Case Studies: Three follicular lymphoma cases treated with oral tazemetostat

Sameh Gaballa, MD (Associate Member, Division of Malignant Hematology at Moffitt Cancer Center)

Sponsored Content by Ipsen Biopharmaceuticals, Inc.

The following contains case studies reflecting actual patient experiences written by Dr. Gaballa. Patient experiences may vary. Information presented does not encompass all considerations for tazemetostat eligibility. Dr. Gaballa was compensated for his time by Ipsen.

The accelerated approval for tazemetostat is based on an open-label, single-arm, multi-center Phase 2 clinical trial evaluating tazmetostat (800 mg oral twice daily) in 99 patients with histologically confirmed FL whose disease had progressed following at least two prior systemic treatment regimens and was inclusive of EZH2 activating mutations (45 patients) and wild-type EZH2 (54 patients).

• Among the EZH2 activating mutation cohort, at the 22 month follow-up, the overall response rate (ORR) was 69% (95% CI; 53%, 82%) with 12% of patients achieving a complete response and 57% achieving a partial response to tazmetostat. The median duration of response (DOR) was 10.9 months.
• Among the wild-type EZH2 cohort, at the 36 month follow-up, ORR was 34% (95% CI; 22%, 48%), with 4% of patients achieving a complete response and 30% achieving a partial response to tazmetostat. The median DOR was 13.0 months.
• Serious adverse reactions, irrespective of attribution, occurred in 30% of patients receiving tazmetostat. Serious adverse reactions in ≥2% of patients who received TAZVERIK were general physical health deterioration, abdominal pain, pneumonia, sepsis, and anemia.
• Eight patients (8%) discontinued due to adverse reaction during the trial. Dosage interruptions due to an adverse reaction occurred in 28% of patients. Dose reduction due to an adverse reaction occurred in 9% of patients.
• Serious adverse reactions, irrespective of attribution, occurred in 30% of patients receiving tazmetostat. Serious adverse reactions in ≥2% of patients who received TAZVERIK were general physical health deterioration, abdominal pain, pneumonia, sepsis, and anemia.
• Eight patients (8%) discontinued due to adverse reaction during the trial. Dosage interruptions due to an adverse reaction occurred in 28% of patients. Dose reduction due to an adverse reaction occurred in 9% of patients.
• The most common (≥20%) adverse reactions were fatigue, upper respiratory tract infection, musculoskeletal pain, nausea and abdominal pain.

Case 1:

A male in his 50s without significant past medical history presented to the emergency room with chest pain and shortness of breath. A computed tomography (CT) chest scan with angiography showed bilateral pulmonary embolism and an ultrasound of his lower extremities revealed bilateral extensive DVTs in his legs reaching up to his iliac veins.

At that time, he had no known risk factors for having a hypercoagulable state. He was initiated on anticoagulation, given extensive thrombosis, and underwent a thrombectomy procedure. The workup for hypercoagulable status included CT imaging, which identified bulky lymphadenopathy above and below the diaphragm. A core needle biopsy of a left groin lymph node came back consistent with low grade lymphoma, WHO grade 1-2.

Given his bulky adenopathy and hypercoagulable status, he was initiated on first-line therapy for follicular lymphoma. After 6 cycles of bendamustine-rituximab chemoimmunotherapy, a positron emission tomography (PET) scan showed partial remission (PR) of the lymphoma with residual adenopathy and a standardized uptake value (SUV) of 8 (Deauville score 4). The patient was then started on maintenance rituximab.

A year later, PET imaging showed the disease progressed, and a repeat lymph node biopsy showed low-grade follicular lymphoma with no evidence of transformation to an aggressive lymphoma.

Given he progressed in less than 24 months from initiation of therapy (POD24), which puts him in a high-risk category, the patient was started on obinutuzumab/lenalidomide for 10 cycles, which was complicated by diarrhea and grade 3 neutropenia requiring dose interruptions followed by dose reductions of the IMiD down to 10 mg. While his PET scan restaging initially showed a partial response (PR), by the end of cycle 10 of treatment he developed progressive adenopathy.

At that point, CAR T-cell therapy was offered to the patient given he failed 2 lines of therapy and had high-risk follicular lymphoma. However, due to family events and professional obligations, the patient was not able to commit the time needed for CAR T-cell therapy. EZH2 testing was performed at the time and he had EZH2 wild-type disease. He was started on oral single agent tazemetostat, and continued to have stable disease on imaging for the next 12 months.

After 12 months, the patient experienced progression and subsequently received CAR T-cell therapy with no response. He then received a bispecific antibody on a clinical trial but had refractory disease after 3 cycles and lymph node biopsies continued to show low grade lymphoma without evidence of transformation to an aggressive lymphoma.

Eventually, he received R-CHOP and achieved a complete response followed by consolidation with an allogeneic stem cell transplant and remained in remission.

