Therapy Of Acute Promyelocytic Leukemia Research Articles

Pseudotumor Cerebri Secondary to All-Trans Retinoic Acid/Arsenic Trioxide Therapy in Acute Promyelocytic Leukemia: A Case Report and Review of the Literature.

Pseudotumor Cerebri Secondary to All-Trans Retinoic Acid/Arsenic Trioxide Therapy in Acute Promyelocytic Leukemia: A Case Report and Review of the Literature.

Immunophenotyping of blood and bone marrow cells as a way to search for differentiation syndrome risk factors in acute promyelocytic leukemia

Background. Differentiation syndrome (DS) is a potentially fatal complication of therapy for acute promyelocytic leukemia (APL) with an incidence of up to 48 %. To date, no reliable DS risk factors have been found, with the exception of leukocytosis at the APL onset.Aim. To determine the risk factors associated with DS in patients with APL during induction therapy with arsenic trioxide (ATO) and tretinoin (ATRA).Materials and methods. The study included 39 patients with APL, 29 (74.4 %) of them were classified as low-risk according to ELN (European Leukemia Net), 10 (25.6 %) were classified as high-risk. At the disease onset, cytological and molecular (chimeric transcript PML::RARα, FLT3-ITD mutation) bone marrow studies were performed, the expression of 28 differentiation antigens by blood and bone marrow blast cells was determined (markers of early precursors, myeloid and lymphoid differentiation, cell adhesion molecules, chemokine receptors, integrins, selectin), body mass index (BMI) and the leukocytes number dynamics during induction course were assessed. All patients received ATRA and ATO therapy. Patients from the high-risk group at the onset received 1–3 injections of idarubicin (12 mg/m2) and dexamethasone (8–10 mg/m2 2 times a day) to prevent DS until leukocytosis reduced. In cases of DS, dexamethasone was prescribed at a dose of 10 mg/m2 2 times a day; in cases of severe DS, the induction course was interrupted.Results. Of the 39 patients, 12 (30.8 %) were diagnosed with DS: 20 % of high-risk patients (2/10) and 34.5 % of low-risk patients (10/29). There was no statistically significant association of leukocytosis more than 10 × 109 /L at onset, microgranular morphology of blast cells, bcr3-variant PML::RARα, FLT3-ITD mutation with DS. In multivariate analysis, the probability of DS was associated with BMI ≥30 kg/m2 and mean fluorescence intensity of CD38 antigen by blast cells, regardless of risk group. based on the results of the ROC-analysis, the threshold value of mean CD38 fluorescence intensity was set at 25,000 cu, if exceeded, DS is highly likely to develop.Conclusion. the high incidence of DS among low-risk patients is probably due to the lack of prophylactic glucocorticosteroids administration for the development of leukocytosis during ATRA and ATO therapy. BMI ≥30 kg/m2 and mean CD38 fluorescence intensity more than 25,000 cu were identified as statistically significant DS risk factors.

Research on different compound combinations of Realgar-Indigo naturalis formula to reverse acute promyelocytic leukemia arsenic resistance by regulating autophagy through mTOR pathway

Ethnopharmacological relevanceIn China, the Chinese patent drug Realgar-Indigo naturalis Formula (RIF) is utilized for the therapy of acute promyelocytic leukemia (APL). Comprising four traditional Chinese herb—Realgar, Indigo naturalis, Salvia miltiorrhiza, and Pseudostellaria heterophylla—it notably includes tetra-arsenic tetra-sulfide, indirubin, tanshinone IIa, and total saponins of Radix Pseudostellariae as its primary active components. Due to its arsenic content, RIF distinctly contributes to the therapy for APL. However, the challenge of arsenic resistance in APL patients complicates the clinical use of arsenic agents. Interestingly, RIF demonstrates a high remission rate in APL patients, suggesting that its efficacy is not significantly compromised by arsenic resistance. Yet, the current state of research on RIF's ability to reverse arsenic resistance remains unclear. Aim of the studyTo investigate the mechanism of different combinations of the compound of RIF in reversing arsenic resistance in APL. Materials and methodsThe present study utilized the arsenic-resistant HL60-PMLA216V-RARα cell line to investigate the effects of various RIF compounds, namely tetra-arsenic tetra-sulfide (A), indirubin (I), tanshinone IIa (T), and total saponins of Radix Pseudostellariae (S). The assessment of cell viability, observation of cell morphology, and evaluation of cell apoptosis were performed. Furthermore, the mitochondrial membrane potential, changes in the levels of PMLA216V-RARα, apoptosis-related factors, and the PI3K/AKT/mTOR pathway were examined, along with autophagy in all experimental groups. Meanwhile, we observed the changes about autophagy after blocking the PI3K or mTOR pathway. ResultsTanshinone IIa, indirubin and total saponins of Radix Pseudostellariae could enhance the effect of tetra-arsenic tetra-sulfide down-regulating PMLA216V-RARα, and the mechanism was suggested to be related to inhibiting mTOR pathway to activate autophagy. ConclusionsWe illustrated that the synergistic effect of different compound combinations of RIF can regulate autophagy through the mTOR pathway, enhance cell apoptosis, and degrade arsenic-resistant PMLA216V-RARα.

