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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.  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
3.  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
4.  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
5.  Age at Diagnosis and the Utility of Prognostic Testing in Patients with Chronic Lymphocytic Leukemia (CLL) 
Cancer  2010;116(20):4777-4787.
To analyze the survival of CLL patients relative to age-matched individuals in the general population and determined the age-stratified utility of prognostic testing.
All 2487 patients diagnosed with CLL between January 1995 and June 2008 and cared for in the Mayo Division of Hematology were categorized by age at diagnosis and evaluated for differences in clinical characteristics, time to first treatment(TFT), and overall survival(OS).
Among Rai stage 0 patients, survival was shorter than the age-matched general population for patients age<55 years(p<0.001), 55-64 years(p<0.001), and 65-74 years(p<0.001) but not those age≥75 at diagnosis(p=NS). CD38, IGHV mutation, and ZAP-70 each predicted TFT independent of stage for all age groups(all p <0.04) but had less value for predicting OS, particularly as age increased. IGHV and FISH predicted OS independent of stage for patients
Survival of CLL patients age<75 is shorter than the age-matched general population regardless of disease stage. Among patients age<75, the simple combinations of stage and IGHV or stage and FISH identifies those with excess risk of death relative to the age-matched population. Although useful for predicting TFT independent of stage for patients of all ages, prognostic testing had little utility for predicting OS independent of stage among patients age≥75.
PMCID: PMC3902481  PMID: 20578179
Annals of epidemiology  2012;22(12):855-862.
To evaluate the association of body mass index (BMI) and physical activity (PA) during adulthood and at age 18 with risk of non-Hodgkin lymphoma (NHL).
We enrolled 950 newly diagnosed NHL patients and 1146 frequency-matched clinic-based controls. Height, weight, and PA (recent adult and at age 18) were self-reported. Odds ratios (OR), 95% confidence intervals (CI), and tests for trend were estimated using unconditional logistic regression adjusted for age, gender, and residence.
BMI at age 18 was associated with an increased NHL risk (OR=1.38 for highest vs. lowest quartile, p-trend=0.0012), which on stratified analysis was specific to females (OR=1.90, p-trend=0.00025). There was no association of adult BMI with NHL risk. Higher physical activity in adulthood (OR=1.03, p-trend=0.85) or at age 18 (OR=0.88, 95%CI: 0.72–1.07) was not associated with risk, but there was an inverse association for adult physical activity that was specific to females (OR=0.71, p-trend=0.039). Only BMI at age 18 remained significantly associated with NHL risk when modeled together with adult or age 18 physical activity. There was little evidence for heterogeneity in these results for the common NHL subtypes.
Early adult BMI may be of greatest relevance to NHL risk, particularly in females.
PMCID: PMC3513768  PMID: 23146413
body mass index; exercise; lymphoma; non-Hodgkin; etiology; case-control studies
British journal of haematology  2012;159(5):572-576.
A recent meta-analysis of three genome-wide association studies of chronic lymphocytic leukaemia (CLL) identified two common variants at the 6p21.31 locus that are associated with CLL risk. To verify and further explore the association of these variants with other non-Hodgkin lymphoma (NHL) subtypes, we genotyped 1196 CLL cases, 1699 NHL cases, and 2410 controls. We found significant associations between the 6p21.31 variants and CLL risk (rs210134: P=0.01; rs210142: P=6.8×10−3). These variants also showed a trend towards association with some of the other NHL subtypes. Our results validate the prior work and support specific genetic pathways for risk among NHL subtypes.
PMCID: PMC3614403  PMID: 23025533
CLL; NHL; SNPs; BAK1; risk locus
British journal of haematology  2008;141(5):10.1111/j.1365-2141.2008.07070.x.
Patients with CLL have a variable clinical course. Identification of modifiable characteristics related to CLL-specific survival may provide opportunities for therapeutic intervention. The absolute number of T-cell and natural kill(NK)-cells was calculated for 166 consecutive patients with CLL evaluated by flow cytometry at Mayo Clinic <2 months of diagnosis. The size of the T-cell/NK-cell compartment relative to the size of the malignant monoclonal B-cell(MBC) compartment was evaluated by calculating NK:MBC and T:MBC ratios. Patients exhibited substantial variation in the absolute number of T and NK-cells as well as T:MBC and NK:MBC ratios at diagnosis. Higher T:MBC and NK:MBC ratios were observed among patients with early stage and mutated IgVH genes(all P<0.0003). As continuous variables, both T:MBC ratio(p value=0.03) and NK:MBC ratio(p value=0.02) were associated with time to treatment(TTT). On multivariate Cox modeling including stage, CD38, absolute MBC count, NK:MBC ratio, and T:MBC ratio, the independent predictors of TTT were stage, T:MBC ratio, and NK:MBC ratio. These findings suggest measurable characteristics of the host immune system relate to the rate of disease progression in patients with newly diagnosed CLL. These characteristics can be modified and continued evaluation of immunomodulatory drugs, vaccination strategies, and cellular therapies to delay/prevent disease progression are warranted.
