Journal of the Dermatology Nurses' Association:
Histone Deacetylase Inhibitors in Cutaneous T-cell Lymphoma: Nursing Considerations
McCann, Sue A.; Story, Sara K.
Sue A. McCann, MSN, RN, DNC, Department of Dermatology, University of Pittsburgh Medical Center, Pittsburgh, PA.
Sara K. Story, MD, Department of Dermatology, University of Pittsburgh Medical Center, Pittsburgh, PA.
The authors have no conflicts of interest to disclose.
Correspondence concerning this article should be addressed to Sue A. McCann, MSN, RN, DNC, Department of Dermatology, University of Pittsburgh, 200 Lothrop Street, Presby South Tower, Suite 3880, Pittsburgh, PA 15213. E-mail: firstname.lastname@example.org
Abstract: Cutaneous T-cell lymphomas (CTCLs) are a diverse group of non-Hodgkin’s lymphomas that include mycosis fungoides and Sézary syndrome subtypes, affecting mainly the skin. Accurate diagnosis of CTCL variants and the stage of disease are both key factors for determining appropriate treatment strategies. Early-stage disease can often be effectively managed with skin-directed therapies. However, patients with more advanced disease benefit from systemic therapies, which are often associated with toxicities that degrade patients’ quality of life. Histone deacetylase (HDAC) inhibitors are a class of targeted agents that prevent deacetylation of histone/nonhistone proteins and affect a wide range of cellular functions regulated by HDACs. Vorinostat and romidepsin are HDAC inhibitors approved for the treatment of CTCL, whereas several others are under clinical evaluation for CTCL and other hematological malignancies. This article reviews important safety considerations with HDAC inhibitors. For dermatology and oncology nurses, identification and management of toxicities are critical to maintaining patient quality of life and ensuring optimal treatment outcomes. Quality nursing care is essential for the successful treatment of patients with CTCL. As newer and more complex options for CTCL are utilized, dermatology and oncology nurses play an important role in educating and managing patients and associated treatment-related toxicities.
OVERVIEW OF CUTANEOUS T-CELL LYMPHOMA
Cutaneous T-cell lymphomas (CTCLs) are a diverse group of non-Hodgkin’s lymphomas affecting mainly the skin, representing approximately 70%–80% of all cutaneous lymphomas (Bradford, Devesa, Anderson, & Toro, 2009; Criscione & Weinstock, 2007). Mycosis fungoides (MF) accounts for approximately 50%–70% of CTCL cases, and Sézary syndrome (SS), a rare leukemic subtype of CTCL, accounts for approximately 1%–3% of cases (Bradford et al., 2009; Criscione & Weinstock, 2007; Willemze et al., 2005). Overall, approximately 2,800 new cases of CTCL are diagnosed each year, including approximately 1,500 cases of MF and SS (Bradford et al., 2009). The prevalence of MF in the United States is estimated to range from 16,000 to 20,000 (Cutaneous Lymphoma Foundation, 2011). Although CTCL is responsive to treatment, MF and SS are thought to be incurable with current treatment approaches (Hymes, 2007; Prince, Whittaker, & Hoppe, 2009), and the only current potential cure is bone marrow transplantation. Although limited data are available to confirm this hypothesis, in a retrospective analysis of poor-prognosis patients with advanced-stage MF/SS, allogeneic transplantation showed an estimated overall survival of 66% and 54% at 1 and 3 years, respectively (Duarte et al., 2010). Many current therapies have significant treatment-related toxicities, and timely management of these is essential for patients to receive and adhere to optimal therapy and improve their disease and quality of life. Histone deacetylase (HDAC) inhibitors are a new class of targeted anticancer agents that have shown clinical activity in a variety of solid tumors and hematological malignancies (Ellis et al., 2008; Gimsing et al., 2008; Marks, 2007). The objectives of this review are to (1) highlight key considerations for the effective management of CTCL, including the use of HDAC inhibitors; (2) summarize the clinical experience on the efficacy and tolerability of HDAC inhibitors in patients with CTCL; and (3) examine the implications of these novel targeted agents for patient management by dermatology and oncology nurses.
