All-trans Retinoic Acid Therapy Research Articles

Acute Promyelocytic Leukemia: Review of Complications Related to All-Trans Retinoic Acid and Arsenic Trioxide Therapy.

The hallmark of acute promyelocytic leukemia (APL) is the presence of the characteristic fusion transcript of the promyelocytic leukemia gene with the retinoic acid receptor α gene (PML::RARA). The PML::RARA fusion is a molecular target for all-trans retinoic acid (ATRA) and arsenic trioxide (ATO). Therapies based on ATRA plus ATO have excellent outcomes in terms of complete remission rates, overall survival, and achievement of deep and durable molecular responses with a very low incidence of relapse. However, although the combination of ATRA and ATO has lower hematologic toxicity than standard chemotherapy, its use is associated with a spectrum of distinctive toxicities, such as differentiation syndrome, liver toxicity, QT interval prolongation, and neurotoxicity. Rigorous monitoring of patients' clinical evolution is indispensable for identifying and addressing each complication. The objective is to maintain an equilibrium between treatment-induced adverse events and therapeutic efficacy. This paper focused on non-hematologic complications associated with the combination of ATRA and ATO. Additionally, we discuss late-onset complications of this therapy. In summary, the majority of treatment-related adverse events are manageable, self-limiting, and reversible. More so, there seems to be a lower incidence rate of secondary neoplasms compared to standard chemotherapy. However, further research is required to assess how the ATRA plus ATO regimen affects the emergence of additional comorbidities.

CD38-Specific Gallium-68 Labeled Peptide Radiotracer Enables Pharmacodynamic Monitoring in Multiple Myeloma with PET.

The limited availability of molecularly targeted low-molecular-weight imaging agents for monitoring multiple myeloma (MM)-targeted therapies has been a significant challenge in the field. In response, a first-in-class peptide-based radiotracer, [68Ga]Ga-AJ206, is developed that can be seamlessly integrated into the standard clinical workflow and is specifically designed to noninvasively quantify CD38 levels and pharmacodynamics by positron emission tomography (PET). A bicyclic peptide, AJ206, is synthesized and exhibits high affinity to CD38 (KD: 19.1 ± 0.99× 10-9 m) by surface plasmon resonance. Further, [68Ga]Ga-AJ206-PET shows high contrast within 60 min and suitable absorbed dose estimates for clinical use. Additionally, [68Ga]Ga-AJ206 detects CD38 expression in cell line-derived xenografts, patient-derived xenografts (PDXs), and disseminated disease models in a manner consistent with flow cytometry and immunohistochemistry findings. Moreover, [68Ga]Ga-AJ206-PET successfully quantifies CD38 pharmacodynamics in PDXs, revealing increased CD38 expression in the tumor following all-trans retinoic acid (ATRA) therapy. In conclusion, [68Ga]Ga-AJ206 exhibits the salient features required for clinical translation, providing CD38-specific high-contrast images in multiple models of MM. [68Ga]Ga-AJ206-PET could be useful for quantifying total CD38 levels and pharmacodynamics during therapy to evaluate approved and new therapies in MM and other diseases with CD38 involvement.

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.

ATRA Can Correct Impaired Proplatelet Formation By Regulating HIF-1α/SPHK2/S1P Axis in ITP

Introduction Under normal physiological conditions, the bone marrow (BM) niche is hypoxic, and sustained and consistent oxygen gradients result in stable physiological hypoxia. Hypoxia inducible factor (HIF) is central to mediating the cellular response to hypoxia. Whether hypoxia gradients regulate megakaryocyte (MK) differentiation and maturation and the possible mechanisms of these actions remain unknown. Our previous data showed that impaired proplatelet formation (PPF) contributed to the development of thrombocytopenia in ITP. Recent studies suggest that the S1P signaling pathway in MKs plays a critical role in PPF ( Blood, 2013; J EXP MED, 2012). To further explore the underlying mechanism of impaired PPF in ITP, we found that HIF-1α/SPHK2/S1P axis-mediated cytoskeletal reorganization was defective in the PPF of ITP. All-trans retinoic acid (ATRA), which has been shown to be a promising treatment option for ITP patients in our clinical studies ( Blood, 2021; Lancet Haematology, 2017; Lancet Haematology, 2021), could restore cytoskeletal reorganization and correct impaired PPF. Methods Thirty patients with newly diagnosed ITP and 30 healthy donors were included in our study. The 30 ITP patients received ATRA at a dose of 10 mg orally twice daily for 12 weeks. Bone marrow samples were taken before the first medication (Day 0) and after 12 weeks of ATRA therapy (Day 85). We employed an imaging cytometry platform to perform a comprehensive quantitative analysis of MK distribution and hypoxic status in the bone marrow microenvironment of ITP. Targeted and untargeted metabolomic profiling through metabolomic analysis was performed to explore the relationship between the metabolome and ITP. Results We analyzed the hypoxic status of MKs in the endosteal niche and perivascular niche. In healthy controls, MKs in the perivascular niche exhibited a hypoxic profile, defined by robust HIF-1α expression and strong retention of pimonidazole. MKs in the endosteal region were less hypoxic. These results reflect a spatial hypoxia gradient in the bone marrow microenvironment. In contrast, we found that, irrespective of their location, ITP MKs displayed less hypoxia with no defined spatial gradients. ITP-MKs in the perivascular niche displayed altered cytoskeletal reorganization and impaired proplatelet formation (PPF). Metabolomics data revealed a decreased S1P level in ITP patients. Downregulated sphingosine kinase 2 (SPHK2) in MKs suppressed S1P production. S1P was essential for cytoskeletal reorganization and PPF regulation. In addition, we demonstrated that hypoxia inducible factor-1α (HIF-1α) mediated SPHK2 activation and S1P production. These data suggested that a disrupted hypoxia gradient contributed to impaired PPF via the HIF-1α/SPHK2/S1P axis. We then investigated the effect of ATRA on PPF. The ITP patients received ATRA at a dose of 10 mg orally twice daily for 12 weeks. For patients who received ATRA, S1P levels, HIF-1α and SPHK2 expression levels were increased compared with the pretreatment levels. And ATRA corrected impaired PPF and restored cytoskeletal reorganization by upregulating HIF-1α. Conclusions A disrupted hypoxia gradient contributed to impaired PPF in the ITP bone marrow environment via the HIF-1α/SPHK2/S1P axis. The ATRA-induced correction of impaired PPF is a potential mechanistic explanation for the clinical efficacy of ATRA in ITP.

