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Table 1 Summary of new therapeutic drugs for AML

From: Recent drug approvals for acute myeloid leukemia

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
CPX-351 [34, 35, 71, 72]: 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
Glasdegib + low dose cytarabineb [42, 74, 75] 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)
Midostaurin + standard chemotherapy d,e [18, 28] 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
[44, 70]
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)
Venetoclax + low dose cytarabinei [44, 78, 79] 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)
Enasidenib [36, 37, 57] 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)
Gilteritinib [41, 80, 81] 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)
Gemtuzumab ozogamicin [38, 82, 83] 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
[12, 38, 77, 84]
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
Ivosidenib [61, 63] 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)
  1. 7 + 3 7 days continuous infusion cytarabine in combination with 3 days intravenous daunorubicin, ADC antibody-drug conjugate, AML acute myeloid leukemia, AML-MRC AML with myelodysplasia-related changes, aza azacitidine, CI confidence interval, CR complete remission, CRh complete remission with partial hematologic recovery, CRi complete remission with incomplete count recovery, dec decitabine, EMA European Medicines Agency, FLT3 Fms-like tyrosine kinase 3, FDA Food and Drug Administration, HiDAC high dose cytarabine, ITD, internal tandem duplication IV intravenous; LDAC low-dose cytarabine, MLFS morphologic leukemia free state, NA not available, NE not estimable, NR not reached, OS overall survival, RFS relapse-free survival, t-AML therapy-related AML; TKD tyrosine kinase domain, V venetoclax
  2. aNote that the second induction (for patients failing for achieve a response with the first induction cycle) uses the same dose of (daunorubicin 44 mg/m2 and cytarabine 100 mg/m2), but on days 1 and 3 only
  3. bCytarabine 20 mg subcutaneously twice daily days 1–10 of each 28-day cycle
  4. cResults in [75] presented data on 132 total patients randomized to glasdegib + LDAC (n = 88) or LDAC (n = 44), including patients with high-risk MDS, a condition for which glasdegib is not approved. The FDA label included the N = 115 patients with confirmed AML randomized to glasdegib + LDAC (n = 77) or LDAC (n = 38) [85]
  5. dDaunorubicin dosed at 60 mg/m2 IV daily on days 1–3. Cytarabine dosed at 200 mg/m2 continuous infusion days 1–7
  6. eHiDAC dose was 3 g/m2 IV every 12 h on days 1, 3, and 5
  7. fAzacitidine 75 mg/m2 IV or subcutaneous days 1–7 of each 28-day cycle. Decitabine 20 mg/m2 IV days 1–5 of each 28-day cycle
  8. gResults in [70] included 145 total patients treated with azacitidine or decitabine in combination with different dose levels of venetoclax. The FDA label included N = 80 patients who were age 75 or older or who had comorbidities that precluded the use of intensive induction chemotherapy and were treated with the recommended dose of venetoclax in combination with azacitidine (n = 67) or decitabine (n = 13) [44]
  9. hDOR defined as the median observed time in remission, i.e. the time from the start of CR to the time of data cut-off date or relapse from CR. Median follow-up was 7.9 months (range 0.4–36) for azacitidine, 11 months (range 0.7–21) for decitabine, and 6.5 months (range 0.3–34) for LDAC [44]
  10. iCytarabine 20 mg/m2 subcutaneously once daily days 1–10 of each 28-day cycle
  11. jResults in included all 82 patients treated with the recommended dose of venetoclax in combination with LDAC. The FDA label included n = 61 patients who were age 75 or older or who had comorbidities that precluded the use of intensive induction chemotherapy [44]
  12. kResults in had cut-off of September 1, 2017 and presented data on all 214 patients treated with enasidenib at the recommended dose. The FDA label included N = 199 patients with IDH2 mutation per the companion diagnostic test treated with the recommended dose, with a data cut date of October 14, 2016 [58]
  13. lThe FDA label includes an interim analysis of CR + CRh in N = 138 patients randomized to the gilteritinib arm that were at least four treatment cycles past the first dose of gilteritinib at the time of the first pre-specified interim analysis [80]
  14. mResults in [77, 84] included 278 randomized patients. FDA considered n = 271 patients in a modified intent-to-treat population based on lack of documentation of informed consent in the remaining patients [12]
  15. nDaunorubicin dosed at 60 mg/m2 IV days 1–3. Cytarabine dosed at 200 mg/m2 continuous infusion days 1–7. Patients could receive a second induction with daunorubicin and cytarabine alone (i.e., no GO for second induction course)
  16. oDaunorubicin dosed at 60 mg/m2 IV day 1 of consolidation course 1 and days 1–2 of consolidation course 2. Cytarabine dosed at 1 g/m2 every 12 h on days 1–4
  17. pNote that the final analysis did not demonstrate a statistically significant benefit in median OS. FDA approval was on the basis of an EFS benefit of 13.6 months GO arm vs. 8.8 months 7 + 3 arm [12]
  18. qResults in [63] had cut-off of May 12, 2017 and presented data on 179 patients with R/R AML and 34 patients with newly diagnosed AML treated with ivosidenib at the recommended dose. The FDA label included N = 174 patients with R/R AML and N = 28 patients with newly-diagnosed AML (the latter with age ≥ 75 years or comorbidities that precluded use of intensive induction chemotherapy) with confirmed IDH1 mutation per the companion diagnostic test and used a data cut-off date of November 10, 2017 in R/R patients [86] and a later data cut-off for newly-diagnosed patients (not yet public, but FDA review will be available soon at https://www.accessdata.fda.gov/scripts/cder/daf/)
  19. rOS reported for the primary efficacy population, which included the first 125 patients with R/R AML with second or later relapse, relapse after stem-cell transplantation, disease refractory to induction or reinduction chemotherapy, or relapse < 12 months after initial therapy who received the recommended dose and whose first dose of ivosidenib was at least 6 months before the analysis cut-off date