Targeting Apoptotic Pathways in Acute Myeloid Leukaemia
Abstract
:1. Introduction
2. Apoptosis and the BCL-2 Family of Proteins
3. Targeting BCL-2 in AML
3.1. Oblimersen (BCL-2 Anti-Sense Oligonucleotide)
3.2. Obatoclax
3.3. ABT-737/ABT-263 (Navitoclax)
3.4. Venetoclax (ABT-199)
3.4.1. Venetoclax Monotherapy in Relapsed/Refractory Patients
3.4.2. Venetoclax + Hypomethylating Agents in Treatment-Naïve Patients
3.4.3. Venetoclax + Low Dose Cytarabine in Treatment-Naïve Patients
3.4.4. Venetoclax + HMA/LDAC in Relapsed/Refractory Patients
3.5. Ongoing Clinical Trials Using Venetoclax in AML
3.5.1. Phase III Trials of Venetoclax + Azacitdine/LDAC in Treatment-Naïve Patients
3.5.2. Venetoclax + Intensive Chemotherapy
3.5.3. Venetoclax + FLT3 Inhibitors
3.5.4. Venetoclax + IDH1/2 Inhibitors
3.5.5. Venetoclax + JAK Inhibitors (Ruxolitinib)
3.5.6. Venetoclax + MCL-1 Inhibitors
3.5.7. Venetoclax + MDM2 Inhibitors
3.6. Predictors of Response to Venetoclax
3.6.1. Molecular Subtypes of AML
3.6.2. BH3 Profiling
4. Conclusions
Author Contributions
Funding
Conflicts of Interest
Abbreviations
AML | Acute Myeloid Leukaemia |
MDS | Myelodysplastic Syndrome |
7+3 | 7 days of cytarabine and days of an anthracycline |
FLAG | Fludarabine, Cytarabine, Granulocyte Colony Stimulating Factor |
FLAG-IDA | Fludarabine, Cytarabine, Granulocyte Colony Stimulating Factor and Idarubicin |
HMA | Hypomethylating agent |
LDAC | Low dose Ara-C |
BCL-2 | B cell lymphoma 2 |
BCL-xL | B cell lymphoma extra large |
MCL-1 | Myeloid Leukemia Cell Differentiation Protein |
FLT3 | Fms like tyrosine kinase 3 |
NPM1 | Nucleophosmin |
IDH1/2 | Isocitrate Dehydrogenase 1/2 |
CR | Complete Remissiob |
CRi | Complete remission with incomplete haematological recovery |
PR | Partial Remission |
R/R | Relapsed and Refractory |
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Clinicaltrials.gov Identifier | Target Group | Phase | Trial |
---|---|---|---|
NCT03484520 | R/R AML (age ≥ 18) | I | A Study of Venetoclax and Dinaciclib (MK7965) in Patients With Relapsed/Refractory Acute Myeloid Leukemia |
NCT03441555 | R/R AML (age ≥ 18) | I | A Study of Venetoclax and Alvocidib in Patients With Relapsed/Refractory Acute Myeloid Leukemia |
NCT02993523 | AML (age ≥ 18; treatment-naïve) | III | A Study of Venetoclax in Combination With Azacitidine Versus Azacitidine in Treatment-Naïve Subjects With Acute Myeloid Leukemia Who Are Ineligible for Standard Induction Therapy |
NCT03874052 | R/R AML (age ≥ 18) | I | Ruxolitinib in Combination With Venetoclax for the Treatment of Relapsed/Refractory Acute Myeloid Leukemia |
NCT03625505 | R/R AML (age ≥ 18) | I | A Study to Assess Safety and Efficacy of Venetoclax in Combination With Gilteritinib in Subjects With Relapsed/Refractory Acute Myeloid Leukemia |
NCT03573024 | AML (ages 18–59; treatment-naïve) | II | Venetoclax and Azacitidine for Non-Elderly Adult Patients With Acute Myeloid Leukemia |
NCT03069352 | AML (age ≥ 18; treatment-naïve) | III | A Study of Venetoclax in Combination With Low Dose Cytarabine Versus Low Dose Cytarabine Alone in Treatment-Naive Patients With Acute Myeloid Leukemia Who Are Ineligible for Intensive Chemotherapy |
NCT03672695 | R/R AML (age ≥ 18) | I | Phase I Dose Escalation Study of Intravenously Administered S64315 (Mcl-1 Inhibitor) in Combination With Orally Administered Venetoclax in Patients With Acute Myeloid Leukaemia |
NCT03844815 | High risk AML (R/R AML, TP53 mutant, adverse cytogenetics; age ≥ 18) | I | Study of Venetoclax in Combination With Decitabine in Subjects With Acute Myeloid Leukemia |
