Acute Myeloid Leukemia (AML) Treatment Protocols

Treatment protocols for acute myeloid leukemia (AML) are provided below, including a general treatment approach and treatment recommendations for relapsed or refractory disease.[1]

General treatment approach for acute myeloid leukemia

Fit patients (< 60-65 years, select patients up to age 75 y) receive intensive therapy. Treatment includes induction therapy and postremission therapy (consolidation). Non–low-risk patients are evaluated for stem cell transplantation in first remission.

Less-fit patients (70-75 years and older, or younger patients with significant comorbidities) receive low-intensity therapy. Select less-fit patients with highly proliferative disease may be considered for intensive therapy

Treatment recommendations for patients < 60y or for select patients ≤ 75y (good performance status, minimal or no comorbidities)

Induction therapy

The combination of cytarabine for 7 days with an anthracycline or anthracenedione for 3 days (the 7+3 regimen) is recommended.[2, 3, 4, 5] Note the following:

• Cytarabine 100-200 mg/m ² continuous IV infusion for 7d plus
• Idarubicin 12 mg/m ²/day for 3d or  daunorubicin 60-90 mg/m ²/day for 3d
• Follow-up bone marrow to assess remission is typically done 7-14d after completion of induction chemotherapy, except in patients with acute promyelocytic leukemia (APL) (see APL guidelines) ^[6]

Regimens combining high-dose cytarabine with anthracycline/anthracenedione are as follows[7, 8] :

• Cytarabine 2-3 g/m ² q12h for 3d plus  idarubicin 12 mg/m ²/day for 3d for one cycle or
• Cytarabine 2-3 g/m ² q12h for 3d plus  daunorubicin 45-60 mg/m ² day for 3d for one cycle ^[6]

Cladribine-based therapy is as follows:

• Cytarabine 200 mg/m2 continuous infusion for 7d plus daunorubicin 60 mg/m2 for 3d plus cladribine 5 mg/m2 for 5d[9]

For newly diagnosed therapy-related (t-AML) or AML with myelodysplasia-related changes (AML-MRC), fixed-dose combination cytarabine/daunorubicin liposomal is as follows[10] :

• Daunorubicin 29 mg/m² plus cytarabine 65 mg/m² liposome IV on Days 1 and 3
• Initiate the first consolidation cycle 5-8 weeks after the start of the last induction cycle

Postremission therapy (consolidation)

All patients should be assessed for risk of relapse. Specific drug regimens are recommended based on a patient’s risk of relapse.[2, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20]

Better-risk patients

Cytogenetics [inv(16) or t(16;16), t(8;21)] and molecular abnormalities (normal cytogenetics: with NPM1 mutation or isolated CEBPA mutation in the absence of FLT3 internal tandem duplication [FLT3-ITD]):

• High-dose cytarabine 3 g/m ² IV over 3h every 12h on days 1, 3, and 5 for four cycles ^[6] or
• High-dose cytarabine 3 g/m ² IV over 3h every 12h on days 1, 3, and 5 for two cycles plus  autologous stem cell transplantation ^[6]

Intermediate-risk patients:

Cytogenetics [normal cytogenetics, +8, t(9;11), other nondefined] and molecular abnormalities [normal cytogenetics: t(8;21), inv(16), t(16;16): with c-KIT mutation]:

• High-dose cytarabine 3 g/m2 IV over 3h every 12h on days 1, 3, and 5 for four cycles, or allogeneic stem cell transplantation

High-risk patients:

Cytogenetics [complex (≥3 clonal chromosomal abnormalities), -5, 5q-, -7, 7q-, 11q23 - non t(9;11), inv(3), t(3;3), t(6;9), t(9;22)] and molecular abnormalities (normal cytogenetics: FLT3-ITD mutation), prior antecedent hematologic disorder (AHD):

• Allogeneic stem cell transplantation or
• Clinical trial or
• High-dose cytarabine 3 g/m ² IV over 3h every 12h on days 1, 3, and 5; if clinical trial not available or
• High-dose cytarabine plus  midostaurin 50 mg PO BID on days 8-21 of each 28-day cycle for up to four consolidation cycles, followed by  continuous midostaurin ^[21]

CD33-positive AML

In adults with newly diagnosed de novo CD33-positive AML, combination therapy that includes gemtuzumab consists of one induction and two consolidation cycles, as follows:

• Gemtuzumab 3 mg/m ² (up to one 4.5 mg vial) on days 1, 4, and 7 in combination with daunorubicin and cytarabine
• For patients requiring a second induction cycle, do not administer gemtuzumab in the second induction cycle.

