Prognostic significance of hyperdiploidy in adult acute myeloid leukemia
Authors: Yasmin Abaza, Jorge Cortes, Farhad Ravandi, Tapan Kadia, Guillermo Garcia‐Manero, Naveen Pemmaraju, Aditya Shetty, Sherry Pierce, Wei Qiao, Hagop M. Kantarjian, Gautam Borthakur
Journal: American Journal of Hematology (2018)

Cytogenetic analysis is essential in the risk stratification of patients with acute myeloid leukemia (AML). Complex karyotype (CK), defined as 3-5 unrelated chromosomal abnormalities, is present in about 10% to 14% of AML patients and is associated with poor prognosis.1 Hyperdiploid karyotype (HK) is an infrequent finding in AML (<2%).2 While typically classified under CK with unfavorable prognosis, the clinical characteristics and outcomes of this group of patients needs further elucidation. The purpose of this study was to evaluate the clinical characteristics, cytogenetic features, and outcomes of newly diagnosed AML patients with HK treated at our institution. Newly diagnosed AML patients treated at our institution from 2003 to 2013 were reviewed. Patients with acute promyelocytic leukemia [APL; t(15;17) (q21;q21)] and core-binding factor AML [CBF-AML; t(8;21) (q22;q22), inv (16) (p13q22), and t(16;16) (p13;q22)] were excluded. Approval was obtained from the University of Texas MD Anderson Cancer Center's institutional review board. Primary objective of the study was to determine the prognostic impact of hyperdiploidy independent from CK. We investigated the clinical, cytogenetic, and molecular characteristics, and outcomes [response rates, complete remission duration (CRD), and overall survival (OS)] of AML patients with HK when compared with patients with diploid, non-HK complex, and trisomy karyotypes. HK was defined as ≥49 chromosomes in ≥2 metaphases while CK was defined as ≥3 chromosomal abnormalities, excluding hyperdiploidy, detected in ≥2 metaphases.2, 3 The HK cohort was subclassified into those with and without adverse cytogenetic abnormalities [deletions of 5q and 7q, abnormalities of 3q or 17p, monosomies of chromosome 5 and 7, t(9;22)(q34;q11), and MLL translocations]. Cytogenetic analysis was performed using G-banding and findings described according to the International Society of Cytogenetic Nomenclature (ISCN).4 Sequencing data was obtained at the time of pretreatment evaluation. FLT3 mutations were assessed using genomic DNA extracted from the bone marrow (BM) aspirate specimens by polymerase chain reaction (PCR) assays followed by capillary electrophoresis, while mutations in NRAS, KRAS, JAK2, and NPM1 were assessed by PCR analysis followed by pyrosequencing. Response were assessed using the 2003 International Working Group Response Criteria.5 Differences in the distribution of variables among subgroups were analyzed using Wilcoxon's rank sum and Fisher's exact tests. OS was calculated from the start of therapy until death or last follow-up. CRD was measured from date of CR until relapse, death, or last follow-up; death in CR was a censored event. OS and CRD were calculated using Kaplan-Meier method and compared using the log-rank test. Cox proportional hazards regression model was used to evaluate the significance of HK on OS. Of the 1312 patients with AML (excluding APL and CBF-AML) treated at our institution, 1261 had cytogenetic data upon presentation. Patients with single autosomal monosomies (N = 28), diploid with structural abnormalities (N = 193), and noncomplex monosomal karyotype (N = 32) were excluded. Of the remaining 1008 patients, 88 (8.7%) had HK (Table 1). Median age for HK patients was 67 years (range, 18-88) with male predominance. Median WBC count and BM blast percentage among HK patients were 2.35 (range, 0.4-119) and 41 (range, 4-98), respectively. Similar to patients with CK, there was a higher rate of therapy-related AML among patients with HK and adverse cytogenetics (28% vs. 21%, respectively) compared with the remaining cohorts (P < .01). .05 Among the 88 patients with HK, 61 (69%) had a modal number from 49 to 65 chromosomes, 10 (11%) had 66 to 89 chromosomes, and 17 (19%) had ≥90 chromosomes (Supporting Information Figure 1A). The most frequently gained chromosomes were chromosomes 8 (49%), 21 (31%), and 22 (30%). However, chromosomes 7 (6%), 16 (3%), and 17 (2%) were the least likely to be gained. Autosomal monosomies were observed in 54 patients (61%), 4/27 (15%) in the group without adverse cytogenetics and 50/61(82%) in the adverse cytogenetics subgroup, with chromosomes 7 (31%) and 5 (23%) being the most frequently lost chromosomes (Supporting Information Figure 1B). Sixty-one patients (69%) with HK had adverse cytogenetics including −5/del(5q) (79%), −7/del7q (59%), MLL translocations (5%), abnormalities of 3q (5%), and abnormalities of 17p (23%). Mutational gene analysis was performed with the following detected; FLT3-ITD and FLT3-D835 mutations detected in 151 (16%) and 49 (5%) out of 952 patients, respectively; NPM1 mutation in 142 out of 625 (23%); RAS mutations in 87 out of 878 (10%); and JAK2 mutation in 18 out of 188 patients (10%). FLT3-ITD and NPM1 mutations were more frequently detected in patients with diploid cytogenetics compared with patients with HK, complex, and trisomy karyotypes (P < .01). JAK2 mutation was significantly higher among patients with CK and HK with adverse cytogenetics compared with the remaining subgroups (P = .04). Forty-one percent of patients with HK achieved CR or CR with incomplete count recovery (CRi) with a median CR