abt-199 and Leukemia--Promyelocytic--Acute

The unraveling of the pathophysiology of acute myeloid leukemia (AML) has resulted in rapid translation of the information into clinical practice. After more than 40 years of slow progress in AML research, the US Food and Drug Administration has approved nine agents for different AML treatment indications since 2017. In this review, we detail the progress that has been made in the research and treatment of AML, citing key publications related to AML research and therapy in the English literature since 2000. The notable subsets of AML include acute promyelocytic leukemia (APL), core-binding factor AML (CBF-AML), AML in younger patients fit for intensive chemotherapy, and AML in older/unfit patients (usually at the age cutoff of 60-70 years). We also consider within each subset whether the AML is primary or secondary (therapy-related, evolving from untreated or treated myelodysplastic syndrome or myeloproliferative neoplasm). In APL, therapy with all-trans retinoic acid and arsenic trioxide results in estimated 10-year survival rates of ≥80%. Treatment of CBF-AML with fludarabine, high-dose cytarabine, and gemtuzumab ozogamicin (GO) results in estimated 10-year survival rates of ≥75%. In younger/fit patients, the "3+7" regimen (3 days of daunorubicin + 7 days of cytarabine) produces less favorable results (estimated 5-year survival rates of 35%; worse in real-world experience); regimens that incorporate high-dose cytarabine, adenosine nucleoside analogs, and GO are producing better results. Adding venetoclax, FLT3, and IDH inhibitors into these regimens has resulted in encouraging preliminary data. In older/unfit patients, low-intensity therapy with hypomethylating agents (HMAs) and venetoclax is now the new standard of care. Better low-intensity regimens incorporating cladribine, low-dose cytarabine, and other targeted therapies (FLT3 and IDH inhibitors) are emerging. Maintenance therapy now has a definite role in the treatment of AML, and oral HMAs with potential treatment benefits are also available. In conclusion, AML therapy is evolving rapidly and treatment results are improving in all AML subsets as novel agents and strategies are incorporated into traditional AML chemotherapy. LAY SUMMARY: Ongoing research in acute myeloid leukemia (AML) is progressing rapidly. Since 2017, the US Food and Drug Administration has approved 10 drugs for different AML indications. This review updates the research and treatment pathways for AML.

Topics: Age Factors; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Arsenic Trioxide; Bridged Bicyclo Compounds, Heterocyclic; Cladribine; Core Binding Factors; Cytarabine; Daunorubicin; Gemtuzumab; Humans; Leukemia, Myeloid, Acute; Leukemia, Promyelocytic, Acute; Maintenance Chemotherapy; Mutation; Myelodysplastic Syndromes; Myeloproliferative Disorders; Neoplasm, Residual; Sulfonamides; Survival Rate; Translational Research, Biomedical; Tretinoin; Vidarabine

Topics: Bridged Bicyclo Compounds, Heterocyclic; Cytoreduction Surgical Procedures; Humans; Leukemia, Promyelocytic, Acute; Sulfonamides

Topics: Arsenic; Arsenic Trioxide; Arsenicals; Bridged Bicyclo Compounds, Heterocyclic; Humans; Leukemia, Promyelocytic, Acute; Oxides; Sulfonamides; Tretinoin

Topics: Antineoplastic Combined Chemotherapy Protocols; Azacitidine; Bridged Bicyclo Compounds, Heterocyclic; Central Nervous System; Humans; Leukemia, Myeloid, Acute; Leukemia, Promyelocytic, Acute; Recurrence; Remission Induction; Sulfonamides

Topics: Bridged Bicyclo Compounds, Heterocyclic; Humans; Leukemia, Promyelocytic, Acute; Oncogene Proteins, Fusion; Promyelocytic Leukemia Zinc Finger Protein; Retinoic Acid Receptor alpha; Sulfonamides; Translocation, Genetic; Tretinoin

Resistance to venetoclax, a selective inhibitor of BCL2 apoptosis regulator (BCL2), is regarded as a clinical problem. However, it is unclear whether resistance to venetoclax induces cross-resistance to other drugs.. Venetoclax-resistant HL60/VEN cells were newly established through continuous exposure of human acute promyelocytic leukemia HL60 cells to venetoclax, and drug sensitivity, apoptotic activity, and mRNA expression were compared between HL60 and HL60/VEN cells.. HL60/VEN cells displayed approximately 3-fold resistance to venetoclax, maintained their ability to synthesize DNA and had low apoptotic activity. HL60/VEN cells also exhibited diverse sensitivity to cytotoxic drugs, especially resistance to ATP binding cassette subfamily B member 1 (ABCB1) substrates, and up-regulation of ABCB1 mRNA. However, the sensitivity of HL60/VEN cells to venetoclax was not restored by ABCB1 inhibitor. ABCB1-overexpressing cells did not show resistance to venetoclax.. HL60/VEN cells exhibited up-regulation of ABCB1 in addition to an alteration in apoptotic activity, and cross-resistance to ABCB1 substrates was clarified. However, sensitivity to venetoclax was hardly affected by ABCB1.

