Managing Side Effects of Tazemetostat in R/R FL

EP: 1.Case Presentation: Relapsed/Refractory Follicular Lymphoma

EP: 2.R/R FL Patient Case Review and Impressions

EP: 3.First-line Therapy Options in ND Follicular Lymphoma

EP: 4.Considerations for Therapy in R/R FL

EP: 5.Second-line Treatment Options for R/R FL Patients

EP: 6.Treatment Challenges Beyond the Second-line in R/R FL

EP: 7.Efficacy of tazemetostat in patients with EZH2m and EZH2wt R/R FL

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EP: 8.Managing Side Effects of Tazemetostat in R/R FL

EP: 9.Future Directions and Unmet Needs in the Treatment of R/R FL

Loretta Nastoupil, MD: I have a couple of takeaways from reviewing the phase 2 data of tazemetostat as a single agent in the third-line or later space. There are very low rates of grade 3 or higher toxicity. We do observe anemia, which is quite common among our patients with follicular lymphoma across a number of different studies. There were rates of grade 1 or 2 alopecia, which was interesting, given that this has a targeted mechanism of action. In my clinical experience, I’ve not seen significant alopecia. There’s likely a role of stress-induced hair loss, although I am mindful that patients might have hair thinning, so I’ve added that into my discussion with patients in terms of potential risks.

Because it’s an oral therapy, it’s not uncommon to see GI [gastrointestinal] complaints such as nausea or constipation. It’s infrequent to see evidence of emesis or diarrhea. Arthralgias, myalgias, and fatigue are common toxicities observed across these studies in the third-line or later follicular lymphoma space. Fortunately, there are low rates of grade 2 or higher toxicity.

As a result of the toxicity profile being quite favorable, there are infrequent instances where patients would have dose modification, dose hold, or even dose discontinuation as a result of toxicity. As a result of this, and based off of observations of efficacy in mutated and wild-type cohorts, it is now being studied in combination strategies. Tazemetostat is being combined with lenalidomide and rituximab in a randomized phase 3 study vs rituximab and lenalidomide and placebo. This will shed some additional light as to the tolerability and potential for synergistic efficacy when partnered with a microenvironment-targeting therapy, such as lenalidomide. We might anticipate efficacy in both mutated and wild-type populations.

It’s been combined with chemotherapy, particularly in germinal center large cell lymphoma, such as with R-CHOP [rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone]. It might have some potential additive efficacy when combined with chemotherapy. Fortunately, in reports to date, it does not appear to have any additive toxicity. Given that the EZH2 mutation is an early event, it’s natural to explore that in earlier lines of therapy. The question is, can you have a fully targeted approach? Or would you combine it with chemoimmunotherapy? Both are reasonable options to consider, given that the toxicity profile lends itself well to combination strategies and well enough to explore in frontline follicular lymphoma, where we have very high expectations and a very low threshold for toxicity.

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