Selected treatment options for patients fit for intensive chemotherapy
| Fit for intensive chemotherapy . | Induction . | Consolidation* . | Maintenance . |
|---|---|---|---|
| AML with FLT3 mutation | Daunorubicin 60 mg/m2 IV d1-3; or idarubicin 12 mg/m2 IV d1-3; and cytarabine 100-200 mg/m2/d CIV d1-7; plus midostaurin 50 mg q12h PO d8-21 Re-induction: either 2nd cycle “7 + 3” or regimen containing higher dose of cytarabine, each plus midostaurin, preferable the latter in patients with no response to 1st cycle | 3-4 cycles of IDAC 1000-1500 mg/m2 IV (500-1000 mg/m2 if ≥60 y old) over 3h q12h d1-3; plus midostaurin 50 mg q12h PO d8-21 (in all cycles)† | Midostaurin 50 mg q12h PO d1-28, q4 wk, over 12 cycles‡ |
| Non-FLT3 mutant§ | Daunorubicin 60 mg/m2 IV d1-3, idarubicin 12 mg/m2 IV d1-3, or mitoxantrone 12 mg/m2 IV d1-3; and cytarabine 100-200 mg/m2/d CIV d1-7 Re-induction: either 2nd cycle “7 + 3” or regimen containing higher dose of cytarabine, preferable the latter in patients with no response | 3-4 cycles of IDAC 1000-1500 mg/m2 IV (500-1000 mg/m2 if ≥60 y old) over 3h q12h d1-3 | Oral azacitidine 300 mg PO daily d1-14, q4 wk, until disease progression∥ |
| Other options∥ | |||
| Gemtuzumab ozogamicin (GO) for CD33-positive AML, favorable (or intermediate) cytogenetic risk | Daunorubicin 60 mg/m2 IV d1-3 and cytarabine 100-200 mg/m2/d CIV d1-7; plus GO 3 mg/m2 (maximum dose 5 mg) IV, d1, 4, 7. GO is also widely administered on day 1 of induction only. Re-induction (if not in CR/CRh/CRi) may be with daunorubicin 60 mg/m2 IV d1-2 and cytarabine 1000 mg/m2 IV (500-1000 mg/m2 if ≥60 y old) over 3h q12h d1-3 without GO | 2-4 cycles of IDAC 1000-1500 mg/m2 IV (500-1000 mg/m2 if ≥60 y old) over 3h q12h d1-3. GO 3 mg/m2 may be added on d1 (in up to 2 cycles). Consider omitting GO if allogeneic HCT is planned to reduce the risk of veno-occlusive disease. | |
| CPX-351 for AML with myelodysplasia-related changes or therapy-related AML¶ | CPX-351 100 U/m2 (daunorubicin 44 mg/cytarabine 100 mg) IV d1, 3, 5 Re-induction (if not in CR/CRh/CRi): CPX-351 100 U/m2 IV d1, 3 only | 1-2 cycles of CPX-351 65 U/m2 (daunorubicin 29 mg/cytarabine 65 mg) IV d1, 3 | |
| Common salvage regimens in patients not responding to initial induction or with relapsed disease who are candidates for intensive therapy | |||
| Gilteritinib (AML with FLT3 mutation) | Gilteritinib 120 mg PO QD d1-28, q4 wk, until disease progression | ||
| Intermediate-dose cytarabine# (with or without anthracycline) | Cytarabine 1000-1500 mg/m2 IV over 3h q12h d1-3 (500-1000 mg/m2 in patients ≥ 60y); with or without daunorubicin 60 mg/m2 IV d1-3; idarubicin 8-10 mg/m2 IV d3-5; or mitoxantrone 8-10 mg/m2 IV d1-3 | ||
| FLAG-IDA** | Fludarabine 30 mg/m2 IV d2-6; cytarabine 1500-2000 mg/m2 IV over 3h, starting 4h after fludarabine infusion, d2-6; idarubicin 10 mg/m2 IV d2-4; G-CSF 5 µg/kg SC d1-5; additional G-CSF may be administered starting 7 d after end of chemotherapy until WBC count > 0.5 × 109/L Consider dose reduction in patients ≥60 y: fludarabine 20 mg/m2; cytarabine 500-1000 mg/m2; idarubicin 8 mg/m2 | ||
| MEC | Mitoxantrone 8 mg/m2 IV d1-5; etoposide 100 mg/m2 IV d1-5; cytarabine 1000 mg/m2 IV d1-5 | ||
| CLAG-M | Cladribine 5 mg/m2 IV d1–5; cytarabine 2000 mg/m2 IV d1–5 (starting 2h after cladribine infusion); mitoxantrone 10 mg/m2 IV d1–3; G-CSF 300 μg SC d0–5 | ||
