Yaozhong Zhao

The Impact of Clone Size on the Prognostic Value of Chromosome Aberrations by Fluorescence In Situ Hybridization in Multiple Myeloma

Purpose: Accumulating evidence indicates that intratumor heterogeneity is prevalent in multiple myeloma and that a collection of multiple, genetically distinct subclones are present within the myeloma cell population. It is not clear whether the size of clonal myeloma populations harboring unique cytogenetic abnormalities carry any additional prognostic value. Experimental Design: We analyzed the prognostic impact of cytogenetic aberrations by fluorescence in situ hybridization at different cutoff values in a cohort of 333 patients with newly diagnosed myeloma and 92 patients with relapsed myeloma. Results: We found that nearly all IgH-related arrangements were observed in a large majority of the purified plasma cells; however, 13q deletion, 17p deletion, and 1q21 amplification appeared in different percentages within the malignant plasma cell population. Based on the size of subclones carrying these cytogenetic aberrations, the patients were divided into four groups: 0%–10%, 10.5%–20%, 20.5%–50%, and >50%. Receiver-operating characteristics analysis was applied to determine the optimal cutoff value with the greatest differential survival and showed that the most powerful clone sizes were 10% for 13q deletion, 50% for 17p deletion, and 20% for 1q21 gains, which provided the best possible cutoffs for predicting poor outcomes. Conclusions: Our study indicated that the impact of clone size on prognostic value varies between specific genetic abnormalities. Prognostic value was observed for even a subgroup of plasma cells harboring the cytogenetic aberration of 13q deletion and 1q21 gains; however, 17p deletion displayed the most powerful cutoff for predicting survival only if the predominant clones harbored the abnormality. Clin Cancer Res; 21(9); 2148–56. ©2015 AACR.

MicroRNA-223 expression is uniformly down-regulated in B cell lymphoproliferative disorders and is associated with poor survival in patients with chronic lymphocytic leukemia

Abstract MicroRNA-223 (miR-223) expression has been demonstrated to be stage-specific in B cell differentiation and associated with the outcome of chronic lymphocytic leukemia (CLL). However, the expression pattern of miR-223 in B cell lymphoproliferative disorders and its association with the outcome of Chinese patients with CLL have not been investigated. In this study, we demonstrated that miR-223 expression was significantly decreased in CLL, mantle cell lymphoma (MCL) and splenic marginal zone lymphoma (SMZL). In CLL, miR-223 expression decreased significantly with progression from early to advanced clinical stages and was significantly lower in patients with elevated β2-microglobulin, unmutated immunoglobulin variable heavy chain (IgVH) gene or with disease progression or death. Using a cut-off determined by receiver operating characteristic (ROC) analysis optimizing concordance with IgVH mutational status, miR-223-negative and -positive groups were defined for 22 and 31 patients, respectively. The median progression-free survival (PFS) and overall survival of the miR-223-negative group were 13 and 40 months, respectively, significantly shorter than for the miR-223-positive group (both not reached; p = 0.002 and p = 0.018, respectively). Multivariate analysis revealed that the absence of miR-223 was the only independent factor capable of predicting shorter PFS. In conclusion, miR-223 is uniformly down-regulated in B-LPDs and is a useful prognostic factor for patients with CLL.

Therapeutic experience of adult acute myeloid leukemia in a single institution of China and its relationship with chromosome karyotype

One hundred and ninety-six untreated de novo acute myeloid leukemia (AML) patients were treated with homoharringtonine + cytosine arabinoside (HA) based induction therapy composed of three chemotherapeutic drugs (HAD/M, D-daunorubicin-DNR, M-mitozantrone-MTZ) used in our hospital for the past 12 years. The patient population was relatively young (median age 37, oldest patient 67), and patients were excluded if they had prior MDS or prior chemotherapy or radiotherapy. Complete remission (CR) rate, disease free survival (DFS) and overall survival (OS) of the patients were calculated. One hundred and fifty-three patients who had karyotype results were divided into four groups according to Southwestern Oncology Group (SWOG) criteria. Differences of CR rate, DFS and OS of different groups were evaluated. The CR rate of all 196 cases was 153/196 (78.1%), and 95.3% of these were within 1 – 2 courses. Median DFS of the 153 CR patients was 23.8 (range from 1.0 to 153) months. DFS rates at 3 years and 5 years were 41.1% and 35.9%, respectively. The median OS of 196 patients was 19.3 (0.5 – 154) months. The probabilities of 3-year and 5-year OS were 31.5% and 29.2%, respectively. CR rate, DFS and OS of the different cytogenetic risk groups were also be analyzed. According to SWOG criteria, patients were classified into favorable, intermediate, adverse and unknown (a group where the meaning of chromosomes are unclear) groups. CR rate, median DFS and OS were 91.9%, 90.8 months and 94.4 months for the favorable group; 86.4%, 22.0 months and 22.8 months for the intermediate group; 59.4%, 9 months and 10.5 months for the adverse group; 76.0%, 22.0 months, 16.1 months for the unknown group, respectively. The differences among the four groups were statistically significant (P = 0.001, 0.0033, 0.0001). We conclude that triple-drugs induction regimens based on HA (HAD/M) are highly effective in adult AML in China. Cytogenetics is the important prognostic factor. SWOG karyotype subtyping criteria was appropriate for our patients, the prognosis of the unknown group was similar to that of the intermediate group.

