Understanding Chronic Lymphocytic Leukemia

compiled by John G. Connor, M.Ac., L.Ac. edited by Barbara Connor, M.Ac., L.Ac.

Table of Contents
  • Introduction
  • Understanding Biomarkers in Chronic Lymphocytic Leukemia
  • Research on Natural Compounds That May be Suppressive Against Chronic Lymphocytic Leukemia Cell Lines
  • Research on Natural Compounds That May Regulate the Immune Response
  • References
Introduction
B-cell CLL (chronic lymphocytic leukemia) is characterized by a highly variable clinical course. Some patients are symptomatic at diagnosis or early thereafter and require early therapy. Others have no or minimal symptoms for many years and may have a normal life expectancy. Treatment in early-stage patients has not been shown to prolong their survival time. Therefore, therapeutic procedures traditionally have been used for advanced-stage or symptomatic disease. The therapeutic options vary markedly with regard to efficacy, toxicity and cost. Therefore, the progress in understanding the pathogenesis and improving outcome prediction becomes clinically relevant to developing curtailed treatments. Genomic aberrations are strong parameters to predict outcome in CLL and help to understand the biological background of clinical heterogeneity of CLL to enable risk-adapted treatment strategies for individual patients. (Lai and Huang 2011)  

Chronic lymphocytic leukemia is the most frequent type of adult leukemia in western countries and is characterized by the accumulation of monoclonal, mainly B, lymphocytes in blood, bone marrow, and lymphoid organs. Despite the recent introduction of many therapeutic regimens, CLL is still an incurable disorder. It can be effectively treated with purine analogues, glucocorticoids, alkylating agents, or monoclonal antibodies; however, some patients with relapsed or refractory disease have limited therapeutic options. Thus, there is an urgent need to discover novel, less toxic, and more effective drugs for CLL patients. Among other options, the use of immunomodulatory agents or plant-derived substances has been reported to improve the results of CLL treatment. (Podhorecka et al 2010)

At some point in their clinical course, up to 5% of CLL cases will undergo a Richter’s transformation, whereby the CLL clone evolves into an aggressive high-grade lymphoma. Risk factors for transformation are poorly defined but include an elevated serum lactate dehydrogenase, monoclonal gammopathy, progressive lymphadenopathy, systemic symptoms, and extranodal involvement. (Parker & Strout 2011)

CLL is caused by the interpolation of tumour cells among immunological cells and mediated by bi-directional cell contact and secretion of cytokines, which both sustain and invigorate the tumour and suppress immunity. (Hamblin A & Hamblin T 2008)

Chronic lymphocytic leukemia is characterized by the gradual accumulation of quiescent, apoptosis resistant, B cells. No cure is available at this time for this disease, although the current therapies involving the use of chemotherapeutical drugs, such as the purine analog F-ara-A, have proven helpful for some patients. However, a significant number of patients will eventually develop refractory disease as a result of the emergence of leukemic clones resistant to drugs, leading to patient demise. Consequently, new therapies are necessary for treating patients with refractory disease. (Kress et al 2007)

Patients with chronic lymphocytic leukaemia (CLL) are all to a degree immunodeficient. The most obvious and well-known abnormality is hypogammaglobulinaemia, which is present in up to 85% of patients. (Hamblin A & Hamblin T 2008)

Infections are the major cause of death in between a quarter and a half of patients with CLL. Bacterial infection of the respiratory tract, skin or urinary tract is the commonest problem, and before the use of purine analogues for treatment, the usual organisms were Streptococcus pneumoniae, Staphylococcus aureus, Streptococcus pyogenes and Escherichia coli. Protection against these organisms is provided principally by antibody, but only 15% of patients with CLL have completely normal serum immunoglobulins. (Hamblin A & Hamblin T 2008)

Apart from bacterial infections, patients with CLL also suffer from the reactivation of herpes viruses.

