CANCER UPDATE: New Treatments for Non-Hodgkin’s Lymphoma

Jennifer Lucas, MD

Non-Hodgkin’s lymphoma (NHL) consists of a diverse group of malignant tumors of the lymphoid tissues derived from the clonal expansion of B-cells, T-cells and natural killer cells or precursors of these cells. The incidence of NHL in the United States is over 65,000 cases per year. The average annual increase in incidence is approximately 2.7%, with an 82% rise in annual incidence since 1975. NHL has been extensively studied, yet the causes and increasing incidence of most forms of NHL are unknown.

The past decade has brought tremendous progress in both diagnostic and treatment approaches for NHL, but we still have a long way to go and face many challenges. The WHO Classification system characterizes over 30 distinct subtypes of NHL, a quantity that can lead to much confusion for both patients and physicians. Meanwhile, hundreds of lymphoma clinical trials are under way, and more than 40 new investigational agents are being studied worldwide.

This article summarizes advances in treatment for the two most common forms of NHL: diffuse large B-cell lymphoma and follicular lymphoma, which together represent more than half the diagnoses of NHL in North America.

Diffuse large B-cell lymphoma

Diffuse large B-cell lymphoma (DLCBL) is an aggressive B-cell malignancy that requires immediate treatment, without which survival is typically measured in weeks to months. With combination immunochemotherapy, however, up to 70% of DLCBL patients can be cured. The addition of rituximab, a monoclonal antibody that targets the CD20 antigen expressed on most B-cell lymphomas, has made the single biggest impact on improving survival rates in the last decade when combined with standard chemotherapy (R-CHOP).

Other strategies for improving outcomes over R-CHOP are under vigorous investigation. Both bone marrow transplant and maintenance rituximab have been studied in patients who achieve a remission, but clinical trials to date have not shown a definitive advantage to either approach. The current consensus is that cure rates will only be improved by adding new biologic agents to induction immunochemotherapy or as maintenance treatment after remission has been achieved.

New biologic approaches such as adding bortezomib or lenalidomide to the R-CHOP regimen are being evaluated in clinical trials. Lenalidomide (a relative to thalidomide) is an immunomodulatory agent that has a broad spectrum of anti-cancer activity and as a single agent has significant activity in relapsed DLBCL.

At Marin Specialty Care, where I practice, we are evaluating a novel compound, RAD001, as maintenance treatment for patients who achieve remission with standard immunochemotherapy. As an mTOR inhibitor, RAD001 interferes with a cell-growth signaling pathway that is dysregulated in lymphoma cells and is key for cell survival.

Another area of research worldwide is the identification of different subtypes of diffuse large-B-cell lymphomas based on gene-expression profiles. Gene-expression profiling measures the activity of thousands of genes at once, to create a global picture of cellular function. These profiles can, for example, distinguish between cells that are aggressively dividing and growing, or show how the cells react to a particular treatment.

Subtypes within DLBCL can now be categorized by gene expression into germinal center B-cell-like (GCB) and nongerminal center B-cell-like (non-GCB). Patients diagnosed with non-GCB type have a poorer prognosis and significantly reduced survival rates. Studies are now being designed to incorporate new drugs with standard treatment in an effort to overcome the inferior outcomes seen in patients with the non-GCB subtype. For example, bortezomib (a proteasome inhibitor) may be effective in non-GCB DLBCL because of its ability to inhibit nuclear factor kappa B, a well-described survival pathway that is upregulated in non-GCB subtypes.

Follicular lymphoma

Follicular lymphoma (FL) is an indolent B-cell malignancy that to date still does not have a universally accepted first-line treatment strategy. Patients typically present with asymptomatic peripheral lymphadenopathy and advanced stage disease. Fifty percent of patients have bone marrow involvement at diagnosis. To date, FL is considered a treatable but invariably relapsing disease with long survival times, typically measured in years. Survival times have continued to improve in recent decades, but FL is still considered incurable.

Depending on the clinical presentation, FL patients have treatment options that range from watchful waiting to bone marrow transplants! A modified prognostic scoring system, the Follicular Lymphoma International Prognostic Index (FLIPI), incorporates patient age, stage, number of involved nodal areas, serum lactate dehydrogenase, and hemoglobin. The resulting FLIPI index has helped oncologists take a risk-stratified treatment approach for FL.

While the FLIPI score is prognostic, the best predictor of outcome is again seen through gene-expression work (not yet commercially available). For instance, a predominance of inflammatory T-cells has a strong and favorable impact on survival and denotes that the patient’s own immune response is critical in keeping the lymphoma in check. Having a prognostic tool that can accurately predict which patients can safely be observed versus which patients should start immediately on treatment could be invaluable.

Treatment approaches for FL are diverse, and treatment choice is highly dependent upon clinical presentation, the biases of the physician, and the goals and expectations of the patient. Monoclonal antibodies, such as rituximab, are used either as a single agent or with chemotherapy (typically alkylators or purine analogues) and have become the cornerstone of therapy. Radioimmunotherapy, an antibody conjugated to a radioactive isotope, is another effective treatment option for patients with FL. Bendamustine, a newer chemotherapeutic agent, has shown excellent activity, even in the refractory setting.

Despite a wide range of therapeutic options for FL, there is a great need for developing new molecularly targeted treatment approaches, such as drugs that target unique biologic abnormalities in FL. The characteristic cytogenetic alteration in FL, for example, is a translocation involving the Bcl-2 gene t(14;18). This translocation, which is present in approximately 85% of FL cases, places Bcl-2 under the control of an immunoglobulin heavy chain enhancer on chromosome 14, resulting in constitutive overexpression of Bcl-2. These Bcl-2 genes are extremely important in regulating apoptosis (cell-programmed death) and have become an attractive target for developing new agents. There are currently several anti-bcl-2 molecules in clinical trials.

The ubiquitin-proteasome pathway plays a key role in the degradation of misfolded or unwanted intracellular proteins in cells and is a key mechanism in determining the activity of cell-cycle regulatory proteins. Pre-clinical studies have demonstrated encouraging results with bortezomib, a proteasome inhibitor in NHL cell lines, and early clinical studies indicate impressive activity in FL.

A large number of novel agents potentially useful in FL patients—including chemotherapeutics, monoclonal antibodies, apoptosis-inducing agents and immunomodulators—are in the clinical trial pipeline. Marin Specialty Care is participating in two such trials. One is measuring various combinations of rituximab and other drugs for high-risk FL, and the other is evaluating a new antibody (ofatumumab) vs. rituximab for patients with relapsing lymphoma.

 

Despite the impressive biological and therapeutic progress made in dealing with FL over the last decade, there is still tremendous room for improving treatment. We need to develop therapies that extend the duration of remission without adding any additional toxicity. Therapy for FL also needs to be adapted to the patient’s individual status while relying on a continuously growing repertoire of salvage therapies.

I am excited to see what the next decade of treatment offers our patients. Perhaps the opportunity to cure follicular lymphoma is right around the corner.

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Dr. Lucas is a medical oncologist and hematologist at Marin Specialty Care in Greenbrae, which is affiliated with the Marin Cancer Institute.

Email: jlucas@marinspecialtycare.com