Table 1.
Landmark trials of newly approved agents for management of acute myeloid leukemia
| Study drugs/arms | Study population | Phase, N | CR, CRi or CRp | OS | Comments |
|---|---|---|---|---|---|
| Intensive therapy options for upfront use | |||||
| 7+3 with vs. without gemtuzumab ozogamicin[34] | 50–70 years with de-novo AML | Phase 3, n=280 | 81% vs. 75%, p=0.2 | 53% vs. 42% at 2 years, p=0.04* | Higher EFS benefit for good-and intermediate-risk AML |
| 7+3 with vs. without midostaurin[38] | <60 years old with FLT3 ITD or TKD mutation | Phase 3, n=717 | 59% vs. 54% CR, p=0.1 | 51% vs. 44% at 4 years, p=0.009 | Similar benefit across FLT3 subtypes, data reflect outcomes in younger adults |
| CPX-351 vs. 7+3[25] | 60–75 years with secondary or therapy-related AML, or AML MRC | Phase 3, n=309 | 48% vs. 33%, p=0.02 | 31% vs. 12% at 2 years, p=0.003 | No CR/CRi or OS benefit in patients with prior HMA exposure (subset analysis)† |
| Low-intensity therapy options for upfront use | |||||
| Venetoclax and hypomethylating agent[77] | Mostly ≥75 years or comorbidities precluding intensive induction | Phase 1b, n=145 | 67% | 17 months; 46% at 2 years | 60% response rate in high- risk AML, 71% in IDH½ mutated AML |
| Venetoclax and LDAC[87, 88] | Mostly ≥75 years or comorbidities precluding intensive induction | Phase ½, n=82 | 42% (54% CR/CRi and 32% MRD response for those treated with 600 mg venetoclax) | 10 months median, 27% at 2 years | 30% response rate in TP53 mutated AML, 72% in IDH½ mutated AML, 44% in FLT3 mutated AML |
| Glasdegib and LDAC vs. LDAC[80] | ≥75 years or comorbidities precluding intensive induction | Randomized phase 2, n= 132 (16 MDS patients) | 24% vs. 5% CR/CRi | 8 vs. 5 months, p=0.002 | OS 4 vs. 2 months in poor- risk patients |
| Gemtuzumab ozogamicin vs. BSC including hydroxyurea[79] | ≥61 years and unfit for intensive induction | Phase 3, n=237 | 27% with gemtuzumab | 24% vs. 10% at 1 year, p=0.005 | 24% of patients ≥81 years‡ |
| Newly approved agents for relapsed or refractory AML | |||||
| Ivosidenib[52] | ≥18 years (median 68 years) with IDH1 mutation (39% with secondary or therapy related AML; 31% with poor-risk AML) | Phase 1, n=258 | 30% | 9 months, median OS | Lower response rate with higher co-mutational burden, with receptor tyrosine kinase pathway mutations, multiple lines of therapies¶ |
| Enasidenib[53] | ≥18 years (median 67 years) with IDH2 mutation (27% with AML MRC, 33% with poor-risk AML) | Phase ½, n=239 | 27% | 9 months, median OS | Lower response rate with higher co-mutational burden, with RAS pathway mutations¶ |
| Gilteritinib[43, 44] | ≥18 years (41% ≥65 years) with FLT3 mutation | Phase III trial, interim analysis of 138 patients | 21% | Not available | No CR/CRi in 12 FLT3 TKD mutated patients |
AML acute myeloid leukemia, BSC best supportive care, CR complete remission, CRi CR with incomplete count recovery, CRp CR with incomplete platelet recovery, EFS event-free survival, HMA hypomethylating agent, LDAC low-dose cytarabine, MRC myelodysplasia-related changes, N number of patients in the trial, OS overall survival
Addition of gemtuzumab improved event-free survival (41% vs. 17% at 2 years), primary endpoint of the study including among subgroups of patients with NPM1 mutated AML and FLT3 ITD mutated AML. OS benefit not seen in subgroup analysis except for FLT3 ITD mutated patients.
For FLT3 mutated patients, CPX-351, compared to 7+3, resulted in a higher CR/CRi rate (68% vs. 27%) without statistically significant increase in OS (median OS, 10 vs. 5 months).
The OS benefit with GO was consistent across most subgroups, and was especially apparent in patients with high CD33 expression status, in those with favorable/intermediate cytogenetic risk profile, and in women.
Variant allele frequency of IDH1 or IDH2 mutation does not affect responses. Also, single co-occurring mutation does not affect responses. Both ivosidenib and enasidenib can achieve molecular remission in a subset of patients who achieve CR.