What is the recommended treatment for a patient with Acute Myeloid Leukemia (AML) who has achieved morphologic remission but has a positive Minimal Residual Disease (MRD) status?

Management of AML with Positive MRD Status After Achieving Morphologic Remission

For patients with Acute Myeloid Leukemia (AML) who have achieved morphologic remission but have positive Minimal Residual Disease (MRD), allogeneic hematopoietic stem cell transplantation (allo-HSCT) with myeloablative conditioning is strongly recommended as the treatment of choice to improve survival outcomes.

Significance of MRD Positivity in AML

• MRD positivity after achieving morphologic remission is associated with significantly higher relapse rates (64.9% vs 17.6% at 2 years) and lower overall survival (30.2% vs 76.6% at 2 years) compared to MRD-negative patients 1
• Patients with MRD-positive AML in morphologic remission have outcomes similar to those with active disease, supporting the need for aggressive intervention 2
• MRD assessment should be performed using multiparametric flow cytometry or molecular methods (RT-PCR for specific mutations like NPM1, RUNX1-RUNX1T1, CBFB-MYH11, or FLT3-ITD) 3

Treatment Algorithm for MRD-Positive AML

First-Line Approach: Allogeneic HSCT

• Allogeneic HSCT should be considered for all eligible patients with MRD-positive AML in morphologic remission 3
• Myeloablative conditioning (MAC) is strongly preferred over reduced-intensity conditioning (RIC) for MRD-positive patients, as it significantly:
  • Reduces relapse risk (3-year cumulative incidence: 19% vs 67%, p<0.001) 4
  • Improves overall survival (3-year OS: 61% vs 43%, p=0.02) 4
• Donor selection should follow standard guidelines with early initiation of donor search to minimize delays 3

Conditioning Regimen Considerations

• The choice of conditioning regimen should be adapted to individual risk factors such as age, disease status, and donor type 3
• For patients with FLT3-ITD mutations, the conditioning regimen should be selected based on other risk factors rather than the FLT3 mutation status itself 3

Post-Transplant Maintenance Therapy

• For patients with FLT3-ITD AML, post-transplant maintenance with a FLT3 inhibitor is recommended 3
• Maintenance treatment should be initiated as soon as possible after disease evaluation and MRD assessment, especially in MRD-positive patients 3
• For FLT3-ITD patients, sorafenib is recommended at 400 mg/day in two divided doses, with increased dosing to 800 mg/day for MRD-positive disease 3
• Maintenance therapy should continue for a minimum of 2 years, depending on tolerance 3

Special Considerations

• For patients who cannot proceed to immediate transplant, alternative approaches include:

  • Clinical trials (preferred option) 3
  • For FLT3-mutated AML: midostaurin or sorafenib-containing regimens 3
  • For IDH1/IDH2-mutated AML: ivosidenib (IDH1) or enasidenib (IDH2) 3
  • Hypomethylating agents (azacitidine, decitabine) 3

• Monitoring recommendations post-treatment:

  • MRD assessment should be performed after 2 cycles of chemotherapy and at the end of treatment 3
  • For patients with molecular markers, MRD should be assessed every 3 months from bone marrow or every 4-6 weeks from peripheral blood for at least 24 months 3

Common Pitfalls and Caveats

• Delaying transplant consultation can reduce the chance of finding a suitable donor in time; donor search should begin early in the treatment course 3
• Underestimating the significance of MRD positivity can lead to suboptimal treatment decisions; MRD-positive patients have outcomes similar to those with active disease 2
• Using reduced-intensity conditioning in MRD-positive patients significantly increases relapse risk and reduces survival 4
• Failure to initiate post-transplant maintenance therapy promptly in FLT3-ITD patients with MRD positivity can compromise outcomes 3