Genome-wide genotype-based risk model for survival in acute myeloid leukaemia patients with normal karyotype.

Single nucleotide polymorphisms (SNP) are inter-individual genetic variations that could explain inter-individual differences of response/survival to chemotherapy. The present study was performed to build up a risk model for survival in 247 patients with acute myeloid leukaemia (AML) with normal karyotype (AML-NK). Genome-wide Affymetrix SNP array 6.0 was used for genotyping in discovery set (n = 118). After identifying significant SNPs for overall survival (OS) in single SNP analysis, a risk model was constructed. Out of 632 957 autosomal SNPs analysed, finally four SNPs (rs2826063, rs12791420, rs11623492 and rs2575369) were introduced into the risk model. The model could stratify the patients according to their OS in discovery set (P = 1·053656 × 10−4). Replication was performed using Sequenom platform for genotyping in the validation cohort (n = 129). The model incorporated with clinical and four SNP risk score was successfully replicated in a validation set (P = 5·38206 × 10−3). The integration of four SNPs and clinical factors into the risk model showed higher area under the curve (AUC) reults than in the model incorporating only clinical or only four SNPs, suggesting improved prognostic stratification power by combination of four SNPs and clinical factors. In conclusion, a genome-wide SNP-based risk model in 247 patients with AML-NK can identify a group of high risk patients with poor survival.

Statins Enhance the Molecular Response in Chronic Myeloid Leukemia when Combined with Tyrosine Kinase Inhibitors.

Previous studies have suggested that statins can be repurposed for cancer treatment. However, the therapeutic efficacy of statins in chronic myeloid leukemia (CML) has not yet been demonstrated. In this study, we retrospectively evaluated the outcomes of 408 CML patients who underwent imatinib therapy. The deep molecular response rates in patients treated with the statin/TKI combination were significantly higher than those in patients treated with TKI alone (p = 0.0016). The statin/TKI combination exerted potent cytotoxic effects against wild-type and ABL1 mutant CML, BaF3, and K562/T315I mutant cells. Furthermore, the statin/TKI combination additively inhibited the colony-forming capacity of murine CML-KLS+ cells in vitro. In addition, we examined the additive growth-inhibitory effects of the statin/tyrosine kinase inhibitor (TKI) combination against CML patient-derived CD34+ cells. The growth-inhibitory effects of the statin/imatinib combination against CD34+/CML primary cells were higher than those against CD34+/Norm cells (p = 0.005), suggesting that the combination of rosuvastatin and imatinib exerted growth-inhibitory effects against CML CD34+ cells, but not against normal CD34+ cells. Furthermore, results from RNA sequencing of control and statin-treated cells suggested that statins inhibited c-Myc-mediated and hematopoietic cell differentiation pathways. Thus, statins can be potentially repurposed to improve treatment outcomes in CML patients when combined with TKI therapy.

Effect of positive bone marrow EBV in situ hybridization in staging and survival of localized extranodal natural killer/T-cell lymphoma, nasal-type.

PURPOSE: The aim of the study was to determine the effect of EBV-encoded RNA-1 in situ hybridization (EBER-1 ISH) in bone marrow specimens on survival outcome in patients with clinical stage I/II natural killer/T-cell lymphoma. EXPERIMENTAL DESIGN: We systematically did EBER-1 ISH on 182 archival bone marrow tissues from 91 patients who were diagnosed of stage I/II natural killer/T-cell lymphoma and analyzed the correlation between bone marrow EBER-1 ISH status and survival. We defined minimal bone marrow involvement and definite bone marrow involvement to distinguish the subgroups who revealed EBV-positive cells from normal marrow by EBER-1 ISH from those who showed typical neoplastic cells in bone marrow biopsies. RESULTS: In total, 17 of the 91 (18.7%) patients showed positivity for EBER-1 ISH at least in one of the bilateral bone marrow biopsies with 14 minimal bone marrow involvements and 3 definite bone marrow involvements. Patients with positive bone marrow EBER-1 ISH showed significantly poorer overall survival than those who were negative for bone marrow EBER-1 ISH (median survival, 16.1 months versus not reached; P = 0.045). CONCLUSION: Considering a high proportion of stage I/II patients (15.4%) with minimal in bone marrow specimens, bone marrow EBER-1 ISH should be routinely done in all patients with localized disease for more accurate staging.