NCT03214562 | Treatment naive and R/R AML (age ≥ 18) | I/II | Study of the BCL-2 Inhibitor Venetoclax in Combination With Standard Intensive Acute Myeloid Leukemia (AML) Induction/Consolidation Therapy With FLAG-IDA in Patients With Newly Diagnosed or Relapsed/Refractory Acute Myeloid Leukemia (AML) |
NCT03709758 | AML (age 18–75; treatment-naïve) | I | Venetoclax in Combination With Intensive Induction and Consolidation Chemotherapy in Treatment-Naïve AML |
NCT03466294 | AML (age ≥ 60; treatment-naïve) | II | Azacitidine and Venetoclax as Induction Therapy With Venetoclax Maintenance in the Elderly With AML |
NCT03629171 | R/R AML (age ≥ 18) with dose expansion cohort B for treatment-naïve | II | Liposome-encapsulated Daunorubicin-Cytarabine (CPX-351) and Venetoclax in Treating Participants With Relapsed, Refractory or Untreated Acute Myeloid Leukemia |
NCT03455504 | AML (age 18–65; treatment-naïve) | II | Venetoclax Add in Combination With Fludarabine, Cytarabine and Idarubicin in Induction for Acute Myeloid Leukemia (V-FIRST) |
NCT03586609 | AML (age ≥ 60; treatment-naïve) | II | Venetoclax, Cladribine, Low Dose Cytarabine, and Azacitidine in Treating Participants With Patients Previously Untreated Acute Myeloid Leukemia |
NCT03735875 | R/R AML (age 18–65) | I/II | Venetoclax and Quizartinib in Treating Patients With FLT3-mutated Recurrent or Refractory Acute Myeloid Leukaemia |
NCT02670044 | R/R AML (age ≥ 60) | I/II | A Study of Venetoclax in Combination With Cobimetinib and Venetoclax in Combination With Idasanutlin in Patients Aged >/= 60 Years With Relapsed or Refractory Acute Myeloid Leukemia Who Are Not Eligible for Cytotoxic Therapy |
NCT03797261 | R/R AML and R/R NHL/DLBCL (age ≥ 18) | I | A Study of Venetoclax and AMG 176 (MCL1 inhibitor) in Patients With Relapsed/Refractory Hematologic Malignancies |
NCT03862157 | Treatment naïve AML with a history of MDS, MPN, MDS/MPN, CNL, aCML, CEL (age ≥ 18) | I/II | Azacitidine, Venetoclax, and Pevonedistat in Treating Patients With Newly Diagnosed Acute Myeloid Leukemia |
NCT03471260 | R/R AML (age ≥ 18) | I/II | Study of Venetoclax With the mIDH1 Inhibitor Ivosidenib (AG120) in IDH1-Mutated Hematologic Malignancies |
NCT03613532 | High risk AML, MDS, MDS/MPN (age ≥ 18) going to Allogeneic SCT | I | Venetoclax Added to Fludarabine + Busulfan Prior to Transplant for AML, MDS, and MDS/MPN |
Clinical Trial | Patients | Response | Response by Cytogenetic/Molecular Subtype |
---|---|---|---|
Venetoclax monotherapy in relapsed/refractory patients (NCT01994837) | n = 32 | CR/CRi = 19% CR = 6% CRi = 13% | IDH1/2 = 33% CR/CRi SRSF2/ZRSR2 = 27% CR/CRi |
Venetoclax + Hypomethylating Agents in treatment-naïve patients >65 years (NCT02203773) | n = 145 | CR/CRi = 67% CR = 37% CRi = 30% | Poor Cytogenetics = 60% CR/CRi Intermediate Cytogenetics = 74% CR/CRi TP53 = 47% CR/CRi FLT3 = 72% CR/CRi IDH1/2 = 71% CR/CRi NPM1 = 91.5% CR/CRi |
Venetoclax + low dose Cytarabine in treatment-naïve patients >60 years (NCT02287233) | n = 82 | All patients CR/CRi = 54% CR = 26% CRi = 28% Without Prior HMA (N = 58) CR/CRi = 62% CR = 34% CRi = 28% | All patients Poor Cytogenetics = 42% CR/CRi Intermediate Cytogenetics = 63% CR/CRi TP53 = 30% CR/CRi FLT3 = 44% CR/CRi IDH1/2 = 72% CR/CRi NPM1 = 89% CR/CRi |
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Sillar, J.R.; Enjeti, A.K. Targeting Apoptotic Pathways in Acute Myeloid Leukaemia. Cancers 2019, 11, 1660. https://doi.org/10.3390/cancers11111660
Sillar JR, Enjeti AK. Targeting Apoptotic Pathways in Acute Myeloid Leukaemia. Cancers. 2019; 11(11):1660. https://doi.org/10.3390/cancers11111660
Chicago/Turabian StyleSillar, Jonathan R., and Anoop K. Enjeti. 2019. "Targeting Apoptotic Pathways in Acute Myeloid Leukaemia" Cancers 11, no. 11: 1660. https://doi.org/10.3390/cancers11111660