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1.  Mapping of the IRF8 gene identifies a 3’ UTR variant associated with risk of chronic lymphocytic leukemia but not other common non-Hodgkin lymphoma subtypes 
Our genome-wide association study (GWAS) of chronic lymphocytic leukemia (CLL) identified 4 highly-correlated intronic variants within the IRF8 gene that were associated with CLL. These results were further supported by a recent meta-analysis of our GWAS with two other GWAS of CLL, supporting the IRF8 gene as a strong candidate for CLL risk.
To refine the genetic association of CLL risk, we performed Sanger sequencing of IRF8 in 94 CLL cases and 96 controls. We then performed fine-mapping by genotyping 39 variants (of which 10 were identified from sequencing) in 745 CLL cases and 1521 controls. We also assessed these associations with risk of other non-Hodgkin lymphoma (NHL) subtypes.
The strongest association with CLL risk was observed with a common SNP located within the 3’ UTR of IRF8 (rs1044873, log additive odds ratio = 0.7, P=1.81×10−6). This SNP was not associated with the other NHL subtypes (all P>0.05).
We provide evidence that rs1044873 in the IRF8 gene accounts for the initial GWAS signal for CLL risk. This association appears to be unique to CLL with little support for association with other common NHL subtypes. Future work is needed to assess functional role of IRF8 in CLL etiology.
These data provide support that a functional variant within the 3’ UTR of IRF8 may be driving the GWAS signal seen on 16q24.1 for CLL risk.
PMCID: PMC3596428  PMID: 23307532
CLL; NHL; SNPs; IRF8; risk locus
2.  Genome-wide Association Study Identifies Multiple Risk Loci for Chronic Lymphocytic Leukemia 
Berndt, Sonja I. | Skibola, Christine F. | Joseph, Vijai | Camp, Nicola J. | Nieters, Alexandra | Wang, Zhaoming | Cozen, Wendy | Monnereau, Alain | Wang, Sophia S. | Kelly, Rachel S. | Lan, Qing | Teras, Lauren R. | Chatterjee, Nilanjan | Chung, Charles C. | Yeager, Meredith | Brooks-Wilson, Angela R. | Hartge, Patricia | Purdue, Mark P. | Birmann, Brenda M. | Armstrong, Bruce K. | Cocco, Pierluigi | Zhang, Yawei | Severi, Gianluca | Zeleniuch-Jacquotte, Anne | Lawrence, Charles | Burdette, Laurie | Yuenger, Jeffrey | Hutchinson, Amy | Jacobs, Kevin B. | Call, Timothy G. | Shanafelt, Tait D. | Novak, Anne J. | Kay, Neil E. | Liebow, Mark | Wang, Alice H. | Smedby, Karin E | Adami, Hans-Olov | Melbye, Mads | Glimelius, Bengt | Chang, Ellen T. | Glenn, Martha | Curtin, Karen | Cannon-Albright, Lisa A. | Jones, Brandt | Diver, W. Ryan | Link, Brian K. | Weiner, George J. | Conde, Lucia | Bracci, Paige M. | Riby, Jacques | Holly, Elizabeth A. | Smith, Martyn T. | Jackson, Rebecca D. | Tinker, Lesley F. | Benavente, Yolanda | Becker, Nikolaus | Boffetta, Paolo | Brennan, Paul | Foretova, Lenka | Maynadie, Marc | McKay, James | Staines, Anthony | Rabe, Kari G. | Achenbach, Sara J. | Vachon, Celine M. | Goldin, Lynn R | Strom, Sara S. | Lanasa, Mark C. | Spector, Logan G. | Leis, Jose F. | Cunningham, Julie M. | Weinberg, J. Brice | Morrison, Vicki A. | Caporaso, Neil E. | Norman, Aaron D. | Linet, Martha S. | De Roos, Anneclaire J. | Morton, Lindsay M. | Severson, Richard K. | Riboli, Elio | Vineis, Paolo | Kaaks, Rudolph | Trichopoulos, Dimitrios | Masala, Giovanna | Weiderpass, Elisabete | Chirlaque, María-Dolores | Vermeulen, Roel C H | Travis, Ruth C. | Giles, Graham G. | Albanes, Demetrius | Virtamo, Jarmo | Weinstein, Stephanie | Clavel, Jacqueline | Zheng, Tongzhang | Holford, Theodore R | Offit, Kenneth | Zelenetz, Andrew | Klein, Robert J. | Spinelli, John J. | Bertrand, Kimberly A. | Laden, Francine | Giovannucci, Edward | Kraft, Peter | Kricker, Anne | Turner, Jenny | Vajdic, Claire M. | Ennas, Maria Grazia | Ferri, Giovanni M. | Miligi, Lucia | Liang, Liming | Sampson, Joshua | Crouch, Simon | Park, Ju-hyun | North, Kari E. | Cox, Angela | Snowden, John A. | Wright, Josh | Carracedo, Angel | Lopez-Otin, Carlos | Bea, Silvia | Salaverria, Itziar | Martin, David | Campo, Elias | Fraumeni, Joseph F. | de Sanjose, Silvia | Hjalgrim, Henrik | Cerhan, James R. | Chanock, Stephen J. | Rothman, Nathaniel | Slager, Susan L.
