Cohen Reviews Current Treatment Options in a Case Study of High-Risk Follicular Lymphoma

Jonathon B. Cohen, MD, MS

Jonathon B. Cohen, MD, MS, recently discussed treatment considerations and decisions in the case of a patient with follicular lymphoma (FL). Cohen, an assistant professor in the Department of Hematology and Medical Oncology and medical director of infusion services at Emory University School of Medicine, discussed the case scenario during a Targeted Oncologylive case-based peer perspectives dinner.

A 65-year-old woman presented to her primary care physician complaining of swelling in the neck. Her past medical history revealed osteoporosis and neurogenic bladder. On physical exam, she was noted to have an enlarged spleen 2 cm below the costal margin, bilateral cervical and axillary lymphadenopathy. At this point, she had an ECOG performance status of 0.

Her laboratory findings were notable for the following: white blood count (WBC): 12 X 10⁹/L; 45% lymphocytes; hemoglobin (Hb): 11.5 g/dL; platelets: 213 X 10⁹/L; lactase dehydrogenase (LDH): 212 U/L. She underwent and excisional biopsy of the lymph nodes. Per immunohistochemistry, she was CD10-positive and BCL2-positive. The patient was diagnosed with FL, grade I-II.

Her bone marrow biopsy showed 40% involvement and a fluorodeoxyglucose (¹⁸FDG)-PET revealed standardized uptake values (SUV)max of 9 with discrete masses bilaterally in the cervical and axillary region and increased uptake in the liver.

What are your general impressions of this patient?

This is a 65-year-old who presented to her primary care physician with neck swelling. She also had an enlarged spleen, but otherwise looked pretty healthy. You can see that she had a fairly mild past medical history. She had an excisional biopsy of the lymph nodes and this came back as a grade I-II FL. FL is frequently CD10-positive per immunophenotyping, which is important to know. Often, you end up getting a needle biopsy and it is low-grade lymphoma and you are trying to figure out what this is. It is easier for me to remember that FL is normally CD10-positive. Additionally, at least our pathologist, will typically grade on a scale of I to III. It has never made sense to me to get grade I to II, grade IIIa, or grade IIIb. There still ends up being 3 different grades, but for whatever reason they group them this way. It has to do with some of the features that they see under the microscope. In this case, the bone marrow biopsy was 40% involved. You can also see that they had masses in the cervical and axillary region, as well as some liver uptake.

How do you stage her?

She has liver and marrow involvement, so she would be stage IV. If I have someone with low-grade lymphoma with a liver mass, I don't always biopsy it if it seems consistent. However, if it doesn't seem right I usually have a pretty low threshold to biopsy to make sure it is either not an aggressive lymphoma, a benign liver lesion, or some other type of cancer. I've had several patients that have prostate cancer or bladder cancer and they go for their surgery and pull out some lymph nodes. It turns out that they have FL. They still have the bladder cancer, for example, but the enlarged lymph nodes were not from the bladder cancer, they were from the lymphoma.

What is her Follicular Lymphoma International Prognostic Index (FLIPI) score?

For FL, we also have an International Prognostic Index. This uses features such as age greater than 60, multiple nodal sites, elevated LDH, Hb, and stage. One of the things I like to point out is that it does not always take much to have a high-risk FLIPI. Those patients do not have the same prolonged overall survival that you expect with some of your other lymphomas.

The FLIPI score is something that I do try to calculate or at least think of in my mind when I'm seeing a patient with FL. If they have an elevated FLIPI, I am often a little bit more likely to pull the trigger sooner and maybe be a little bit more aggressive with their treatment in general. In this case, this patient was anemic, had advanced-stage disease, and multiple extranodal sites. She is considered high-risk per FLIPI scoring.

Does this patient require treatment?

There is the Groupe d’Etude des Lymphomes Folliculaires (GELF) criteria that we frequently use to determine therapy. However, there are patients that may or may not meet criteria for treatment on paper, but that you still feel you want to treat. I have a hard time sitting on patients that have documented organ involvement. Those are folks that you are worried will all of a sudden show up with marked liver function test abnormalities or something else.

What are the options, and which would you choose?

Cohen:The National Comprehensive Cancer Network guidelines have become increasingly challenging. Most people have been using bendamustine (Treanda) plus rituximab (Rituxan; BR), but now we also have obinutuzumab (Gazyva)—the newer CD20 antibody—in combination with bendamustine (BO). Even rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) is not an unreasonable option. It has fallen out of favor, but it seems like it is making a bit of a comeback. We are starting to see some increased infectious toxicities associated with bendamustine. Therefore, I am seeing people use R-CHOP more frequently. I am typically using BR, which this patient received, however, I think BO would also be a reasonable option.

The patient was started on BR for 6 cycles. She achieved a partial response (PR) with a 75% reduction in tumor volume.

Have you started using subcutaneous rituximab?

Our practice has started to use subcutaneous rituximab. We haven’t done it inpatient so far, but we have been doing it outpatient and most of our patients have been very happy with it. It is a 12 mL subcutaneous injection. Especially with our nursing staff, it took a lot of training and helping them to realize it was safe to do. It is a lot bigger than what you would normally do. In general, especially with maintenance, people have really liked it. Of note, there have been some local-site reactions that have been described. I haven’t experienced this myself.

Would you use maintenance therapy after BR?

I am a little bit conscious with maintenance after bendamustine based on some of the infection data. Typically, I will give it but have a low threshold to stop it if I have someone who is having recurrent infections. I do think it still has a benefit, especially in someone like this who had a PR. Those people may be particularly likely to benefit.

After 32 months, the patient complained of her symptoms returning and her CT showed disease progression in the axillary and hilar lymph nodes. A PET scan also revealed a SUV of 11.

What are the options for subsequent therapy?

I think this is a particularly challenging area. I do often use radiation a lot because most of the time they are going to have a long-term disease course and I often try to avoid therapy. There are a number of options at this point. If they have had a prolonged response you can sometimes retreat them, although I usually don't. If they had BR the first time, I might give them R-CHOP at relapse. The other regimen that I often use is lenalidomide (Revlimid) plus rituximab (R²). This tends to be effective in relapsed FL. It was also evaluated in a large study presented at the American Society of Clinical Oncology in the frontline—R²versus R chemotherapy—basically they found that there was no difference. Some people interpreted that to say it is equivalent, so you can use it. Other people said if it is not better than chemotherapy, why would I use it? I would say that it hasn't really made its way into the frontline, but R²does appear to be an effective option in relapsed disease.

A re-biopsy of the lymph node was consistent with FL grade IIIa. The patient was then referred to an academic center for treatment. She was enrolled in an open-label clinical trial of R²for 12 cycles. She achieved stable disease after 3 months, but 12 months later the patient presented with low-grade fever and chills. She was otherwise well-appearing and continued to exercise regularly. Her ECOG performance status remained 0; however,PET-CT showed further progression in the axillary lymph nodes.

Reference:

Fowler NH, Morschhauser F, Feugier P, et al. RELEVANCE: phase III randomized study of lenalidomide plus rituximab (R²) versus chemotherapy plus rituximab, followed by rituximab maintenance, in patients with previously untreated follicular lymphoma.J Clin Oncol. 2018;36(suppl 15; abstr 7500). doi: 10.1200/JCO.2018.36.15_suppl.7500.