Therapy-related myeloid neoplasms in 39 Korean patients: a single institution experience.

BACKGROUND: Therapy-related myeloid neoplasms (t-MN) occur as late complications of cytotoxic therapy. This study reviewed clinical and cytogenetic characteristics of patients with t-MN at a single institution in Korea. METHODS: The study subjects included 39 consecutive patients diagnosed with t-MN. Each subject's clinical history of previous diseases, treatments, and laboratory data was reviewed, including cytogenetics. The primary diagnosis was hematologic malignancy in 14 patients and solid tumor in 25 patients. RESULTS: Therapy-related acute myeloid leukemia (t-AML, 66.7%) was found to be more common than therapy-related myelodysplastic syndrome (t-MDS). Primary hematologic malignancies that were commonly implicated included mature B-cell neoplasm and acute leukemia. Breast cancer was the most common primary solid tumor. The mean time interval from cytotoxic therapy initiation to t-MN detection was 49 months. Chromosomal aberrations were observed in 35 patients, and loss of chromosome 5, 7, or both accounted for 41% of all cases. Balanced rearrangements occurred in 13 patients; these patients showed shorter latency intervals (mean, 38 months) than patients with loss of chromosome 5 or 7 (mean, 61 months). CONCLUSIONS: In this study, we determined the clinical and cytogenetic characteristics of Korean patients with t-MN. Although our results were generally consistent with those of previous reports, we found that t-MN resulting from de novo leukemia was common and that t-AML was more common than t-MDS at presentation. Multi-institutional studies involving a larger number of patients and additional parameters are required to investigate the epidemiology, genetic predisposition, and survival rate of t-MN in Korea.

Novel mutations in CEBPA in Korean Patients with acute myeloid leukemia with a normal karyotype.

Mutations in the transcription factor CCAAT/enhancer binding protein α gene (CEBPA) are found in 5-14% of the patients with AML and have been associated with a favorable clinical outcome. In this study, we aimed to assess the frequencies and characteristics of mutations in CEBPA. Between 2006 and 2009, CEBPA mutations were assessed using archival DNA samples obtained from 30 consecutive adult patients diagnosed with AML with a normal karyotype at our institution. CEBPA mutations were detected using direct sequencing analyses. These mutations were detected and described with reference to GenBank Accession No. NM_004364.3. In our series, CEBPA mutations were detected in 4 patients (13.3%). These mutations occurred as double mutations in all 4 patients. Among the 8 mutant alleles, 5 were novel (c.179_180dupCG, c.50_53delGCCA, c.178_182delACGTinsTTT, c.243_244insGTCG, and c.923_924insCTC). The frequency of occurrence of CEBPA mutations in Korean patients with AML is comparable to that in previous reports. Long-term follow-up data from a larger series of patients with comprehensive molecular profiling are needed to delineate the prognostic implications.

Clinical features of severe acquired ADAMTS13 deficiency in thrombotic thrombocytopenic purpura: the Korean TTP registry experience.

