemotaxis and reducing ROS production. The effect on neutrophil function does not, however, seem to impact infection susceptibility in our patients, indicating that the enhanced functionality might compensate for the lowered neutrophil count.

Ultrathin 2D As2Se3 Nanosheets for Photothermal-Triggered Cancer Immunotherapy.

Arsenic trioxide (As2O3) has achieved groundbreaking success in the treatment of acute promyelocytic leukemia (APL). However, its toxic side effects seriously limit its therapeutic application in the treatment of solid tumors. To detoxify the severe side effects of arsenic, herein we synthesized innovative 2D ultrathin As2Se3 nanosheets (As2Se3 NSs) with synergistic photothermal-triggered immunotherapy effects. As2Se3 NSs are biocompatible and biodegradable under physiological conditions and can release As(III) and Se(0). Furthermore, selenium increases the immunomodulatory efficacy of arsenic treatments, facilitating reprogramming of the tumor microenvironment by As2Se3 NSs by enhancing the infiltration of natural killer cells and effector tumor-specific CD8+ T cells. The synergistic combination of photothermal therapy and immunotherapy driven by As2Se3 NSs via a simple but effective all-in-one strategy achieved efficient anticancer effects, addressing the key limitations of As2O3 for solid tumor treatment. This work demonstrates not only the great potential of selenium for detoxifying arsenic but also the application of 2D As2Se3 nanosheets for cancer therapy.

CPX-351 and allogeneic stem cell transplant for a therapy-related acute myeloid leukemia that developed after treatment of acute promyelocytic leukemia: a case report and review of the literature

Therapy-related myeloid neoplasms (t-MNs), which develop after cytotoxic, radiation, or immunosuppressive therapy for an unrelated disease, account for 7%–8% of acute myeloid leukemia (AML). Worse outcomes and consequently shortened survival are associated with t-MNs as compared with de novo AML. Therapy-related MNs are being reported with increasing frequency in successfully treated acute promyelocytic leukemia (APL), in particular, before the introduction of all-trans retinoic acid (ATRA) plus arsenic trioxide (ATO). Considering the high curability of APL, t-MNs represent one of the prognosis-limiting factors in this setting of leukemia. We report our experience with a patient who developed t-AML 15 years after treatment for APL. Treatment included three cycles of chemotherapy with CPX-351 (Vyxeos, Jazz Pharmaceuticals) followed, as in remission, by an allogeneic hematopoietic stem cell transplant. A review of available literature was also included.

Pseudotumorcerebri – a rare complication of ATRA based treatment of Acute Promyelocytic Leukaemia

Acute promyelocytic leukaemia is a highly curable sub type of acute myeloid leukaemia and about 90% of these patients have good chance of survival with current all transretinoic acid based arsenic tri oxide or chemotherapy. However, a rare complication, pseudotumour cerebri may arise following All Trans Retinoic Acid (ATRA) therapy, which may provide obstacle to continue this promising therapy. We present the case report of a young female patient with acute promyelocytic leukaemia treated with Arsenic trioxide (ATO) and ATRA that subsequently develop abrupt onset of lateral rectus palsy and decreased visual acuity due to pseudotumour cerebri. We treated the patient with acetazolamide and kept her at frequent follow up. There was significant improvement of her lateral rectus palsy as well as visual acuity following treatment with acetazolamide that allowed us to continue the primary All Trans Retinoic Acid (ATRA) based treatment. J Bangladesh Coll Phys Surg 2024; 42: 105-108

Cross-sectional network analysis of plasma proteins/metabolites correlated with pathogenesis and therapeutic response in acute promyelocytic leukemia.

