A Q&A with Andrew D. Zelenetz, MD, PhD, medical oncologist specializing in lymphoma at Memorial Sloan-Kettering Cancer Center, New York City.
Andrew D. Zelenetz, MD, PhD
Targeted Oncologyinterviewed Andrew D. Zelenetz, MD, PhD, a medical oncologist specializing in lymphoma at Memorial Sloan-Kettering Cancer Center, about the challenges of indolent non-Hodgkin lymphomas.
Targeted Oncology: Letâ€™s start with how indolent NHLs are categorized.
Dr. Zelenetz:Indolent Non-Hodgkin lymphomas (NHLs) include both B- and T-cell lymphomas. The most typical indolent T-cell lymphoma, cutaneous T-cell lymphoma, is relatively rare. The indolent low-grade B-cell lymphomas are more common. The most common in the United States and Europe is follicular lymphoma (FL). We also see small lymphocytic lymphoma, which is on the continuum with chronic lymphocytic leukemia (CLL). There is also marginal zone lymphoma (MZL) and WaldenstrÃ¶m's macroglobulinemia. MZL includes extra nodal marginal zone lymphoma, often involving the gastrointestinal tract, lung, or skin; nodal marginal zone lymphoma; and splenic marginal zone lymphoma, involving the spleen, marrow, and blood. The subtypes of MZL are all different diseases based on the molecular lesions involved.
Despite the fact that lymphoma is the fifth or sixth most common cancer in the United States, the existence of so many different subtypes makes each one an orphan disease. This raises challenges in drug development that are compounded, because as oncologists we are not very good about emphasizing the importance in taking part in prospective clinical trials. Only about 3% of cancer patients are going onto clinical trials. That number should be more like 30% or 50%.
Do the indolent NHLs progress to more aggressive types, or are they different biologically from aggressive NHL?
Indolent lymphoma can progress or "transform" to aggressive lymphoma. In FL, about 40% to 50% of patients will undergo transformation within 15 to 18 years, with a much lower risk thereafter. The molecular basis for this natural history is poorly understood. The risk of transformation is about 3% per year during the first 15 to 18 years. The prognosis of the transformed disease depends on the timing of transformationâ€”those who transform early, especially with localized disease, do relatively well; in contrast, late transformation after several treatments can have median overall survival of 3 to 6 months. When FL transforms, the histology now looks like diffuse large B-cell lymphoma, an aggressive type of disease.
What is the current prognosis for patients with indolent NHL, and what are the major challenges?
The major challenge is that these indolent NHLs have variable natural histories. There are FL patients who will die of their disease 2 years after diagnosis, and patients who have never received a treatment 25 years after diagnosis. Under the microscope, the histology looks the same for both of these patients. Localized nodal MZL and localized FL are potentially curable, but in general we do not consider the indolent NHLs curable. Extranodal MZL sometimes presents as highly localized disease, and this is potentially curable with localized radiation. Most types of indolent NHLs are treatable and can respond many times to treatment, and that is why the survival prognosis is good for these patients. Indolent NHL patients who have some disease generally do not feel any different than patients who are in remission. This is important because these patients can be observed without active therapy until they develop symptoms.
FL has a median survival of 12 to 16 years, substantially longer than two decades ago. The improved survival is related to improved therapeutics, particularly rituximab and other effective second-line treatments like bendamustine. Nodal MZL has a similar prognosis to FL. Patients with splenic MZL do a bit better than FL because they respond to single-agent rituximab, and if the spleen is removed, many patients will live close to a normal lifespan.
We previously thought that if you were over 70, and certainly over 80, you would die of nonlymphoma causes. But recently, we have evidence that 40% of people with FL over the age of 80 die of lymphoma-related causes. This makes us rethink the prognosis of these patients because people are now less likely to die of cardiovascular disease and other causes, and as a result, now the lymphoma is a major issue.
How are these diseases diagnosed?
There are number of molecular and cytogenetic tests we do in conjunction with standard pathology of the lymph node to refine the diagnosis and chose the best treatment. Using immunohistochemistry and the cell morphology, we identify the type of lymphoma that is present. For small lymphocytic lymphoma (SLL), knowing the cytogenetics is important for the selection of treatment, for example. This is the era of genomics, and so we are now identifying recurrent mutations through sequencing studies that have not been identified previously. These are potential targets for therapies. TheMLL2gene was recently identified as the most frequent mutation in FL.
What are the challenges in approaching treatment for a newly diagnosed patient?
Because of the varying natural history of the diseases, treatment must be very individualized. The first question is always whether the patient needs treatment and how we can identify which patients do not need treatment. If the disease is highly localized, we would start with a localized treatment that is potentially curative. For patients with advanced disease, active monitoring is also an option. If the patient needs treatment, the issues include whether there are adverse factors such as high proliferation fraction or threatening sites of disease, where fast-acting treatment is needed such as rituximab plus CHOP.
Another frontline treatment is rituximab plus bendamustine. The role of rituximab plus lenalidomide is also now being investigated. Patients treated with chemo-immunotherapy followed by maintenance rituximab can have a first remission that lasts 5 to 7 years. Trials have shown that maintenance rituximab prolongs progression-free survival (PFS), but unfortunately, the data have not yet shown that this prolongs survival. But unlike other cancers, there is a risk of late recurrence with indolent lymphomas beyond 7 years and often it is the same tumor.
How long do patients typically receive maintenance rituximab therapy?
The trials have tested maintenance therapy for 2 years and in the community I think there are doctors who prescribe the treatment for longer, but my concern is that there are published data showing these patients can end up with infections that require IV immunoglobulin support.
What are the ways to identify patients who are more likely to recur? Does this remain a challenge?