Arsenic-induced neurotoxicity in patients with acute promyelocytic leukaemia.

Arsenic trioxide is an essential component of therapy for acute promyelocytic leukaemia (APL) and is currently dosed on actual body weight with no upper limit. Arsenic-induced neurotoxicity is a well-recognised complication; however, there is uncertainty about its relationship to arsenic dose and obesity. We conducted a large multicentre retrospective study of 487 patients with APL treated with arsenic-based therapy across 23 sites in Australia from 2008 to 2023. The primary outcome was incidence of neurotoxicity, and secondary outcomes included relationship of neurotoxicity to obesity and cumulative arsenic dose. Any-grade neurotoxicity occurred in 113 (23%) patients, predominantly peripheral neuropathy (91%). Most events were grade 1-2 severity (85%), with grade 3 events in 12% and grade 4-5 in 3%. The incidence of neurotoxicity increased with BMI (non-obese: 16%, obesity class I: 25%, obesity class II-III: 41%; p < 0.001). On univariable analysis, obesity class I (OR 1.81, p = 0.036), obesity class II-III (OR 3.93, p < 0.001), weight >100 kg (OR 2.72, p < 0.001), daily arsenic trioxide dose >15 mg (OR 5.05, p < 0.001) and cumulative induction dose >500 mg (OR 3.95, p < 0.001) were all significantly associated with neurotoxicity. Obesity class II-III and induction dose >500 mg remained significant on multivariable analysis. Our study highlights the strong association between BMI, arsenic trioxide dose and neurotoxicity. Pre-emptive dose reductions should be considered for obese patients receiving high doses of arsenic.

Incidence, risk factors, and outcomes of second neoplasms in patients with acute promyelocytic leukemia: the PETHEMA-PALG experience

The most important challenges in acute promyelocytic leukemia (APL) is preventing early death and reducing long-term events, such as second neoplasms (s-NPLs). We performed a retrospective analysis of 2670 unselected APL patients, treated with PETHEMA “chemotherapy based” and “chemotherapy free” protocols. Only de novo APL patients who achieved complete remission (CR) and completed the three consolidation cycles were enrolled into the analysis. Out of 2670 APL patients, there were 118 (4.4%) who developed s-NPLs with the median latency period (between first CR and diagnosis of s-NPL) of 48.0 months (range 2.8–231.1): 43.3 (range: 2.8–113.9) for s-MDS/AML and 61.7 (range: 7.1–231.1) for solid tumour. The 5-year CI of all s-NPLs was of 4.43% and 10 years of 7.92%. Among s-NPLs, there were 58 cases of s-MDS/AML, 3 cases of other hematological neoplasms, 57 solid tumours and 1 non-identified neoplasm. The most frequent solid tumour was colorectal, lung and breast cancer. Overall, the 2-year OS from diagnosis of s-NPLs was 40.6%, with a median OS of 11.1 months. Multivariate analysis identified age of 35 years (hazard ratio = 0.2584; p < 0.0001) as an independent prognostic factor for s-NPLs. There were no significant differences in CI of s-NPLs at 5 years between chemotherapy-based vs chemotherapy-free regimens (hazard ratio = 1.09; p = 0.932). Larger series with longer follow-up are required to confirm the potential impact of ATO+ATRA regimens to reduce the incidence of s-NPLs after front-line therapy for APL.

