🧵Just out in Blood @BloodPortfolio: Rapid clonal selection within early hematopoietic cell compartments presages outcome to ivosidenib combination therapy https://t.co/aT9L5oSpKj We study how resistance and durable remission emerge in IDH1-mutant AML.

Great collaboration with @MDAndersonNews courtney dinardo @mkonople @CLachowiez and the top crew in our lab esp @SvenTurkalj @FARadtke @BilyanaStoilova Rabea and @angusgroom Data that has wide implications

This work with @vyas_lab @pvyas_oxford @MRC_WIMM @MRC_MHU was a fantastic collaboration particularly with rising star @SvenTurkalj (now @DanaFarber @harvardmed), Rabea Mecklenbrauck, @mkonople, Courtney DiNardio, @CLachowiez @MDAndersonNews @EinsteinMed https://t.co/08gZJq0Kv1

Our finding that genes regulated by menin-MLL were upregulated in resistant cells months before relapse suggests that menin inhibitors could help prevent or treat relapse after ivosidenib and venetoclax therapy. We will be testing if this is the case in future studies.

🏥 Clinical implication: Early molecular surveillance of immature compartments could identify patients destined to relapse months before overt failure.

IVO+VEN±AZA acts as a powerful selective pressure. Early hematopoietic compartments undergo rapid Darwinian sorting, either eradicating LSCs (→ remission) or selecting resistant ones (→ relapse).

Finding 3: Two patients remain in long-term remission (>4 yrs). In both, leukemic clones were eradicated early and replaced by wild-type cells or clones harboring clonal hematopoiesis mutations.

⏱️ Importantly, these transcriptional programs were detectable as early as cycle 3, while patients were still in complete remission. Molecular relapse appeared to precede clinical relapse by months to years.

This transcriptional convergence implies a common adaptive state: a stem-like, metabolically rewired program rather than a single genetic mutation conferring resistance.

Finding 2: Resistance wasn’t genetically uniform but the transcriptional programs were. Across genetically distinct resistant clones, we found shared signatures: Stemness Branched-chain amino acid metabolism Menin target gene activation

The resistant clones dominated populations with known leukemic stem cell (LSC) potential: LMPP, GMP, CMP; suggesting that selection occurs at the stem/progenitor level.

Two genetic routes of resistance were observed: 1️⃣ Newly detected subclones arising under therapy pressure. 2️⃣ Pre-existing minor clones that gained advantage upon exposure to IVO+VEN. Both routes converged in early progenitors.

Finding 1: In all 6 relapsing patients, resistant clones were selected within small, immature bone marrow compartments, well before relapse became clinically evident. Selection often occurred months to years before failure.

One key question: When does therapy resistance begin? Is it late clonal escape, or early selection of resistant subclones? Spoiler: resistance starts early, within the first 1–3 cycles.

We studied IDH1-mutant AML patients treated with IVO+VEN±AZA who initially responded. 6 relapsed; 2 remain in remission for >4 years. We tracked clonal and transcriptional dynamics using TARGET-seq+, integrating single-cell genotyping, RNA-seq, and immunophenotyping.

🔬 Background: IVO (ivosidenib) + VEN (venetoclax) ± AZA is an emerging therapy for IDH1-mutant AML. Many patients respond, but relapses are common, we don’t fully understand when and where resistant clones arise.

Conversations like these remind us that compassion is essential in meeting the world’s toughest health challenges. Thank you to our speakers, panellists, and participants for sharing your often deeply personal stories. RDS looks forward to seeing you all again next year.

sharing space to address vital topics of resource scarcity in medicine: care in conflict zones, refugee health, and global surgery, with a special focus on children’s surgery.

Grateful to everyone who joined us for the Richard Doll Society’s Conference Beyond Borders: Global Healthcare in Times of Crisis @greentempleton @UniofOxford . It was an honour, and felt deeply impactful, to host this as the RDS President,

The program is a lovely opportunity to engage in a number of exciting projects with peer researchers and faculty.