Bone marrow neoplastic

• MDS biTP53 (MDS with biallelic TP53 inactivation) is a new subtype per WHO 5th edition, 2022
• Detection of ≥ 1 TP53 mutation, meeting molecular diagnostic criteria of biallelic TP53 mutations (Nat Med 2020;26:1549)
• 33% of TP53 mutated MDS patients had monoallelic mutations whereas 67% had multiple hits (multihit) consistent with biallelic targeting (Nat Med 2020;26:1549)
• MDS biTP53 is characterized by increased blast counts, higher risk of leukemic transformation and higher risk of mortality
• TP53 mutated myeloid neoplasms (MN) represent a unique entity with very poor prognosis, irrespective of whether the blast percentage indicates MDS or AML or whether the disease is therapy related or de novo in its ontogeny (Blood Adv 2022;6:2847)

• TP53 suppressor gene is mutated in about half of human tumors (Nat Med 2020;26:1549)
• TP53 gene encodes for the p53 protein, which plays a crucial role in regulating various cellular processes, such as the cell cycle and cell death, which is usually triggered by oxidative stress (WHO 5); thus, the inactivation of p53 allows tumor initiation and its evasion from cell death (Nat Rev Cancer 2018;18:89)
• It is hypothesized that monoallelic TP53 inactivation may contain biallelic TP53 inactivation subclones that can negatively affect disease outcomes, as patients with single TP53 and VAF of > 23% have similar outcomes to biallelic TP53 patients
  • In addition, biallelic inactivation can be also formed from subclonal TP53 mosaicism (Res Sq 2023 Mar 9 [Preprint])
• Patients with TP53 mutations were found to have fewer comutated genes; however, they more commonly exhibit del(5q) chromosomal abnormality, monosomal karyotype and complex karyotype (Leukemia 2019;33:1747)
• Neurofibromin 1 (NF1), which is a negative regulator of Ras signaling, and del(12p), which includes ETV6, were found to be prevalent in TP53 inactivation AML / MDS cases (Blood Adv 2023;7:4586)
• TP53 mutated MN represents a unique entity with very poor prognosis, irrespective of whether the blast percentage indicates MDS or AML or whether the disease is therapy related or de novo in its ontogeny (Blood Adv 2022;6:2847)
  • Current assignment of these cases into MDS, AML with myelodysplasia related changes (AML MRC) or therapy related myeloid neoplasms (t-MN) appears to divide a biologically similar disease into different diagnostic groups
• TP53 mutations play an important role in the pathogenesis of many cases of t-AML / t-MDS (Nature 2015;518:552)
  • Loss of TP53 provides a selective advantage for neoplastic growth; TP53 mutations are resistant to chemotherapy and expand preferentially after treatment

WHO 4R	WHO 5th	ICC classification
Not an entity TP53 mutation is listed as a one of the common genetic mutations in MDS Prognostic impact is adverse Mutation should be correlated with morphological findings	MDS with biallelic TP53 inactivation Fulfilling diagnostic criteria of MDS 2 or more TP53 mutations or 1 mutation with TP53 copy number loss or cnLOH Myeloblasts < 20% bone marrow (BM) and peripheral blood (PB)	MDS with mutated TP53 Multihit TP53 Blasts 0 - 9% in BM / PB AML / MDS with mutated TP53 Any somatic TP53 mutation (VAF > 10%) Blasts 10 - 19% in BM / PB

ICC classification of MDS with mutated TP53
MDS with mutated TP53	AML / MDS with mutated TP53
Any cytopenia Blasts: 0 - 9% Genetics: multihit TP53, TP53 mutation (VAF > 10%) and complex karyotype often with loss 17p	Any cytopenia Blasts: 10 - 19% Genetics: any somatic TP53 mutation (VAF > 10%)