Abstract B032: Outcomes of patients with acute promyelocytic leukemia treated at John Peter Smith Hospital

Abstract Background: Acute Promyelocytic Leukemia (APL) is a subtype of Acute Myeloid Leukemia (AML), accounting for about 10% of all AML cases. Historically, APL was considered to be the subtype of AML with the worst prognosis because most newly diagnosed patients died within a few weeks, and only 35% to 45% of patients achieved long-term survival. The discovery and application of all trans retinoic acid (ATRA) improved complete remission (CR) rate and overall survival (OS) to 70%. Combination of ATRA, a vitamin A derivative, and arsenic trioxide (ATO) as induction therapy for APL resulted in 90-95% CR and &amp;gt;90% 5-year OS. Even though CR and OS has improved, early death (5%-10%) remains the most challenging issue for the disease, especially in resource poor settings. Since APL is rare, oncologists in community may not be fully equipped to treat early complications. John Peter Smith hospital (JPS) is a safety-net hospital serving the needs of underserved population in north Texas. We report outcomes of patients with APL treated at JPS. Methods: Data was obtained from the JPS Oncology Registry. Patients were diagnosed with APL from 1/1/2017 to 12/31/2020 with partial or complete treatment at JPS. We collected non-identifiable patient demographics, diagnosis and initial treatment and complication details. Remission documentation by disappearance of the chromosome abnormality, time from diagnosis to date of death (if applicable) or last activity in medical chart (any phone call with patient, office visit) before 6/12/2023 were obtained. Time to CR and any use of consolidation or maintenance treatment was also collected. Results: 8 APL patients were included- 3 were high-risk patients and 5 were low-risk. Half were male. Age ranged from 22 to 64 years. 5 were under the age of 40 years, 2 were in their 40s and 1 was in 60s at diagnosis. Hispanic:4, Black:3, Asian:1. Induction treatment included ATRA+ATO in 6 patients, while 2 high risk patients received ATRA plus anthracycline-based chemotherapy. Bone marrow morphology post induction was negative in all patients indicating CR (median time to CR was 41.5 days). During induction, treatment complications occurred in all patients including bleeding (75%), clotting (63%), neutropenic fever (50%). Differentiation syndrome (50%) and DIC (50%). All patients underwent ATRA+ATO consolidation treatment for 8-10 months. No patients relapsed. All patients were alive at the time of last medical chart entry (6/12/2023) without active cancer. Conclusions: All patients were in CR post induction treatment. 4 had minimal residual disease post induction. All patients received consolidation with ATRA+ATO, eventually there was no disease detected at molecular level. No patients relapsed. All patients were alive with no active disease at their last follow-up. Excellent outcomes in APL are possible at safety-net setting but will need diligent care to prevent, predict and treat early complications; this may require communication with academic leukemia specialists when transfer to leukemia treatment centers is not possible. Citation Format: Kavya Athipatla, Kari Teigen, Kalyani Narra. Outcomes of patients with acute promyelocytic leukemia treated at John Peter Smith Hospital [abstract]. In: Proceedings of the 16th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2023 Sep 29-Oct 2;Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2023;32(12 Suppl):Abstract nr B032.

Fertility and Parenthood in Patients with Acute Promyelocytic Leukemia Treated with Arsenic Trioxide and All-Trans Retinoic Acid

