Clinical outcomes, including response, survival, and notable toxicities in clinical trials of current frontline acute myeloid leukemia therapies
| Phase . | Patient population . | Therapy arms . | Sample size . | CR . | Other clinical parameters: duration of response, PFS, OS . | Notable toxicities . | Reference . | Take-Home . | |
|---|---|---|---|---|---|---|---|---|---|
| Grade ≥3 AEs . | Frequency . | ||||||||
| 3 | Age 17-60 y Treatment-naïve AML | Daunorubicin 45 mg/m2 × 3 d + cytarabine 100 mg/m2 × 7 d | 318 | 57.3%* | OS 15.7 mo* | Cardiac | 7.2% (ns) | Fernandez et al47 | Daunorubicin 90 mg/m2 improves upon 45 mg/m2 |
| F + N | 34.9% (ns) | ||||||||
| Death | 4.5% (ns) | ||||||||
| Daunorubicin 90 mg/m2 × 3 d + cytarabine 100 mg/m2 × 7 d | 315 | 70.6%* | OS 23.7 mo* | Cardiac | 7.9% (ns) | ||||
| F + N | 35.9% (ns) | ||||||||
| Death | 5.5% (ns) | ||||||||
| 3 | Age ≥60 y Treatment-naïve AML | Daunorubicin 45 mg/m2 × 3 d + Cytarabine 200 mg/m2 × 7 d | 411 | 54%* | 2-y EFS (age 60-65 y) 14%* | Infection | 79%* | Löwenberg et al48 | Daunorubicin 90 mg/m2 improves upon 45 mg/m2 but up to age 65 y |
| 2-y OS (age 60-65 y) 23%* | 30-d mortality | 12% (ns) | |||||||
| Daunorubicin 90 mg/m2 × 3 d + cytarabine 200 mg/m2 × 7 d | 402 | 64%* | 2-y EFS (age 60-65 y) 29%* | Infection | 87%* | ||||
| 2-y OS (age 60-65 y) 38%* | 30-d mortality | 11% (ns) | |||||||
| 3 | Age 16-72 y Treatment-naïve AML | Daunorubicin 60 mg/m2 × 3 d + cytarabine 100 mg/m2 × 7 d | 602 | 75% (ns) | 2-y OS 60% (ns) | 60-d mortality | 5%* | Burnett et al49 | Daunorubicin 90 mg/m2 is not superior to 60 mg/m2 |
| 2-y RFS 48% (ns) | |||||||||
| Daunorubicin 90 mg/m2 × 3 d + cytarabine 100 mg/m2 × 7 d | 604 | 73% (ns) | 2-y OS 59% (ns) | 60-d mortality | 10%* | ||||
| 2-y RFS 51% (ns) | |||||||||
| 3 | Age 18-59 y Treatment-naïve AML | Placebo + daunorubicin 60 mg/m2 × 3 d + cytarabine 200 mg/m2 × 7 d | 354 | 53.5% (ns) | mOS 25.6 mo* | F + N | 82% (ns) | Stone et al50 | Midostaurin with induction chemotherapy is approved for newly diagnosed FLT3-mutant AML |
| 4-y OS 44.3% (ns) | |||||||||
| Midostaurin + daunorubicin 60 mg/m2 × 3 d + cytarabine 200 mg/m2 × 7 d | 335 | 58.8% (ns) | mOS 74.7 mo* | F + N | 82% (ns) | ||||
| 4-y OS 51.4% (ns) | |||||||||
| 3 | Age 50-70 y Treatment-naïve AML, CD33 expression not required | Daunorubicin 60 mg/m2 × 3 d + cytarabine 200 mg/m2 × 7 d | 139 | 72% (ns) | 2-y EFS 17.1%* | TRM | 8% (P = .051) | Castaigne et al51 | GO + induction chemotherapy is approved for newly diagnosed CD33+ AML |
| 2-y OS 41.9% | |||||||||
| 2-y RFS 22.7%* | |||||||||
| Daunorubicin 60 mg/m2 × 3 d + cytarabine 200 mg/m2 × 7 d + gemtuzumab ozogamicin (3 mg/m2) | 139 | 73% (ns) | 2-y EFS 40.8%* | TRM | 2% (P = .051) | ||||
| 2-y OS 53.2%* | |||||||||
