What is the prognosis for an elderly male patient with a history of recurrent Acute Myeloid Leukemia (AML), currently presenting with a third relapse, who is Fluorescence In Situ Hybridization (FISH) panel positive for CBFB and RUNX1T1, and has previously been treated with chemotherapy alone followed by a stem cell transplant after the first relapse?

Prognosis for Elderly Male with Third Relapse of CBF-AML Post-Transplant

The prognosis is extremely poor, with an expected 3-year survival probability of only 12% based on relapse occurring 20 months post-allogeneic transplant, and this third relapse indicates highly chemotherapy-resistant disease biology that is unlikely to respond to further salvage attempts. 1

Understanding the Prognostic Context

Baseline CBF-AML Biology vs. Current Clinical Reality

While CBFB-MYH11 and RUNX1-RUNX1T1 fusions typically confer favorable-risk status in newly diagnosed AML, this favorable prognosis applies only to treatment-naïve disease with adequate MRD response. 2 Your patient's situation fundamentally differs:

• Multiple prior relapses: Third relapse indicates highly resistant clonal evolution that has escaped both intensive chemotherapy and the graft-versus-leukemia effect. 1
• Post-transplant relapse timing: Relapse at 20 months post-allogeneic transplant carries a dismal 12% 3-year survival probability according to CIBMTR data. 2, 1
• Loss of favorable-risk status: The initial favorable cytogenetics become clinically irrelevant after multiple treatment failures, as acquired mutations drive resistance. 2, 3

Critical Prognostic Factors in This Scenario

Age and fitness: At elderly age (context suggests >60 years based on "elderly male"), tolerance for intensive salvage regimens is significantly reduced, and outcomes are substantially worse than younger patients. 2, 1

Duration of remissions: The first remission lasted only "a few months" before relapse—this short duration (<6 months) places the patient in the worst prognostic category for relapsed AML. 2, 3

Post-transplant relapse: Relapse after allogeneic transplant indicates disease that has overcome the most potent anti-leukemic therapy available, with survival probabilities of only 4-12% at 3 years depending on timing. 2, 1

Immediate Diagnostic Steps Required

Molecular Testing to Guide Targeted Therapy

Urgent repeat molecular profiling is essential to identify any actionable mutations that may have emerged during clonal evolution:

• FLT3-ITD and FLT3-TKD testing: Gilteritinib monotherapy provides median overall survival of 9.3 months versus 5.6 months with chemotherapy in FLT3-mutated relapsed/refractory AML. 2, 1
• IDH1 and IDH2 mutation analysis: Ivosidenib (IDH1 inhibitor) or enasidenib (IDH2 inhibitor) show activity as single agents in relapsed/refractory disease with these mutations. 2, 1
• KIT mutation status: While KIT mutations worsen prognosis in CBF-AML, no specific targeted therapy is currently approved, but this informs overall risk assessment. 2, 4

Donor Chimerism Studies

Assess donor cell engraftment status through chimerism studies to determine if there is any residual graft-versus-leukemia effect that could be augmented with donor lymphocyte infusion (DLI). 1

Treatment Options and Expected Outcomes

If Targetable Mutations Identified

For FLT3-mutated disease: Gilteritinib monotherapy is the preferred option, with median overall survival of 9.3 months and potential bridge to second allogeneic transplant or DLI if response achieved. 2, 1

For IDH1/IDH2-mutated disease: Single-agent IDH inhibitors (ivosidenib or enasidenib) represent reasonable options with manageable toxicity profiles suitable for elderly patients. 2, 1

If No Targetable Mutations

Azacitidine monotherapy is the preferred hypomethylating agent for patients not eligible for intensive chemotherapy, with median overall survival of 6.7 months and complete remission/CRi rate of only 16.3%. 2, 1 This represents palliative disease control rather than curative intent.

Intensive salvage chemotherapy (such as FLAG-Ida or high-dose cytarabine combinations) carries substantial toxicity with minimal chance of durable remission in this heavily pretreated, elderly patient with multiple prior relapses. 2

Consideration of Second Allogeneic Transplant or DLI

Second allogeneic transplant or DLI may induce long-term survival only in highly selected patients relapsing >5 months post-transplant who achieve remission with salvage therapy. 2 Given the 20-month relapse timing, this patient falls within the 6-24 month window with 12% 3-year survival probability. 2, 1 However, achieving remission with salvage therapy in third relapse is highly unlikely.

Clinical Algorithm for Management

1. Obtain urgent molecular testing for FLT3, IDH1, and IDH2 mutations within 48-72 hours. 2, 1
2. Assess donor chimerism to evaluate residual graft-versus-leukemia potential. 1
3. If FLT3-mutated: Initiate gilteritinib monotherapy. 1
4. If IDH1/IDH2-mutated: Initiate appropriate IDH inhibitor. 1
5. If no targetable mutations and patient desires treatment: Initiate azacitidine with realistic discussion of palliative intent. 1
6. Strongly consider clinical trial enrollment at any stage, as this offers the best chance for improved outcomes beyond standard therapies. 1
7. If patient achieves remission with targeted therapy: Evaluate for second allogeneic transplant or DLI in consultation with transplant center. 2, 1

Common Pitfalls to Avoid

Do not assume favorable-risk cytogenetics predict favorable outcomes in multiply relapsed disease: The initial CBFB-MYH11 and RUNX1-RUNX1T1 fusions become prognostically irrelevant after multiple treatment failures and clonal evolution. 2, 3

Do not pursue intensive salvage chemotherapy without targetable mutations: In elderly patients with third relapse post-transplant, intensive chemotherapy carries prohibitive toxicity with negligible chance of durable benefit. 2, 1

Do not delay molecular testing: Actionable mutations (FLT3, IDH1/2) represent the only realistic opportunity for meaningful disease control, and testing should be expedited. 2, 1

Supportive Care Considerations

Transfusion support: Maintain platelet count >10,000/μL for prophylaxis (higher if bleeding or procedures planned), and transfuse red cells for symptomatic anemia. 1

Infection surveillance: Implement aggressive infection monitoring and prompt treatment given high neutropenia risk in heavily pretreated patient. 1

Goals of care discussion: Given the extremely poor prognosis (12% 3-year survival), early palliative care involvement and honest discussion of treatment goals versus hospice care is appropriate. 2, 1