PMCID: PMC3840945  PMID: 18384436
CLL; prognosis; immune system; T-cells; natural killer cells
Antioxidants, primarily from fruits and vegetables, have been hypothesized to protect against non-Hodgkin lymphoma (NHL). The Oxygen Radical Absorbance Capacity (ORAC) assay, which measures total antioxidant capacity of individual foods and accounts for synergism, can be estimated using a food-frequency questionnaire (FFQ). We tested the hypothesis that higher intake of antioxidant nutrients from foods, supplements, and FFQ-based ORAC values are associated with a lower risk of NHL in a clinic-based study of 603 incident cases and 1007 frequency-matched controls. Diet was assessed with a 128-item FFQ. Logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals adjusted for age, sex, residence and total energy. Dietary intake of α-tocopherol (OR=0.50; p-trend=0.0002), β-carotene (OR=0.58; p-trend=0.0005), lutein/zeaxanthin (OR=0.62; p-trend=0.005), zinc (OR=0.54; p-trend=0.003) and chromium (OR=0.68; p-trend=0.032) were inversely associated with NHL risk. Inclusion of supplement use had little impact on these associations. Total vegetables (OR=0.52; p-trend<0.0001), particularly green leafy (OR=0.52; p-trend<0.0001) and cruciferous (OR=0.68; p-trend=0.045) vegetables, were inversely associated with NHL risk. NHL risk was inversely associated with both hydrophilic ORAC (OR=0.61, p-trend=0.003) and lipophilic ORAC (OR=0.48, p-trend=0.0002), although after simultaneous adjustment for other antioxidants or total vegetables only the association for lipophilic ORAC remained significant. There was no striking heterogeneity in results across the common NHL subtypes. Higher antioxidant intake as estimated by the FFQ-ORAC, particularly the lipophilic component, was associated with a lower NHL risk after accounting for other antioxidant nutrients and vegetable intake, supporting this as potentially useful summary measure of total antioxidant intake.
PMCID: PMC3306533  PMID: 22038870
Diet; non-Hodgkin lymphoma; vegetables; antioxidants; ORAC
Leukemia & lymphoma  2010;51(4):620-627.
Treatment of autoimmune cytopenia complicating progressive chronic lymphocytic leukemia (CLL) is constrained by intolerance of myelosuppression and the risk of exacerbation of autoimmune cytopenia by purine analogs particularly when used as single agents. We report on 20 such patients treated with rituximab, cyclophosphamide, vincristine, and prednisone (R-CVP). Autoimmune cytopenia responded in 19 patients (14 complete remissions (CR), five partial remissions (PR)) with a median time to next treatment (TTT) for autoimmune cytopenia of 21.7 months. Progressive CLL responded in 17 patients (nine CR/complete clinical response, eight PR) with a median TTT of 27.7 months. Five patients have not required any re-treatment at 15–30 months. Grade 3–4 toxicities were infections (n = 3) and drug-induced pneumonitis (n = 1). No patient required blood cell transfusions after cycle 1 of therapy. We conclude that R-CVP is effective and tolerable therapy for autoimmune cytopenia complicating progressive CLL, but the duration of response is suboptimal.
PMCID: PMC3448550  PMID: 20302386
Chronic lymphocytic leukemia; autoimmune hemolytic anemia; immune thrombocytopenia; pure red blood cell aplasia; therapy
Leukemia & lymphoma  2011;53(2):211-217.