| 2-y RFS 50.3%* | |||||||||
| 3 | Age 60-75 y t-AML, s-AML, or de novo AML with MDS-related cytogenetic abnormalities | Daunorubicin 60 mg/m2 × 3 d + cytarabine 100 mg/m2 × 7 d | 156 | 25.6%* | mOS 5.95* | F + N | 70.9% (ns) | Lancet et al7 | CPX-351 is approved for t-AML, s-AML, or de novo AML with MDS-related changes |
| mEFS 1.31mo* | |||||||||
| CPX-351 100 U/m2 (44mg/m2 daunorubicin and 100mg/m2 cytarabine) | 153 | 37.3%* | mOS 9.56mo* | F + N | 68% (ns) | ||||
| mEFS 2.53mo* | |||||||||
| 3 | Primarily age >60 y | Hydroxyurea | 99 | 1%* | OS odds ratio 0.61* | Cardiac | 11% (ns) | Burnett et al52 | Single-agent LDAC is a low-intensity option |
| LDAC 20 mg bid | 103 | 18%* | Cardiac | 10% (ns) | |||||
| 3 | Age ≥65 y Treatment-naïve AML, >30% bone marrow blasts | Conventional care regimens (induction, LDAC, BSC only) | 247 | 21.9% (ns) | mOS 6.5 mo* | F + N | 30% (ns) | Dombret et al53 | Single-agent azacitidine is a low-intensity option |
| 1-y OS 34.2%* | |||||||||
| mEFS 4.8 mo (ns) | |||||||||
| mRFS 10.5 mo (ns) | |||||||||
| Azacitidine 75 mg/m2 | 241 | 19.5% (ns) | mOS 10.4 mo* (benefit driven by comparison of azacitidine with BSC) | F + N | 28% (ns) | ||||
| 1-y OS 46.5%* | |||||||||
| mEFS 6.7 mo (ns) | |||||||||
| mRFS 9.3 mo (ns) | |||||||||
| 3 | Age ≥65 y Treatment-naïve AML with poor- or intermediate-risk cytogenetics | Treatment choice (supportive care, LDAC 20 mg/m2) | 243 | CR + CRp: 7.8%* | mOS (ITT) 5.0 mo* | F + N | 22% | Kantarjian et al54 | Single-agent decitabine is a low-intensity option |
| Decitabine 20 mg/m2 | 242 | CR + CRp: 17.8%* | mOS (ITT) 7.7 mo* | F + N | 32% | ||||
| 3 | Age ≥75 y Treatment-naïve AML, ineligible for standard therapy | Placebo + azacitidine 75/mg/m2 | 145 | 17.9%* | 9.6 mo* | F + N | 19% | DiNardo et al5 | Led to accelerated approval for venetoclax + HMA for patients ineligible for intensive therapy |
| Venetoclax 400mg + azacitidine 75 mg/m2 | 286 | 36.7%* | 14.7 mo* | F + N | 42% | ||||
| 3 | Age ≥ 18 y Treatment-naïve AML, ineligible for intensive chemotherapy | Placebo + LDAC 20 mg bid | 68 | 7%* | mOS 4.1 mo* | F + N | 29% | Wei et al 10 | Led to accelerated approval for venetoclax + LDAC for patients ineligible for intensive therapy |
| Venetoclax 600 mg + LDAC 20 mg bid | 143 | 27%* | mOS 8.4 mo* | F + N | 32% | ||||
| 2 | Age ≥55 y Treatment-naïve AML, ineligible for standard therapy; high-risk MDS included | LDAC 20mg bid | 44 | 2.3%* | mOS 4.9mo* | F + N | 24.4% | Cortes et al11 | Glasdegib + LDAC approved for patients ineligible for intensive therapy |
| Glasdegib + LDAC 20mg bid | 88 | 17.0%* | mOS 8.8mo* | F + N | 35.7% | ||||
| 1 | Age 64-87 y IDH1-mutated, treatment-naïve AML, ineligible for standard therapy | Single-agent ivosidenib 500 mg | 34 | 30.3% | mOS 12.6 mo | F + N | 6% | Roboz et al33 | Led to approval of ivosidenib for adults age ≥75 y with IDH1-mutant AML |
