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Case study: RE is a 26-year-old male newly diagnosed with metastatic epithelioid sarcoma. His PMH is significant for a fall 3 years ago, damaging the lateral side of his left knee. Although it healed, he developed a cellulitis in the left lower extremity, which his provider treated with antibiotics. A year later, he noticed some discomfort and pain in the left knee again when walking. His provider diagnosed him with cellulitis again in the same area and prescribed antibiotics. One month ago, he presented with hemoptysis for unclear reasons. At that point, a PET/CT scan revealed multiple small nodules in his lungs. Further imaging of the left lower extremity revealed extensive muscle and soft tissue thickening with multiple subcutaneous nodules and inguinal lymph node enlargement. RE’s provider diagnosed him with epithelioid sarcoma. What signs and symptoms did RE have that are recognizable in hindsight?

INTRODUCTION

Soft tissue sarcomas are considered rare in the oncology world, consisting of less than 1% of all cancers.¹ They are more common in pediatrics, occurring in about 15% of patients.¹ Soft tissue sarcomas comprise over 70 different tumor subtypes that all have a common progenitor, the mesenchymal cell. Epithelioid sarcomas are only one of these subtypes, making up less than 1% of all soft tissue sarcomas.^1,2 As researchers gain more information about the human genome, they are discovering new drugs to treat a variety of cancers known to affect specific gene mutations. This is the case with epithelioid sarcoma and tazemetostat, a first in its class methyltransferase EZH2 inhibitor.^1,3,4

Background knowledge of soft tissue sarcomas is helpful to understand epithelioid sarcomas. Soft tissue sarcomas are notoriously resistant to chemotherapy and surgery is needed for curative intent. Patients with metastatic disease need systemic therapy to control disease. The most active chemotherapy agent to date is doxorubicin, which the United States (U.S.) Food and Drug Administration approved in 1974. Adding ifosfamide to doxorubicin increases efficacy to some extent but also increases toxicity. Providers use gemcitabine, usually in combination with docetaxel, second line for soft tissue sarcoma treatment. Although there are a wide variety of sarcomas that differ greatly from each other, only a couple of cytotoxic agents actually show activity against most soft tissue sarcomas. There are some exceptions to the rule, such as Ewing sarcoma and rhabdomyosarcoma, but it still holds true for the majority.^5,6

Through genome mapping, scientists are identifying more gene mutations, translocations, or deletions that may contribute to cancer development. This is especially true in sarcomas, as the activation or silencing of different signaling pathways causes varying characteristics in this group of tumors.

Epithelioid Sarcomas

Epithelioid sarcoma incidence is only about 0.01 to 0.05 cases per 100,000 adults, making it 1 of the rarer soft tissue sarcomas.^2,7–9 It occurs most often between 20 and 40 years of age and more rarely in children.¹⁰ It is also more prominent in males.^7,11 Epithelioid sarcoma often appears as painless, firm nodule, and it can be well-circumscribed or appear as a cluster of lobulated masses.^8,12 It can be located in the superficial dermis of the subcutaneous tissue of extremities, although it can less commonly occur in deep soft tissue of the extremities or trunk.^2,7,11 It is often a non-descript nodule, but it may have the appearance of an ulcer, wart, or nonhealing wound infection.^2,8 Superficial bleeding or necrosis may also be present. Some patients may experience pain, usually when the tumor is located near joints.⁸ This benign appearance and slow growth over years often leads to a delayed diagnosis.¹²

Case continued: Patients and providers can easily miss signs and symptoms of epithelioid sarcoma, and its benign presentation can lead to delayed diagnosis. RE had a superficial cellulitis of the left lower extremity that reoccurred with associated pain in the area. There are usually no clearly visible or recognizable symptoms that will prompt a quick diagnosis. What is RE’s prognosis based on his presentation?

