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 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.

Figure 1.

Peripheral Blood and bone marrow morphologic features of MDS/MPN-U with and without isolated i(17q). Top panel: Representative images of typical BM morphological features of MDS/MPN-U with i(17q) [top panel] showing frequent pseudo-Pelger Huet neutrophils on bone marrow aspirate smear (A) and peripheral blood (B) smears with frequent dysplastic small hypolobated megakaryocytes (C, biopsy; inset: aspirate smear). Bottom panel: In contrast, cases of MDS/MPN-U without isolated i(17q) showed dysgranulopoiesis of all types such as hypogranulation of cytoplasm and neutrophilic nuclear hyperlobulation on bone marrow aspirate smear (D) and peripheral blood (E) smears. Megakaryocytic dysplasia was less frequent (F).

Figure 2.

Mutational landscape. Cases of MDS/MPN-U with isolated i(17q) shows significantly higher frequency of mutations in SETBP1 and SRSF2 compared to cases of MDS/MPN-U without i(17q). There were no significant differences in mutational frequencies in other genes such as ASXL1 and TET2. TP53 mutations were rare. Cases of MDS/MPN-U with clonal mutations in one of the MPN-associated genes that included JAK2, CALR and MPL were excluded.

Figure 3.

Differences in mutational frequencies (single and combination of gene mutations) between MDS/MPN-U with i(17q) and other specific WHO-defined subgroups of MDS/MPN show similarities and differences. The significant differences are highlighted in color (P value represented using different colors).

Figure 4.

Overall survival analysis. A. Kaplan-Meier curve showing significantly different overall survival of myelodysplastic/ myeloproliferative neoplasms with and without isolated i(17q). B. Multivariable analysis demonstrating that both i(17q) [HR: 1.3; P = 0.026] and splenomegaly [HR: 1.94; P = 0.001] retained independent predictive value for overall survival.