Alexander Coltoff, MD

🚨 Spectrum, prevalence, and clinical correlates of PPM1D mutations in patients with clonal hematopoiesis and clonal cytopenias. I am very pleased with this collaborative effort. Grateful to @MrinalPatnaik for his mentorship. Paper highlights 👇🏽 🧬 PPM1D mutations in clonal hematopoiesis – what really happens after chemo? Multi center study of 337 CH/CCUS patients dissects how #PPM1D and #TP53 mutations shape therapy-related clonal hematopoiesis. 👇 1️⃣ PPM1D is the signature of therapy-related CH •50% had PPM1D-mut/TP53-WT •7% had PPM1D-mut/TP53-mut •These genotypes were highly enriched in therapy-related CH/CCUS (up to 80% of cases). 2️⃣ All PPM1D mutations were truncating exon-6 variants Median VAF only 6% — small clones, but biologically meaningful. 3️⃣ Latency after genotoxic therapy was strikingly short Median time from last chemo/radiation to detection: •PPM1D-mut groups: ~6 months •TP53-mut only: ~11 months •WT/WT: ~24 months → PPM1D clones emerge fast after DNA-damaging therapy. 4️⃣ Strong link with PARP inhibitors & radioligand therapy In therapy-related CH/CCUS: •PARPi exposure: 24–26% in PPM1D-mut vs 0–3% in WT groups •Radioligand therapy: ~25–26% in PPM1D-mut vs near-zero otherwise. 5️⃣ Despite this… PPM1D clones rarely progressed Rates of transformation to MDS/CMML: •PPM1D-mut/TP53-WT: 2% •PPM1D-mut/TP53-mut: 4% •TP53-mut only: 18% •WT/WT: 12% AML transformation occurred only in WT/WT group. 6️⃣ When both PPM1D & TP53 are present, neither always “wins” Among co-mutated patients: •~⅓ #PPM1D-dominant •~⅓ #TP53-dominant •~⅓ co-dominant Therapy-related CH showed more co-dominant competing clones, suggesting chemo creates a “Darwinian battlefield”. 7️⃣ The size of the PPM1D clone matters Using ROC-derived cut-off: •PPM1D VAF ≥13% → independently predicts worse PFS & OS (HR ~2.3 for both). Multiple PPM1D mutations ≠ worse outcome — it’s the clone size, not count. 8️⃣ Clinical message #PPM1D mutations are: •Common after chemo/PARPi/radioligand therapy •Often small, fast-emerging clones •Surprisingly low risk for malignant transformation, even with TP53 — unless the VAF climbs ≥13%. Take-home: PPM1D-mut CH appears to be a therapy-selected, early-emerging, usually indolent precursor state — but rising clone size may signal real danger. doi.org/10.1182/bloodadvance…

🚨 Latest paper from #COMMAND_consortium, reporting heterogeneity in clinical outcomes in #TP53m MPN, one of largest cohort of TP53m MPN: 1. Multihit TP53 had inferior outcome in chronic phase MPN, not so in MPN-AP or BP. Similar to our reports in HR-MDS/AML. 2. MH TP53 commonly seen in MF or MPN-AP/BP. Rare in PV/ET. 3. Allo-HCT improves outcome, less so with MH TP53/complex CG. 4. TP53 with low VAF commonly seen in PV/ET and does not impact disease progression significantly. @Dr_RoryShallis @Irumkhan_hem @ChenyuLinMD @AlexColtoff @Anand_88_Patel @Wang_Yu_Hung et al. @MPN_Hub British Journal of Haematology | Wiley Online Library onlinelibrary.wiley.com/doi/…

#EHA2024 #EHA24 #poster_session #TP53m #MPN #mpnsm Genomic landscape, impact allelic burden, time to progression from CP-AP/BP in TP53m MPN—> AML TP53m with VAF>40 had poorer outcome. No significant impact of type of induction on outcome. Special thanks to #COMMAND_consortium @MobasherK @Anand_88_Patel @Dr_RoryShallis #Jan_Bewersdorf #Ehab_Atallah #Aron_Goldberg #Kashish_Shah #Alex_Coltoff