Selection of RCTs randomly evaluating modifications in intensive chemotherapy in newly diagnosed fit patients
| Target population/AML subgroup* . | Age (years) . | Experimental agent/intervention . | Experimental arm . | Control arm . | Primary endpoint† . | Planned patient number . | PI, country (cooperative group) . | Registry number . |
|---|---|---|---|---|---|---|---|---|
| • All comers | 18-65 | Venetoclax | Venetoclax + 7 + 3 | 7 + 3 | EFS | 300 | Wang, China | NCT05356169 |
| • Intermediate or favorable cytogenetics • In CR/CRi after intensive induction | ≥60 | Venetoclax | Chemo consolidation with venetoclax + cytarabine | Chemo consolidation with idarubicin + cytarabine | RFS | 134 | Pigneux, France (FILO) | NCT04968015 |
| • AML/MDS-EB2, • No FLT3 mut | ≥18 | Venetoclax | Venetoclax + 7 + 3 | 7 + 3 | EFS | 650 | Döhner, Germany (AMLSG/HOVON) | NCT04628026 |
| • Favorable/intermediate risk • No CBF-AML | 18-60 | Venetoclax | Venetoclax + IDAC as consolidation | IDAC as consolidation | RFS | 200 | Peterlin/Gastaud, France (FILO/ALFA) | NCT02416388 |
| • All comers • No CBF-AML and FLT3 mut | 18-65 | Venetoclax | Venetoclax + DAC | Placebo + DAC | EFS | 311 | Wierzbowska, Poland, (PALG) | EudraCT 2023-503394-37-00 |
| • AML or MDS-EB2 with FLT3-ITD and/or FLT3-TKD | ≥18 | Gilteritinib | Gilteritinib + 7 + 3 | Midostaurin + 7 + 3 | EFS | 768 | Raajimakers, Netherlands (HOVON/AMLSG/SAKK, ALFA, FILO, ALLG, CETLAM) | NCT04027309 |
| • FLT3 mut • No CBF-AML | 18-70 | Gilteritinib | Gilteritinib + 7 + 3 | Midostaurin + 7 + 3 | CR/CRi FLT3 negative | 181 | Luger, USA (PrECOG) | NCT03836209 |
| • FLT3-ITD or FLT3-TKD AML | 18-60 | Crenolanib | Crenolanib + 7 + 3 | Midostaurin + 7 + 3 | EFS | 510 | AROG, USA | NCT03258931 |
| • CBF-AML | 18-65 | Sorafenib | Sorafenib + 7 + 3‡ | 7 + 3 | CRmol | 88 | Shi, China | NCT05404516 |
| • CBF-AML | 18-70 | Midostaurin | Midostaurin + GO + 7 + 3 | GO + 7 + 3 | EFS | 66 | Röllig, Germany (SAL-AMLCG) | NCT04385290 |
| • AML or MDS-EB2 with IDH1 or IDH2 mut | ≥18 | Ivosidenib, enasidenib | Ivosidenib or enasidenib + 7 + 3 | Placebo + 7 + 3 | EFS | 968 | Wouters, Netherlands (HOVON/AMLSG/SAKK, ALFA, FILO, ALLG, CETLAM) | NCT03839771 |
| • Favorable/intermediate risk (ELN2017) • No FLT3-ITD, -TKD | 18-60 | Glasdegib | 7 + 3 + GO and postremission treatment, followed by glasdegib maintenance | 7 + 3 + GO and postremission treatment | DFS | 414 | Venditti, Italy (GIMEMA) | NCT04168502 |
| • FLT3 mut AML | 18-70 | GO | GO + midostaurin +7 + 3 | Midostaurin +7 + 3 | EFS | 130 | Röllig, Germany (SAL-AMLCG) | NCT04385290 |
| • All comers • No CBF-AML • No -5 or -7 • No FLT3-ITD or –TKD | ≥18 | Selinexor | Selinexor + 7 + 3 | 7 + 3 | OS | 100 | Pardee/NCI, USA | NCT02835222 |
| • All comers • No FLT3-ITD or –TKD | 18-75 | Pembrolizumab | Pembrolizumab + 7 + 3 | 7 + 3 | MRDneg CR | 124 | Zeidan/NCI, USA | NCT04214249 |
| • AML MR (WHO 2022) or AML with MR genetic changes (ICC 2022) or AML from MDS/MPN | 18- 75 | Pomalidomide | Pomalidomide + CPX-351 | CPX-351 | CR/CRi | 78 | Zeidner/NCI, USA | NCT04802161 |
| • MDS-IB2, MDS/AML, AML • Increased TRM score (less fit) | ≥18 | CPX-351 | CPX-351 | CLAG-M | OS | 60 | Walter, USA | NCT04195945 |
| • HR-MDS, AML ≤30% blasts | 18-75 | CPX-351 | CPX-351 before alloHCT | 7 + 3 or Aza before alloHCT | EFS | 150 | Platzbecker, Germany (SAL) | NCT04061239 |
