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1.  Commentary: Chronic Lymphocytic Leukemia—The Price of Progress 
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.
doi:10.1634/theoncologist.2010-0090
PMCID: PMC3227992  PMID: 20463087
3.  Chemoimmunotherapy for Relapsed/Refractory and Progressive 17p13 Deleted Chronic Lymphocytic Leukemia (CLL) Combining Pentostatin, Alemtuzumab, and Low Dose Rituximab is Effective and Tolerable and Limits Loss of CD20 Expression by Circulating CLL Cells 
American journal of hematology  2014;89(7):757-765.
Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL) patients with purine analogue refractory disease or TP53 dysfunction still have limited treatment options and poor survival. Alemtuzumab containing chemoimmunotherapy regimens can be effective but frequently cause serious infections. We report a phase II trial testing the efficacy and tolerability of a short duration regimen combining pentostatin, alemtuzumab, and low dose high frequency rituximab (PAR) designed to decrease the risk of treatment associated infections and limit loss of CD20 expression by CLL cells. The study enrolled 39 patients with progressive CLL that was either relapsed/refractory (n=36) or previously untreated with 17p13 deletion (17p13-)(n=3). Thirteen (33%) patients had both 17p13- and TP53 mutations predicted to be dysfunctional and eight patients had purine analogue refractory CLL without TP53 dysfunction. Twenty-six (67%) patients completed therapy with only five (13%) patients having treatment limiting toxicity, and no treatment related deaths. Twenty-two (56%) patients responded to treatment with 11 (28%) complete responses (four with incomplete bone marrow recovery). Median progression free survival was 7.2 months, time to next treatment 9.1 months, and overall survival 34.1 months. The majority of deaths (82%) were caused by progressive disease including transformed diffuse large B cell lymphoma (n=6). Correlative studies showed that low dose rituximab activates complement and NK cells without a profound and sustained decrease in expression of CD20 by circulating CLL cells. We conclude that PAR is a tolerable and effective therapy for CLL and that low dose rituximab therapy can activate innate immune cytotoxic mechanisms without substantially decreasing CD20 expression.
doi:10.1002/ajh.23737
PMCID: PMC4280857  PMID: 24723493
Chronic lymphocytic leukemia/small lymphocytic lymphoma; CLL/SLL; relapsed/refractory; TP53/p53/17p13 deletion; alemtuzumab and low dose rituximab; trogocytosis
4.  Ofatumumab-based chemoimmunotherapy is effective and well tolerated in patients with previously untreated CLL 
Cancer  2013;119(21):3788-3796.
Purpose
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.
Methods
Previously untreated CLL patients in need of therapy received 6 cycles of CIT induction with pentostatin, cyclophosphamide and ofatumumab (PCO) followed by response assessment.
Results
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]).
Conclusion
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.
doi:10.1002/cncr.28292
PMCID: PMC3894149  PMID: 23922059
chronic lymphocytic leukemia(CLL; small lymphocytic lymphoma(SLL); treatment; ofatumumab; chemoimmunotherapy
5.  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.
Summary
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.
doi:10.1111/bjh.12458
PMCID: PMC4098845  PMID: 23841899
transformation; aggressive lymphoma; stem cell transplantation; purine analogues; RS survival score
6.  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 
Background
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.
Methods
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.
Results
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).
Conclusions
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.
Impact
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.
doi:10.1158/1055-9965.EPI-12-1217
PMCID: PMC3596428  PMID: 23307532
CLL; NHL; SNPs; IRF8; risk locus
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.
doi:10.1080/10428190902777467
PMCID: PMC3928100  PMID: 19373657
CLL; treatment; relapsed; thalidomide; angiogenesis
8.  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
9.  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.
doi:10.3109/10428194.2010.486877
PMCID: PMC3913168  PMID: 20496995
10.  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.
doi:10.1038/ng.2652
PMCID: PMC3729927  PMID: 23770605
11.  Age at Diagnosis and the Utility of Prognostic Testing in Patients with Chronic Lymphocytic Leukemia (CLL) 
Cancer  2010;116(20):4777-4787.
PURPOSE
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.
METHODS
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).
RESULTS
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
CONCLUSIONS
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.
doi:10.1002/cncr.25292
PMCID: PMC3902481  PMID: 20578179
Cancer  2011;118(7):1827-1837.
Background
The impact of physicians’ disease-specific expertise on patient outcome is unknown. While previous studies suggest a survival advantage for cancer patients cared for at high volume centers, these observations may simply reflect referral bias or better access to advanced technologies, clinical trials, and multidisciplinary support at large centers.
Methods
We evaluated time to first treatment(TTFT) and overall survival(OS) of patients with newly diagnosed chronic lymphocytic leukemia/small lymphocytic lymphoma(CLL) at a single academic center based on whether they were cared for by a hematologist/oncologist who sub-specializes in CLL(CLL hematologist) or a hematologist/oncologist with expertise in other areas(non-CLL hematologist).