Diagnosis and Classification

Epithelioid sarcomas are often still small at diagnosis (i.e., diameter less than 5 cm), but they can be multifocal in about 10% to 20% of cases.⁸ Metastases occur most commonly in nearby lymph nodes but can spread to the bones, brain, and lungs. Other less common metastases have been reported in areas such as the digestive tract, kidneys, liver, musculoskeletal system, and scalp. About 20% of patients will present with metastases at diagnosis.⁸ Of interest, about 25% of epithelioid sarcomas are located in areas associated with prior trauma or scar tissue.^8,11,12

Soft tissue sarcomas can be generally more difficult to identify, so a pathologist experienced in sarcoma diagnosis should review an epithelioid sarcoma tumor biopsy. Formerly, there were a number of sarcomas with similar morphology. Now, an important part of the diagnostic process is using immunohistochemistry to determine a loss of integrase interactor 1 (INI1) expression in the tissue, which is a hallmark of this tumor.^2,7

Epithelioid sarcoma is split into 2 classifications: the classic (i.e., distal) subtype and the proximal subtype. Both subtypes usually have loss of INI1, which is present in about 90% of epithelioid sarcomas.^2,3 The classic subtype is more common in younger patients, while the median age of patients with the proximal subtype is 40 years.⁸ The classic subtype most often occurs in the superficial dermis of subcutaneous tissue with a propensity to occur in the extremities, especially the arms.^7,11,12 The proximal subtype accounts for less than one-third of all epithelioid sarcomas. It is typically deeper in the soft tissues of proximal limbs.¹¹ This subtype can also occur in more central locations, such as the genital tract, pelvis, or perineum. The proximal subtype is more aggressive than the classic subtype, and tumor necrosis can occur.^7,8,11 For this reason, it usually responds better to radiation and chemotherapy.¹¹

Prognostic Factors

Overall survival rates of epithelioid sarcoma vary widely, ranging from 25% to 92%.^8,12 Factors associated with prognosis include⁹

• tumor size
• higher grade of tumor (denotes it as more aggressive)
• age greater than 55 years
• tumor necrosis greater than 50%
• presence of vascular invasion
• proximal subtype
• metastasis at diagnosis

Given its rarity, most evaluations of epithelioid sarcoma have only included small numbers of patients. Elsamna et al. used Surveillance, Epidemiology, and End Results data to identify 998 cases and assess overall survival, recurrence, and metastasis rates.¹³ Patient characteristics included white 80%, male 55%, proximal subtype 60%, metastasis at diagnosis 22%, and 78% diagnosed after the year 2000. These researchers found that age, anatomical tumor site, grade, tumor staging, treatment modality, and year of diagnosis were independent predictors of survival in multivariate analysis.¹² The 5-year overall survival was 60% and 10-year survival was 50%. About 63% of patients experienced a recurrence, and 40% of patients developed metastases. Interestingly, investigators found that patients diagnosed after 2000 had worse outcomes compared to those diagnosed before, but they did not identify a reason.¹²

Case continued: RE had already developed metastases of the lung (hemoptysis with nodules found on imaging) at diagnosis, so his prognosis is poor. Based on the characteristics, it is likely that he has the classic subtype of epithelioid sarcoma, which is less aggressive and may confer a slightly better outcome. If RE had been diagnosed 3 to 5 years ago, what therapy would have most likely been appropriate?

STANDARD THERAPY FOR EPITHELIOID SARCOMA

Limited Stage Disease

Similar to all soft tissue sarcomas, surgery is the mainstay of treatment for localized disease with 5-year survival rates of 75%.² In children and adolescents, multi-modality therapy with surgery, chemotherapy and radiation has been utilized.¹⁰ Adults typically undergo a wide surgical resection, but the role of perioperative radiation and/or chemotherapy is poorly understood. Given the risk of spread to regional lymph nodes, providers may perform a sentinel lymph node biopsy with subsequent therapeutic lymph node dissection if the sentinel node is positive. Amputation may be necessary in some cases.⁸

The addition of neoadjuvant or adjuvant radiation therapy or chemotherapy may reduce the risk of local recurrence even after clear surgical resection. Recurrence rates at 5 years can be as high as 70% even with good local control at the beginning.^7,8 Epithelioid sarcoma is generally considered resistant to radiation therapy, even in comparison to other soft tissue sarcomas. However, providers still use it in an attempt to prevent local recurrence.⁸ Radiation is an accepted standard therapy in conjunction with surgery in certain cases and is usually based on the tumor size and location.¹⁰ More clinical trials are needed to fully determine the benefit of radiation therapy in localized tumors and in what setting it is appropriate.⁸

