The latest 2024 NCCN guidelines for Acute Myeloid Leukemia (AML) have been published, presenting significant revisions compared to the 2023, Version 6 update. The new edition brings substantial updates in areas such as intensive induction therapy for AML, post-induction follow-up and reinduction therapy, consolidation, and maintenance treatments.

Major Modifications in Induction Therapy: More Specific and Individualized Risk-Based Regimens

The 2024 NCCN guidelines have introduced substantial changes in AML’s intensive induction therapy, post-cytarabine-based induction follow-up and reinduction, low-intensity induction, and consolidation and maintenance treatments.

Intensive Induction Therapy

The new guidelines provide more detailed risk stratification for AML patients eligible for intensive induction therapy, which has led to updates in the induction regimens for intermediate- and low-risk AML.

• Intermediate and Low-Risk AML: Subcategories include cytogenetically low-risk AML (CBF-AML), low-risk AML with molecular mutations (NPM1-mutated/FLT3 wild-type AML, bZIP in-frame CEBPA-mutated AML), intermediate-risk AML, and FLT3-mutated AML.
• High-Risk AML: This includes therapy-related AML (excluding CBF-AML), AML from preceding MDS/chronic myelomonocytic leukemia (CMML), AML with myelodysplasia-related changes (AML-MRC), high-risk AML without TP53 mutations or del(17p) abnormalities, and high-risk AML with TP53 mutations or del(17p) abnormalities.

Updated and Revised Annotations

1. New Annotation q: Cladribine may be substituted for fludarabine when the latter is unavailable.
2. Annotation r Revised: Adjust cytarabine dosage based on age and renal function. Due to neurotoxicity, use ≥2 g/m² of cytarabine with caution in patients aged ≥60 or with renal impairment.
3. New Annotation t: Gemtuzumab ozogamicin may be beneficial for NPM1-mutated AML, though its effect in CEBPA-mutated AML remains unclear.
4. Annotation Modified: The RATIFY trial studied FLT3-ITD mutated AML in patients aged 18-60. Data extrapolation suggests that patients aged 61-70 with FLT3-ITD mutations and eligible for the 7+3 regimen should receive midostaurin due to survival benefits without increased toxicity.
5. Annotation Modified: There is limited data supporting the use of this regimen in patients under 60. For AML-MRC patients with prior exposure to hypomethylating agents (HMAs), there is no significant difference in benefit between standard induction and CPX-351/cytarabine and daunorubicin liposome treatment.
6. Annotation aa Modified: The use of ≥2 g/m² cytarabine in induction therapy remains controversial outside clinical trials. Studies indicate similar remission rates for 100-200 mg/m² and ≥2 g/m² doses, though high-dose treatment resulted in faster marrow blast clearance after one cycle.
7. Deleted Annotations: (1) Adjust cytarabine dose based on age and renal function. (2) Gemtuzumab ozogamicin-containing regimens have limited benefit in high-risk patients.

Follow-up and Reinduction Therapy Post-Cytarabine-Based Induction

Bone marrow biopsy follow-up between days 14-21 after treatment initiation is categorized as residual disease and reduced proliferation, with adjustments made accordingly. The updated guidelines suggest follow-up after 14-21 days, specifically for bone marrow aspiration and biopsy. For patients with reduced proliferation, the guidelines recommend allowing time for recovery.

Updated and Revised Annotations

1. New Annotation cc: Consider delaying bone marrow biopsy to day 21 when using cytarabine-based induction at 100-200 mg/m².
2. Annotation ff Modified: For reinduction therapy, no evidence indicates that 1-2 g/m² doses of cytarabine are superior to intermediate or high doses of ≥2 g/m².

Low-Intensity Induction Therapy

Patients unsuitable for intensive induction or with low-response potential AML include those with IDH1 mutations and those without. These patients should receive low-intensity induction therapy.

Updated and Revised Annotations

1. Annotation oo Revised: The recommendation for a 10-day decitabine regimen in TP53-mutated AML patients was removed. Instead, the guidelines advise that response may not be evident in the first 3-4 cycles of HMA therapy, and treatment should continue if the patient can tolerate it until disease progression.
2. New Annotation jj: For patients who decline induction chemotherapy and/or targeted therapy, optimal supportive care may include hydroxyurea and/or transfusion support.

Consolidation Therapy

Substantial adjustments were made to consolidation therapy regimens for FLT3-mutated AML and intermediate-risk AML.

Updated and Revised Annotations

1. Annotation tt Revised: Reports are available on cytarabine alternative doses for post-remission therapy. Due to neurotoxicity risks, cytarabine doses ≥2 g/m² should be used with caution in patients aged ≥60 or with renal impairment.
2. Annotation ww Revised: Patients awaiting donor availability may need at least one cycle of cytarabine-based consolidation to maintain remission. If a donor is found, proceed to transplant once remission is achieved.
3. Annotation xx Revised: In patients with intermediate cytogenetic risk, no evidence indicates a cytarabine dose ≥2 g/m² is superior to doses of 1-2 g/m².
4. New Annotation yy: Allogeneic hematopoietic stem cell transplantation is recommended for patients with favorable prognosis who cannot complete consolidation therapy or have high-risk features such as MRD positivity or KIT mutation.
5. Deleted: Medium-dose cytarabine as an alternate dosing option.

Maintenance Therapy

In the maintenance phase, the new guidelines adjusted risk stratification and the eligible population from “patients with moderate or poor risk (excluding CBF-AML)” to “non-CBF AML-type patients.” The recommendation level for decitabine under the HMA maintenance therapy option has been upgraded from Category 2B to 2A.

Updated and Revised Annotations

1. Annotation zz Revised: This regimen does not replace consolidation chemotherapy. AML patients may benefit from hematopoietic stem cell transplant upon achieving their first complete remission, with no data suggesting that oral azacitidine maintenance can substitute for transplant.

References: NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) Acute Myeloid Leukemia, Version 1.2024.