CLINICAL FEATURES OF CTCL AND TREATMENT CONSIDERATIONS
MF is an often indolent T-cell lymphoma that presents as localized skin disease in early stages and may involve lymph nodes and visceral organs in more advanced stages (Demierre, Gan, Jones, & Miller, 2006; Paulli & Berti, 2004; Willemze et al., 2005). Skin manifestations of MF range from scaly patches or plaques to general erythroderma and ulcerated tumors (Willemze et al., 2005). Physical symptoms, such as pruritus, painful or sensitive skin/lesions, fissuring of palms and soles, and hyperkeratosis, limit daily activities and negatively impact patients’ emotional and social well-being (Demierre et al., 2006). Infectious complications are a potential risk factor for increased morbidity and mortality (Paulli & Berti, 2004). Most patients with MF present with early-stage indolent disease, characterized by a variable and unpredictable time course for disease progression through cutaneous stages (Girardi, Heald, & Wilson, 2004; Prince et al., 2009). Patients with stage IA disease have a normal life expectancy (Whittaker, Marsden, Spittle, & Russell Jones, 2003), whereas those with stages IB and IIA have a median survival of approximately 10–12 years (Kim, Liu, Mraz-Gernhard, Varghese, & Hoppe, 2003; Scarisbrick, 2006). A number of factors contribute to poorer prognosis, including more advanced disease (i.e., stage IIB or worse), age at diagnosis, the degree of skin involvement, and the extension of disease to lymph nodes and visceral organs (Scarisbrick, 2006; Whittaker et al., 2003). SS, a leukemic subtype of CTCL, is an aggressive disease characterized by distinct clinical features such as erythroderma, circulating malignant T-cells (Sézary cells), lymphadenopathy, and severe debilitating pruritus (Li et al., 2012; Whittaker et al., 2003). Patients with SS have a relatively poor prognosis, with a median survival of approximately 32 months. Figure 1 shows images of patients with CTCL and typical cutaneous manifestation of MF and SS.
Accurate diagnosis and staging of MF/SS as opposed to other rarer variants of CTCL is important to appropriately tailor patient management strategies to achieve best outcomes (Prince et al., 2009; Whittaker et al., 2003). Skin and lymph node biopsy (if lymphadenopathy present), extent of skin tumor burden, tissue and blood flow cytometry, and PET/CT scans are essential elements of the diagnostic work-up and staging process. Subsequent selection of treatment is also critically dependent on the stage of disease (Prince et al., 2009). For the initial treatment of CTCL in patients with early-stage disease (stages IA–IIA), skin-directed therapies (e.g., topical corticosteroids, chemotherapeutic agents, phototherapy, and others), including combined topical therapies, are often used (Molin, Thomsen, Volden, & Groth, 1981; National Comprehensive Cancer Network [NCCN], 2012; Ramsay, Meller, & Zackheim, 1995; Zackheim, Kashani-Sabet, & Amin, 1998). For patients with advanced disease (i.e., stage IIB or worse), multiagent systemic therapies may provide rapid responses but are associated with toxicities (Hymes, 2007). These treatment-related toxicities can degrade quality of life and compromise optimal treatment of disease (Demierre et al., 2006).
The goals of treatment for CTCL are to reduce tumor burden in skin (extent and severity of cutaneous patch, plaque, tumor, or erythroderma), lymph nodes, blood, and viscera; induce sustainable disease remission; prevent disease progression; provide symptomatic relief from itch; and improve or restore skin integrity (Li et al., 2012; McCann, 2007). The International Society for Cutaneous Lymphomas, the United States Cutaneous Lymphoma Consortium, and the Cutaneous Lymphoma Task Force of the EORTC have developed consensus guidelines for standardizing a scoring system to assess overall tumor burden, utilizing the TNMB (tumor, node and metastasis blood) criteria (Li et al., 2012; McCann, 2007). The T score qualifies the skin’s tumor burden (1–4), the N score evaluates the extent of tumor involvement in lymph nodes (0–3), the M score (0–1) indicates the absence/presence of visceral involvement, and the B score (0–2) indicates the degree of peripheral blood involvement.