CpG oligonucleotide 7909 (CpG 7909, PF-03512676), a synthetic 24mer single stranded agonist of TLR9 expressed by B cells and plasmacytoid dendritic cells, is immunomodulatory and can cause activation-induced death of chronic lymphocytic leukemia (CLL) cells. We report a phase I study of CpG 7909 in 41 patients with early relapsed CLL. A single intravenous dose of CpG 7909 was well tolerated with no clinical effects and no significant toxicity up to 1.05 mg/kg. Single dose subcutaneous CpG 7909 had a maximum tolerated dose (MTD) of 0.45 mg/kg with dose limiting toxicity of myalgia and constitutional effects. Multiple weekly subcutaneous doses at the MTD were well tolerated. CpG 7909 administration induced immunologic changes in CLL and non-malignant cells that were dose and route dependent. We conclude that multidose therapy with subcutaneous CpG 7909 (0.45 mg/kg) could be used in future phase II combination clinical trials for CLL.
PMCID: PMC3438221  PMID: 21812536
Chronic lymphocytic leukemia; CLL; CpG oligonucleotide 7909; PF-03512676; CpG 2006; TLR9
The t(14;18)(q32;q21) is the most commonly observed chromosomal translocation in non-Hodgkin lymphoma (NHL), resulting in constitutive Bcl-2 expression and apoptosis inhibition. In addition, germline variation in both BCL2L11 (BIM) and CASP9, known regulators of apoptosis, have recently been linked to NHL risk. We conducted a comprehensive evaluation of 36 apoptosis pathway genes with risk of NHL.
We genotyped 226 single nucleotide polymorphisms (SNPs) from 36 candidate genes in a clinic-based study of 441 newly diagnosed NHL cases and 475 frequency matched controls. We used principal components analysis to assess gene-level associations, and logistic regression to assess SNP-level associations. MACH was used for imputation of SNPs in BCL2L11 and CASP9.
In gene level analyses, BCL2L11 (p=0.0019), BCLAF1 (p=0.0097), BAG5 (p=0.026) and CASP9 (p=0.0022) were associated with NHL risk after accounting for multiple testing (tail strength 0.38; 95% CI 0.05, 0.70). Two of the 5 BCL2L11 tagSNPs (rs6746608 and rs12613243), both genotyped BCLAF1 tagSNPs (rs797558 and rs703193), the single genotyped BAG5 tagSNP (rs7693), and 3 of the 7 genotyped CASP9 tagSNPs (rs6685648, rs2020902, rs2042370) were significant at p<0.05. We successfully imputed BCL2L11 and CASP9 SNPs previously linked to NHL, and replicated all 4 BCL2L11 and 2 of 3 CASP9 SNPs.
We replicated the association of BCL2L11 and CASP9 with NHL risk at the gene and SNP-level, and identified novel associations with BCLAF1 and BAG5.
Closer evaluation of germline variation of genes in the apoptosis pathway with risk of NHL and its subtypes is warranted.
PMCID: PMC2976783  PMID: 20855536
Bcl-2 pathways; caspases; molecular epidemiology; non-Hodgkin lymphoma
The Oncologist  2010;15(6):601-602.
The study looks at the high cost of new treatments for chronic lymphocytic leukemia and calls for the consideration of a standardized and transparent method to determine the price of new drugs based on comparative effectiveness.
PMCID: PMC3227992  PMID: 20463087
Cancer  2010;116(9):2201-2207.
Patients with relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL) often have chemotherapy resistant disease resulting in a poor prognosis. The aim of this study was to learn if inhibition of the mammalian target of rapamycin (mTOR) would produce tumor responses.
This was a phase II study of oral single-agent everolimus (10 mg/day) for relapsed/refractory indolent lymphoid malignancies including CLL.
Four of 22 patients with CLL (18%, 95% CI: 5–40%) achieved a partial remission to therapy. An unanticipated finding in this study was an increase in the absolute lymphocyte count (ALC) associated with a decrease in lymphadenopathy in 8 (36%) patients. The ALC increased a median of 4.8 fold (range, 1.9 – 25.1), and the clinically measurable lymphadenopathy decreased a median of 75.5% (range, 38 – 93) compared to baseline measurements.
Everolimus has modest anti-tumor activity against CLL and can mobilize malignant cells from nodal masses into the peripheral circulation in a subset of CLL patients. Because CLL cells in lymphatic tissue and bone marrow can be more resistant to therapy than circulating CLL cells, the ability of everolimus to mobilize CLL cells into the circulation could be utilized in combination therapeutic regimens.