Differentiation Syndrome; Post-ATRA/ATO Induction Therapy in Acute Promyelocytic Leukemia

Acute promyelocytic leukemia (APL) is a disease described as definite morphological and cytogenetical abnormalities and leads to coagulopathy leaving the patient in a life-threatening condition. A specific chromosomal translocation of 15 and 17 chromosomes leads to retinoic acid receptor-α (RARα) and promyelocytic leukemia (PML) genes fusion that produces an abnormal gene mutation forming an oncogenic protein which is (PML-RARα). Those APL patients, who have been treated with all-trans retinoic acid (ATRA) or arsenic trioxide (ATO) commonly lead a complicated condition called differentiation syndrome which is rarely severe. This case report explains the 37-years old male diagnosed with acute promyelocytic leukemia and later developed a differentiation syndrome after initiation of all-trans retinoic acid and arsenic trioxide induction therapy.

Folic acid supplementation rescues bladder injury in fetal rats with myelomeningocele.

Bladder dysfunction has been linked to the progression of renal failure in children with neurogenic bladder (NB) dysfunction. The purpose of this study was to determine whether bladder injuries in fetal rats with myelomeningocele (MMC) may be treated with folic acid. Pregnant Sprague-Dawley rats were randomly divided into three groups. On the 10th day of gestation, pregnant rats were intragastrically injected with all-trans retinoic acid (ATRA) (60 mg/kg) to induce MMC fetal rats. The same amount of olive oil was put into the control group to create normal fetal rats. The rats in the rescue group were given folic acid (40 mg/kg) by gavage 0.5 and 12 hr after ATRA therapy. Bladders were obtained via cesarean section on embryonic day E20.5 and examined for MMC. The histology of the fetuses was examined using hematoxylin and eosin staining, and immunohistochemistry (IHC) was utilized to determine the expression of α-smooth muscle actin (α-SMA) and neuron-specific nuclear-binding protein (NeuN). Furthermore, the levels of neuromuscular development-related and apoptotic proteins were determined by western blotting. The incidence of MMC in the model group was 60.6% (20/33) while it was much lower in the rescue group (21.4%). In comparison to the model group, the weight and crown-rump length of the fetal rats in the rescue group were significantly improved. IHC revealed that there was no significant difference in the expression of α-SMA and NeuN between the control and ATRA groups, while the expression levels decreased significantly in the MMC group. Western blot analysis showed that there was no significant difference between the model and ATRA groups, but the expression of the α-SMA protein and the β3-tubulin was much lower in the MMC group than in the control group. After the administration of folic acid, the α-SMA and β3-tubulin proteins considerably increased in the folic acid-rescued MMC group and folic acid-rescued ATRA group. Meanwhile, in the control group, the expression of cleaved caspase-3 in the bladder tissue was significantly higher, and the expression of poly (ADP-ribose) polymerase (PARP) protein was significantly lower compared to the control group. Folic acid therapy reduced cleaved caspase-3 expression while increasing PARP expression in comparison to the MMC group. NB in MMC fetal rats is associated with the reduction of bladder nerve and smooth muscle-related protein synthesis. However, folic acid therapy can help improve these functional deficiencies. Folic acid also exhibits strong anti-apoptotic properties against NB in MMC fetal rats.