As patient management requires an individualized approach and is often complex and interdisciplinary, nurses are particularly instrumental in coordinating patient care among other healthcare providers (e.g., dermatologists, oncologists, radiation therapists, primary care physicians). The delivery of optimal individualized therapy is dependent on the appropriate assessment and management of disease symptoms and treatment-related toxicities by nurses who play a central role in patient education by ensuring adherence to therapy and optimal patient outcomes (McCann, 2007). Therefore, it is important for nurses to be knowledgeable of the potential side effects with available treatment options for CTCL to effectively educate patients about treatment-related symptoms and the importance of reporting them so they can be appropriately managed.
HDAC inhibitors are now being explored in a variety of solid tumors and hematological malignancies as potential treatment options (Ellis et al., 2008; Gimsing et al., 2008; Marks, 2007) and are a relatively new (since 2006) option for the treatment of MF/SS. The mechanism of action for HDACs are complex but important for the nurse to understand when caring for patients with CTCL. HDACs are enzymes that catalyze the removal of acetyl groups from DNA-associated histone—as well as nonhistone—proteins, which play an important role in regulating a wide range of cellular functions. HDAC inhibitors prevent the removal of acetyl groups by HDACs, subsequently affecting gene transcription, cell cycle regulation (e.g., effects on p53 and related transcription factors, alpha-tubulin, heat shock protein 90, and other signaling intermediates), tumor differentiation, and sensitivity to apoptosis (Figure 2; Condorelli, Gnemmi, Vallario, Genazzani, & Canonico, 2008; Kim, Bang, & Robertson, 2006; Marks & Xu, 2009). The current NCCN guidelines indicate that HDAC inhibitors can be administered to patients with advanced (stage IIB or above) CTCL (NCCN, 2012). The United States Food and Drug Administration has approved two HDAC inhibitors as second-line treatment for CTCL (Table 1). Vorinostat (suberoylanilide hydroxamic acid, Zolinza) was approved in October 2006 for the treatment of cutaneous manifestations of CTCL in patients with progressive, persistent, or recurrent disease on or after two systemic therapies (Merck & Co., Inc., 2011). Romidepsin (depsipeptide, FK228, Istodax) was approved in November 2009 for the treatment of CTCL in patients who received at least one prior systemic therapy (Celgene Corporation, 2012). Several other HDAC inhibitors (e.g., panobinostat [LBH589], belinostat [PDX101], and quisinostat [JNJ-26481585]) are in advanced stages of clinical development and have shown activity in MF/SS and other hematological malignancies (Ellis et al., 2008; Gimsing et al., 2008).
CLINICAL EXPERIENCE WITH HDAC INHIBITORS IN CTCL
The safety and efficacy of HDAC inhibitors in hematological malignancies, including CTCL, has been investigated in numerous trials; Table 2 provides a summary of later-stage trials examining HDAC inhibitors in patients with CTCL (Advani et al., 2007; Duvic et al., 2008, 2007; Zinzani et al., 2013; Olsen et al., 2007; Piekarz et al., 2009; Whittaker et al., 2010). Two phase 1 studies of oral vorinostat and one study where vorinostat was administered intravenously (iv) as a 2-hour infusion were conducted in patients with solid or hematological malignancies. The most common grade 3 or 4 drug-related adverse events (AEs; evaluated according to the National Cancer Institute Common Toxicity Criteria, version 2.0) in these studies were fatigue, thrombocytopenia, hyperglycemia, thrombosis, and diarrhea (Garcia-Manero et al., 2008; Kelly et al., 2005, 2003). A phase 2 dose-ranging study evaluated vorinostat in patients with refractory CTCL (n = 33; Duvic et al., 2007). The most common grade 3 or 4 (more serious) drug-related AEs in the study were thrombocytopenia and dehydration. Cardiac safety has been a concern with the HDAC inhibitor class of drugs. Although not common, grade 1–2 corrected Q–T (QTc) prolongation was reported in 3 out of 86 (3.5%) patients in CTCL clinical studies who were treated with 400 mg of oral vorinostat daily (Merck & Co., Inc., 2011). Antitumor activity with vorinostat was observed in eight patients (24%) who achieved a partial response (PR): one patient with early-stage disease and seven patients with advanced-stage disease (including four patients with SS). A pivotal phase 2b study treated patients with persistent, progressive, or recurrent MF/SS with 400 mg of oral vorinostat daily (n = 74; Olsen et al., 2007). In this study, the objective response rate (ORR) was 30%, and the median time to progression was 4.9 months. The most common grade 3 or 4 AEs included fatigue, pulmonary embolism, and thrombocytopenia (5% each).