*
Most commonly this involves herpes zoster. In one series from before the era of treatment with purine analogues, the incidence of herpes zoster was given as 28.6%, with 3.5% having recurrent attacks. Particularly important is the observation that attacks of shingles frequently precede the clinical diagnosis of CLL, suggesting that the underlying immune defect does not depend on either hypogamma-globulinaemia or the physical overwhelming of immune organs by infiltrating tumour cells. (Hamblin A & Hamblin T 2008)

* Be careful about using high doses of arginine because sometimes it triggers herpes in those who are susceptible.In most patients with CLL, T-cell numbers are increased. This increase mainly affects CD8+ cells, but CD4+ cells are also increased, though the CD4/CD8 ratio is reversed. There are other changes in T-cell function, but it seems clear that many of the changes observed in the T-cell population in CLL are a consequence of the immune system having to ‘work harder’ to control latent herpes virus infections, especially cytomegalovirus (CMV). Investigators envisage that the anti-CMV response might be harnessed and redirected to attack the CLL itself. (Hamblin A & Hamblin T 2008)

The peripheral lymphoid organs host the proliferative core of CLL. The chemokine stromal-derived factor 1α, also known as CXCL12, recruits CLL cells towards the secondary lymphoid organs via their specific CXCR4 receptor. Within the secondary lymphoid organs, they form proliferation centres or pseudofollicles. These are indeed parodies of lymphoid follicles in which the CLL cells are able to subvert the normal helper function to their own use while denying it to normal B-cells. Experiments suggest that T-cells expressing CD154 interact with CLL B-cells through their CD40 receptor activating them and upregulating CD38 and ZAP-70. The effect of this interaction on CLL cells in the proliferation centre is to increase proliferation rate (though it remains less than that of normal B-cells in normal individuals) but also to induce cell cycle arrest and resistance to apoptosis. (Hamblin A & Hamblin T 2008)

Infections are a major factor in the clinical course of CLL. Up to 50% of patients with CLL will develop infectious complications during their disease course, and infections still account for 30% to 50% of all deaths from CLL. The pathogenesis of infections in CLL is related to a combination of hypo-γ-globulinemia, T-cell deficiency and the immunosuppressive effect of treatment. Hypo-γ-globulinemia caused by a progressive decline in B-cell numbers and function is correlated with recurrent severe bacterial infections. Decreased IgG and IgA levels have been associated with reduced survival. Neutropenia (abnormally low numbers of neutorophils) from progressive bone marrow infiltration and chemotherapy also predispose patients to bacterial and fungal infections. T-cell dysfunction and depletion as a result of suboptimal antigen presentation and inhibition of T-cell responses by cytokines secreted by the malignant cells also can lead to opportunistic infections. Recent advances in treatment for CLL have altered the pattern and type of infections encountered. It was demonstrated that fludarabine and alemtuzumab improved response rates compared with traditional alkylating agents but also caused significant immunosuppression. (Francis et al 2006)

Chronic lymphocytic leukemia therapy has evolved over the past few decades as modern chemo-immunotherapy significantly improved the response and survival of CLL patients. However, treatment toxicity of the intensive chemo-immunotherapy often limits its use in the mostly elderly population of patients. Further, the disease eventually relapses and additional therapy options are required. Of particular interest are molecular targeted therapies that interfere with critical signal transduction pathways controlling cell growth and survival. (Ma & Rosen 2011)

There is an ever growing interest in treatment with natural compounds as an adjuvant cancer therapy along with conventional cancer therapy. (Virk-Baker et al 2010) For example the combination of a natural VEGF inhibitor along with lower doses of a pharmacological agent may prove helpful in reducing the unwanted side effects of chemotherapy. (Wargovich et al 2010)

Individual studies estimate that as many as 69% of US cancer patients employ some type of complementary and alternative medicine, 76% of patients in a study of Midwestern cancer patients and 95% of radiation oncology patients in another study.  (Wargovich et al 2010)

Understanding Biomarkers in Chronic Lymphocytic Leukemia
Overexpression of both Bcl-2 and TRAF1 is a hallmark of human CLL cells. Bcl-2 overexpression largely accounts for the apoptosis resistant phenotype of CLL cells. TRAF1 is frequently overexpressed in CLL cells from patients with refractory disease, suggesting that TRAF1 might be involved in disease progression. (Kress et al 2007)

In a study which investigated clinical characteristics and survival patterns of patients with CLL over the last 40 years in Israel it was found that older age, high-beta 2-microglobulin level, and expression of ZAP-70 predicted shorter survival. (Lev et al 2011) 