Like other pediatric cancers, providers use neoadjuvant or adjuvant systemic chemotherapy in pediatric patients epithelioid sarcomas.¹⁰ In clinical trials, neoadjuvant chemotherapy with doxorubicin and ifosfamide, with or without radiation, provided a partial response in 50% of patients.⁸ In the adult population, it is less well defined with responses ranging from 0% to 15%. Providers use systemic therapy most often with large, high-grade tumors with or without incomplete resections or in the setting of known metastases.⁸ Isolated limb perfusion has also been used, which consists of very high doses of chemotherapy restricted only to the affected extremity with no systemic exposure. In some cases, isolated limb perfusion may decrease tumor size enough for a surgical resection. Regimens used in isolated limb perfusion include⁹

• tumor necrosis factor with doxorubicin
• vincristine, doxorubicin, ifosfamide, and dactinomycin
• cyclophosphamide, vincristine, doxorubicin, and dacarbazine

Local disease recurrence, even after definitive surgery, has been reported in 33% to 77% of adult patients.⁸ Little data is available for pediatric patients in this setting, so optimal therapy is unknown.¹⁰ There is little data to support radiation of recurrent disease in adults. Providers may utilize brachytherapy in an attempt to radiate in or near a previously radiated area.⁸

Advanced Disease

Advanced epithelioid sarcoma is unresectable or metastatic disease. About 20% of patients will have metastases at diagnosis⁸ and disease recurrence with metastatic spread occurs in approximately 50% of patients.^2,12 Other data show that at 5 years from primary tumor diagnosis, 30% to 75% of patients have metastatic spread.⁸ An epithelioid sarcoma that cannot be completely resected cannot be cured.³ Due to these tumors’ rarity, all data on systemic chemotherapy are based on small, mostly retrospective studies. Objective response rates (ORR) range from 15% to 22% for first-line chemotherapy and 9% to 11% for subsequent lines of therapy.³

An international collaborative retrospective study across 17 referral sarcoma centers in Europe, the U.S., and Japan reported the largest case series of systemic therapy for locally advanced or metastatic epithelioid sarcoma to date (see Table 1).¹⁰ Between 1990 and 2016, researchers identified 115 patients, 70% male, with a median age of 32 years. This study reported on 3 different groups of patients receiving anthracyclines, gemcitabine, or pazopanib. Twenty-four of the patients received more than 1 treatment. Anthracycline-based therapy had an ORR of 22% and median progression free survival (PFS) of 6 months.¹⁰ This was compared to 3 previous retrospective reports that demonstrated an ORR ranging from 0% to 43% and PFS of 3 to 8 months. Investigators reported a 27% ORR and 4-month median PFS with gemcitabine-based therapy.¹⁰ This was comparable to 1 other report that demonstrated an ORR of 58% and a PFS of 8 months with gemcitabine.¹³ This international study was the first to report on pazopanib outcomes. While there were no objective responses, 9 patients had stable disease (SD) with 2 patients reporting long median PFS of 27 and 21 months.⁹

The European Organization for Research and Treatment of Cancer cooperative group completed a subgroup analysis of pooled patients from 4 of their prospective trials.⁸ The selected trials assessed the use of doxorubicin, doxorubicin and ifosfamide, trabectedin, or pazopanib in patients with soft tissue sarcomas. Of 976 patients across the 4 trials, 27 (2.8%) patients with epithelioid sarcoma were included in their subanalysis. The median age at diagnosis for this group was 50 years and 63% of patients were male. Investigators reported an overall median PFS of 3.8 months for all therapies. Table 2 lists the outcomes for first-line therapy with each regimen. This does not include 9 patients who were assessed in a second or later line of therapy. The best first-line therapy response overall was a 22% partial response and 56% SD.⁸ There were no complete responses. Researchers assessed another 9 patients who received pazopanib as a second or later line of therapy and reported 1 partial response (11%), 4 SD (44%), and an ORR of 11%.⁸ The authors noted that survival rates for patients with epithelioid sarcoma in the subgroup analysis were less than for soft tissue sarcomas as a whole in each trial.⁷

