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• W3139456495 abstract "blood cancer research: blood cancer researchWith approximately 14,000 cases per year, follicular lymphoma (FL) is the most common indolent lymphoma diagnosed in the United States. It is a highly heterogeneous disease with varying prognosis, influenced by differences in clinical, laboratory, and disease parameters between patients (Blood Cancer J 2020; https://doi.org/10.1038/s41408-020-00340-z). Although FL is considered an incurable disease, improvements in diagnosis and therapeutic advances have improved outcomes. Clinicians may choose to treat their patients with FL by a method of watch and wait for those with indolent disease. In more advanced stages, such as for patients with grades 3A and 3B FL, clinicians may use one or more chemotherapy drugs or the monoclonal antibody rituximab, alone or in combination with other agents. Common combination regimens include: R-Bendamustine (rituximab and bendamustine); R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone); and R-CVP (rituximab, cyclophosphamide, vincristine, and prednisone). A Difficult-to-Treat Population Presently, median survival ranges from 8 to 15 years (American Cancer Society: Cancer Facts and Figures 2021). Unfortunately, most patients have a relapsing and remitting pattern of illness, requiring numerous treatments during their lifetime. Treatment for relapsed or refractory FL (R/R FL) is influenced by initial first-line therapy and the duration and quality of the response. Currently, there is no consensus for the treatment of patients with relapsed disease. Consequently, patients with R/R FL represent a difficult-to-treat population with limited treatment options. For patients with FL that is R/R to rituximab, obinutuzumab plus bendamustine followed by maintenance obinutuzumab was approved by the FDA in February 2016 based in part on results from the Phase III GADOLIN trial (NCT01059630). Additionally, duvelisib is indicated for recurrent or relapsed FL after at least two prior systemic therapies. However, novel therapies are needed for patients who progress through chemotherapy and other available options. Recently, the treatment landscape was enriched with another approval for two indications in this setting. Tazemetostat Shows Antitumor Activity In a study published in the The Lancet Oncology, Franck Morschhauser, MD, PhD, of Université de Lille in France, and an international team of colleagues investigated the efficacy and safety of tazemetostat, an oral EZH2 inhibitor, in patients with R/R FL who either had an EZH2 mutation or EZH2 wild-type disease (2020; doi:https://doi.org/10.1016/S1470-2045(20)30441-1). Approximately 15-20 percent of FL patients have mutations in EZH2, an epigenetic regulator of gene expression and cell fate decision that is required for normal B cell biology (Nat Med 2016; doi: 10.1038/nm.4036). Expression of the mutant allele synergizes with deregulation of BCL2, which fast-tracks the progression of lymphomas and offers a rationale for EZH2 inhibition in FL. Study Details In the international, open-label, single-arm, Phase I/II trial at 38 institutions in nine countries (NCT01897571), 99 patients were enrolled between July 2015 and May 2019 into cohorts categorized by EZH2 mutation (EZH2mut cohort, n=45) and wild-type EZH2 (EZH2WT cohort, n=54). EZH2 mutations were identified prospectively using formalin-fixed, paraffin-embedded tumor samples, which were centrally tested using the cobas EZH2 Mutation Test. Patients had grade 1, 2, 3a, or 3b disease that had relapsed or was refractory to two or more systemic therapies. Patients in the EZH2mut cohort had a median age of 62 years and patients in the EZH2WT cohort had a median age of 61 years. Patients were treated with 800 mg of oral tazemetostat given twice a day until confirmed disease progression or unacceptable toxicity. At data cutoff (August 9, 2019), the median follow-up duration was 22.0 months for the EZH2mut cohort and 35.9 months for the EZH2WT cohort. The dual primary outcome measures were overall response rate (ORR) and duration of response (DOR), based on the 2007 International Working Group Non-Hodgkin Lymphoma (IWG-NHL) criteria as assessed by Independent Review Committee. Secondary endpoints were progression-free survival and safety. Results The findings revealed that tazemetostat demonstrated clinically durable, single-agent activity in patients with R/R FL, including high-risk subgroups, and marked responses in patients with EZH2 mutations. The first-in-class EZH2 inhibitor led to an ORR in 42 patients with EZH2 mutant FL of 69 percent (95% CI: 53%, 82%), with 12 percent complete responses and 57 percent partial response. Median DOR in these patients was 10.9 months (95% CI: 7.2, NE). The ORR in 53 patients with EZH2 wild-type FL was 34 percent (95% CI: 22%, 48%), with 4 percent complete responses and 30 percent partial responses. Median DOR was 13 months (95% CI: 5.6, NE). Of responders in the EZH2mut cohort, 19 (61%) had response of ≥ 6 months, seven (23%) for ≥ 12 months, and six (19%) for ≥ 18 months. Among responders in the EZH2WT cohort, 10 (53%) had response of ≥ 6 months, seven (37%) for ≥ 12 months, and four (21%) for ≥ 18 months. Median overall survival was not reached in either cohort. Tazemetostat also demonstrated a favorable safety and tolerability profile. The most common (≥20%) adverse reactions were fatigue, upper respiratory tract infection, musculoskeletal pain, nausea, and abdominal pain. Notably, serious adverse reactions, irrespective of attribution, arose in 30 percent of patients receiving tazemetostat. Serious adverse reactions in ≥ 2 percent of patients were general physical health deterioration, abdominal pain, pneumonia, sepsis, and anemia. Second primary malignancy, which was the most common reason for treatment discontinuation, was reported in 2 percent of patients. There were no reported deaths during the study. Conclusions The authors concluded, “Tazemetostat monotherapy showed clinically meaningful, durable responses and was generally well tolerated in heavily pretreated patients with relapsed or refractory follicular lymphoma. Tazemetostat is a novel treatment for patients with follicular lymphoma.” On June 18, 2020, the FDA granted accelerated approval to tazemetostat for adult patients with R/R FL whose tumors are positive for an EZH2 mutation as detected by an FDA-approved test or for patients with relapsed or refractory FL who have no satisfactory alternative treatment options. Dibash Kumar Das is a contributing writer." @default.
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• W3139456495 date "2021-03-20" @default.
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• W3139456495 title "Advances in the Treatment of Patients With R/R Follicular Lymphoma" @default.
• W3139456495 doi "https://doi.org/10.1097/01.cot.0000741736.66789.ec" @default.
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