Multiple myeloma patients with low proportion of circulating plasma cells had similar survival with primary plasma cell leukemia patients.

The common features shared by primary plasma cell leukemia (pPCL) and multiple myeloma (MM) with circulating plasma cells (CPCs) are peripheral blood invasion and expansion of plasma cells independent of the protective bone marrow (BM) microenvironment niche. However, few studies have addressed the relationship between pPCL and MM with CPCs. Here, we quantitated the number CPCs by conventional morphology in 767 patients with newly diagnosed MM; their clinic features were compared with those of 33 pPCL cases. When the presence of CPCs was defined as more than 2xa0% plasma cells per 100 nucleated cells on Wright–Giemsa stained peripheral blood smears, the incidence of MM with CPCs was 14.1xa0% in newly diagnosed MM. Patients with CPCs shared many clinical features with pPCL, especially clinical parameters related to tumor burden. However, no commonalities were found in immunophenotyping and cytogenetics. The prognosis of pPCL was poor, with a median progression free survival (PFS) of 12xa0months and an overall survival (OS) of 15xa0months. MM patients with CPCs had a clearly inferior PFS and OS as compared with the control cohort. Most interestingly, although the CPCs were not high enough to meet the diagnostic criteria for pPCL, the survival of MM patients with CPCs was comparable with that of pPCL, with a median PFS of 17xa0months and an OS of 25xa0months.

Additional chromosomal abnormalities and their prognostic significance in adult Philadelphia-positive acute lymphoblastic leukemia: with or without imatinib in chemotherapy

The study analyzed the characteristics and prognostic significance of additional chromosomal abnormalities in 110 Chinese adults with Philadelphia chromosome-positive (Ph-positive) acute lymphoblastic leukemia (ALL). Secondary aberrations were present in 60.9% of the cases. All chromosomes were involved in secondary aberrations, and chromosomes 9, 7, 21, 18, and 14 were most frequently abnormal. Fifty of 110 patients (45.5%) had at least one normal metaphase cell in their chromosome preparations at diagnosis. Patients with additional aberrations had shorter disease-free survival (DFS) and overall survival (OS) in chemotherapy combined with imatinib (ICT) group and only shorter DFS in conventional chemotherapy (CT) group. The existence of normal metaphase cells was associated with a superior survival in CT group, but not in ICT group. Patients with loss of chromosomes 7, 7p, 9, and 9p had inferior outcome compared to patients with other secondary aberrations and those without secondary aberrations, in both CT and ICT group.

Elevated neutrophil-to-lymphocyte ratio and monocyte-to-lymphocyte ratio and decreased platelet-to-lymphocyte ratio are associated with poor prognosis in multiple myeloma

Elevated inflammatory markers are associated with poor outcomes in various types of cancers; however, their clinical significance in multiple myeloma (MM) have seldom been explored. This study investigated the prognostic relevance of neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and monocyte-to-lymphocyte ratio (MLR) in MM. Totally 559 MM patients were included in this study. NLR, PLR and MLR were calculated from whole blood counts prior to therapy. Kaplan-Meier curves and multivariate Cox proportional models were used for the evaluation of the survival. It has shown that newly diagnosed MM patients were characterized by high NLR and MLR. Elevated NLR and MLR and decreased PLR were associated with unfavorable clinicobiological features. Applying cut-offs of 4 (NLR), 100 (PLR) and 0.3 (MLR), elevated NLR, MLR and decreased PLR showed a negative impact on outcome. Importantly, elevated NLR and decreased PLR were independent prognostic factors for progression-free survival. Thus, elevated NLR and MLR, and decreased PLR predict poor clinical outcome in MM patients and may serve as the cost-effective and readily available prognostic biomarkers.