PMCID: PMC2861142  PMID: 20166206
CLL; mTOR; inhibitor; everolimus; rapamycins; mobilization
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
We present the design features and implementation of a clinic-based case-control study on the molecular epidemiology of lymphoma conducted at the Mayo Clinic (Rochester, Minnesota, USA), and then assess the internal and external validity of the study. Cases were newly diagnosed lymphoma patients from Minnesota, Iowa and Wisconsin seen at Mayo and controls were patients from the same region without lymphoma who had a pre-scheduled general medical examination, frequency matched on age, sex and residence. Overall response rates were 67% for cases and 70% for controls; response rates were lower for cases and controls over age 70 years, cases with more aggressive disease, and controls from the local area, although absolute differences were modest. Cases and controls were well-balanced on age, sex, and residence characteristics. Demographic and disease characteristics of NHL cases were similar to population-based cancer registry data. Control distributions were similar to population-based data on lifestyle factors and minor allele frequencies of over 500 SNPs, although smoking rates were slightly lower. Associations with NHL in the Mayo study for smoking, alcohol use, family history of lymphoma, autoimmune disease, asthma, eczema, body mass index, and single nucleotide polymorphisms in TNF (rs1800629), LTA (rs909253), and IL10 (rs1800896) were at a magnitude consistent with estimates from pooled studies in InterLymph, with history of any allergy the only directly discordant result in the Mayo study. These data suggest that this study should have strong internal and external validity. This framework may be useful to others who are designing a similar study.
PMCID: PMC3110384  PMID: 21686124
Case-control study; etiology; lymphoma; molecular epidemiology; validity
British journal of haematology  2009;148(4):544-550.
Deletion 13q14 on fluorescence in situ hybridization (FISH) analysis is the most common cytogenetic abnormality in chronic lymphocytic leukemia (CLL), and is a favorable prognostic biomarker when detected as a sole abnormality. We intensively interrogated clinical outcome in 323 consecutive, untreated CLL patients with isolated 13q- identified within two years of diagnosis. We also analyzed outcome in 217 additional patients with deletion 11q22.3 or 17p13.1, or trisomy 12 based on whether these occurred in isolation or in conjunction with 13q-. Patients with a heterozygous 13q- and those with a homozygous deletion had similar time to first treatment (TFT) and overall survival (OS). In contrast, a higher percentage of 13q- nuclei was associated with significantly shorter TFT (p<0.001). The 5-year untreated rate was 79% for patients with isolated 13q- in ≤65.5% of nuclei compared to 38% among those with 13q- in >65.5% of nuclei (p<0.001). The percentage of nuclei exhibiting 13q- remained an independent predictor of TFT after controlling for ZAP-70, IgVH, or CD38 (all p<0.001). Among patients with 13q- plus one other FISH abnormality, concomitant 13q- appeared to attenuate the shorter survival associated with 17p- (p=0.019). The clinical implications of 13q- in CLL appear more complex than originally appreciated.
PMCID: PMC2866061  PMID: 19895615
Chronic lymphocytic leukemia; 13q deletion; 17p deletion
Cytometry. Part B, Clinical cytometry  2010;78(Suppl 1):S35-S41.
The pathology and clinical course of patients with CD5+ chronic B-cell lymphoproliferative disorders, excluding those that present with typical chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL) or mantle cell lymphoma, (i.e. CD5+B-CLPD) are poorly defined.
We studied patients with CD5+B-CLPD to 1) more completely define the clinical features and pathology of CD5+B-CLPD, 2) compare these features to patients presenting with typical CLL, and 3) test the hypothesis that a subset of patients with CD5+B-CLPD could have a unique B-cell malignancy.
We identified 229 patients with CD5+B-CLPD. A definitive pathological diagnosis was made in all 61 (27%) CD5+B-CLPD patients with non-bone marrow (BM) biopsy specimens considered adequate for a comprehensive pathological examination. The most common diagnosis among these 61 patients was CLL (44%) followed by the leukemic phase of marginal zone lymphoma (34%), lymphoplasmacytic lymphoma (11%), diffuse large B cell lymphoma (8%), and high grade B cell lymphoma not otherwise specified (2%). In contrast, among 168 patients without a non-BM tissue biopsy specimen, a specific diagnosis could be made on review of all available data in only 24 (14%) with 144 (86%) remaining “unclassified”.
In patients with CD5+B-CLPD, a definitive diagnosis can be made on an adequate non-BM tissue biopsy suggesting that this entity does not include a novel disease. We recommend that all patients with CD5+B-CLPD should have a non-BM tissue biopsy to make a definitive diagnosis prior to initiation of treatment.
PMCID: PMC2943034  PMID: 20568273
CD5; chronic lymphoproliferative disorders; CLL; SLL; lymphoma
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
Journal of Clinical Oncology  2009;27(24):3959-3963.
