Novel and Emerging Strategies
Normalizing Markers of Inflammation
Interleukin-6. Interleukin-6 (IL-6) is a cytokine (cell-signaling molecule) that stimulates the growth and maturation of B cells and T cells; it is also a major driver of inflammation (Wang 2009; Erta 2012; Hirano 2010). IL-6 levels are related to prognosis and survival of DLBCL patients (Giachelia 2012). Elevated serum levels of IL-6 are found with more advanced grade, type, B symptoms, and stage in NHL (Yee 1989; Kurzrock 1993; Giachelia 2012).
Abnormal IL-6 production has been observed during lymphoma progression, whereby the lymphoma cells secrete IL-6 continuously (Freeman 1989; Reynolds 2002). This is thought to lead to lymphoma cell growth mediated by IL-6 receptors (soluble IL-6R [sIL-6R]). Soluble IL-6R expression is augmented in NHL patients relative to healthy individuals (Lavabre-Bertrand 1995). Plasma IL-6 levels are significantly lower in patients whose lymphomas are in complete remission as compared to those in partial remission or those having progressive disease (Wang 2011).
One’s IL-6 level can be monitored with a blood test and some integrative interventions have been shown to suppress it. For example, coenzyme Q10 (CoQ10) at a dosage of 150 mg daily decreased IL-6 in patients with coronary artery disease, and mistletoe extract (eg, Iscador) also has been shown to reduce IL-6 levels (Lee 2012; Kovacs 2002). Non-steroidal anti-inflammatory drugs (NSAIDs) such as diclofenac and indomethacin also modulate the IL-6 pathway and may benefit lymphoma patients; although more research is needed in this area (Tsuboi 1995; Fiebich 1996; Mahdy 2002).
Aspirin has recently received considerable attention for its emerging role as a chemopreventive agent against a variety of cancers, including lymphoma. It is a powerful inhibitor of inflammation that works in large part by blocking the action of cyclooxygenase enzymes, which normally drive the formation of inflammatory molecules called prostaglandins and thromboxanes. Moreover, aspirin disrupts IL-6 signaling, which is an important mechanism thought to play a role in the anti-cancer action of the drug (Tian 2011; Slattery 2007; Kim 2009).
Several studies have examined the relationship between aspirin use and lymphoma risk. A study published in 2004 showed that regular use of aspirin was associated with a considerably reduced risk of HL (Chang 2004). In this study, 565 HL patients and 679 healthy control subjects reported their average use of acetaminophen, NSAIDs, and aspirin over the previous 5 years. Results revealed a statistically robust 40% reduction in HL risk among aspirin users, but other NSAIDs were not linked to reduced risk; acetaminophen use was actually linked to an increased risk of the disease. In a 2010 study conducted in Denmark, aspirin use was assessed in 478 HL patients and 4780 control subjects. The researchers observed modest evidence for a roughly 30% reduced risk of HL among aspirin users compared to non-users or those who took aspirin only rarely. This study also found that other NSAIDs were not associated with protection against HL (Chang 2010). Another study conducted in Denmark revealed similar results: long-term aspirin use was associated with modestly strong evidence for a 35% reduction in HL risk among 1659 HL patients who were matched to as many as 5 control subjects each. Again, other NSAIDs were not linked to reduced risk (Chang 2011).
It also appears that aspirin may reduce risk of NHL. In a study of 625 people with NHL and 2512 controls, regular aspirin use was associated with an 18% reduced risk for the cancer among men. Interestingly, this study also reported an increased risk for NHL in association with greater acetaminophen use (Baker 2005).
Although there is compelling evidence that aspirin may reduce risk of some lymphomas, certain lymphoma subtypes may respond differently to the drug. For example, one study found that aspirin might enhance the ability of a lymphoma cell line (ie, Molt-4 T lymphoma cells) to evade destruction by chemotherapeutic drugs, although this was under laboratory conditions in an experiment conducted on cells taken from a patient who relapsed after multi-drug therapy (Flescher 2000; CLS 2013).
