Table 1:
Summary of targeted therapies and clinical trials in relapsed or refractory AML.
| Inhibitor Type | Target | FDA Approval | Clinical Trials | Trial Overview | Outcome | |
|---|---|---|---|---|---|---|
| FLT3-Tyrosine Kinase Inhibitors | ||||||
| Midostaurin | Type 1 1st generation |
FLT3, PKC, SYK, FLK-1, AKT, KIT, FGR, PDGFR, VEGFR 1/212 | Yes* 2017 | 125,126 | • Phase 2: 17/20 with FLT3-ITD or FLT3-TKD RR AML125 • Phase 2: 85/89 RR AML; 35/95 FLT3-ITD or FLT3-TKD126 |
• CR 0/20, PR 1/20 (5%)125 • CR or CRi 0/92 (0%), 1/92 patients PR (1%)126 |
| Gilteritinib | Type 1 2nd generation |
FLT3, LTK, ALK, AXL12 | Yes† 2018 | 18 | Phase 3: FLT3-ITD or FLT3-TKD RR AML Control-Chemotherapy |
OS 9.3 vs 5.6 months CR/CRi: 84/247 (34%) vs 19/124 |
| Lestaurtinib | Type 1 1st generation |
FLT3, JAK, TRK12 | No | 127 | Phase 1/2: FLT-3-ITD or FLT3-TKD mutated RR AML | 1/17 blast reduction to <5% |
| Crenolanib | Type 1 2nd generation |
FLT3, PDGFRB12 |
No | 128,129 | Phase 2: FLT3-ITD or FLT3-TKD RR AML | CRi: 4/34 (12%)129 and 7/18 (39%)128 |
| Sorafenib | Type 2 1st generation | FLT3, RAF, VEGFR, PDGFRB, KIT, RET12 | No | 21,130–132 | Monotherapy: • Retrospective: FLT3-ITD RR AML130 • Phase 2: FLT3-ITD RR AML21 Combination: FLT3-ITD RR AML • Phase 2: AZA131 • Case review-Decitabine132 |
• CR or CRi in 15/65 (23%)130 • CRi 6/13 (46%)21 Combination • AZA: CR or CRi 16/37 (43.2%)131 • Decitabine: 4/5 CRi (80%)132 |
| Quizartinib | Type 2 2nd generation |
FLT3, KIT, PDGFR12 | No | 19 | Phase 3: FLT3-ITD mutated RR AML. Control-Chemotherapy | OS 6.2 vs 4.7 months |
| Isocitrate Dehydrogenase 1/2 | ||||||
| Ivosidenib | IDH 1 | IDH1 | Yes‡ 2018 | 58 | Phase 1: IDH1-mutated RR AML | CR or CRi in 54/179 (30%) |
| Enasidenib | IDH 2 | IDH2 | Yes† 2017 | 59 | Phase 1/2: IDH2-mutated RR AML | CR or CRi in 29/109 (27%) Median OS 9.3 months |
| BCL-2 | ||||||
| Venetoclax | BH-3 Mimetic | BCL-2 | Yes* 2020 | 70 | Phase 1/2: RR AML in 94% | CR or CRi 6/32 (19%) |
| 73–79 | Retrospective: LDAC/HMA in RR AML§ | CR or CRi 21–51%; OS 3–7.8 months§ | ||||
Food and Drug Administration (FDA). RR: Relapsed or Refractory. CR: Complete Remission. CRi: Complete remission with incomplete hematologic recovery, PR: partial response, OS: Overall Survival. LDAC: low dose cytarabine, HMA: hypomethylating agent, AZA: Azacitidine
*
FDA Approval is in combination therapy for newly diagnosed AML.
†
Approved as monotherapy in relapsed or refractory AML.
‡
Approved as monotherapy in relapsed or refractory disease or newly diagnosed AML >75 years old with IDH1 mutation meeting treatment criteria58,133.
§
Data combined from series of reports with dynamic range listed for response rate and survival as available.