What is the significance of persistent cytogenetic abnormalities in a patient with trilineage dysplasia in sustained clinical remission on azacitidine (Aza) + venetoclax (Ven)?

Persistent Cytogenetic Abnormalities in Sustained Clinical Remission on Aza+Ven

The presence of low-level cytogenetic abnormalities [der(13)t(1;13) in 3/20 metaphases] and minimal FISH abnormalities (32/200 cells) after 2 years of sustained clinical remission with trilineage dysplasia on azacitidine-venetoclax represents residual clonal disease that warrants immediate transplant evaluation while continuing current therapy as a bridge to allogeneic HCT. 1

Clinical Significance of Current Bone Marrow Findings

Interpretation of Cytogenetic Results:

• The mosaic karyotype showing der(13)t(1;13)(q12;11.2) in 15% of metaphases (3/20) with normal cells comprising 85% (17/20) indicates persistent low-level clonal disease despite clinical remission 1
• The FISH results showing CDKN2C and CKS1B abnormalities in 16% of nuclei (32/200) corroborate the presence of residual cytogenetic abnormalities 1
• Trilineage dysplasia persisting after 2 years of therapy, even with controlled blast counts, represents morphologic evidence of ongoing MDS/AML biology that requires definitive therapy 1

Recommended Management Strategy

Immediate Actions:

• Refer urgently for allogeneic hematopoietic cell transplantation (allo-HCT) evaluation, as this is the only potentially curative treatment for higher-risk MDS/AML with persistent dysplasia and cytogenetic abnormalities 2, 1
• Continue azacitidine-venetoclax as bridging/maintenance therapy until transplant, as the regimen has demonstrated disease control evidenced by sustained clinical remission and cytogenetic improvement from baseline 2, 1
• Most transplant centers require evidence of response to hypomethylating agents before proceeding to allo-HCT, which this patient has achieved through sustained clinical remission 1

Rationale for Transplant Priority:

• The NCCN recommends allo-HCT for patients who achieve response to HMAs with or without venetoclax, particularly when blast counts are controlled 1
• Persistent cytogenetic abnormalities and trilineage dysplasia indicate residual clonal disease that will eventually progress without definitive therapy 2, 1
• Early referral for transplant evaluation allows efficient transition to transplant while maintaining disease control 1

Monitoring During Continued Aza+Ven Therapy

Surveillance Strategy:

• Perform bone marrow re-evaluation every 3-6 months to assess blast percentage and monitor for dysplasia progression 2, 1
• Monitor for treatment failure, defined as loss of response or disease progression (rising blasts, worsening cytopenias, or increasing cytogenetic abnormalities) 2, 1
• If counts worsen over time, rule out relapsed disease with repeat bone marrow biopsy before attributing changes to treatment-related cytopenias 2

Dose Adjustments if Needed:

• If morphologic remission continues but blood counts worsen, consider decreasing the duration and/or dose of venetoclax and/or azacitidine 2
• Continue treatment with up to 14-day interruptions between cycles for count recovery and/or growth factor support if needed 2
• Growth factors should be considered for patients with neutropenia who are in morphologic remission but whose counts have not recovered 2

Alternative Considerations if Disease Progresses

If Loss of Response Occurs:

• For patients without actionable mutations who progress on azacitidine-venetoclax, enrollment in clinical trials is recommended 1
• High-intensity chemotherapy may be considered as a bridge to transplant in select cases, particularly for patients with high-risk disease features, though this carries significant toxicity risk 2, 1
• Patients who fail to respond to azacitidine or are primary refractory to HMAs have extremely poor survival (median <6 months) except for those who proceed to allo-HCT 2

Critical Pitfall to Avoid:

• Do not continue indefinite maintenance therapy with aza+ven in the presence of persistent dysplasia and cytogenetic abnormalities without pursuing transplant evaluation 2, 1
• While venetoclax-azacitidine can maintain remissions, it is not curative for MDS/AML with persistent clonal disease 2, 3
• Delaying transplant referral risks disease progression to a state where transplant is no longer feasible 2, 1

Prognostic Context

Response Quality Assessment:

• The sustained clinical remission for 2 years demonstrates treatment sensitivity and favorable disease biology 3
• However, persistent trilineage dysplasia and cytogenetic abnormalities indicate incomplete disease eradication 1
• Patients with IDH1/2 wild-type AML treated with venetoclax-azacitidine who have poor-risk cytogenetics have inferior outcomes compared to those with complete cytogenetic normalization 3

Transplant Timing:

• Pre-transplant debulking to reduce marrow blasts to <5% is recommended to reduce post-transplant relapse risk, which this patient has achieved 1
• The current state of controlled disease with low blast burden represents an optimal window for proceeding to transplant 1