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

Abstract

Classification of myeloid neoplasms with isolated 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 which 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.

High-resolution structural variant profiling of myelodysplastic syndromes by optical genome mapping uncovers cryptic aberrations of prognostic and therapeutic significance

“…All patients underwent BM aspiration and biopsy for diagnosis per 2016 WHO criteria [7] and standard-of-care testing in CLIA-certified laboratories that included targeted 81-gene NGS panel (Supplementary Table S1) [31][32][33][34][35][36], CBA by traditional G-banding and FISH/CMA (as needed) per standard protocols described elsewhere [37][38][39][40]. Additional FISH or CMA testing was performed to confirm most of the clinically significant OGM findings that were cryptic by CBA.…”

Myeloproliferative Neoplasms: Contemporary Review and Molecular Landscape

“…This is shown by the new provisional creation of a new sub-entity MDS/MPN with isolated isochromosome (17q) categorized under MDS/MPN NOS in the ICC classification [82], which has a unique preservation of the TP53 allele. These cases were found to have shorter medial overall survival [83]. Isochromosome 17q abnormalities do exist in MF/MPN as part of non-driver mutations and are of prognostic relevance but do not exist as a distinct clinicopathologic entity.…”

Atypical chronic myeloid leukemia and myelodysplastic/myeloproliferative neoplasm, not otherwise specified: 2023 update on diagnosis, risk stratification, and management

“…Compared to MDS/MPN‐NOS, MDS/MPN with i(17q) had a higher prevalence of splenomegaly and increased peripheral blood blasts. Somatic mutational profiling identified a high frequency of SETBP1 (69%), ASXL1 (67%), and SRSF2 (63%) mutations, with SETBP1 and SRSF2 mutations being statistically enriched in MDS/MPN with i(17q) 36 . Interestingly, only 1 patient had a somatic TP53 mutation with a VAF of 4.48%, indicating that in most cases these patients have monoallelic inactivation of TP53 .…”

“…BCR::ABL1 fusions and MLN-TK fusions must be excluded, along with MPN-associated driver mutations such as JAK2, MPL, and CALR (especially with variant allele fractions ≥25%). 36 Reactive causes of bone marrow overlap features, especially concomitant administration of growth factors, which must be factored in and serve as exclusionary criteria. The formation of i(17q) is associated with loss of 17p and loss of 1 TP53 allele at 17p13.1.…”