All Trans Retinoic Acid: A Cerebral Friend or Foe? (P3-5.002)

<h3>Objective:</h3> NA <h3>Background:</h3> All-trans retinoic acid (ATRA) is an initial treatment for acute promyelocytic leukemia (APL). Studies suggest that ATRA has neuroprotective effects since it reduces atherosclerosis and neural inflammation. We present a case series of patients that developed acute recurrent ischemic strokes and demonstrated rapid progression of intracranial and extracranial stenosis in the setting of ATRA therapy. <h3>Design/Methods:</h3> NA <h3>Results:</h3> <h3>Case 1:</h3> A 47-year-old female with a history of hypertension presented with symptoms concerning for myocardial infarction, deep venous thrombosis, and thrombocytopenia which led to a diagnosis of APL. She was treated with ATRA and two days later developed left gaze deviation, facial droop, and left hemiparesis. Vessel imaging revealed a right middle cerebral artery (MCA) occlusion. Despite successful thrombectomy, the patient continued to decline. Repeat imaging showed re-occlusion of the right MCA as well as a new left MCA infarct. She later developed diffuse cerebral edema and fatal herniation. <h3>Case 2:</h3> A 41-year-old female with a history of hypertension and APL treated with ATRA had multiple recent strokes involving bilateral frontal, left occipital and watershed territories. Vessel imaging during the first admission did not show any stenosis. Over the course of the next seven months, she had multiple admissions for recurrent strokes with rapid progression and worsening of her intracranial stenosis despite dual antiplatelet and statin therapy. Cerebrospinal fluid analysis including cell count, protein, cytology and flow cytometry was unremarkable. She subsequently developed extensor posturing with paraparesis due to malignant cerebral edema and died. <h3>Conclusions:</h3> The underlying mechanism of accelerated vessel stenosis in the above cases is unknown. Further research should explore whether ATRA use in APL is indeed associated with the progression and/or poor clinical outcomes in the setting of acute ischemic stroke. Clinicians should remain vigilant about the concomitant use of ATRA in patients with a history of vascular risk factors. <b>Disclosure:</b> Mannyam, MD (Jackson, MS); Maryam

The immunomodulatory effects of all-trans retinoic acid and docosahexaenoic acid combination treatment on the expression of IL-2, IL-4, T-bet, and GATA3 genes in PBMCs of multiple sclerosis patients

ABSTRACT Objectives Multiple sclerosis (MS) is a potentially disabling autoimmune disease of the central nervous system. Neither the pathogenesis nor the effectiveness of treatment of MS has been fully understood. This in vitro trial evaluated the beneficial immunomodulatory effects of single and combined treatments of all-trans retinoic acid (ATRA) and docosahexaenoic acid (DHA) on the peripheral blood mononuclear cells (PBMCs) of relapsing-remitting MS (RRMS) patients who were receiving interferon beta (IFN-β). Methods The PBMCs of 15 RRMS patients were isolated, cultured, and treated with single and combined treatments of ATRA and DHA. The expressions of IL-2, IL-4, T-bet, and GATA3 genes were evaluated using real-time PCR. Results The results showed that a single treatment of ATRA could significantly suppress the gene expression of the pro-inflammatory cytokine, IL-2 (P < 0.05), and related transcription factor, T-bet (P < 0.001). The gene expression level of the anti-inflammatory cytokine, IL-4, and its transcription factor, GATA3, were not significantly changed. The expression of IL-2 and T-bet genes was significantly decreased in combination treatments of ATRA and DHA (P < 0.001). Significant suppression of IL-2 and T-bet (P < 0.001) was observed in ATRA and DHA combination therapy with half doses of their single treatment, which suggested a synergistic effect of these components. Discussion Co-administration of vitamin A and DHA, an omega-3 fatty acid derivative, may exert a synergistic effect in modulating the immune system in MS patients; however, more studies are needed to evaluate the exact effects and mechanism of their actions on the immune cells.

Atypical Rearrangements in APL-Like Acute Myeloid Leukemias: Molecular Characterization and Prognosis.

Acute promyelocytic leukemia (APL) accounts for 10–15% of newly diagnosed acute myeloid leukemias (AML) and is typically caused by the fusion of promyelocytic leukemia with retinoic acid receptor α (RARA) gene. The prognosis is excellent, thanks to the all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) combination therapy. A small percentage of APLs (around 2%) is caused by atypical transcripts, most of which involve RARA or other members of retinoic acid receptors (RARB or RARG). The diagnosis of these forms is difficult, and clinical management is still a challenge for the physician due to variable response rates to ATRA and ATO. Herein we review variant APL cases reported in literature, including genetic landscape, incidence of coagulopathy and differentiation syndrome, frequent causes of morbidity and mortality in these patients, sensitivity to ATRA, ATO, and chemotherapy, and outcome. We also focus on non-RAR rearrangements, complex rearrangements (involving more than two chromosomes), and NPM1-mutated AML, an entity that can, in some cases, morphologically mimic APL.

