Junyuan Qi

Vorinostat or placebo in combination with bortezomib in patients with multiple myeloma (VANTAGE 088): a multicentre, randomised, double-blind study

BACKGROUNDnWe aimed to assess efficacy and tolerability of vorinostat in combination with bortezomib for treatment of patients with relapsed or refractory multiple myeloma.nnnMETHODSnIn our randomised, double-blind, placebo-controlled, phase 3 trial, we enrolled adults (≥18 years) at 174 university hospitals in 31 countries worldwide. Eligible patients had to have non-refractory multiple myeloma that previously responded to treatment (one to three regimens) but were currently progressing, ECOG performance statuses of 2 or less, and no continuing toxic effects from previous treatment. We excluded patients with known resistance to bortezomib. We randomly allocated patients (1:1) using an interactive voice response system to receive 21 day cycles of bortezomib (1·3 mg/m(2) intravenously on days 1, 4, 8, and 11) in combination with oral vorinostat (400 mg) or matching placebo once-daily on days 1-14. We stratified patients by baseline tumour stage (International Staging System stage 1 or stage ≥2), previous bone-marrow transplantation (yes or no), and number of previous regimens (1 or ≥2). The primary endpoint was progression-free survival (PFS) in the intention-to-treat population. We assessed adverse events in all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number 00773747.nnnFINDINGSnBetween Dec 24, 2008, and Sept 8, 2011, we randomly allocated 317 eligible patients to the vorinostat group (315 of whom received at least one dose) and 320 to the placebo group (all of whom received at least one dose). Median PFS was 7·63 months (95% CI 6·87-8·40) in the vorinostat group and 6·83 months (5·67-7·73) in the placebo group (hazard ratio [HR] 0·77, 95% CI 0·64-0·94; p=0·0100). 312 (99%) of 315 patients in the vorinostat group and 315 (98%) of 320 patients in the placebo group had adverse events (300 [95%] adverse events in the vorinostat group and 282 [88%] in the control group were regarded as related to treatment). The most common grade 3-4 adverse events were thrombocytopenia (143 [45%] patients in the vorinostat group vs 77 [24%] patients in the placebo group), neutropenia (89 [28%] vs 80 [25%]), and anaemia (53 [17%] vs 40 [13%]).nnnINTERPRETATIONnAlthough the combination of vorinostat and bortezomib prolonged PFS relative to bortezomib and placebo, the clinical relevance of the difference in PFS between the two groups is not clear. Different treatment schedules of bortezomib and vorinostat might improve tolerability and enhance activity.nnnFUNDINGnMerck.

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.

A pivotal role of bone remodeling in granulocyte colony stimulating factor induced hematopoietic stem/progenitor cells mobilization

The majority of hematopoietic stem/progenitor cells (HSPCs) reside in bone marrow (BM) surrounded by a specialized environment, which governs HSPC function. Here we investigated the potential role of bone remodeling cells (osteoblasts and osteoclasts) in homeostasis and stress‐induced HSPC mobilization. Peripheral blood (PB) and BM in steady/mobilized state were collected from healthy donors undergoing allogeneic transplantation and from mice treated with granulocyte colony stimulating factor (G‐CSF), parathyroid hormone (PTH), or receptor activator of nuclear factor kappa‐B ligand (RANKL). The number and the functional markers of osteoblasts and osteoclasts were checked by a series of experiments. Our data showed that the number of CD45−Ter119− osteopontin (OPN)+ osteoblasts was significantly reduced from 4,085u2009±u2009135u2009cells/femur on Day 0 to 1,032u2009±u200955u2009cells/femur on Day 5 in mice (Pu2009=u20090.02) and from 21.38u2009±u20090.66 on Day 0 to 14.78u2009±u20090.65 on Day 5 in healthy donors (Pu2009<u20090.01). Decrease of osteoblast number leads to reduced level of HSPC mobilization regulators stromal cell‐derived factor‐1 (SDF‐1), stem cell factor (SCF), and OPN. The osteoclast number at bone surface (OC.N/B.s) was significantly increased from 1.53u2009±u20090.12 on Day 0 to 4.42u2009±u20090.46 on Day 5 (Pu2009<u20090.01) in G‐CSF‐treated mice and from 0.88u2009±u20090.20 on Day 0 to 3.24u2009±u20090.31 on Day 5 (Pu2009<u20090.01) in human. Serum TRACP‐5b level showed a biphasic trend during G‐CSF treatment. The ratio of osteoblasts number per bone surface (OB.N/B.s) to OC.N/B.s was changed after adding PTH plus RANKL during G‐CSF treatment. In conclusion, short term G‐CSF treatment leads to reduction of osteoblasts and stimulation of osteoclasts, and interrupting bone remodeling balance may contribute to HSPC mobilization. J. Cell. Physiol.