Features of Extramedullary Disease of Multiple Myeloma: High Frequency of P53 Deletion and Poor Survival: A Retrospective Single-Center Study of 834 Cases

BACKGROUNDnMultiple myeloma (MM) is a heterogeneous disease in which most patients have myeloma restricted to the bone marrow, and some patients develop extramedullary disease (EMD) at the time of diagnosis or during follow-up, and show different clinical characteristics and a dismal prognosis.nnnPATIENTS AND METHODSnWe studied 834 consecutive MM patients in a single center in China and compared clinical features of patients with and without EMD.nnnRESULTSnIn general, the prevalence of EMD was 4.8% at the time of diagnosis and 3.4% during follow-up, with a significant increase in recent years. MM patients with EMD at the time of diagnosis had remarkably greater prevalence of P53 deletion determined using fluorescence in situ hybridization (FISH) analysis (34.5% vs. 11.9%; P = .037) and higher level of lactate dehydrogenase (LDH) (P = .003) compared with patients without EMD. EMD relapse/progression during follow-up was correlated with EMD presentation at diagnosis, immunoglobulin (Ig)D subtype and P53 deletion in FISH analysis, but not previous treatment (thalidomide, bortizomib, or transplantation). With respect to prognosis, multivariate analysis showed that EMD was an independent adverse prognostic factor. The overall survival of patients with and without EMD at diagnosis were 16.5 and 40 months, respectively (P < .001), and the time to disease progression of the 2 groups was 11.5 and 25 months, respectively (P < .001).nnnCONCLUSIONnMM patients with EMD at the time of diagnosis showed remarkably greater prevalence of P53 deletion in FISH analysis and higher LDH levels. EMD relapse/progression was correlated with EMD presentation at diagnosis, IgD subtype, and P53 deletion in FISH analysis, but not previous exposure to new drugs or transplantation. The presence of EMD involvement negatively affected survival.

miR-29c down-regulation is associated with disease aggressiveness and poor survival in Chinese patients with chronic lymphocytic leukemia

Abstract Aberrant expression of microRNAs in chronic lymphocytic leukemia (CLL) has been reported to be associated with clinical outcome and improve prognostic stratification. The aim of this study was to explore the association of miR-29c expression with clinical parameters and survival in 53 Chinese patients with CLL. We showed that the miR-29c expression level decreased significantly from early to advanced clinical stages, and was significantly lower in patients with β2-microglobulin higher than 3.5 mg/L or with disease progression or death. With the cut-off determined by receiver operating characteristic (ROC) curve analysis, optimizing concordance with immunoglobulin heavy chain (IgVH) mutation status, miR-29c negative and positive groups were defined as including 17 and 36 patients, respectively. The miR-29c negative group had a higher percentage of patients with trisomy 12 or deletion of 11q or 17p (70.6% vs. 34.3%; p = 0.014) compared to the miR-29c positive group. The median progression-free survival and overall survival of the miR-29c negative group were 21 and 92 months, respectively, significantly shorter than in the miR-29c positive group (both not reached; p = 0.002 and p = 0.042, respectively), and miR-29c down-regulation was an independent prognostic factor for PFS. In conclusion, down-regulation of miR-29c is associated with higher tumor burden and significantly predicts short survival in Chinese patients with CLL.

Clinical characteristics and outcomes of adults with Philadelphia chromosome positive and/or bcr-abl positive acute lymphoblastic leukemia: a single center study from China

The study reviewed 389 adult patients with acute lymphoblastic leukemia (ALL) and 110 patients (28.3%) were diagnosed as Philadelphia chromosome positive (Ph-positive) and/or bcr-abl positive ALL. The special group had the same clinical characteristics as other studies, except for relatively young age and high incidence of both P190 and P210 fusion proteins expression. The complete remission (CR) rate in conventional chemotherapy (CT) group and in chemotherapy combined with imatinib (ICT) group was 84.7% and 96.0%, respectively. The 2-year disease-free survival (DFS) and overall survival (OS) were 0 and 23.6u2009±u20096.9%, respectively in CT group; the 2-year DFS and OS were 22.1u2009±u20098.8% and 41.6u2009±u200910.0%, respectively in ICT group; and in allogeneic stem cell transplantation (SCT) group, the 2-year DFS and OS were 48.2u2009±u200913.9% and 53.1u2009±u200912.7%, respectively. The results of the study indicated that introducing imatinib into treatment of patients with Ph-positive ALL could improve CR rate and survival, especially as early as possible, and allogenic SCT was still the first choice for these patients if they had suitable donors.

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.