Validation of the 5th edition of the World Health Organization and International Consensus Classification guidelines for TP53-mutated myeloid neoplasm in an independent international cohort
Abstract The World Health Organization (WHO-5) and International Consensus Classification (ICC) acknowledge the poor prognosis of TP53-mutated (TP53 mut) myeloid neoplasm (MN). However, there are substantial differences between the two classifications that may lead to under- or overestimation of the...
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2025-05-01
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| Series: | Blood Cancer Journal |
| Online Access: | https://doi.org/10.1038/s41408-025-01290-0 |
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| author | Mithun Vinod Shah Kevin Hung Anmol Baranwal Gauri Wechalekar Aref Al-Kali Carla R. Toop Patricia Greipp Monika M. Kutyna Aasiya Matin Dariusz Ladon Antoine Saliba Dong Chen Kebede Begna Anna Brown Danielle Rud Mark R. Litzow William J. Hogan Peter Bardy Talha Badar Sharad Kumar David T. Yeung Mrinal M. Patnaik James M. Foran Rong He Naseema Gangat Mehrdad Hefazi Hamish S. Scott Cecilia Y. Arana Yi Hassan Alkhateeb Abhishek A. Mangaonkar Daniel Thomas Christopher N. Hahn Attilio Orazi Daniel A. Arber Chung Hoow Kok Ayalew Tefferi Devendra Hiwase |
| author_facet | Mithun Vinod Shah Kevin Hung Anmol Baranwal Gauri Wechalekar Aref Al-Kali Carla R. Toop Patricia Greipp Monika M. Kutyna Aasiya Matin Dariusz Ladon Antoine Saliba Dong Chen Kebede Begna Anna Brown Danielle Rud Mark R. Litzow William J. Hogan Peter Bardy Talha Badar Sharad Kumar David T. Yeung Mrinal M. Patnaik James M. Foran Rong He Naseema Gangat Mehrdad Hefazi Hamish S. Scott Cecilia Y. Arana Yi Hassan Alkhateeb Abhishek A. Mangaonkar Daniel Thomas Christopher N. Hahn Attilio Orazi Daniel A. Arber Chung Hoow Kok Ayalew Tefferi Devendra Hiwase |
| author_sort | Mithun Vinod Shah |
| collection | DOAJ |
| description | Abstract The World Health Organization (WHO-5) and International Consensus Classification (ICC) acknowledge the poor prognosis of TP53-mutated (TP53 mut) myeloid neoplasm (MN). However, there are substantial differences between the two classifications that may lead to under- or overestimation of the prognostic risk. We retrospectively applied WHO-5 and ICC to 603 MN cases harboring TP53 mut (variant allele frequency, VAF ≥ 2%). WHO-5 and ICC would not classify 64% and 20% of these cases as TP53 mut MN, respectively. Moreover, of those classified, 67.5% would be classified discrepantly. Primary drivers of discrepancies included: (i) prognostic importance of TP53 mut acute myeloid leukemia (AML), (ii) interaction of the blast percentage and allelic status, (iii) 17p.13.1 deletion detected by cytogenetics, (iv) complex karyotype (CK) as multi-hit equivalent, and (v) TP53 mut VAF threshold, we analyzed survival outcomes of each of these groups with an aim to provide clarity. TP53 mut AML was associated with significantly poor survival compared to TP53-wild type TP53 wt AML, myelodysplasia-related (AML, MR 4.7 vs. 18.3 months; P < 0.0001), supporting its inclusion within TP53 mut MN as a distinct subentity. Secondly, the survival of TP53 mut with blast 10–19% was poor regardless of the allelic status. Thirdly, for cases with a single TP53 mut with VAF < 50%, 17p13.1 del or CK serve as practical surrogates of biallelic inactivation, obviating the need for an additional copy number analysis. Finally, TP53 mut AML, MDS multi-hit/multi-hit equivalent with VAF < 10% had significantly poorer survival compared to TP53 mut MDS VAF < 10% without CK and 17p del, and were comparable to those with VAF ≥ 10% (14.1 vs. 48.8 vs.7.8 months, P < 0.0001). Collectively, these findings address key areas of contention and provide valuable insights that will guide future revisions of the WHO and ICC classifications. |
