1. Role of Vitamin D in Blood Malignancies Dr Imran Hilal

4. Background  Inverse association between sunlight exposure and NHL risk in 6 of 9 published studies, and a review and discussion of this association has been previously published by Armstrong and Kricker in 2007

5. Figure 1. Proposed mechanism. It is hypothesized that extra-renal conversion of 25(OH)D to the active vitamin D metabolite (1,25(OH)2D) results in autocrine and paracrine signaling to control lymphocyte cell proliferation and decrease lymphoma risk.

6.  There is evidence of an immunomodulatory effect of 1,25(OH)2D on activated lymphocytes and dendritic cells, such that T cell responses are shifted away from inflammatory Th1 responses, and antigen presentation by dendritic cells is decreased

8.  Furthermore, evidence of an effect of 1,25(OH)D on lymphoma cells in particular has been demonstrated both in the laboratory, with observed promotion of differentiation and antiproliferative effects on a variety of lymphoma cells line in vitro

9.  In an early study demonstrating tumor response to alfacalcidol in 24% of 36 low grade follicular, small- cleaved cell type, lymphoma

10.  B cell lymphomas that are associated with immunosuppressed states may be polyclonal, which may support the notion that these tumors arise from a lymphoproliferative state in the context of immune suppression, and thus decreased immune surveillance, particularly by T cells, of any DNA mutations that may result in the lymphoproliferative process

11.  Evidence of increased VDR expression on cycling keratinocytes suggests that proliferating cells, such as expanding B cells as a result of chronic antigen stimulation, may be a target for 1,25(OH)2D activity, providing indirect evidence of potential link between vitamin D status and not only lymphoma etiology but potentially lymphoma prognosis as well.

12.  Survival benefit with higher vitamin D levels has been observed in a number of malignancies, and trials evaluating the use of vitamin D in the treatment of advanced prostate cancer are ongoing

13.  in light of the effect of 25(OH)D metabolism on increasing p27 levels, a study published in 2001 by Bai, et al,52 reports that among 80 de novo diffuse large B cell cases examined, p27 expression was low/null in 73%, and low p27 status correlated with an increased expression of cyclin A, involved in G1 → S transition53. Not only do these results suggest impairment of cell- cycle control involving the cdk inhibitor p27 in enhanced lymphoma proliferation, they additionally lend support to the proposed hypothesis, and may also identify a potential therapeutic target for 1,25(OH)2D.

14.  NHL incidence has been historically higher among men and whites as compared to women and blacks, respectively, the notable increase in NHL rates over the past 30 years, as previously discussed, has been disproportionately high among blacks and older women  This observation is consistent with the hypothesized association between vitamin D status and NHL risk due to the reduced capacity for vitamin D production in response to sun exposure among those with dark skin and with increased age

19.  The evidence presented in the literature to date provides limited support for an association between vitamin D status and NHL.  With the exception of the findings by Polesel et al, and Lim et al., the published estimates of association with dietary vitamin D intake or serum 25(OH)D and NHL risk are largely weak or null.  Limitations inherent to both retrospective dietary vitamin D assessment and the epidemiologic investigation of NHL etiology may be obscuring a true influence of vitamin D status on NHL risk.

21.  Total Patient: 105  Malignancy targeted: acute and chronic leukemias, myelodysplastic syndromes, monoclonal gammapathies, and chronic lymphoid disorders  Duration: 6 months

22.  25(OH)D deficiency (<20 ng/ml) appeared very common and an direct relationship was observed between 25(OH)D levels and the response to therapy: lower levels being related to poorer response  In acute leukemias, a significant difference was noted between patients with long-term disease-free survival in those tested at diagnosis or in those tested at the time of relapse

23.  Similarly in patients with Philadelphia- positive leukemias, there was a correlation between molecular response and levels of 25(OH)D  Lower levels of circulating 25(OH)D appeared related to a progressive stage of the disease and poor response to therapy, and, therefore, to the aggressiveness of the disease.  It is a potential marker of prognosis in patients with leukemia