Topics: ATP Binding Cassette Transporter, Subfamily B; Bridged Bicyclo Compounds, Heterocyclic; Cell Proliferation; Cell Survival; Drug Resistance, Neoplasm; Gene Expression Regulation, Neoplastic; HL-60 Cells; Humans; Leukemia, Promyelocytic, Acute; Sulfonamides; Up-Regulation

Acute promyelocytic leukemia (APL) is one of the most curable cancers. However, relapse of the disease is a difficult issue in clinical practice and it remains a great challenge that patients have a poor effect of conventional treatment in the clinic. Therefore, new and more effective therapeutic measures are urgently needed. Herein, we report a case of relapsed and refractory APL harboring a RARA-LBD region mutation successfully treated with venetoclax (VEN).. A 37-years-old woman was admitted to our hospital with worsening spontaneous gingival bleeding and skin ecchymosis. Physical examination revealed multiple petechiae and ecchymosis in the extremities.. The patient was diagnosed with L-type PML-RARα-positive APL, harboring a RARA-LBD region mutation, low-risk, based on bone marrow cytology, immunophenotypic analysis by flow cytometry, karyotype analysis, and molecular analysis.. Complete remission was achieved after the first induction therapy of all-trans retinoic acid (ATRA) combined with arsenic trioxide, but relapse was observed only after 11 months. Reinduction with ATRA and arsenic trioxide combined with anthracycline failed. Therefore, we tried to provide a new treatment with the Bcl-2 inhibitor VEN orally (100 mg d1, 200 mg d2 to d18, followed by 300 mg daily continuously).. Clinical symptoms and laboratory indicators improved rapidly with VEN treatment. A complete hematologic response was achieved with VEN-based therapy.. Related drug resistance gene monitoring should be performed canonically in relapsed and refractory APL. Some relapsed and refractory APL that failed to respond to conventional treatment were at risk of death. Bcl-2 inhibitors are expected to be an effective salvage therapy for patients with resistance to ATRA, which is worthy of further discussion.

Topics: Adult; Antineoplastic Agents; Arsenic Trioxide; Bridged Bicyclo Compounds, Heterocyclic; Ecchymosis; Female; Humans; Leukemia, Promyelocytic, Acute; Mutation; Proto-Oncogene Proteins c-bcl-2; Recurrence; Salvage Therapy; Sulfonamides; Treatment Outcome; Tretinoin

Topics: Adult; Antineoplastic Agents; Bridged Bicyclo Compounds, Heterocyclic; Combined Modality Therapy; Female; Gene Rearrangement; Hematopoietic Stem Cell Transplantation; Heterogeneous-Nuclear Ribonucleoprotein Group C; High-Throughput Nucleotide Sequencing; Humans; Leukemia, Promyelocytic, Acute; Oncogene Proteins, Fusion; Promyelocytic Leukemia Protein; Proto-Oncogene Proteins c-bcl-2; Remission Induction; Retinoic Acid Receptor alpha; Sulfonamides; Transcription Factors; Tretinoin

Since cancer cells have different mitochondrial bioenergetic requirements than non-cancerous cells, therapeutic inhibition of its mitochondrial functionality continues to be an important target for anticancer drug discovery. In this study, a series of acylhydroquinones with different acyl-chain length, and their chlorinated derivatives, in the aromatic ring, synthesized by Fries rearrangement under microwave irradiation, were evaluated for their anticancer activity in two leukemia cell lines. Findings from the primary and secondary screening of the 18 acylhydroquinones, tested at 5 µM on acute promyelocytic leukemia HL-60 and acute lymphoblastic leukemia CEM cells lines, identified an acylchlorohydroquinone (12) with a highly selective anti-proliferative effect toward HL-60 cells. This compound induced S-phase arrest in the cell cycle progression of HL-60 cells with insignificant toxicity on leukemic CEM cells and non-cancerous Hs27 cells. In HL-60 leukemic cells, 12 triggered increased mitochondrial NADH oxidation, increased respiration in presence of oligomycin (state 4o), mitochondrial depolarization, and ROS production, suggesting an uncoupling of OXPHOS. This provoked a metabolic adaptation dependent on AMPK/ACC/autophagy axis, having the mitochondrial β-oxidation a pro-survival role since the combination of 12 and etomoxir, a carnitine palmitoyl-transferase (CPT) inhibitor promoted extensive HL-60 cell death. Finally, 12-induced metabolic stress sensitized to HL-60 cells to cell death by the FDA-approved anti-leukemic drug ABT-199, a BH3 mimetic. Therefore, our results suggest that acylchlorohydroquinone is a promising scaffold in anti-promyelocytic leukemia drug research.

Topics: AMP-Activated Protein Kinases; Antineoplastic Agents; Apoptosis; Bridged Bicyclo Compounds, Heterocyclic; Cell Cycle Checkpoints; Cell Line, Tumor; Humans; Hydroquinones; Leukemia, Promyelocytic, Acute; Membrane Potential, Mitochondrial; Mitochondria; Oxidative Phosphorylation; Proto-Oncogene Proteins c-bcl-2; Reactive Oxygen Species; Signal Transduction; Structure-Activity Relationship; Sulfonamides

Topics: Bridged Bicyclo Compounds, Heterocyclic; Humans; Leukemia, Myeloid, Acute; Leukemia, Promyelocytic, Acute; Myeloid-Lymphoid Leukemia Protein; Oncogene Proteins, Fusion; Phenotype; Proto-Oncogene Proteins c-bcl-2; Sulfonamides; Treatment Outcome