| Allogeneic HCT | Consider transplantation for patients with primary refractory disease, for patients in second CR (or CRh, CRi) or with major cytoreduction but still active disease following salvage therapy. Consider second transplantation under certain conditions. Perform early HLA typing. | ||
| Salvage options if not a candidate for intensive chemotherapy | |||
| Gilteritinib (AML with FLT3 mutation)†† | 120 mg PO QD d1-28, q4 wk, until disease progression | ||
| Ivosidenib (AML with IDH1 mutation)‡‡ | 500 mg PO QD d1-28, q4 wk, until disease progression | ||
| Enasidenib (AML with IDH2 mutation)a | 100 mg PO QD d1-28, q4 wk, until disease progression | ||
| Fit for intensive chemotherapy . | Induction . | Consolidation* . | Maintenance . |
|---|---|---|---|
| AML with FLT3 mutation | Daunorubicin 60 mg/m2 IV d1-3; or idarubicin 12 mg/m2 IV d1-3; and cytarabine 100-200 mg/m2/d CIV d1-7; plus midostaurin 50 mg q12h PO d8-21 Re-induction: either 2nd cycle “7 + 3” or regimen containing higher dose of cytarabine, each plus midostaurin, preferable the latter in patients with no response to 1st cycle | 3-4 cycles of IDAC 1000-1500 mg/m2 IV (500-1000 mg/m2 if ≥60 y old) over 3h q12h d1-3; plus midostaurin 50 mg q12h PO d8-21 (in all cycles)† | Midostaurin 50 mg q12h PO d1-28, q4 wk, over 12 cycles‡ |
| Non-FLT3 mutant§ | Daunorubicin 60 mg/m2 IV d1-3, idarubicin 12 mg/m2 IV d1-3, or mitoxantrone 12 mg/m2 IV d1-3; and cytarabine 100-200 mg/m2/d CIV d1-7 Re-induction: either 2nd cycle “7 + 3” or regimen containing higher dose of cytarabine, preferable the latter in patients with no response | 3-4 cycles of IDAC 1000-1500 mg/m2 IV (500-1000 mg/m2 if ≥60 y old) over 3h q12h d1-3 | Oral azacitidine 300 mg PO daily d1-14, q4 wk, until disease progression∥ |
| Other options∥ | |||
| Gemtuzumab ozogamicin (GO) for CD33-positive AML, favorable (or intermediate) cytogenetic risk | Daunorubicin 60 mg/m2 IV d1-3 and cytarabine 100-200 mg/m2/d CIV d1-7; plus GO 3 mg/m2 (maximum dose 5 mg) IV, d1, 4, 7. GO is also widely administered on day 1 of induction only. Re-induction (if not in CR/CRh/CRi) may be with daunorubicin 60 mg/m2 IV d1-2 and cytarabine 1000 mg/m2 IV (500-1000 mg/m2 if ≥60 y old) over 3h q12h d1-3 without GO | 2-4 cycles of IDAC 1000-1500 mg/m2 IV (500-1000 mg/m2 if ≥60 y old) over 3h q12h d1-3. GO 3 mg/m2 may be added on d1 (in up to 2 cycles). Consider omitting GO if allogeneic HCT is planned to reduce the risk of veno-occlusive disease. | |
| CPX-351 for AML with myelodysplasia-related changes or therapy-related AML¶ | CPX-351 100 U/m2 (daunorubicin 44 mg/cytarabine 100 mg) IV d1, 3, 5 Re-induction (if not in CR/CRh/CRi): CPX-351 100 U/m2 IV d1, 3 only | 1-2 cycles of CPX-351 65 U/m2 (daunorubicin 29 mg/cytarabine 65 mg) IV d1, 3 | |
| Common salvage regimens in patients not responding to initial induction or with relapsed disease who are candidates for intensive therapy | |||
| Gilteritinib (AML with FLT3 mutation) | Gilteritinib 120 mg PO QD d1-28, q4 wk, until disease progression | ||
| Intermediate-dose cytarabine# (with or without anthracycline) | Cytarabine 1000-1500 mg/m2 IV over 3h q12h d1-3 (500-1000 mg/m2 in patients ≥ 60y); with or without daunorubicin 60 mg/m2 IV d1-3; idarubicin 8-10 mg/m2 IV d3-5; or mitoxantrone 8-10 mg/m2 IV d1-3 | ||