C-reactive protein. C-reactive protein (CRP) is normally present in minute amounts in the blood, but levels increase with the presence of infection, inflammation, and lymphoma. CRP is produced by liver cells as a response to inflammatory cytokines, especially IL-6, which is increased in the tumor microenvironment (Wang 2009).
Suppression of serum C-reactive protein levels has become a surrogate marker of IL-6 inhibition in cancer studies (Voorhees 2013). Measurement of serum high-sensitivity CRP (hs-CRP) is simple and readily available via blood testing (Wang 2009).
CRP can be reduced by exercising moderately and regularly. A moderate-intensity exercise intervention reduced CRP for 12 months among 115 obese women (Campbell 2009). In one study, a therapeutic lifestyle modification intervention, including exercise, low-calorie diet, health education and counseling for 6 months, was found to be effective for improving patient inflammatory states and significantly decreased CRP levels in a group of 52 women (Oh 2013). In another clinical study on 652 sedentary individuals, a 20-week exercise training program was found to reduce CRP levels (median reduction of 1.34 mg/L) in individuals with high initial CRP levels (Lakka 2005).
There is no standard therapy for relapsed or refractory (treatment-resistant) aggressive NHL in patients who have received two prior lines of chemotherapy. On May 10, 2012, the European Commission issued a conditional marketing authorization valid throughout the European Union for pixantrone for the treatment of adult patients with multiply relapsed or refractory aggressive non-Hodgkin B-cell lymphoma (Péan 2013). The FDA granted fast track designation (FDA 2010) for pixantrone in patients who had previously been treated with two or more lines of therapy for relapsed or refractory aggressive NHL (Mukherji 2009).
Pixantrone is a novel anthracycline derivative developed with the aim to retain the efficacy of anthracyclines and be less cardiotoxic. In combination with rituximab, pixantrone has been shown to be superior to other single-agent therapies for the salvage treatment of relapsed/refractory aggressive NHL (Mukherji 2009).
In relapsed aggressive NHL, weekly pixantrone (85 mg/m2) for 3 weeks every 4 weeks was associated with a 27% overall response rate and a 15% complete response rate. When used in combination chemotherapy regimens, overall response rates of 58-74% and complete response rates of 37-57% were achieved (El-Helw 2007).
In a trial of pixantrone for patients with relapsed or refractory aggressive NHL, the rate of confirmed and unconfirmed remissions in patients treated with pixantrone was significantly higher than in those receiving other agents, as was the overall response rate and progression-free survival (Papadatos-Pastos 2013). Pixantrone could be a treatment option for patients whose aggressive NHL has failed to respond to at least two previous chemotherapy regimens (Pettengell 2012).
With single-agent pixantrone, neutropenia (low neutrophils) is the most common dose-limiting toxicity. The most common side effects with pixantrone are bone marrow suppression (neutropenia), nausea, vomiting, and weakness (Pettengell 2012; Péan 2013).
Vaccines aim to prevent lymphoma recurrence after standard treatment, particularly for the incurable, slow-growing, or inactive lymphoma types. They are a form of immunotherapy that can be used alone or in combination with chemotherapy regimens, with a goal of extending overall survival (Thomas 2012; Rezvani 2011; Iurescia 2012).
A 2011 clinical study (phase III trial) has shown that a vaccine targeting a unique molecular structure on certain lymphoma cells improved disease-free survival in follicular lymphoma patients who were already in a minimal residual disease state (ie, had a complete response after 6 to 8 months of combination chemotherapy) (Schuster 2011). Based on the positive results of this study, a next-generation DNA vaccine has been developed using residual patient tumor and blood samples from patients vaccinated in the phase III clinical study. This new vaccine will be tested for the first time in patients with asymptomatic-phase lymphoplasmacytic lymphoma (Thomas 2012; Iurescia 2012).
DNA vaccines are being developed as highly specifically-targeted vaccines aimed at certain lymphoma cell surface markers and use multiple genes to enhance immunity and have lower risk than conventional vaccines. One of the most clinically advanced among therapeutic vaccines, BiovaxID®, is not yet available to the patients who need it – those diagnosed with a slow growing or inactive subtype of B-cell lymphoma. The clinical trials that have examined BiovaxID® indicate that it is clinically effective, but they were not large enough (did not enroll enough patients) to satisfy regulatory approval by the FDA. Therefore, unfortunately, more clinical trials will have to be successfully completed in order to make BiovaxID® available to B-cell lymphoma patients (Villanueva 2011; Iurescia 2012).
