Table 1.
Summary of main trials with new targets and therapies for acute myeloid leukemia.
| Autor (Reference) | Design (Phase/Patients) | Targeted-Therapy | Efficacy | ||
|---|---|---|---|---|---|
| First-line for “fit” patients | Gemtuzumab ozogamicin (GO) | Castaigne S et al., 2012 [7] | CTX + GO vs. placebo (phase III/280) | CD33+ AML | 2-year OS: 53.2% vs. 41.9% (p = 0.037) RFS: 50.3% vs. 22.7% (p = 0.0003) 2-year EFS: 40.8% vs. 17.1% (p = 0.0003) |
| Vyxeos (CPX-351) |
Lancet JE et al., 2018 [15] | Vyxeos vs. 7 + 3 induction (phase III/309) | s-AML, t-AML, AML-MRC | OS: 9.5 vs. 5.9 m (p = 0.003) ORR: 47.7% vs. 33.3% (p = 0.016) |
|
| Midostaurin | Stone RM, et al., 2017 [18] | CTX + midostaurin vs. placebo (phase III/3277) | FLT3-mut AML | 4-year OS: 51.4% vs. 44.3% (p = 0.009) EFS: HR 0.78 (p = 0.002) |
|
| Quizartinib | Erba H, et al., 2022 [22] | CTX + quizartinib vs. placebo (phase 3/3468) | FLT3-mut AML | OS: 31.9 vs. 15.1 m (HR 0.77; 95% CI 0.61–0.97) RFS: HR 0.733; 95% CI 0.55–0.97 |
|
| Venetoclax | Chua CC, et al., 2020 [23] | Venetoclax + 5 + 2 induction (phase Ib/51) | Bcl-2 inhibitor | ORR: 72% (97% de novo, 43% secondary AML) | |
| Ivosidenib/ enasidenib |
Stein EM, et al., 2021 [24] | CTX + ivo/ena (phase 1/60–91) | IDH1/IDH2-mut AML | ORR/CR: 77%/55% (ivosidenib), 63%/47% (enasidenib) | |
| First-line for “unfit” patients | Venetoclax | DiNardo CD, et al., 2020 [29] | AZA + venetoclax vs. placebo (phase III/431) | Bcl-2 inhibitor | OS: 14.7 vs. 9.6 m (p < 0.001) CR: 36.7 vs. 17.9% (p < 0.001) |
| Wei AH, et al., 2020 [32] | LDAC + venetoclax vs. placebo (phase III/211) | OS: 8.4 vs. 4.1 m (p = 0.04) CR + CRi: 48% vs. 13% |
|||
| Glasdegib | Cortes JE, et al., 2019 [35] | LDAC + glasdegib (phase II/132) |
Hedgehog inhibitor | OS: 8.8 vs. 4.9 m (p = 0.0004) CR: 17% vs. 2.3% |
|
| Ivosidenib | Montesinos P, et al., 2022 [37] | AZA+ ivosidenib vs. placebo (phase III/146) | IDH-1 mut AML | OS: 24 vs. 7.9 m (p = 0.001) 12-months EFS: 38% vs. 12% (p = 0.002) |
|
| Magrolimab | Daver NG, et al., 2022 [40] | Magrolimab + AZA (phase Ib/72) | TP53-mut AML | OS: 10.8 m; median duration of CR 7.7 m. ORR: 48.6% (CR 33.3%) |
|
| APR-246 (Eprenetapopt) | Sallman DA, et al., 2021 [43] | APR-246 + AZA (phase Ib-II/55) |
TP53-mut AML | ORR: 64% (CR 36%) OS: 10.8 m. |
|
| Quizartinib | Bergua-Burgues JM, et al., 2022 [44] | AZA/LDAC + venetoclax + quizartinib (phase 1-2/45) | TKI-inhibitor | ORR: 54% Infections (n = 35) |
|
| Satabolimab | Brunner AM, et al., 2021 [68] | Sabatolimab + HMAs (phase I/48) | Anti-TIM3 antibody | ORR: 41.2% 12 m-PFS rate: 44% |
|
| Maintenance treatment | CC-486 | Wei AH, et al., 2020 [47] | CC-486 vs. placebo (phase III/472) | Oral azacitidine | OS: 24.7 vs. 14.8 m (p < 0.001) RFS: 10.2 vs. 4.8 m (p < 0.001) |
| De Lima, et al., 2018 [49] | CC-486 as maintenance after allo-HCT (phase II/30) | Acute GHVD (10%), chronic GVHD (30%). 1-year EFS: 86% |
|||
| Sorafenib | Burchert A, et al., 2020 [51] | Sorafenib vs. placebo (phase II/83) | FLT3-mut AML | HR relapse or death 0.39 (95% CI 0.18–0.85; p = 0.013) 2-year RFS 85% vs. 53.3% (p = 0.002) |
|
| Refractory and relapsed AML | Gilteritinib | Perl AE, et al., 2019 [55] | Gilteritinib vs. salvage CXT (phase III/371) | FLT3-mut AML | OS: 9.3 vs. 5.6 m (p < 0.001) EFS: 2.8 vs. 0.7 m (HR 0.79; 95% CI 0.58–1.09) CR/CRi: 34% vs. 15.4% |
| Enasidenib/ Ivosidenib |
IDHENTIFY study (NCT02577406) |
Enasidenib vs. salvage CXT (phase III) |
IDH-1 mut AML |
Failed to meet the primary endpoint (OS) | |
| Idasanutlin | Konopleva MY, et al., 2022 [61] | Cytarabine + idasanutlin (phase III/447) |
MDM2 inhibitor | Failed to meet the primary endpoint (OS) ORR (38.8% vs. 22%); OR (2.25 95% CI 1.36–3.72) |
|
| Emavusertib (CA-4948) | García-Manero G, et al., 2022 [62] | Emavusertib in monotherapy (phase Ia/49) | IRAK-4 inhibitor | 40% CR/CRi (AML with spliceosome mutations). | |
| Uproleselan | DeAngelo DJ, et al., 2022 [63] | Uproleselan + MEC (phase 1-2/47) | E-selectin antagonist | CR/CRi 41% (CR 35%) OS: 8.8 m |
|
| MENIN inhibitors | Miao H, et al., 2020 [65] |
NCT04067336 NCT04811560 |
KMT2a rearranged and NPM1-mut AML | ||
| Flotetuzumab (bispecific antibody) | Uy GL, et al., 2021 [69] | Flotetuzumab in monotherapy (phase 1-2/88) | CD123xCD3 | ORR: 30% (CR 26.7%) OS: 10.2 m. |
|
AML: acute myeloblastic leukemia; CTX: chemotherapy; m: months; OS: overall survival; RFS: relapse-free survival; EFS: event-free survival; ORR: overall response rate; CR: complete response; CRi: complete response with incomplete hematologic recovery; GO: gemtuzumab ozogamicin; AZA: azacitidine; LDAC: low-doses Ara-C; GVHD: graf-versus-host disease. s-AML: secondary AML, t-AML: therapy-related AML, AML-MRC: AML with myelodysplastia-related changes.