<i>TP53</i>mutation in therapy-related myeloid neoplasm defines a distinct molecular subtype

Hiwase, Devendra; Hahn, Christopher N.; Tran, Elizabeth Ngoc Hoa; Chhetri, Rakchha; Baranwal, Anmol; Al‐Kali, Aref; Sharplin, Kirsty; Ladon, Dariusz; Hollins, Rachel; Greipp, Patricia T.; Kutyna, Monika M; Alkhateeb, Hassan B.; Badar, Talha; Wang, Paul Po-Shen; Ross, David M.; Singhal, Deepak; Shanmuganathan, Naranie; Bardy, Peter; Beligaswatte, Ashanka; Yeung, David T.; Litzow, Mark R.; Mangaonkar, Abhishek A.; Giri, Pratyush; Lee, Cindy H.; Yong, Angelina; Horvath, Noemi; Singhal, Nimit; Gowda, Raghu; Gangat, Naseema; Patnaik, Mrinal M.; Begna, Kebede H.; Wei, Andrew H.; Kumar, Sharad; Brown, Anna L.; Scott, Hamish S.; Thomas, Daniel; Kok, Chung Hoow; Tefferi, Ayalew; Shah, Mithun Vinod

doi:10.1182/blood.2022018236

Cited by 13 publications

(16 citation statements)

References 7 publications

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“…Consistent with our previous observation [ 20 ], the OS was not significantly different between the single- and multi-hit TP53 mut t-MN (Fig. 2J ).…”

Section: Resultssupporting

confidence: 93%

“…Furthermore, in MDS and AML with CK, the single- or multi-hit TP53 mut was the only disease-related factor predicting survival [ 14 ]. We recently demonstrated that TP53 mut t-MN is associated with poor survival irrespective of single or multi-hit status [ 20 ], suggesting that the prognostic impact of allelic loss of TP53 mut MN is context dependent.…”

Section: Introductionmentioning

confidence: 99%

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TP53 mutation variant allele frequency of ≥10% is associated with poor prognosis in therapy-related myeloid neoplasms

et al. 2023

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Revised diagnostic criteria for myeloid neoplasms (MN) issued by the International Consensus Classification (ICC) and the World Health Organization (WHO) recommended major change pertaining to TP53-mutated (TP53mut) MN. However, these assertions have not been specifically examined in therapy-related myeloid neoplasm (t-MN), a subset enriched with TP53mut. We analyzed 488 t-MN patients for TP53mut. At least one TP53mut with variant allele frequency (VAF) ≥ 2% with or without loss of TP53 locus was noted in 182 (37.3%) patients and 88.2% of TP53mut t-MN had a VAF ≥10%. TP53mut t-MN with VAF ≥ 10% had a distinct clinical and biological profile compared to both TP53mut VAF < 10% and wild-type TP53 (TP53wt) cases. Notably, TP53mut VAF ≥ 10% had a significantly shorter survival compared to TP53wt (8.3 vs. 21.6 months; P < 0.001), while the survival of TP53mut VAF < 10% was comparable to TP53wt. Within TP53mut VAF ≥ 10% cohort, the inferior outcomes persisted irrespective of the single- or multi-hit status, co-mutation pattern, or treatments received. Finally, survival of TP53mut patients was poor across all the blast categories and MDS patients with >10% blasts had inferior survival compared to <5%. In summary, TP53mut VAF ≥10% signified a clinically and molecularly homogenous cohort regardless of the allelic status.

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“…Consistent with our previous observation [ 20 ], the OS was not significantly different between the single- and multi-hit TP53 mut t-MN (Fig. 2J ).…”

Section: Resultssupporting

confidence: 93%

Section: Introductionmentioning

confidence: 99%

TP53 mutation variant allele frequency of ≥10% is associated with poor prognosis in therapy-related myeloid neoplasms

et al. 2023

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“…However, the mechanism for the relative preponderence of TP53 mutations in MDS‐del(5q), which by definition requires the absence of complex karyotype, remains obscure; the possibility of a contributory role from therapy‐related disease is suggested, in the current study, by the non‐significantly higher frequency of TP53 mutation in therapy‐related disease (30% vs. 19%), as was the case for TP53 VAF ≥22% (Table 1). In the latter scenario regard, we have previously shown that TP53 mutation with ≥10% VAF was prognostically detrimental in therapy‐related myeloid neoplasms, regardless of allelic state or BM blast count 16 ; in the particular study, TP53 mutation frequency was 37.3% in patients with <5% BM blast percentage vs. 38.1%–38.2% in those with 5%–19% blast percentage; furthermore, overall survival was similar between different blast categories of MDS harbouring <20% BM blast percentage.…”