A series of phase 2 studies have also shown efficacy with romidepsin in patients with CTCL. Because electrocardiogram abnormalities have been observed in preclinical and phase 1 studies with romidepsin, a phase 2 study monitored the cardiac function of relapsed or refractory patients with CTCL treated with 18 mg/m2 iv romidepsin (n = 42; Piekarz et al., 2006). Results showed that treatment with romidepsin was not associated with any impairment in cardiac function. Another phase 2 study evaluated this same dose of romidepsin in patients with recurrent CTCL who had received two or fewer prior cytotoxic regimens (n = 71; Piekarz et al., 2009). The observed ORR was 34%, and the median duration of response was 13.7 months. The most common grade 3 or 4 AEs were hematological and included lymphopenia, leukopenia, and granulocytopenia. Finally, in a pivotal phase 2b study, patients with CTCL who had failed prior therapy were treated with 14 mg/m2 iv romidepsin (n = 96; Whittaker et al., 2010). The ORR was observed in 33 patients (34%), including six patients with complete responses (CRs). Overall, few grade 3 or 4 drug-related AEs were observed—the most common were asthenic conditions (6%), nausea (2%), and anemia (2%).
Panobinostat has been evaluated in phase 1 and 2 studies of advanced cancer patients (Giles et al., 2006; Prince et al., 2007). In a phase 1 study, patients were treated with 15-, 20-, or 30-mg oral panobinostat (n = 32; Prince et al., 2007). The most common AEs were anorexia, nausea, and fatigue. Activity of panobinostat was observed in patients with CTCL: two patients had a CR, four patients had a PR, and seven patients had stable disease (SD). In another phase 1 study, patients with refractory hematological malignancies were treated with dose levels of panobinostat ranging from 4.8 to 14.0 mg/m2 (n = 15; Giles et al., 2006). The most commonly observed AEs were nausea (40%), diarrhea (33%), and vomiting (33%). In a phase 2 trial, patients with CTCL who had received prior therapy were treated with 20-mg oral panobinostat (Duvic et al., 2008). Responses (as based on a composite score of skin and systemic disease assessments) were observed in 11 patients (18%) treated with bexarotene (n = 62) and four patients (12%) who were bexarotene-naive (n = 33). The most common grade 3 or 4 AEs were thrombocytopenia, neutropenia, and pruritus.
The efficacy of belinostat has also been evaluated in patients with advanced malignancies. In a phase 1 study, patients with advanced hematological neoplasms were treated with iv belinostat ranging from 600 to 1000 mg/m2 per day (n = 16; Gimsing et al., 2008). The only grade 3 or 4 AEs observed were lymphopenia (one event) and renal failure (two events). Although there were no CRs or PRs, SD was observed in five patients (31%). Another phase 1 study evaluated belinostat at six dose levels ranging from 150 to 1200 mg/m2 per day in patients with advanced solid tumors (n = 46; Steele et al., 2008). SD was observed in 18 patients (39%). The most common AEs were nausea (72%), vomiting (72%), and lethargy (15%). In a phase 2 study, patients with recurrent or refractory peripheral T-cell lymphoma or CTCL were treated with 1000 mg/m2 belinostat (Advani et al., 2007). In the CTCL arm (n = 16), four objective responses were observed (25%). Belinostat was well tolerated, and the most common AEs (mostly grade 1 or 2) were nausea, fatigue, and constipation.
