Current VEN-based combination regimens in AML
| All molecular subgroups . | Cycle 1 . | Cycle 2+ . | Comments . |
|---|---|---|---|
| Azacitidine+ venetoclax | Azacitidine 75 mg/m2 daily; days 1-7 Venetoclax 400 mg daily; days 1-28 | Same as C1 | Obtain day 21-28 bone marrow biopsy. If CR/CRi/aplasia, hold therapy and consider reduction of venetoclax duration for cycle 2 onward. Use of G-CSF for ANC support appropriate once response. |
| LDAC+ venetoclax | LDAC 20 mg/m2 subQ daily; days 1-10 Venetoclax 600 mg daily; days 1-28 | Same as C1 | Obtain day 21-28 bone marrow biopsy. If CR/CRi/aplasia, hold therapy and consider reduction of venetoclax duration for cycle 2 onward. Use of G-CSF for ANC support appropriate once response |
| Cladribine+ LDAC+ venetoclax (NCT 03586609) | Cladribine 5 mg/m2 daily; days 1-5 LDAC 20 mg subQ twice daily; days 1-10 Venetoclax 400 mg daily; days 1-21 | Alternating cycles of cladribine+LDAC+venetoclax and HMA+venetoclax every 2 cyclesa | Obtain day 21-28 bone marrow biopsy. If CR/CRi/aplasia, hold therapy and consider reduction of venetoclax duration for cycle 2 onward. Use of G-CSF for ANC support once response. |
| All molecular subgroups . | Cycle 1 . | Cycle 2+ . | Comments . |
|---|---|---|---|
| Azacitidine+ venetoclax | Azacitidine 75 mg/m2 daily; days 1-7 Venetoclax 400 mg daily; days 1-28 | Same as C1 | Obtain day 21-28 bone marrow biopsy. If CR/CRi/aplasia, hold therapy and consider reduction of venetoclax duration for cycle 2 onward. Use of G-CSF for ANC support appropriate once response. |
| LDAC+ venetoclax | LDAC 20 mg/m2 subQ daily; days 1-10 Venetoclax 600 mg daily; days 1-28 | Same as C1 | Obtain day 21-28 bone marrow biopsy. If CR/CRi/aplasia, hold therapy and consider reduction of venetoclax duration for cycle 2 onward. Use of G-CSF for ANC support appropriate once response |
| Cladribine+ LDAC+ venetoclax (NCT 03586609) | Cladribine 5 mg/m2 daily; days 1-5 LDAC 20 mg subQ twice daily; days 1-10 Venetoclax 400 mg daily; days 1-21 | Alternating cycles of cladribine+LDAC+venetoclax and HMA+venetoclax every 2 cyclesa | Obtain day 21-28 bone marrow biopsy. If CR/CRi/aplasia, hold therapy and consider reduction of venetoclax duration for cycle 2 onward. Use of G-CSF for ANC support once response. |
| IDH1-mutated AML . | Cycle 1 . | Cycle 2+ . | Comments . |
|---|---|---|---|
| Azacitidine+ ivosidenib | Azacitidine 75 mg/m2 daily; days 1-7 Ivosidenib 500 mg daily; days 1-14 | Same as C1 | Monitor for QT prolongation, IDH-DS. |
| Azacitidine+ venetoclax+ ivosidenib (NCT03471260) | Azacitidine 75 mg/m2 daily; days 1-7 Venetoclax 400 mg daily; days 1-14 Ivosidenib 500 mg daily; days 15-28 | Azacitidine 75 mg/m2 daily; days 1-7 Venetoclax 400 mg daily; days 1-14 Ivosidenib 500 mg daily; days 1-28 | Currently in phase 2 expansion studies. |
| Decitabine/cedazuridine (DEC-C)+ venetoclax+ ivosidenib (NCT04774393) | DEC-C 35 mg/100 mg daily; days 1-5 Venetoclax 600 mg daily; days 1-14 Ivosidenib 500 mg daily; days 8-28 | DEC-C 35 mg/100 mg daily; days 1-7 Venetoclax 600 mg daily; days 1-14 Ivosidenib 500 mg daily; days 1-28 | Currently in phase 2 expansion studies. Venetoclax 600 mg selected for phase 2 due to Cyp inducing properties of IVO. Monitor for IDH-DS, QT prolongation with ivosidenib. |
| IDH1-mutated AML . | Cycle 1 . | Cycle 2+ . | Comments . |
|---|---|---|---|
| Azacitidine+ ivosidenib | Azacitidine 75 mg/m2 daily; days 1-7 Ivosidenib 500 mg daily; days 1-14 | Same as C1 | Monitor for QT prolongation, IDH-DS. |
