Vesanoid (tretinoin)

P1, N=80, Active, not recruiting, Astex Pharmaceuticals, Inc. | Recruiting --> Active, not recruiting

P1, N=18, Recruiting, Dwight Owen | Trial primary completion date: Dec 2023 --> Dec 2024

P1, N=2, Terminated, OHSU Knight Cancer Institute | Active, not recruiting --> Terminated; Low accrual

M3-like patients exhibited distinct genomic features, low immune activity and better clinical survival. The initiative identification of patients similar to M3 subtype may help to identify more patients that would benefit from ATO/ATRA treatment and deepen our understanding of the molecular mechanism of AML pathogenesis.

The gene transcription profile and metabolites of FLT3-ITD mutant cells changes significantly after treatment, which might be related to the anti-FLT3-ITD AML effect. The screened DEGs, differential metabolites pathway are helpful in studying the mechanism of anti-leukemia effects and drug targets.

P1/2, N=200, Active, not recruiting, Merck Sharp & Dohme LLC | Recruiting --> Active, not recruiting

P1/2, N=90, Active, not recruiting, Merck Sharp & Dohme LLC | Recruiting --> Active, not recruiting

P3, N=158, Active, not recruiting, Children's Oncology Group | Trial completion date: Oct 2025 --> Sep 2024

A panel of FDA-approved drugs with biologically validated activity in DMG were selected for each group: panobinostat/ponatinib, everolimus/topotecan, tolnaftate/tretinoin, and carmofur/eltrombopag...These properties were further validated in efficacy studies in DMG animal models. The proclivity of many drugs to be rapidly effluxed from the brain after CED generates a vulnerability that can be exploited for the development of novel therapeutic regimens, such as with pharmacokinetics-informed drug selection or concomitant dosing of ET-inhibiting drugs.

P2, N=112, Recruiting, Mario Negri Institute for Pharmacological Research | Trial completion date: Sep 2023 --> Sep 2024 | Trial primary completion date: Aug 2023 --> Aug 2024

P1/2, N=26, Active, not recruiting, University of Colorado, Denver | Trial completion date: Aug 2023 --> Aug 2024

P2, N=151, Recruiting, M.D. Anderson Cancer Center | Trial completion date: Dec 2026 --> Dec 2025

Both options of treatment (ATRA-ATO and ATRA-chemotherapy) were discussed with patients with low- and intermediate-risk APL, pros and cons explained in details, and treatment regimen selected after getting informed written consent. Fifteen patients liked to be treated with all-trans retinoic acid (ATRA) and arsenic trioxide (ATO), while rest of the 15 patients preferred treatment with ATRA and chemotherapy. Combination of ATRA and ATO is equally effective, less toxic, and more feasible in comparison to ATRA and chemotherapy for patients with low- and intermediate-risk APL and is a viable option for this subset of patients, especially in countries with limited resources.

Immunoblotting confirmed that ATO-resistant cells were unable to undergo apoptosis as levels of pro-apoptotic (cleaved caspase-3, cleaved-PARP, BAX), anti-apoptotic (Bcl2, Bcl-xL, XIAP), and PML-RARA proteins remain unchanged in ATO-resistant cells except for downregulation of Bcl2 and upregulation of cleaved caspase-3 in UF1 following ATO/ATRA treatment. Our results indicate that venetoclax+ATO cooperates in inducing apoptosis of ATO-resistant cells through mitochondrial stress-induced ROS production coupled with PML-RARA degradation.

Even in the case of relapses, most patients obtain a new remission as a result of therapy with ATO and ATRA, but an effective consolidation treatment is necessary to maintain it. However, there is a variety of controversial aspects related to the role of HSCT in APL, ranging from the fact that outcome data are obtained almost exclusively from retrospective studies and historical analyses to questions related to the type of transplantation, the impact of minimal residual disease, conditioning regimens, or the role of other therapeutic options. All these questions justify the need for controlled prospective studies in the following years.

Tailored treatment with all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) has revolutionized the outcome of acute promyelocytic leukemia (APL) from a uniformly fatal disease to one of the most curable malignant diseases in humans. Due to its high efficacy, ATO/ATRA is the standard first-line therapy in younger adult, non-high-risk APL patients...Besides the treatment of newly diagnosed patients, managing toxicities and complications remains challenging. This review discusses the approach to the treatment of APL in elderly and pediatric patients.

