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Hypomethylating agents
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Azacitidine
Dombret 2015
37
Azacitidine, n = 241 vs
CCR, n = 247 (BSC, n = 45;
LDAC, n = 158;
IC, n = 44)
|
Newly diagnosed de novo or secondary AML >30% blasts Aged ≥65 y (54% were ≥75 y) Cytogenetics: intermediate (65%) or poor risk (35%) ECOG PS ≤2 WBC ≤15 × 109/L -
Excluded: AML with inv(16)(p13.1q22),
t(16;16)(p13.1;q22), t(8;21)(q22;q22), t(9;22)(q34;q11.2)
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OS vs CCR: 10.4 vs 6.5 mo (HR = 0.85; P = .101) OS vs BSC: 5.8 vs 3.7 mo (HR = 0.60; P = .29) -
CR + CRi vs CCR: 28% vs 25%
BSC: 0% LDAC: 26% IC: 48%
RBC TI vs CCR: 44% vs 31% Platelet TI vs CCR: 59% vs 43%
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Grade 3–4 AEs: febrile neutropenia (28%), neutropenia (26%), thrombocytopenia (24%), pneumonia (19%) 30‐d and 60‐d mortality: 7% and 16% Hospital days for AEs vs CCR: 28.5 vs 38.3 d (P <0.001)
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Decitabine
Kantarjian 2012
38
Decitabine, n = 242 vs
Treatment choice (BSC, n = 28; LDAC, n = 215)
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Newly diagnosed de novo or secondary AML ≥20% blasts Aged ≥65 y (71% were ≥70 y) Cytogenetics: intermediate (63%) or poor risk (36%) ECOG PS ≤2 (24% ECOG PS = 2) WBC ≤40 × 109/L Excluded: t(8;21) or inv(16) karyotypes, comorbidities: unstable angina, NYHA class 3/4 CHF
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Grade 3–4 AEs vs LDAC: thrombocytopenia (40% vs 35%), anemia (34% vs 27%) 30‐d mortality vs LDAC: 9% vs 8% 60‐d mortality: 19.7% vs 23% for LDAC and 34.5% for BSC
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Venetoclax
|
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Venetoclax + LDAC
Wei 2019
40
n = 82
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Newly diagnosed de novo or secondary AML (49%) Aged ≥60 y unsuitable for IC due to comorbidity or other factors (not specifically defined) Cytogenetics: intermediate (60%) or poor risk (32%) ECOG PS ≤2 for patients aged ≥75 y and ≤3 for patients aged 60–74 y WBC ≤25 × 109/L Excluded: NYHA class >2 cardiovascular disability
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Venetoclax + LDAC
Wei 2020
41
Venetoclax + LDAC, n = 143 vs
LDAC, n = 68
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Newly diagnosed de novo or secondary AML (41% vs 34% LDAC) Aged ≥75 y (57% vs 59%) OR Aged 18–74 y and unsuitable for IC due to ≥1 of following criteria: ECOG PS = 2–3, CHF requiring treatment, LVEF ≤50%, chronic stable angina, DLCO ≤65%, FEV1 ≤65%, creatinine clearance ≥30 to <45 mL/min, moderate hepatic impairment (bilirubin >1.5 to ≤3.0 × ULN), or other comorbidity precluding IC
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OS vs LDAC: 7.2 vs 4.1 mo (HR = 0.75; P = .11) CR + CRi vs LDAC: 48% vs 13% (P <.001) CR vs LDAC: 27% vs 7% (P <.001) TI vs LDAC: 37% vs 16% (P <.001)
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Grade 3–4 hematologic AEs vs LDAC: thrombocytopenia (45% vs 37%), neutropenia (46% vs 16%), febrile neutropenia (32% vs 29%), anemia (25% vs 22%) Selected serious AEs vs LDAC: febrile neutropenia (16% vs 18%), pneumonia (13% vs 10%), sepsis (6% each), thrombocytopenia (5% vs 3%), anemia (3% vs 0%), and neutropenia (3% vs 0%) 30‐d mortality vs LDAC: 13% vs 16%
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Venetoclax + azacitidine or decitabine
DiNardo 2019
10
n = 145
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Newly diagnosed AML Aged ≥65 y (36% ≥75 y) Cardiac disease, prior anthracycline, secondary AML (25%), high probability of treatment‐related mortality permitted Cytogenetics: intermediate (51%) or poor risk (49%) ECOG PS ≤2 Excluded: favorable‐risk cytogenetics
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OS: 17.5 mo (95% CI: 12.3‐not reached) CR: 37%, CRi: 30% ORR (CR + CRi + PR): 68% Among CRi responders, 34/43 (79%) achieved RBC TI and 40/43 (93%) achieved platelet TI
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Grade 3–4 AEs: febrile neutropenia (43%), decreased WBC count (31%), anemia (25%), thrombocytopenia (24%) AEs were generally similar between venetoclax + azacitidine and venetoclax + decitabine No tumor lysis syndrome reported 30‐d and 60‐d mortality: 3%, 8%
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Glasdegib
|
|
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Glasdegib + LDAC
Cortes 2019
11
Glasdegib + LDAC, n = 88 vs
LDAC alone, n = 44
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Newly diagnosed untreated AML (88%) or high‐risk MDS (12%; blasts: 10%–19%) Aged ≥55 y Cytogenetics: good/intermediate (58%) or poor risk (42%) -
≥1 of following criteria:
Aged ≥75 y (58%) Serum creatinine >1.3 mg/dL Severe cardiac disease, eg, LVEF <45% ECOG PS = 2 (53%; PS = 0 or 1 eligible if they met ≥1 other inclusion criteria)