| Azacitidine+ venetoclax+ ivosidenib (NCT03471260) | Azacitidine 75 mg/m2 daily; days 1-7 Venetoclax 400 mg daily; days 1-14 Ivosidenib 500 mg daily; days 15-28 | Azacitidine 75 mg/m2 daily; days 1-7 Venetoclax 400 mg daily; days 1-14 Ivosidenib 500 mg daily; days 1-28 | Currently in phase 2 expansion studies. |
| Decitabine/cedazuridine (DEC-C)+ venetoclax+ ivosidenib (NCT04774393) | DEC-C 35 mg/100 mg daily; days 1-5 Venetoclax 600 mg daily; days 1-14 Ivosidenib 500 mg daily; days 8-28 | DEC-C 35 mg/100 mg daily; days 1-7 Venetoclax 600 mg daily; days 1-14 Ivosidenib 500 mg daily; days 1-28 | Currently in phase 2 expansion studies. Venetoclax 600 mg selected for phase 2 due to Cyp inducing properties of IVO. Monitor for IDH-DS, QT prolongation with ivosidenib. |
| IDH2-mutated AML . | Cycle 1 . | Cycle 2+ . | Comments . |
|---|---|---|---|
| Decitabine/cedazuridine (DEC-C)+ venetoclax+ enasidenib (NCT04774393) | DEC-C 35 mg/100 mg daily; days 1-5 Venetoclax 400 mg daily; days 1-14 Enasidenib 100 mg daily; days 8-28 | DEC-C 35 mg/100 mg daily; days 1-5 Venetoclax 400 mg daily; days 1-14 Enasidenib 100 mg daily; days 1-28 | Currently in phase 2 expansion studies. Monitor for IDH-DS, hyperbilirubinemia with enasidenib. |
| IDH2-mutated AML . | Cycle 1 . | Cycle 2+ . | Comments . |
|---|---|---|---|
| Decitabine/cedazuridine (DEC-C)+ venetoclax+ enasidenib (NCT04774393) | DEC-C 35 mg/100 mg daily; days 1-5 Venetoclax 400 mg daily; days 1-14 Enasidenib 100 mg daily; days 8-28 | DEC-C 35 mg/100 mg daily; days 1-5 Venetoclax 400 mg daily; days 1-14 Enasidenib 100 mg daily; days 1-28 | Currently in phase 2 expansion studies. Monitor for IDH-DS, hyperbilirubinemia with enasidenib. |
| FLT3-mutated AML . | Cycle 1 . | Cycle 2+ . | Comments . |
|---|---|---|---|
| FLT3-ITD/TKD Azacitidine+ venetoclax+ gilteritinib (NCT04140487) | Azacitidine 75 mg/m2 daily; days 1-7 Venetoclax 400 mg daily; days 1-14 Gilteritinib 80 mg daily; days 1-28 | Azacitidine 75 mg/m2 days 1-5 Venetoclax 400 mg days 1-7 Gilteritinib 80 mg days 1-28 | Currently in dose-ranging and expansion studies (NCT05520567). Perform bone marrow examination on C1D14 and interrupt therapy if CR/CRi or aplasia obtained to permit hematopoietic recovery. Monitor for QT prolongation and differentiation syndrome with gilteritinib. |
| FLT3-ITD only Decitabine+ venetoclax+ quizartinib (NCT03661307) | Decitabine 20 mg/m2 daily; days 1-10 Venetoclax 400 mg daily; days 1-21 Quizartinib 30-40 mg daily days 1-14 | Decitabine 20 mg/m2 daily; days 1-5 Venetoclax 400 mg daily; days 1-14 Quizartinib 30-40 mg daily; days 1-28 | Perform bone marrow examination on C1D14 and interrupt therapy if CR/CRi or aplasia obtained to permit hematopoietic recovery. Monitor for QT prolongation with quizartinib. |
| FLT3-mutated AML (R/R) Venetoclax+ gilteritinib (NCT03625505) | Venetoclax 400 mg daily; days 1-28 Gilteritinib 120 mg daily; days 1-28 | Venetoclax 400 mg daily; days 1-28 Gilteritinib 120 mg daily; days 1-28 | Perform bone marrow examination on C1D14 and interrupt therapy if CR/CRi or aplasia obtained to permit hematopoietic recovery. Monitor for QT prolongation and differentiation syndrome with gilteritinib. |
| FLT3-mutated AML . | Cycle 1 . | Cycle 2+ . | Comments . |
|---|---|---|---|
