Blood Podcast Episode Summary

Podcast: Blood Podcast (American Society of Hematology)
Episode: Biologic Insights and Clinical Trial Design for AML
Date: February 5, 2026
Host: Dr. James Griffin (Dana Farber Cancer Institute)
Guests: Dr. Paresh Vyas (University of Oxford), Dr. Andrew Hantel (Dana Farber Cancer Institute)

Overview

This episode explores two influential papers recently published in Blood focusing on acute myeloid leukemia (AML):

1. Mechanisms of response and resistance to combination therapy in IDH1-mutated AML (Dr. Paresh Vyas)
2. How modernizing clinical trial eligibility criteria can increase access and representation in AML trials (Dr. Andrew Hantel)

1. Rapid Clonal Selection and Resistance in IDH1-Mutated AML

Presented by: Dr. Paresh Vyas
Segment: [01:06 – 10:49]

Main Focus

• Investigating how early clonal dynamics in hematopoietic compartments forecast response or resistance to ivocitinib (an IDH1 inhibitor) in combination regimens for AML.

Key Discussion Points & Insights

• Background

  • ~8% of AML patients carry mutations in the isocitrate dehydrogenase 1 (IDH1) gene.
  • Ivocitinib, targeting mutant IDH1, is widely available and now used in combination with other treatments.
  • Initial studies combining ivocitinib with other therapies show >90% response rates, but durability and resistance remain unclear ([01:23]).

• The Study

  • Deep, single-cell longitudinal bone marrow analysis using Target SEQ (combining genotyping and transcriptome analysis) was performed on patients from trial entry through response, relapse, or years-long remission ([03:00]).
  • Found that within three months, response patterns in early cell compartments predicted long-term outcomes:
    • Patients in long-term remission cleared leukemic mutations or had clonal hematopoiesis (DNMT3A/TET2 only).
    • Patients who later relapsed often had a resistant clone emerge within the first three months, sometimes undetectable at trial entry ([04:30]).

• Mechanisms of Resistance

  • Surprisingly, common resistance mechanisms emerged (especially involving menin gene activation), even in genetically diverse relapse clones, suggesting menin inhibitors could benefit patients beyond current indications ([05:30]).
  • “We found that there were common mechanisms of resistance across these patients, despite the fact they had heterogeneous mutational profile in the relapse clone.” – Dr. Vyas [05:55]
  • Additional resistance details are available in the publication.

• Generalizable Insights

  • Rapid clonal selection or clearance in progenitor compartments can be tracked at the single-cell level and this general approach may have utility beyond AML ([06:40]).
  • Common resistance mechanisms may open new therapeutic avenues.

Notable Quotes & Moments

• “The response in the bone marrow across the stem, progenitor and mature cell compartments really presaged the long term outcome of these patients.”
  – Dr. Vyas [03:45]

• “It came as a complete surprise to find that these patients had common signatures of menin gene activation, despite the fact that they didn’t necessarily have an NPM1 mutation or a KMT2A rearrangement.”
  – Dr. Vyas [05:36]

Q&A Highlights

• On clinical applicability of single-cell analysis technology
  • Translation to practice will require partnering with industry/diagnostics to make simpler, scalable, sensitive tests. Clinical validation is ongoing ([08:03]).
• On delayed relapse despite early resistant clone
  • Complex dynamics: no further clonal evolution detected, suggesting factors like immune response or clonal competition may suppress resistant clones ([09:13]).
  • “There are often translocation positive leukemias in intensive chemotherapy and, for example, the NPM1 mutation is often associated with good risk. These are immunogenic neoantigens and I suspect we should be looking for autologous immune responses against them.”
    – Dr. Vyas [09:43]

2. Modernizing Eligibility Criteria in AML Clinical Trials

Presented by: Dr. Andrew Hantel
Segment: [11:12 – 22:33]

Main Focus

• Examining how updating eligibility criteria for AML clinical trials, per FDA and professional society guidance, could increase trial access, diversity, and generalizability without compromising safety.

