Bingcheng Liu

Some novel features of IDH1-mutated acute myeloid leukemia revealed in Chinese patients.

Mutations of isocitrate dehydrogenase 1 (IDH1) have recently been reported in acute myeloid leukemia (AML). However, the characteristics of IDH1-mutated AML are still not known clearly. We analyzed 416 Chinese AML patients and found 28 patients (6.7%) carried this mutation. One homozygous IDH1 mutant in AML was found. The IDH1 mutations were associated with NPM1 mutations (P=0.043) and could coexist with recurrent transcription factor aberrations including AML1-ETO (6/50), PML-RARα (3/77) and CBFβ-MYH11 (1/15). For AML with AML1-ETO fusion gene, IDH1(mut) patients may have worse disease-free survival (DFS) than IDH1(wild-type) patients.

EUTOS score predicts survival and cytogenetic response in patients with chronic phase chronic myeloid leukemia treated with first-line imatinib

Sokal, Euro and newly developed EUTOS scoring systems were validated in 220 Chinese chronic phase chronic myeloid leukemia (CP-CML) patients treated with frontline imatinib. In the EUTOS low-risk and high-risk groups, the 5-year OS was 98.7% vs. 71.4% (P<0.0001), and the 5-year cumulative incidence of complete cytogenetic response (CCyR) was 92.4% vs. 53.8% (P<0.0001). EUTOS score also predicted progression-free survival and duration of CCyR. Low EUTOS index predicted for CCyR. However, Sokal and Euro scores mainly could not discriminate the intermediate-risk from high-risk group in either survival or CCyR. EUTOS score forecasts the prognosis of CP-CML patients treated with first-line imatinib.

Clinical and laboratory studies of 17 patients with acute myeloid leukemia harboring t(7;11)(p15;p15) translocation

The cellular and molecular genetic aberrations of hematopoietic and lymphoid tissues are increasingly important in leukemia classification and are prognostically significant. Although some recurrent molecular cytogenetic abnormalities in AML have been extensively studied, others including t(7;11)(p15;p15) have not been well characterized. In this paper, seventeen AML patients with t(7;11)(p15;p15) were retrospectively reviewed for cell morphology, immuno-phenotype, cytogenetics as well as clinical features and prognosis. Among them, thirteen were female; nine were AML-M2. Six patients who were newly diagnosed were alive, one was lost for followed up and ten died. The median survival was 8 months. Taking together, AML with t(7;11)(p15;p15) is a rare and distinct disease. Most patients with this translocation are female at younger age and have special clinical and hematological characteristics such as M2-subtype of AML, easy to relapse and poor prognosis.

IKZF1 alterations and expression of CRLF2 predict prognosis in adult Chinese patients with B-cell precursor acute lymphoblastic leukemia.

Abstract 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.

Monitoring of WT1 and its target gene IRF8 expression in acute myeloid leukemia and their significance

Sir, Wilm’s tumor gene 1(WT1) is considered to be a tumor marker expressed in many cancer types. Approximately 90% of acute myeloid leukemia (AML) patients had defective or abnormal WT1 expression, suggesting its involvement in tumor occurrence [1]. The protein products of the WT1 have been shown to directly bind to the interferon regulatory factor 8 (IRF8) promoter and suppress its activity, demonstrating that IRF8 can be regulated by WT1 [2]. Bansal et al. [3] reported that WT1 expression was decreased in the KG-1 cell line after IFNa and IFN-b treatment, providing a potentially new strategy for the treatment of AML. We analyzed the expression levels of WT1 and IRF8 in AML patients and determined the correlation between these two genes with AML outcome. We also evaluated the feasibility of using the expression of these genes as prognostic factors and markers of minimal residual disease in AML. Bone marrow samples from 9 normal donors and 138 patients with de novo AML were collected at the Institute of Hematology and Blood Disease Hospital of Chinese Academy of Medical Sciences and Peking Union Medical College hospital (Clinical data listed in Table S1). The chemotherapy strategy has been reported previously [4, 5]. Mononuclear cells were separated, mRNA was extracted, and reverse transcription were used to prepare cDNA for further evaluation. Gene expression was detected by RT-PCR method (Taqman Probes) with the following primers: WT1: forward 50-CGCTA TTCGC AATCA GGGTT A-30, reverse 50-GGGCG TGTGA CCGTA GCT-30, probe: 50-FAM-AGCAC GGTCA CCTTC GACG GGA-TAMRA-30, product length: 67 bp (the primers detect all four isoforms of WT1); IRF8: forward 50-GAGAG CTGCA GCAGT TCTAT AACA-30, reverse 50-CTGTA TGTCC GGCAA CTGGC-30, probe: 50-CCAAA CTCAT TCTCG TGCAG ATTGA GCA G-30, product length: 148 bp; ABL: forward 50-TGGAG ATAAC ACTCT AAGCA TAACT AAAGG T-30, reverse 50-TGGGT CCCAA GCAAC TACAT C-30, probe: 50-AATGG TGTGA AGCCC AAACC AAAAA TGG-30, product length: 124 bp. Expression levels are presented as the log10 transformation of target gene copy number/10 ABL copy number.