| FLT3-ITD/TKD Azacitidine+ venetoclax+ gilteritinib (NCT04140487) | Azacitidine 75 mg/m2 daily; days 1-7 Venetoclax 400 mg daily; days 1-14 Gilteritinib 80 mg daily; days 1-28 | Azacitidine 75 mg/m2 days 1-5 Venetoclax 400 mg days 1-7 Gilteritinib 80 mg days 1-28 | Currently in dose-ranging and expansion studies (NCT05520567). Perform bone marrow examination on C1D14 and interrupt therapy if CR/CRi or aplasia obtained to permit hematopoietic recovery. Monitor for QT prolongation and differentiation syndrome with gilteritinib. |
| FLT3-ITD only Decitabine+ venetoclax+ quizartinib (NCT03661307) | Decitabine 20 mg/m2 daily; days 1-10 Venetoclax 400 mg daily; days 1-21 Quizartinib 30-40 mg daily days 1-14 | Decitabine 20 mg/m2 daily; days 1-5 Venetoclax 400 mg daily; days 1-14 Quizartinib 30-40 mg daily; days 1-28 | Perform bone marrow examination on C1D14 and interrupt therapy if CR/CRi or aplasia obtained to permit hematopoietic recovery. Monitor for QT prolongation with quizartinib. |
| FLT3-mutated AML (R/R) Venetoclax+ gilteritinib (NCT03625505) | Venetoclax 400 mg daily; days 1-28 Gilteritinib 120 mg daily; days 1-28 | Venetoclax 400 mg daily; days 1-28 Gilteritinib 120 mg daily; days 1-28 | Perform bone marrow examination on C1D14 and interrupt therapy if CR/CRi or aplasia obtained to permit hematopoietic recovery. Monitor for QT prolongation and differentiation syndrome with gilteritinib. |
| NPM1/KMT2Ar AML . | Cycle 1 . | Cycle 2+ . | Comments . |
|---|---|---|---|
| Azacitidine+ venetoclax+ revumenib (REV) (NCT03013998) | Azacitidine 75 mg/m2 daily; days 1-7 Venetoclax 400 mg daily; days 1-28 Revumenib 113/163 mg Every 12 hours; days 1-28 | Same as C1 | Randomized expansion cohorts of dose level 1a (REV 113 mg) and dose level 2a (REV 163 mg) are ongoing to determine optimal dosing in triplet combination. |
| (R/R) Decitabine-cedazuridine (DEC-C)+ venetoclax+ revumenib (NCT05360160) | DEC-C 35 mg/100 mg daily; days 1-5 Venetoclax 400 mg daily; days 1-14 Revumenib 113 mg Q12H; days 1-28 | DEC-C 35 mg/100 mg daily; days 1-5 Venetoclax 400 mg daily; days 1-14 Revumenib Q12H; days 1-28 | Phase 1b dose-finding cohort enrollment ongoing. Monitor for differentiation syndrome associated with menin inhibitors. |
| NPM1/KMT2Ar AML . | Cycle 1 . | Cycle 2+ . | Comments . |
|---|---|---|---|
| Azacitidine+ venetoclax+ revumenib (REV) (NCT03013998) | Azacitidine 75 mg/m2 daily; days 1-7 Venetoclax 400 mg daily; days 1-28 Revumenib 113/163 mg Every 12 hours; days 1-28 | Same as C1 | Randomized expansion cohorts of dose level 1a (REV 113 mg) and dose level 2a (REV 163 mg) are ongoing to determine optimal dosing in triplet combination. |
| (R/R) Decitabine-cedazuridine (DEC-C)+ venetoclax+ revumenib (NCT05360160) | DEC-C 35 mg/100 mg daily; days 1-5 Venetoclax 400 mg daily; days 1-14 Revumenib 113 mg Q12H; days 1-28 | DEC-C 35 mg/100 mg daily; days 1-5 Venetoclax 400 mg daily; days 1-14 Revumenib Q12H; days 1-28 | Phase 1b dose-finding cohort enrollment ongoing. Monitor for differentiation syndrome associated with menin inhibitors. |
Consolidation therapy for cladribine+LDAC+venetoclax for cycle 2 onward was as follows: cycle 2 consisted of cladribine 5 mg/m2 on days 1 to 3, LDAC 20 mg subQ twice daily on days 1 to 10, and venetoclax 400 mg on days 1 to 21. Cycle 3 and 4 consisted of azacitidine 75 mg/m2 on days 1 to 7 with venetoclax 400 mg on days 1 to 21. Treatment would then alternate every 2 cycles between the triplet and doublet regimens (the duration of venetoclax was modified for patients in CR/CRi and based on MRD status).
ANC, absolute neutrophil count; G-CSF, granulocyte colony stimulating factor; R/R, relapsed/refractory AML.