Another group sought to explore the real-world experience of locally advanced and metastatic epithelioid sarcoma in the U.S. Five U.S. cancer centers conducted a retrospective medical records review for any patients 10 years of age or older who initiated systemic chemotherapy between 2000 and 2017.² Their population consisted of 74 patients, 72% male, with a median age of 33 years. First-line therapies included anthracycline-based therapies (54.1%), gemcitabine-based therapies (24.3%), and pazopanib (5.4%). During the study period, 92% of patients died.² Table 3 provides outcomes for first and second or later lines of therapy. Half of all patients (51.4%) experienced treatment-related toxicity. The most common adverse effects were febrile neutropenia (14%) and pain (10%), and 5% of patients experienced anemia, dyspnea, fever, thrombocytopenia, and/or transaminitis.²

There are 2 studies that characterize epithelioid sarcoma in the pediatric population. The first study identified patients from 2 international prospective trials with a subset analysis of patients with epithelioid sarcoma less than 30 years old.¹⁵ Researchers conducted the prospective trials between 2005 and 2015, which included 63 epithelioid sarcoma patients, 52% male, with a median age of 13 years. They characterized the tumors as high, intermediate, or low risk based on size, location, grade, and presence of metastases. They found a 5-year survival rate of 86.4% in low-risk, 63.5% in intermediate-risk, and 0% in high-risk patients.¹⁵ Predictors of survival in patients without metastasis included locoregional lymph node involvement, extent of tumor invasiveness, grade, and extent of resection.¹⁴

The second study in pediatric patients reported the findings of a number of German trials of patients with endothelial sarcomas between 1981 and 2016.¹¹ The 67 patients included had a median age of 14 years. They found a 5-year event free survival of 35% and OS of 58% in patients with localized disease. Patients with metastatic disease had a 5-year event free survival of 7% and OS of 9%.¹⁰

Case continued: For a patient like RE with metastatic disease, the primary treatment would have most likely been systemic chemotherapy with an anthracycline-based regimen, which was the most common first-line regimen in all studies. There was some effort to distinguish between the potential benefits of an anthracycline-based regimen versus a gemcitabine-based regimen. However, the numbers were too small to determine a clear benefit of 1 over the other as first or subsequent lines of therapy. As RE was diagnosed within the last month, what benefit should he achieve with the newest therapy available?

After assessing the various retrospective studies in both children and adult populations, it is clear that cytotoxic chemotherapy provides little long-term benefit in patients with epithelioid sarcoma. Anthracyclines and gemcitabine, despite their low response rate of only 15% to 30% in soft tissue sarcomas, are still the most commonly utilized agents.⁵ In epithelioid sarcoma, recurrence rates and progression to metastatic disease clearly demonstrate the need for better therapies.

Other Targeted Agents

Beyond pazopanib use in epithelioid sarcoma as described above, providers have used several other targeted agents in an attempt to control epithelioid sarcomas, as well as other rare sarcomas. An open-label, single-arm trial of 109 patients evaluated dasatinib, but only 7 patients had epithelioid sarcomas.¹⁶ Two of the 7 patients achieved objective responses, and median PFS was 7.9 months with a 6-month PFS rate of 57%. However, 2 year OS rate was only 21%.¹⁵ There is 1 case report of sunitinib providing long-term stable disease of greater than 32 months as third-line therapy in 1 patient.¹⁶

It is easy to recognize that treatment for epithelioid sarcoma remains suboptimal. Given the tumor’s rarity, studies consist of retrospective reviews of previous patients over a number of decades when surgical procedures, imaging, and diagnostic pathology has changed dramatically. Due to the low efficacy of cytotoxic chemotherapy in soft tissue sarcoma treatment, researchers are pursuing new targeted therapy options. They have identified abnormalities in genetics and signaling pathways in an attempt to find treatment targets for this sarcoma.

TARGETING MOLECULAR ALTERATIONS IN EPITHELIOID SARCOMA

INI1 is a hallmark of epithelioid sarcoma that researchers first associated with these sarcomas in 2005.¹⁷ The gene SMARCB1encodes INI1, which is a member of the SWItch/Sucrose Non-Fermentable (SWI/SNF) chromatin remodeling complex. The SWI/SNF complex is involved in moving nucleosomes to expose unwound deoxyribonucleic acid to transcription factors. It also has a tumor suppressive role, controlling diverse cellular processes including differentiation and proliferation. Within the SWI/SNF complex, INI1 is supposed to regulate enhancer of zeste homolog 2 (EZH2). Therefore, INI1 expression loss and dysfunction leads to EZH2 activation, causing oncogenic activity.