One marker that could explain this patient’s atypical disease presentation and ultimate poor prognosis is her CD38 status, with 85% of lymphocytes being positive for this marker. Patients with CLL tend to have lower overall survival and progression-free survival if more than 30% of their lymphocytes are positive for CD38. (Esfahani et al 2011)

Serum ceruloplasmin level positively correlated with serum ceruloplasmin oxidase activity in patients with advanced stage. In conclusion, increased serum ceruloplasmin oxidase activity, ceruloplasmin, a-1-acid glycoprotein, copper levels and decreased transferrin and albuminumin, unchanged manganese levels are associated with CLL and appear to be a consequence of the disease itself. (Gundogdu et al 2007) 

Chronic lymphocytic leukemia (CLL) is a common disorder characterized by the monoclonal * accumulation of B lymphocytes with a distinct phenotype (CD5-positive, CD23-positive, CD22-negative and low level of surface Ig) and a highly variable clinical course. A different clinical outcome has been associated with peculiar cellular and molecular markers and/or specific genomic alterations. In particular, the mutational status of the immunoglobulin heavy-chain variable (IGHV) gene defines two disease subgroups; one subgroup is characterized by the absence of somatic mutation* in CLL cells and has the worst clinical course and outcome, whereas the other, with somatic mutations in IGHV genes, has a more benign prognosis and outcome. (Maura et al 2011)

Survival analysis showed that the patients with Ig paraproteinemia had significantly shorter survival times than the patients without serum Ig paraprotein. Binet stage, high levels of lactate dehydrogenase (LDH), IgG paraproteinemia, IgM paraproteinemia, ZAP-70-positive, DAT-positive, unmutated IGHV status, and del(17p13) were the adverse factors in determining overall survival (OS). Del(17p13), ZAP-70, and IgM paraproteinemia were the variables strongly associated with OS by multivariate Cox regression analysis. It was showed that serum Ig paraprotein might be applied for the assessment of prognosis in patients with CLL. (Xu et al 2011)Chronic lymphocytic leukemia results from the expansion of malignant CD5+ B cells that usually express IgD and IgM. These leukemic cells can give rise in vivo to clonally related IgG+ or IgA+ elements. (Cerutti et al 2002)

Higher cKi-67 index values were significantly associated with shorter survival. The results of this study suggest that the plasma cKi-67 index, along with B2M level, is a strong predictor of clinical behavior in CLL. (Bruey et al 2010)Wild-type p53 up-regulates and activates B-cell CLL/lymphoma 2 (BCL-2)-associated X protein (BAX), and it down-regulates and inactivates BCL-2. The small-molecule BCL-2 inhibitor ABT-737 induces apoptosis in a BAX-dependent and BCL-2 homologous antagonist-killer (BAK)-dependent manner. The current data indicated that p53 dysfunction may lead to decreased apoptosis induction by ABT-737. (Kojima et al 2011)

The soluble transferrin receptor (sTfR) is a parameter of erythropoietic activity and iron deficiency. The sTfR concentration directly reflects the tumor burden in CLL. Therefore, sTfR may be of clinical value in monitoring disease activity, response to treatment and disease progression. (Metzgeroth et al 2007)

TNF-α  – Although multiple apoptosis inhibiting factors other than TNF-α have been identified in B-CLL, several data indicate that TNF-α is a central mediator in apoptosis resistance of malignant lymphocytes in B-CLL. TNF-α is constitutively produced by B-CLL cells, and it may act as an autocrine factor for their growth and survival. Moreover, in B-CLL patients, TNF-α serum levels and soluble TNF-α receptor (sTNFR) levels are increased, and a correlation with disease progression has been demonstrated, associated with an adverse prognosis; it has been hypothesized that high levels of TNF-α and sTNFR can predict outcome in lymphoma patients. Ferraioli et al confirmed the relationship between TNF-α plasma levels and the severity of B-CLL suggesting they be monitored along with other markers.(Balato et al 2011)

The inhibition of VEGF receptor activation with either tyrosine kinase inhibitors or VEGF neutralizing antibodies inhibit VEGF receptor phosphorylation, decrease p-STAT-3 (serine 727), Mcl-1, and induces cell death in CLL B cells. Thus, a VEGF-VEGF receptor pathway in CLL B cells can be linked to activation of STAT proteins that are able to enhance their apoptotic resistance. (Lee et al 2005)