Quisinostat is a novel second-generation HDAC inhibitor that has shown promising broad-spectrum activity in preclinical studies. In a first-in-human phase 1 study, patients with advanced cancers were treated with oral quisinostat. The initial once-daily dosing in 3 weekly cycles was poorly tolerated, and intermittent dose schedules were explored. The most common AEs were fatigue, anorexia, and nausea. One patient with melanoma achieved a PR (1.4%), and eight patients (11%) had SD (Venugopal et al., 2013). A recent phase 2 study enrolled 26 patients with previously treated CTCL (Zinzani et al., 2013). Patients were treated at the recommended phase 2 dose of 12-mg oral quisinostat on days 1, 3, and 5 of each week in 21-day treatment cycles. Nausea (23%), diarrhea (19%), asthenia (15%), hypertension (12%), thrombocytopenia (12%), vomiting (12%), lethargy (8%), palpitations (8%), and pruritus (8%) were the most common treatment-related AEs occurring in at least 5% of patients. No dose-limiting neutropenia or thrombocytopenia or grade 2 or higher QTc prolongation were observed in the study. Six patients had confirmed cutaneous responses (one CR and five PRs); the reported cutaneous response rate was 24%, and the global response rate was 23%. In addition, 28% of patients had SD of over 12 weeks.
MANAGING AES WITH HDAC INHIBITORS AND PRACTICAL CONSIDERATIONS FOR NURSES CARING FOR PATIENTS WITH CTCL
When treating patients with CTCL, a risk/benefit analysis of the proposed treatment regimen must be conducted, with consideration given to patient goals, available resources, access to care, and overall state of health. A frank discussion with the patient is required to weigh the pros and cons of each agent in association with the clinician’s recommendation for agent choice. In general, oral dosing may be preferred over iv dosing when considering patient preferences/convenience, compliance, venous access issues, or access to experienced infusion centers, especially with prolonged use. Intravenous administration, if required via a central catheter, increases the risk of line sepsis in patients with CTCL, whose skin is typically colonized with Staphylococcus aureus bacteria (Duvic et al., 2007), and should be avoided whenever feasible. If venous access is or will become a limiting factor, an implanted port access may be considered once the patient’s skin has cleared from treatment. Ironically, depending on the type of prescription coverage the patient has, a hospital-based infusion may be the most affordable treatment model available to a patient. Pharmacy copays for oral dosing may be cost prohibitive for patients, especially with long-term use, and should be explored for financial feasibility for each patient. However, for patients with financial concerns (e.g., pharmacy copay and coverage issues), pharmaceutical assistance (for noninsured patients) and copay assistance programs for eligible patients should be considered and explored. In addition to prescription, compliance, and financial issues, the proper management of common HDAC inhibitor-associated toxicities is especially important in patients with CTCL (Table 3), as AEs (e.g., anorexia, diarrhea, nausea, vomiting, fatigue, skin issues, pruritus, and thrombocytopenia) associated with HDACs can lead to drug interruption and/or discontinuation (Celgene Corporation, 2012; Merck & Co., Inc., 2011).
Patients experiencing nausea and vomiting while receiving treatment with HDAC inhibitors can be managed with antiemetics (Subramanian, Bates, Wright, Espinoza-Delgado, & Piekarz, 2010). For example, granisetron and lorazepam have been effective in patients treated with romidepsin (de Bono et al., 2008; Steele et al., 2008; Subramanian et al., 2010). Thrombocytopenia, along with cardiac abnormalities, requires careful monitoring of patients—this includes proper patient selection before initiation of treatment and monitoring hematological parameters during treatment (Celgene Corporation, 2012; Merck & Co., Inc., 2011). Cardiac monitoring could include avoidance of agents known to prolong the QTc interval or agents that may interfere with metabolism and replacement of electrolytes to maintain serum potassium and magnesium levels. Although cardiotoxicity was once thought to be a class effect of HDAC inhibitors, recent studies have shown that treatment with vorinostat does not prolong the QTc interval (Munster et al., 2009). Changes in food palatability, which often affects food intake, is another side effect associated with HDAC inhibitors. Patients often complain that foods they like no longer taste the same. This can be managed by encouraging experimentation with different types of foods, sauces, and spices they previously did not use; the use of mints and chewing gum may also be helpful. Patients can also experience weight loss because of these changes in taste (dysgeusia), which may be improved with the use of supplements as well as smaller, more frequent meals and appetite stimulants. It is also important that patients with CTCL remain adequately hydrated—this can be encouraged through the use of flavoring for water and other beverages.