Loss of INI1 function also leads to elevated expression and recruitment of EZH2 to target genes that become trimethylated on histone H3 lysine 2 and repressed. This results in the upregulation of several oncogenic signaling pathways, including Sonic Hedgehog, Wnt/beta-catenin, and MYC. Patients can also lose INI1 expression in the absence of a SMARCB1 mutation, but this is due to another mechanism that is still under investigation. There are several genetic and epigenetic mechanisms that can also lead to INI1 expression loss. This loss leads to unopposed oncogenic EZH2 activation.^1,3,4,18

This mechanism is complex. In short, when INI1 loses its regulatory function, EZH2 activity is de-regulated, allowing EZH2 to play an oncogenic role, promoting tumor growth.¹

Tazemetostat

Tazemetostat is a first-in-class, oral, selective inhibitor of EZH2, which plays a crucial role in epithelioid sarcoma tumor initiation and growth. In January 2020, this became the first therapy FDA-approved for epithelioid sarcomas, which have few other therapy options.⁴ Tazemetostat also plays a role in a variety of other cancers, including follicular and diffuse large B-cell lymphomas, synovial sarcoma, prostate cancer, and mesothelioma. It can also treat tumors that have an isolated EZH2 mutation or loss of INI1.¹

A phase 1 study of tazemetostat included 2 patients with epithelioid sarcoma, both achieving stable disease for more than 20 months.¹⁹ Adverse effects were manageable with grade 1 or 2 nausea and fatigue being the most common toxicities.¹⁹

Researchers conducted a phase 2 basket study with tazemetostat to assess its activity in tumors with loss of INI1/SMARCB1.³ Basket trials allow investigators to assess 1 drug in a number of different malignancies that are affected by the same mutation or biomarker. This allows studies to move more quickly through the clinical trial process and is also helpful in studying rare tumors that have specific genetic changes. This basket trial included a total of 32 sites on multiple continents and divided patients into 7 cohorts, each with a different INI1 negative solid tumor.³ Cohort 5 comprised the endothelial sarcomas. Patients eligible for the cohort had to be at least 16 years of age with locally advanced or metastatic epithelioid sarcoma. Documented loss of INI1 expression by immunohistochemistry, biallelic SMARCB1 alterations, or both were required. Investigators reviewed all pathology centrally and patients were required to have measurable disease. Patients received tazemetostat 800 mg by mouth twice daily in continuous 28-day cycles until disease progression, unacceptable toxicity, or withdrawal of consent.³

From December 2015 to July 2017, 62 patients were enrolled on the trial.³ The average age was 34 years (range of 25 to 46 years), 63% of patients were male, and 90% had a confirmed loss of INI1. The primary endpoint was ORR and results are shown in Table 4. Patients who reached 2 years of tazemetostat were allowed to enroll in an open-label rollover study to continue therapy if they were benefitting from treatment.³

Case continued: RE would be receiving tazemetostat, the newest treatment available, as first-line therapy. In clinical trials, patients on this treatment had an overall PFS of 5.5 months, but those receiving it as first-line therapy had a median PFS of almost 10 months. Overall survival was 19 months but median OS in first-line therapy has not been reached yet so he may potentially gain even more time. These are all median values, so he may have more or less time that the group as a whole. Based on the basket trial, what grade 3 or 4 adverse effects is RE most likely to encounter on tazemetostat therapy?

Tazemetostat Safety

Tazemetostat’s safety profile is tolerable, as most adverse effects are grade 1 or 2 based on Version 5 of the Common Toxicity Criteria for Adverse Events.²⁰ This criteria helps to define the difference between grades of severity in all adverse effects. There are specific grading guidelines for each adverse effect but the general grading definitions are listed in Table 5.

