A 76-Year-Old Man With Relapsed/Refractory Follicular Lymphoma - Episode 3

The Role of Tazemetostat in Relapsed Refractory Follicular Lymphoma

A hematologist/oncologist discusses the tazemetostat as a treatment option for patients with relapsed/refractory follicular lymphoma.

Perry Cook, MD: What is tazemetostat? It’s an EZH2-directed therapy. We’ve come to understand that EZH2 is an important epigenetic regulator of B-cell physiology, which is particularly pertinent in follicular lymphoma. About 20% of patients with follicular lymphoma have gain-of-function mutations in EZH2; 80% of them don’t, but they have alternative mutations in the CREB system that makes them more vulnerable to developing follicular lymphoma. EZH2 is important to the physiology of patients with follicular lymphoma, whether they’re EZH2-mutated or not. About 70% of the mutated patients will demonstrate a measurable response to EZH2-directed therapy with tazemetostat. In contrast, only about 35% of patients with wild type EZH2 will demonstrate a response. Interestingly, the median duration of response is several months longer in patients who are EZH2 wild type. The FDA approval for the use of tazemetostat is in mutated patients who’ve had at least 2 lines of therapy, and for unmutated patients who lack a good alternative therapy. This means that tazemetostat may be introduced as early as second-line therapy for patients like the one we reviewed, who are EZH2 wild type at diagnosis and progress early after initial chemoimmunotherapy.

The question is, who should we consider for tazemetostat? I think I’d be guided by the FDA guidelines, so patients with follicular lymphoma who’ve had at least 2 prior lines of therapy and are EZH2 mutated are appropriate candidates for tazemetostat. Patients who are EZH2 wild type are appropriate as early as second-line therapy if they do poorly with first-line therapy. Now, who should get tested? I’ve run up against insurance difficulties for patients who’ve already had 2 lines of therapy, because the insurance company says, “You’re going to treat with tazemetostat whether they’re mutated or not.” So far, I haven’t had an answer to that. I’m curious, because I’d like to know if my patient has a 70% chance of response or a 35% chance of response. Honestly, the insurance company may be right in that it’s still the drug that I would use, so it may not be critical. It’s not routinely obtained at the time of initial diagnoses. It can be determined on formalin-fixed tissue, so you can go back to the initial biopsy and determine whether there is an EZH2 mutation. This finding is stable over time, so if you determine it at time of initial diagnoses, it will be the same at time of progression, you don’t have to recheck it.

What’s the tolerability of tazemetostat? The answer from the literature, and also from my experience, is that this drug is quite well tolerated and has a very low incidence of significant cytopenias. They do occasionally occur, but quite infrequently. On the other hand, there is toxicity associated with it, and its asthenia. There’s a fairly high incidence of sense of fatigue, or asthenia, which could require interruption of therapy in some patients. In my experience, I tell patients to anticipate this and to work actively to maintain their performance status in the course of therapy. If your body tells you that you need rest and relaxation, I will beg to differ. This is a misleading sensation and you should try to maintain your activity level through treatment. If this proves to be impossible, then the drug should be stopped for a short period until the patient recovers from the sense of fatigue and then [it should be] resumed. If this continues to be a problem, dose reduction may be necessary. Dose reduction is also used if there are significant cytopenias. Dose interruption and subsequent dose reduction, in my experience, have not been an issue, but it is reported in the literature.

Will tazemetostat remain as a second- or fourth-line therapy in the future? I think that’s unclear. EZH2 mutation is present in a significant percentage, about 20%, of patients with large B-cell lymphoma, so tazemetostat may have a role there as well. It seems to have a global impact on lymphocyte biology and has a tolerable [adverse] effect profile, so one could anticipate that tazemetostat might be incorporated along with other therapies. There is nothing about it that would prohibit concurrent use, say, with a CD20 agent. It might be added to other chemotherapy agents because it has a modest impact on cytopenias. I think the future is open and being explored in terms of where tazemetostat will sort out in therapy for our patients with B-cell lymphoma. Right now, the FDA restricts it to the third line or beyond in EZH2 mutated, and as early as second line in EZH2 wild type.

This transcript has been edited for clarity.

Case: A 76-Year-Old Man With Relapsed/Refractory Follicular Lymphoma

Initial presentation

  • A 76-year-old man complains of a 4-month history of bloating, fevers, and unintended weight loss of 9 lbs
  • PMH: Medically-controlled hypertension, brittle diabetes, CABG 10 years prior
  • SH: Lives by himself 2.5 hours from the clinic; only daughter lives out of state
  • PE: palpable right axillary lymph nodes, ~ 3 cm and bilateral cervical lymph nodes, ~ 2 cm; spleen palpable 4.5 cm below left costal margin

Clinical workup

  • Labs: ANC 1.6 x 109/L, WBC 11.4 x 109/L, 45% lymphocytes, Hb 9.5 g/dL, plt 96 x 109/L, LDH 426 U/L, B2M 3.4 µg/mL; HBV negative
  • GFR 59 ml/min
  • 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: EZH2 wild type
  • PET/CT showed right axillary, bilateral cervical, and mediastinal lymphadenopathy (3.3 cm, 3.4, cm and 2.6 cm, and 3.2 respectively)
  • Ann Arbor Stage IV; ECOG 1

Treatment

  • He was treated with bendamustine and rituximab for 6 cycles, achieved complete response and continued on rituximab maintenance
    • Side effects included grade 3 diarrhea with BR
  • 16 months later he complained of fevers and chills with increasing frequency
    • Repeat PET/CT revealed progression of disease
    • He received R-CHOP for 6 cycles and continued on rituximab maintenance
  • 11 months later he had worsening fatigue and increased weight loss and work up revealed progressive disease
    • He was started on tazemetostat 800 mg BID