Target-specific next-generation sequencing technology was used to analyze 112 genes in adult patients with acute lymphoblastic leukemia (ALL). This sequencing mainly focused on the specific mutational hotspots. Among the 121 patients, 93 patients were B-ALL (76.9%), and 28 patients (23.1%) were T-ALL. Of the 121 patients, 110 (90.9%) harbored at least one mutation. The five most frequently mutated genes in T-ALL are NOTCH1, JAK3, FBXW7, FAT1, and NRAS. In B-ALL, FAT1, SF1, CRLF2, TET2, and PTPN1 have higher incidence of mutations. Gene mutations are different between Ph+ALL and Ph−ALL patients. B-ALL patients with PTPN11 mutation and T-ALL patients with NOTCH1 and/or FBXW7 mutations showed better survival. But B-ALL with JAK1/JAK2 mutations showed worse survival. The results suggest that gene mutations exist in adult ALL patients universally, they are related with prognosis.Electronic supplementary materialThe online version of this article (doi:10.1186/s13045-017-0431-1) contains supplementary material, which is available to authorized users.
Although pediatric-like treatment regimen has remarkably improved the survival rates of adults with acute lymphoblastic leukemia (ALL), the outcome of some adult patients is still poor owing to adverse genetic features. These molecular abnormalities, especially gene deletions, may be considered for the prognosis assessment for adult patients with ALL. In this study, using multiplex ligation-dependent probe amplification (MLPA) method, gene deletions were analyzed in from 211 adult B-ALL patients treated in our center. The data showed that 68.2% (144/211) adult B-ALL patients carried gene deletions, and the frequency is much higher in Ph+B-ALL patients. IKZF1 gene deletion is the most common gene deletion in adult B-ALL, followed by CDKN2A/B deletion. In Ph-B-ALL patients, the overall survival of patients with gene deletions is inferior to that of patients without any gene deletions. More obviously, patients with IKZF1 or CDKN2A/B deletion had a worse prognosis, whereas, allogeneic hematopoietic stem cell transplantation could improve OS in patients with IKZF1 deletion, but not in patients with CDKN2A/B deletion. Moreover, the outcome of Ph-B-ALL patients with double deletion of IKZF1and CDKN2A/B may be much worse than that of patients with IKZF1 or CDKN2A/B alone. Minimal residual disease (MRD) was also analyzed together with gene deletions and demonstrated that gene deletions have a negative impact on survival only in MRD positive Ph-B-ALL patients. In conclusion, gene deletions are closely related with the prognosis of adult Ph-B-ALL patients.
Abstract. The multiplex ligation-dependent probe amplification (MLPA) method was used to detect the copy number alterations (CNAs) of IKAROS family zinc finger 1 (IKZF1), paired box 5 (PAX5), ETS variant 6 (ETV6), RB transcriptional corepressor 1 (RB1), BTG anti-proliferation factor 1 (BTG1), early B-cell factor 1 (EBF1), cyclin dependent kinase inhibitor 2A/2B (CDKN2A/2B) and cytokine receptor like factor 2 (CRLF2) genes in 87 adults with acute lymphoblastic leukemia (ALL) in China. The effects of CNAs on prognosis were analyzed. Gene deletions were detected in 58/87 (66.7%) ALL patients. The most common deletions were observed in the following genes: IKZF1 (40.6%), CDKN2A (31.9%), CDKN2B (29%), PAX5 (21.7%), RB1 (14.5%) and BTG1 (10.1%). B cell-ALL (B-ALL) patients with CDKN2A/2B deletions exhibited poor 2-year overall survival (OS; P=0.055) and relapse-free survival (RFS; P=0.054) rates. CDKN2A/2B deletions were associated with poor 2-year OS (P=0.045) and RFS (P= 0.071) rates in Philadelphia chromosome positive (Ph
Methotrexate (MTX) has an antitumor effect when used for the treatment of acute lymphoblastic leukemia (ALL). This study aims at evaluating the associations between 14 polymorphisms of six genes involved in MTX metabolism with serum MTX concentration and toxicity accompanying high-dose MTX. Polymorphisms in 183 Chinese patients with ALL were analyzed using TaqMan single nucleotide polymorphism genotyping assay. The serum MTX concentration was determined using homogeneous enzyme immunoassay. MTX-related toxicities were also evaluated. Renal toxicity was significantly associated with higher serum MTX concentrations at 24, 48, and 72 hours, and MTX elimination delay (P = 0.001, P < 0.001, P < 0.001, and P < 0.001, respectively), whereas SLCO1B1 rs4149056 was associated with serum MTX concentrations at 48 and 72 hours, and MTX elimination delay in candidate polymorphisms (P = 0.014, P = 0.019, and P = 0.007, respectively). SLC19A1 rs2838958 and rs3788200 were associated with serum MTX concentrations at 24 hours (P = 0.016, P = 0.043, respectively). MTRR rs1801394 was associated with serum MTX concentrations at 72 hours (P = 0.045). Neutropenia was related to SLC19A1 rs4149056 (odds ratio [OR]: 3.172, 95% confidence interval [CI]: 1.310-7.681, P = 0.011). Hepatotoxicity was associated with ABCC2 rs2273697 (OR: 3.494, 95% CI: 1.236-9.873, P = 0.018) and MTRR rs1801394 (OR: 0.231, 95% CI: 0.084-0.632, P = 0.004). Polymorphisms of SLCO1B1, SLC19A1, ABCC2, and MTRR genes help predict higher risk of increased MTX levels or MTX-related toxicities in adult ALL patients.