Since the introduction of all-trans retinoic acid (ATRA), acute promyelocytic leukemia (APL) has become a highly curable malignancy, especially in combination with arsenic trioxide (ATO)...Furthermore, recent super-enhancer (SE) analysis has identified a novel AML subgroup characterized by high expression of RARα through strong SE levels in the gene locus and increased sensitivity to tamibarotene. Combined with a hypomethylating agent, synthetic retinoids have shown synergistic anti-leukemic effects in non-APL AML preclinical models and are now being studied in phase II and III clinical trials.

We explored the overall microbial flora by 16S rRNA genes analysis in fecal samples from acute promyelocytic leukemia (APL) patients treated with arsenic trioxide (ATO) plus all-trans retinoic acid (ATRA)...In the most common gut bacteria Bacteroides fragilis, arsenic resistance genes were significantly induced by arsenic exposure in anaerobic pure culture experiments. Without an animal model, without taking arsenicals passively, the results evidence that arsenic exposure by drug treatment is not only associated with alterations in intestinal microbiome development at the abundance and diversity level, but also induced arsenic biotransformation genes (ABGs) at the function levels which may even extend to arsenic-related health outcomes in APL.

P1, N=2, Active, not recruiting, OHSU Knight Cancer Institute | Recruiting --> Active, not recruiting | N=40 --> 2 | Trial completion date: Feb 2026 --> Jun 2027 | Trial primary completion date: Feb 2023 --> Jun 2025

The use of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) is highly effective making this now the most curable subtype of AML...On COG AAML1331, pediatric patients with HR APL were enrolled on a treatment arm that included the anthracycline idarubicin only in induction using a ATO-ATRA based regimen without maintenance therapy...Standard risk APL using a cytotoxic free ATO-ATRA induction also frequently results in hyperleukocytosis (elevated white blood cell count from blast differentiation) requiring cytoreduction. Thus, careful monitoring of these potential complications and aggressive supportive care to correct coagulopathy and treat differentiation syndrome and/or hyperleukocytosis is critical to prevent early death and ensure excellent cure rates.

He was found to have persistent leukocytosis despite treatment with IV ampicillin–sulbactam...He was started on induction therapy with ATRA at 45mg/m 2 /day in 2 divided doses, systemic chemotherapy with 4 doses of idarubicin (12mg/m 2 on day 1,3,5,7), followed by arsenic trioxide (ATO) on day 8 at 0.15 mg/kg IV daily until hematological response. He received a brief course of cytoreductive therapy with hydroxyurea 1500 mg twice daily during the initial phase of treatment for high-risk APLv (white cell count >10 × 10⁹/l)...He was managed as differentiation syndrome with dexamethasone and symptomatic improvement within 24 hours of initiation of steroid therapy...2010; 115(25):5137-5146) based consolidation regimen was chosen with addition of cytarabine combined with ATRA and idarubicin in the 1 st and 3 rd consolidation cycles for a total of 3 monthly cycles. BM biopsy at cell count recovery with platelets (> 100x10 9 /L) and neutrophils (> 1x10 9 /L) post-induction showed complete remission with a morphologic response (<5% blasts) and normal cytogenetic analysis. Despite the achievement of complete morphologic remission, there were concerns for the relative refractoriness of the APLv to ATO+ATRA alone, although scant with fewer data on ATO sensitivity. Thus, a chemotherapy-based consolidation approach was chosen vs ATRA+ATO alone.

Background: APL, once regarded as the most rapidly fatal acute myeloid leukemia (AML), is now curable in 75-90% of patients using targeted agents [All-trans retinoic acid (ATRA)+Arsenic Trioxide (ATO)] or ATRA combined with chemotherapy (ATRA+Idarubicin, AIDA-based). This first analysis on the Harmony APL project shows a significant survival advantage of patients treated with the ATRA-ATO chemo-free regimen at 10 year-follow-up, irrespective of the Sanz-risk score. The latter maintains its prognostic relevance in patients treated with the AIDA regimen. Age resulted significantly associated with OS, irrespective of treatment.

The use of AAA-based regimens in newly-diagnosed APL significantly improved early deaths, OS and RFS independent of conventional risk grouping. Acute promyelocytic leukemia, Oral, Arsenic trioxide, ALL-trans retinoic acid (ATRA)

We performed a retrospective analysis of 2670 unselected APL patients, diagnosed and treated with PETHEMA protocols: chemotherapy based (APL1996, 1999, 2005, 2012 and 2017 for high risk) and "chemo free" ATO+ATRA (2017 for low/intermediate risk). The s-NPLs are relatively frequent and severe late complication in APL. Age >= 35 years is a potential risk factorfor development of s-NPLs. Chemotherapy free regimens had lower CI of s-NPLs at 5 years, nevertheless more data and follow-up are required.

