Myelodysplastic/myeloproliferative neoplasms-unclassifiable with isolated isochromosome 17q represents a distinct clinico-biologic subset: a multi-institutional collaborative study from the Bone Marrow Pathology Group.
Journal
Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc
ISSN: 1530-0285
Titre abrégé: Mod Pathol
Pays: United States
ID NLM: 8806605
Informations de publication
Date de publication:
04 2022
04 2022
Historique:
received:
24
06
2021
accepted:
14
10
2021
revised:
12
10
2021
pubmed:
15
11
2021
medline:
5
4
2022
entrez:
14
11
2021
Statut:
ppublish
Résumé
Classification of myeloid neoplasms with isolated isochromosome i(17q) [17p deletion with inherent monoallelic TP53 loss plus 17q duplication] is controversial. Most cases fall within the WHO unclassifiable myelodysplastic/myeloproliferative neoplasms (MDS/MPN-U) category. The uniformly dismal outcomes warrant better understanding of this entity. We undertook a multi-institutional retrospective study of 92 adult MDS/MPN-U cases from eight institutions. Twenty-nine (32%) patients had isolated i(17q) [MDS/MPN-i(17q)]. Compared to MDS/MPN without i(17q), MDS/MPN-i(17q) patients were significantly younger, had lower platelet and absolute neutrophil counts, and higher frequency of splenomegaly and circulating blasts. MDS/MPN-i(17q) cases showed frequent bilobed neutrophils (75% vs. 23%; P = 0.03), hypolobated megakaryocytes (62% vs. 20%; P = 0.06), and a higher frequency of SETBP1 (69% vs. 5%; P = 0.002) and SRSF2 (63% vs. 5%; P = 0.006) mutations that were frequently co-existent (44% vs. 0%; P = 0.01). TP53 mutations were rare. The mutation profile of MDS/MPN-U-i(17q) was similar to other myeloid neoplasms with i(17q) including atypical chronic myeloid leukemia, chronic myelomonocytic leukemia, myelodysplastic/myeloproliferative neoplasm with ring sideroblasts and thrombocytosis, myelodysplastic syndrome and acute myeloid leukemia, with frequent concomitant SETBP1/SRSF2 mutations observed across all the diagnostic entities. Over a median follow-up of 52 months, patients with MDS/MPN-i(17q) showed a shorter median overall survival (11 vs. 28 months; P < 0.001). The presence of i(17q) retained independent poor prognostic value in multivariable Cox-regression analysis [HR 3.686 (1.17-11.6); P = 0.026] along with splenomegaly. We suggest that MDS/MPN-i(17q) warrants recognition as a distinct subtype within the MDS/MPN-U category based on its unique clinico-biologic features and uniformly poor prognosis.
Identifiants
pubmed: 34775472
doi: 10.1038/s41379-021-00961-0
pii: S0893-3952(22)00291-5
pmc: PMC8967812
mid: NIHMS1748628
doi:
Substances chimiques
Biological Products
0
Types de publication
Journal Article
Multicenter Study
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
470-479Subventions
Organisme : NCI NIH HHS
ID : P30 CA015083
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA016672
Pays : United States
Commentaires et corrections
Type : ErratumIn
Informations de copyright
© 2021. The Author(s), under exclusive licence to United States & Canadian Academy of Pathology.
Références
Barbouti, A. et al. The breakpoint region of the most common isochromosome, i(17q), in human neoplasia is characterized by a complex genomic architecture with large, palindromic, low-copy repeats. Am. J. Hum. Genet. 74, 1–10 (2004).
doi: 10.1086/380648
Visconte, V. et al. Clinicopathologic and molecular characterization of myeloid neoplasms harboring isochromosome 17(q10). Am. J. Hematol. 89, 862 (2014).
doi: 10.1002/ajh.23755
Meggendorfer, M. et al. The landscape of myeloid neoplasms with isochromosome 17q discloses a specific mutation profile and is characterized by an accumulation of prognostically adverse molecular markers. Leukemia 30, 1624–1627 (2016).
doi: 10.1038/leu.2016.21
Kanagal-Shamanna, R. et al. Myeloid neoplasms with isolated isochromosome 17q demonstrate a high frequency of mutations in SETBP1, SRSF2, ASXL1 and NRAS. Oncotarget 7, 14251–14258 (2016).
doi: 10.18632/oncotarget.7350
McClure, R. F., Dewald, G. W., Hoyer, J. D. & Hanson, C. A. Isolated isochromosome 17q: a distinct type of mixed myeloproliferative disorder/myelodysplastic syndrome with an aggressive clinical course. Br. J. Haematol. 106, 445–454 (1999).
