Prognosis
Risk stratification vs actual outcome, 28+ months post-HSCT
IPSS-M Score Very High
2.976
Very High (threshold >1.5), Bernard et al. NEJM Evid 2022
ELN 2022
Adverse
Monosomy 7 overrides IDH2
Median OS
9.7 months
ELN Adverse, newly diagnosed
Actual OS Alive
28+ months
MRD negative, full chimerism
Drivers Unprecedented
5
On 5 convergence axes + monosomy 7
Expected vs Actual
Source: Median OS values from published
cohort studies. Actual survival as of March 2026.
Risk Model Comparison
| Model | Category | Median OS | Source |
|---|---|---|---|
| IPSS-M | Very High (2.976) | 1.0 year | Bernard et al. NEJM Evid 2022 |
| ELN 2022 | Adverse | 9.7 months | Lachowiez et al. Blood Adv 2023 |
| Chr7-aberrant + PTPN11 | HR 2.24 | N/A | Halik et al. J Hematol Oncol 2024 |
| Chr7-aberrant + IDH2 | HR 0.51 (protective) | N/A | Halik et al. 2024 |
| VenAza (RAS pathway) | Lower-benefit | 5.5 months | Döhner et al. Blood 2024 |
| R/R AML + PTPN11 | Adverse | 4.6 months | Shahswar et al. Leukemia 2025 |
Note: HR = hazard ratio. IPSS-M
13
[13] E 2022
Molecular International Prognostic Scoring System for Myelodysplastic Syndromes. NEJM Evid (2022)
trained on 2,957 MDS patients. ELN
2022
14[14] H 2022
Diagnosis and management of AML in adults: 2022 ELN recommendations. Blood (2022)
risk stratification. AML genomic
classification per Papaemmanuil et al.
12[12] E 2016
Genomic Classification and Prognosis in Acute Myeloid Leukemia. N Engl J Med (2016)
.
Outside the Model
Every scoring system places this profile in its worst category. But the
scoring systems are built on population data. This mutation profile does
not exist in the population. The patient scores not just worst:
the patient is outside the system's ability to score.
IPSS-M 13
And the patient is alive. MRD-negative. Full donor chimerism. 28 months post-HSCT. With multi-organ GvHD that went untreated for 26 months. That is also outside the model.
This is a data point worth studying: the most adverse profile documented in 31,000+ patients has survived 28+ months post-HSCT.
With EZH2 V662A now confirmed as a fifth driver mutation 10
EZH2-mutant MDS with chromosome 7 abnormalities carries the worst survival among EZH2-mutant subgroups 11
PyClone-VI 16
Type 1 progression mutations 15
And the patient is alive. MRD-negative. 28+ months post-HSCT. That is the other side of being outside the model.
IPSS-M 13
[13] E 2022
Molecular International Prognostic Scoring System for Myelodysplastic Syndromes. NEJM Evid (2022)
was trained on 2,957 patients. None
had this quadruple combination. The model extrapolates from patients who
are less complex and assumes the pattern continues linearly. It likely
does not.
And the patient is alive. MRD-negative. Full donor chimerism. 28 months post-HSCT. With multi-organ GvHD that went untreated for 26 months. That is also outside the model.
This is a data point worth studying: the most adverse profile documented in 31,000+ patients has survived 28+ months post-HSCT.
With EZH2 V662A now confirmed as a fifth driver mutation 10
[10] A 2020
Mutational mechanisms of EZH2 inactivation in myeloid neoplasms. Leukemia (2020)
, a novel variant never
described in literature, carrying 0/20,739 carriers in GENIE. The
profile moves from unprecedented to genuinely unknown. The quintuple
expected frequency is ~7.7×10-13, or approximately 1 in
1.3 trillion. No prognostic model was designed to handle this.
EZH2-mutant MDS with chromosome 7 abnormalities carries the worst survival among EZH2-mutant subgroups 11
[11] S 2023
Clinical characteristics and outcomes of EZH2-mutant myelodysplastic syndrome. Leuk Res (2023)
. SETBP1 + monosomy 7 co-occurrence was
first characterized by Makishima et al.
2[2] H 2013
Somatic SETBP1 mutations in myeloid malignancies. Nat Genet (2013)
as a hallmark of aggressive
myeloid transformation.