Skin and quality-of-life assessments should also be routinely performed in patients with CTCL. Nurses caring for CTCL patients should assess for (1) infections that are caused by an infection-prone environment (e.g., bacterial colonization, fissuring, excoriations, ulcerated plaques, and tumors), (2) discomfort and pain associated with ulcerated plaques and tumors, (3) skin swelling, (4) fissuring of palms and soles, (5) psychosocial issues (e.g., depression, noncompliance, work-related and financial issues, fear of dying, self-image), (6) constitutional symptoms (e.g., fatigue and weight changes), (7) homeostasis abnormalities (e.g., cold or heat intolerance, electrolyte imbalances, anemia of chronic disease), and (8) mobility-related issues (e.g., fissures and hyperkeratosis that limit functionality).
There are a number of practical considerations specific to the administration of romidepsin. Administration via a peripheral iv is preferred to minimize the risk of line sepsis—strict aseptic technique for iv insertion should be followed. The administration of romidepsin requires a 4-hour infusion that can be accompanied by both prehydration and posthydration to minimize side effects and provide additional support to prevent dehydration. Patients must be advised of the time required to complete a standard regimen (i.e., iv infusion weekly for 3 weeks with 1 rest week), although changes in regimen (i.e., dose reductions or dose escalations) may occur (Celgene Corporation, 2012). Also, clinical laboratory values must be monitored before each infusion to determine the safety of dosing. In particular, absolute neutrophil count and platelets should be within general guidelines for dosing safety (≥1000/mcL and ≥75,000/mcL, respectively). Magnesium and potassium must be replaced before dosing if below 2.0 mg/dL and 4.0 mEq/L, respectively.
There are also some practical considerations specific to the administration of vorinostat, which is administered at a daily maximum dose of 400 mg. Careful monitoring of blood cell counts and chemistry tests (electrolytes including potassium, magnesium and calcium, glucose, and serum creatinine) is recommended every 2 weeks during the first 2 months of therapy, followed by monthly monitoring thereafter. In some cases, electrocardiograms should be performed before the start of therapy and continued monthly. Low levels of magnesium and potassium should also be corrected before the administration of vorinostat. Intolerance and side effects (e.g., bone marrow suppression effects, gastrointestinal side effects) can be managed with dose reductions (the prescribing information states that dose may be reduced to 300 mg; from personal experience at our institution, we have dosed patients with vorinostat ranging anywhere from 100 mg daily [in combination with other agents] up to 400 mg daily) and the timing of the dose (i.e., generally after an evening meal to minimize the amount of awake time with gastrointestinal effects; Merck & Co., Inc., 2011).
HDACs regulate a wide range of cellular activities; therefore, blockade with HDAC inhibitors provided a strong rationale for their use in patients with CTCL. Ongoing clinical trials continue to characterize HDAC inhibitors for the management of CTCL and the potential use in combination regimens in these patients. HDAC inhibitors provide symptomatic relief, especially from pruritus, and have improved outcomes in patients with CTCL who have received prior therapy (Demierre, 2010). Prompt identification and management of treatment-related toxicities are critical to maintaining patient quality of life and achieving optimal therapeutic outcomes.
For patients living with a chronic disease such as CTCL, establishing and maintaining ongoing care with healthcare professionals experienced in the treatment of CTCL is essential. As part of the interdisciplinary team, nurses play an important role in helping patients navigate through all aspects of living with and managing their disease. Providing emotional support and reassurance is a critical component of this nursing care in addition to managing and educating patients regarding diagnosis and staging, CTCL disease process and symptom management, and treatment-related toxicities. In addition to ensuring proper management of side effects that may be experienced by patients undergoing therapy for CTCL, nurses can also direct patients and caregivers to additional resources and services available to patients during the course of their treatment (Table 4). Dermatology and oncology nurses have an exceptional opportunity to positively affect the experiences of all patients within the healthcare system, improve their quality of life, and influence the successful treatment of their CTCL.
Medical writing and editorial assistance were provided by Joseph J. Abrajano, PhD, and Kakuri M. Omari, PhD, of Integrus Scientific, a division of Medicus International New York (NY). This assistance was funded by Merck & Co., Inc., Whitehouse Station, NJ. The authors were fully responsible for all content and editorial decisions and received no financial support or other compensation related to the development of the manuscript.
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adverse event management; CTCL; dermatology; HDAC inhibitors; nurses; oncology
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