The treatment of PML/RARA+ acute promyelocytic leukemia (APL) with all-trans-retinoic acid and arsenic trioxide (ATRA/ATO) has been recognized as a model for translational medicine research. Though an altered microenvironment is a general cancer hallmark, how APL blasts shape their plasma composition is poorly understood. Here, we reported a cross-sectional correlation network to interpret multilayered datasets on clinical parameters, proteomes, and metabolomes of paired plasma samples from patients with APL before or after ATRA/ATO induction therapy. Our study revealed the two prominent features of the APL plasma, suggesting a possible involvement of APL blasts in modulating plasma composition. One was characterized by altered secretory protein and metabolite profiles correlating with heightened proliferation and energy consumption in APL blasts, and the other featured APL plasma-enriched proteins or enzymes catalyzing plasma-altered metabolites that were potential trans-regulatory targets of PML/RARA. Furthermore, results indicated heightened interferon-gamma signaling characterizing a tumor-suppressing function of the immune system at the first hematological complete remission stage, which likely resulted from therapy-induced cell death or senescence and ensuing supraphysiological levels of intracellular proteins. Overall, our work sheds new light on the pathophysiology and treatment of APL and provides an information-rich reference data cohort for the exploratory and translational study of leukemia microenvironment.

In vitro bioaccessibility and intestinal transport of retinoic acid in ethyl cellulose-based microparticles and impact of meal co-ingestion

The development of carrier-based delivery systems for oral administration of retinoic acid (RA), that provides its release and absorption at intestinal level, is of major relevance in the treatment of acute promyelocytic leukemia. The aim of this work was to evaluate RA bioaccessibility and intestinal transport on ethyl cellulose (EC)- and EC + polyethylene glycol (ECP)-based microparticles and to understand the impact of meal co-ingestion by applying in vitro assays. RA-loaded microparticles were produced by spray-drying with an encapsulation efficiency higher than 90 % for both formulations. The gastric bioaccessibility of RA (after in vitro static digestion of RA-loaded particles) was lower than 3 % for both types of microparticles, with and without meal co-ingestion. Whereas after intestinal digestion, RA bioaccessibility was significantly higher and affected by the type of microparticles and the presence of meal. The digestion of EC- and ECP-based microparticles without diet enabled a significantly higher bioaccessibility of RA when compared to the one recorded for the co-digestion of these microparticles with diet. Herein, RA bioaccessibility decreased from 84 ± 1 to 24 ± 6 % (p < 0.0001) for microparticles EC and 54 ± 4 to 25 ± 5 % (p < 0.001) for microparticles ECP. Moreover, comparing both types of microparticles, RA bioaccessibility was significantly higher for EC-based microparticles digested without diet (p < 0.0001). At last, the bioaccessibility of RA was similar among EC- and ECP-based microparticles when co-digested with diet. Intestinal transport experiments performed in Caco-2 monolayers evidenced that after 2 h of transport the amount of RA retained in the apical compartment was higher than the amount that reached the basolateral compartment evidencing a slow transport at intestinal level that was higher when RA is spiked in the blank of digestion and the meal digestion samples compared to RA dissolved in HBSS (44 ± 6 (p < 0.01) and 38 ± 1 (p < 0.05) vs 26 ± 2 %, respectively).

Arsenic trioxide: applications, mechanisms of action, toxicity and rescue strategies to date.

Arsenical medicine has obtained its status in traditional Chinese medicine for more than 2,000years. In the 1970s, arsenic trioxide was identified to have high efficacy and potency for the treatment of acute promyelocytic leukemia, which promoted many studies on the therapeutic effects of arsenic trioxide. Currently, arsenic trioxide is widely used to treat acute promyelocytic leukemia and various solid tumors through various mechanisms of action in clinical practice; however, it is accompanied by a series of adverse reactions, especially cardiac toxicity. This review presents a comprehensive overview of arsenic trioxide from preclinical and clinical efficacy, potential mechanisms of action, toxicities, and rescue strategies for toxicities to provide guidance or assistance for the clinical application of arsenic trioxide.