Section: Discussionmentioning

confidence: 97%

TP53 variant allele frequency and therapy‐related setting independently predict survival in myelodysplastic syndromes with del(5q)

Tefferi,

Fleti,

Chan

et al. 2023

Br J Haematol

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SummaryAmong 210 patients with myelodysplastic syndromes (MDSs) with del(5q), molecular information was available at diagnosis or at least 3 months before leukaemic transformation in 146 cases. Multivariate analysis identified therapy‐related setting (p = 0.02; HR 2.3) and TP53 variant allele frequency (VAF) ≥22% (p < 0.01; HR 2.8), but not SF3B1 mutation (p = 0.65), as independent risk factors for survival. Median survival was 11.7 versus 4 years (5/10‐year survival 73%/52% vs. 42%/14%) in the absence (N = 112) versus presence (N = 34) of ≥1 risk factors; leukaemia‐free survival was affected by TP53 VAF ≥22% (p < 0.01). Such information might inform treatment decision‐making in MDS‐del(5q) regarding allogeneic stem cell transplant.

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“…Concerning general characteristics and genetic features of t‐AML patients, as others, we reported more frequent abnormal karyotypes compared to de novo AML 2,15,17,18,45,46 and no difference in the incidence and distribution of mutated NPM1 and FLT3‐ITD between t‐AML and de novo AML 47 . TP53 mutations or 17p abnormalities are frequently observed in t‐MNs and associated with complex karyotype, a reduced probability of achieving response after induction chemotherapy and a poor outcome, as shown by Lindsley et al 48 Nowadays, prognosis of TP53 mutated t‐AML, according to new AML classifications 26 must consider variant allelic frequency, single or multihit characteristic and presence of comutations 49 . Due to NGS nonavailability at the beginning of our study, we reported only few results of genomic assessment in 13 patients with 2 or more mutations and TP53 mutations in 46% co‐occurring, in half of them with chromosome 17 abnormalities.…”

Section: Discussionmentioning

confidence: 99%

Clinical outcome of therapy‐related acute myeloid leukemia patients. Real‐life experience in a University Hospital and a Cancer Center in France

Belhabri,

Heiblig,

Morisset

et al. 2023

Cancer Medicine

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Backgroundt‐AML occurs after a primary malignancy treatment and retains a poor prognosis.AimsTo determine the impact of primary malignancies, therapeutic strategies, and prognostic factors on clinical outcomes of t‐AML.ResultsA total of 112 adult patients were included in this study. Fifty‐Five patients received intensive chemotherapy (IC), 33 non‐IC, and 24 best supportive care. At t‐AML diagnosis, 42% and 44% of patients presented an unfavorable karyotype and unfavorable 2010 ELN risk profile, respectively. Among treated patients (n = 88), 43 (49%) achieved complete remission: four out of 33 (12%) and 39 out of 55 (71%) in non‐IC and IC groups, respectively. With a median follow‐up of 5.5 months, the median overall survival (OS) and disease‐free survival (DFS) for the whole population were 9 months and 6.3 months, respectively, and for the 88 treated patients 13.5 months and 8.2 months, respectively. Univariate analysis on OS and DFS showed a significant impact of high white blood cells (WBC) and blast counts at diagnosis, unfavorable karyotype and ELN classification. Multivariate analysis showed a negative impact of WBC count at diagnosis and a positive impact of chemotherapy on OS and DFS in the whole population. It also showed a negative impact of previous auto‐HCT and high WBC count on OS and DFS and of IC on OS in treated patients which disappeared when we considered only confounding variables (age, previous cancers, marrow blasts, and 2010 ELN classification). In a pair‐matched analysis comparing IC treated t‐AML with de novo AML, there was no difference of OS and DFS between the two populations.ConclusionWe showed, in this study that t‐AML patients with unfavorable features represented almost half of the population. Best outcomes obtained in patients receiving IC must be balanced by known confounding variables and should be improved by using new innovative agents and therapeutic strategies.

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TP53mutation in therapy-related myeloid neoplasm defines a distinct molecular subtype

Abstract: Key Points Not applicable Not applicable

Cited by 13 publications

References 7 publications

TP53 mutation variant allele frequency of ≥10% is associated with poor prognosis in therapy-related myeloid neoplasms

TP53 mutation variant allele frequency of ≥10% is associated with poor prognosis in therapy-related myeloid neoplasms

TP53 variant allele frequency and therapy‐related setting independently predict survival in myelodysplastic syndromes with del(5q)

Clinical outcome of therapy‐related acute myeloid leukemia patients. Real‐life experience in a University Hospital and a Cancer Center in France

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