What is the prognosis for a 64-year-old male with a history of Acute Myeloid Leukemia (AML), currently undergoing treatment with Vidaza (Azacitidine) and Venclexta (Venetoclax) for his third recurrence, with previous treatments including chemotherapy and stem cell transplant, and cytogenetic abnormalities including CBFB gene rearrangement and an extra signal for the RUNX1T1 gene region?

Prognosis for Third Recurrence AML with CBFB Rearrangement After Stem Cell Transplant

This patient faces an extremely poor prognosis with a median overall survival likely under 6 months, as third recurrence AML after stem cell transplant represents highly chemoresistant disease with exhausted salvage options. 1

Interpretation of Cytogenetic Findings

The FISH results reveal critical prognostic information:

• CBFB gene rearrangement (42% of cells) indicates core binding factor AML, typically considered favorable-risk at diagnosis, but this favorable biology is negated by multiple relapses and post-transplant recurrence 2
• Extra RUNX1T1 signal (7% of cells) represents additional chromosomal instability, suggesting clonal evolution and more aggressive disease biology 2
• Persistence from previous specimens confirms this is the same resistant clone that has survived both intensive chemotherapy and stem cell transplant 2

The absence of TP53 deletion is one of the few positive findings, as TP53 abnormalities confer the worst prognosis in relapsed AML 2

Prognostic Assessment for Third Recurrence

Expected Survival Outcomes

Median overall survival for third recurrence post-transplant AML is approximately 3-6 months, with very few patients surviving beyond 1 year. 1 The evidence shows:

• Patients relapsing within 20 months after stem cell transplant (as in this case) have 3-year survival probabilities of only 4-12% even at first relapse 1
• By third recurrence, patients have exhausted standard salvage options, developed resistant disease biology, and accumulated treatment-related organ damage 1
• The 30-day mortality with intensive salvage chemotherapy in heavily pretreated patients reaches 14% or higher, making aggressive treatment highly questionable 1, 3

Current Treatment: Azacitidine + Venetoclax

The patient just started this regimen 6 days ago. While this combination shows promise in newly diagnosed elderly AML, the evidence for third relapse is limited:

For relapsed/refractory AML, azacitidine-venetoclax achieves only 37% overall response rate (13% CR, 8% CRi), compared to 58% in newly diagnosed patients. 4 Specifically:

• Median overall survival in relapsed/refractory AML treated with venetoclax-azacitidine is 5.9 months versus 9.4 months in newly diagnosed patients 4
• Adverse cytogenetics (which includes evolved clones with additional abnormalities) predicts treatment failure with this regimen 4
• The combination requires multiple cycles to demonstrate response, as hypomethylating agents need active DNA replication to work 3, 5

Treatment Expectations and Management

Response Assessment Timeline

• Do not assess response before 8-12 weeks (2-3 cycles), as hypomethylating agents require time to demonstrate efficacy 2, 3
• Bone marrow evaluation should occur after hematologic recovery following cycle 2-3 2
• Early discontinuation due to perceived lack of response is a critical error to avoid 3, 5

Infectious Complications Management

Febrile neutropenia occurs in 30-61% of patients on venetoclax-azacitidine, with infections (any grade) in 84% of patients. 2 Essential supportive measures include:

• Antibacterial and antifungal prophylaxis is mandatory when combining hypomethylating agents with venetoclax 2
• If posaconazole is used for antifungal prophylaxis, reduce venetoclax dose by 75% due to CYP3A4 inhibition 2
• Consider dose interruptions between cycles to allow hematologic recovery, particularly after cycle 1 bone marrow assessment 2
• Prophylactic growth factor support may be needed if severe neutropenia persists despite good response 2

Alternative Considerations if Current Therapy Fails

Clinical trial enrollment should be the absolute first priority if azacitidine-venetoclax fails. 1 If no trial is available:

• Best supportive care focusing on transfusion support, cytoreductive therapy with hydroxyurea if needed, and palliative care consultation is the most appropriate option 1, 3
• Second allogeneic stem cell transplant is NOT an option, as the patient relapsed at only 20 months post-transplant (requires >5 months minimum, but realistically needs much longer) 1
• Donor lymphocyte infusion combined with chemotherapy is rarely effective long-term in post-transplant relapse 1
• Intensive salvage chemotherapy carries prohibitive mortality risk (≥14%) without meaningful survival benefit in third relapse 1, 3

Critical Prognostic Factors Affecting This Patient

Adverse Features Present:

• Third recurrence (most significant negative factor) 1
• Post-transplant relapse at 20 months (indicates aggressive biology) 1
• Age 64 years (older age is adverse prognostic factor) 2
• Clonal evolution (extra RUNX1T1 signal suggests genomic instability) 2

Potentially Favorable Features:

• Absence of TP53 deletion (TP53 abnormalities occur in two-thirds of complex karyotype cases and confer worst prognosis) 2
• CBFB rearrangement (though favorable at diagnosis, this is negated by multiple relapses) 2

Realistic Outcome Expectations

The most likely scenario is that this patient will achieve at best a brief partial response or stable disease with azacitidine-venetoclax, with median survival of 3-6 months from this third relapse. 1, 4 Key points to communicate:

• Complete remission is unlikely but possible (13% CR rate in relapsed/refractory AML with this regimen) 4
• Even if remission is achieved, duration will be brief (median leukemia-free survival 9.4 months in responders) 4
• Quality of life considerations should guide all treatment decisions at this stage 1, 3
• Early palliative care involvement is essential 1