INTRODUCTION Advances in the treatment of Acute Promyelocytic Leukemia (APL) have enabled a large majority of the patients to be cured of this disease. However, with high cure rates now being achieved using Arsenic Trioxide (ATO) and All Trans Retinoic Acid (ATRA) in the frontline setting, there is greater interest in looking at potential long-term side effects. In particular, the information regarding the potential impact on fertility has not been well studied. ATO has been shown to be associated with adverse pregnancy outcomes in animal models, while studies in humans have mixed results. We looked to study the impact on fertility of patients with APL treated at our center over the past 17 years. METHODS We retrospectively analysed all patients with classical APL treated at our center with ATO and ATRA from 2006-2022. Patients between the age of 18 and 40 years, who had completed therapy, were in molecular remission and on regular follow-up were included in the study. All patients were treated with ATO and ATRA during induction therapy, followed by 3 cycles of consolidation with ATRA and ATO, each 1 month apart. Patients with intermediate and high-risk APL also received maintenance therapy for 1 year with ATRA, 6 Mercaptopurine and Methotrexate. The details of the treatment protocol are shown in Figure 1. Patients were interviewed telephonically and details regarding any pregnancies post-therapy completion as well as any adverse pregnancy outcomes, including preterm birth, miscarriage and spontaneous abortion were noted. Information was also gathered regarding presence of any physical anomalies in children born after therapy completion. RESULTS Sixty patients were included in the study with an equal number of male and female patients in the study (30 each). The median age of the patients at diagnosis was 23 years (Range 18 - 33 years). Three patients were unmarried and hence were excluded from the study. Forty-six patients (80.7%) did not try to conceive a child post therapy. Most patients cited their family being complete as the reason for not trying to conceive another child (N=40; 86.9%). Four patients did not try to conceive a child post therapy due to fear of disease returning, while 1 patient each did not try to conceive a child due to fear of risk to the unborn child and because they had not yet planned for a family. Eleven patients (19.3%) had 12 children post therapy, including 7 male and 4 female patients. The median time from therapy completion to first successful conception was 1.5 years (Range 0.5 - 3 years). Seven of these eleven patients did not have children prior to the diagnosis and therapy for APL. The median cumulative ATO dose during therapy was 996mg (Range 648mg - 1188mg). All patients who tried to conceive a child were able to successfully conceive and have a successful pregnancy post treatment for APL. None of the patients used any fertility therapy for conception of pregnancy. There was no history of pre-term birth, miscarriages or spontaneous abortions in any patient. None of the children had any obvious congenital abnormalities as reported by the patients. CONCLUSION All patients (male and female) who wanted to conceive children were able to successfully conceive and bear children post therapy for APL in our study. ATO and ATRA can safely be used for the treatment of patients with APL and appears to have little, if any, impact on long term fertility.

Improved Prevention and Treatment Strategy of Differentiation Syndrome Contribute to Reduce Early Death of Patients with Acute Promyelocytic Leukemia

Purpose: All-trans retinoic acid (ATRA) with arsenic trioxide (ATO) has been the standard of care for acute promyelocytic leukemia (APL) with high efficacy in china.However,early death (ED) still remains the major reason for treatment failure.Severe differentiation syndrome (DS) with no response to full dose dexamethasone is one of direct or indirect important causes of ED.Therefore,to further optimize prevention and treatment strategy of DS is critical for APL therapy success. Patients and Methods： The APL-01 study was a prospective and single-arm clinical trial in patients with newly diagnosed APL from June 2019 to December 2021.111 eligible patients aged between 18 and 70 years classified as Low-risk APL (WBC count at diagnosis＜10*10 9/L n=78) or High-risk APL (WBC count at diagnosis≥10*10 9/L n=33) received induction therapy consisted of ATRA and intravenous arsenic trioxide or oral tetra-sulfide arsenic formulation (Realgar-Indigo naturalis formula,RIF) with chemotherapy-free or chemotherapy-substantially reduced protocol in China. During the course of induction therapy,we used different intravenous doses of dexamethasone to prevent DS according to the WBC count at presentation or after the initiation of ATRA.For example,if WBC counts≥ 5*10 9/l and &amp;lt;10*10 9/l,5mg per day;if ≥10 *10 9/l,10mg per day.And we gave patients dexamethasone 10mg per 12h as preemptive therapy once DS was suspected.Ruxolitinib was administered when steroids therapy were considerd insensitive. We evaluated the effect of selective steroids prophylaxis and preemptive therapy on the incidence and severity of DS,which contributed to increased early mortality rate. The safety and feasibility of Ruxolitinib as second-line therapy for DS was also explored. Results： In this study,41 of 111 patients (36.9%) experienced DS,16 (14.4%) were severe cases and 25 (22.5%) were moderate cases. Univariate analysis identified the following prognostic factors as regards developing DS（P-value&amp;lt;0.1）:age,sex and WBC count were included for exploring the difference between DS and Non-DS patients Increased WBC count (&amp;gt;4*10*109/l )(OR (95% CI)=1.241 (1.131-1.361)) were potential risk factors for patients with DS.We further investigated the difference between severe DS and moderate DS using age,sex,ECOG,WBC and PLT count.We found that only advanced age (over 40 years old)(OR (95% CI)=12.200 (1.640-90.772)) was associated with developing severe DS. Dyspnea (71%),weight gain (85%) and pulmonary infiltrates(78%) were the most common symptoms of patients with DS.Compared with moderate DS,severe DS patients had more frequency of dyspnea (Fishers exact P=0.013),pleuropericardial effusion (χ2=5.577, P=0.018)and acute renal dysfunction (Fishers exact P=0.018). Among the 41 patients with DS,23 patients were treated effectively with dexamethasone 10mg per 12h.18 patients with steroid resistance received Ruxolitinib to control the cytokine release storm（CRS）,12 of which showed immediate remission, however,the situations of the remaining 6 patients did not alleviate until ATRA was suspended temporarily.All of them（6/41）recovered with the help of noninvasive mechanical ventilation. The total 30-day mortality rate was 1.8% (2/111).During induction treatment,no death owing to DS or infection occurred.Two patients with high-risk APL died due to intracranial hemorrhage,one occurred on day 8 and the other on day 9 after ATRA were initiated. Of all the 109 patients evaluable,78 (100%)Low-risk patients and 31 (100%) high-risk patients achieved complete remission (CR)at the end of induction therapy,respectively.The median follow-up time was 34 months,estimated 2-year overall survival (OS) was 98.7% in the Low-risk group and was 93.9% in the High risk group. Conclusions: Our study suggests individualized steroids prevention,preemptive treatment and Ruxolitinib as second-line therapy for DS contribute to control DS,which in verse lessen the discontinuation of ATRA, consequently decreasing early death due to DS and hemorrhage in APL patients.(clinicaltrials.gov NCT04446806) Keywords: acute promyelocytic leukemia;early death;prophylaxis strategy;pulmonary hemorrhage;differentiation syndrome;retinoid acid syndrome;Ruxolitinib;steroid-resistance;cytokine release syndrome;