Nature genetics  2013;45(8):868-876.
PMCID: PMC3729927  PMID: 23770605
3.  Immnuophenotypic and Gene Expression Analysis of Monoclonal B Cell Lymphocytosis Shows Biologic Characteristics Associated With Good Prognosis CLL 
Monoclonal B cell lymphocytosis (MBL) is a hematologic condition wherein small B cell clones can be detected in the blood of asymptomatic individuals. Most MBL have an immunophenotype similar to chronic lymphocytic leukemia (CLL), and “CLL-like” MBL is a precursor to CLL. We used flow cytometry to identify MBL from unaffected members of CLL kindreds. We identified 101 MBL cases from 622 study subjects; of these, 82 individuals with MBL were further characterized. Ninety-one unique MBL clones were detected: 73 CLL-like MBL (CD5+CD20dimsIgdim), 11 atypical MBL (CD5+CD20+sIg+), and 7 CD5neg MBL (CD5negCD20+sIgneg). Extended immunophenotypic characterization of these MBL subtypes was performed, and significant differences in cell surface expression of CD23, CD49d, CD79b, and FMC-7 were observed among the groups. Markers of risk in CLL such as CD38, ZAP70, and CD49d were infrequently expressed in CLL-like MBL, but were expressed in the majority of atypical MBL. Interphase cytogenetics was performed in 35 MBL cases, and del 13q14 was most common (22/30 CLL-like MBL cases). Gene expression analysis using oligonucleotide arrays was performed on 7 CLL-like MBL, and showed activation of B cell receptor associated pathways. Our findings underscore the diversity of MBL subtypes and further clarify the relationship between MBL and other lymphoproliferative disorders.
PMCID: PMC3164475  PMID: 21617698
4.  Common Occurrence of Monoclonal B-cell Lymphocytosis Among Members of High-Risk CLL Families 
British journal of haematology  2010;151(2):152-158.
Monoclonal B-cell lymphocytosis (MBL) is an asymptomatic haematological condition characterized by low absolute levels of B-cell clones with a surface immunophenotype similar to that of chronic lymphocytic leukaemia (CLL). In the general population, MBL increases with age with a prevalence of 5–9% in individuals over age 60 years. It has been reported to be higher among first-degree relatives from CLL families. We report results of multi-parameter flow cytometry among 505 first-degree relatives with no personal history of lymphoproliferative disease from 140 families having at least two cases of CLL. Seventeen percent of relatives had MBL. Age was the most important determinant where the probability for developing MBL by age 90 years was 61%. MBL clustered in certain families but clustering was independent of the number of known CLL cases in a family. As is the case with CLL, males had a significantly higher risk for MBL than did females (p=0.04). MBL patients had significantly higher mean absolute lymphocyte counts (2.4 × 109/l) and B-cell counts (0.53 × 109/l) than those with a normal B-cell immunophenotype. Our findings show that MBL occurs at a very high rate in high risk CLL families. Both the age and gender distribution of MBL are parallel to CLL, implying a shared inherited risk.
PMCID: PMC2966536  PMID: 20738309
chronic lymphocytic leukaemia; high risk families; monoclonal B-cell lymphocytosis; flow cytometry
5.  Genetic susceptibility variants for chronic lymphocytic leukemia 
There is strong and consistent evidence that a genetic component contributes to the etiology of chronic lymphocytic leukemia (CLL). A recent genome-wide association study (GWAS) of CLL identified 7 genetic variants that increased the risk of CLL within a European population.
