Panobinostat offers limited activity in refractory or relapsed Hodgkin's lymphoma
Last Updated: 2012-05-30 19:55:26 -0400 (Reuters Health)
By Will Boggs MD
NEW YORK (Reuters Health) - The investigational drug panobinostat shows durable antitumor activity in some patients with refractory or relapsed Hodgkin's lymphoma, a new study shows.
"Histone deacetylase (HDAC) inhibitors, as a class, have good activity in patients with relapsed Hodgkin's lymphoma," Dr. Anas Younes, who led the study from the University of Texas MD Anderson Cancer Center, in Houston, told Reuters Health by email. "These drugs work by several mechanisms, including a direct antiproliferative effect and immunomodulatory effects."
In the April 30th online issue of the Journal of Clinical Oncology, Dr. Younes and colleagues reported on a phase II trial of panobinostat in 129 patients with relapsed or refractory Hodgkin's lymphoma after autologous stem-cell transplantation (ASCT).
The primary efficacy variable was the objective response rate, defined as the proportion of patients with a best overall disease response of complete response or partial response.
Patients were heavily pretreated. More than two-thirds (68%) had received prior radiotherapy, 78% had received subsequent therapy after ASCT, and 41% were characterized as not responding to their therapy just before panobinostat.
The objective response rate was 27% (30 partial responses, 5 complete responses). Seventy additional patients demonstrated a best response of stable disease, for a disease control rate of 82%. Tumors shrank in 74% of the patients.
Response rates were similar for patients with poor prognostic factors when compared with the overall patient population.
The median progression-free survival was 6.1 months (range, 0 to 17.2 months).
The median overall survival had not been reached as of the data cutoff date, when the one-year overall survival rate was estimated at 78%.
Lower-than-median treatment-associated reductions of the biomarker TARC (thymus and activation-regulated chemokine) were associated with a 2.41-fold greater risk of progression and a lower median progression-free survival (4.9 months) compared with higher-than-median reductions (10.6 months).
Two-thirds of the patients required dose reductions, most commonly due to an adverse event.
Common nonhematologic adverse events related to panobinostat included diarrhea (66%), nausea (60%), vomiting (33%), and fatigue (38%). One in 10 patients had grade 1 to 2 hypothyroidism.
Grade 3 to 4 drug-related adverse events included thrombocytopenia (79%), anemia (21%), and neutropenia (21%), although only two patients experienced febrile neutropenia. One death from sepsis 45 days after the last dose of panobinostat was considered related to the study drug, although that patient had begun a new regimen (vincristine and mechlorethamine) three days after discontinuing panobinostat.
"This order of myelotoxicity would certainly limit the ability to combine panobinostat with other myelotoxic drugs," writes Dr. George P. Canellos from Dana-Farber Cancer Institute, Boston, Massachusetts in an editorial. "The relatively low response rate and its toxicity will diminish the enthusiasm for this drug."
Dr. Younes disagrees. "Although panobinostat induced partial and complete remission in only 24% of the patients, which is lower than the 75% response rate reported with brentuximab vedotin, almost 70% of the patients treated with panobinostat had some degree of tumor shrinkage. Therefore, panobinostat is a great drug for combination strategies," he said.
"We just completed a phase-I study combining panobinostat with the mTOR inhibitor everolimus," Dr. Younes added. "This rationally designed combination is based on the single agent activity of each drug and synergistic effect seen in preclinical experiments. We also have an ongoing study of panobinostat plus ICE (ifosfamide-carboplatin-etoposide) chemotherapy in pre-transplant patients."
The study was supported by Novartis Pharmaceuticals, which employs three of the authors and has financial relationships with six others.
J Clin Oncol 2012.
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