Daunorubicin (50mg/m 2 /day intravenously for 3 days) was administered to patients < 65 years old with high-risk disease. The use of an entirely oral AAA-based induction in a risk-adapted strategy that minimized chemotherapy was highly effective and safe in newly-diagnosed APL of all risk categories, and induced deep molecular responses. ALL-trans retinoic acid (ATRA), Oral, Acute promyelocytic leukemia, Arsenic trioxide

Patients from the high-risk group got idarubicin 8–12 mg/m2 (1–3 administrations) at the beginning of the induction course for cytoreduction, and patients with clinically significant hyperleukocytosis got cytarabine 100 mg/m2 (1–3 administrations). Risk-adapted strategy for non-chemotherapeutic treatment of acute promyelocytic leukemia based on combination of tretinon and arsinic trioxide allows to achieve 99.0% 3-year disease-free survival in patients as from the low-risk group as from the high-risk group. The main reason for unsuccessful therapy according to the ATO+ATRA protocol was early mortality in patients from the high-risk group. ALL-trans retinoic acid (ATRA), Acute promyelocytic leukemia, Arsenic trioxide

P2, N=112, Recruiting, Mario Negri Institute for Pharmacological Research | Unknown status --> Recruiting | Trial completion date: Jun 2021 --> Sep 2023 | Trial primary completion date: Jun 2021 --> Aug 2023

Our study shows APL is a highly curable malignancy and outcomes have improved with newer non chemotherapy based therapies. It can also be concluded that outcomes of APL gradually improved over the past 2 decades due to improvement in supportive care, provision of blood products and use of newer protocols. The prognosis remains less favourable in high risk patients.

Hydroxyurea was given for cytoreduction (up to 2gm q2hourly) on physician discretion if the TLC>5x109/L...Patients with Intermediate and High-risk disease received 2 years of maintenance with ATRA for 15 days once every 3 months, daily 6-Mercaptopurine and weekly oral Methotrexate. After a protocol modification in 2015, oral Prednisolone (0.5-1mg/kg/day for 14 days followed by taper) was added to the induction therapy and maintenance therapy was reduced to 1 year...The estimated 5-year EFS and OS in the entire cohort were 79 ± 5.8% and 80 ± 5.8%, respectively. CONCLUSION Treatment of all risk classes of APML with ATO and ATRA without chemotherapy is associated with excellent long-term outcomes in the real-world setting.

Then they were randomized to receive consolidation therapy including ATRA plus ATO or ATRA plus RIF. Interim results of this study proved efficacy of ATRA plus RIF was non-inferior to ATRA plus intravenous ATO for consolidation therapy in standard-risk APL. The toxicity is almost equivalent except slightly advantage of ATRA-RIF group on coagulation. No relapses may be attributed to simultaneous administer of ATRA and ATO/RIF.

Using an integrated approach of transcriptomic and metabolomic profiling, t(11; 14) MM cells were confirmed to retain features of B-cell biology, including lower Mito metabolism that results in increased sensitivity to BCL-2 inhibition by Ven. Although these biological features are closely linked to t(11; 14), B-cell gene or Mito gene signatures did not serve as better biomarkers for predicting efficacy to Ven compared with t(11; 14) alone.

The acute promyelocytic leukemia (APL) driver ZBTB16/RARα is generated by the t(11;17) (q23;q21) chromosomal translocation, which is resistant to combined treatment of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) or conventional chemotherapy, resulting in extremely low survival rates...We showed that Z/R fusion protein expressed in HeLa cells was resistant to ATO, ATRA, and conventional chemotherapeutic agents...Furthermore, SIAH2 was identified as the E3 ligase participating in hyperthermia-induced ubiquitination of ZBTB16/RARα. In short, these results demonstrate that hyperthermia could effectively destabilize and subsequently degrade the ZBTB16/RARα fusion protein in an NCoR-dependent manner, suggesting a thermal-based therapeutic strategy that may improve the outcome in refractory ZBTB16/RARα-driven APL patients in the clinic.