We evaluated the association of these variants, or variants in linkage disequilibrium (LD) with these variants, with CLL risk in an independent sample of 438 CLL cases and 328 controls.
Of these 7 SNPs, 6 had p-trend < 0.05 and had estimated odds ratios (ORs) that were strikingly comparable to those of the previous study. Associations were seen for rs9378805 (OR = 1.47, 95% CI: 1.19, 1.80, p-trend = 0.0003) near IRF4 and rs735665 near GRAMD1B (OR= 1.47; 95% CI: 1.14, 1.89; p-trend = 0.003). However, no associations (P> 0.05) were found for rs11083846, nor were any found for any SNPs in LD with rs11083846.
Our results confirm the previous findings and further support the role of a genetic basis in the etiology of CLL; however, more research is needed to elucidate the causal SNP(s) and the potential manner in which these SNPs or linked SNPs function in CLL pathogenesis.
PMCID: PMC2852480  PMID: 20332261
IRF4; CLL; genetic association
6.  Genome-wide association study of follicular lymphoma identifies a risk locus at 6p21.32 
Nature genetics  2010;42(8):661-664.
To identify susceptibility loci for non-Hodgkin lymphoma (NHL) subtypes, we conducted a three-stage genome-wide association study. We identified two variants associated with follicular lymphoma (FL) in 1,465 FL cases/6,958 controls at 6p21.32 (rs10484561, rs7755224, r2=1.0; combined p-values=1.12×10-29, 2.00×10-19), providing further support that MHC genetic variation influences FL susceptibility. Confirmatory evidence of a previously reported association was also found between chronic lymphocytic leukemia/small lymphocytic lymphoma and rs735665 (combined p-value=4.24×10-9).
PMCID: PMC2913472  PMID: 20639881
7.  N9986: a phase II trial of thalidomide in patients with relapsed chronic lymphocytic leukemia 
Leukemia & lymphoma  2009;50(4):588-592.
We enrolled 28 eligible patients with relapsed chronic lymphocytic leukemia (CLL) to a phase II study of single agent thalidomide (200 mg/d, with dose escalation up to 1000 mg/d over 60 days). The median age was 66 years and 71% were males. Study participants received a median of 2 (range 1–7) prior treatment regimens and 61% had Rai stage 3–4 disease at enrollment. Grade 3 or higher hematologic toxicity was observed in 13 (46%) and 16 (57%) had grade 3 or higher non-hematologic toxicity. Grade 3–4 tumor flare was observed in five (18%) patients. The overall response rate was 11% (3 of 28) with one (4%) complete remission and two (7%) partial remissions. Duration of response for these three responders was 3, 14 and 15 months. Fourteen (50%) patients had stabilisation of disease for a median duration of 8 months (95% CI: 7–16 months). Median time to progression for all 28 patients was 7.3 months. Although thalidomide appears to have modest clinical activity in pretreated/relapsed CLL primarily based on reduction of the absolute lymphocyte count, in our opinion the toxicity profile precludes it from more active investigation in CLL.
PMCID: PMC3928100  PMID: 19373657
CLL; treatment; relapsed; thalidomide; angiogenesis
8.  Quantitative DNA Methylation Analysis Identifies a Single CpG Dinucleotide Important for ZAP-70 Expression and Predictive of Prognosis in Chronic Lymphocytic Leukemia 
Journal of Clinical Oncology  2012;30(20):2483-2491.
Increased ZAP-70 expression predicts poor prognosis in chronic lymphocytic leukemia (CLL). Current methods for accurately measuring ZAP-70 expression are problematic, preventing widespread application of these tests in clinical decision making. We therefore used comprehensive DNA methylation profiling of the ZAP-70 regulatory region to identify sites important for transcriptional control.
Patients and Methods
High-resolution quantitative DNA methylation analysis of the entire ZAP-70 gene regulatory regions was conducted on 247 samples from patients with CLL from four independent clinical studies.
Through this comprehensive analysis, we identified a small area in the 5′ regulatory region of ZAP-70 that showed large variability in methylation in CLL samples but was universally methylated in normal B cells. High correlation with mRNA and protein expression, as well as activity in promoter reporter assays, revealed that within this differentially methylated region, a single CpG dinucleotide and neighboring nucleotides are particularly important in ZAP-70 transcriptional regulation. Furthermore, by using clustering approaches, we identified a prognostic role for this site in four independent data sets of patients with CLL using time to treatment, progression-free survival, and overall survival as clinical end points.