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.

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 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.

Further stratification of patients with multiple myeloma by International Staging System in combination with ratio of serum free κ to λ light chains.

The serum free light chain (sFlc) levels were measured for 122 Chinese patients with newly diagnosed symptomatic multiple myeloma (NDSMM), and κ/λ ratios (rFlc) were calculated. The data were analyzed for the roles of sFlc and rFlc in the diagnosis and prognosis of MM. Abnormal sFlc and/or rFlc were detected in 99.2% of patients, demonstrating that the FLC assay is much more sensitive than the commonly used methods. Baseline sFlc and rFlc successfully predicted the overall survival (OS). The median OS was not reached (NR) versus 23 months for the low sFLC group (sFLC-κu2009 180 mg/L or sFLC-λ u2009592.5 mg/L) and high sFLC group (sFLC-κ ≥u2009180 mg/L or sFLC-λ ≥u2009592.5 mg/L) (p =u20090.001), and NR versus 21 months for the low rFLC group (0.04 ≤ rFLC ≤u200925) and high rFLC group (pu20090.001), respectively. Interestingly, the significant differences in OS between the low and high rFLC groups were not changed by bortezomib chemotherapy. In addition, patients were further stratified by three novel poor-prognosis factors (β2-microglobulin [β2-MG] u20093.5 mg/L, albumin [ALB] u200935 g/L, rFLC u200925 or rFLC u20090.04) that were developed from combination of the rFlc with the International Staging System (ISS): the low risk group (no factor), the low-intermediate risk group (one factor), the high-intermediate risk group (two factors) and the high risk group (three factors). The median OS for those groups was NR, NR, 24 months and 13 months, respectively (pu20090.05). In conclusion, the sFLC assay was highly sensitive in the diagnosis of MM in Chinese patients. The prognostic potential of the ISS may be improved with the addition of rFLC.

High incidence of MYC and BCL2 abnormalities in mantle cell lymphoma, although only MYC abnormality predicts poor survival

The incidence and prognostic role of MYC and BCL2 rearrangements in mature B-cell lymphomas have been extensively studied, except the infrequent mantle cell lymphoma (MCL). Here, we analyzed the MYC and BCL2 abnormalities and other cytogenetic aberrations by fluorescence in situ hybridization (FISH) in 50 MCL patients with bone marrow involvement. Eighteen patients (36.0%) had MYC gains and/or amplifications, and twelve patients (24.0%) had BCL2 gains and/or amplifications. Among the 18 patients with MYC abnormality, four had simultaneous MYC translocations, but no BCL2 translocation was detected among patients with BCL2 abnormality. Only two patients (4.0%) had both MYC and BCL2 abnormalities. The patients with a MYC abnormality had a significantly higher tumor burden, a higher percentage of medium/high risk MIPI group and genomic instability compared to those without this abnormality. However, no significant difference was observed between patients with or without a BCL2 abnormality in terms of clinical and cytogenetic factors. Patients with a MYC abnormality had poorer progress-free survival (PFS) (9.0 vs. 48.0 months, p = .000) and overall survival (OS) (12.0 vs. 94.5 months, p = .000), but the presence of a BCL2 abnormality did not significantly influence either PFS or OS. In multivariate analysis, the MYC abnormality was the independent adverse factor for both PFS and OS, and intensive chemotherapy did not improve the outcome of these patients. Thus, the presence of a MYC but not BCL2 abnormality predicted the poor survival of MCL patients, and a new treatment strategy should be developed for these patients.