| • All comers with • No FLT3-ITD or –TKD, no NPM1 • No CBF or APL • No AML-MRC | ≥50 | CPX-351 | CPX-351 | 7 + 3 | MRDneg CR/CRi | 210 | Foussat, France (ALFA) | NCT05260528 |
| • Intermediate/adverse risk (ELN2017) including AML-MRC and tAML | ≥18 | CPX-351 | CPX-351 | 7 + 3 | OS in de novo AML | 882 | Döhner, Germany (AMLSG) | NCT03897127 |
| • All comers in CR after intensive induction | 60-75 | Idarubicin | Idarubicin + IDAC§ for consolidation | IDAC for consolidation | RFS | 320 | Hu, China | NCT04216771 |
| • FLT3-ITD AML | 18-65 | Treatment intensification based on early blast clearance during 7 + 3 + midostaurin | HIDAC-based second induction and early alloHCT | Standard second induction and postremission treatment | EFS | 172 | Vannucchi, Italy (GIMEMA) | NCT04174612 |
| • Intermediate risk in CR after induction | 14-60 | Decitabine | Decitabine + IDAC consolidation | IDAC consolidation | MRD | 100 | Jiang, China | NCT03417427 |
| • CBF-AML in CR after intensive induction | 18-60 | Fludarabine | Fludarabine + IDAC for consolidation | HDAC for consolidation | Relapse rate | 200 | Song, China | NCT02926586 |
| Target population/AML subgroup* . | Age (years) . | Experimental agent/intervention . | Experimental arm . | Control arm . | Primary endpoint† . | Planned patient number . | PI, country (cooperative group) . | Registry number . |
|---|---|---|---|---|---|---|---|---|
| • All comers | 18-65 | Venetoclax | Venetoclax + 7 + 3 | 7 + 3 | EFS | 300 | Wang, China | NCT05356169 |
| • Intermediate or favorable cytogenetics • In CR/CRi after intensive induction | ≥60 | Venetoclax | Chemo consolidation with venetoclax + cytarabine | Chemo consolidation with idarubicin + cytarabine | RFS | 134 | Pigneux, France (FILO) | NCT04968015 |
| • AML/MDS-EB2, • No FLT3 mut | ≥18 | Venetoclax | Venetoclax + 7 + 3 | 7 + 3 | EFS | 650 | Döhner, Germany (AMLSG/HOVON) | NCT04628026 |
| • Favorable/intermediate risk • No CBF-AML | 18-60 | Venetoclax | Venetoclax + IDAC as consolidation | IDAC as consolidation | RFS | 200 | Peterlin/Gastaud, France (FILO/ALFA) | NCT02416388 |
| • All comers • No CBF-AML and FLT3 mut | 18-65 | Venetoclax | Venetoclax + DAC | Placebo + DAC | EFS | 311 | Wierzbowska, Poland, (PALG) | EudraCT 2023-503394-37-00 |
| • AML or MDS-EB2 with FLT3-ITD and/or FLT3-TKD | ≥18 | Gilteritinib | Gilteritinib + 7 + 3 | Midostaurin + 7 + 3 | EFS | 768 | Raajimakers, Netherlands (HOVON/AMLSG/SAKK, ALFA, FILO, ALLG, CETLAM) | NCT04027309 |
| • FLT3 mut • No CBF-AML | 18-70 | Gilteritinib | Gilteritinib + 7 + 3 | Midostaurin + 7 + 3 | CR/CRi FLT3 negative | 181 | Luger, USA (PrECOG) | NCT03836209 |
| • FLT3-ITD or FLT3-TKD AML | 18-60 | Crenolanib | Crenolanib + 7 + 3 | Midostaurin + 7 + 3 | EFS | 510 | AROG, USA | NCT03258931 |
| • CBF-AML | 18-65 | Sorafenib | Sorafenib + 7 + 3‡ | 7 + 3 | CRmol | 88 | Shi, China | NCT05404516 |
| • CBF-AML | 18-70 | Midostaurin | Midostaurin + GO + 7 + 3 | GO + 7 + 3 | EFS | 66 | Röllig, Germany (SAL-AMLCG) | NCT04385290 |
| • AML or MDS-EB2 with IDH1 or IDH2 mut | ≥18 | Ivosidenib, enasidenib | Ivosidenib or enasidenib + 7 + 3 | Placebo + 7 + 3 | EFS | 968 | Wouters, Netherlands (HOVON/AMLSG/SAKK, ALFA, FILO, ALLG, CETLAM) | NCT03839771 |