Arsenic As a Therapy in Cancer: A Short Review

Acute myeloid leukemia (AML) is a cancer of the blood and bone marrow in which the bone marrow produces immature white blood cells, called myeloblasts. AML (acute myeloid leukemia) prevents these myeloblasts from developing into mature, healthy blood cells, as a result they accumulate and crowd out other healthy cells, such as red blood cells, white blood cells, and platelets. Sometimes acute myeloid leukemia(AML) can also spread to other organs, such as the brain, spinal cord, liver, or spleen. Without prompt treatment, AML can be life-threatening. There has been 2–3 cases per 100,000 people annually. Compared to women, men are more likely to experience it. acute myeloid leukemia(AML) makes up roughly 3% of all malignancies, with a median age of 32 years, according to the population-based Cancer Registry for Delhi. Among the various drugs for treatment of leukemia arsenic has been one of the most effective in treating it. Arsenic has been known as poison over 4000years.Long-term exposure to as has led to various adverse effects on health, but after the discovery of chemo therapeutic properties of As the understanding has been changed from poison to drug. Arsenic trioxide (ATO) is the most active antileukemia agent in treatment of acute promyelocytic leukemia(APL). Arsenic trioxide (ATO) cause degradation of PML RAR alpha promoting differentiation. Not only this but also arsenic induces apoptosis via mitochondrial caspase or formation of reactive oxygen species (ROS) and deleting GSH content of cell. This article focuses on the therapeutic effect of arsenic on acute myeloid leukemia

Impact of Arsenic Trioxide in the Treatment of Higher Risk Acute Promyelocytic Leukemia

INTRODUCTION: Acute promyelocytic leukemia (APL) accounts for 5-8% of all cases of acute myeloid leukemia (AML). The combination of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) without chemotherapy is currently the reference treatment of standard APL (ie with baseline white blood count (WBC)&amp;lt;10 G/L), curing about 90% of the patients. However, the prognosis of high-risk APL (ie with WBC&amp;gt;10 G/L) remains more challenging, with higher rates of early death and relapse. Here we compared the French practices for the treatment of high-risk APL patients whether patients were treated with ATRA-Chemo or ATRA-ATO according to physician decision, and evaluate the response rates, overall survival (OS) and leukemia-free survival (LFS) in the real-life settings. PATIENTS AND METHODS: ATO (in combination with ATRA) became accessible in France for the first line treatment of standard risk APL in 2012, but some patients with high-risk APL also received the same combination (generally with some form of cytoreductive chemotherapy) from that date. We retrospectively analyzed cases of high-risk APL diagnosed between 2010 and 2021 in 12 French centers, constituting a cohort of 135 patients with diagnostic of APL confirmed by cytogenetic, FISH and molecular biology assays. RESULTS: Among the 135 patients with WBC&amp;gt;10 G/L, 88 (65%) were classified as APL variant according to FAB classification. Median age was 46 years (range 18-89) and 62 % were male. Median diagnostic WBC was 39.1 G/L (range 10-270) and median platelet count was 27 G/L (range 5-344). At diagnosis, 112 patients (83%) had hemorrhagic manifestations and disseminated intravascular coagulation (DIC) was observed in 124 patients (92%). Pulmonary and cerebral leucostasis were reported in 10 (7%) and 14 (10%) patients, respectively. Eighty-five patients received corticosteroid prophylaxis (81 (95%) with Dexamethasone and 5 (5%) with Prednisolone). Induction therapy consisted in ATRA-ATO for 50 patients (38%) while 85 patients (62%) were treated with ATRA combined with chemotherapy (anthracycline and cytarabin) but without ATO. All patients treated with ATO were cytoreduced: 7 with Hydroxyurea (14%), 17 with Idarubicin (34%) and 26 with both (52%). 29 patients treated without ATO during induction were cytoreduced with Hydroxurea (34%). Most patients experienced one or more adverse events during induction, including sepsis (49 in the ATO group versus 71 in the non ATO group, 98% versus 83.5%, p=0.01), differentiation syndrome (20 in the ATO group versus 27 in the non ATO group, 40% versus 31.7%, p=0.33), transaminase increased (14 in ATO group versus 11 in the non ATO group, 28% versus 12.9%, p=0.03), and bleeding (7 in the ATO group versus 13 in the non ATO group, 14% versus 15.3%, p=0.8). Following induction, 110 patients (81%) achieved complete remission (CR): 45 in the ATO group and 65 in the non ATO group (90% versus 76.4%, p=0.052). One patient (receiving ATRA with chemotherapy) was refractory, and 24 patients experienced early death (5 in the ATO group and 19 in the non ATO group, 10% versus 22.3%, p=0.069) mostly due to hemorrhage or sepsis. Median time between diagnosis and early death was 4.5 days (0-42). Relapse was observed in 6 (5.5 %) patients (5 patients treated without ATO and 1 patient with ATO during induction). After a median follow-up of 34.6 months (0-121.1), OS at 3 years was significantly higher for the ATO group (89.9% (81.8-98.7) versus 75.1% (66.3-84.9) for the non ATO group, p= 0.035, Figure). LFS at 3 years was significantly higher for the ATO group (87.6% (78.7-97.4) versus 71.2% (62-81.7) for the non ATO group, p=0.028). CONCLUSIONS: The survival outcomes were significantly poorer in high-risk APL patients treated without ATO during induction, regardless of the cytoreduction strategy. The toxicity profile of ATO was acceptable. Combining ATO and ATRA limits the use of cytotoxic chemotherapy, which could reduce myelosuppression and long-term complications such as cardiotoxicity and secondary myeloid neoplasms. Early disease-related mortality, due to haemorrhagic or infectious complications, remains the major issue for these patients but tend to be reduced in those receiving ATRA-ATO based regiment. This retrospective study shows that ATO-ATRA and limited chemotherapy could be a better approach than ATRA and standard intensive chemotherapy in terms of early deaths, LFS and OS.