Comprehensive quantitative DNA methylation analysis of the ZAP-70 gene in CLL identified important regions responsible for transcriptional regulation. In addition, loss of methylation at a specific single CpG dinucleotide in the ZAP-70 5′ regulatory sequence is a highly predictive and reproducible biomarker of poor prognosis in this disease. This work demonstrates the feasibility of using quantitative specific ZAP-70 methylation analysis as a relevant clinically applicable prognostic test in CLL.
PMCID: PMC3397783  PMID: 22564988
9.  Progressive but Previously Untreated CLL Patients with Greater Array CGH Complexity Exhibit a Less Durable Response to Chemoimmunotherapy 
Cancer genetics and cytogenetics  2010;203(2):161-168.
To better understand the implications of genomic instability and outcome in B-cell CLL, we sought to address genomic complexity as a predictor of chemosensitivity and ultimately clinical outcome in this disease. We employed array-based comparative genomic hybridization (aCGH), using a one-million probe array and identified gains and losses of genetic material in 48 patients treated on a chemoimmunotherapy (CIT) clinical trial. We identified chromosomal gain or loss in ≥6% of the patients on chromosomes 3, 8, 9, 10, 11, 12, 13, 14 and 17. Higher genomic complexity, as a mechanism favoring clonal selection, was associated with shorter progression-free survival and predicted a poor response to treatment. Of interest, CLL cases with loss of p53 surveillance showed more complex genomic features and were found both in patients with a 17p13.1 deletion and in the more favorable genetic subtype characterized by the presence of 13q14.1 deletion. This aCGH study adds information on the association between inferior trial response and increasing genetic complexity as CLL progresses.
PMCID: PMC3026606  PMID: 21156228
CLL; aCGH; genotype; prognosis
10.  Acquired Chromosomal Anomalies in Chronic Lymphocytic Leukemia (CLL) Patients Compared to >50,000 Quasi-normal Subjects 
Cancer genetics  2014;207(0):19-30.
Pre-therapy CLL patients from US Intergroup trial E2997 were analyzed with single nucleotide polymorphism microarrays to detect acquired chromosomal anomalies. The four CLL-typical anomalies (11q-, +12, 13q- and 17p-) were found at expected frequencies. Acquired anomalies in other regions account for 70% of the total detected and their number per subject has a significant effect on progression-free survival after adjusting for the effects of 17p- (and other covariates). These results were compared with a previous study of >50,000 subjects from the GENEVA consortium of genome-wide association studies, which analyzed individuals with a variety of medical conditions and healthy controls. The percentage of individuals with acquired anomalies is vastly different between the two studies (GENEVA 0.8%; E2997 80%). The composition also differs, with GENEVA having a higher percentage of acquired uniparental disomies and a lower percentage of deletions. The four common CLL anomalies are among the most frequent in GENEVA subjects, some of whom may have CLL-precursor conditions or early stages of CLL. However, the patients from E2997 (and other studies of symptomatic CLL) have recurrent acquired anomalies that were not found in GENEVA subjects, thus identifying genomic changes that may be unique to symptomatic stages of CLL.
PMCID: PMC4074414  PMID: 24613276
Chromosomal aberration; Chromosomal mosaic; Chronic Lymphocytic Leukemia; Cancer precursor condition; Cytogenetics
11.  Pentostatin and Rituximab Therapy for Previously Untreated B-CLL 
Cancer  2010;116(9):2180-2187.
We have shown that the combination of pentostatin (P), cyclophosphamide (C) and rituximab (R) achieves an overall response (OR) rate >90% with more than 40% complete responses (CR) in patients with untreated CLL. To evaluate if the tolerability of this regimen could be enhanced without sacrificing efficacy, we conducted a phase II trial of P and R without cyclophosphamide, using a higher P dose (4 mg/m2). Among the 33 patients enrolled, 82% were male, median age was 65 (9 patients ≥70 years) and 64% were Rai stage III-IV. The OR rate was 76% with 9 CR (27%), 5 nPR, and 11 PRs. At the time of this analysis, 29/33 patients are still alive and the median follow up for patients still alive is 14 months (range: 1-34.8 months). Four (12%) patients experienced grade 3 or higher hematologic toxicity and 5 (15%) experienced grade 3 or higher non-hematologic toxicity. Comparison of this trial to our previous PCR trial showed that patients treated with PCR had a higher OR rate (91% vs. 76%) and CR rate (41% vs. 27%) compared to patients treated with PR. Median treatment-free survival for all accrued patients was notably longer in PCR treated patients compared to PR (30 vs. 16 months). These findings suggest that increasing the dose of the purine nucleoside analogue does not eliminate the need for cyclophosphamide in chemoimmunotherapy for treatment of CLL.