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.

Risk factors for a differentiation syndrome in patients with acute promyelocytic leukemia

Differentiation syndrome (DS) is a severe complication of acute promyelocytic leukemia and its treatment, which is one of the causes of high early mortality. the similarity of clinical manifestations of DS and other complications that may develop during acute promyelocytic leukemia therapy makes it difficult to diagnose ds. at the same time, untimely initiation of DS therapy with glucocorticosteroids can lead to the patient’s death. The only generally accepted risk factor for ds is initial leukocytosis. Specific markers confirming ds have not yet been found. A number of studies show that in patients with diagnosed DS, the expression of CD56, CD54, CD2, CD15, CD13, markers of immature granulocytes, β2-integrins was more often found on blast cells. exposure to tretinoin increased the expression of chemokine receptors, chemokines, and cytokines by blast cells and vascular endothelium. The influence exerted by atypical promyelocytes, due to their biological characteristics, on the coagulation system suggests an association between hemostasis state and ds development. However, the value of the above markers as predictors or signs of DS still needs to be tested, especially when it comes to non-chemotherapeutic treatment of acute promyelocytic leukemia with arsenic trioxide.

Targeting DHODH reveals therapeutic opportunities in ATRA-resistant acute promyelocytic leukemia

Although all-trans retinoic acid (ATRA)-induced differentiation has transformed acute promyelocytic leukemia (APL) from the most fatal to the most curable hematological disease, resistance to ATRA in high-risk APL patients remains a clinical challenge. In this paper, we discovered that dihydroorotate dehydrogenase (DHODH) inhibition overcame ATRA resistance. 416, a potent DHODH inhibitor previously obtained in our group, inhibited the occurrence of APL in cells and model mice. Excitingly, 416 effectively overcame ATRA resistance in vitro and in vivo by inducing apoptosis and differentiation. Further mechanistic studies showed that PML/RARα lost the regulation of Bcl-2 and c-Myc in NB4-R1 cells, which probably contributed to ATRA resistance. Notably, 416 maintained its Bcl-2 and c-Myc down-regulation effect in NB4-R1 cells and overcome ATRA resistance by inhibiting DHODH. In conclusion, our study highlights the potential of 416 for APL therapy and overcoming ATRA resistance, supporting the further development of DHODH inhibitors for clinical use in refractory and relapsed APL.

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.

Treatment of Pediatric Acute Promyelocytic Leukemia with Retinoic Acid and Arsenic Trioxide along with Chemotherapy.

