What is the prognosis for a 64‑year‑old man with relapsed acute myeloid leukemia 20 months after allogeneic stem‑cell transplantation, now on azacitidine (Vidaza) and venetoclax, who received liposomal daunorubicin (Mylotarg), and has CBFB‑MYH11 inversion, derivative chromosome 1;18, trisomy 8, low donor chimerism in myeloid and CD34⁺ cells, and NRAS G12D and WT1 splice‑site mutations?

Prognosis for Recurrent AML Post-Transplant with High-Risk Features

This patient faces a grave prognosis with an expected median overall survival of 6-9 months, driven by multiple adverse factors: early post-transplant relapse (20 months), emergence of the derivative chromosome 1;18 abnormality (associated with poor prognosis), near-complete loss of donor chimerism in CD34+ progenitor cells (0% donor DNA), and persistent disease despite venetoclax-azacitidine therapy. 1

Critical Prognostic Factors

Timing of Post-Transplant Relapse

• Relapse at 20 months (approximately 671 days) post-transplant places this patient in the intermediate-risk category for post-transplant relapse, with 3-year survival probability of only 12-26%. 2, 3
• Patients relapsing 6-24 months after allogeneic transplant have significantly worse outcomes compared to those relapsing beyond 2 years (38% 3-year survival for >3 years vs. 12% for 6-24 months). 2

Cytogenetic Evolution and High-Risk Features

• The emergence of the derivative chromosome 1;18 represents clonal evolution with gain of 1q and loss of 18p—a new abnormality explicitly associated with poor prognosis in the cytogenetic report. 1
• While the original CBFB rearrangement (inv(16)) is typically favorable-risk, the persistence of this abnormality with additional high-risk features (der(1;18), trisomy 8) transforms the disease biology into an adverse-risk category. 2
• The presence of two distinct clones indicates genetic heterogeneity and treatment resistance. 1

Chimerism Analysis: Critical Red Flag

• Complete loss of donor chimerism in CD34+ progenitor cells (0% donor DNA) indicates that the leukemia has entirely replaced the donor graft in the stem cell compartment—this is the most ominous finding. 1
• Myeloid lineage chimerism of only 31% donor DNA demonstrates predominant recipient (leukemic) cells in the myeloid compartment. 1
• This pattern indicates graft failure at the stem cell level and loss of graft-versus-leukemia effect. 2

Molecular Mutations

• NRAS G12D mutation (34.7% allele frequency) and WT1 splice-site mutation (25.8% allele frequency) represent additional adverse molecular features associated with treatment resistance. 1
• RAS pathway mutations are associated with resistance to venetoclax-based therapy. 1

Post-Treatment Bone Marrow Findings

• Persistent cytogenetic abnormalities (extra chromosome 1 and derivative 1;18) after chemotherapy indicate chemoresistant disease. 1
• The appearance of a non-clonal deletion 13(q12q22) suggests ongoing genomic instability. 1

Treatment Response and Expected Outcomes

Current Regimen Efficacy

• Venetoclax-azacitidine in the relapsed/refractory post-transplant setting achieves overall response rates of only 21-43%, with complete remission rates of 24-31%. 2, 1
• The median overall survival for relapsed/refractory AML treated with azacitidine or decitabine is 6.7 months, with CR/CRi rates of 16.3%. 2
• Given the persistent disease after venetoclax-azacitidine therapy (as evidenced by persistent cytogenetic abnormalities), this patient appears to have primary refractory disease to this regimen. 1

Age and Performance Status Considerations

• At 64 years old, this patient falls into the higher-risk age category (>45 years at relapse), which independently predicts worse outcomes with a relative risk of 1.42 for mortality. 3
• Intensive salvage chemotherapy with high-dose cytarabine cannot be safely applied in patients aged 60 years or older due to unacceptably high toxicity risk. 2

Realistic Treatment Options and Their Limitations

Second Allogeneic Transplant

• A second allogeneic transplant represents the only realistic chance for long-term survival but carries substantial risk and requires achieving remission first. 2, 1
• Second transplant is only considered for patients relapsing >5 months after first transplant (this patient qualifies at 20 months). 2, 4
• However, the complete loss of donor chimerism in CD34+ cells (0%) and persistent disease after current therapy make achieving the remission necessary for second transplant highly unlikely. 1
• Patients with active/persistent disease who undergo second transplant have dismal outcomes and should ideally be enrolled in clinical trials. 5

