Hypercholesterolemia in CLL and Response to Statin Therapy

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1 Hypercholesterolemia in CLL and Response to Statin Therapy 10 th Annual Canadian CLL Meeting Winnipeg, MB Sept 18, 2014 Signy Chow, MD, FRCPC Sunnybrook Health Sciences Centre, Toronto, ON

2 Outline Hypercholesterolemia is associated with cancer and possibly CLL Epidemiologic evidence Causal relationship Statins Reduce cholesterol What is the effect on CLL?

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4 High Serum Free Fatty Acid Levels Are Found In CLL Patients Higher levels of FFA in CLL patients compared to normal controls (NS) Higher levels of FFA associated with higher CLL disease risk (p <0.001) Masoodi M et al. Leukemia (2014) 28: 1381

5 High Serum FFA in CLL patients statin x

6 LDL-C Increases Proliferation & STAT3 Phosphorylation In Primary CLL Cells 6 days Cell counts x10(4) control P=0.04 P=0.32 LDL (0.5mM) HDL (0.5mM) Pt.40 Pt.55 Pt.27 Pt.9 Pt.72 Pt.47 Pt.46 Pt.100 Pt.44 Pt.43 Pt.105 Pt.99 Proliferation θ cycd chol LDL pstat Lipoproteins (mm) βactin

7 High Fat Diets Promote Engraftment Of human CLL Cells In NOG-SCID Mice

8 Is Cholesterol Metabolism A Therapeutic Target in CLL? You haven't been taking your cholesterol medication, have you?

9 FL and statins 228 DLBCL, 293 FL registry enrolled ( ) Median followup 47months Statin-exposed vs. non-exposed newly diagnosed lymphoma Follicular Lymphoma Statins associated with improved event free survival HR 0.45 ( ) Initial watchful waiting: [HR 0.38 ( )]

10 686 patients from Mayo clinic database Rai stage 0-1 ( ), seen within 3 months of diagnosis Compared Statin or NSAID use at time of diagnosis Overall survival and time to first treatment 136/686 patients on statins (20%) More men on statins (68% vs 59% p=0.05) Older age on statins (median 65 vs 69) Median Time to First Therapy 7.9y (statin) vs 11.8y (no statin), p=0.52 Overall Survival 10.1 (statin) vs 11.4y (no statin), p=0.10 Fig 1. Time to first treatment among patients with Rai 0 CLL (p=0.52)

11 Title 335 pts evaluated 254 patients with data on statin use, 65 on statins at diagnosis No difference in baseline characteristics 26% statin use No difference in overall or treatment free survival Reduced need for therapy at diagnosis (p=0.04) 98/198 (52%) patients not on statins 24/65 (37%) patients on statins Stratification by sex: Female patients on statins significantly less likely to ever be treated than females not on statins (p<0.001) Male patients on statins at diagnosis no difference in eventual need for therapy

12 CLL and statins in combination? ----No ASA/No Statin 192/ ASA/No Statin 16/ No ASA/Statin 12/ ASA+Statin 10/20 Retrospective analysis of 280 relapsed/refractory CLL treated with FCR( ) With or without statins or ASA 58 on statins, ASA or both Outcomes ORR (p<0.01) Statins + ASA 100% Statins alone 82% ASA alone 81% Neither 72% PFS 6.1y, OS 9.2y (statin and ASA) PFS 1.6y, OS 3.7y (no statin or ASA) Multivariate adjusted model Statins+ASA associated with favorable outcome for PFS and OS Single agent did not affect PFS or OS Consistent with in vitro synergism of simvastatin and purine analogs No ASA/No Statin 169/ ASA/No Statin 15/ No ASA/Statin 11/ ASA+Statin 9/20 1 Podhorecka M, Ann Hematol 2010; 89:

13 Cases: 67F, Rai 0, CD38+ Co-morbidities: temporal arteritis, PVD, CAD, Barrett s, osteoporosis Medications: ASA, HCTZ/Triamterine, Losartan, Acetaminophen 18months post diagnosis Lymphocytes 9.7x10 6 to 46.5x10 6 cells/ ml Lipid profile: TC 7.28mM, HDL 1.73mM, LDL-C 4.99mM, non-hdl-c 5.5mM Simvastatin 5mg OD for 4 weeks, increased to 10mg OD thereafter Decrease in LDL-C: 3.8mM to 3.0mM Lymphocytes 10.1x10 6 cells/ml at 6 months, 2.1x 10 6 cells/ml at 8 months 62M, Rai 0, CD38- Co-morbidities: CABG, HSP, renal colic, sinusitis Medications: ASA, vitamins 67months post diagnosis Lymphocytes 6.9X10 6 to 58.6x10 6 cells/ml (Rai 1) Lipid Profile: TC 5.19mM, HDL-C 1.36mM, LDL-C 3.36mM, total non-hdl-c 3.83mM Lovastatin 20mg OD Decrease in LDL-C: 3.4mM to 2.7mM Lymphocytes: 20.1x10 6 cells/ml at 5 months 2.2x10 6 cells/ml at 9 months 2.4x10 6 cells/ml at 24months

14 Statin Induced Remissions? Case 1 LDL Lymphocyte count (x 10^6) Case 2 LDL Days from Statin Initiation

15 CLL and Statins: Questions What is the incidence of hyperlipidemia in CLL patients? Do patients on statins have a different clinical course? What is the effect on CLL in initiating statin therapy?