Outcomes of childhood acute promyelocytic leukemia (APL) have exceeded 90% in the era of differentiating agents. In resource-limited settings, early mortality secondary to coagulopathy remains a significant challenge. Differentiation syndrome is a unique complication of APL therapy that requires a high degree of suspicion for timely initiation of therapy. A retrospective study of children ≤15 y of age with APL diagnosed between January-2013 and June-2019 treated at a tertiary cancer centre was conducted. Patients with a total leukocyte count ≥10,000/µL were risk stratified as high-risk. Treatment included differentiating agents, all-trans retinoic acid and arsenic trioxide along with chemotherapy. Baseline demographics, clinical complications and outcomes were analysed. Out of 90 patients treated, 48 (53%) had high-risk APL and 25 (28%) presented with significant bleeding manifestations. Response to therapy was excellent with 96% of evaluable patients achieving molecular remission by the end of consolidation phase. Differentiation syndrome occurred in 23 (25%) patients of which two expired. Early mortality rate was 5.5% and was due to severe hemorrhage most often at the time of presentation. The 3-y overall survival of the entire cohort was 91% (95%CI: 85-97%). Two of 4 patients with relapse of disease could be salvaged with only differentiating agents followed by autologous transplantation. Long-term outcomes of Indian children with APL are excellent. Timely management of coagulopathy and prompt initiation of differentiating agents along with appropriate cytoreductive measures is critical. Efforts to build academic-community partnerships to ensure timely diagnosis and emergency care in order to reduce early mortality are needed.

Dual inhibition of EZH2 and G9A/GLP histone methyltransferases by HKMTI-1-005 promotes differentiation of acute myeloid leukemia cells.

All-trans-retinoic acid (ATRA)-based differentiation therapy of acute promyelocytic leukemia (APL) represents one of the most clinically effective examples of precision medicine and the first example of targeted oncoprotein degradation. The success of ATRA in APL, however, remains to be translated to non-APL acute myeloid leukemia (AML). We previously showed that aberrant histone modifications, including histone H3 lysine 4 (H3K4) and lysine 27 (H3K27) methylation, were associated with this lack of response and that epigenetic therapy with small molecule inhibitors of the H3K4 demethylase LSD1/KDM1A could reprogram AML cells to respond to ATRA. Serving as the enzymatic component of Polycomb Repressive Complex 2, EZH2/KMT6A methyltransferase plays a critical role in normal hematopoiesis by affecting the balance between self-renewal and differentiation. The canonical function of EZH2 is methylation of H3K27, although important non-canonical roles have recently been described. EZH2 mutation or deregulated expression has been conclusively demonstrated in the pathogenesis of AML and response to treatment, thus making it an attractive therapeutic target. In this study, we therefore investigated whether inhibition of EZH2 might also improve the response of non-APL AML cells to ATRA-based therapy. We focused on GSK-343, a pyridone-containing S-adenosyl-L-methionine cofactor-competitive EZH2 inhibitor that is representative of its class, and HKMTI-1-005, a substrate-competitive dual inhibitor targeting EZH2 and the closely related G9A/GLP H3K9 methyltransferases. We found that treatment with HKMTI-1-005 phenocopied EZH2 knockdown and was more effective in inducing differentiation than GSK-343, despite the efficacy of GSK-343 in terms of abolishing H3K27 trimethylation. Furthermore, transcriptomic analysis revealed that in contrast to treatment with GSK-343, HKMTI-1-005 upregulated the expression of differentiation pathway genes with and without ATRA, while downregulating genes associated with a hematopoietic stem cell phenotype. These results pointed to a non-canonical role for EZH2, which was supported by the finding that EZH2 associates with the master regulator of myeloid differentiation, RARα, in an ATRA-dependent manner that was enhanced by HKMTI-1-005, possibly playing a role in co-regulator complex exchange during transcriptional activation. In summary, our results strongly suggest that addition of HKMTI-1-005 to ATRA is a new therapeutic approach against AML that warrants further investigation.

Higher than normal mitochondrial DNA content associated with better outcome in acute promyelocytic leukaemia? Maybe.

Mitochondrial biology may influence the outcome of therapy for acute promyelocytic leukemia if arsenic trioxide is not part of the treatment. Inclusion of arsenic trioxide in the treatment regimen may cancel the adverse impact of certain mitochondrial abnormalities frequently associated with the disease. Commentary on: Pereira-Martins et al. Clinical significance of mitochondrial DNA content in acute promyelocytic leukaemia. Br J Haematol 2023;200:170-174.

