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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Keywords:Copyright © 2013 by the Dermatology Nurses' Association.
adverse event management; CTCL; dermatology; HDAC inhibitors; nurses; oncology