	WHO 5th edition, 2022	ICC 2022
Morphologically defined
Lineage	Subclassification using dysplastic lineages removed, replaced with MDS LB (MDS with low blasts)	MDS, NOS SLD MDS, NOS MLD
Excessive blast counts in bone marrow (5 - 9%) or in peripheral blood (2 - 4%)	MDS IB1	MDS EB (blast count 5 - 9% in bone marrow, 2 - 4% in peripheral blood)
Excessive blast counts in bone marrow (10 - 19%) or in peripheral blood (5 - 19%)	MDS IB2	MDS AML (blast count 10 - 19% in bone marrow and 2 - 4% in peripheral blood)
Others	cMDS (MDS of childhood) MDS-h (hypoplastic MDS) MDS-f (MDS with fibrosis, blasts 5 - 19% in bone marrow, 2 - 19% in peripheral blood)	MDS, NOS (without dysplasia)
Defining genetic abnormalities
SF3B1 mutation	MDS SF3B1 (MDS with low blasts and SF3B1 mutation or MDS with ring sideroblasts if SF3B1 wild type)	MDS SF3B1 (MDS with mutated SF3B1) or MDS, NOS (with ring sideroblasts and SF3B1 wild type)
del(5q)	MDS 5q (MDS with low blasts and 5q deletion) [5q deletion alone or with 1 other genetic aberration other than del(7q) / -7]	MDS with del(5q) [del(5q) is isolated or with up 1 genetic aberration except del(7q) / -7 or multihit TP53]
TP53	MDS biTP53 (MDS with biallelic TP53 inactivation)	MDS with mutated TP53 Multihit TP53 Includes MDS, MDS / AML, AML

• Factors associated with significant decrease in survival in MDS patients with TP53 mutations include (Leukemia 2019;33:1747)
  • Severe anemia (hemoglobin < 8.0 g/dL), NRAS mutation, SF3B1 mutation, TP53 mutation, elevated blast percentage (> 10%), abnormal 3q, abnormal 9 and monosomy 7 as having the greatest survival risk
• Monosomal karyotype, high complexity and TP53 mutation are individually associated with shorter overall survival (Leukemia 2019;33:1747)
• Type and abundance of TP53 mutation (VAF) in question may further refine its prognostic impact (Leukemia 2019;33:1747)
• TP53 mutant CK MDS patients also had significantly higher bone marrow blast proportion and lower platelet counts, 2 factors strongly associated with elevated prognostic risk considered by clinical scoring systems like the IPSS-R (Leukemia 2019;33:1747)
• Some studies have shown that the effect of TP53 on survival is significant in both TP53 monoallelic and TP53 multihit (Blood Adv 2022;6:2847)
  • No TP53 mutation (median: 33.9 months)
  • TP53 monoallelic (median: 12.5 months)
  • TP53 multihit (median: 9.4 months)
  • No significant influence of TP53 VAF as a continuous variable or using VAF cutoffs (Blood Adv 2022;6:2847)
• Some studies have shown that only MDS with TP53 multihit shows poor outcomes and response to therapy compared to MDS with TP53 monoallelic mutations (Nat Med 2020;26:1549)
  • Median OS in MDS TP53 multihit state was 8.7 months
  • Median OS in MDS TP53 monoallelic patients was 2.5 years
  • Median OS wild type patients was 3.5 years
  • Patients with monoallelic TP53 mutations and VAF > 22% (n = 38) had increased risk of death compared to wild type patients; monoallelic TP53 mutations and VAF ≤ 22% (n = 87) had OS similar to wild type patients

Contributed by Hatem Kaseb, M.D., Ph.D., M.P.H.

Which of the following is correct regarding myelodysplastic neoplasm (MDS) with TP53 inactivation / multihit?

1. Associated with 5q loss
2. Association with SF3B1 mutation is common
3. Favorable outcome among MDS types
4. Rarely transforms to acute myeloid leukemia
5. TP53 VAF > 49% supports the diagnosis

E. TP53 VAF > 49% supports the diagnosis. This is one of the criteria of MDS with multihit TP53 as laid out by WHO 5th edition. Answer C is incorrect because the disease is associated with unfavorable outcome. Answer D is incorrect because the patients usually progress to acute myeloid leukemia. Answer B is incorrect because the disease is not associated with SF3B1 mutation. Answer A is incorrect because the disease is not associated with 5q loss.

Comment Here

Reference: MDS with biallelic TP53 inactivation

Which of the following is correct regarding myelodysplastic neoplasm (MDS) with TP53 inactivation / multihit?

1. Blast count must be < 10% in bone marrow
2. Disease shows specific flow cytometry findings
3. Dysmegakaryopoiesis is the most common dysplastic finding
4. MDS TP53 monoallelic patients typically show similar prognosis to MDS TP53 multihit patients
5. Usually associated with complex karyotype

E. Usually associated with complex karyotype. MDS with multihit TP53 is commonly associated with complex karyotype and this association predicts an unfavorable prognosis. Answer B is incorrect because the disease does not show a specific flow cytometry finding. Answer C is incorrect because no distinct dysplasia in a certain lineage has been found to be common in this disease entity. Answer A is incorrect because the blast count must be < 19% in bone marrow. Answer D is incorrect because the majority of papers have shown that the prognosis of MDS TP53 multihit patients is worse than MDS TP53 monoallelic.

Comment Here

Reference: MDS with biallelic TP53 inactivation