PMCID: PMC2919331  PMID: 20187101
pentostatin; rituximab; cyclophosphamide; chemoimmunotherapy; response rates; B-CLL
12.  Familial CLL: What Does It Mean to Me? 
Clinical lymphoma & myeloma  2009;9(Suppl 3):S194-S197.
While B-Chronic Lymphocytic Leukemia (CLL) is known to be a heterogeneous disease, it is only recently that the familial component of CLL has been more thoroughly investigated. This entity is seen in approximately 5–10% of all CLL patients and can be associated with earlier age of diagnosis, more female prevalence, and increased incidence of other lymphoproliferative disorders (LPD), such as non-Hodgkin Lymphoma and the more recently described monoclonal B cell lymphocytosis CLL in family members. The prognostic parameters and clinical course of familial CLL is not clearly distinguishable from that of sporadic disease. In addition, it is not clear that the treatment responses for progressive disease has any discernible difference in familial vs. sporadic CLL. The genetic etiology of CLL is unknown and early work on familial CLL has not yet uncovered any obvious gene or group of genes that can be clearly related to the pathophysiology of CLL. However, the detailed genetic study of familial CLL is likely to be critical in uncovering relevant genes. At present it is best to indicate to concerned CLL patients that their relatives are at relatively low risk of developing CLL or other LPD.
PMCID: PMC3061547  PMID: 19778840
Familial CLL; Sporadic CLL; genetics; prognosis; clinical course
13.  Autoimmune Complications in Chronic Lymphocytic Leukemia (CLL) 
Patients with B-chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL) have a 5–10% risk of developing autoimmune complications which primarily cause cytopenia. These autoimmune cytopenias can occur at any stage of CLL and do not have independent prognostic significance. The most common autoimmune complication is autoimmune hemolytic anemia with a lower frequency of immune thrombocytopenia and pure red blood cell aplasia and only rare patients with autoimmune granulocytopenia. Autoimmune cytopenia should always be considered in the differential diagnosis of cytopenia in patients with CLL. Patients with CLL can also have more than one form of autoimmune cytopenia which can occur together with bone marrow failure. Treatment is usually effective but rarely curative for autoimmune cytopenia complicating CLL. Optimal therapy will depend on a timely and accurate diagnosis of autoimmune cytopenia and should be individualized according to the severity of the cytopenia and the presence or absence of concomitant progressive CLL requiring therapy.
PMCID: PMC2909690  PMID: 20620970
Chronic lymphocytic leukemia; small lymphocytic lymphoma; autoimmune hemolytic anemia; immune thrombocytopenia; pure red blood cell aplasia
15.  Bi-directional Activation between Mesenchymal Stem Cells and CLL B-Cells: Implication for CLL Disease Progression 
British journal of haematology  2009;147(4):471-483.
It was hypothesized that contact between chronic lymphocytic leukemia (CLL) B-cells and marrow stromal cells impact both cell types. To test this hypothesis, we utilized a long-term primary culture system from bone biopsies that reliably generates a mesenchymal stem cell (MSC). Co-culture of MSC with CLL B-cells protected the latter from both spontaneous apoptosis and drug-induced apoptosis. The CD38 expression in previously CD38 positive CLL B-cells was up-regulated with MSC co-culture. Up-regulation of CD71, CD25, CD69 and CD70 in CLL B-cells was found in the co-culture. CD71 up-regulation was more significantly associated with high-risk CLL, implicating CD71 regulation in the microenvironment predicting disease progression. In MSC, rapid ERK and AKT phosphorylation (within 30 min) were detected when CLL B-cells and MSC were separated by transwell; indicating that activation of MSC was mediated by soluble factors. These findings support a bi-directional activation between bone marrow stromal cells and CLL B-cells.