| 12-mo OS 51.1% | Differentiation syndrome | 9% | |||||||
| 1/2 | Age 58-87 y IDH2-mutant, treatment-naïve AML, ineligible for standard therapy | Single-agent enasidenib | 39 | 18% | ORR 30.8% | TLS | 8% | Pollyea et al55 | Enasidenib as frontline therapy for IDH2-mutant AML has some benefit but is not yet approved |
| mOS 11.3 mo | Differentiation syndrome | 10% | |||||||
| mEFS 5.7 mo | |||||||||
| 2 | Age >60 y Newly diagnosed AML, newly diagnosed sAML, treated sAML, relapsed/refractory AML, high-risk MDS | Venetoclax 400 mg + 10 d of decitabine 20 mg/m2 | 184 | CR + CRi or marrow CR: 86% (newly-diagnosed AML) | mOS 18.1 mo (newly diagnosed AML) | F + N with infection | 46% | Maiti et al44 | Venetoclax with 10-d decitabine is an emerging treatment option |
| 67% (untreated sAML) | mOS 7.8 mo (untreated sAML) | F + N | 28% | ||||||
| 39% (treated sAML) | mOS 6.0 mo (treated sAML) | ||||||||
| 42% (R/R AML) | mOS 7.8 mo (R/R AML) | ||||||||
| Phase . | Patient population . | Therapy arms . | Sample size . | CR . | Other clinical parameters: duration of response, PFS, OS . | Notable toxicities . | Reference . | Take-Home . | |
|---|---|---|---|---|---|---|---|---|---|
| Grade ≥3 AEs . | Frequency . | ||||||||
| 3 | Age 17-60 y Treatment-naïve AML | Daunorubicin 45 mg/m2 × 3 d + cytarabine 100 mg/m2 × 7 d | 318 | 57.3%* | OS 15.7 mo* | Cardiac | 7.2% (ns) | Fernandez et al47 | Daunorubicin 90 mg/m2 improves upon 45 mg/m2 |
| F + N | 34.9% (ns) | ||||||||
| Death | 4.5% (ns) | ||||||||
| Daunorubicin 90 mg/m2 × 3 d + cytarabine 100 mg/m2 × 7 d | 315 | 70.6%* | OS 23.7 mo* | Cardiac | 7.9% (ns) | ||||
| F + N | 35.9% (ns) | ||||||||
| Death | 5.5% (ns) | ||||||||
| 3 | Age ≥60 y Treatment-naïve AML | Daunorubicin 45 mg/m2 × 3 d + Cytarabine 200 mg/m2 × 7 d | 411 | 54%* | 2-y EFS (age 60-65 y) 14%* | Infection | 79%* | Löwenberg et al48 | Daunorubicin 90 mg/m2 improves upon 45 mg/m2 but up to age 65 y |
| 2-y OS (age 60-65 y) 23%* | 30-d mortality | 12% (ns) | |||||||
| Daunorubicin 90 mg/m2 × 3 d + cytarabine 200 mg/m2 × 7 d | 402 | 64%* | 2-y EFS (age 60-65 y) 29%* | Infection | 87%* | ||||
| 2-y OS (age 60-65 y) 38%* | 30-d mortality | 11% (ns) | |||||||
| 3 | Age 16-72 y Treatment-naïve AML | Daunorubicin 60 mg/m2 × 3 d + cytarabine 100 mg/m2 × 7 d | 602 | 75% (ns) | 2-y OS 60% (ns) | 60-d mortality | 5%* | Burnett et al49 | Daunorubicin 90 mg/m2 is not superior to 60 mg/m2 |
| 2-y RFS 48% (ns) | |||||||||
| Daunorubicin 90 mg/m2 × 3 d + cytarabine 100 mg/m2 × 7 d | 604 | 73% (ns) | 2-y OS 59% (ns) | 60-d mortality | 10%* | ||||
| 2-y RFS 51% (ns) | |||||||||