The diagnosis of monoclonal B-cell lymphocytosis (MBL) is used to characterize patients with a circulating population of clonal B cells, a total B-cell count of less than 5 × 109/L, and no other features of a B-cell lymphoproliferative disorder including lymphadenopathy/organomegaly. The natural history of clinically identified MBL is unclear. The goal of this study was to explore the outcome of patients with MBL relative to that of individuals with Rai stage 0 chronic lymphocytic leukemia (CLL).
Patients and Methods
We used hematopathology records to identify a cohort of 631 patients with newly diagnosed MBL or Rai stage 0 CLL. Within this cohort, 302 patients had MBL (B-cell counts of 0.02 to 4.99 × 109/L); 94 patients had Rai stage 0 CLL with an absolute lymphocyte count (ALC) ≤ 10 × 109/L; and 219 patients had Rai stage 0 CLL with an ALC more than 10 × 109/L. Data on clinical outcome were abstracted from medical records.
The percentage of MBL patients free of treatment at 1, 2, and 5 years was 99%, 98%, and 93%, respectively. B-cell count as a continuous variable (hazard ratio [HR] = 2.9, P = .04) and CD38 status (HR = 10.8, P = .006) predicted time to treatment (TTT) among MBL patients. The likelihood of treatment for MBL patients was lower (HR = 0.32, P = .04) than that of both Rai stage 0 CLL patients with an ALC less than 10 × 109/L (n = 94) and Rai stage 0 CLL patients with an ALC more than 10 × 109/L (n = 219; P = .0003).
Individuals with MBL identified in clinical practice have a low risk for progression at 5 years. Because B-cell count seems to relate to TTT as a continuous variable, additional studies are needed to determine what B-cell count should be used to distinguish between MBL and CLL.
PMCID: PMC2734397  PMID: 19620484
British journal of haematology  2009;145(5):614-623.
Germline mutations in complement genes have been associated with susceptibility to infections and autoimmune diseases, conditions that are associated with non-Hodgkin lymphoma (NHL) risk. To test the hypothesis that common genetic variation in complement genes affect risk of NHL, we genotyped 167 single nucleotide polymorphisms (SNPs) from 31 genes in 441 NHL cases and 475 controls. Principal components (PC) and haplotype analyses were used for gene-level tests of NHL risk, while individual SNPs were modeled as having a log-additive effect. In gene level PC analyses, C2 (p=0.023), C5 (p=0.0032) and C9 (p=0.020) were associated with NHL risk; haplotype analyses showed similar results, as well as a haplotype association for C7 (p=0.046). When all 4 genes were considered simultaneously, only C5 and C9 remained significant (p<0.05). In SNP level results from these genes, 10 SNPs had a p<0.05. However, after correcting for multiple testing, only the C5 SNPs rs7026551 (q=0.015; OR=1.54, 95% CI 1.21-1.95) and rs2416810 (q=0.015; OR=1.57; 95% CI 1.22-2.01), and the C9 SNP rs187875 (q=0.015; OR=0.68; 95% 0.56-0.84) remained noteworthy. Associations were similar for the common NHL subtypes. In summary, we provide evidence for a role of genetic variation in complement genes, particularly C5 and C9, and NHL risk.
PMCID: PMC2820509  PMID: 19344414
non-Hodgkin lymphoma; genetic variation; complement genes; epidemiology
Journal of Clinical Oncology  2009;27(11):1844-1849.
Smudge cells are ruptured chronic lymphocytic leukemia (CLL) cells appearing on the blood smears of CLL patients. Our recent findings suggest that the number of smudge cells may have important biologic correlations rather than being only an artifact of slide preparation. In this study, we evaluated whether the smudge cell percentage on a blood smear predicted survival of CLL patients.
Patients and Methods
We calculated smudge cell percentages (ratio of smudged to intact cells plus smudged lymphocytes) on archived blood smears from a cohort of previously untreated patients with predominantly early-stage CLL enrolled onto a prospective observational study. The relationship between percentage of smudge cells, patient survival, and other prognostic factors was explored.
Between 1994 and 2002, 108 patients were enrolled onto the study and had archived blood smears available for review; 80% of patients had Rai stage 0 or I disease. The median smudge cell percentage was 28% (range, 1% to 75%). The percentage of smudge cells was lower in CD38+ versus CD38– patients (P = .019) and in Zap70-positive versus Zap70-negative patients (P = .028). Smudge cell percentage as a continuous variable was associated with prolonged survival (P = .042). The 10-year survival rate was 50% for patients with 30% or less smudge cells compared with 80% for patients with more than 30% of smudge cells (P = .015). In multivariate analysis, the percentage of smudge cells was an independent predictor of overall survival.
