Romidepsin Reduces Disease Burden and Skin Symptoms in Patients with Previously Treated Cutaneous T-Cell Lymphoma

Summary

In a clinical trial, romidepsin (Istodax®), a type of targeted therapy called a histone deacetylase inhibitor, reduced the symptoms and tumor burden of cutaneous T-cell lymphoma in many patients with advanced disease. The drug also reduced skin itching and discomfort even in patients whose tumors did not shrink in response to treatment.

Source

The Journal of Clinical Oncology, October 10, 2010 (see the journal abstract).

Background

Cutaneous T-cell lymphoma (CTCL) is a rare type of non-Hodgkin lymphoma. In its early stages, the disease primarily affects the skin, causing patches, plaques, tumors, and erythroderma (redness and itching). As the disease progresses, it can spread to the blood, lymph nodes, and internal organs.

Treatments for early-stage CTCL usually target the skin and include photodynamic (light) therapy, steroid creams, and radiation therapy using electron beams, which do not penetrate deep into the body.

Even if CTCL is found in an early stage, however, it is difficult to cure, and the disease usually returns after initial treatment. Treatment options for advanced or recurrent CTCL aim to reduce symptoms and extend life. These options include chemotherapy; a targeted therapy known as denileukin diftitox; and interferon-alpha, a biological therapy that slows cancer cell division.

Researchers have recently found that drugs known as histone deacetylase (HDAC) inhibitors have activity against CTCL. In a phase II trial of the HDAC inhibitor romidepsin that was carried out by researchers at the National Cancer Institute (NCI) and published in 2009, the drug reduced tumor burden in patients with both early and advanced CTCL and halted tumor progression in some patients.

The Study

To confirm the activity of romidepsin in CTCL, researchers from 33 treatment centers in 8 countries enrolled 96 patients in a single-arm phase II clinical trial. In single-arm trials, the drug under study is not compared with another drug or a placebo.

All participants were 18 years of age or older and had experienced disease relapse after one or more systemic treatments (treatments that affect the whole body, such as chemotherapy). Patients with known heart problems were excluded because early studies had suggested that romidepsin may cause heart rhythm irregularity. Levels of potassium and magnesium were verified as being in the normal range before romidepsin administration because CTCL can be associated with low blood levels of these electrolytes.

Participants received romidepsin as a 4-hour intravenous infusion on days 1, 8, and 15 of each 28-day cycle. They could receive up to six cycles of romidepsin. Patients whose disease stabilized or shrank could continue to receive romidepsin after the trial ended.

The researchers assessed the effect of romidepsin on disease sites in the skin, lymph nodes, and peripheral blood on the first day of each treatment cycle and 30 days after the last cycle. Patients also reported their levels of pruritus (itching skin) monthly.

The study was lead by Sean J. Whittaker, M.D., of St. Thomas Hospital in London. The research was supported by Gloucester Pharmaceuticals, the manufacturer of romidepsin.

Results

The 96 participants had received a median of three earlier systemic therapies, and 68 patients (71 percent) had advanced CTCL. All received at least one dose of romidepsin, although 61 patients (64 percent) discontinued treatment before the end of six cycles, mainly because of disease progression (21 patients), a decision to leave the trial (21 patients), or adverse events (17 patients, of whom 14 experienced drug-related side effects).

Overall, 33 patients (34 percent) experienced either a partial (28 percent) or complete (6 percent) response to romidepsin treatment. Of the 68 patients with advanced disease, 26 (38 percent) achieved a response. The responses lasted a median of 15 months. Thirty-eight patients (40 percent) had an improvement in skin symptom score of at least 50 percent. Most (92 percent) of the 65 patients who reported moderate to severe pruritis at the start of the study experienced an improvement in that symptom. This relief lasted for a median of 6 months.

The most common side effects of treatment were gastrointestinal disturbances, including nausea and vomiting, and fatigue. Most patients experienced only mild to moderate side effects.

Very similar results were seen in the NCI trial, which tested romidepsin in 71 patients. In that study, 34 percent of patients experienced either a partial (28 percent) or complete (6 percent) response, and the median duration of response was 13.7 months. In November 2009, based on the results of both trials, the U.S. Food and Drug Administration approved romidepsin for treatment of CTCL in patients who have received at least one prior systemic therapy.

Limitations

Romidepsin presents several challenges related to administration of the drug and the disease process, explained Dr. Bates.

Although romidepsin has been administered to some patients for a very long time (over 5 years in one patient in the NCI study) without major side effects, some patients are very sensitive to the nausea and fatigue that the drug can cause. Why some patients experience side effects and others do not is not understood, but antinausea medications can be helpful for patients who experience that side effect.

In addition, the low blood levels of potassium and magnesium that can be associated with CTCL may aggravate irregular heart rhythms. Therefore, levels of these electrolytes should be normalized in patients before treatment with romidepsin. However, careful study has shown no evidence that the drug will cause cumulative heart effects. Nevertheless, because patients with known cardiac disorders were excluded from this trial, explained Dr. Susan Bates, head of the Molecular Therapeutics Section in NCI’s Center for Cancer Research, whose group performed the NCI study, “we can’t be certain that romidepsin is safe in patients with heart disorders. Patients with cardiac disorders should get the drug under close monitoring,” she said.

In addition, patients with CTCL have high levels of bacteria on the skin and are especially vulnerable to infections. Therefore, to reduce the risk of infectious bacteria entering the body from the skin, Dr. Bates explained that doctors should not use any type of permanent catheter placed in the veins while the disease is active. Patients should have regular baths with antibacterial soap to reduce the risk of infection.

Comments

Although the trial was not designed to test whether romidepsin can extend overall survival, “the symptoms of cutaneous T-cell lymphoma are so distressing that a drug that causes reproducible responses is clearly of benefit to patients even if it doesn’t change survival,” said Dr. Bates. “Romidepsin is an effective agent—the median duration of response in this study was 15 months. That’s better than many of the other agents available to treat CTCL,” she continued.

The authors of the study noted that more research is required to determine the optimal use of romidepsin. “Despite this new therapy, CTCL remains a chronic illness that, in advanced stages, requires fairly constant therapy… By combining romidepsin with other drugs, regimens that result in even more significant and durable responses may be identified,” they concluded.