| format | Article |
| id | doaj-art-bbabb2b74b3c4651a79a6cdbdd972397 |
| institution | Kabale University |
| issn | 2044-5385 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Blood Cancer Journal |
| spelling | doaj-art-bbabb2b74b3c4651a79a6cdbdd9723972025-08-20T03:53:08ZengNature Publishing GroupBlood Cancer Journal2044-53852025-05-0115111110.1038/s41408-025-01290-0Validation of the 5th edition of the World Health Organization and International Consensus Classification guidelines for TP53-mutated myeloid neoplasm in an independent international cohortMithun Vinod Shah0Kevin Hung1Anmol Baranwal2Gauri Wechalekar3Aref Al-Kali4Carla R. Toop5Patricia Greipp6Monika M. Kutyna7Aasiya Matin8Dariusz Ladon9Antoine Saliba10Dong Chen11Kebede Begna12Anna Brown13Danielle Rud14Mark R. Litzow15William J. Hogan16Peter Bardy17Talha Badar18Sharad Kumar19David T. Yeung20Mrinal M. Patnaik21James M. Foran22Rong He23Naseema Gangat24Mehrdad Hefazi25Hamish S. Scott26Cecilia Y. Arana Yi27Hassan Alkhateeb28Abhishek A. Mangaonkar29Daniel Thomas30Christopher N. Hahn31Attilio Orazi32Daniel A. Arber33Chung Hoow Kok34Ayalew Tefferi35Devendra Hiwase36Division of Hematology, Mayo ClinicDepartment of Haematology, Royal Adelaide Hospital, Central Adelaide Local Health NetworkDivision of Hematology, Mayo ClinicDepartment of Haematology, Royal Adelaide Hospital, Central Adelaide Local Health NetworkDivision of Hematology, Mayo ClinicDepartment of Haematology, Royal Adelaide Hospital, Central Adelaide Local Health NetworkLaboratory Medicine and Pathology, Mayo ClinicDepartment of Haematology, Royal Adelaide Hospital, Central Adelaide Local Health NetworkDivision of Hematology, Mayo ClinicGenetic and Molecular Pathology, SA PathologyDivision of Hematology, Mayo ClinicDivision of Hematopathology, Mayo ClinicDivision of Hematology, Mayo ClinicGenetic and Molecular Pathology, SA PathologyDivision of Hematology, Mayo ClinicDivision of Hematology, Mayo ClinicDivision of Hematology, Mayo ClinicDepartment of Haematology, Royal Adelaide Hospital, Central Adelaide Local Health NetworkDepartment of Hematology/Oncology, Mayo ClinicCentre for Cancer Biology, University of South Australia and SA PathologyDepartment of Haematology, Royal Adelaide Hospital, Central Adelaide Local Health NetworkDivision of Hematology, Mayo ClinicDepartment of Hematology/Oncology, Mayo ClinicDivision of Hematology, Mayo ClinicDivision of Hematology, Mayo ClinicDivision of Hematology, Mayo ClinicGenetic and Molecular Pathology, SA PathologyHematology/Oncology, Mayo ClinicDivision of Hematology, Mayo ClinicDivision of Hematology, Mayo ClinicDepartment of Haematology, Royal Adelaide Hospital, Central Adelaide Local Health NetworkGenetic and Molecular Pathology, SA PathologyTexas Tech University Health Sciences CenterUniversity of ChicagoAdelaide Medical School, University of AdelaideDivision of Hematology, Mayo ClinicDepartment of Haematology, Royal Adelaide Hospital, Central Adelaide Local Health NetworkAbstract The World Health Organization (WHO-5) and International Consensus Classification (ICC) acknowledge the poor prognosis of TP53-mutated (TP53 mut) myeloid neoplasm (MN). However, there are substantial differences between the two classifications that may lead to under- or overestimation of the prognostic risk. We retrospectively applied WHO-5 and ICC to 603 MN cases harboring TP53 mut (variant allele frequency, VAF ≥ 2%). WHO-5 and