PMCID: PMC2783570  PMID: 19751240
B-cells; cell signalling; chronic lymphocytic leukaemia; mesenchymal cells; stromal cell
16.  Ofatumumab-based chemoimmunotherapy is effective and well tolerated in patients with previously untreated CLL 
Cancer  2013;119(21):3788-3796.
Although rituximab-based chemoimmunotherapy (CIT) has substantially improved clinical outcomes in chronic lymphocytic leukemia (CLL), only 40-50% of patients achieve a complete remission (CR). There remains interest in identifying new approaches to improve the effectiveness of CIT. Ofatumumab is a fully human anti-CD20 monoclonal antibody with greater apparent single agent activity than rituximab in CLL patients.
Previously untreated CLL patients in need of therapy received 6 cycles of CIT induction with pentostatin, cyclophosphamide and ofatumumab (PCO) followed by response assessment.
Of the 48 patients enrolled, 77% completed PCO induction. Adverse events during induction included grade 3+ hematologic toxicity (27%) and grade 3+ non-hematologic toxicity (23%). Median CD4 count post induction and 6 months later were 186 ×106/L and 272 ×106/L. The overall response rate was 96% (46/48) and the CR rate was 46% (22/48). Among the 38 patients who underwent minimal residual disease (MRD) evaluation, 7 (18%) were MRD negative. After median follow-up of 24 months, 10 (21%) patients have progressed and 8 (17%) have required retreatment. The efficacy and toxicity of ofatumumab-based CIT compare favorably to our historical trials of rituximab-based CIT using an identical chemotherapy backbone (n=64). Time to retreatment also appeared longer for ofatumumab-based CIT (free of retreatment at 24 months: 86% [95%CI: 75-99] vs 68% [95% CI: 56-81]).
Ofatumumab-based CIT is well tolerated in patients with previously untreated CLL. The efficacy of ofatumumab-based CIT compares favorably to historical trials of rituximab-based CIT suggesting randomized trials comparing ofatumumab-based CIT and rituximab-based CIT should be considered.
PMCID: PMC3894149  PMID: 23922059
chronic lymphocytic leukemia(CLL; small lymphocytic lymphoma(SLL); treatment; ofatumumab; chemoimmunotherapy
17.  Diffuse Large B-Cell Lymphoma (Richter Syndrome) in Patients with Chronic Lymphocytic Leukaemia: A Cohort Study of Newly Diagnosed Patients 
British journal of haematology  2013;162(6):774-782.
Nearly all information about patients with chronic lymphocytic leukaemia (CLL) who develop diffuse large B-cell lymphoma (Richter syndrome [RS]) is derived from retrospective case series or patients treated on clinical trials. We used the Mayo Clinic CLL Database to identify patients with newly diagnosed CLL (1/2000–7/2011). Individuals who developed biopsy-proven RS during follow-up were identified. After median follow-up of 4 years, 37/1641 (2.3%) CLL patients developed RS. The rate of RS was approximately 0.5%/year. Risk of RS was associated with advanced Rai stage at diagnosis (p<0.001), high-risk FISH (p<0.0001), unmutated IGHV (p=0.003), and expression of ZAP-70 (p=0.02) and CD38 (p=0.001). The rate of RS doubled in patients treated for CLL (1%/year). Stereotyped B-cell receptors (odds-ratio=4.2; p=0.01) but not VH4–39 was associated with increased risk of RS. Treatment with combination of purine analogues and alkylating agents increased the risk of RS 3-fold (odds-ratio= 3.26, p=0.0003). Median survival after RS diagnosis was 2.1 years. The RS prognosis score stratified patients into three risk groups with median survivals of 0.5 years, 2.1 years and not reached. Both underlying characteristics of the CLL clone and subsequent CLL therapy influence the risk of RS. Survival after RS remains poor and new therapies are needed.
PMCID: PMC4098845  PMID: 23841899
transformation; aggressive lymphoma; stem cell transplantation; purine analogues; RS survival score
18.  Phase II study of interleukin-12 for treatment of plateau phase multiple myeloma (E1A96): A trial of the Eastern Cooperative Oncology Group✩ 
Leukemia research  2009;33(11):1485-1489.
