Podcast Summary

The Fellow on Call: The Heme/Onc Podcast

Episode 126: AML Series, Pt 12 – Treatment of Patients with Relapsed/Refractory Disease
Date: January 8, 2025
Hosts: Roanoke (A), Vivek (B), Dan (C)
Institution: Rouleaux University Medical Center

Brief Overview

This episode concludes The Fellow on Call’s in-depth series on Acute Myeloid Leukemia (AML) by tackling the complex topic of relapsed and refractory disease. The hosts break down classification, current management strategies, the evolving therapeutic landscape (including targeted therapies and clinical trials), and provide practical frameworks for learners and practitioners alike. The discussion is grounded in recent evidence and expert opinion, with the panel highlighting the rapid evolution of the field and the need for individualized patient care.

Key Discussion Points & Insights

1. Case Presentation and Definition of Primary Induction Failure (03:14–06:58)

• Case: 61-year-old male with TP53-mutated AML, monosomal karyotype, and persistent disease after one intensive induction.
• ELN 2022 Criteria:
  • Primary Induction Failure (Refractory Disease):
    • Intensive induction: Persistent disease (>5% blasts) after two cycles.
    • Less-intensive induction regimens: No clear consensus; timeframes for CR range 90–180 days.
• Outcomes Based on Risk:
  • Favorable: ~75% CR rate
  • Intermediate: 66%
  • Adverse: 45%
  • Highlight: “Patients who had both TP53 mutated AML and complex karyotype had a 5 year overall survival of zero percent.” – Dan (06:06)

2. Current Framework for Salvage Therapy (06:58–09:23)

• Salvage Strategies:
  • Clinical trial referral is always preferred if feasible.
  • Re-induction chemotherapy regimens (e.g., FLAG, FLAG-IDA, CLAG, CLAG-M) are standard backbones for patients requiring debulking.
  • Consideration of HMA + Venetoclax for less fit or chemorefractory patients.
  • Targeted therapies for identified mutations:
    • IDH1, IDH2, FLT3 mutations, and new menin inhibitors for KMT2A-rearranged AML.
• Evolving Practice: “This landscape has been changing pretty rapidly…We don’t have robust randomized data in this setting.” – Roanoke (07:29)

3. Historical Perspective: Evolution of Intensive Regimens (09:43–15:22)

• High-Dose Cytarabine (HDAC): Foundation of salvage regimens since the 1980s.
• Combining Agents:
  • Etoposide & Mitoxantrone led to the MEC regimen (mitoxantrone, etoposide, cytarabine); ~40% CR rates.
  • Fludarabine or cladribine (purine analogs) potentiates cytarabine’s effect via increased intracellular activation (ARA-CTP).
  • GCSF added to push AML cells into S-phase.
• Regimens Explained:
  • FLAG: Fludarabine, cytarabine, GCSF
  • CLAG: Cladribine, cytarabine, GCSF
  • Addition of anthracyclines: FLAG-IDA, CLAG-M.
• Evidence Gap: “There was never a randomized study evaluating differences in MEC, CLAG, FLAG, CLAGM, or FLAG-IDA...In the end, all of these are reasonable options.” – Vivek (14:10)

4. The Role of Venetoclax in Salvage Therapy (17:03–20:07)

• Mechanism: Venetoclax is a BCL-2 inhibitor promoting apoptosis in AML cells.
• Efficacy in R/R AML:
  • Single-agent activity limited (~10% CR); always combined with a HMA or chemotherapy.
  • Key Studies:
    • MD Anderson, Phase 2: Decitabine 10-day + Venetoclax in R/R AML (CR rate ~40%).
    • Real-world French study: HMA + Ven (CR 44%).
    • City of Hope study: HMA + Ven (TP53-mutated, CR rate 50%).
    • FLAG-IDA + Ven (MD Anderson Phase 1b/2): 66% CR.
• Practice Note: “In summary, HMA and venetoclax and FLAG IDA venetoclax are both reasonable options in this relapse refractory setting.” – Dan (19:52)

5. Case Resolution and Clinical Pearls (20:07–22:09)

• Host Approach: Azacytidine + Venetoclax led to CR, followed by allogeneic transplant, maintaining remission at one year.
• “We have a laundry list of options that we can use.” – Vivek (21:23)

6. FLT3, IDH1, IDH2, and Menin Inhibitors for Targeted Therapy (22:09–30:57)

FLT3 Inhibitors

• Gilteritinib (Admiral trial):
  • 34% CR, improved OS vs. salvage chemo (9 vs. 6 months),
  • Survival rate at 2-yr: 20% in Gilt arm.
• “Once again it has presented us with another option for patients that may have that FLT3 mutation.” – Roanoke (23:22)

IDH1/IDH2 Inhibitors

• IDH1: Ivosidenib, olutasidenib
  IDH2: Enasidenib
• Memory Aids from Dan (23:50):
  • “I in ivosidenib looks like A1... IDH1.”
  • “Enasidenib, the letter N, that’s like a two on its side...IDH2.”
• CR rates ~20%, ORR 46%, OS median 9 months (IDH1).
• Identify Study (Enasidenib): No OS benefit over controls, but higher CR (30% vs 6%) and transfusion independence (30% vs 10%).

Menin Inhibitor

• Revumenib (AUGMENT101 Trial):
  • R/R KMT2A-rearranged or NPM1-mutated AML.
  • Composite CR: 23%, median time to CR 1.9 months.
  • Differentiation syndrome: 25%
  • Noted for benefit even in heavily pretreated/venetoclax-exposed population.

Notable Quotes & Memorable Moments

• On TP53/Complex Karyotype:
  “Patients who had both TP53 mutated AML and complex karyotype had a 5 year overall survival of zero percent. I'll say that again...zero percent.” – Dan (06:06)
• On Evolving Therapy:
  “We don’t have robust randomized data in this setting...The best thing that you can do is refer for consideration of a clinical trial.” – Roanoke (07:29)
• On Regimen Choice:
  “There was never a randomized study evaluating differences in MEC, CLAG, FLAG, CLAGM, or FLAG-IDA...all of these are reasonable options.” – Vivek (14:10)
• Clinical Trial Imperative:
  “Remember clinical trials…this is how we’ve improved outcomes for these patients and is so critical.” – Vivek (32:06)

Key Timestamps

• Case Introduction & Definitions: 03:14–06:58
• Management Framework & Targeted Therapy Overview: 06:58–09:23
• History of Salvage Chemotherapy Protocols: 09:43–15:22
• Venetoclax in R/R AML: 17:03–20:07
• FLT3/IDH/Menin Inhibitors Discussion: 22:09–30:57
• Discussion Wrap-up/Big Picture: 30:57–32:34

Takeaways & Final Thoughts

• No single “best” approach exists; regimen selection requires individualization based on patient characteristics, prior exposures, molecular profile, and institutional preferences.
• Relapsed/refractory AML remains a high-risk population, but the landscape is rapidly changing with the emergence of targeted therapies and combination approaches.
• Clinical trial enrollment is paramount.
• Quality of life metrics, such as transfusion independence, are increasingly valued as endpoints.
• Ongoing/future research will evaluate the optimal sequencing and combinations (e.g., HMA+VEN+targeted agent triplets), with a focus on moving new therapies into earlier lines.

For More Information

• Check referenced phase studies and institutional protocols (e.g., via hemonc.org).
• Review prior episodes in the AML series for foundational knowledge.

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