| FLAG-IDA** | Fludarabine 30 mg/m2 IV d2-6; cytarabine 1500-2000 mg/m2 IV over 3h, starting 4h after fludarabine infusion, d2-6; idarubicin 10 mg/m2 IV d2-4; G-CSF 5 µg/kg SC d1-5; additional G-CSF may be administered starting 7 d after end of chemotherapy until WBC count > 0.5 × 109/L Consider dose reduction in patients ≥60 y: fludarabine 20 mg/m2; cytarabine 500-1000 mg/m2; idarubicin 8 mg/m2 | ||
| MEC | Mitoxantrone 8 mg/m2 IV d1-5; etoposide 100 mg/m2 IV d1-5; cytarabine 1000 mg/m2 IV d1-5 | ||
| CLAG-M | Cladribine 5 mg/m2 IV d1–5; cytarabine 2000 mg/m2 IV d1–5 (starting 2h after cladribine infusion); mitoxantrone 10 mg/m2 IV d1–3; G-CSF 300 μg SC d0–5 | ||
| Allogeneic HCT | Consider transplantation for patients with primary refractory disease, for patients in second CR (or CRh, CRi) or with major cytoreduction but still active disease following salvage therapy. Consider second transplantation under certain conditions. Perform early HLA typing. | ||
| Salvage options if not a candidate for intensive chemotherapy | |||
| Gilteritinib (AML with FLT3 mutation)†† | 120 mg PO QD d1-28, q4 wk, until disease progression | ||
| Ivosidenib (AML with IDH1 mutation)‡‡ | 500 mg PO QD d1-28, q4 wk, until disease progression | ||
| Enasidenib (AML with IDH2 mutation)a | 100 mg PO QD d1-28, q4 wk, until disease progression | ||
CIV, continuous IV; IDAC; intermediate-dose cytarabine; PO, per os; QD, once daily; SC, subcutaneously.
Results from assessment of MRD should be taken into account for selecting the appropriate consolidation therapy.
In the trial that led to the regulatory approval of midostaurin for FLT3-mutated AML, consolidation cycles included high-dose cytarabine at 3000 mg/m2, whereas intermediate dose levels of cytarabine (1000-1500 mg/m2) are nowadays more commonly applied in AML therapeutics.
The value of maintenance treatment with midostaurin remains uncertain.
Alternative active frontline induction regimens that are sometimes used include FLAG-IDA (defined below under common salvage regimens).
Data regarding the role of oral azacitidine maintenance therapy in younger patients (< 55 y) or patients with core-binding factor AML are lacking; in addition, data are lacking for oral azacitidine after GO-based or CPX-351 induction/consolidation therapy.
Data in younger adult patients (< 60 y) and for AML post myeloproliferative neoplasm are lacking. No benefit compared with “7 + 3” induction was shown in patients with antecedent MDS with prior hypomethylating agent exposure.
Regimens containing higher doses of cytarabine are generally considered as the best option for patients not responding to a first cycle of “7 + 3.” Single-agent IDAC should not be used in patients relapsing within 6 mo following consolidation with higher doses of cytarabine.
Idarubicin may be replaced by mitoxantrone 10 mg/m2 IV d2-4 (FLAG-MITO); or by amsacrine 100 mg/m2 IV d2-4 (FLAG-AMSA).
Gilteritinib as a salvage option has only been validated in a randomized trial after prior intensive chemotherapy.
Based on single-arm data.
Although enasidenib did not show improved overall survival in a randomized study in comparison with conventional therapy in late-stage IDH2-mutant AML, clinically useful single-agent anti-leukemic activity has been demonstrated.