Case 2:

A male in his 60s with a history of morbid obesity, status post gastric bypass, was incidentally found to have bulky retroperitoneal lymph nodes upon CT imaging done during workup of suspected GI bleeding. A retroperitoneal core needle biopsy came back consistent with follicular lymphoma, grade 3A. Given that he had bulky disease, he received 6 cycles of R-CHOP and achieved a complete remission. About 18 months later, surveillance imaging identified progressive disease with new left inguinal adenopathy and a T4 paraspinal mass, which were 18F-Fluorodeoxyglucose (FDG)-avid on PET imaging with a standardized uptake value (SUV) of 7.8. A biopsy from the inguinal lymph node was consistent with relapsed follicular lymphoma, grade 1-2. He subsequently underwent radiation to the T4 paraspinal mass followed by R2 and achieved complete remission again. However, 13 months afterwards, he complained of left lower extremity pain and was found to have relapsed disease with bulky FDG-avid pelvic adenopathy on PET imaging in addition to other FDG-avid adenopathy above and below the diaphragm. The highest SUV was less than 10 in the pelvic area and a pelvic lymph node biopsy showed follicular lymphoma without evidence of transformation to an aggressive lymphoma. At that point CAR T-cell therapy was discussed, but the patient lived more than 2 hours away from the medical center and did not have a caregiver, which was a prerequisite to getting CAR T-cell therapy. EZH2 testing was performed on a prior lymph node biopsy which was positive for an EZH2 mutation. He was initiated on oral tazemetostat and achieved a partial remission and remained without progression at his last follow up visit 18 months later.

Case 3:

A female in her early 80s* presented for management of relapsed low grade follicular lymphoma. She had an extensive medical history, including coronary artery disease status post stent placements, cerebrovascular stroke without residual motor or sensory deficits, diabetes, and chronic kidney disease. She initially presented with right inguinal mass and right lower extremity edema. Work-up at the time revealed FDG avid bulky adenopathy in the inguinal, pelvic, retroperitoneal, and bilateral axillary areas. The max SUV was 9 in the pelvic area and a biopsy from a pelvic lymph node was consistent with follicular lymphoma, low grade 1-2. She received therapy with mini-R-CHOP, which she tolerated reasonably well and achieved complete remission. Three years later, she was found to have relapsed disease when she again developed right lower extremity edema and imaging revealed adenopathy in the inguinal and pelvic area. A restaging PET revealed FDG-avid adenopathy in the inguinal and pelvic regions. She received radiation therapy to the pelvic and inguinal lymph nodes and was again in remission which lasted 12 months when she was found to have recurrent adenopathy in the axillary and retroperitoneal regions on surveillance imaging. She remained on active surveillance, but then developed left lower extremity edema and was found to have recurrent left pelvic adenopathy. A repeat lymph node biopsy was done which showed follicular lymphoma grade 1-2 without evidence of transformation and EZH2 testing came back as EZH2-wild type. Given her age, comorbid conditions, and performance status, she was deemed not a good candidate for further chemoimmunotherapy and was started on oral tazemetostat. She achieved a partial remission for the next 14 months. Eventually she developed recurrent disease with FDG-avid adenopathy with SUV 17 and a lymph node biopsy showed transformation to diffuse large B-cell lymphoma. She was subsequently treated with an anti-CD19 monoclonal antibody and achieved a partial remission for 4 months, but then relapsed and received hospice care.

IMPORTANT SAFETY INFORMATION

Warnings and Precautions

• Secondary Malignancies

The risk of developing secondary malignancies is increased following treatment with TAZVERIK. Across clinical trials of 758 adults who received TAZVERIK 800 mg twice daily as monotherapy, myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), or B-cell acute lymphoblastic leukemia (B-ALL) occurred in 1.7% of patients. One pediatric patient developed T-cell lymphoblastic lymphoma (T-LBL). Monitor patients long-term for the development of secondary malignancies.

• Embryo-Fetal Toxicity

Based on findings from animal studies and its mechanism of action, TAZVERIK can cause fetal harm when administered to pregnant women. There are no available data on TAZVERIK use in pregnant women to inform the drug-associated risk. Administration of tazemetostat to pregnant rats and rabbits during organogenesis resulted in dose-dependent increases in skeletal developmental abnormalities in both species beginning at maternal exposures approximately 1.5 times the adult human exposure (area under the plasma concentration time curve [AUC0‑45h]) at the 800 mg twice daily dose.

Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with TAZVERIK and for 6 months after the final dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with TAZVERIK and for 3 months after the final dose.

Adverse Reactions

In 99 clinical study patients with relapsed or refractory follicular lymphoma receiving TAZVERIK 800 mg twice daily: Serious adverse reactions occurred in 30% of patients who received TAZVERIK. Serious adverse reactions occurring in ≥2% were general physical health deterioration, abdominal pain, pneumonia, sepsis, and anemia. The most common (≥20%) adverse reactions were fatigue (36%), upper respiratory tract infection (30%), musculoskeletal pain (22%), nausea (24%), and abdominal pain (20%).

Drug Interactions

Avoid coadministration of strong or moderate CYP3A inhibitors with TAZVERIK. If coadministration of moderate CYP3A inhibitors cannot be avoided, reduce TAZVERIK dose.

Avoid coadministration of moderate and strong CYP3A inducers with TAZVERIK, which may decrease the efficacy of TAZVERIK.

Coadministration of TAZVERIK with CYP3A substrates, including hormonal contraceptives, can result in decreased concentrations and reduced efficacy of CYP3A substrates.

Lactation

Because of the potential risk for serious adverse reactions from TAZVERIK in the breastfed child, advise women not to breastfeed during treatment with TAZVERIK and for one week after the final dose.

To report SUSPECTED ADVERSE REACTIONS, contact Ipsen Biopharmaceuticals, Inc. at 1-855-463-5127 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Please see full Prescribing Information.

TAZVERIK is a registered trademark of Epizyme, Inc., an Ipsen company.

June 2024 TAZ-US-002966

*Clinical studies of tazemetostat did not include sufficient numbers of patients with epithelioid sarcoma or relapsed or refractory follicular lymphoma aged 65 and over to determine whether they respond differently from younger subjects.