doi: 10.1046/j.1365-2141.1999.01537.x
Kanagal‐Shamanna, R. et al. Myeloid neoplasms with isolated isochromosome 17q represent a clinicopathologic entity associated with myelodysplastic/myeloproliferative features, a high risk of leukemic transformation, and wild‐type TP53. Cancer 118, 2879–2888 (2012).
doi: 10.1002/cncr.26537
Arber, D. A. et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood 127, 2391–2405 (2016).
doi: 10.1182/blood-2016-03-643544
Weinberg, O. K. et al. Reproducibility and prognostic significance of morphologic dysplasia in de novo acute myeloid leukemia. Mod. Pathol. 28, 965–976 (2015).
doi: 10.1038/modpathol.2015.55
Della Porta, M. G. et al. Minimal morphological criteria for defining bone marrow dysplasia: a basis for clinical implementation of WHO classification of myelodysplastic syndromes. Leukemia 29, 66–75 (2015).
doi: 10.1038/leu.2014.161
Thiele, J. et al. European consensus on grading bone marrow fibrosis and assessment of cellularity. Haematologica 90, 1128–1132 (2005).
pubmed: 16079113
Barosi, G. et al. Response criteria for myelofibrosis with myeloid metaplasia: results of an initiative of the European Myelofibrosis Network (EUMNET). Blood 106, 2849–2853 (2005).
doi: 10.1182/blood-2005-04-1520
Montalban-Bravo, G. et al. NPM1 mutations define a specific subgroup of MDS and MDS/MPN patients with favorable outcomes with intensive chemotherapy. Blood Adv. 3, 922–933 (2019).
doi: 10.1182/bloodadvances.2018026989
Wang, S. et al. Refractory anemia with ringed sideroblasts associated with marked thrombocytosis harbors JAK2 mutation and shows overlapping myeloproliferative and myelodysplastic features. Leukemia 20, 1641–1644 (2006).
doi: 10.1038/sj.leu.2404316
Cannella, L., Breccia, M., Latagliata, R., Frustaci, A. & Alimena, G. Clinical and prognostic features of patients with myelodysplastic/myeloproliferative syndrome categorized as unclassified (MDS/MPD-U) by WHO classification. Leuk. Res. 32, 514–516 (2007).
doi: 10.1016/j.leukres.2007.07.004
Malcovati, L. et al. Molecular and clinical features of refractory anemia with ringed sideroblasts associated with marked thrombocytosis. Blood 114, 3538–3545 (2009).
doi: 10.1182/blood-2009-05-222331
Jeromin, S. et al. High frequencies of SF3B1 and JAK2 mutations in refractory anemia with ring sideroblasts associated with marked thrombocytosis strengthen the assignment to the category of myelodysplastic/myeloproliferative neoplasms. Haematologica 98, e15–e17 (2013).
doi: 10.3324/haematol.2012.072538
Visconte, V. et al. SF3B1, a splicing factor is frequently mutated in refractory anemia with ring sideroblasts. Leukemia 26, 542–545 (2012).
doi: 10.1038/leu.2011.232
Jeromin, S. et al. Refractory anemia with ring sideroblasts and marked thrombocytosis cases harbor mutations in SF3B1 or other spliceosome genes accompanied by JAK2V617F and ASXL1 mutations. Haematologica 100, e125–e127 (2015).
doi: 10.3324/haematol.2014.119032
Patel, S. S. et al. Clinicopathologic and genetic characterization of nonacute NPM1-mutated myeloid neoplasms. Blood Adv. 3, 1540–1545 (2019).
doi: 10.1182/bloodadvances.2019000090
Geyer, J. T. et al. Oligomonocytic chronic myelomonocytic leukemia (chronic myelomonocytic leukemia without absolute monocytosis) displays a similar clinicopathologic and mutational profile to classical chronic myelomonocytic leukemia. Mod. Pathol. 30, 1213–1222 (2017).
doi: 10.1038/modpathol.2017.45
Valent, P. et al. Proposed diagnostic criteria for classical chronic myelomonocytic leukemia (CMML), CMML variants and pre-CMML conditions. Haematologica 104, 1935–1949 (2019).
doi: 10.3324/haematol.2019.222059
Montalban-Bravo, G. et al. Clinical outcomes and influence of mutation clonal dominance in oligomonocytic and classical chronic myelomonocytic leukemia. Am. J. Hematol. 96, E50–E53 (2021).
pubmed: 33156969
Calvo, X. et al. Oligomonocytic and overt chronic myelomonocytic leukemia show similar clinical, genomic, and immunophenotypic features. Blood Adv. 4, 5285–5296 (2020).
doi: 10.1182/bloodadvances.2020002206
Mangaonkar, A. A. et al. Clinicopathologic characteristics, prognostication and treatment outcomes for myelodysplastic/myeloproliferative neoplasm, unclassifiable (MDS/MPN-U): Mayo Clinic-Moffitt Cancer Center study of 135 consecutive patients. Leukemia 34, 656–661 (2020).
doi: 10.1038/s41375-019-0574-x
Shallis, R. M. & Zeidan, A. M. Myelodysplastic/myeloproliferative neoplasm, unclassifiable (MDS/MPN-U): more than just a “catch-all” term? Best Pract. Res. Clin. Haematol. 33, 101132 (2020).
