Thank you to our fearless leader and incredible mentor @AlexBickMDPhD!! Forever grateful to dream team @rheumrob
@yash_pershad
@DrFlashHeart
@brettheimlich
@LeoLuoMD
@FerrellLabVUMC
@SavonaNashville
@YaominXu1

SAMPLE SIZE EXAMPLES for cytopenia prevention trials:

High-risk CHIP patients (≥4 factors):

40% drug efficacy → 544 patients total (80% power)
60% drug efficacy → 200 patients total (80% power)

Compare this to 50,000+ needed for myeloid neoplasm endpoints!

For clinical trial design in CHIP prevention trials we need

Before our study: Need 50,000+ patients, 10+ years for MN endpoint

After our study: Need 400-1,000 patients, 2-3 years for cytopenia endpoint

Following @dpsteensma's vision of actionable CHIP endpoints!

TET2 mutations → ↑ cytopenia risk (HR=1.19)

Spliceosome genes (SF3B1, SRSF2) → ↑↑ risk (HR=1.93)

TP53 pathway → ↑ risk (HR=1.28)

IDH1/2 mutations → ↑↑ risk (HR=2.24)

Building on @LDWeeks_MD @NEJMEvidence
work on CHIP risk prediction!

We identified 7 key risk factors for cytopenia in CHIP patients:

Age ≥65 (HR=1.41)
Male sex (HR=1.45)
Smoking (HR=1.17)
≥2 mutations (HR=1.95)
High-risk genes (HR=1.48)
MCV ≥100 fL (HR=2.12)
RDW ≥15% (HR=2.59)

MASSIVE SCALE gives us confidence:

805,249 participants (All of Us, BioVU, UK Biobank)
9374 CHIP cases + 24749 controls
Follow-up: 2006-2023 (up to 17 years!)
190 myeloid neoplasms, 4,151 cytopenias

The largest longitudinal CHIP study ever conducted!

Previous landmark studies by @SJaiswal_MD (NEJM 2014) and Genovese et al. (NEJM 2014) showed CHIP affects 10-20% of people >70 years, with ~0.5-1% annual myeloid neoplasm.

But designing prevention trials seemed IMPOSSIBLE due to huge sample sizes needed.