16 CLL and Statins: Study Lipid profiling of CLL patients in a specialized CLL clinic at Sunnybrook Health Sciences Centre Initiation of statin therapy for elevated LDL-C All other usual CLL care

17 CLL and Statins: Study Methods Baseline Characteristics: Demographics, Stage, Prognostic Factors (cytogenetics, CD38, beta 2 microglobulin) Lipid profile Inclusion Patients seen in clinic Jan 2012 Feb 2014 (26months) CLL, SLL Exclusion Other lymphoproliferative disorders (MCL, SMZL) Outcomes: Association with known prognostic factors Time to First Treatment Need for Therapy

18 CLL and Statins: Study Prevalence of Dyslipidemia 281 patients with CLL seen in a specialized CLL clinic from Jan 2012 Feb without cholesterol profiles 7 with MBL 231 patients for evaluation 107 patients on statins 10 additional with dyslipidemia not on therapy 114 patients with diagnosed no lipid abnormalities or statin therapy 62 patients with LDL-C 2.5mmol/L 18 of which had LDL-C 3.5mmol/L ( =135)/231 patients (58.4%) with abnormal lipids

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20 CLL and Statins: Significant differences between statin/non statin groups: Age [median 65 (no statins) vs 69 (statins)] LDL [2.70 ± 0.91 (no statins) vs 2.38 ± 1.15 (statins)] HDL [1.30 ± 0.47 (no statins) 1.12 ± 0.42 (statins)] No differences: Stage Cytogenetics CD38 expression Beta 2 microglobulin level Gender

21 CLL and Statins: Therapy Need for Treatment Time to First Treatment Date of diagnosis until date of first treatment Treatment = chemoimmunotherapy or high dose glucocorticoids

22 CLL and Statins: Therapy Need for Treatment (p=0.50) Treated patients: Total: 96/ % No statins: 54/ % Statins: 42/ % Median Time to First Treatment (p=0.02): Total: 48 (24, 83) months (n= 89) No Statin: 36 (11, 100) months (n=51) Statin: 57.5 (32, 77) months (n=38)

23 CLL and Statins: Therapy Time to First Treatment Time to First Therapy Comparison N = 89 [Median (Q1, Q3)] P-value Statin Use Statin (32, 77) 0.02 No Statin (11, 100) Gender Female (36, 118) 0.02 Male (16, 76) Cytogenetics Normal/13q (34, 100) Trisomy 12/11q (42, 118) Complex/17p (7, 56) Multivariate analysis Statin use and gender are significant after adjusting for each other Neither are significant after accounting for cytogenetics (available in 73 of 89 treated patients) Power Calculation (α=0.05, β=0.80) Sample size of 94 patients in each group required to achieve an 80% power to detect a 50% difference in TFT between groups

24 CLL and Statins: Therapy Time to First Treatment by Statin Initiation No statin (N=124) Statin Started (N=40) Statin Previous (N=67) P-value W&W 1 (%) Available TFT data/total 51/54 13/13 25/27 Treated 2 Median TFT (Q1, Q3) (mo) 36 (11, 100) 74 (62, 96) 45 (30, 64) 0.04 Initiation of statin therapy prolonged time to first treatment Median Duration of follow up Statin: 68months Non-statin: 79.5months Proportion of watchful waiting not affected

25 Conclusions LDL-C promotes the growth of CLL cells in vitro and possibly in mice CLL patients have an increased incidence of abnormal lipid metabolism And lipid profiling should be included in their diagnostic work-up There is a Role for Statins in CLL Therapy May be a useful intervention in watch and wait phase of CLL treatment to prolong time to first treatment

26 Acknowledgements Sunnybrook Odette Cancer Centre David Spaner Rena Buckstein Spaner Lab Lindsay McCaw YongHong Shi Statistics Liying Zhang University of Toronto

27 Total No Statin Statin Use P value Total Male 142 (61.5) 70 (56.5) 72 (67.3) 0.09 Median Age (Q1, Q3) 67 (60, 74) 65 (58, 73) 69 (63, 76) 0.01 RAI stage N 171 (74.0%) 83 (66.9%) 88 (82.2%) Lipid Profile HDL (mmol/l) 1.22 ± ± ± LDL (mmol/l) 2.55 ± ± ± TC/HDL 3.95 ± ± ± Non HDL-C (mmol/l) 3.22 ± ± ± B2M ( mg/ml) 0.31 Mean Std Dev 3.24 ± ± ± 1.98 CD38 status 0.28 Unknown 70 (30.3%) 39 (32.8%) 31 (29.0%) CD CD Partial Cytogenetics Unknown 118 (51.1%) 56 (45.1%) 62 (57.9%) 13q q p Normal >1 abnormality

28 All Patients Initiated on Statin Therapy Lymphocyte Count (x 10^6) Days from Initiation of Statin Therapy