Changes in White Blood Cell Counts Early during Treatment of Acute Leukemia Using Differentiating Chemotherapies

Background: Differentiation syndrome (DS) is a life-threatening complication that can occur with a number of therapies used for the treatment of acute myeloid leukemia (AML). It is best characterized in patients treated with All-trans retinoic acid (ATRA) and Arsenic for acute promyelocytic leukemia (APL), or for patients receiving an IDH inhibitor for IDH1/2 mutant AML, but can also be seen with other therapies such as with FLT3 inhibitors, and in novel therapies under development such as menin inhibitors. It is critical to identify DS early, as corticosteroids can mitigate complications. The diagnosis of DS is made by recognizing a constellation of symptoms, typically including a rising white blood cell count, peripheral edema, rash, shortness of breath, pulmonary edema, and fevers. We evaluated white blood cell (WBC) count changes during treatment according to whether patients DS or not on chemotherapy. Methods: We identified adult patients who received ATRA+Arsenic for newly diagnosed APL, as well as patients with AML harboring a mutation in IDH1 or IDH2 who were treated with monotherapy IDH inhibitors (enasidenib or ivosidenib) at any point during their treatment for active AML and treated at MGH. Patients were treated at MGH between 2015 and 2023. Patients were 18 or older and had a confirmed pathological diagnosis. We interrogated the medical record to identify patients with clinical documentation of DS during treatment, as well as the treatments used for management and clinical complications. Descriptive statistics were used to identify differences in median WBC counts between patients with DS and those without DS, and comparisons were made using Wilcoxon or chi square testing as appropriate. Results: We identified 33 patients with APL who received ATRA+Arsenic, and 35 patients with AML harboring an IDH1/2 mutation treated with monotherapy IDH inhibition. Our analysis revealed that 26% (18/68) of patients had clinical documentation of differentiation syndrome, including 21% (14/33) of patients treated with ATRA+Arsenic and 11% (4/35) of patients on IDH inhibitors. In APL, the median day of a recorded diagnosis of DS was 4 days after treatment start (range 1-14 days). Patients with APL who developed DS had a higher initial WBC at treatment start compared to those who did not develop DS (6.7 vs 1.05 K/uL, p=0.03). There was no difference in hemoglobin, platelets, ANC, and percentage of peripheral blood blasts (Table 1). The WBC in DS patients started rising during the first week of treatment and peaked on Day 15 (Figure 1). Regarding treatment approaches for DS, the majority of patients were treated with steroids, (78%, 11/14) while 43% (6/14) received cytoreduction, most commonly with gemtuzumab. In IDH-mutant AML, the median day of a recorded diagnosis of DS was 35 days after treatment start (range 16-69 days). Patients with IDH-mutated AML on IDH Inhibitor monotherapy who experienced DS had a similar finding of an early temporal rise in WBC to those with APL on ATRA+Arsenic, although this rise started on day 12 and peaked on day 16 of monotherapy. Of note, these peaks occurred prior to the documentation of a clinical DS diagnosis. In contrast to APL, patients with IDH-mutant AML who developed DS had a lower baseline ANC (p=0.03) and higher percentage of peripheral blasts circulating than those without DS (p=0.03). All patients with IDH inhibitor associated DS received dexamethasone. Discussion: Patients with DS during treatment for APL on ATRA+Arsenic, as well as patients with DS with IDHmut AML on IDH inhibitors, had similar early peaks in the WBC count, occurring around 2 weeks from the start of treatment. In this small group, the IDHmut AML showed a rise in WBC that preceded the actual DS diagnosis. Understanding the timing of and risk factors for DS may help to identify at risk patients early for mitigation strategies.

