Last Updated: 2010-03-03 16:13:01 -0400 (Reuters Health)

By David Douglas

NEW YORK (Reuters Health) - Adding bortezomib to rituximab, or using single-agent everolimus therapy, look like promising approaches for patients with relapsed or refractory Waldenstrom macroglobulinemia, according to two separate phase II studies reported online February 8th in the Journal of Clinical Oncology.

The trial of bortezomib plus rituximab "provides significant advances" in the treatment of this rare hematological disease, said lead author Dr. Irene M. Ghobrial in email to Reuters Health. "We had very high responses and minimal toxicity, especially minimal neurologic toxicity."

Dr. Ghobrial of the Dana-Farber Cancer Institute, Boston and colleagues treated 37 patients with bortezomib (1.6 mg/m2 IV) on days 1, 8 and 15 every 28 days for 6 cycles. During cycles 1 and 4, patients also received weekly rituximab, "one of the most widely used...agents" for Waldenstrom macroglobulinemia.

The researchers assessed responses on the basis of monoclonal protein and immunoglobulin M levels, in addition to established consensus guidelines.

One patient (3%) achieved complete remission, another (3%) had near complete remission, 17 (46%) had partial remission, and 11 (30%) had minimal remission.

Median overall survival has not been reached. The median time to progression was 16.4 months. Estimated median progression-free-survival was 15.6 months, with 57% surviving at 12 months and 45% at 18 months.

The most common grade 3 and 4 therapy-related adverse events included reversible neutropenia (16%), thrombocytopenia (14%), and anemia (11%). Only two patients had Grade 3 peripheral neuropathy.

Dr. Ghobrial is also the lead author on the second paper, which reports on a trial of single-agent everolimus in a similar patient population.

Taken daily, oral everolimus "produced a 42% partial remission rate in patients with previously treated and relapsed Waldenstrom macroglobulinemia," said Dr. Thomas E. Witzig of the Mayo Clinic, Rochester, Minnesota, the paper's senior author.

Dr. Witzig told Reuters Health by email that everolimus "works to inhibit an important enzyme" - mammalian target of rapamycin, or mTOR - "in the cancer cell. The effect on the cell is to decrease the secretion of monoclonal protein."

In this study, the researchers treated 50 patients with everolimus, 10 mg daily, subject to monthly evaluation. Clinical response was assessed after monthly cycles 2 and 6 and then every three cycles until progression.

Based on monoclonal protein levels and consensus guidelines, none of the patients had complete remission, but 70% had at least a minimal response, including the 21 (42%) who had partial remissions.

Grade 3 or higher toxicities developed in 56% of patients; toxicity led to dose reduction in 52%.

The median duration of response to everolimus and median progression-free survival have not been reached. The estimated progression-free survival is 75% at 6 months and 62% at 12 months.

Everolimus "is now being combined with other agents in an attempt to further increase the response rate and depth of response," Dr. Witzig said. "We are excited to be able to offer...something new" to patients with Waldenstrom macroglobulinemia.

Dr. Ghobrial added, "We are building on the success of this trial with another trial using the combination of everolimus with bortezomib and rituximab."

J Clin Oncol 2010.