Pseudotumor Cerebri in the Setting of Differentiation Syndrome in a Patient with Acute Promyelocytic Leukemia Treated with All-trans Retinoic Acid During Induction Therapy

Introduction: Differentiation syndrome, a well-known complication of all-trans retinoic acid (ATRA) in patients with acute promyelocytic leukemia (APML), can very rarely have ophthalmic manifestations. Pseudotumor cerebri (PC) in the setting of differentiation syndrome (DS) in patients undergoing induction with all-trans retinoic acid has rarely been reported elsewhere. We herein report one such case. Case Presentation: A 28-year-old, non-obese female diagnosed as acute promyelocytic leukemia underwent induction with all- trans retinoic acid and Idarubicin. On day 4 of the treatment, she developed high grade fever (104 – 105 F), dry cough, hypotension, tachycardia, and tinnitus. Chest X ray showed floppy shadows in bilateral lungs. On physical examination, bilateral lower limb edema was noted. She also experienced sudden weight gain of 5 kilogram in 48 hours. After careful exclusion of systemic infection, she was suspected as having DS. She also noticed a reduction in vision in right eye. On eye examination, her best-corrected visual acuity (VA) was 6/60 in the right eye (RE) and 6/6 in the left eye (LE). Fundus evaluation revealed bilateral disc edema with peripapillary hemorrhages along with slight tortuosity of vessels and a yellowish lesion over the fovea in RE. Suspecting DS, she was treated with injection dexamethasone 10 mg twice daily and all- trans retinoic acid was temporarily discontinued. Immediately after its discontinuation, her headache lessened and vision improved gradually. After 2 weeks, her VA was 6/12 in RE and 6/6 in LE which improved to 6/6 in both eyes at 3 months. The patient was also receiving oral voriconazole for fungal prophylaxis and the potentiation effect of all- trans retinoic acid could thus be explained. Conclusion: Pseudotumor cerebri associated with all-trans retinoic acid treatment in acute promyelocytic leukemia, even though frequently reported in pediatric patients, is rare in adults. Ophthalmological evaluation is mandatory in all these patients under all-trans retinoic acid therapy.

Assessment of Arsenic Trioxide and All-trans Retinoic Acid for the Treatment of Pediatric Acute Promyelocytic Leukemia

All-trans retinoic acid (ATRA) and arsenic trioxide therapy without the use of maintenance therapy has been found to be beneficial for the treatment of adults with standard-risk acute promyelocytic leukemia (APL). However, it is unclear whether similar regimens are safe and beneficial for the treatment of high-risk APL or pediatric patients with standard-risk APL. To assess whether treatment with an ATRA and arsenic trioxide-based regimen is safe and allows for the elimination or substantial reduction of chemotherapy use among pediatric patients with standard-risk or high-risk APL, respectively. The Children's Oncology Group AAML1331 study is a nonrandomized, noninferiority trial that examined survival outcomes among 154 pediatric patients with APL compared with a historical control group of patients with APL from the AAML0631 study. Patients aged 1 to 21 years were enrolled at 85 pediatric oncology centers (members of the Children's Oncology Group) in Australia, Canada, and the US from June 29, 2015, to May 7, 2019, with follow-up until October 31, 2020. All patients had newly diagnosed APL and were stratified into standard-risk APL (white blood cell count <10 000/μL) and high-risk APL (white blood cell count ≥10 000/μL) cohorts. All patients received ATRA and arsenic trioxide continuously during induction therapy and intermittently during 4 consolidation cycles. Patients with high-risk APL received 4 doses of idarubicin during induction therapy only. The duration of therapy was approximately 9 months, and no maintenance therapy was administered. Event-free survival (EFS) at 2 years after diagnosis. Among 154 patients (median age, 14.4 years [range, 1.1-21.7 years]; 81 male participants [52.6%]) included in the analysis, 98 patients (63.6%) had standard-risk APL, and 56 patients (36.4%) had high-risk APL. The median follow-up duration was 24.7 months (range, 0-49.5 months) for patients with standard-risk APL and 22.8 months (range, 0-47.7 months) for patients with high-risk APL. Patients with standard-risk APL had a 2-year EFS rate of 98.0% and an overall survival rate of 99.0%; adverse events included 1 early death during induction therapy and 1 relapse. Patients with high-risk APL had a 2-year EFS rate of 96.4% and an overall survival rate of 100%; adverse events included 2 relapses and 0 deaths. These outcomes met predefined noninferiority criteria (noninferiority margin of 10% among those with standard-risk APL and 14.5% among those with high-risk APL). In this nonrandomized, noninferiority trial, pediatric patients with standard-risk APL who received treatment with a chemotherapy-free ATRA and arsenic trioxide regimen experienced positive outcomes. Patients with high-risk APL also had positive outcomes when treated with a novel ATRA and arsenic trioxide-based regimen that included 4 doses of idarubicin during induction therapy only and no maintenance therapy. The 2-year EFS estimates were noninferior to the historical comparator group, and advantages of the regimen included shorter treatment duration, lower exposure to anthracycline and intrathecal chemotherapy, and fewer days hospitalized. ClinicalTrials.gov Identifier: NCT02339740.