Impact of risk stratification on the duration of caspofungin therapy for invasive fungal disease in acute leukemic patients

AIM We retrospectively analyzed 141 acute leukemia patients with unclassified invasive fungal disease episodes during chemotherapy to determine the optimum duration of antifungal treatment. PATIENTS & METHODS Patients were divided into standard-risk and high-risk groups and treated with intravenous caspofungin for either 1 or 2 weeks, followed by oral voriconazole. RESULTS Favorable responses occurred in 75.9% of patients (107/141) overall. Although there were no significant differences in response rates between patients receiving 1 or 2 weeks in the standard-risk group (p = 0.12 and p = 0.19, respectively), in the high-risk group, response rates were significantly higher in the 2-week than the 1-week treatment group (p = 0.01 and p = 0.02, respectively). CONCLUSION The duration of caspofungin treatment for patients with unclassified invasive fungal diseases may be optimized by risk stratification.

Prognostic significance of copy number alterations detected by multi‑link probe amplification of multiple genes in adult acute lymphoblastic leukemia

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+) B-ALL patients, as well as in the high risk (HR) B-ALL group (P=0.037 and P=0.047, respectively). Patients with PAX5 deletions displayed poor 2-year OS (P=0.004) and RFS (P=0.016) rates in Philadelphia chromosome negative (Ph-) B-ALL patients. Patients with ≥3 gene deletions exhibited a poorer prognosis than other patients (OS, P=0.001; RFS, 0.002).

Distinct genetic alteration profiles of acute myeloid leukemia between Caucasian and Eastern Asian population

Racial and ethnic disparities in malignancies attract extensive attention. To investigate whether there are racial and ethnic disparities in genetic alteration between Caucasian and Eastern Asian population, data from several prospective AML trials were retrospectively analyzed in this study. We found that there were more patients with core binding factor (CBF) leukemia in Eastern Asian cohorts and there were different CBF leukemia constitutions between them. The ratios of CBF leukemia are 27.7, 22.1, 21.1, and 23.4%, respectively, in our (ChiCTR-TRC-10001202), another Chinese, Korean, and Japanese Eastern Asian cohorts, which are significantly higher than those in ECOG1900, MRC AML15, UK NCRI AML17, HOVON/SAKK AML-42, and German AML2003 (15.5, 12.5, 9.3, 10.2, and 12%, respectively). And CBFbeta-MYH11 occurred more prevalently in HOVON/SAKK AML- 42 and ECOG1900 trials (50.0 and 54.3% of CBF leukemia, respectively) than in Chinese and Japanese trials (20.1 and 20.8%, respectively). The proportion of FLT3-ITD mutation is 11.2% in our cohort, which is lower than that in MRC AML15 and UK NCRI AML17 (24.6 and 17.9%, respectively). Even after excluding the age bias, there are still different incidence rates of mutation between Caucasian and Eastern Asian population. These data suggest that there are racial and ethnic disparities in genetic alteration between Caucasian and Eastern Asian population.

Flow cytometric analysis of cerebrospinal fluid in adult patients with acute lymphoblastic leukemia during follow-up

To explore the value of flow cytometric (FCM) analysis of cerebrospinal fluid (CSF) in the diagnosis of central nervous system involvement in adult patients with acute lymphoblastic leukemia (ALL) during follow‐up.

The number of CD34+CD38+CD117+HLA-DR+CD13+CD33+ cells indicates post-chemotherapy hematopoietic recovery in patients with acute myeloid leukemia

Hematopoietic recovery is considered to be associated with the number of multipotent hematopoietic stem cells in the bone marrow, as observed in functional assays involving stem cell transplantation. However, there is little evidence related to hematopoietic recovery in non-transplantation settings, which is accomplished by endogenous hematopoietic cells. A recent study suggested that progenitors are the main contributors during this steady-state hematopoiesis, which differs from exogenous transplantation. We hypothesized that endogenous progenitor support post-chemotherapy hematopoietic recovery. To investigate the potential impact of these progenitor cell percentage on hematopoietic recovery, we retrospectively analyzed the percentage of CD34+CD38+CD117+HLA-DR+CD13+CD33+ cells (P cells) and hematopoietic recovery in 223 newly diagnosed acute myeloid leukemia patients during two courses of consolidation chemotherapy after complete remission. We found that a lower P cell percentage was significantly associated with prolonged neutropenia recovery time after the first and second courses of consolidation chemotherapy (p = 0.001; p = 0.045, respectively). We also observed similar results with regard to platelet recovery time after the first course of consolidation chemotherapy (p = 0.000). Univariate analysis showed that P cell percentage and consolidation chemotherapy regimens, and not gender, age, induction chemotherapy regimens, infection grade, WHO classification and NCCN risk category, were associated with neutrophil recovery after chemotherapy. Multivariate analysis demonstrated that P cell percentage is an independent factor affecting neutrophil recovery capacity for both the first and second courses (p = 0.008; p = 0.032, respectively). Our results indicate that CD34+CD38+CD117+HLA-DR+CD13+CD33+ cells before each course of chemotherapy is independently associated with chemotherapy-related hematopoietic reconstitution capacity. These findings may help modify future chemotherapy regimens based on progenitor cell percentages.