Venetoclax in Acute Myeloid Leukemia: Molecular Basis, Evidences for Preclinical and Clinical Efficacy and Strategies to Target Resistance
Abstract
:Simple Summary
Abstract
1. Introduction
2. Molecular Basis for BCL-2 Homology 3 (BH3)-Mimetics Drugs in Cancer Therapy
2.1. Apoptotic Pathway
2.2. The BH3-Mimetics Class in Cancer Therapy
2.3. Rationale for Targeting BCL-2 in AML
2.4. BCL-2 Inhibitors in AML, Preclinical Studies
3. Clinical Studies of VEN in AML
3.1. VEN Monotherapy
3.2. Venetoclax in Combination with HMA
3.2.1. Phase I Study
3.2.2. Phase II Study
3.2.3. Phase III Study (VIALE-A Trial)
3.3. Combination with LDAC
3.3.1. Phase I/II Study
3.3.2. Phase III Study (VIALE-C)
3.4. HMA or LDAC-Based Combinations in Patients with RR AML
3.5. Combination with Intensive Chemotherapy
3.5.1. High Dose Cytarabine + Idarubicin-Based Regimens
3.5.2. FLAG-IDA Regimen
3.5.3. CPX-351
3.5.4. Cladribine-Based Regimen
3.5.5. Other Studies
3.6. Combination with Targeted Agents
3.6.1. IDH Inhibitors
3.6.2. FLT3 Inhibitors
4. Molecular Factors Driving Resistance
4.1. Genetic Factors
4.1.1. TP53
4.1.2. Other Genes
4.2. Non-Genetic Factors
4.2.1. BH3 Protein Expression and Occupation
4.2.2. Cellular Differentiation
4.2.3. Metabolic Factors
4.2.4. Mitochondrial Structure and Machinery
5. Future Directions
5.1. Clinical Studies
5.2. Preclinical Studies
5.3. In Vitro Preclinical Screening
6. Conclusions
Author Contributions
Funding
Conflicts of Interest
References
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Combination Therapy | Phase; Name; ID | Study Population | Venetoclax Doses | Other Agents Administration Regimens | Response Rate | Survival Rate | Ref |
---|---|---|---|---|---|---|---|
no | I; NCT01994837 | RR AML | 800 mg D1 to D28 | no | 19% (ORR) | 4.7 months (median OS) 2.3 months (median LFS) | [39] |
HMA | I; (M14-358); NCT02203773 | ND AML ineligible for chemotherapy | 400–800–1200 mg D1 to D28 | AZA 75 mg/m2, D1 to D7 or DEC 20 mg/m2, D1 to D5 | 37% (CR), 68% (ORR) 83% (cCR) | 17.5 months (median OS) | [40,41] |
II; NCT03404193 | ND patients with AML > 60 yrs RR patients > 18 years | 400 mg D1 to D28 (D1 to D21 if blasts < 5%) | DEC 20 mg/m2, D1 to D10 (induction) DEC 20 mg/m2, D1 to D5 (consolidation) | 63% (CR + CRi), 74% (ORR) | 18.1 months (median OS) | [42,43] | |
III; (VIALE-A); NCT02993523 | ND AML ineligible for chemotherapy | 400 mg D1 to D28 vs. placebo | AZA 75 mg/m2, D1 to D7 | 36.7% vs. 17.9% (CR) 64.7% vs. 22.8% (CR + CRi) | 14.7 months vs. 9.6 months (median OS) | [44] | |
LDAC | I/II; NCT02287233 | ND AML ineligible for chemotherapy | 600 mg D1 to D28 | LDAC 20 mg/m2 days D1 to D10 | 26% (CR) 28% (CRi) | 10.1 months (median OS) | [45] |
III; (VIALE-C); NCT03069352 | ND AML ineligible for chemotherapy | 600 mg D1 to D28 vs. placebo | LDAC 20 mg/m2 D1 to D10 | 27% vs. 7% (CR) 21% vs. 6% (CRi) | 7.2 months vs. 4.1 months (median OS) | [46] | |
Anthracyclin-based chemotherapy | I | ND AML <60 years | 200 to 600 mg D1 to D11 | DAUNO 60 mg/m2/d D2 to D4 CYTA 200 mg/m2/d D2 to D8 | ND | ND | [47] |
Ib; (CAVEAT); ACTRN12616000445471 | ND AML ≥ 65 years (>60 years if monosomal karyotype) | Induction 50 to 600 mg D-6 to D7 | CYTA 100 mg/m2/d D1 to D5 IDA 12 mg/m2/d D2 to D3 | 72% (ORR) 41% (CR) 31% (CRi) | 11.2 months (median OS) | [48] | |
Consolidation 50 to 600 mg (4 cycles) D-6 to D7 | CYTA (bolus) 100 mg/m2/d D1 to D2 IDA 12 mg/m2/d D1 | ||||||
