A Phase II Study of Curcumin and Vitamin D in Previously Untreated Patients with Early Stage Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Lymphoma (SLL)

Abstract

B ackground: Current therapies for CLL/SLL have frequent toxicities, are non-curative, and several trials have demonstrated that early treatment of the disease doesn't result in longer overall survival. In high doses, both curcumin (CM), from turmeric, and vitamin D (VD) have been shown to be safe in multiple clinical trials of solid tumors. Curcumin was shown to disrupt CLL cell interactions with the microenvironment, induce apoptosis independent of DNA damage, and upregulate vitamin D receptor (VDR) in malignant lymphoid cells. We hypothesized that the combination of CM and VD is safe and active in CLL/SLL and would delay disease progression. Methods: This was an open-label phase II trial for previously untreated patients with asymptomatic,Rai stage 0-II CLL/SLL not currently meeting National CancerInstitute Working Group (NCI-WG) Criteria for treatment. All patients received 8 gm of CM and 10,000 IU of vitamin D3 (VD) orally daily. VD was started 1 week after CM and both agents were maintained for up to six 4-week cycles. The primary endpoint was the overall response rate (ORR) based on NCI-WG criteria. Secondary endpoints were event-free (EFS), overall survival (OS), and time to next treatment (TTNT). VD-25-OH and CM major metabolites; CM glucuronide (COG) and CM sulfate (COS), were measured in plasma by liquid chromatography-tandem mass spectrometry. Phosphorylated-NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells), a validated pharmacodynamic marker of CM activity, as well as VDR, were measured in CLL cells by flow cytometry. Results: A total of 35 patients (pts), 51% males, were accrued to the trial, 30 (86%) were evaluable for response. Median age was 60 years (range 45-80). Most had CLL (97%); 51% were Rai stage 0 and 49% were Rai stage 1. Cytogenetic abnormalities included del13q14 (37%), trisomy 12 (11%), del 11q22 (11%) and del 17p (3%); 20% had ZAP-70 levels >20%. Median number of cycles received was 5 (range 1-6) and treatment was well tolerated overall. The most frequent adverse effects (AE) were diarrhea/gastrointestinal upset in 69% of patients (14% were grade 3). No serious AEs were observed. Eighteen pts (51%) completed all 6 cycles of treatment; 10 (29%) withdrew consent, 4 (11%) discontinued treatment because of diarrhea, and 3 (9%) patients progressed on treatment. Best response was stable disease in 28/30 (93%) evaluable pts. After a median follow up of 29 months, EFS was 72.0% (95% CI 52.1 - 84.7%), 74.1% (95% CI 58.7-89.6%) had not started new CLL treatment, and OS was 100%. Median VD-25-OH levels were 28.75ng/ml (range 12.5-55.6) at baseline and 49.5 ng/ml (24.8-69) at 28 days. Median COG/COS levels were 15.8 (2.73-75)/6.71(0-33.5) and 18 (0-75.9)/7.21(0-35.2) ng/ml at 8 and 28 days, respectively. Flow cytometric analysis of CLL cells showed no significant change in VDR or Phosphorylated-NF-κB with CM-VD treatment. Conclusion: Curcumin and high-dose vitamin D combination is safe and well tolerated in patients with early stage CLL. Although no responses were seen, the majority of patients maintained stable disease on treatment. Longer follow up is planned on this study to determine long - term CLL progression rates of patients treated with CM-VD. Disclosures Afable: Eli Lilly: Employment. Lazarus:Pluristem Ltd.: Consultancy. Nagabhushanam:Sabinsa Corporation: Employment. Grote:BTR Group Inc: Employment. Kunati:Symrise AG: Employment.

Synergistic Antioncogenic Activity of Azacitidine and Curcumin in Myeloid Leukemia Cell Lines and Patient Samples

“…However, we considered that, given the morphological variability between the lines, this assay should be performed in other leukemic lines as well as in human samples in order to confirm the absence of differentiation. Based on these initial and other more recent reports (23), future studies adding vitamin D to the AZA/CUR combination would be useful.…”

“…The combination of AZA and CUR has not yet been tested in hematological neoplasms, but in solid tumors a positive interaction between these drugs has been observed (21). Interestingly, CUR has also been tested in several clinical trials and proved to be safe, non-toxic and efficient as a single agent or combined with other therapies (9,22,23). Finally, although the low water solubility of CUR hinders its initial bioavailability in the bloodstream, it has recently been reported that combining it with organometallic compounds enhances significantly its transport to cancer cells (24).…”

The Calcitriol/Vitamin D Receptor System Regulates Key Immune Signaling Pathways in Chronic Lymphocytic Leukemia

“…In CLL, a clinical trial carried out by the Mayo Clinic showed that vitamin D substitution in CLL patients with insufficient vitamin D levels is safe and feasible, however could not provide evidence that vitamin D can delay disease progression [ 17 ]. More recently, the combination of vitamin D with curcumin was reported to be safe in previously untreated patients with early stage CLL or small lymphocytic lymphoma (SLL), yet event-free and overall survival did not show any alteration [ 47 ]. Obviously, therefore, further studies are required in order to reach definitive conclusions regarding the role, if any, of vitamin D in the management of patients with B cell malignancies, including CLL.…”

A natural supplement formula reduces anti-oxidative stress and enhances osteo-chondrogenic differentiation potential in mesenchymal stem cells

“…(1) Since natural supplements are complex mixtures, their net efficacy results from multiple interactions among the constituents. (2)(3)(4) Effects of natural dietary supplements have been published in various fields, such as their ability to improve in mitochondrial dysfunction. (5) Interest in natural supplements is growing, and many relevant studies are ongoing around the world.…”

“…Several papers have reported that those natural supplements show synergism. (2)(3)(4) Jerzynska et al (3) reported that co-administration of vitamin D supplements and Lactobacillus rhamnosus showed better immunological response than individual administration in pediatric allergy rhinitis patients. These natural supplements show similar properties, but combining them can generate additive or synergistic effects on the human body.…”