24.  Set back: Previously identified factors, such as age, season, gender, or nutritional index, were not related to circulating 25(OH)D levels

26. AIM  Evaluated the relationship of 25(OH)D serum levels with time-to- treatment (TTT) and overall survival (OS) in newly diagnosed CLL patients participating in a prospective cohort study and a separate cohort of previously untreated patients participating in an observational study

27.  Of 390 CLL patients in the discovery cohort, 119 (30.5%) were 25(OH)D insufficient. After a median follow-up of 3 years, TTT and OS were shorter for 25(OH)D-insufficient patients

28.  After a median follow-up of 9.9 years, TTT and OS were again shorter for 25(OH)D-insufficient patients  Vitamin D insufficiency is associated with inferior TTT and OS in CLL patients.

29.  Whether normalizing vitamin D levels in deficient CLL patients would improve outcome merits clinical testing

31.  Nineteen patients, 12 men and seven women, with MDS were included  Refractory anemia with ringed sideroblasts – 7  Refractory anemia -- 5  Refractory anemia with excess of blasts –1  Chronic myelomonocytic leukaemia - - 6

32.  Mean follow-up period was 26.21 months, range 9-75  Responders: granulocyte or platelet count increase by 50%, or haemoglobin increase of 1.5 g/dl or transfusion needs decrease by 50%

33.  How it was conducted: The first five patients received 266 microg of calcifediol three times a week and the other 14 received calcitriol (0.25- 0.75 microg/d).

34. Results  Response was observed in 11 patients. In the calcifediol treated group, one case responded, three were nonresponders, and one showed progression. In the calcitriol group, 10 were responders (two with major response), and four were non- responders

35. Conclusion of this study  No correlation was observed between baseline levels of vitamin D metabolites and the presence of response.  No hypercalcaemia was observed.  Treatment with vitamin D3 metabolites could induce a long-standing response of the haematological disturbance in some low-intermediate risk MDS patients without inducing hypercalcaemia.

37. Patient and method Hypothesis that circulating 25- hydroxyvitamin D [25(OH)D] levels are predictive of event-free survival (EFS) and overall survival (OS) in a prospective cohort of 983 newly diagnosed patients with NHL. 25(OH)D and 1,25-dihydroxyvitamin D [1,25(OH)(2)D] levels were measured by liquid chromatography-tandem mass spectrometry.

38.  Mean age at diagnosis was 62 years (range, 19 to 94 years)  44% of patients had insufficient 25(OH)D levels (< 25 ng/mL) within 120 days of diagnosis  Duration: Median follow-up was 34.8 months; 404 events and 193 deaths (168 from lymphoma) occurred

39.  After adjusting for known prognostic factors and treatment, 25(OH)D insufficient patients with diffuse large B-celllymphoma (DLBCL) had inferior EFS and OS; 25(OH)D insufficient patients with T-cell lymphoma also had inferior EFS

40.  No associations with EFS for the other NHL subtypes  Among patients with DLBCL and T- cell lymphoma, higher 1,25(OH)(2)D levels were associated with better EFS and OS, suggesting that any putative tumor 1-α-hydroxylase activity did not explain the 25(OH)D associations

41. Conclusion 25(OH)D insufficiency was associated with inferior EFS and OS in DLBCL and T-cell lymphoma. Whether normalizing vitamin D levels in these patients improves outcomes will require testing in future trials.

42. Summary  Vit D may have a role in malignancies  Not much work has been done yet

44.  Sample size: 123  Vit D deficiency: ≤50 nmol/L  Vit D deficiency: ≤50 nmol/L  Vit D Insufficiency: insufficiency

45.  Mean level: 41.1±9.6 nmol/L  90% had low level of 25OH  69.9% were deficient and 21.1% had insufficient levels of 25OHD

46.  High proportion of apparently healthy adults are at risk of developing musculoskeletal and other chronic diseases

47.  Thank you