The Eastern Cooperative Oncology Group (ECOG) conducted a phase II trial of interleukin-12 (IL-12) for plateau phase multiple myeloma. Patients were initially treated with IL-12 250 ng/kg I.V. daily for 5 days every 3 weeks. The trial was modified due to toxicity after the first 16 patients. IL-12 was given 300 ng/kg subcutaneously twice weekly for 24 weeks. Of 48 eligible patients, there were 4 objective responses (8.3%), all CR. The median survival and progression-free survival were 42.8 and 11.4 months. Unacceptable grade 3 or 4 non-hematologic toxicity (31% with IL-12 subcutaneously and 63% with IL-12 intravenously) was observed.
PMCID: PMC4070590  PMID: 19243818
Multiple myeloma; Interleukin-12; Immunomodulatory therapy
19.  Stimulation of Chronic Lymphocytic Leukemia (CLL) Cells with CpG Oligodeoxynucleotide (ODN) Gives Consistent Karyotypic Results among Laboratories: a CLL Research Consortium (CRC)h Study 
Cancer genetics and cytogenetics  2010;203(2):134-140.
Cytogenetic abnormalities in CLL are important prognostic indicators. Historically, only interphase cytogenetics was clinically useful in CLL because traditional mitogens are not effective mitotic stimulants. Recently, CpG-oligodeoxynucleotide (ODN) stimulation has shown effectiveness in CLL. The CLL Research Consortium (CRC) tested the effectiveness and reproducibility of CpG-ODN stimulation to detect chromosomally abnormal clones by five laboratories. More clonal abnormalities were observed after culture of CLL cells with CpG-ODN than with pokeweed mitogen (PWM)+12-O-tetradecanoyl-phorobol-13-acetate (TPA). All clonal abnormalities in PWM+TPA cultures were observed in CpG-ODN cultures, whereas CpG-ODN identified some clones not found by PWM+TPA. CpG-ODN stimulation of one normal control and 12 CLL samples showed that excepting clones of del(13q) in low frequencies and one translocation, results in all five laboratories were consistent, and all abnormalities were concordant with FISH. Thus, abnormal clones in CLL are more readily detected with CpG-ODN stimulation than with traditional B-cell mitogens. After CpG-ODN stimulation, abnormalities were reproducible among cytogenetic laboratories. CpG-ODN did not appear to induce aberrations in cell culture and enhanced detection of abnormalities and complexity in CLL. Since karyotypic complexity is prognostic and is not detectable by standard FISH analyses, stimulation with CpG-ODN is useful to identify this additional prognostic factor in CLL.
PMCID: PMC3018693  PMID: 21156225
20.  Experimental Designs for Array Comparative Genomic Hybridization (aCGH) Technology 
Cytogenetic and genome research  2013;139(4):250-257.
Array comparative genomic hybridization (aCGH) technology is commonly used to estimate genome-wide copy number variation and to evaluate associations with copy number and disease. Although aCGH technology is well developed and there are numerous algorithms available for estimating copy number, little attention has been paid to the important issue of statistical experimental design. Herein, we review classical statistical experimental designs and discuss their relevance to aCGH technology as well as their importance for down-stream statistical analyses. Furthermore, we provide experimental design guidance for various study objectives.
PMCID: PMC3728659  PMID: 23548696
21.  Critical Signal Transduction Pathways in CLL 
Receptor tyrosine kinases (RTKs) are cell-surface transmembrane receptors that contain regulated kinase activity within their cytoplasmic domain and play a critical role in signal transduction in both normal and malignant cells. Besides B-cell receptor (BCR) signaling in CLL, multiple RTKs have been reported to be constitutively active in CLL B-cells resulting in enhanced survival and resistance to apoptosis of the leukemic cells induced by chemotherapeutic agents. In addition to increased plasma levels of various types of cytokines/growth factors in CLL, we and others have detected that CLL B-cells spontaneously produce multiple cytokines in vitro which may constitute an autocrine loop of RTK activation on the leukemic B-cells. Moreover, aberrant expression and activation of non-RTKs, for example Src/Syk kinases, induce resistance of the leukemic B-cells to therapy. Based on current available knowledge, we detailed the impact of aberrant activities of various RTKs/non-RTKs on CLL B-cell survival and the potential of using these signaling components as future therapeutic targets in CLL therapy.