THIS DYSPNEA FEELS DIFFERENT: A CASE OF DIFFERENTIATION SYNDROME

TOPIC: Pulmonary Manifestations of Systemic Disease TYPE: Medical Student/Resident Case Reports INTRODUCTION: Acute Promyelocytic Leukemia Differentiation Syndrome (DS) also known as Retinoic Acid Syndrome (RAS) is a potentially lethal complication of All-Trans Retinoic Acid (ATRA) treatment. Symptoms are initially nonspecific from dyspnea, weight gain, fever and weakness. Major findings seen in DS includes bilateral infiltrates on chest imaging with possible pleural and pericardial effusion. Patients respond favorably to steroids in the form of Dexamethasone while ATRA is being held. CASE PRESENTATION: A 70-year-old male presented to the hospital with dyspnea and body aches, with initial diagnosis of pneumonia and subsequently started on antibiotics. Chest X-Ray showed right lower lobe infiltrate. Labs also showed Pancytopenia which prompted Flow Cytometry and Bone marrow biopsy revealing Acute Promyelocytic Leukemia. Patient was started on chemotherapeutic agents including Arsenic Trioxide and Tretinoin. The following day, patient's dyspnea worsening requiring BiPAP, his CT chest revealed new bilateral infiltrates with pleural and pericardial effusions. His labs showed worsening leukocytosis of 61, increased creatinine to 1.6. Due to the symptoms mentioned above as well as a high clinical suspicion, patient was started on Dexamethasone. Patient's respiratory status drastically improved over the next 2-3 days. Patient was subsequently discharged to continue Tretinoin outpatient. DISCUSSION: Differentiation Syndrome has unknown epidemiology, however, there have been varying reports that it has an incidence between 2-48% of patients treated with ATRA. The pathogenesis of DS is unclear however the most widely accepted theory is massive cytokine release by blast cells leading to a systematic inflammatory response syndrome and increased vascular permeability leading to both hypotension and organ hypoperfusion. There is currently no universally accepted diagnostic criteria for DS, however common findings are dyspnea, unexplained fever, weight gain >5 kg and hypotension. Lab findings in DS are nonspecific and not pathognomonic, leukocytosis is often seen in approximately half the patient. The presence of 3 of the previous findings warrants empiric therapy with Dexamethasone. Prospective and retrospective studies show a mortality of 1% in patients with DS who are treated with steroids. CONCLUSIONS: Differentiation Syndrome is a potentially fatal complication of ATRA therapy with no universally accepted diagnostic criteria. A high clinical suspicion is required to diagnose and treat DS for a favorable outcome. REFERENCE #1: Stahl M, Tallman MS. Differentiation syndrome in acute promyelocytic leukaemia. Br J Haematol. 2019 Oct;187(2):157-162. doi: 10.1111/bjh.16151. Epub 2019 Aug 13. PMID: 31410848. DISCLOSURES: No relevant relationships by Sreevastav teja Kalangi, source=Web Response Owner/Founder relationship with Palaniandy K. Kogulan, M.D., PLLC Please note: since 2010 Added 05/13/2021 by Palaniandy Kogulan, source=Web Response, value=Salary No relevant relationships by Mohamed Mohamed, source=Web Response

Prospective Evaluation of Thrombo-Hemorrhagic Events and Hypercoagulation Markers in Patients with Acute Promyelocytic Leukemia (APL) Receiving All-Trans Retinoic Acid (ATRA) Plus Chemotherapy