A treatment course of gemtuzumab as a single agent for adults with newly-diagnosed CD33-positive AML consists of the following:

• Induction – Gemtuzumab 6 mg/m ² on Day 1, then 3 mg/m ² on Day 8, for one cycle
• Continuation therapy – Gemtuzumab 2 mg/m ² on Day 1 every 4 weeks, for up to eight cycles ^[22]

FLT3-positive AML

For newly diagnosed AML that is FLT3 mutation positive, midostaurin may be included. Cycles are 28 days. Induction is as follows[21] :

• Cytarabine 200 mg/m ² IV on Days 1-7 plus
• Daunorubicin IV 60 mg/m ²/day on Days 1-3 plus
• Midostaurin 50 mg PO BID on Days 8-21
• Up to two induction cycles may be used

Consolidation therapy is as follows:

• High-dose cytarabine 3 g/m ² IV over 3h every 12h on Days 1, 3, and 5

For treatment of adult patients with newly diagnosed AML that is FLT3 ITD–positive, quizartinib is used in combination with standard cytarabine and anthracycline induction and cytarabine consolidation, and as maintenance monotherapy following consolidation chemotherapy.[23]

Induction therapy is as follows:

• Quizartinib 35.4 mg PO qDay on Days 8-21, plus
• 7 + 3 regimen (cytarabine 100 or 200 mg/m ²/day IV on Days 1-7 plus daunorubicin 60 mg/m ²/day IV or idarubicin 12 mg/m ²/day IV on Days 1-3)
• Optional second induction: Quizartinib plus 7 + 3 or 5 + 2 regimen (5 days cytarabine plus 2 days daunorubicin or idarubicin); if 5 + 2 regimen is used in second induction cycle, administer quizartinib on Days 6-19

Consolidation therapy is as follows:

• Quizartinib 35.4 mg PO qDay on Days 6-19, plus
• Cytarabine 1.5-3 g/m ² q12hr on Days 1, 3, and 5 for up to 4 cycles

Maintenance therapy is as follows:

• Quizartinib 26.5 mg PO qDay on Days 1-14 of the first cycle if absolute QT interval corrected for heart rate by Fridericia's formula (QTcF) ≤450 ms
• Increase dose to 53 mg once daily on Day 15 of first cycle if QTcF ≤450 ms
• Maintain 26.5 mg PO qDay if QTcF >500 ms was observed during induction or consolidation
• Duration is once daily with no break between cycles for up to 36 cycles

Treatment in older patients

There is no standard therapy for patients age 60 years and older; clinical trial participation is preferred. The following low-intensity therapies are recommended for these patients[24, 25, 26, 27] :

• Azacitidine 75 mg/m ² IV or SC for 7d every 4-5wk or
• Azacitidine (Onureg) 300 mg PO qDay on Days 1-14 every 28 days; continue until disease progression or unacceptable toxicity ^[28]   or
• D ecitabine 20 mg/m ² IV daily for 5d every 4-5wk or
• Low-dose cytarabine 20 mg SC BID for 10d every 4wk
• In patients with a high WBC count (especially > 30,000/μL) who are unlikely to respond to low-intensity therapy, consider therapies as in younger patients; however, tolerance and response may be poor

Treatment recommendations for relapsed or refractory disease

See the list below:

• Response rates depend on duration of first remission ^[29]
• Patients in complete remission (CR) longer than 2y have a 60% chance of responding to front-line regimens
• Patients in CR for 1-2y have a 40% chance of responding to front-line regimens; clinical trials are preferred
• Patients in CR less than 1y are unlikely to respond to front-line regimens and should be referred for clinical trials
• The prognosis for patients beyond first salvage is very poor ^[30]

