Newly diagnosed AML | ||||||||
Drug | Study | Mechanism of action | Indication | Dosing | Country approval | Response Rate (RR) with 95% CI | Median Overall Survival (95% confidence interval) | Duration of Response (DOR) with 95% CI |
Phase III clinical trial comparing CPX-351 (n = 153) to 7 + 3 (n = 156) | CPX-351 is a liposomal formulation of fixed 1:5 M ratio encapsulated daunorubicin and cytarabine and it delivers stable synergistic drug ratios to AML cells [73]. | t-AML or AML-MRC | Induction:a (daunorubicin 44 mg/m2 and cytarabine 100 mg/m2) IV, days 1, 3, and 5 Consolidation: (daunorubicin 29 mg/m2 and cytarabine 65 mg/m2) IV, days 1 and 3 | -FDA United States 2017 -EMA 2018 | Publication: CR + CRi: 48% vs. 33% in 7 + 3 group CR: 37% versus 26% in 7 + 3 group FDA label: CR: 38% versus 26% | Median OS 9.6 (6.6–11.9) months versus 5.9 (5.0–7.8) in 7 + 3 arm | Not reported | |
BRIGHT AML 1003 phase II randomized clinical trial comparing glasdegib+LDAC (n = 77) to LDAC alone (n = 38)c | Glasdegib is an oral inhibitor of the Hedgehog pathway. It binds to and inhibits Smoothened, a transmembrane protein involved in hedgehog signal transduction. When aberrantly activated, the Hedgehog signaling pathway leads to leukemias by promoting cancer stem cell maintenance. By inhibiting the Hedgehog signaling pathway, leukemic stem cells are reduced [76]. | Adults ≥ 75 years or comorbidities that preclude use of intensive induction chemotherapy | Glasdegib 100 mg daily continuously in combination with LDACc | -FDA United States 2018 | Publication:c CR 17% versus 2% LDAC arm CR + CRi + MLFS: 27% versus 5% LDAC arm FDA label:c CR 18% (10–29) versus 3% (0.1–14) LDAC arm | Publication:c Median OS 8.8 months versus 4.9 months LDAC arm FDA label: c Median OS 8.3 months (4.4–12.2) versus 4.3 months (1.9–5.7) LDAC arm | Publication:c CR DOR: glasdegib+LDAC 9.9 months (0.03–28.8) | |
RATIFY phase III clinical trial comparing midostaurin + chemotherapy (n = 360) to placebo + chemotherapy (n = 357) | Midostaurin is a multi-targeted tyrosine kinase inhibitor that inhibits the activity of wild type FLT3 and FLT3 mutant kinases (ITD and TKD), among others [28]. | FLT3 mutation positive as detected by FDA-approved test, in combination with standard cytarabine and daunorubicin induction and cytarabine consolidation | 50 mg oral, twice daily with food on days 8 to 21 in combination with Induction: 7 + 34 for up to 2 cycles. Consolidation: HiDAC for up to 4 cycles.e Maintenance: Continuous dosing up to 12 cycles. | -FDA United States 2017 -EMA 2017 | Publication: CR 59% (54–64) vs 54% (48–59) in the placebo group | Publication: 74.7 months (31.5-not reached) vs 25.6 months (18.6–42.9) in the placebo arm FDA label: Median survival could not be reliably estimated as survival curves plateaued before reaching the median. HR for OS 0.77 (95% CI 0.63–0.95; p = 0.016) | Not reported | |
Venetoclax + hypomethylating agentf | Study M14–358, non-randomized, phase Ib open-label clinical trial studying venetoclax in combination with azacitidine (n = 67) or decitabine (n = 13)g | Venetoclax is a selective, oral inhibitor of BCL-2 [44] B cell lymphoma 2 (BCL-2) protein plays an important role in the survival and persistence of AML blasts. BCL2 is an important regulator of the mitochondrial apoptotic pathway [66]. | Adults ≥ 75 years old or comorbidities that preclude use of intensive induction