Introduction: Patients with APL typically present with a life-threatening thrombo-hemorrhagic syndrome (THS), due to the consumption of coagulation factors and platelets, secondary to clotting activation. Presently, all- trans retinoic acid (ATRA) has greatly improved the management of APL, but has not significantly changed the rate of early hemorrhagic deaths and may actually promote thrombosis.Characterizing the coagulopathy and identifying predictive markers of bleeding/clotting complications remain critical issues. Aim: In newly diagnosed APL patients, in the first month after diagnosis, we wanted prospectively to: 1. register thrombo/hemorrhagic events; 2. evaluate, the profiles of circulating hypercoagulation markers and the molecular expression of Tissue Factor (TF), before and during ATRA therapy; and 3. verify whether changes in the biomarker profiles correlate with the occurrence of thrombo-hemorragic events. Methods: Sixty consecutive APL patients receiving ATRA+Idarubicin for remission induction (GIMEMA protocol AIDA2000) were enrolled from January 2005 to March 2017. Blood samples from a subgroup of 30 patients (F/M= 11/19) were obtained at the onset (T0), and on days 7, 14 and 28 (T7, T14, T28) of remission induction therapy. Plasma levels of activated factor VII-antithrombin complex (FVIIa-AT), thrombin-antithrombin complex (TAT), and D-dimer were measured by ELISA; TF mRNA levels in peripheral blood mononuclear cells (PBMC) was evaluated in 16 APL patients by real time-polymerase chain reaction. Results: At enrolment (T0), before starting ATRA, 13.3% of APL patients presented with early major hemorrhages, including 3 (5%) fatal intracranial bleeding and 5 (8.3%) non-fatal major bleeding (i.e. gengivorrhagia, gastrointestinal bleeding, epistaxis, menorrhagia). At T0, the prevalence of thrombosis in the total group of 60 APL patients was 6.6%, including 1 fatal pulmonary embolism (PE), 2 non-fatal venous thrombosis (1 PE, 1 lower limb deep vein thrombosis [DVT]), and 1 non-fatal arterial thrombosis (acute myocardial infarction [AMI]). During ATRA therapy, 8.3% of APL patients developed major bleeding: including 2 fatal intracranial hemorrhage after 3 days of ATRA treatment and 3 non-fatal major bleeding (i.e. gengivorrhagia, epistaxis, menorrhagia) after 7, 10 and 17 days of ATRA. Two more patients developed non-fatal thrombosis (i.e. 1 AMI and 1 DVT) after 9 and 20 days of ATRA treatment, respectively. The laboratory sub-study of 30 subjects showed that, at T0, before starting therapy, the plasma levels of FVIIa-AT, TAT and D-dimer were significantly higher in APL patients compared to controls (p<0.05). During induction therapy with ATRA, the levels of TAT and D-dimer significantly (p<0.05) and progressively decreased at T7 and T14, reaching the lowest value at 28 days. Differently, FVIIa-AT levels were unchanged at T7 and T14, and dropped significantly only at T28 (p<0.05 vs T0). In addition, in APL PBMC from 16 patients, the levels of TF mRNA, initially elevated compared to healthy control PBMC (p<0.05), during induction therapy were significantly decreased by 68% and 90%, at T7 and T28, respectively. In these 16 APL patients, a statistically significant correlation (p<0.05) was found between decrease in TF mRNA and FVIIa-AT levels during ATRA therapy. Of the 30 patients included in the laboratory sub-study, 3 had non-fatal thrombosis at diagnosis, no major hemorrhages were recorded. The predictive value of THS of thrombotic markers could not be calculated. Conclusions: Our data show a significant rate (31%) of severe (fatal and non-fatal) thrombo/hemorrhagic events in our cohort of APL patients in the first 3 weeks of diagnosis, with 4 fatal events (6.6%) occurring early, before starting ATRA. Laboratory data show for the first time that, while TAT and D-dimer confirm to be sensitive to ATRA downregulation, differently FVIIa-AT levels persist at high level over time, showing the perseverance of TF-dependent clotting activation. Future large prospective clinical trials should include FVIIa-AT to evaluate persistent clotting activation during ATRA. DisclosuresFalanga:Advisory Board: Bayer, Janssen Speakers' bureau: Rovi, BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Rambaldi:Novartis, Roche/Genentech, Amgen, Italfarmaco: Consultancy; Novartis, Amgen, Celgene, Sanofi: Other: Travel, Accomodations, Expenses. Lo Coco:Lundbeck: Honoraria, Speakers Bureau; TEVA: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau.

Weight Gain during Induction Therapy of Acute Promyelocytic Leukemia Patients: A Preventable Problem