Results
Among 1309 newly diagnosed patients with CLL cared for between 1999–2009, 773(59%) were cared for by CLL hematologists and 536 were cared for by non-CLL hematologists. Among early stage patients(Rai 0-I), median TTFT(9.2 vs. 6.1 years; p<0.001) and OS(10.5 years vs. 8.8 years; p<0.001) were superior for patients cared for by CLL hematologists. For all patients, OS was superior for patients cared for by CLL hematologists(10.5 years vs. 8.4 years; p=0.001). Physician’s disease-specific expertise remained an independent predictor of OS after adjusting for age, stage, sex, and lymphocyte count. Patients seen by a CLL hematologist were also more likely participate in clinical trials(48% vs. 16%; p<0.001).
Conclusion
Physician disease-specific expertise appears to influence outcome in patients with CLL. To the greatest extent possible, patients should be cared for by a hematologist/oncologist expert in the care of their specific malignancy. When not possible, practice guidelines developed by disease-specific experts should be followed.
doi:10.1002/cncr.26474
PMCID: PMC3893049  PMID: 22009554
chronic lymphocytic lymphoma(CLL); small lymphocytic lymphoma (SLL); prognosis; physician expertise
Annals of epidemiology  2012;22(12):855-862.
Purpose
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).
Methods
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.
Results
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.
Conclusions
Early adult BMI may be of greatest relevance to NHL risk, particularly in females.
doi:10.1016/j.annepidem.2012.10.002
PMCID: PMC3513768  PMID: 23146413
body mass index; exercise; lymphoma; non-Hodgkin; etiology; case-control studies
British journal of haematology  2012;159(5):572-576.
Summary
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.
doi:10.1111/bjh.12070
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.
doi:10.1111/j.1365-2141.2008.07070.x
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.
doi:10.1002/ijc.26491
PMCID: PMC3306533  PMID: 22038870
Diet; non-Hodgkin lymphoma; vegetables; antioxidants; ORAC
Cancer causes & control : CCC  2012;23(7):1017-1029.
Purpose
It has been hypothesized that vitamin D mediates the inverse relationship between sun exposure and non-Hodgkin lymphoma (NHL) risk reported in several recent studies. We evaluated the association of self-reported sun exposure at ages <13, 13–21, 22–40, and 41+ years and 19 single nucleotide polymorphisms (SNPs) from 4 candidate genes relevant to vitamin D metabolism (RXR, VDR, CYP24A1, CYP27B1) with NHL risk.
Methods
This analysis included 1,009 newly diagnosed NHL cases and 1,233 frequency-matched controls from an ongoing clinic-based study. Odds ratios (OR), 95 % confidence intervals (CI), and tests for trend were estimated using unconditional logistic regression.
Results
There was a significant decrease in NHL risk with increased sun exposure at ages 13–21 years (OR≥15 vs. ≤3 h/week = 0.68; 95 % CI, 0.43–1.08; ptrend = 0.0025), which attenuated for older ages at exposure. We observed significant main effect associations for 3 SNPs in VDR and 1 SNP in CYP24A1: rs886441 (ORper-allele = 0.82; 95 % CI, 0.70–0.96; p = 0.016), rs3819545 (ORper-allele = 1.24; 95 % CI, 1.10–1.40; p = 0.00043), and rs2239186 (ORper-allele = 1.22; 95 % CI, 1.05–1.41; p = 0.0095) for VDR and rs2762939 (ORper-allele = 0.85; 95 % CI, 0.75–0.98; p = 0.023) for CYP24A1. Moreover, the effect of sun exposure at age 13–21 years on overall NHL risk appears to be modified by germline variation in VDR (rs4516035; pinteraction = 0.0066). Exploratory analysis indicated potential heterogeneity of these associations by NHL subtype.
Conclusion
These results suggest that germline genetic variation in VDR, and therefore the vitamin D pathway, may mediate an association between early life sun exposure and NHL risk.
doi:10.1007/s10552-012-9967-0
PMCID: PMC3589750  PMID: 22544453
Ultraviolet radiation; Vitamin D; VDR; Molecular epidemiology; Non-Hodgkin lymphoma
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.
doi:10.3109/10428191003682767
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.
doi:10.3109/10428194.2011.608451
PMCID: PMC3438221  PMID: 21812536
Chronic lymphocytic leukemia; CLL; CpG oligonucleotide 7909; PF-03512676; CpG 2006; TLR9
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.
doi:10.1038/leu.2011.117
PMCID: PMC3164475  PMID: 21617698
Background
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.
Methods
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.
Results
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.
Conclusion
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.
Impact
Closer evaluation of germline variation of genes in the apoptosis pathway with risk of NHL and its subtypes is warranted.
doi:10.1158/1055-9965.EPI-10-0581
PMCID: PMC2976783  PMID: 20855536
Bcl-2 pathways; caspases; molecular epidemiology; non-Hodgkin lymphoma
British journal of haematology  2010;151(2):152-158.
Summary
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.
doi:10.1111/j.1365-2141.2010.08339.x
PMCID: PMC2966536  PMID: 20738309
chronic lymphocytic leukaemia; high risk families; monoclonal B-cell lymphocytosis; flow cytometry
Cancer  2010;116(9):2201-2207.
Background
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.
Methods
This was a phase II study of oral single-agent everolimus (10 mg/day) for relapsed/refractory indolent lymphoid malignancies including CLL.
Results
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.
Conclusion
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.
doi:10.1002/cncr.25005
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.
doi:10.1002/cncr.25028
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

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