P2, N=151, Recruiting, M.D. Anderson Cancer Center | Trial completion date: Dec 2023 --> Dec 2026 | Trial primary completion date: Dec 2022 --> Dec 2025

P2, N=14, Completed, Icahn School of Medicine at Mount Sinai | Active, not recruiting --> Completed

P2, N=14, Active, not recruiting, Icahn School of Medicine at Mount Sinai | Recruiting --> Active, not recruiting | N=20 --> 14 | Trial primary completion date: Feb 2022 --> May 2022

Resembling acute promyelocytic leukemia (APL) is a unique subtype of APL who sharing clinical, morphological, and immunophenotypic features with typical APL, but lacking evidence of PML-RARA fusion gene and usually insensitive to arsenic trioxide (ATO) and all-trans retinoic acid (ATRA)...They usually were resistant to ATO and ATRA but partially sensitive to anthracycline-based chemotherapy...The patient with RARG-HNRNPM was benefited from a combined chemotherapy homoharringtonine, cytarabine, and aclacinomycin (HAA) regimen with no relapse. RARG rearrangement resembling APL are various. The treatment should be switched from ATRA/ATO to AML combined chemotherapy regimen early.

Aims To report on the use of arsenic trioxide (ATO) combined with ATRA in a pediatric patient with very late APL extramedullary relapse. Therefore, she received the association ATO-ATRA in second line, obtaining the second complete remission with a chemo-free regimen. This case shows that the association ATO-ATRA as single therapy in pediatric patients is safe and effective also for relapses and that the best second line therapeutic regimen should be chosen considering the treatment history of each patient.

Background All-trans retinoid acid (ATRA) and arsenic trioxide (ATO) have changed the treatment paradigm of acute promyelocytic leukemia (APML)...Results We registered 149 patients during the study period.The median age was 37 years(range 15-72 years, male 56.6%, female-37%).93 patients (62.4%) were stratified as low risk and 56 patients (37.5%) as high risk based on Sanz’s score.The induction therapy for high risk APML was single agent ATO (42.8%),ATO/ATRA/anthracycline (26.7%),ATO/anthracycline (25%),and ATO/ATRA (5%).The consolidation for high risk APML includes ATRA/daunorubicin (50%),ATO/ATRA (26.8%),HIDAC (4%) and APL 2000 in one patient.All low-risk APML patients received ATO-ATRA in induction and consolidation.Anthracycline was added to three patients in induction to decease white cell count.The proportion of deaths that occurred in first week include 6.5% in low risk and 9% in high risk group.The median follow up was 42 months.The hematological CR at the end of induction was 85%.(128/149 patients,expired during induction-14,lost to follow up-7).The rate of end of consolidation PCR negativity was 83%.Differentiation syndrome occurred in 75% of patients.For the overall patient population, the 3-year probability for OS, EFS, DFS was 88.1% (95% C.I, 82.9 93.6), 75.9% (95% C.I, 68.9-83.5), 81.4% (95% C.I, 75-88.4) respectively. The 3-year survival probability for OS, EFS, and DFS for low risk APML was 90% (95% C.I, 84.1-96.4), 80.1% (95% C.I, 72-89.1), 84.5% (95% C.I, 76.9-92.7) respectively whereas for high risk APML was 84.7% (95% C.I, 75.3-95.2), 68.6% (95% C.I, 56.9-82.9), 76.1% (95% C.I-65-89) respectively.The total number of relapses were 11.The median time to relapse for low risk and high risk was 23months(18-32months) and 20months(range 5-39months) respectively. Conclusion Treatment with ATO and ATRA based regimen are effective in real world setting.The emphasis should be to reduce the early death rate due to bleeding and infectious complications.

Methods Primary leukemic blasts from APL mice (n=4) and patients (age, 25-52y; n=10) were treated with VEN (250-500nM), ATO, ATRA (1µM), and S64315 (10-50nM) monotherapies and combinations and evaluated for cell survival. Finally, in vivo CLDX model revealed limited effect of VEN and S64315 monotherapy, while the combination was able to effectively reduce the leukemic burden, resulting in increased overall survival (vehicle:15 vs Combo:42 days). Conclusion The combination of BCL2 and MCL1 inhibition is a potential effective treatment in ATO/RA resistant APL patients and could be clinically explored in this category of patients with very poor prognosis.

P2, N=150, Recruiting, M.D. Anderson Cancer Center | Trial completion date: Dec 2021 --> Dec 2023 | Trial primary completion date: Dec 2021 --> Dec 2022

FLT3-ITD mutation did not influence survival outcome in adult APL treated with ATO and ATRA-based therapeutic regimen.