chemotherapy | Dose ramp-up: 100 mg day 1, 200 mg day 2, 400 mg day 3 and beyond, once daily continuously in combination with azacitidine or decitabinej | -FDA United States 2018 | Publication:g CR + CRi: 67% CR and CRi rates were 37% and 30% respectively FDA label:g V + aza: CR 37% (26–50), CRh 24% (14–36) V + dec: CR 54% (25–81), CRh 8% (0.2–36) | Publication:7 Median OS for all patients was 17.5 months (12.3-NR) | Publication:g CR DOR: 12.5 months (11-NR) CRi DOR: 6.8 months (4.1-NR). CR + CRi DOR: 11.3 months (8.9-NR) FDA label:g V + aza: CR DORh 5.5 months (range 0.4–30) V + dec: CR DORh 4.7 months (range 1–18) |
Study M14–387, phase Ib/II non-randomized, open-label clinical trial studying venetoclax in combination with LDAC (n = 61)j | Adults ≥ 75 years old or comorbidities that preclude use of intensive induction chemotherapy | Dose ramp-up 100 mg day 1, 200 mg day 2, 400 mg day 3, and 600 mg day 4 and beyond once daily continuously in combination with LDACi | -FDA United States 2018 | Publication:j CR and CRi: 54% (42–65) CR: 26% CRi 28% FDA label:j CR: 21% (12–34) CRh: 21% (12–34) | Publication:j Median OS was 10.1 months (5.7–14.2) | Publication:j CR DOR: 8.1 months (5.3–14.9) FDA label:j CR DOR:h 6.0 months (range 0.03–25) | ||
Relapsed/Refractory AML | ||||||||
Drug | Study | Mechanism of action | Indication | Dosing | Country approval | Response Rate (RR) with 95% CI | Median Overall Survival (95% confidence interval) | Median DOR (95% CI) |
Phase I/II clinical trial studying enasidenib monotherapy (n = 199)k | Enasidenib is an oral, selective inhibitor of mutant IDH2 enzyme variants R140Q, R172S, and R172K [36]. Mutated IDH2 leads to neomorphic proteins that synthesize 2-hydroxyglutarate, which results in DNA and histone hypermethylation. This in turn blocks cellular differentiation [54,55,56]. | IDH2 mutation as detected by an FDA-approved test | 100 mg orally once daily until disease progression or unacceptable toxicity | -FDA United States 2017 | Publication: CR: 19.6% (14.5–25.6) CRi/CRp: 9.3% FDA label: CR: 19% (13–25) CRh: 4% (2–8) CR + CRh: 23% (18–30) | Publication: 8.8 months (7.7–9.6)k | Publication: DOR: 5.6 months (3.8–7.4) FDA label: CR DOR: 8.2 months (4.7–19.4) CRh DOR: 9.6 months (0.7-NA) CR + CRh DOR: 8.2 (4.3–19.4) | |
ADMIRAL phase III clinical trial comparing gilteritinib (n = 247)l to salvage chemotherapy (n = 124) | Gilteritinib inhibits multiple receptor tyrosine kinases including FLT3 and demonstrated preclinical activity against FLT3-ITD and FLT3-D835 mutations [41]. | FLT3 mutation as detected by an FDA-approved test | 120 mg orally once daily | -FDA United States 2018 -PMDA Japan 2018 | Interim analysis:l CR or CRh: 21%, (15–29) CR: 12% (7–18) CRh: 9% (5–16) Final analysis: CR 14% (10–19) vs 11% (6–17) in the control group | 9.3 (7.7–10.7) months versus 5.6 months (4.7–7.3) for standard chemotherapy | Interim analysis:l CR + CRh DOR: 4.6 months (0.1–15.8) CR DOR: 8.6 months (1–13.8) CRh DOR: 2.9 months (0.1–15.8) Final analysis:l CR DOR: 14.8 months (0.6–23.1+) vs. 1.8 months (< 0.1+ − 1.8) in the control arm | |
Newly diagnosed and Relapsed/ Refractory (R/R) AML | ||||||||
Drug | Study | Mechanism of action | Indication | Dosing | Country approval | Response Rate (RR) with 95% CI | Median Overall Survival (95% confidence interval) | Median DOR (95% CI) |