ICC would not classify 64% and 20% of these cases as TP53 mut MN, respectively. Moreover, of those classified, 67.5% would be classified discrepantly. Primary drivers of discrepancies included: (i) prognostic importance of TP53 mut acute myeloid leukemia (AML), (ii) interaction of the blast percentage and allelic status, (iii) 17p.13.1 deletion detected by cytogenetics, (iv) complex karyotype (CK) as multi-hit equivalent, and (v) TP53 mut VAF threshold, we analyzed survival outcomes of each of these groups with an aim to provide clarity. TP53 mut AML was associated with significantly poor survival compared to TP53-wild type TP53 wt AML, myelodysplasia-related (AML, MR 4.7 vs. 18.3 months; P < 0.0001), supporting its inclusion within TP53 mut MN as a distinct subentity. Secondly, the survival of TP53 mut with blast 10–19% was poor regardless of the allelic status. Thirdly, for cases with a single TP53 mut with VAF < 50%, 17p13.1 del or CK serve as practical surrogates of biallelic inactivation, obviating the need for an additional copy number analysis. Finally, TP53 mut AML, MDS multi-hit/multi-hit equivalent with VAF < 10% had significantly poorer survival compared to TP53 mut MDS VAF < 10% without CK and 17p del, and were comparable to those with VAF ≥ 10% (14.1 vs. 48.8 vs.7.8 months, P < 0.0001). Collectively, these findings address key areas of contention and provide valuable insights that will guide future revisions of the WHO and ICC classifications.https://doi.org/10.1038/s41408-025-01290-0 |
| spellingShingle | Mithun Vinod Shah Kevin Hung Anmol Baranwal Gauri Wechalekar Aref Al-Kali Carla R. Toop Patricia Greipp Monika M. Kutyna Aasiya Matin Dariusz Ladon Antoine Saliba Dong Chen Kebede Begna Anna Brown Danielle Rud Mark R. Litzow William J. Hogan Peter Bardy Talha Badar Sharad Kumar David T. Yeung Mrinal M. Patnaik James M. Foran Rong He Naseema Gangat Mehrdad Hefazi Hamish S. Scott Cecilia Y. Arana Yi Hassan Alkhateeb Abhishek A. Mangaonkar Daniel Thomas Christopher N. Hahn Attilio Orazi Daniel A. Arber Chung Hoow Kok Ayalew Tefferi Devendra Hiwase Validation of the 5th edition of the World Health Organization and International Consensus Classification guidelines for TP53-mutated myeloid neoplasm in an independent international cohort Blood Cancer Journal |
| title | Validation of the 5th edition of the World Health Organization and International Consensus Classification guidelines for TP53-mutated myeloid neoplasm in an independent international cohort |
| title_full | Validation of the 5th edition of the World Health Organization and International Consensus Classification guidelines for TP53-mutated myeloid neoplasm in an independent international cohort |
| title_fullStr | Validation of the 5th edition of the World Health Organization and International Consensus Classification guidelines for TP53-mutated myeloid neoplasm in an independent international cohort |
| title_full_unstemmed | Validation of the 5th edition of the World Health Organization and International Consensus Classification guidelines for TP53-mutated myeloid neoplasm in an independent international cohort |
| title_short | Validation of the 5th edition of the World Health Organization and International Consensus Classification guidelines for TP53-mutated myeloid neoplasm in an independent international cohort |
| title_sort | validation of the 5th edition of the world health organization and international consensus classification guidelines for tp53 mutated myeloid neoplasm in an independent international cohort |
| url | https://doi.org/10.1038/s41408-025-01290-0 |
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