Research on Natural Compounds That May be Suppressive Against Chronic Lymphocytic Leukemia Cell Lines 
All of the major signaling pathways, which are deregulated in cancer, and which have been examined as targets for cancer prevention, can be modified by one or more dietary components. These include but are not limited to, carcinogen metabolism, DNA repair, cell proliferation, apoptosis, inflammation, immunity, differentiation and angiogenesis. (Davis et al 2010) 

Curcumin –treatment was able to overcome stromal protection of CLL B cells on in vitro testing and to synergize with EGCG when administered in a sequential fashion. Additional evaluation of curcumin as a potential therapeutic agent for treatment of CLL seems warranted. (Ghosh et al 2009)

Dihydroartemisinin (DHA) – Dihydroartemisinin is a water-soluble active metabolite of artemisinin derivatives. DHA exhibited high anticancer activity in leukemia HL60 cells; MTT assay and growth inhibition assay showed that DHA could specifically inhibit the growth of HL60 cells in a dose-dependent (0.25-8 micromol/l) and time-dependent (12-72 h) manner. DHA-induced DNA fragmentation also induced the activation of caspase-3 and influenced the expression of Bcl-2 and Bax. Taken together, these data from our study show that DHA can induce HL60 cell apoptosis via the effect of downregulation TfR (transferrin receptor) expression resulting in an induction of apoptosis through the mitochondrial pathway, and it might be a potential antileukemia strategy for leukemia therapy. (Zhou & Wang 2008)

Forskolin – In this study, we find that treatment of freshly isolated CLL cells with the PDE4 inhibitor rolipram and the adenylate cyclase activator forskolin induces a series of events characteristic of a “mitochondrial” pathway of apoptosis, with mitochondrial depolarization, cytochrome c release, and activation of caspase-9. In addition, we observe activation of more “distal” apoptotic events such as caspase-3 activation, PARP cleavage, and the accumulation of hypodiploid leukemic cells. These results suggest that PDE4 inhibitors may induce CLL apoptosis by activating PP2A-induced dephosphorylation of proapoptotic BH3-only Bcl-2 family members such as Bad (B-cell lymphoma 2 (Bcl-2)–associated death promoter homolog). (Moon & Lerner 2003) 

Green tea extract –  We have previously shown that the green tea extract, epigallocatechin-3 gallate (EGCG), inhibits vascular endothelial growth factor receptor activation and induces apoptosis in primary CLL B cells. (Ghosh et al 2009) 

Honokiol – These data indicate that honokiol is a potent inducer of apoptosis in B-CLL cells and should be examined for further clinical application either as a single agent or in combination with other anticancer agents. (Battle et al 2005) 

Parthenolide (PTL) – decreased nuclear levels of the antiapoptotic transcription factor nuclear factor-kappa B and diminished phosphorylation of its negative regulator IkappaB. Chronic lymphocytic leukemia cells were more sensitive towards PTL than were normal T lymphocytes or CD34(+) haematopoietic progenitor cells. Killing of CLL cells by PTL was apparently independent of p53 induction. This is the first report showing the relative selectivity of PTL towards CLL cells. The data here warrant further investigation of this class of natural product as potential therapeutic agents for CLL. (Steele et al 2006)

Resveratrol – The results of our study revealed that resveratrol induced apoptosis in CLL cells in a tumor-specific manner but did not affect non-leukemic cells. Here, we report for the first time that both resveratrol + fludarabine and resveratrol + cladribine caused a higher rate of apoptosis in comparison to the rate caused by a single drug. (Podhorecka et al 2010) 

Research on Natural Compounds That May Regulate the Immune Response
Spontaneous regression of advanced cancer has long been recognized in metastatic melanoma and metastatic renal cell carcinoma, and, in fact, such observations have motivated the interest in immunotherapy in these settings. (Zahl et al 2008)Conventional cytotoxic cancer treatments weaken the immune system yet the immune system is necessary because it fights against the cancer.  Cancer can weaken as well as evade the immune system.  For example, over-expression of the immunosuppressive cytokine TGF-beta stimulates IL-17 and is a strategy that tumors have developed to evade effective immune surveillance. (Cancer Res 2008)

