R/R FL Patient Case Review and Impressions
Loretta Nastoupil, MD, describes the role of molecular testing used in risk stratification of patient with FL
Loretta Nastoupil, MD: Most patients with follicular lymphoma will present with adenopathy, something that is palpable on examination and is detected by the patient or their primary care physician during routine wellness exams. More often than not, they don’t have accompanying B symptoms, though they can. What’s interesting about this case is she had palpable adenopathy, symptoms that were consistent with B symptoms, and imaging consistent with most typical presentations, where patients will have lymph node involvement on both sides of the diaphragm.
About half of patients will have bone marrow involvement at diagnosis. Because of that, it’s still recommended to consider bone marrow as part of the initial staging. FLIPI [Follicular Lymphoma International Prognostic Index score] is still prognostic in the modern era. This was a patient with high-risk FLIPI and in need of therapy based off of symptoms in her presenting imaging studies. The most common frontline approaches in the United States include a bendamustine-based approach with a CD20 antibody. The GALLIUM study does raise the question of whether to replace rituximab with obinutuzumab, given significant improvement in progression-free survival among patients who had obinutuzumab over rituximab when combined with chemotherapy followed by 2 years of maintenance. However, that was also associated with higher rates of grade 3 infusion reaction, grade 3 or higher neutropenia, and infection. It’s also more dose-dense with the first cycle among patients who receive obinutuzumab. Therefore, it’s still common practice in the United States for patients to receive bendamustine with rituximab or obinutuzumab.
The first remission duration is of prognostic importance. Most patients who have a first remission duration of more than 24 months, which is the majority of cases and true for this case, will actually have a normal life expectancy based on observational data from the National Lymphocare Study in validation with a French study. Patients who progress within 24 months have less favorable outcomes. In the modern era, questions arise as to whether that’s being driven by transformation that’s undiagnosed with the use of PET [positron emission tomography]. In some of our more modern therapies, we’re seeing less frequent occurrences of progression within 24 months, which is good news for patients. When it does occur, it’s still an inferior prognosis. At relapse, I recommend a biopsy to confirm that we know what we’re treating, whether it’s follicular lymphoma, transformed lymphoma, etc. Sometimes I’ve seen reactive changes on biopsies. I don’t necessarily get a biopsy at every single recurrence, but I do think it is important, particularly with the first occurrence, to ensure that we know we’re treating follicular lymphoma.
In recent developments, we now have a targeted therapy approved for patients with an EZH2 mutation, which occurs in about 20% to 30% of follicular lymphoma cases. Tazemetostat is FDA approved for patients with an EZH2 mutation who’ve had 2 prior lines of therapy, as well as in the relapsed setting for patients who do not have the mutation and don’t have an acceptable alternative, based off of the favorable safety profile. Because EZH2 is thought to be an early event in lymphomagenesis, testing for EZH2 can be done at the initial diagnostic sample. It can also be done in the relapsed setting.
As part of our standard work-up for follicular lymphoma, similar to what was done in this case, we frequently look for translocation (14;18), which is the hallmark of this disease. Unfortunately, it does not appear to be the driver of this disease. Therapeutically targeting the translocation (14;18) in the way of a BCL2 inhibitor does not seem to have significant therapeutic impact, but because this is commonly seen among patients with follicular lymphoma, cytogenetics are commonly pursued. EZH2 is the first molecular finding with a therapeutic option. It is also important to note that because tazemetostat is FDA approved, even for wild-type patients, it’s not absolutely necessary to have that information when making a treatment decision. Immunohistochemistry and flow cytometry are commonly pursued, either at diagnosis or in the relapsed setting, to discern whether you have a clonal B-cell population in this phenotype. Follicular lymphoma is a germinal center-derived lymphoma. As this implies, CD10 is often positive in addition to other common B-cell markers, such as CD20 and BCL2.
This transcript has been edited for clarity.
Case: A 75-Year-Old Woman With Relapsed/Refractory Follicular Lymphoma
Initial presentation
- A 75-year-old woman complains of a 3-month history of fatigue, occasional fevers, decreased appetite, fatigue, and a 12-lb weight loss
- PMH: Medically-controlled hypertension, osteoporosis, hypercholesterolemia managed with diet and exercise
- PE: palpable bilateral axillary and left cervical lymph nodes, ~ 3 cm in both axillae and 2 cm in the cervical nodes; spleen palpable 4 cm below left costal margin
Clinical workup
- Labs: ANC 1.6 x 109/L, WBC 11.4 x 109/L, 43% lymphocytes, Hb 9.8 g/dL, plt 98 x 109/L, LDH 325 U/L, B2M 3.7 µg/mL; HBV negative
- Excisional biopsy of the axillary lymph node on IHC showed CD 20+, CD 3+, CD5+, CD 10+, BCL2+; follicular lymphoma grade 2
- Bone marrow biopsy showed paratrabecular lymphoid aggregates, 42% involvement
- Cytogenetics: t(14;18) (q32;q21)
- Molecular testing: EZH2m+
- PET/CT showed bilateral axillary, left cervical, and mediastinal lymphadenopathy (3.3 cm, 3.1, cm and 4.6 cm respectively)
- Ann Arbor Stage IV; ECOG 1
Treatment
- She was treated with bendamustine and rituximab for 6 cycles, achieved partial response and continued rituximab maintenance
- 24 months later she complained of ULQ discomfort, loss of appetite, fevers new onset itching; she was currently taking antibiotics for her 2nd bacterial infection in the past 6 months
- Repeat PET/CT revealed progression of disease
- She was started on R-CHOP for 6 cycles and continued on rituximab maintenance
- Repeat lymph node biopsy grade 2 follicular lymphoma
- 12 months later she complained of continued weight loss, increased itching and worsening fatigue; recurrent infections continued
- She was started on tazemetostat 800 mg BID
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