| 3 | Age 18-59 y Treatment-naïve AML | Placebo + daunorubicin 60 mg/m2 × 3 d + cytarabine 200 mg/m2 × 7 d | 354 | 53.5% (ns) | mOS 25.6 mo* | F + N | 82% (ns) | Stone et al50 | Midostaurin with induction chemotherapy is approved for newly diagnosed FLT3-mutant AML |
| 4-y OS 44.3% (ns) | |||||||||
| Midostaurin + daunorubicin 60 mg/m2 × 3 d + cytarabine 200 mg/m2 × 7 d | 335 | 58.8% (ns) | mOS 74.7 mo* | F + N | 82% (ns) | ||||
| 4-y OS 51.4% (ns) | |||||||||
| 3 | Age 50-70 y Treatment-naïve AML, CD33 expression not required | Daunorubicin 60 mg/m2 × 3 d + cytarabine 200 mg/m2 × 7 d | 139 | 72% (ns) | 2-y EFS 17.1%* | TRM | 8% (P = .051) | Castaigne et al51 | GO + induction chemotherapy is approved for newly diagnosed CD33+ AML |
| 2-y OS 41.9% | |||||||||
| 2-y RFS 22.7%* | |||||||||
| Daunorubicin 60 mg/m2 × 3 d + cytarabine 200 mg/m2 × 7 d + gemtuzumab ozogamicin (3 mg/m2) | 139 | 73% (ns) | 2-y EFS 40.8%* | TRM | 2% (P = .051) | ||||
| 2-y OS 53.2%* | |||||||||
| 2-y RFS 50.3%* | |||||||||
| 3 | Age 60-75 y t-AML, s-AML, or de novo AML with MDS-related cytogenetic abnormalities | Daunorubicin 60 mg/m2 × 3 d + cytarabine 100 mg/m2 × 7 d | 156 | 25.6%* | mOS 5.95* | F + N | 70.9% (ns) | Lancet et al7 | CPX-351 is approved for t-AML, s-AML, or de novo AML with MDS-related changes |
| mEFS 1.31mo* | |||||||||
| CPX-351 100 U/m2 (44mg/m2 daunorubicin and 100mg/m2 cytarabine) | 153 | 37.3%* | mOS 9.56mo* | F + N | 68% (ns) | ||||
| mEFS 2.53mo* | |||||||||
| 3 | Primarily age >60 y | Hydroxyurea | 99 | 1%* | OS odds ratio 0.61* | Cardiac | 11% (ns) | Burnett et al52 | Single-agent LDAC is a low-intensity option |
| LDAC 20 mg bid | 103 | 18%* | Cardiac | 10% (ns) | |||||
| 3 | Age ≥65 y Treatment-naïve AML, >30% bone marrow blasts | Conventional care regimens (induction, LDAC, BSC only) | 247 | 21.9% (ns) | mOS 6.5 mo* | F + N | 30% (ns) | Dombret et al53 | Single-agent azacitidine is a low-intensity option |
| 1-y OS 34.2%* | |||||||||
| mEFS 4.8 mo (ns) | |||||||||
| mRFS 10.5 mo (ns) | |||||||||
| Azacitidine 75 mg/m2 | 241 | 19.5% (ns) | mOS 10.4 mo* (benefit driven by comparison of azacitidine with BSC) | F + N | 28% (ns) | ||||
| 1-y OS 46.5%* | |||||||||
| mEFS 6.7 mo (ns) | |||||||||
| mRFS 9.3 mo (ns) | |||||||||
| 3 | Age ≥65 y Treatment-naïve AML with poor- or intermediate-risk cytogenetics | Treatment choice (supportive care, LDAC 20 mg/m2) | 243 | CR + CRp: 7.8%* | mOS (ITT) 5.0 mo* | F + N | 22% | Kantarjian et al54 | Single-agent decitabine is a low-intensity option |
| Decitabine 20 mg/m2 | 242 | CR + CRp: 17.8%* | mOS (ITT) 7.7 mo* | F + N | 32% | ||||
| 3 | Age ≥75 y Treatment-naïve AML, ineligible for standard therapy | Placebo + azacitidine 75/mg/m2 | 145 | 17.9%* | 9.6 mo* | F + N | 19% | DiNardo et al5 | Led to accelerated approval for venetoclax + HMA for patients ineligible for intensive therapy |