| • Favorable/intermediate risk (ELN2017) • No FLT3-ITD, -TKD | 18-60 | Glasdegib | 7 + 3 + GO and postremission treatment, followed by glasdegib maintenance | 7 + 3 + GO and postremission treatment | DFS | 414 | Venditti, Italy (GIMEMA) | NCT04168502 |
| • FLT3 mut AML | 18-70 | GO | GO + midostaurin +7 + 3 | Midostaurin +7 + 3 | EFS | 130 | Röllig, Germany (SAL-AMLCG) | NCT04385290 |
| • All comers • No CBF-AML • No -5 or -7 • No FLT3-ITD or –TKD | ≥18 | Selinexor | Selinexor + 7 + 3 | 7 + 3 | OS | 100 | Pardee/NCI, USA | NCT02835222 |
| • All comers • No FLT3-ITD or –TKD | 18-75 | Pembrolizumab | Pembrolizumab + 7 + 3 | 7 + 3 | MRDneg CR | 124 | Zeidan/NCI, USA | NCT04214249 |
| • AML MR (WHO 2022) or AML with MR genetic changes (ICC 2022) or AML from MDS/MPN | 18- 75 | Pomalidomide | Pomalidomide + CPX-351 | CPX-351 | CR/CRi | 78 | Zeidner/NCI, USA | NCT04802161 |
| • MDS-IB2, MDS/AML, AML • Increased TRM score (less fit) | ≥18 | CPX-351 | CPX-351 | CLAG-M | OS | 60 | Walter, USA | NCT04195945 |
| • HR-MDS, AML ≤30% blasts | 18-75 | CPX-351 | CPX-351 before alloHCT | 7 + 3 or Aza before alloHCT | EFS | 150 | Platzbecker, Germany (SAL) | NCT04061239 |
| • All comers with • No FLT3-ITD or –TKD, no NPM1 • No CBF or APL • No AML-MRC | ≥50 | CPX-351 | CPX-351 | 7 + 3 | MRDneg CR/CRi | 210 | Foussat, France (ALFA) | NCT05260528 |
| • Intermediate/adverse risk (ELN2017) including AML-MRC and tAML | ≥18 | CPX-351 | CPX-351 | 7 + 3 | OS in de novo AML | 882 | Döhner, Germany (AMLSG) | NCT03897127 |
| • All comers in CR after intensive induction | 60-75 | Idarubicin | Idarubicin + IDAC§ for consolidation | IDAC for consolidation | RFS | 320 | Hu, China | NCT04216771 |
| • FLT3-ITD AML | 18-65 | Treatment intensification based on early blast clearance during 7 + 3 + midostaurin | HIDAC-based second induction and early alloHCT | Standard second induction and postremission treatment | EFS | 172 | Vannucchi, Italy (GIMEMA) | NCT04174612 |
| • Intermediate risk in CR after induction | 14-60 | Decitabine | Decitabine + IDAC consolidation | IDAC consolidation | MRD | 100 | Jiang, China | NCT03417427 |
| • CBF-AML in CR after intensive induction | 18-60 | Fludarabine | Fludarabine + IDAC for consolidation | HDAC for consolidation | Relapse rate | 200 | Song, China | NCT02926586 |
Selection of trials currently recruiting or planned at the time of writing. Trials for unfit patients, children, APL, relapsed or refractory disease and with purely maintenance or conditioning questions were excluded.
CBF, core binding factor; CRi, complete hematologic remission with incomplete hematologic recovery; CRmol, molecular CR; DA, daunorubicin plus cytarabine (ara-c); EFS, event-free survival; GO, gemtuzumab ozogamicin; HDAC, high-dose cytarabine; IDAC, intermediate-dose cytarabine; LDAC, low-dose cytarabine; MRD, measurable residual disease; MRDneg, MRD negativity; mut, mutation; OS, overall survival; PI, principal investigator; RFS, relapse-free survival; TRM, treatment-related mortality.
sAML/tAML/HMA pretreatment not accounted for/mentioned in table.
“7 + 3” stands for all variations of standard-dose cytarabine plus anthracycline/mitoxantrone and includes intensive consolidation for patients ineligible for allogeneic HCT. †Secondary end points for all trials include response rates, MRD, tolerability, rate of allogeneic HCT, patient-reported outcomes, and survival end points. §IDAC = intermediate-dose cytarabine.