EVEROLIMUS FOR WALDENSTROM MACROGLOBULINEMIA

February 18, 2010 — Waldenström's macroglobulinemia (WM) is a relatively rare condition and, to date, there are no agents approved for its treatment by the US Food and Drug Administration. However, everolimus (Afinitor, Novartis) has potential as a new therapeutic strategy among patients with relapsed/refractory WM, according to a new study published online February 8 in the Journal of Clinical Oncology.

When used as a single agent, researchers reported an overall response rate of 70%; a partial response was achieved by 42% of patients, and a minimal response was achieved by 28%. None of the patients achieved a complete response.

In addition, stable disease occurred in 16% of the cohort, and 8% had disease progression without a response. Toxicity was considered manageable, even though grade 3 or higher events were observed in more than half (56%) of patients.

A Distinct Disease Without Its Own Treatment

WM is a distinct low-grade B-cell lymphoma that is characterized by the presence of lymphoplasmacytic cells in bone marrow, a high level of immunoglobulin (Ig)M, and elevated serum viscosity. Even though advances have been made in treatment, the disease remains incurable, note the authors. Thus, there is a great need for the development and evaluation of novel therapeutic agents.

"WM is a unique lymphoplasma proliferative disorder," said study author Thomas Witzig, MD, a professor of medicine at the Mayo Clinic in Rochester, Minnesota. "It is distinctly different from [chronic lymphocytic leukemia], ordinary lymphoma, and multiple myeloma."

However, many of the drugs that work for those disorders might also work for WM, he told Medscape Oncology. "The main difficulty is the paucity of patients; therefore, it takes a long time to develop new drugs specifically for that disease and then prove that they are actually better than the standard."

Dr. Witzig explained that he and his colleagues are investigating the mechanisms of WM cell growth. "Understanding how the cell survives provides clues as to what type of drugs will be effective," he said, "When we are testing a new drug, we often test the agent in a variety of B-cell malignancies, and then expand the trial to the specific B-cell malignancy that responded."

And that is precisely the case with this trial, Dr. Witzig pointed out.

The study was designed for any type of lymphoma, but when they found that the patients with WM were responding to everolimus, that group of the trial expanded to quickly accrue 50 patients. "This study does demonstrate that one can accrue patients with relapsed WM rather rapidly if you have an effective drug," he said.

Everolimus is an inhibitor of mTOR (mammalian target of rapamycin), a serine-threonine kinase. The mTOR pathway is dysregulated in several human cancers, and inhibition of mTOR by everolimus has been shown to reduce cell proliferation, angiogenesis, and glucose uptake in in vitro and/or in vivo studies. In addition, the researchers point out that in their own preclinical studies, mTOR inhibition with rapamycin had a significant antiproliferative effect on malignant B-cells.

They also note that in clinical trials of temsirolimus (Torisel, Wyeth), another mTOR inhibitor, patients with mantle-cell lymphoma and other B-cell non-Hodgkin's lymphomas demonstrated overall response rates of 40%.

Response Duration and Progression-Free Survival Not Yet Reached

Dr. Witzig and colleagues from the Mayo Clinic and the Dana-Farber Cancer Center, Boston, Massachusetts, investigated the safety and antitumor activity of single-agent everolimus in 50 patients with relapsed and/or refractory WM. All had measurable disease, received everolimus 10 mg orally daily, and were evaluated at monthly intervals. They were assessed for tumor response after cycles 2 and 6, and then every 3 cycles until progression.

The median age was 63 years (range, 43 to 85 years), and all except 2 patients had previously received rituximab-based (Rituxan) therapy; 64% of patients had previously received alkylator-based therapies. On the basis of the international scoring system for WM, half of the patients were considered to be at intermediate or high risk.

Patients who achieved a partial response did so after a median of 2 months (range, 1 to 10 months) of treatment. The median duration of response for this group, as well as median duration of progression-free survival, has not yet been reached. Currently, after a median follow-up of 6.6 months (range, 1.0 to 18.2+ months), 16 (of 21) patients are still responding. The researchers did not find any association between response status and factors such as age, hemoglobin level at baseline, or IgM level at baseline.

At this time, 21 patients remain on therapy after a median of 7.3 months (range, 4.1 to 25.0 months) of treatment, explained Dr. Witzig; 29 patients discontinued therapy, with a median time to discontinuation of active treatment of 7.3 months. "The study remains open for follow-up and is also open for compassionate use," he said.

To date, 26% of patients have experienced disease progression and 14% have died, with 4 deaths due to progressive WM.

Can Be Considered a Reasonable Option

The most common adverse events were hematologic toxicities with cytopenias, and pulmonary toxicity occurred in 10% of patients. The authors note that patients with grade 1 thrombocytopenia were eligible to enroll in this trial, and all patients were able to continue full dosing as long as their platelet count was at least 40,000 × 10⁶/L on day 1 of each cycle. These factors most likely explain the level of thrombocytopenia observed in this study, they write.

The pulmonary toxicity that occurred during this trial was manageable, and dose reductions due to toxicity occurred in 52% of patients.

Even though this was a phase 2 trial, Dr. Witzig feels that for relapsed patients, everolimus could be a reasonable option. The drug, however, has only been approved for relapsed renal cell carcinoma, not for this indication, he added.

It is not known whether a phase 3 trial will be conducted. "This is a rare disease, and performing a phase 3 study is difficult," he said. "It is probably more likely that the phase 2 study will be repeated as a registrational study."

The study was funded by Novartis Inc, the International Waldenström's Macroglobulinemia Foundation, and the National Institute of Health. Dr. Witzig reports receiving research funding from Novartis. Several of the study's coauthors report financial relationships, which are detailed in the paper.

J Clin Oncol. Published online February 8, 2010. Abstract