Complications during Induction Chemotherapy in Acute Promyelocytic Leukemia: An Institutional Experience.

Stalin Chowdary BalaIntroduction Acute promyelocytic leukemia (APL) has transformed from a highly fatal disease to a highly curable one. Induction deaths continue to represent one of the major impediments in modern therapy of APL. Sepsis, hemorrhage, and differentiation syndrome are the major complications during induction therapy in APL. The present study reports the incidence and prognostic factors of major complications during induction chemotherapy in patients with newly diagnosed APL. Materials and Methods The present study was a single institutional, observational, retrospective study. All cases of APL diagnosed by morphology and confirmed by RT PCR (PML RARα) were included in this study. Data were analyzed using Statistical Package for the Social Sciences (SPSS) version 25. Results A total of 73 patients were analyzed. The median age at presentation was 30 years (range, 3-60 years) with a female to male ratio of 1.02:1. The most common symptom at presentation was fever (80%), followed by fatigue (56%) and gum bleeding (37%). The majority of the patients at presentation were high risk (42.4%), followed by intermediate risk (38.4%) and low risk (19.2%). Fifty-seven (78%) patients achieved complete hematological remission and 16 (22%) succumbed during induction chemotherapy. Infection was the most common cause of induction death (50%), followed by hemorrhage (37.5%) and differentiation syndrome (12.5%). On univariate analysis of prognostic factors, bcr3 variant, grade 3/4 bleeding during induction, and low levels of albumin at presentation were significant for induction mortality ( p = 0.034, 0.041, and 0.008 respectively). On multivariate analysis, only serum albumin < 3.5 g/dL was an independent predictor for induction mortality ( p = 0.043). Conclusion The majority of patients were high risk at presentation. Sepsis was the most common complication during induction and also the leading cause of induction death. Identifying induction complications at the earliest and providing aggressive supportive measures can further improve outcomes in APL.

How retinoic acid and arsenic transformed acute promyelocytic leukemia therapy.

Acute promyelocytic leukemia (APL) is associated with severe coagulopathy leading to rapid morbidity and mortality if left untreated. The definitive diagnosis of APL is made by identifying a balanced reciprocal translocation between chromosomes 15 and 17. This t(15;17) results in a fusion transcript of promyelocytic leukemia (PML) and retinoic acid receptor alpha (RARA) genes and the expression of a functional PML/RARA protein. Detection of a fused PML/RARA genomic DNA sequence using fluorescence in situ hybridization (FISH) or by detection of the PML/RARA fusion transcript via reverse transcriptase polymerase chain reaction (RT-PCR) has revolutionized the diagnosis and monitoring of APL. Once confirmed, APL is cured in over 90% of cases, making it the most curable subtype of acute leukemia today. Patients with low-risk APL are successfully treated using a chemotherapy-free combination of all-trans retinoic acid and arsenic trioxide (ATO). In this review, we explore the work that has gone into the modern-day diagnosis and highly successful treatment of this once devastating leukemia.

AML-372 Acute Promyelocytic Leukemia: A Case of Pseudotumor Cerebri Syndrome During Treatment Consolidation

Acute promyelocytic leukemia (APL) is a subtype of acute myeloid leukemia with distinctive morphological, clinical, and genetic features. Pseudotumor cerebri, also known as idiopathic intracranial hypertension, describes a neurologic syndrome characterized by headache, visual changes, papilledema without cerebral mass lesion, venous sinus thromboses, or obstructive hydrocephalus. Risk factors for the development of pseudotumor cerebri are obesity, women in the childbearing years, and hypervitaminosis A. The modified Dandy criteria are used for pseudotumor cerebri syndrome (PTCS) diagnosis. This complication has a high incidence in the pediatric population, particularly within 2-3 weeks of induction treatment for APL. Pseudotumor cerebri is a rare complication during consolidation therapy for APL. The reported incidence of "probable" PTCS is 1.7% in APL patients treated with ATRA. Case Report: We report here the case of a 20-year-old woman, obese with a BMI of 34.5 kg/m2, diagnosed with low-/intermediate-risk APL and treated with ATRA and ATO as induction treatment. After induction, she achieved MRD-negative complete morphological remission. During the first 2 weeks of the first cycle of consolidation-ATRA and ATO-the patient developed progressive diplopia and headaches without response to standard analgesic therapy. Additionally, she complained of nausea and vomiting. The ophthalmological exam with fundus examination revealed bilateral papilledema. The neurological exam was normal. There were no abnormal findings in the head CT scan or MRI of the brain. Thus, a diagnosis of "probable" pseudotumor cerebri was established. ATRA was discontinued and she received acetazolamide and dexamethasone with resolution of neurological symptoms within the next 7 days. Upon the next consolidation ATRA and ATO, the headaches resumed. The patient received all the ATRA consolidation cures as scheduled but with a dose reduction to 80% of the initial dose and in association with acetazolamide. She completed consolidation treatment and continues to be in molecular complete remission. Conclusions: This case report highlights the possibility of pseudotumor cerebri development in young adult patients with APL during consolidation therapy. The neurological symptoms were reversible, and the patient received all the ATRA consolidation. It is important to exclude other causes of intracranial hypertension including thromboses, infections, and disease involvement.