Acute Lymphoblastic Leukemia (ALL) is a common hematological malignancy in children, with a prognosis much worse in adults. The molecular characterization of ALL and its correlated prognostic significance are largely unknown. In this study, we analyzed the frequency of IKZF1 deletions, IK6 isoform, and CRLF2 overexpression in 118 Chinese adult B-cell precursor ALL (B-ALL) patients to explore their associations with clinical prognosis. Our data showed that IKZF1 deletions and IK6 isoform were highly detected in adult patients, and both of them were related with worse prognosis in Ph B-ALL, HR group of Ph B-ALL, and/or B-ALL patients. Though the frequency of CRLF2 overexpression was similar to children, it had an independent prognostic significance for standard-risk and Ph adult patients. Our study provided insights into the prognostic significance of certain genetic features in B-ALL patients. Further therapeutic strategies targeting these abnormalities potentially improving the prognosis of B-ALL are warranted.
Very few reports elucidate the prognosis of patients with TP53 aberrations using both measurable residual disease (MRD) and the status of having undergone allogeneic hematopoietic stem cell transplantation (allo-SCT). In this study, aberrations of TP53 were analyzed using next-generation sequencing (NGS) and fluorescence in situ hybridization (FISH) in patients with Philadelphia chromosome-negative (Ph−) ALL enrolled in a prospective single-arm clinical trial at our leukemia center. We analyzed the survival of the patients grouped according to the MRD level at the third month and whether or not received allo-SCT. We found that allo-SCT could improve the OS in patients with TP53 aberrations; Patients having negative MRD at the third month still showed worse 3-year OS and 3-year DFS without undergoing allo-SCT, which is different from previous studies, moreover, the prognostic significance of TP53 deletions was as important as TP53 mutations, the importance of screening both TP53 deletions and mutations in adult Ph− ALL at diagnosis should be emphasized.
Summary
The prognostic factors to stratify acute myeloid leukaemia (AML) with double‐mutated CCAAT/enhancer‐binding protein alpha (CEBPAdm) into different risk groups remains to be determined. In this retrospective study, we evaluated 171 consecutive patients with newly diagnosed AML with CEBPAdm by a Cox proportional hazards regression model. In univariate analyses, colony stimulating factor 3 receptor (CSF3R) and Wilms tumour 1 (WT1) mutations were associated with poor relapse‐free survival (RFS). The induction regimens including homoharringtonine (omacetaxine mepesuccinate) or intermediate‐dose cytarabine was associated with favourable RFS and overall survival (OS). The induction regimen including both homoharringtonine and intermediate‐dose cytarabine was associated with the most favourable RFS (3‐year RFS 84.7%) and OS (3‐year OS 92.8%) compared to the conventional cytarabine and daunorubicin regimen (3‐year RFS 27.7%, hazard ratio [HR] 0.126, 95% confidence interval [CI] 0.051–0.313, Wald p < 0.001; and 3‐year OS 56.4%, HR 0.179, 95% CI 0.055–0.586, Wald p = 0.005). In multivariate analyses, the induction regimen including intermediate‐dose cytarabine (HR 0.364, 95% CI 0.205–0.646, Wald p < 0.001) and CSF3R mutations (HR 2.667, 95% CI 1.276–5.572, Wald p = 0.009) were independently associated with RFS. Taken together, we found that induction regimen and CSF3R mutations were independent prognostic factors for AML with CEBPAdm.
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