The aforementioned basket trial indicated that the most common reason for discontinuing tazemetostat therapy was disease progression, which occurred in 45 patients (73%).³ The median dose was 795.9 mg twice daily, and 1 patient’s dose was reduced due to decreased appetite. Only 1 patient discontinued therapy for unacceptable toxicity (grade 2 mood disorder), and there were no treatment-related deaths.³ These results support the idea that patients tolerated therapy well overall. Grade 3 or 4 treatment-related adverse events included anemia in 4 patients (6%) and weight loss in 2 patients (3%). Serious treatment-related adverse events occurred in 2 patients (3%), including seizure in 1 patient and hemoptysis in another.³

Case continued: Anemia and weight loss are potential adverse effects for RE. He already experienced hemoptysis leading to his diagnosis, so he will likely be at higher risk for recurrence. While on therapy, RE visits his dentist who prescribes him a several-day course of erythromycin for an infected tooth. What is an appropriate pharmacist intervention?

Future Directions

Researchers continue to study tazemetostat in epithelioid sarcoma, as well as other tumors. A phase 1b/3 multi-center, international, randomized, double-blind study of tazemetostat with or without doxorubicin as first-line therapy is ongoing.²¹ This trial opened for accrual in late 2019 with a goal accrual of 164 patients. Another study that has completed accrual and included epithelioid sarcomas was a phase 1 trial of doxorubicin plus cixutumumab, an anti-insulin growth factor-1 receptor inhibitor.²² There are some additional early phase clinical trials that include epithelioid sarcomas and use therapies such as ribociclib plus doxorubicin²³ and Notch signaling²⁴ pathway inhibitors (also called Hedgehog inhibitors).

Researchers has also tested other potential targets for epithelioid sarcoma in vitro, alone and in combination with each other⁹:

• epidermal growth factor receptor
• mammalian target of rapamycin
• mesenchymal epithelial transition factor pathway inhibitors

PHARMACIST CONSIDERATIONS FOR TAZEMETOSTAT

Patients take 4-200 mg tablets (800 mg total) by mouth twice daily with or without food.²⁵ They usually continue this therapy until disease progression or unacceptable toxicity. Patients on this drug should avoid moderate or strong cytochrome P450 (CYP) 3A4 inhibitors, as they may increase plasma tazemetostat concentrations, leading to increased toxicity. If moderate CYP3A inhibitor use is unavoidable, providers should reduce the tazemetostat dose as shown in Table 6. Once the moderate inhibitor is discontinued, wait 3 half-lives of the inhibitor before resuming the previous tazemetostat dose.

Patients should also avoid concomitant treatment with moderate or strong CYP3A inducers (e.g., carbamazepine, phenytoin, rifampin), as this may decrease plasma tazemetostat levels. Tazemetostat is also a mild CYP3A inhibitor, so it can also decrease the levels of sensitive CYP3A substrates, including hormonal contraceptives. Tazemetostat does not increase the corrected QT interval. Also, drugs that raise stomach pH do not affect its absorption, so patients can take proton pump inhibitors or histamine-2 receptor antagonists if needed.^4,25

Case continued: Erythromycin is a moderate CYP3A inhibitor, which RE should avoid while taking tazemetostat. The pharmacist should recommend an alternative antibiotic for RE’s infection, if possible, to prevent the interaction. If there is no other option for his infected tooth, then the pharmacist should recommend that RE’s oncology provider decrease the tazemetostat dose as recommended. Should the pharmacist recommend an antiemetic for patients who are initiating tazemetostat?

Treatment-Related Toxicities with EZH2 Inhibitors

Adverse effects of tazemetostat have been tolerable in most patients with epithelioid sarcoma, although this is based only on 62 patients in the phase 2 trial.³ Grade 1 or 2 toxicities are most common. Severe adverse effects of concern occurring in 3% of patients or greater are dyspnea, hemorrhage, pain, pleural effusion, respiratory distress, and skin infection. The most common adverse effects causing dose interruptions in 3% of patients or greater were hemorrhage and increased transaminases. If a dose reduction is necessary due to adverse effects, providers should first reduce tazemetostat to 600 mg twice daily. They can consider a second dose reduction to 400 mg twice daily, but patients should permanently discontinue tazemetostat if they are unable to tolerate this lower dose.²⁵

Table 7 lists the adverse effects experienced by 20% or more patients with epithelioid sarcoma in clinical trials. Other adverse effects that occurred in less than 20% of patients included cough (18%), dyspnea (16%; grade 3/4, 4.8%), headache (18%), and decreased weight (16%, grade 3/4, 7%).²⁵ Investigators reported that 18% of patients experienced hemorrhage, which included wound hemorrhage, rectal hemorrhage, pulmonary hemorrhage, intracranial hemorrhage, cerebral hemorrhage, and hemoptysis. Hemorrhage was grade 3 or 4 in 4.8% of patients.²⁵