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OS vs LDAC: 8.8 vs 4.9 mo (HR = 0.51; P <.001); there was no difference in OS for 16 patients with MDS (10.9 vs 10.3 mo) CR vs LDAC: 17% vs 2% (P <.05) AML patients ORR (CR + CRi + MLFS) vs LDAC: 27% vs 5%
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Grade 3–4 AEs vs LDAC: anemia (42% vs 37%), febrile neutropenia (36% vs 24%), thrombocytopenia (31% vs 24%), pneumonia (17% vs 15%) Death due to any AE occurred in 29% vs 42% Abnormal Frederica QTc: 9 patients receiving glasdegib + LDAC and 5 patients receiving LDAC
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IDH1/2 Inhibitors
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Enasidenib (IDH2 inhibitor)
Stein 2017
46
;
Pollyea 2017
45
Relapsed/refractory AML cohort, n = 176;
Untreated AML ≥60 y cohort, n = 37
|
|
-
Relapsed/refractory AML patients
Untreated AML ≥60 y (62% ≥75 y) CR: 19% ORR: 38% OS: 10.4 mo (95% CI: 5.7–15.1)
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Among all 239 patients: grade 3/4 AEs: hyperbilirubinemia (12%), IDH‐inhibitor–associated differentiation syndrome (retinoic acid syndrome; 6%), thrombocytopenia (6%), anemia (5%) 30‐d and 60‐d mortality: 5.1% and 13.1%
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Ivosidenib (IDH1 inhibitor)
DiNardo 2018
48
Relapsed/refractory cohort, n = 179;
Newly diagnosed cohort, n = 28
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Gemtuzumab ozogamicin
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Gemtuzumab ozogamicin
Amadori 2016
52
Gemtuzumab ozogamicin, n = 118 vs
BSC, n = 119
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Newly diagnosed, untreated de novo or secondary (31%), CD33+ AML -
Ineligible/unwilling for IC for ≥1 of following criteria:
Cytogenetics: favorable/intermediate (44%) or adverse risk (27%) Serum creatinine and liver function tests ≤1.5 × ULN WBC <30 × 109/L
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Grade 3–4 AEs vs BSC: infection (35% vs 34%), febrile neutropenia (18% vs 24%), bleeding (13% vs 12%), fatigue (12% vs 21%) Death due to any AE: 17% vs 20%
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FLT3 Inhibitors
|
|
|
|
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Midostaurin + azacitidine
Gallogly 2017
56
n = 26
(ongoing phase 1/2 study)
|
Newly diagnosed de novo or secondary (27%) AML
FLT3 mutations not required (no patients had FLT3‐ITD mutations) Aged ≥70 y or ineligible for IC ECOG PS ≤2 (PS = 1 in 54%) Adequate hepatic and renal function (≤1.5 × ULN) Complex cytogenetics = 42%
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Gilteritinib + azacitidine
Esteve 2018
59
n = 15 (safety cohort to determine dose of gilteritinib to use in combination with azacitidine)
|
Newly diagnosed FLT3+ AML -
Ineligible for IC with ≥1 of following criteria:
Aged ≥75 y -
Comorbidities:
CHF NYHA class ≤3 or LVEF ≤50% Creatinine >2 mg/dL, dialysis, prior renal transplant Pulmonary disease (decreased DLco and/or oxygen ≤2 L/min) ECOG PS ≥2 Cumulative anthracycline dose >400 mg/m2 doxorubicin
Hepatic function (bilirubin ≤1.5 × ULN, LFTs ≤2.5 × ULN)
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CR: 27% CRi: 40% PR: 13% ORR: 80%
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Quizartinib
Cortes 2019
60
Quizartinib, n = 245 vs salvage chemotherapy, n = 122
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Relapsed/refractory FLT3‐ITD AML with (24%) or without HCT Aged ≥18 y (4% ≥75 y) Cytogenetics: favorable (5%), intermediate (74%), or unfavorable risk (10%) ECOG PS ≤2 Adequate hepatic and renal function (bilirubin and creatinine ≤1.5 × ULN, LFTs ≤2.5 × ULN)
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Grade 3–4 AEs vs salvage chemotherapy: thrombocytopenia (35% vs 34%), anemia (30% vs 29%), febrile neutropenia (31% vs 21%), neutropenia (32% vs 24%), sepsis/septic shock (19% for both treatment groups), hypokalemia (12% vs 9%)
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CPX‐351
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CPX‐351
Lancet 2018
33
CPX‐351, n = 153 vs conventional 7 + 3 IC, n = 156
|
-
One of the following AML types:
ECOG PS ≤2 Serum creatinine <2.0 mg/dL Serum total bilirubin <2 mg/dL LFTs <3 × ULN LVEF ≥50%
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OS vs 7 + 3: 9.56 vs 5.95 mo (HR = 0.69; P = .003) CR + CRi vs 7 + 3: 48% vs 33% (OR = 1.77; P = .016) Patients proceeding to HCT vs 7 + 3: 34% vs 25% (P = .098)
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Grade 3–4 AEs were similar between treatment groups: febrile neutropenia (68%, 71%), pneumonia (20%, 15%), hypoxia (13%, 15%) Median time to neutrophil and platelet recovery in patients who achieved CR + CRi: 35.0 and 36.5 d for CPX‐351 and 29 d for both counts for 7 + 3 30‐d and 60‐d mortality: 6%, 14% for CPX‐351 vs 11% and 21% for 7 + 3
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