duration of 8.7 months (range, 5-18.7); similar to patients with CK (46%) and significantly worse compared with the diploid and trisomy subgroups (Supporting Information Figure 2A; P < .01). This translated into an inferior OS for patients with HK with a median OS of 8.7 months (range, 5.6-11.5) (Supporting Information Figure 2B). Allogeneic SCT had a favorable impact on OS among patients with HK with the median OS improving from 5.6 months in nontransplant patients to 14.5 months among transplant recipients (Supporting Information Figure 2G, P < .001). This survival advantage may be attributed to the younger age, lower rate of secondary AML, and higher CR rate in transplant vs. nontransplant recipients (Supporting Information Table 1). In multivariate analysis adjusting for age, WBC count, platelet count, LDH level, hemoglobin, BM blast percentage, and de novo/secondary leukemia, HK was found to be independently associated with reduced OS among AML patients [hazard ratio: 1.6, 95% CI: 1.28-2.03; P < .01]. Upon further stratification, patients with HK and adverse cytogenetics had the worst outcomes, including response rate, CRD, and OS (Table 1; Supporting Information Figure 2C,D). OS for patients with HK and adverse cytogenetics remained inferior even when compared with patients with CK with and without adverse cytogenetic abnormalities (Supporting Information Figure 2E, P = .007). Furthermore, we stratified patients with HK into those with high hyperdiploidy (HH; 49-65 chromosomes) and triploid/tetraploid (TT; >65 chromosomes) karyotypes. Baseline characteristics were comparable between both groups except for the higher rate of secondary AML among patients with HH (Supporting Information Table 2). There was a trend towards inferior OS for patients with TT compared with HH; however, the difference was not statistically significant (Supporting Information Figure 2F; 6.2 vs. 8.7 months; P = .06). Consistent with the previous reports, patients with HK and adverse cytogenetics had significantly inferior outcomes compared with the remaining HK patients.2, 3, 6 Interestingly, despite the presence of adverse cytogenetic abnormalities in both cohorts, patients with HK and adverse cytogenetics had worse OS compared with patients with CK plus adverse cytogenetics suggesting the need to recognize this small subset of HK patients with dismal prognosis. Unlike Lazarevic et al., patients with TT had a trend towards inferior OS compared with patients with HH.6 In the studies conducted by both Chilton and Luquet et al.2, 3 the subgroup of HK patients who had pure numerical changes had significantly better outcomes compared with those with adverse cytogenetics suggesting the need to reclassify the former subgroup of HK patients to the intermediate risk group rather than assigning all HK patients to the adverse risk category. In our study, only 7 patients (8%) had pure numerical changes hindering our ability to draw similar conclusions. Given the prognostic heterogeneity within HK, only patients with adverse cytogenetic abnormalities should be assigned to the adverse risk group. Despite being a retrospective study, our results suggest that patients with HK without adverse cytogenetics have a more favorable outcome compared with both CK and HK with adverse aberrations, consistent with the previous studies.3, 6 These results also suggest that the subset of patients with HK AML without adverse cytogenetics may be better classified into the intermediate risk group; however, larger prospective studies are needed to confirm these results. None. The authors disclose no relevant conflicts related to this article. Conception and design: Yasmin Abaza and Gautam Borthakur. Provision of study materials or patients: Jorge Cortes, Farhad Ravandi, Tapan Kadia, Guillermo Garcia-Manero, Naveen Pemmaraju, Sherry Pierce, Hagop M. Kantarjian, and Gautam Borthakur. Collection and assembly of data: Yasmin Abaza, Aditya Shetty, Sherry Pierce, and Wei Qiao. Data analysis and interpretation: Yasmin Abaza, Aditya Shetty, Wei Qiao, and Gautam Borthakur. Manuscript writing: Yasmin Abaza and Gautam Borthakur. Final approval of manuscript: All authors reviewed and approved the manuscript. Supplemental Table 1. Clinical Characteristics of Transplant versus Non-Transplant Recipients with Hyperdiploid Karyotypes Supplemental Table 2. Clinical Characteristics of Patients with High Hyperdiploid Karyotype Compared to Triploid/Tetraploid Karyotypes Supplemental Figure 1. Cytogenetic characteristics of acute myeloid leukemia patients with hyperdiploid karyotype. (A) Modal number of chromosomes among patients with hyperdiploid karyotype. (B) Pattern of chromosomal loss and gain among patients with hyperdiploid acute myeloid leukemia Supplemental Figure 2. Outcomes of acute myeloid leukemia patients stratified by karyotype. (A) Complete remission duration (CRD) of all patients with hyperdiploid karyotype (HK) compared to the remaining cytogenetic groups. (B) Overall Survival (OS) of all patients with HK compared to the remaining cytogenetic groups. (C) CRD of patients with HK stratified by adverse cytogenetic abnormalities (D) OS of patients with HK stratified by adverse cytogenetic abnormalities. (E) OS of patient with CK and HK stratified by adverse cytogenetic abnormalities (F) OS of patients with high hyperdiploidy compared to triploid/tetraploid karyotypes (G) OS of HK patients stratified by stem cell transplant status. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.