Histone Deacetylase Inhibitors
Epigenetics refers to changes in genetic expression and cellular phenotype without specific alterations in the DNA sequence. Changes in the cellular epigenetic environment play an important role in tumor formation, progression, and treatment resistance. Modulation of histone aceylation has been shown to be important in the treatment of certain cancers. Two histone deacetylase (HDAC) inhibitors, vorinostat (Zolinza) and romidepsin (Istodax), have been approved for use in patients with cutaneous T-cell lymphoma (CTCL). The HDAC inhibitors cause DNA damage within the cell nucleus via an alteration of DNA structure (by loosening the structure of the chromatin proteins surrounding the DNA) and activation and/or repression of key genes in the cell cycle and apoptotic cycle.
Vorinostat was approved in 2006 for cutaneous manifestations of CTCL in patients who have progressive, persistent, or recurrent disease while on treatment, or following treatment, with two systemic therapies. The ORR was 32% in patients who had received at least two prior therapies, and was 30% for patients with advanced CTCL. Approximately 32% of the patients treated experienced relief of pruritus.
Toxicity. The most common side effects of vorinostat were diarrhea, fatigue, nausea, and anorexia. Most of the adverse events were grade 2 or lower. The most common grade 3/4 side effects were fatigue, pulmonary embolism, thrombocytopenia, and nausea. Vorinostat is not immunosuppressive; however, some degree of bone marrow suppression can occur with its use.
Romidepsin was approved in 2009 and also is indicated for the treatment of patients with CTCL. In prior clinical trials, median time to response was 2 months among patients achieving a major response (CR or PR). The median duration of response was 13.7 months.
Toxicity. Side effects of romidepsin include nausea, fatigue, vomiting, and anorexia. Reported hematologic toxicity includes leukopenia, granulocytopenia, lymphopenia, thrombocytopenia, and anemia.
Transient elevation of liver function tests has also been noted, as well as hyperuricemia and hypophosphatemia. EKG changes, consisting of T-wave flattening or ST segment depression, have been reported. Infections, including bacterial infections of the skin; upper respiratory, gastrointestinal, and urinary tracts; and lung were reported, but they were not related to neutropenia.
Besides histone modifications, DNA methylation is another primary epigenetic modification, and it is also potentially reversible. Hypermethylation of various genes is relatively common in MDS and AML. Therefore, inhibition of hypermethylation is an interesting target for the management of MDS and AML.
Azacitidine (Vidaza) was approved by the FDA in 2004 for the management of MDS. It also has been used in AML, especially in the elderly. Azacitidine can be administered either intravenously or subcutaneously, with similar bioavailability. It is rapidly absorbed when given subcutaneously. Prior studies with azacitidine included not only patients with MDS but also some with AML. In an international, open-label randomized phase III study, patients treated with azacitidine had an improved survival compared with those who received conventional therapy (24.5 months vs 15 months, respectively). In a separate randomized controlled phase III study of adult patients with low marrow blast count (20%–30%) WHO-defined AML, the median survival of patients with AML treated with azacitidine was 24.5 months, compared with 16 months for the conventional treatment group. In prior studies, a median of 3.8 cycles of treatment was necessary before a response was seen. This finding has been confirmed in additional studies of azacitidine, and therefore treatment with at least 4 cycles of therapy is recommended before deeming the treatment unsuccessful in its ability to achieve a response.
Toxicity. Myelosuppression is the most common toxicity with azacitidine; however, it is difficult to attribute the level of myelosuppression, since most patients with MDS will have myelosuppression as a component of their disease before starting therapy. Nausea and vomiting also occur in a small number of patients. Constipation occurs in approximately 31% of patients receiving azacitidine, and abdominal pain has been reported also. Fatigue is noted during the days of treatment with azacitidine. Injection site erythema is common. Rarely, gout and acute renal failure may occur. Serum sickness is rare. Abnormal liver function tests can occur in approximately 7% of patients receiving azacitidine, and generalized weakness, muscle tenderness, and lethargy are also uncommon.
Decitabine (Dacogen) is approved for the treatment of adults with MDS, at a dose of 15 mg/m2 every 8 hours for 3 days. An alternate schedule has also been studied in which patients were treated with decitabine at a dose of 20 mg/m2 IV administered over a 1-hour period daily for 5 consecutive days. Cycles were repeated every 28 days. The ORR was 25%, with a 24% CR rate. The median time from first dose to achieve a CR was 126 days. The median survival was 7.7 months from the start of treatment with decitabine. This dosing schedule is now commonly used in the treatment of AML.
Toxicity. Myelosuppression is very common with decitabine. Other common side effects include febrile neutropenia and fatigue. Additional side effects include thrombocytopenia, anemia, dyspnea, bacteremia, and pneumonia. Nausea and vomiting can occur, but are usually mild to moderate. Stomatitis can occur in a small number of patients. Pyrexia, along with rigors, occurs in more than half of patients treated with decitabine. Peripheral edema affects about 25% of patients, and patients may experience arthralgias .
The proteasome is an intracellular enzyme complex that degrades ubiquitin-tagged proteins. It is through this process that protein levels are regulated within the cell. Proteasome inhibitors have been shown to be effective in the management of multiple myeloma and mantle cell lymphoma. Bortezomib(Drug information on bortezomib) is currently the only proteasome inhibitor approved by the FDA. It is administered at a dose of 1.3 mg/m2 either via the IV route or subcutaneously on days 1, 4, 8, and 11 in 21-day cycles. The largest trial investigating the use of bortezomib in mantle cell lymphoma reported a response rate of 33% with an 8% CR rate.
The most common grade 3 or higher adverse events with bortezomib in the trial by Fisher et al were peripheral neuropathy, fatigue, and thrombocytopenia. About one-quarter of patients discontinued their therapy due to toxicity. Other common toxicities occurring in more than 20% of cases include: rash, constipation, diarrhea, nausea, vomiting, decreased appetite, anemia, asthenia, dizziness, headache, insomnia, mental or mood changes, cough, dyspnea, and fever.
The management of leukemias and lymphomas now includes the use of many targeted therapies. More targets are being discovered and therapies developed to better manage these hematologic malignancies. Nurses need to have an understanding of the targeted therapies and their side effects so they can appropriately manage the side effects that their patients with leukemias and lymphomas may experience (see Table 3).
The nonprofit Leukemia & Lymphoma Society (www.lls.org), the world’s largest voluntary organization dedicated to blood cancers, provides support for patients and educational materials about a variety of leukemia and lymphoma types and their treatment, to share and discuss with patients and their families. The Lymphoma Research Foundation (www.lymphoma.org) also provides support to patients with lymphoma including the distribution of educational materials. The Cutaneous Lymphoma Foundation (www.clfoundation.org) is a nonprofit patient advocacy organization that provides information on the various cutaneous lymphomas and their treatment.
In addition, the Cancer.Net website of the American Society of Clinical Oncology (ASCO; www.cancer.net) and the website of the National Cancer Institute (www.cancer.gov) are good sources of patient information.
Barbara Rogers serves on speakers bureaus for Celgene, Millennium, Teva/Cephalon, Allos, and Seattle Genetics.
This article contains reference to drugs approved by the US Food and Drug Administration (FDA) that are used in off-label situations in the management of leukemias and lymphomas. No non–FDA-approved investigational agents are mentioned in the context of management of lymphomas and leukemias.