High-dose Vorinostat Effective at Treating Relapsed Lymphomas, Study Finds


Key Points

  • Researchers found that giving patients with lymphoma high doses of vorinostat in combination with rituximab, ifosfamide, carboplatin, and etoposide, resulted in a 70% response rate.
  • The best responses were seen in patients who had Hodgkin lymphoma and diffuse large B-cell lymphoma.
  • The study sets the stage for the use of a new class of drugs called histone-deacetylase inhibitors to sensitize tumor cells to chemotherapy.

Reporting the results of a phase I clinical trial to test the effectiveness of a new class of drugs to augment standard chemotherapy, a team led by Fred Hutchinson Cancer Research Center scientists found that giving patients high doses of vorinostat (Zolinza) in combination with another round of commonly used second-line drugs resulted in a 70% response rate, including several patients whose lymphoma cells disappeared entirely.

According to Ajay Gopal, MD, Associate Member of the Fred Hutchinson Clinical Research Division and corresponding author of the paper, published online in the British Journal of Haematology, the study results may help solve the dilemma of how to effectively treat patients when standard drugs fail in the first-line setting. And, he said, it sets the stage for the use of a new class of drugs called histone-deacetylase inhibitors, of which vorinostat is one, to sensitize tumor cells to chemotherapy.

Best Responses in Aggressive Lymphomas

Patients treated in the trial had several types of lymphoma, but the best responses were seen in those who had Hodgkin lymphoma and diffuse large B-cell lymphoma, two of the most aggressive types that typically require a stem cell transplant if they are not cured after the first line of treatment.

“The better the response, the better the outcome will be when patients proceed to a stem cell transplant designed to cure them of their disease,” said Elizabeth Budde, MD, PhD, a Research Associate in the Fred Hutchinson Clinical Research Division and first author of the study.

The researchers noted that while the current front-line chemotherapy agents are the most effective yet against lymphomas, patients who relapse after receiving them are less likely to achieve long-term, disease-free survival when current second-line or salvage therapies are applied. This is because the cancers develop resistance to the drugs or the tumor’s biology changes in some way to reduce their effectiveness.

Preclinical studies at Fred Hutchinson and other institutions have found vorinostat to be effective when used in combination with rituximab (Rituxan), ifosfamide, carboplatin, and etoposide. Vorinostat works by blocking signals to tumor-suppressor genes, which allows those genes to induce tumor cell death.

Vorinostat is approved by the FDA to treat cutaneous T-cell lymphoma. The standard dose is 400 mg per day. It is manufactured by Merck & Co.

Phase I Trial Details

The phase I trial involved 27 patients at about a dozen sites that are members of the Puget Sound Oncology Consortium. Because the drugs can be taken orally, the patients could self-treat at home. A novel two-stage dose escalation schedule developed at Fred Hutchinson was used to speed the time it took to determine the maximum effective dose of vorinostat with the fewest side effects, which was 500 mg twice a day.

Some level of response was observed in 19 patients, including eight complete responses. The most common side effects were gastroenterological, which led researchers to recommend giving future patients preventive medicines while taking vorinostat.

Because many of the patients were destined for an autologous hematopoietic stem cell transplant as the next treatment step, researchers also evaluated the ability to mobilize and collect the patients’ peripheral blood stem cells after the drug therapy was administered. They were successful in 20 of 21 patients.

Next Steps

Dr. Budde said the next step is to conduct a phase II study of patients who have diffuse B-cell lymphoma because the drug regimen worked best in these patients and it is the most aggressive of lymphomas.

The study was funded by several sources, including the National Institutes of Health, Lymphoma Research Foundation, Leukemia and Lymphoma Society, the Mary A. Wright Memorial Research Fund, Washington Life Sciences Discovery Fund, and Merck Sharp & Dohme Corp. Drs. Budde and Gopal received funding support from Merck Sharp & Dohme Corp.

In addition to Drs. Budde and Gopal, study coauthors included researchers at the University of Washington; Massachusetts General Hospital, Valley Medical Center in Renton, Washington; Great Falls Clinic in Great Falls, Montana; and Yakima Regional Medical & Cardiac Center in Yakima, Washington.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.