Newly diagnosed: Phase III EORTC-GIMEMA AML-19 clinical trial comparing GO (n = 118) to best supporting care (n = 119) | GO is a CD-33 directed ADC. The drug conjugate consists of a small molecule portion, N-acetyl gamma calicheamicin, which is a cytotoxic agent covalently bound to the antibody via a linker. GO acts through binding of the ADC to CD33-expressing cancer cells [38]. | Newly diagnosed: CD33-positive AML in adults | Newly diagnosed: Induction: 6 mg/m2 IV on day 1 and 3 mg/m2 IV on day 8 Continuation: 2 mg/m2 IV day 1 every 4 weeks for up to 8 cycles | FDA United States 2017 | Newly diagnosed: CR: 15% CRi: 12% CR + CRi: 27% | Newly diagnosed: 4.9 months (4.2–6.8) versus 3.6 months (2.6 to 4.2 months) in the best supportive care group | Newly diagnosed: Median DFS CR/CRi patients 5.3 months (95% CI 3.1–8.0) | |
R/R: MyloFrance-1, phase II, single-arm, open-label clinical trial studying GO monotherapy (n = 57) | R/R: CD33 positive AML in adults and pediatric patients 2 years and older | R/R: 3 mg/m2 (up to one 4.5 mg vial) IV on days 1, 4, and 7 of a single course | R/R: CR 26% (16–40%) CR and CRp 33% | R/R: Median OS 8.4 months | R/R: Median RFS CR patients: 11.6 months | |||
Gemtuzumab ozogamicin (GO) + standard chemotherapy | Newly diagnosed: ALFA-0701: a randomized, open-label, phase III study comparing GO+  7 + 3 (n = 135) to 7 + 3 alone (n = 136)m | Newly diagnosed: CD33-positive AML in adults | Newly diagnosed: Induction: 3 mg/m2 (up to one 4.5 mg vial) IV days 1, 4, and 7 in combination with 7 + 3n Consolidation: 3 mg/m2 (up to one 4.5 mg vial) IV day 1 in combination with daunorubicin and cytarabine for up to 2 cycleso | -FDA United States 2017 -European medicines agency 2018 | Newly diagnosed: CR: 73% versus 72% in 7 + 3 group. CRp: 8% versus 3% in 7 + 3 group CR and CRp: 81% versus 75% in the 7 + 3 group | Newly diagnosed: 25.4 months versus 20.8 months in the 7 + 3 groupp | Newly diagnosed: Not reported | |
Phase I/II clinical trial studying ivosidenib monotherapy (n = 174 R/R, n = 28 newly diagnosed)q | Ivosidenib is a small molecule inhibitor that targets the mutant IDH1 enzyme. This targeted treatment is a potent inhibitor of 2-hydroxyglutarate, a neomorphic protein produced by a mutated IDH1 enzyme. 2-hydroxyglutarate competitively inhibits α-ketoglutarate–dependent enzymes and causes epigenetic alterations and impaired hematopoietic differentiation [54,55,56]. Ivosidenib leads to differentiation and maturation of malignant cells [54,55,56]. | Newly diagnosed: Adults ≥ 75 years or with comorbidities that preclude use of intensive induction chemotherapy | 500 mg orally daily until disease progression or unacceptable toxicity | Newly diagnosed: FDA United States 2019 | Newly diagnosed: Publication:q CR: 21% (9–38) CR + CRh: 35% (20–54) FDA label:q CR: 29% (13, 49) CR + CRh: 43% (25, 63). | Newly diagnosed: Not reported | Newly diagnosed: Publication:q CR DOR: NE (5.6-NE) CR + CRh DOR: NE (1.0-NE) FDA label:q CR DOR: NE (4.2-NE) CR + CRh DOR: NE (4.2-NE) | |
R/R: IDH1 mutation as detected by an FDA-approved test | R/R: FDA United States 2018 | R/R: Publication:q CR: 22% (16–29) CR or CRh: 30% (24–38) FDA label:q CR: 25% (19–32) CRh: 8% (5–13) CR + CRh: 33% (26–40) | R/R: Publication: 8.8 months (6.7 to 10.2)r | R/R: Publication:q CR DOR: 9.3 months (5.6–12.5) CR + CRh DOR: 6.5 months (5.5–11.1) FDA label:q CR DOR: 10.1 months (6.5–22.2) CRh DOR: 3.6 months (1–5.5) CR + CRh DOR: 8.2 months (5.6–12) |