The clinical significance of ADAMTS13 activity for response to treatment, mortality rate, recurrence, and prognosis is unclear. Therefore, we investigated the characteristics of severe ADAMTS13 deficiency and evaluated its prognostic features in Thrombotic thrombocytopenic purpura (TTP). The Korean TTP Registry includes 66 patients from 13 teaching hospitals in Korea who received the diagnosis of TTP from January 2005 to December 2008. Blood samples obtained upon admission were sent for ADAMTS13 analysis (multimer analysis by sodium dodecyl sulfate electrophoresis) to a central laboratory along with patient clinical information. Patients with severe ADAMTS13 deficiency had lower serum creatinine levels (P = 0.001) than patients with non-severe ADAMTS13 deficiency. Although severe ADAMTS13 deficiency was associated with better response rate (75 vs. 53%, P = 0.145), remission rate (81 vs. 61%, P = 0.209), and mortality rate (19 vs. 31%, P = 0.508) than non-severe ADAMTS13 deficiency, treatment outcomes did not differ significantly between groups. After adjusting for clinical and laboratory features, multivariate analysis did not reveal any independent risk factors for TTP-associated mortality. Patients with severe ADAMTS13 deficiency had lower serum creatinine levels at presentation, but severe ADAMTS13 activity deficiency at TTP diagnosis does not appear to have prognostic significance.

Acute myeloid leukemia with del(X)(p21) and cryptic RUNX1/RUNX1T1 from ins(8;21)(q22;q22q22) revealed by atypical FISH signals.

A 57-yr-old woman was diagnosed with acute myeloid leukemia (AML) with maturation, based on morphological and cytochemical/immunophenotypic findings on bone marrow studies. Conventional cytogenetic analysis using bone marrow cells revealed terminal deletion of the short arm of an X chromosome as 46,X,del(X)(p21)[8]/46,XX[12]. On the other hand, fluorescence in situ hybridization (FISH) for the RUNX1/RUNX1T1 (formerly AML1/ETO) rearrangement revealed 86% interphase nuclei with one fusion signal, which was found to be on the long arm of chromosome 8 on metaphase FISH, indicating the RUNX1/RUNX1T1 rearrangement by cryptic insertion of the RUNX1 gene. Molecular genetic study by reverse transcriptase polymerase chain reaction (RT-PCR) confirmed the presence of the chimeric transcript. The final karyotype was 46,X,del(X)(p21).ish ins(8;21)(q22;q22q22)(RUNX1T1+,RUNX1+;RU NX1+,RUNX1T1-)[8]/46,XX[12]. In addition to the cryptic RUNX1/RUNX1T1 rearrangement, this is the first report of partial deletion of an X chromosome as an additional cytogenetic aberration in AML with RUNX1/RUNX1T1.

Extranodal natural killer T-cell lymphoma, nasal-type: a prognostic model from a retrospective multicenter study.

PURPOSE: Patients with natural killer T (NK/T) -cell lymphomas have poor survival outcome, and for this condition there is no optimal therapy. The purpose of this study was to design a prognostic model specifically for extranodal NK/T-cell lymphoma, which can identify high-risk patients who need more aggressive therapy. PATIENTS AND METHODS: This multicenter retrospective study was comprised of 262 patients who were diagnosed with NK/T-cell lymphoma. RESULTS: After a median follow-up duration of 51.2 months, 5-year overall survival rate in 262 patients was 49.5%. Prognostic factors for survival were "B" symptoms (P = .0003; relative risk, 2.202; 95% CI, 1.446 to 3.353), stage (P = .0006; relative risk, 2.366; 95% CI, 1.462 to 3.828), lactate dehydrogenase (LDH) level (P = .0005; relative risk, 2.278; 95% CI, 1.442 to 3.598), and regional lymph nodes (P = .0044; relative risk, 1.546; 95% CI, 1.009 to 2.367). Of 262 patients, 219 had complete information on four parameters. We identified four different risk groups: group 1, no adverse factor; group 2, one factor; group 3, two factors; and group 4, three or four factors. The new model showed a superior prognostic discrimination as compared with the International Prognostic Index (IPI). Notably, the distribution of patients was balanced when a new model was adopted (group 1, 27%; group 2, 31%; group 3, 20%; group 4, 22%), whereas 81% of patients were categorized as low or low-intermediate risks using IPI. CONCLUSION: The newly proposed model for extranodal NK/T-cell lymphoma demonstrated a more balanced distribution of patients into four groups with better prognostic discrimination as compared with the IPI.