Patients (pts) with AML presenting with CK, defined as a karyotype with ≥3 chromosome abnormalities other than reciprocal translocations or inversions, constitute 10-12% of all AML pts and have a very poor clinical outcome. CKs in AML are very heterogeneous with regard to the number of chromosome aberrations detected (varying from 3 to ~30 in rare cases) and the involvement of specific chromosomes in cytogenetic abnormalities. The most common are unbalanced abnormalities resulting in loss of material from the chromosome 5 long arm (5q; seen in ~80% of pts with CK), and from 7q (~50% of pts with CK) and the short arm of chromosome 17 (17p; ~50% of pts with CK). These abnormalities often occur together and ~85% of pts with CK harbor at least 1 of them. CKs with 5q, 7q and/or 17p abnormalities have been denoted as "typical" and those lacking these abnormalities as "atypical" CKs.
Since our knowledge of molecular features of CK-AML is relatively poor, we analyzed mutational status of 80 leukemia/cancer-associated genes using a customized targeted next-generation sequencing panel (Miseq) in a clinically well-characterized cohort of 136 AML pts with centrally reviewed CKs and material available for molecular analysis. The pts were treated on Cancer and Leukemia Group B/Alliance for Clinical Trials in Oncology clinical trials. Pts who did not receive allogeneic transplantation (n=113) were included in outcome analyses.
First, we compared pts with "atypical" (n=41) and "typical" (n=95) CKs, and found the former carried TP53 mutations less often (5% vs 52%; P <.001) and more frequently had mutations in PHF6 (15% vs 2%; P=.009), MED12 (7% vs 0%; P=.03), and FLT3 -TKD (10% vs 1%; P=.03). Clinically, pts with "atypical" CKs were younger (median age, 54 vs 58 y; P= .02), had higher white blood cell counts (23.8 vs 5.8 x 109/l; P <.001), % of bone marrow (BM; 77 vs 46; P <.001) and blood (62 vs 28 x 109/l; P=.004) blasts, higher complete remission (CR) rates (60% vs 33%; P=.01) and longer overall survival (OS; P <.001; Figure).
"Atypical" CKs can be further subdivided into CKs with exclusively or almost exclusively numerical abnormalities (n=15) and CKs with mostly structural rearrangements (n=26). Molecularly, pts with "numerical atypical" CKs had more mutations than pts with "structural atypical" CKs (median, 3 vs 2; P=.06), and were the only ones who had mutations in RUNX1 (27% vs 0%; P=.01), ASXL1 (20% vs 0%; P=.04), SRSF2 (20% vs 0%; P=.05), KRAS (14% vs 0%; P=.12) and STAG2 (13% vs 0%; P=.13). "Numerical atypical" CK pts had lower platelet counts (32 vs 69 x 109/l; P=.01), but there were no other significant clinical differences.
We also performed exploratory analyses of 7 subtypes of the "typical" CK present in 95 pts, which were delineated by various combinations of 5q, 7q and 17p abnormalities (i.e., all present, 5q and 7q, 5q and 17p, 5q only, 7q and 17p, 7q only and 17p only). Pts with 7q but not 5q or 17p abnormalities (n=12) differed molecularly and clinically from the remaining pts combined (n=83). They generally had more mutations (median, 3 vs 2; P=.03), carried less often TP53 mutations (17% vs 57%; P=.01), and more often FLT3- ITD (25% vs 2%; P=.01), and mutations in BCOR (25% vs 2%; P=.01), NPM1 (18% vs 0%; P=.01), WT1 (17% vs 0%; P=.01) and DNMT3A (33% vs 7%; P=.02). Moreover, pts with 7q but not 5q or 17p abnormalities had lower platelet counts (34 vs 56 x 109/l; P=.03) and higher % of BM blasts (59 vs 44; P=.02), and longer OS (P=.002) than other "typical" CK-AML pts.
We conclude that 1) compared to pts with "typical" CK, those with "atypical" CK harbor TP53 mutations significantly less frequently and PHF6 and MED12 mutations and FLT3 -TKD more often, have better CR rates and longer OS, and thus might be considered as a separate entity; 2) within the "atypical" CK category, pts with CK with numerical abnormalities are clinically similar to pts with CK with mostly structural abnormalities, but generally harbor more mutations, which include mutations in RUNX1, ASXL1, SRSF2, KRAS and STAG2 that are not detected at all in pts with "atypical" CK with mostly structural abnormalities; 3) among pts with "typical" CK, those with CK with abnormalities of 7q but not of 5q or 17p carried more mutations, had TP53 mutations less often and more frequently FLT3 -ITD, BCOR, NPM1, WT1 and DNMT3A mutations, and had longer OS than other pts with "typical" CK; 4) application of next-generation sequencing substantially increased our understanding of molecular heterogeneity of CK-AML.
Uy: GlycoMimetics: Consultancy; Novartis: Consultancy, Other: Travel Suppport; Boehringer Ingelheim: Consultancy. Blum: Astellas: Consultancy; Pfizer: Consultancy; Boerhinger Ingelheim: Research Funding. Stone: Ono: Consultancy; Jazz: Consultancy; Pfizer: Consultancy; Abbvie: Consultancy; Agios: Consultancy; Novartis: Consultancy; Celgene: Consultancy; Fuji Film: Consultancy; Sumitomo: Consultancy; Astellas: Consultancy; Arog: Consultancy; Amgen: Consultancy. Byrd: The Ohio State University: Patents & Royalties: OSU-2S; Pharmacyclics: Research Funding; Acerta Pharma: Research Funding; Janssen: Research Funding; Genentech: Research Funding.
Asterisk with author names denotes non-ASH members.