Introduction:Differentiation syndrome can be a major complication of all-trans retinoic acid (ATRA) and/or arsenic trioxide (ATO) therapy in acute promyelocytic leukemia (APL) patients. The incidence of DS in studies varies widely and reported between 2-27% mainly due to the definition used for the diagnosis of DS. Dyspnea, unexplained fever, weight gain greater than 5 kg, unexplained hypotension, acute renal failure, and presence of infiltrates and/or pleural, pericardial effusions on chest radiographs are regarded as the signs and symptoms associated with DS. Four or more of these criteria is required for a diagnosis of severe DS but any single criteria is not diagnostic. Weight gain of 5 kg is seen in up to 38% of moderate DS (2-3 criteria) and 68% of severe DS patients. APL patients characteristically have a bleeding tendency at presentation requiring aggressive transfusion support that leads to fluid overload and weight gain unless meticulously monitored. Herein we report our observations with weight gain in APL patients during induction period.Methods:Chart review of APL patients managed between 01/2006 and 04/2017 was conducted and patients who gained more than 5kg from baseline at admission were identified. Patients from 09/2013 to 04/17 were managed on an algorithm designed to reduce induction mortality in APL patients and care was provided by physicians dedicated to the management of this disease. The outcomes in these patients was compared to those prior to implementation of the algorithm. The algorithm was a two-page set of guidelines directed at preventing or treating the major causes of early death including meticulous monitoring of the weight as well as aggressive diuresis in the event of weight gain. Institutional review board approval was obtained. for this review.Results:130 patients were managed during this time period. 57 patients (trial group TG) were managed on the algorithm while 73 (pre-trial, PG) were managed prior to this implementation. Median age was higher in trial patients 48 vs 45 years, range being 21-81 in TG vs 19-80 in PG. Median WBC was (4.2 vs 2.7) and high risk (WBC > 10,000/mm3) were higher in the PG vs TG. Median platelet counts were similar. The predominant induction combination was ATRA with chemotherapy in PG (66%) whereas ATRA/Arsenic combination was used in the TG (75%). Median weight gain in the TG was less than PG. (3.15 vs 3.5 kg, range 0-12.8kg vs 0-35 kg). 3 patients in the PG and 1 in the TG did not get treatment and were discharged with comfort care. Excluding these patients, 26 % of patients in TG and 38% in PG gained more than 5kg. The mortality was higher in the PG group at 38% in those that gained more than 5 kg compared to 20 % in the TG. In contrast, the mortality was lower in both TG and PG patients with weight gain <5 Kg at 7.1% and 7.4%. Five patients in the PG group did not have follow up weights checked but there was documentation that would satisfy definition of severe DS and all 5 patients died between 4-14 days after admission. The incidence of severe DS was also lower in trial patients (6% vs 18%).Conclusions:Management of APL patients utilizing an algorithm might lead to better monitoring of complications like weight gain and preventing fluid overload seen during the treatment of APL. The impact of the weight gain on outcomes in comparison to other variables that might impact survival in our cohort will be evaluated further. DisclosuresKota:Incyte: Consultancy; Leukemia Lymphoma Society: Research Funding; Takeda Pharmaceuticals: Consultancy; Xcenda: Consultancy; Pfizer: Consultancy; Novartis: Consultancy. Arellano:Cephalon Oncology: Research Funding.

Revisiting Cytochemical Myeloperoxidase (MPO) Stain for Early Diagnosis of Acute Promyelocytic Leukemia (APML) in Areas with Limited Resources: An Experience from a Tertiary Care Center in India

Introduction- Acute Promyelocytic leukemia (APML) needs to be suspected early so that All-Trans Retinoic Acid (ATRA) therapy can be started as soon as possible. Flow cytometry shows absence of CD34 and HLADR in most cases and so can aid in diagnosis along with the usual morphological clues. However, it may have confusing patterns as in hypogranular APML and sometimes may be positive for HLA- DR and CD34. RT-PCR for detection of characteristic APML translocations (t(15;17),t(17;17) and others) is gold standard for APML diagnosis which is time consuming and often not possible especially in resource limited areas. Cytochemical MPO stain is a robust laboratory test that can be a valuable aid to morphology in early diagnosis of APML. In this study, the role of cytochemical MPO was evaluated for early diagnosis of APML.Method- This study included all the cases of APML that were diagnosed in a tertiary care center in India from May 2011 to May 2014. Cytochemical stains (MPO, Non- specific Esterase (NSE), Periodic- acid Schiff (PAS) stains were performed on peripheral smear and bone marrow aspirates. Flow cytometry was performed on peripheral blood/bone marrow aspirate in EDTA on Beckman Coulter Flow Cytometer (FC500) using a panel of markers. RT-PCR was not available. However, all the above cases responded immediately to trial of ATRA (diagnosis confirmed by response to treatment trial with ATRA). The study was approved by Institutional Ethics committee.Results & Discussion- 13 cases of APML (6 males, 7 females) were identified with age ranging from 2-36 years. On flow cytometry, side scatter was moderate in 4 cases and high in 9 cases. The former were AML M3v (hypogranular variant) whereas the latter were classic APML. CD13 was heterogeneously dim to moderate positive in 12/13 cases .CD 33 was homogenously positive in all 13 cases (dim positive in 3; moderate positive in 10). CD34 was positive in 1/13 case and HLA-DR was positive in 2/13cases. All cases showed 3+ cytochemical MPO positivity, diffuse flush PAS positivity and NSE positivity. All cases went into immediate remission on treatment with ATRA.Thus even though flow cytometry was helpful in diagnosing APML, there were still some variations in the patterns. It is concluded that, though flow cytometric pattern of APML is often characteristic, occasionally it may have moderate side scatter and positive HLA-DR and CD34. In such situations and also in places with limited availability of flow cytometry/ RT PCR , strong (3+) cytochemical MPO staining in addition to characteristic morphologic features helps in the quick suspicion of APML and early treatment trial with ATRA. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Tumor suppressor function of Gata2 in acute promyelocytic leukemia

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Characteristics and outcome of patients with low-/intermediate-risk acute promyelocytic leukemia treated with arsenic trioxide: an international collaborative study.