Key Discussion Points & Insights

• Rationale

  • Eligibility criteria aim to ensure safety and define populations, but may be unnecessarily restrictive, selecting “artificially healthier” patients and undermining generalizability ([11:38]).
  • FDA/ASH/ASCO now recommend aligning criteria with known/anticipated drug-specific safety signals rather than precedent or excessive caution ([12:00]).

• Study Design

  • Reviewed 190 phase 2 & 3 AML trials, extracting their written eligibility criteria.
  • Applied both the original ("trial-based") and alternative, safety-based criteria (per modern guidance) to a cohort of 2,200+ US AML patients ([12:38]).

• Findings

  • Using trial-based criteria, only ~50% of real-world patients were eligible for trials.
  • Applying safety-based criteria increased eligibility rates to ~80%, expanding access dramatically ([13:26]).
  • Adjustments (e.g., removing age-based restrictions) still resulted in significant increases in eligibility.
  • Specific restrictive criteria involved cardiac disease, liver function, upper age limits, and prior malignancy ([14:45]).
  • Not only did broadening criteria boost inclusion, it also reduced eligibility gaps across racial/ethnic demographics ([14:10]).

• Conclusions & Generalizability

  • Criteria should be intentional, justified, and evidence-based, not “loosened indiscriminately.”
  • Aligning with federated guidance can enhance access, equity, and real-world relevance ([15:51]).
  • The approach is applicable to other hematologic and solid tumors ([16:50]).

Notable Quotes & Moments

• “Our key takeaway is really that eligibility criteria should not be loosened indiscriminately, but…should be intentional, justified and evidence based. They’re really design choices.”
  – Dr. Hantel [15:51]

• “Trial access, patient safety and scientific validity are really deeply connected here. And by aligning eligibility criteria with drug safety rather than habit or precedent, we can really design trials to better reflect the patients that we actually treat…”
  – Dr. Hantel [16:09]

Q&A Highlights

• Next Steps for Implementation
  • Ongoing projects aim to educate trial sponsors and regulatory bodies to ground eligibility in safety data, adjusting through all trial phases ([17:55]).
  • Training IRBs to use federal/professional guidance is also underway.
• On safety and real-world outcomes
  • Including more diverse/older/sicker patients may affect outcomes, but excluding them leads to trial evidence that doesn't reflect real-world patients ([18:40]).
• Does this address real-world/clinical trial “efficacy gap”?
  • That is the goal: tracking how inclusion of broader patients affects trial outcomes ([20:48]).
• Application to solid tumors
  • Similar efforts apply, with particular focus on parallel criteria in other cancers ([21:55]).

Timestamps for Key Segments

• [01:06] – Dr. Vyas introduces study on clonal selection and resistance in AML
• [05:36] – Discovery of menin gene activation as a common resistance pathway
• [08:03] – Discussing how to scale single-cell assays to clinical practice
• [09:13] – On immune response, clonal competition, delayed relapse
• [11:12] – Dr. Hantel on modernizing eligibility criteria in AML trials
• [13:26] – Major increase in trial eligibility with safety-based criteria
• [15:51] – Need for intentional, evidence-based trial design
• [17:55] – Implementation and safety assessment for new criteria
• [20:48] – Will this reduce the efficacy “decline” in real-world practice?

Memorable Quotes

• Dr. Vyas [05:55]:
  “We found that there were common mechanisms of resistance across these patients, despite the fact they had heterogeneous mutational profile in the relapse clone.”

• Dr. Hantel [15:51]:
  “Eligibility criteria should not be loosened indiscriminately, but…should be intentional, justified and evidence based. They’re really design choices.”

Tone

The discussion is technical, inquisitive, and critically engaged, focusing on nuanced interplay between laboratory discoveries, clinical trial design, and implications for patient care.

For more details, read the full articles at bloodjournal.org.