PyClone-VI 16
[16] S 2020
PyClone-VI: scalable inference of clonal population structures using whole genome data. BMC Bioinformatics (2020)
clonal reconstruction shows linear
evolution: DNMT3A (CCF 1.00) → EZH2 (0.92) → SETBP1 (0.87)
→ PTPN11 (0.74) → IDH2 (0.05). The founding clone carries
three epigenetic regulators (DNMT3A + EZH2 + IDH2's metabolic effect on
TET2), creating what may be described as a triple epigenetic catastrophe.
No existing treatment protocol addresses this combination.
Type 1 progression mutations 15
[15] H 2017
Dynamics of clonal evolution in myelodysplastic syndromes. Nat Genet (2017)
. The signaling pathway hits
(PTPN11, IDH2) acquired during transformation define the clonal
trajectory from MDS to AML.
And the patient is alive. MRD-negative. 28+ months post-HSCT. That is the other side of being outside the model.
OncoKB Actionability
| Variant | OncoKB Level | Actionable Drug | Status |
|---|---|---|---|
| IDH2 R140Q | Level 1 | Enasidenib | FDA-approved 2017 |
| PTPN11 E76Q | Level 3B | SHP2 inhibitors (TNO155; SHP2i+venetoclax synergy) | Clinical trials |
| DNMT3A R882H | Oncogenic | Azacitidine (indirect) | Standard of care |
| SETBP1 G870S | Oncogenic | None (PP2A activators experimental) | Preclinical |
| EZH2 V662A | Likely Oncogenic | Tazemetostat CONTRAINDICATED (LoF) | N/A |
Only 2 of 5 drivers have FDA-approved targeted therapy (IDH2:
enasidenib
21
[21] EM 2017
Enasidenib in mutant IDH2 relapsed or refractory acute myeloid leukemia. Blood (2017)
) or active clinical trials (PTPN11:
SHP2 inhibitors
23[23] MJ 2020
Identification of TNO155, an Allosteric SHP2 Inhibitor for the Treatment of Cancer. J Med Chem (2020)
). The remaining 3 have no direct
inhibitors. SHP2 inhibitor + venetoclax synergy
22[22] B 2023
Allosteric SHP2 inhibition increases apoptotic dependency on BCL2 and synergizes with venetoclax in AML. Cell Rep Med (2023)
is the most promising combination
strategy. This is a targetability gap that underscores the complexity of
this profile.
References
- Bernard E, Tuechler H, Greenberg PL, et al. Molecular International Prognostic Scoring System for Myelodysplastic Syndromes. NEJM Evid (2022). DOI
- Döhner H, Wei AH, Appelbaum FR, et al. Diagnosis and management of AML in adults: 2022 ELN recommendations. Blood (2022). PubMed
- Papaemmanuil E, Gerstung M, Bullinger L, et al. Genomic Classification and Prognosis in Acute Myeloid Leukemia. N Engl J Med (2016). PubMed
- Chase A, Score J, Lin F, et al. Mutational mechanisms of EZH2 inactivation in myeloid neoplasms. Leukemia (2020). PubMed
- Ball S, Aguirre LE, Jain AG, et al. Clinical characteristics and outcomes of EZH2-mutant myelodysplastic syndrome. Leuk Res (2023). PubMed
- Makishima H, Yoshida K, Nguyen N, et al. Somatic SETBP1 mutations in myeloid malignancies. Nat Genet (2013). PubMed
- Gillis S, Roth A. PyClone-VI: scalable inference of clonal population structures using whole genome data. BMC Bioinformatics (2020). DOI
- Makishima H, Yoshizato T, Yoshida K, et al. Dynamics of clonal evolution in myelodysplastic syndromes. Nat Genet (2017). PubMed
- Stein EM, DiNardo CD, Pollyea DA, et al. Enasidenib in mutant IDH2 relapsed or refractory acute myeloid leukemia. Blood (2017). PubMed
- LaMarche MJ, Acker M, Argintaru A, et al. Identification of TNO155, an Allosteric SHP2 Inhibitor for the Treatment of Cancer. J Med Chem (2020). PubMed
- Popescu B, Stahlhut C, Tarver TC, et al. Allosteric SHP2 inhibition increases apoptotic dependency on BCL2 and synergizes with venetoclax in AML. Cell Rep Med (2023). PubMed
- Chakravarty D, Gao J, Phillips SM, et al. OncoKB: A Precision Oncology Knowledge Base. JCO Precis Oncol (2017). PubMed