Percentage of smudge cells on blood smear is readily available and an independent factor predicting overall survival in CLL.
PMCID: PMC2668708  PMID: 19255329
Cancer  2008;113(8):2110-2118.
CLL patients are usually only treated for progressive disease. However, the discovery of biological predictors of high risk of disease progression together with the development of newer more targeted therapies could change this paradigm. In this phase 2 study we tested the safety and efficacy of early treatment of high risk CLL patients with alemtuzumab and rituximab.
Patients were eligible for treatment if they were 1) previously untreated 2) had no NCI-Working Group 1996 criteria for treatment and 3) had at least one marker of high risk disease (17p13−, 11q22−, or combination of unmutated IgVH and CD38+/ZAP70+). Treatment consisted of subcutaneous alemtuzumab (initial dose escalation followed by 30 mg on Monday-Wednesday-Friday for 4 weeks) and intravenous rituximab (375 mg/m2/week × 4 doses). All patients received PCP and herpes virus prophylaxis and were monitored for CMV reactivation.
Twenty seven of thirty (90%) patients responded to therapy with 11 (37%) complete responses (CR). Five (17%) patients with CR had no detectable minimal residual disease. Median duration of response was 14.4 months and only nine patients have required re-treatment for progressive disease to date (median follow 17.6 months). Study patients had a significantly longer time from diagnosis to first treatment for CLL using conventional indications than a comparison cohort with similar biologic risk profiles.
The therapy regimen was safe and effective for high-risk, early stage patients. Further studies are required to determine if this early treatment strategy decreases morbidity and mortality for high-risk CLL.
PMCID: PMC2849723  PMID: 18759253
Chronic lymphocytic leukemia; CLL; high risk; early stage; alemtuzumab; rituximab
Leukemia research  2008;33(2):263-270.
We evaluated patients’ satisfaction with the physician caring for them as part of an international web-based survey of quality of life(QOL) in patients with chronic lymphocytic leukemia(CLL; n=1482). Over half(55.9%) of patients thought about their diagnosis daily. Although >90% felt their doctor understood how their disease was progressing(i.e., stage, blood counts, nodes), <70% felt their physician understood how CLL affected their QOL(anxiety, worry, fatigue). Reported satisfaction with their physician in a variety of areas strongly related to patients’ measured emotional and overall QOL(all p<0.001). Physician use of specific euphemistic phrases to characterize CLL (e.g., “CLL is the ‘good’ leukemia”) was also associated with lower emotional QOL among patients (p<0.001). These effects on QOL remained(p<0.001) after adjustment for age, co-morbid health conditions, fatigue, and treatment status. The effectiveness with which physicians help patients adjust to the physical, intellectual, and emotional challenges of CLL appears to impact patient QOL.
PMCID: PMC2643424  PMID: 18656259
leukemia; supportive care; quality of life
Cancer  2009;115(2):363-372.
The clinical course of chronic lymphocytic leukemia (CLL) is highly variable. A prognostic index based on widely available clinical and laboratory features was recently developed to predict survival among patients with previously untreated CLL. This index requires validation in an independent series of patients before widespread use can be recommended.
We used the Mayo Clinic CLL database to evaluate the validity and reproducibility of the new prognostic index.
We identified 440 patients with newly diagnosed CLL who were seen at Mayo Clinic within 12 months of diagnosis and who had data to calculate index score. Patients were classified as low, intermediate, or high risk using the prognostic index. The estimated median survival times were: not reached for low risk; 10.1 years for intermediate risk; and 7.2 years for high risk. Estimated median and 5 year survival by prognostic index category were similar to those originally reported. The prognostic index added predictive value beyond that of Rai risk alone (p=0.004). Prognostic index risk category remained a predictor of survival when analysis was limited to Rai stage 0 (p=0.03) and non-referred patients (p<0.0001) and also predicted time to treatment (p<0.0001).
We confirm the ability of a newly developed prognostic index to predict survival among patients with previously untreated CLL. We also extend the utility of the index by demonstrating that it is useful at diagnosis, retains prognostic value when applied exclusively to Rai stage 0 patients, is effective in non-referred patients, and predicts time to treatment.
PMCID: PMC2629134  PMID: 19090008
CLL; prognosis; stage; survival

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