The aim of this study was to characterize a large series of 154 patients with acute promyelocytic leukemia (median age, 53 years; range, 18-90 years) and evaluate real-life outcome after up-front treatment with arsenic trioxide and all-trans retinoic acid. All patients were included in the prospective NAPOLEON registry (NCT02192619) between 2013 and 2019. The acute promyelocytic leukemia was de novo in 91% (n=140) and therapy-related in 9% (n=14); 13% (n=20) of the patients were older than 70 years. At diagnosis bleeding/hemorrhage was present in 38% and thrombosis in 3%. Complete remission was achieved in 152 patients (99%), whereas two patients (1%) experienced induction death within 18 days after starting therapy. With a median follow-up of 1.99 years (95% confidence interval: 1.61-2.30 years) 1-year and 2-year overall survival rates were 97% (95% confidence interval: 94-100%) and 95% (95% confidence interval: 91-99%), respectively. Age above 70 years was associated with a significantly shorter overall survival (P<0.001) compared to that of younger patients. So far no relapses have been observed. Six patients (4%) died in complete remission at a median of 0.95 years after diagnosis (range, 0.18-2.38 years). Our data confirm the efficiency and durability of arsenic trioxide and all-trans retinoic acid therapy in the primary management of adults with low-/intermediate-risk acute promyelocytic leukemia in the real-life setting, irrespective of age.

Combined Therapy of ATRA and Imatinib Mesylate Decreases BCR-ABL and ABCB1/MDR1 Expression Through Cellular Differentiation in a Chronic Myeloid Leukemia Model.

Chronic Myeloid Leukemia (CML) is a clonal myeloproliferative disease, and a major challenge for the eradication of CML is to understand the cause of the permanence of minimal residual disease (DRM). This work aimed to induce the maturation of leukemic stem cells with All-trans-retinoic acid (ATRA), making them sensitive to treatment with Imatinib (IM). K562 cells were treated with IM and with the combined therapy of ATRA together with IM for 48 and 72 h. The expression of BCR-ABL gene and multidrug resistance gene ABCB1 were evaluated using RT-qPCR. The combined ATRA and IM therapy showed a discreet cell differentiation pattern, evidenced by the panoptic morphology analysis at 48 and 72 h of treatment. The BCR-ABL expression showed no statistical difference when treated alone with IM, however in combination with ATRA, the expression was statistically significant in 48 and 72 h (p≤0.0001) and when the treatment groups were compared to each other (p≤0.001). The ABCB1 gene expression showed a decrease in isolated IM therapy (p≤0.05) and in the combination in 48 and 72 h (p≤0.0001). Combined ATRA and IM therapy was shown to be effective in decreasing BCR-ABL and ABCB1 genes, possibly through the differentiation of blast cells, demonstrating that the therapy could be potentially effective in the blast crisis of the disease and for those patients who develop resistance to available CML treatments.

Molecular Remission in PML/RARα-Positive Acute Promyelocytic Leukemia by Combined All-trans Retinoic Acid and Idarubicin (AIDA) Therapy

AbstractTwo hundred fifty-three patients with newly diagnosed acute promyelocytic leukemia (APL) were eligible to enter the multicentric GIMEMA-AIEOP “AIDA” trial during the period July 1993 to February 1996. As a mandatory prerequisite for eligibility, all patients had genetic evidence of the specific t(15; 17) lesion in their leukemic cells confirmed by karyotyping or by reverse transcription-polymerase chain reaction (RT-PCR) of the PML/RARα fusion gene (the latter available in 247 cases). Median age was 37.8 years (range, 2.2 to 73.9). Induction treatment consisted of oral all-trans retinoic acid (ATRA), 45 mg/m2/d until complete remission (CR), given with intravenous Idarubicin, 12 mg/m2/d on days 2, 4, 6, and 8. Three polychemotherapy cycles were given as consolidation. Hematologic and molecular response by RT-PCR was assessed after induction and after consolidation. At the time of analysis, 240 of the 253 eligible patients were evaluable for induction. Of these, 11 (5%) died of early complications and 229 (95%) achieved hematologic remission. No cases of resistant leukemia were observed. Of 139 cases studied by RT-PCR after induction, 84 (60.5%) were PCR-negative and 55 (39.5%) PCR-positive. One hundred sixty-two patients were evaluable by RT-PCR at the end of consolidation. Of these, 159 (98%) tested PCR-negative and 3 (2%), PCR-positive. After a median follow up of 12 months (range, 0 to 33), the estimated actuarial event-free survival for the whole series of 253 eligible patients was 83% ± 2.6% and 79% ± 3.2% at 1 and 2 years, respectively. This study indicates that the AIDA protocol is a well-tolerated regimen that induces molecular remission in almost all patients with PML/RARα-positive APL. Preliminary survival data suggest that a remarkable cure rate can be obtained with this treatment.

Practice Patterns and Real-Life Outcomes for Patients with Acute Promyelocytic Leukemia

Practice Patterns and Real-Life Outcomes for Patients with Acute Promyelocytic Leukemia