Palomo, L. et al. Molecular landscape and clonal architecture of adult myelodysplastic/myeloproliferative neoplasms. Blood 136, 1851–1862 (2020).
doi: 10.1182/blood.2019004229
Meggendorfer, M. et al. Specific molecular mutation patterns delineate chronic neutrophilic leukemia, atypical chronic myeloid leukemia, and chronic myelomonocytic leukemia. Haematologica 99, e244–e246 (2014).
doi: 10.3324/haematol.2014.113159
Meggendorfer, M., Jeromin, S., Haferlach, C., Kern, W. & Haferlach, T. The mutational landscape of 18 investigated genes clearly separates four subtypes of myelodysplastic/myeloproliferative neoplasms. Haematologica 103, e192–e195 (2018).
doi: 10.3324/haematol.2017.183160
Zhang, H. et al. Genomic landscape of neutrophilic leukemias of ambiguous diagnosis. Blood 134, 867–879 (2019).
doi: 10.1182/blood.2019000611
Coltro, G. et al. Clinical, molecular, and prognostic correlates of number, type, and functional localization of TET2 mutations in chronic myelomonocytic leukemia (CMML)—a study of 1084 patients. Leukemia 34, 1407–1421 (2020).
doi: 10.1038/s41375-019-0690-7
Patnaik, M. et al. Prognostic interaction between ASXL1 and TET2 mutations in chronic myelomonocytic leukemia. Blood Cancer J. 6, e385–e385 (2016).
doi: 10.1038/bcj.2015.113
Patnaik, M. et al. Number and type of TET2 mutations in chronic myelomonocytic leukemia and their clinical relevance. Blood Cancer J. 6, e472–e472 (2016).
doi: 10.1038/bcj.2016.82
Piazza, R., et al. SETBP1 and CSF3R Mutations In Atypical Chronic Myeloid Leukemia (American Society of Hematology Washington, DC, 2013).
Meggendorfer, M. et al. SETBP1 mutations occur in 9% of MDS/MPN and in 4% of MPN cases and are strongly associated with atypical CML, monosomy 7, isochromosome i(17)(q10), ASXL1 and CBL mutations. Leukemia 27, 1852–1860 (2013).
doi: 10.1038/leu.2013.133
Faisal, M. et al. Comprehensive mutation profiling and mRNA expression analysis in atypical chronic myeloid leukemia in comparison with chronic myelomonocytic leukemia. Cancer Med. 8, 742–750 (2019).
doi: 10.1002/cam4.1946
Bose, P. et al. Mutational landscape of myelodysplastic/myeloproliferative neoplasm-unclassifiable. Blood 132, 2100–2103 (2018).
doi: 10.1182/blood-2018-05-848473
Al-Kali, A. et al. Hypomethylating agents (HMAs) effect on myelodysplastic/myeloproliferative neoplasm unclassifiable (MDS/MPN-U): single institution experience. Leuk. Lymphoma 59, 2737–2739 (2018).
doi: 10.1080/10428194.2018.1436705
Adema, V. et al. Correlation of myelodysplastic syndromes with i(17)(q10) and TP53 and SETBP1 mutations. Br. J. Haematol. 171, 137–141 (2015).
doi: 10.1111/bjh.13355
Bernard, E. et al. Implications of TP53 allelic state for genome stability, clinical presentation and outcomes in myelodysplastic syndromes. Nat. Med. 26, 1549–1556 (2020).
doi: 10.1038/s41591-020-1008-z
DiNardo, C. D. et al. Myelodysplastic/myeloproliferative neoplasms, unclassifiable (MDS/MPN, U): natural history and clinical outcome by treatment strategy. Leukemia 28, 958–961 (2014).
doi: 10.1038/leu.2014.8
Nguyen, N. et al. Interaction with XPO1 is essential for SETBP1 to induce myeloid transformation. Leukemia 33, 2758–2762 (2019).
doi: 10.1038/s41375-019-0521-x
Steensma, D. P. et al. Phase I First-in-Human Dose Escalation Study of the oral SF3B1 modulator H3B-8800 in myeloid neoplasms. Leukemia 25 (2021). https://doi.org/10.1038/s41375-021-01328-9 . Online ahead of print.