Follicular lymphoma is a disease that affects 2.7 per 100,000 individuals each year, with a five-year survival rate of 89.7%. It is the most common subtype of indolent non-Hodgkin's lymphoma; about 22% of newly diagnosed non-Hodgkin lymphoma cases are follicular lymphoma. The development of novel therapies offers new treatment options for patients living with follicular lymphoma. In this interview, Dr. Loretta J. Nastoupil, MD, Section Chief of New Drug Development in the Department of Lymphoma/Myeloma at The University of Texas MD Anderson Cancer Center in Houston, Texas, speaks with Oncology Data Advisor about follicular lymphoma and how to treat patients with this disease.
What are the most significant challenges of managing follicular lymphoma?
Loretta Nastoupil, MD: There is tremendous heterogeneity in patient and disease characteristics with a paucity of biomarkers to inform treatment decisions. Fortunately for patients, there are many treatment strategies and outcomes are favorable, which is why we do not have an agreed upon gold standard approach. The impact of many possible treatment options and a paucity of randomized studies make it nearly impossible to define the optimal treatment at any given line of therapy, or to define the most effective sequence of therapy. This makes it challenging for us to know how new therapies should impact the treatment landscape and where they should be incorporated.
How do you use POD24 (progression of disease within 24 months) to guide treatment decisions? Are there any other notable predictors of survival, and how do these impact decision making?
Dr. Nastoupil: POD24 has been recognized across a number of datasets as a poor prognostic feature. The potential limitation is how much transformed disease is driving the poor outcomes. With the utilization of positron emission tomography/computed tomography (PET/CT) and biopsies of worrisome lesions, we know that approximately 40% of the POD24 population is likely transformed disease. Therefore, in my practice, I generally will biopsy worrisome lesions (defined by PET) to exclude the possibility of transformation. In cases of follicular lymphoma and POD24, I generally will pursue a trial and would highlight the SWOG 1608 study that is currently enrolling this population as this is an important randomized study that may identify the preferred approach. Other therapies that are promising for these patients include targeted treatment and chimeric antigen receptor (CAR) T-cell therapy. I do feel POD24 is a poor risk feature and novel therapy or a clinical trial is the preferred approach. Outside of POD24, FLIPI (Follicular Lymphoma International Prognostic Index) can be important in regard to risk stratification, but it has limitations in regards to informing treatment selection.
Can you discuss how you decide on which therapies to use for patients in the second-line and beyond, given the many options for treatment?
Dr. Nastoupil: I take into account patient and disease specific features. At the second-line I am quick to move away from chemotherapy unless I have clinical concerns for transformed disease such as B symptoms (fever, night sweats, weight loss), elevated lactate dehydrogenase, and hypercalcemia. If there is any concern for transformed disease, I will favor a CHOP (cyclophosphamide/doxorubicin/vincristine/prednisone)-based approach with obinutuzumab or rituximab. If there are no concerns for transformation, I will consider patient specific features (age, comorbidities, performance status, goals of care, quality of life concerns), disease burden (based on GELF, or The Groupe d'Etude des Lymphomes Folliculaires criteria), prior therapy, and duration of response to that therapy. I generally will pursue R2 (lenalidomide/rituximab) in second-line for most patients. In third-line or later, I consider all the same patient and disease characteristics and prior therapy. For high-risk patients (POD24, clinical concern for transformation) I will consider CAR T-cell therapy. For all others, I will consider EZH2 status and will likely choose tazemetostat over a phosphoinositide 3-kinase (PI3K) inhibitor if EZH2 mutated. In fourth-line or later, I once again have the same considerations and will consider CAR T-cell therapy for appropriate patients given that we see the longest progression-free survival with CAR T-cell therapy in this setting and then PI3K or EZH2 if appropriate.
When deciding whether to treat patients with idelalisib, how do you balance the efficacy with the toxicity risks, including increased risk of death?
Dr. Nastoupil: There are now four PI3K inhibitors—idelalisib was the first approved and unfortunately, we learned most of the issues surrounding toxicity identification and management with idelalisib as a result of it being first. The efficacy appears to be more similar than different, but the toxicity profiles vary according to which PI3K subunit/units the agent is inhibiting and likely informs treatment selection as well as the route of administration (oral versus intravenous). The PI3K inhibitors are effective for half of patients and have a meaningful progression-free survival; they should be considered in third- or fourth-line and later. Educating patients and staff on typical toxicities and holding the drug when these toxicities arise with appropriate monitoring and dose adjustment when the toxicity resolves will result in successful management for most patients.
What are strategies you use to manage the various adverse effects of the obinutuzumab/lenalidomide regimen?
Dr. Nastoupil: The toxicity associated with lenalidomide and CD20 combinations are predictable and more similar to chemotherapy type toxicities. Cytopenias, particularly neutropenia, are common, generally occur between cycles 3-6, and can be managed with drug interruption, growth factors, and dose modification if necessary. Gastrointestinal complaints, nausea, constipation, and diarrhea are similarly very manageable. The unique side effects, including rash, tumor flare, fatigue, and fever are seen during the first cycle. This is generally self-limiting. If the side effects are significant (grade 3 or higher), I hold the drug until it resolves and resume with cycle 2. Risk for deep vein thrombosis is lower in lymphoma than myeloma, but all patients are started on prophylactic aspirin if there are no high-risk features—and anticoagulation if high risk.
What are some of the most promising novel agents in development to treat follicular lymphoma? How do you see treatment evolving in the future?
Dr. Nastoupil: Bispecifics look very promising, particularly for follicular lymphoma. I anticipate they will be approved in the third-line space as single agents and will likely move into earlier lines in combination.
About Dr. Nastoupil
Loretta J. Nastoupil, MD, is an Associate Professor in the Department of Lymphoma/Myeloma, Division of Cancer Medicine, at The University of Texas MD Anderson Cancer Center in Houston, Texas. She is also the Director of the Lymphoma Outcomes Database, Section Chief of New Drug Development, and Section Chief of Indolent Lymphoma at MD Anderson Cancer Center. The focus of her research is examining disparities in lymphoma survival and identifying opportunities to improve outcomes for high-risk patients. Dr. Nastoupil has authored numerous publications on lymphoma and has presented her work at the American Society of Clinical Oncology meetings.