PMCID: PMC3918736  PMID: 24014299
CLL; Signal Transduction; RTK; Non-RTK; Apoptosis; Kinase Inhibitor; Therapy
22.  Autoimmune Cytopenia in Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL): Changes in Clinical Presentation and Prognosis 
Leukemia & lymphoma  2009;50(8):1261-1268.
Improved medical care could have altered the clinical presentation and survival of patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL) complicated by autoimmune cytopenia (AID cytopenia). We reviewed the clinical characteristics, treatment, and outcome of AID cytopenia that was diagnosed in 75 (4.3%) of 1750 CLL patients seen at a single institution over 10 years. Compared to historical reported data, our study shows a lower rate of autoimmune hemolytic anemia (2.3%), and similar rates of immune thrombocytopenia (2.0%) and pure red blood cell aplasia (0.5%). AID cytopenia occurred at all stages of CLL, responded well to treatment, did not alter overall survival, and contributed to death in only 6 (12%) patients. We propose that more sensitive and accurate diagnostic methods for CLL have decreased the perceived prevalence of AID cytopenia and that improvements in management could have increased the survival of these patients.
PMCID: PMC3917557  PMID: 19811329
23.  Statin and Non-steroidal Anti-inflammatory Drug (NSAID) Use In Relation to Clinical Outcome Among Patients with Rai Stage 0 Chronic Lymphocytic Leukemia (CLL) 
Leukemia & lymphoma  2010;51(7):1233-1240.
Statins and nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most commonly prescribed medications. In vitro studies suggest that statins and NSAIDs may have potential as anti-cancer therapies in low grade non-Hodgkin lymphomas including chronic lymphocytic leukemia (CLL) and a recent observational study found statin use was associated with improved event free survival in patients with follicular lymphoma. Other studies have suggested that statins reduce the efficacy of rituximab by inhibiting binding to CD20. We therefore conducted an observational cohort study of 686 patients with newly diagnosed Rai stage 0 CLL to evaluate whether statin or NSAID use was related to their clinical outcome or influenced the efficacy of rituximab therapy. At diagnosis, 136 (20%) patients took statins and 230 (34%) scheduled daily aspirin, ibuprofen, or naproxen. No difference in time to treatment was observed based on statin or NSAID use. Among patients receiving a rituximab containing first-line therapy, no difference in time to salvage treatment was observed based on statin use. Although previous studies suggested statins may improve event free survival among patients with follicular lymphoma, we find no impact of statins on time to initial therapy in this large study of patients with Rai stage 0 CLL. The in vitro observation that statins reduce rituximab efficacy does not appear to have clinical significance in CLL care.
PMCID: PMC3913168  PMID: 20496995
25.  Phase 2 Trial of Daily, Oral Polyphenon E in Patients with Asymptomatic, Rai Stage 0-II Chronic Lymphocytic Leukemia(CLL) 
Cancer  2012;119(2):363-370.
To follow-up the results of phase I testing by evaluating the clinical efficacy of the green tea extract Polyphenon E for patients with early stage chronic lymphocytic leukemia(CLL).
Previously untreated patients with asymptomatic, Rai stage 0-II CLL and an absolute lymphocyte count(ALC) ≥10 ×109/L were eligible for this phase II trial. Polyphenon E with a standardized dose of epigallocatechin-3-gallate(2000 mg per dose) was administered twice daily.
Forty-two patients received Polyphenon E 2000 mg twice daily for up to 6 months. Among these, 29 (69%) had Rai stage I-II disease. Patients received a median of 6 cycles of treatment(range: 1-6). The most common grade 3 side effects were transaminitis (n=1), abdominal pain(n=1) and fatigue(n=1). Clinical activity was observed with 13(31%) patients experiencing a sustained ≥20% reduction in ALC and 20 of 29(69%) patients with palpable adenopathy experiencing at least a 50% reduction in the sum of the products of all nodal areas. EGCG plasma levels after 1 month of therapy correlated with reductions in lymphadenopathy (correlation 0.44; p=0.02). Overall, 29(69%) patients fulfilled the criteria for a biologic response with either a sustained ≥20% decline in ALC and/or a ≥30% reduction in the sum of the products of all nodal areas at some point during the 6 months of active treatment.
Daily oral EGCG in the Polyphenon E preparation was well tolerated by CLL patients in this phase II trial. Durable declines in ALC and/or lymphadenopathy were observed in the majority of patients.
PMCID: PMC3902473  PMID: 22760587

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