  1. Echinacea – We found many functional immune assays were affected by Echinacea preparations, suggesting that Echinacea not only stimulates innate immunity, but also enhances adaptive immunity. (Zhai et al 2007)
  2. Ganoderma lucidum – polysaccharides (especially beta glucans) are immune enhancing. The beta glucans attract Natural Killer cells to attack tumors and they work very well with monoclonal antibodies.  Together they puncture tumor cells.  There is good data on beta glucans working synergistically with Rituxan and monoclonal antibodies. (Hong et al 2003) 
  3. Lactoferrin – is a natural forming iron-binding glycoprotein with antibacterial, antioxidant and anti-carcinogenic effects. Lactoferrin also has the capacity to induce apoptosis and inhibit proliferation in cancer cells as well as restore white and red blood cell levels after chemotherapy. (Gibbons et al 2011) Colostrum is the richest source of lactoferrin. Lactoferrin stimulates IL-18, IL-α & IL-γ which stimulates NK cells.
  4. Propolis – Propolis activated macrophages to stimulate interferon (IFN)-gamma production in association with the secondary activation of T-lymphocytes, resulting in a decrease in IgG and IgM production. Cytokines released from macrophages in mouse peripheral blood after Propolis administration activated helper T-cells to proliferate. In addition, activated macrophages in association with the secondary T-lymphocyte activation increased IFN-gamma production and stimulated proliferation of cytotoxic T-cells and suppressor T-cells, indicating the activation of cell-mediated immune responses. (Takagi et al 2005)
References
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  1. Gullet, Norleena P, Ruhul Arnin, Soley Bayraktar, et al, “Cancer Prevention With Natural Compounds”, Seminars in Oncology, Vol 37, No 3, June 2010, pp 258-281
  1. Heber, David, Editor-in –Chief, Nutritional Oncology, Second Edition, Academic Press, London, 2006
  1. McKenna, Dennis J., PhD,  Kenneth Hones & Kerry Hughes, Botanical Medicines, The Desk Reference for Major Herbal Supplements, Second Edition, The Haworth Herbal Press, New York, 2002
  1. Mills, Simon and Kerry Bone, Principles and Practice of Phytotherapy, Churchill Livingstone, Edinburgh, 2000
  1. Neal, Michael J., Medical Pharmacology at a Glance, Sixth edition, Wiley-Blackwell, Oxford, 2009
  1. Stargrove, Mitchell, Jonathan Treasure & Dwight L. McKee, Herb, Nutrient, and Drug Interactions, Mosby Elsevier, St. Louis,  2008
  1. Weiss, Rudolf, MD & Volker Fintelmann, MF, Herbal Medicine, Thieme, New York, 2000
  1. Yance, Donald, “Donald Yance’s Eclectic Triphasic Medical System (ETMS): An Integrative Wholistic Approach to Treating and Preventing Cancer”, (Monograph) 2010
  1. Yance, Donald, Herbal Medicine, Healing & Cancer, Keats Publishing, Lincolnwood (Chicago) IL, 1999

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Compassionate Acupuncture and Healing Arts, providing craniosacral acupuncture, herbal and nutritional medicine in Durham, North Carolina. Phone number 919-309-7753.

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3 Responses to Understanding Chronic Lymphocytic Leukemia

  1. flossie says:

    I recently came across your blog and have been reading along. I thought I would leave my first comment. I don’t know what to say except that I have enjoyed reading. Nice blog. I will keep visiting this blog very often.

    Susan

    Low Platelets Treatment and Natural Remedies

  2. flossie says:

    I recently came across your blog and have been reading along. I thought I would leave my first comment. I don’t know what to say except that I have enjoyed reading. Nice blog. I will keep visiting this blog very often.

    Susan

    Low Platelets Treatment and Natural Remedies

  3. Hi friends,

    Thanks for providing these useful tips over here. Chronic lymphocytic leukemia is a monoclonal disorder characterized by a progressive accumulation of functionally incompetent lymphocytes. It is a slow increase in white blood cells called B lymphocytes or B cells…

    CD4 Antibody

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