Targeting Infectious Agents to Treat Some Lymphomas
H. pylori and gastric mucosa associated lymphoid tissue lymphoma (MALT). There is compelling evidence that infection with the bacterium H. pylori causes gastric mucosa associated lymphoid tissue lymphoma (MALT) and that eradication of the bacteria results in lymphoma remission in many patients (Fischbach 2013).
As eradication of H. pylori infection cures gastric MALT in many cases, it is quite plausible that eradication of known causative infectious agents may cure other lymphomas (Kanakry 2013). This suggests it would be reasonable to test for suspected infectious agents (Grudeva-Popova 2013) and treat the infections (Poullot 2013).
For example, eradication of a suspected causative bacterium of mantle cell lymphoma (Borrelia burgdorferi) could possibly cure this lethal type of lymphoma (Fühler 2010; Schöllkopf 2008).
Borrelia burgdorferi and cutaneous B-cell lymphoma (CBCL). Borrelia burgdorferi (B. burgdorferi) is well known as the bacterium that causes Lyme disease. Lyme disease diagnosed early is generally successfully treated with antibiotics (eg, doxycycline, amoxicillin, cefuroxime) for 14 days (Wormser 2006). However, for complicated infections, intravenous antibiotics are often used (Klempner 2001; Pfister 1991). B. burgdorferi DNA has been detected in patients with cutaneous B-cell lymphoma (CBCL) and a response of CBCL to antibiotics has been observed. Physicians in Germany treated a patient with marginal zone lymphoma and B. burgdorferi infection with the antibiotic ceftriaxone, which resulted in lymphoma regression (Fühler 2010).
Therefore, patients with mantle cell lymphoma, CBCL, or marginal zone lymphoma who have been newly diagnosed (and have B. burgdorferi infection) or who have exhausted all other available treatment options, may wish to try the typical course of antibiotics used to treat Lyme disease (Fühler 2010; Hofbauer 2001).
Hepatitis C and Hodgkin lymphoma. In 2012 a documented case of a HL patient with HCV infection who experienced lymphoma regression following interferon-based antiviral therapy was reported. The authors state that “[t]his unique case […] confirms the efficacy of antiviral therapy for [Hodgkin lymphoma].” This case highlights the extent of the involvement of HCV in causing HL and moreover, the power of antiviral therapy in eliminating the causative virus (HCV) and hence the lymphoma itself (Takahashi 2012).
Other evidence suggests that HCV-positive lymphoma (marginal zone lymphoma) may respond to antiviral therapy with interferon and ribavirin (Ignatova 2012; Kelaidi 2004; Hermine 2002). Two cases of large granular lymphocyte (LGL) leukemia associated with B-cell lymphoma (B-NHL) and HCV infection that were successfully treated with antiviral therapy were reported. The researchers state, “HCV screening should be performed in all cases of LGL leukemia or B-NHL at diagnosis. Antiviral therapy may be attempted as first-line treatment for HCV-infected patients with indolent [inactive] B-NHL or LGL leukemia to prevent the side effects of chemotherapy or immunosuppressive treatment” (Poullot 2013).
"Antivirals" in the treatment of adult T cell leukemia/lymphoma. Adult T cell leukemia/lymphoma (ATLL) is a T cell lymphoma caused by infection with the human T-lymphotropic virus type 1 (HTLV-1). Aggressive subtypes of ATLL have a poor survival rate partly due to chemotherapy resistance (Fields 2012).
In a study of 254 lymphoma (and leukemia) patients, the 5-year overall survival rate was 46% for patients who received antiviral therapy alone, 14% for those who never received antiviral therapy, and 12% for those who received chemotherapy followed by antiviral therapy. Consequently, patients who received antiviral therapy in their initial treatment had a better overall survival rate. Moreover, patients with chronic or smoldering (slow-growing) ATLL significantly benefited from antiviral therapy, with a 100% 5-year overall survival rate in contrast to a 42% 5-year survival in those treated with chemotherapy alone (Fields 2012).