Recommended chemotherapy regimens for relapsed or refractory disease

Mitoxantrone, etoposide, and cytarabine (MEC)[31] :

• Etoposide 80 mg/m ² IV over 1h plus
• Cytarabine 1 g/m ² IV over 6h plus
• Mitoxantrone 6 mg/m ²; all three drugs should be given daily for 6d or

CLAG-M (cladribine, cytarabine, mitoxantrone, and filgrastim)[32] :

• Cladribine 5 mg/m ² IV over 2h daily for 5d plus
• Cytarabine 2 g/m ² IV over 4h daily for 5d, with each dose starting 2h after cladribine plus
• Mitoxantrone 10 mg/m ² IV for 3d plus
• Filgrastim (Neupogen) 300 µg for 6d starting 24h prior to chemotherapy or

FLAG-IDA (fludarabine, cytarabine, idarubicin, and filgrastim)[33] :

• Fludarabine 30 mg/m ²/day IV over 30min on days 1-5
• Cytarabine (Ara-C) 2 g/m ²/day IV over 4h; 4h after fludarabine on days 1-5
• Idarubicin 10 mg/m ²/day IV on days 1-3
• Filgrastim  5 µg/kg/day SC to begin on day 6 until neutrophil recovery

For relapsed or refractory CD33-positive AML (single-agent regimen)[22] :

• Gemtuzumab 3 mg/m ² (up to one 4.5-mg vial) on days 1, 4, and 7

For relapsed or refractory IDH1-positive AML:

• Ivosidenib 500 mg PO once daily with or without food, until disease progression or unacceptable toxicity ^[34]
• Olutasidenib 150 mg PO BID (on empty stomach 1 h before or 2 h after meals) until disease progression or unacceptable toxicity ^[35]   

For relapsed or refractory IDH2-positive AML:

• Enasidenib 100 mg PO once daily with or without food, until disease progression or unacceptable toxicity ^[36]

For relapsed or refractory FLT3-positive AML[37, 38] :

• Gilteritinib 120 mg PO once daily for at least 6 months for a clinical response or until disease progression or unacceptable toxicity

Adults ≥75 years, or adults with comorbidities that preclude intensive induction chemotherapy for newly diagnosed AML

Newly diagnosed IDH1-mutated AML[39]  

• Ivosidenib 500 mg PO once daily with or without food, until disease progression or unacceptable toxicity

Glasdegib plus low-dose cytarabine[40]  

• Glasdegib 100 mg PO once daily on days 1-28 plus cytarabine 20 mg SC BID on days 1-10 of each 28-day cycle for minimum of six cycles

Venetoclax plus low-dose cytarabine (28-day cycle)[41]

• Day 1: Venetoclax 100 mg PO once
• Day 2: Venetoclax 200 mg PO once
• Day 3: Venetoclax 300 mg PO once
• Day 4 and beyond: Venetoclax 600 mg PO once daily
• Days 1-10: Cytarabine 20 mg/m ² SC once daily beginning on cycle 1 day 1
• Continue until disease progression or unacceptable toxicity

Venetoclax plus azacitidine (28-day cycle)[42]

• Day 1: Venetoclax 100 mg PO once
• Day 2: Venetoclax 200 mg PO once
• Day 3: Venetoclax 300 mg PO once
• Day 4 and beyond: Venetoclax 400 mg PO once daily; continue until disease progression or unacceptable toxicity
• Days 1-7: Azacitidine 75 mg/m ² IV/SC once daily beginning on cycle 1 day 1
• Continue until disease progression or unacceptable toxicity

Venetoclax plus decitabine (28-day cycle)[42]

• Day 1: Venetoclax 100 mg PO once
• Day 2: Venetoclax 200 mg PO once
• Day 3: Venetoclax 300 mg PO once
• Day 4 and beyond: Venetoclax 400 mg PO once daily
• Days 1-5: Decitabine 20 mg/m ² IV once daily beginning on cycle 1 day 1
• Continue until disease progression or unacceptable toxicity