Donor Lymphocyte Infusion (DLI)

• DLI combined with chemotherapy or targeted agents is rarely effective in the long term for post-transplant relapse, particularly with low disease burden and longer time since first transplant. 4, 6
• The complete loss of donor chimerism in stem cells suggests DLI alone would be ineffective, as there is no residual graft-versus-leukemia effect to augment. 1
• Venetoclax-azacitidine combined with DLI achieved 61.5% overall response rate in one study, but this patient is already on venetoclax-azacitidine with persistent disease. 6

Clinical Trial Enrollment

• Clinical trial enrollment should be the highest priority given the poor prognosis and limited standard options. 1, 4
• Novel triplet combinations (e.g., adding pevonedistat to venetoclax-azacitidine) showed 46.7% overall response rate in relapsed/refractory AML, with 71.4% CR rate in HMA-naive patients. 7
• However, this patient has already received azacitidine, which may limit efficacy of HMA-based combinations. 7

Targeted Therapy Considerations

• The patient lacks FLT3, IDH1, or IDH2 mutations that would make them eligible for targeted monotherapy with gilteritinib, ivosidenib, or enasidenib. 2, 1
• NRAS mutations do not currently have approved targeted therapies. 1

Quantitative Survival Estimates

Short-Term Survival (1 Year)

• Based on the relapse timing (6-24 months post-transplant), expected 1-year survival is approximately 12-23%. 2, 3
• The presence of persistent disease after venetoclax-azacitidine likely places survival at the lower end of this range. 1

Long-Term Survival (3-5 Years)

• 3-year survival probability is 12% for patients relapsing 6-24 months post-transplant. 2
• 5-year survival is realistically <5% without achieving complete remission and proceeding to second transplant or achieving durable response to novel therapy. 2, 1

Median Overall Survival

• Median overall survival is expected to be 6-9 months from current assessment. 1
• This estimate assumes continuation of venetoclax-azacitidine or transition to best supportive care. 1

Critical Caveats and Clinical Pitfalls

Avoid Intensive Chemotherapy

• Do not pursue intensive salvage chemotherapy (high-dose cytarabine-based regimens) in this 64-year-old patient due to prohibitive toxicity risk and low likelihood of benefit. 2
• 30-day mortality with intensive salvage chemotherapy in heavily pretreated patients can reach 14% or higher. 4

Realistic Goal-Setting

• Treatment goals must shift from cure to disease control and quality of life optimization. 1
• Long-term survival without additional transplant is unlikely, and achieving remission adequate for second transplant appears improbable given current disease trajectory. 1

Palliative Care Integration

• Early palliative care consultation should be initiated to address symptom management, transfusion support, and goals of care discussions. 2, 4
• Best supportive care with cytoreductive therapy (hydroxyurea, 6-mercaptopurine) should be offered if the patient cannot tolerate or declines active treatment. 2

Monitoring for Complications

• Close monitoring for infectious complications, bleeding (given thrombocytopenia), and tumor lysis syndrome is essential. 8
• The patient's low donor chimerism and immunosuppression place them at high risk for opportunistic infections. 1

Summary of Prognostic Determinants

This patient's prognosis is determined by the convergence of multiple adverse factors:

• Early post-transplant relapse (20 months = intermediate-risk timing) 2
• Complete loss of donor chimerism in CD34+ cells (0% donor DNA) 1
• Emergence of high-risk cytogenetic abnormality (der(1;18)) 1
• Persistent disease despite venetoclax-azacitidine therapy 1
• Adverse molecular mutations (NRAS G12D, WT1 splice-site) 1
• Age >60 years precluding intensive salvage chemotherapy 2
• Clonal evolution with multiple cytogenetic clones 1

The median overall survival of 6-9 months represents the most realistic expectation, with clinical trial enrollment or novel combination therapy offering the only meaningful chance to extend survival beyond this timeframe. 1