Epigenetic Therapy of Lymphoma using Histone Deacetylase Inhibitors (HDACIs)
One group of compounds receiving considerable attention in cancer research are called histone deacetylase inhibitors or HDACIs. These compounds modify gene expression without directly affecting the DNA sequence (Riddihough 2010; Bell 2011). Epigenetic modification by HDACIs has recently been proposed as a potential new therapy for lymphoma and leukemia.
Clinical trials indicate that HDACIs have specific anticancer effects on cutaneous T-cell lymphoma (CTCL), Hodgkin lymphoma, and myeloid tumors (Wada 2012; Mercurio 2010). Pharmacologic HDACIs (vorinostat and romidepsin) have been FDA-approved for the treatment of CTCL and peripheral T-cell lymphoma (Guo 2012; Howman 2011).
Hodgkin lymphoma is often curable with a 5-year survival rate of over 80% (Aleman 2007; Leukemia & Lymphoma Society 2013b). However, patients who relapse and become non-responsive to first- or second-line treatments (refractory) generally have a poor prognosis and early death. Recent clinical trials have shown that HDACIs have promising effects on refractory Hodgkin lymphoma (Buglio 2010).
In addition, it is worth noting that curcumin and resveratrol, both natural compounds, can exert epigenetic influences and are being investigated as cancer therapeutics (Cotto 2010; Frazzi 2013; Howells 2011; Kanai 2013).
Valproic acid. Valproic acid (VPA) was first used in 1963 to treat seizures, acute mania (Emrich 1981), bipolar disorder, and migraine headaches (Terbach 2009). Recent laboratory and animal studies show that VPA also functions as an HDACI, causing cell growth arrest and inducing differentiation in cancer cells. Preclinical studies show that VPA initiates cancer cell death by triggering apoptotic (programmed cell death) pathways in chronic lymphocytic leukaemia (CLL) (Bokelmann 2008). VPA is undergoing evaluation in India as a therapy for CLL (Szwajcer 2011).
The standard treatment for DLBCL patients is the CHOP chemotherapy regimen (cyclophosphamide, doxorubicin, vincristine and prednisone), often combined with rituximab (R-CHOP). However, this chemotherapy regimen achieves a long-term cure in only 50-60% of patients. A 2013 Swedish study reports that VPA sensitizes DLBCL lines to CHOP-induced cell death. VPA alone or in combination with CHOP decreased lymphoma cell proliferation and survival. Therefore, VPA may be a promising novel treatment that can be used in combination with R-CHOP for patients with DLBCL to increase response rate and improve long-term patient outcomes (Ageberg 2013).
Targeting B-Cell Lymphomas with Engineered T Cells
Researchers on the cutting edge of immunological science have developed a method for modifying the immune system that allows for targeted eradication of B cells. This approach involves isolating patients’ T cells and inserting genetic information into them using a virus (viral vector). This new genetic information causes the T cells to target a specialized protein called CD19 on the surface of B cells. Once the engineered T cells are reintroduced into the patient, they seek out and destroy B cells, including those affected by B-cell lymphomas (Gill 2014; Kochenderfer, Rosenberg 2013). Results obtained using this approach have been very intriguing. In December 2013, scientists at the 55th annual meeting of the American Society of Hematology reported that of 14 patients with chemotherapy-refractory diffuse large B-cell lymphoma treated with this new procedure, 5 achieved complete remission and 6 achieved partial remission (Kochenderfer, Dudley 2013). Amazingly, one patient who had previously undergone 3 different chemotherapy treatment regimens but still had relapsing primary mediastinal B-cell lymphoma achieved a complete remission in response to the engineered T cell treatment.
This approach appears very promising as side effects seem to be generally manageable and the intervention is typically well tolerated by patients. Research is ongoing to determine ways to maximize the benefits of these engineered T cells, but few other B-cell lymphoma treatment strategies are garnering as much attention among oncologists and hematologists (Xu 2013).