Improving Clinical Outcomes in APL: Weight Maintenance Strategies to Reduce Complications during Induction Therapy

Introduction: The combination of all-trans-retinoic acid (ATRA) and arsenic trioxide (ATO) has revolutionized the treatment of acute promyelocytic leukemia (APL). However, despite a remission rate exceeding 96% and 5-year disease-free and overall survival rates reaching 96% and 88%, respectively, death during induction in clinical trials occurs in 4% of patients. Differentiation syndrome (DS) is a significant complication during ATRA and/or ATO induction therapy. The signs and symptoms of DS include dyspnea, unexplained fever, weight gain greater than 5 kg, unexplained hypotension, acute renal failure, and the presence of infiltrates and/or pleural/pericardial effusions on chest radiographs. The occurrence of 4 or more of these findings is considered diagnostic. In APL, patients are at risk for fluid overload secondary to multiple blood product transfusions and intravenous hydration. Acute hypoxic respiratory failure (AHRF) and septic shock are common indications for ICU admission in this patient population. At our institution, we monitored patients' daily weights intending to maintain the admission weights with diuresis or intravenous fluids as needed. We assessed the impact of maintaining euvolemia and daily weight monitoring to reduce the incidence of DS and ICU admissions among the APL patients treated at our institution. Methods: A retrospective chart review was conducted on 60 patients with APL who received treatment at our institution between 2016 and 2021. A total of 17 patients who were either not induced at our institution or did not have daily weight monitoring were omitted. Patient demographics, median age at diagnosis, hospitalization complications, ICU admission, and DS were analyzed. Patients were grouped based on if their daily weights were maintained at their admission level, plus or minus 3 kilograms. Only standing weights and weights before ICU transfer were considered. Results: Of the 43 patients who underwent induction therapy at our institution, 25.6% (n=11) had their weight maintained via diuresis and intravenous fluids, and none required ICU admission. Of the remaining 32 patients, 34.4% (n=11) were transferred to the ICU. Of the 11 patients transferred to the ICU, 6 were for AHRF, 2 were for septic shock, 1 was for adrenal insufficiency with vasopressor requirements, 1 was for subdural and epidural hemorrhage, and 1 was for intracranial hemorrhage. Maintaining euvolemia and weight within 3 kilograms of admission level correlated with fewer ICU admissions (OR = 0.085, 95% CI = 0.0046-1.5761) (p=0.0980). Of the 11 patients whose weights were followed and maintained, 9% (n=1) developed DS. Of the 32 patients who did not have their weights followed and maintained, 28% (n=9) met the criteria for DS (OR = 0.256, 95% CI = 0.028-2.296) (p=0.223). Conclusion: Volume overload is a significant concern in APL and its treatment. Our findings suggest that maintaining euvolemia and daily weight monitoring can lead to effective management of patients on the floor and may prevent unnecessary ICU transfers. Although there are limitations to the study due to its retrospective nature and low sample size, the cost-effectiveness and noninvasive methods of maintaining euvolemia support its potential addition to the standard treatment protocols. While maintaining euvolemia and monitoring daily weights is a simple intervention, it represents a promising strategy to improve the management of APL patients during induction therapy by decreasing the incidence of DS and ICU admissions. Further prospective studies are warranted to validate and expand upon these findings.