Maintenance (7 cycles) 50 to 600 mg D1 to D14 | no | ||||||
Ib/II; NCT03214562 | ND, RR AML or high-risk MDS with > 10% blasts | Induction (1 or 2) 400 mg D1 to D14 | modified FLAG-IDA FLUDA 30 mg/m2 D1 to D14 CYTA 1.5 g/m2 D2 to D6 IDA 8 mg/m2 D4 to D6 (ND AML) or 6 mg/m2 D5 to D6 (RR AML) | 82 % (ORR) 37% (CR) 15% (CRh) 7% (CRi) | NR (median OS), 18 months (median EFS) | [49] | |
II; NCT03629171 | 18–65 years ND >18 years RR AML | 400 mg D2 to D22 (decreased to 300 mg D2 to D8 due to toxicities) | induction, CPX-351 D1, D3, D5 | 44% (ORR) 6% (CR) 33% (CRi) 6% (MLFS) | 6.1 months (median OS) | [50] | |
Cladribin-based chemotherapy | II; NCT02115295 | ND AML < 65 years | 400 mg D2 to D8 | Induction: Cladribine 5 mg/m2 D1 to D5 CYTA (1.5 g/m2 for pts < 60 years and 1 g/m2 for pts aged ≥ 60 years) D1 to D5 IDA 10 mg/m2/d D1 to D3 | 84% (CR) 94% (ORR) | NR (median OS and EFS) | [51] |
Consolidation, Cladribine 5 mg/m2 D1 to D3 CYTA 1 g/m2 (for patients aged <60 yrs) and 0.75 g/m2 (for patients aged ≥60 yrs) D1 to D5, IDA 8 mg/m2/d D1 to D2 | |||||||
II; NCT03586609 | ND AML > 60 years or <60 years unfit for conventional chemotherapy | Induction 100–400 mg D1 to D21 | Cladribine 5 mg/m2 D1 to D5 LDAC 20 mg/m2 D1 to D10 | 78% (CR) 15% (CRi) | NR (median OS) | [52] | |
consolidation VEN 100–400 mg D1 to D14 (Patients with MRD negativity received only 7 days of VEN) | Alternance of 2 cycles of A and B A, Cladribine 5 mg/m2 D1 to D3; LDAC 20 mg/m2 D1 to D10 B, AZA 75 mg/m2 D1 to D7 | ||||||
consolidation VEN 100–400 mg D1 to D14 (Patients with MRD negativity received only 7 days of VEN) | Alternance of 2 cycles of A and B A, Cladribine 5 mg/m2 D1 to D3; LDAC 20 mg/m2 D1 to D10 B, AZA 75 mg/m2 D1 to D7 | ||||||
IDH inhibitor (ivosidenib) | Ib/II; NCT03471260 | >18 years old IDH1mut MDS, ND secondary AML, or RR AML | Cohort 1 IVO + VEN 400 mg D1 to D14 Cohort 2 IVO + VEN 800 mg Cohort 3 IVO + VEN 400 mg + AZA | IVO; 500 mg daily from D15, +/− AZA; 75mg/m2 D1 to D7 every 28 days. | 92% (ORR), 84% cCR (CR + CRi + CRh) | NR (median OS). 68% (1-year OS) | [53] |
FLT3 inhibitors | Ib; NCT03625505 | RR FLT3mut AML | 400 mg D1 to D28 | GILT 150 mg D1-D28 | 83.8% (modified cCR = CR + CRi + CRh + MLFS), | 5.1 months (median EFS) | [54] |
II; NCT03404193 | ND patients with AML >60 years RR patients >18 years | DEC10-VEN | GILT, SORA and MIDO at recommended doses | 92% (cCR, ND AML), 62% (cCR, RR AML) | NR (median OS in ND AML) 6.8 months (median OS in RR AML) | [42,55] |
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Garciaz, S.; Saillard, C.; Hicheri, Y.; Hospital, M.-A.; Vey, N. Venetoclax in Acute Myeloid Leukemia: Molecular Basis, Evidences for Preclinical and Clinical Efficacy and Strategies to Target Resistance. Cancers 2021, 13, 5608. https://doi.org/10.3390/cancers13225608
Garciaz S, Saillard C, Hicheri Y, Hospital M-A, Vey N. Venetoclax in Acute Myeloid Leukemia: Molecular Basis, Evidences for Preclinical and Clinical Efficacy and Strategies to Target Resistance. Cancers. 2021; 13(22):5608. https://doi.org/10.3390/cancers13225608
Chicago/Turabian StyleGarciaz, Sylvain, Colombe Saillard, Yosr Hicheri, Marie-Anne Hospital, and Norbert Vey. 2021. "Venetoclax in Acute Myeloid Leukemia: Molecular Basis, Evidences for Preclinical and Clinical Efficacy and Strategies to Target Resistance" Cancers 13, no. 22: 5608. https://doi.org/10.3390/cancers13225608