Down-regulation of hepatic cytochromes P450 1A1 and 1A2 by arsenic trioxide (ATO) in vivo and in vitro: A role of heme oxygenase 1

Arsenic trioxide (ATO) has evolved from an environmental threat to a successful therapy for acute promyelocytic leukemia (APL) and probably for solid tumors in the future. However, its efficacy comes at a cost of multi-organ toxicity whose mechanism remains unresolved. Arsenicals have been reported to modulate cytochrome P450 1A (CYP1A) enzymes, thus modifying activation/detoxification of drugs/procarcinogens. Therefore, this study aimed to investigate the possible effects of ATO on CYP1A1 and CYP1A2, in absence and presence of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) using in vivo and in vitro models. For this purpose, C57BL/6 mice were intraperitoneally injected with 8 mg/kg ATO with or without 15 μg/kg TCDD for 6 and 24 h. Furthermore, HepG2 cells were treated with ATO (1, 5, and 10 μM) with or without 1 nM TCDD for 6 and 24 h. ATO significantly inhibited TCDD-mediated induction of CYP1A1/1A2 mRNA, protein, and activity in both models. ATO differentially modulated CYP1A1/1A2 basal levels in vivo. We also demonstrated that ATO downregulates CYP1A through inhibiting the transcriptional activation of its regulatory element at both basal and inducible levels. Additionally, ATO significantly induced mRNA and protein of heme oxygenase 1 (HMOX1) in vivo and in vitro. In HepG2 cells, inhibition of HMOX1 by tin (IV) mesoporphyrin (IX) (SnMP) resulted in a partial restoration of the TCDD-mediated induction of CYP1A1 activity that was inhibited by ATO co-exposure. Our findings show that ATO alters both constitutive and inducible CYP1A1/1A2 expressions through transcriptional and HMOX1-mediated post-translational mechanisms. This implies the possible involvement of ATO in clearance-related consequences for the substrates of these enzymes such as drug-drug interactions or suboptimal toxicant elimination.

Low specificity of HLA-DR expression for diagnosis of acute promyelocytic leukemia

Contemporary therapy of acute promyelocytic leukemia (APL) is based on the use of all-trans retinoic acid, which is effective against tumor cells harboring RARa gene rearrangements (most common – t(15;17)(q24;q21)/PML::RARa). In several studies, it was suggested to use typical immunophenotypic features of APL (HLA-DR-negativity, etc) for prediction of RARa rearrangements presence. In this study, we aimed to evaluate the range of genetic aberrations that could be found in the HLA-DR-negative acute myeloid leukemia (AML). Our study was approved by the Independent Ethics Committee of the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology. Among studied 806 pediatric AML patients, HLA-DR-negativity was found in 253 cases. Only in 45.4% of them t(15;17)(q24;q21)/PML::RARa was found, while in remaining 54.6% normal karyotype or other genetic aberrations without RARa involvement. Frequency of the most common immunophenotypic features of APL, such as total CD117, CD33 and MPO expression with the lack of CD34, was higher in patients with t(15;17)(q24;q21)/PML::RARa, although only two thirds of APL cases were found to have all these signs. Moreover, the percentage of cells positive or negative for mentioned antigens varied significantly in APL group. Thus we can conclude, that all “typical” immunophenotypic characteristics of APL including HLA-DR-negativity, are very unspecific and cannot be used for reliable prediction of presence of t(15;17)(q24;q21)/PML::RARa.