Providers should monitor hematologic laboratory values in all patients as bone marrow suppression is likely to occur and may require dose adjustments. In clinical trials, investigators reported decreased hemoglobin in 49% of patients (grade 3/4, 15%), decreased lymphocytes in 36% (grade 3/4, 13%), and decreased white blood cell count in 19%. There are specific recommendations for holding and reinitiating therapy if myelosuppression occurs.²⁵

Other laboratory values that providers should monitor at baseline are liver function tests, a comprehensive metabolic panel, triglycerides and cholesterol levels, partial thromboplastin time, and serum creatinine. There are no dose adjustments needed for renal dysfunction, including end stage renal disease. Researchers have only studied tazemetostat in mild hepatic impairment (i.e., total bilirubin or aspartate aminotransferase less than 1.5 times the upper limit of normal) with no adjustments needed.²⁵

Providers must verify pregnancy status prior to beginning tazemetostat therapy in women of childbearing age, as this drug could affect an unborn baby. Female patients should use effective contraception during treatment and for 6 months after stopping the drug. Providers should also remind patients that hormonal contraceptives may be ineffective due to a drug interaction with tazemetostat. Males with female partners of reproductive potential should use effective contraception during treatment and for 3 months after their last dose. Patients should avoid breastfeeding while on therapy and for at least 1 week after the final dose.²⁵

Adverse effects in follicular lymphoma, tazemetostat’s other indication, are slightly different, which researchers attribute to the differences in tumor types. Of concern is the risk of secondary malignancies, which is listed as a warning in tazemetostat’s package insert, regardless of tumor type. In 729 adults in various trials of different diagnoses using 800 mg twice daily, myelodysplastic syndrome and acute myeloid leukemia occurred in 0.7% of patients. One pediatric patient developed T-cell lymphoblastic lymphoma.²⁵

Patient Education

Patient education is crucial to the safety and efficacy of tazemetostat. Providers should monitor adherence and make appropriate therapy modifications to minimize adverse effects and maximize quality of life while on the drug. As tazemetostat is only available as 200mg tablets patients need to take 4 tablets twice daily, adding to any existing pill burden. Patients can take tazemetostat with or without food, but it cannot be cut, crushed, or chewed. If the patient misses a dose or vomits it up, they should take a dose at the next scheduled time not double their dose.²⁵

The most common adverse effects that the patients may experience are nausea, vomiting, and decreased appetite. They may also experience fatigue, pain, and constipation, although these are usually mild. Although rare, providers should advise patients of the potential to develop a secondary cancer and ensure that they will be monitored closely.²⁵

Providers should make patients aware of potential drug interactions and patients should report any medications, over-the-counter products, herbals, or supplements that they plan to take concomitantly. Patients using tazemetostat should avoid grapefruit and grapefruit juice, as it could inhibit CYP3A4 and increase tazemetostat plasma concentrations. Patients can safely use proton pump inhibitors or histamine-2 receptor antagonists concomitantly with this therapy. Hormonal contraceptives may not be effective while on tazemetostat and patients should use alternative forms of birth control.²⁵

Remind patients if they or their partner are of childbearing potential that they should use effective contraceptives. Women taking tazemetostat should use non-hormonal birth control while on therapy and for 6 months after stopping. Males taking tazemetostat should use contraception while on therapy and for 3 months after stopping.²⁵

Case continued: About 30% to 40% of patients experience nausea and vomiting on tazemetostat, but it is usually low grade. However, it would still be wise for patients to have an oral antiemetic that they can take at home as needed for the first week in the event that nausea and/or vomiting are intolerable. Addressing potential adverse effects will encourage patient adherence.

CONCLUSION

Tazemetostat is a first-in-class methyltransferase EZH2 inhibitor that affects a rare mutation found in a small number of cancers. Epithelioid sarcoma, a tumor that affects young adults in the prime of life, has seen little therapy advancement over the past 40 years. Tazemetostat offers another potential treatment for these patients with the hope that further research will provide additional ways to utilize this drug effectively and build upon disease mechanism knowledge.

References

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