| Venetoclax 400mg + azacitidine 75 mg/m2 | 286 | 36.7%* | 14.7 mo* | F + N | 42% | ||||
| 3 | Age ≥ 18 y Treatment-naïve AML, ineligible for intensive chemotherapy | Placebo + LDAC 20 mg bid | 68 | 7%* | mOS 4.1 mo* | F + N | 29% | Wei et al 10 | Led to accelerated approval for venetoclax + LDAC for patients ineligible for intensive therapy |
| Venetoclax 600 mg + LDAC 20 mg bid | 143 | 27%* | mOS 8.4 mo* | F + N | 32% | ||||
| 2 | Age ≥55 y Treatment-naïve AML, ineligible for standard therapy; high-risk MDS included | LDAC 20mg bid | 44 | 2.3%* | mOS 4.9mo* | F + N | 24.4% | Cortes et al11 | Glasdegib + LDAC approved for patients ineligible for intensive therapy |
| Glasdegib + LDAC 20mg bid | 88 | 17.0%* | mOS 8.8mo* | F + N | 35.7% | ||||
| 1 | Age 64-87 y IDH1-mutated, treatment-naïve AML, ineligible for standard therapy | Single-agent ivosidenib 500 mg | 34 | 30.3% | mOS 12.6 mo | F + N | 6% | Roboz et al33 | Led to approval of ivosidenib for adults age ≥75 y with IDH1-mutant AML |
| 12-mo OS 51.1% | Differentiation syndrome | 9% | |||||||
| 1/2 | Age 58-87 y IDH2-mutant, treatment-naïve AML, ineligible for standard therapy | Single-agent enasidenib | 39 | 18% | ORR 30.8% | TLS | 8% | Pollyea et al55 | Enasidenib as frontline therapy for IDH2-mutant AML has some benefit but is not yet approved |
| mOS 11.3 mo | Differentiation syndrome | 10% | |||||||
| mEFS 5.7 mo | |||||||||
| 2 | Age >60 y Newly diagnosed AML, newly diagnosed sAML, treated sAML, relapsed/refractory AML, high-risk MDS | Venetoclax 400 mg + 10 d of decitabine 20 mg/m2 | 184 | CR + CRi or marrow CR: 86% (newly-diagnosed AML) | mOS 18.1 mo (newly diagnosed AML) | F + N with infection | 46% | Maiti et al44 | Venetoclax with 10-d decitabine is an emerging treatment option |
| 67% (untreated sAML) | mOS 7.8 mo (untreated sAML) | F + N | 28% | ||||||
| 39% (treated sAML) | mOS 6.0 mo (treated sAML) | ||||||||
| 42% (R/R AML) | mOS 7.8 mo (R/R AML) | ||||||||
*Denotes statistical significance with p < 0.05. AE, adverse event; AML, acute myeloid leukemia; bid, twice daily; CR, complete remission; CRi, complete remission with incomplete count recovery; HMA, hypomethylating agent; ITT, intention to treat; LDAC, low-dose cytarabine; MDS, myelodysplastic syndrome; OS, overall survival; PFS, progression-free survival; t-AML, therapy-related acute myeloid leukemia. TLS, tumor lysis syndrome; sAML, secondary AML; R/R, relapsed/refractory; ns, not statistically significant with p > 0.05; F+N, fever and neutropenia; GO, gemtuzumab ozogamicin; mRFS, median relapse-free survival; mEFS, median event-free survival; mOS, median overall survival; EFS, event-free survival; CBF, core binding factor; BSC, best supportive care; CRp; CR without platelet recover.