Phase II trial of the oral mammalian target of rapamycin inhibitor everolimus in relapsed or refractory Waldenstrom macroglobulinemia

Abstract

PURPOSE The phosphatidylinositol 3-kinase/mammalian target of rapamycin (mTOR) signal transduction pathway controls cell proliferation and survival. Everolimus is an oral agent targeting raptor mTOR (mTORC1). The trial's goal was to determine the antitumor activity and safety of single-agent everolimus in patients with relapsed/refractory Waldenström macroglobulinemia (WM). PATIENTS AND METHODS Eligible patients had measurable disease (immunoglobulin M monoclonal protein > 1,000 mg/dL with > 10% marrow involvement or nodal masses > 2 cm), a platelet count more than 75,000 x 10(6)/L, a neutrophil count more than 1,000 x 10(6)/L, and a creatinine and bilirubin less than 2 x the laboratory upper limit of normal. Patients received everolimus 10 mg orally daily and were evaluated monthly. Tumor response was assessed after cycles 2 and 6 and then every three cycles until progression. Results Fifty patients were treated. The median age was 63 years (range, 43 to 85 years). The overall response rate (complete response plus partial remission [PR] plus minimal response [MR]) was 70% (95% CI, 55% to 82%), with a PR of 42% and 28% MR. The median duration of response and median progression-free survival (PFS) have not been reached. The estimated PFS at 6 and 12 months is 75% (95% CI, 64% to 89%) and 62% (95% CI, 48% to 80%), respectively. Grade 3 or higher related toxicities were observed in 56% of patients. The most common were hematologic toxicities with cytopenias. Pulmonary toxicity occurred in 10% of patients. Dose reductions due to toxicity occurred in 52% of patients. CONCLUSION Everolimus has high single-agent activity with an overall response rate of 70% and manageable toxicity in patients with relapsed WM and offers a potential new therapeutic strategy for this patient group.

Fig 1.

CONSORT diagram. (*) Patients who subsequently obtain complete remission (CR)/CR unconfirmed (CRu) receive two additional cycles and follow the schema for CR/CRu. (†) If discontinued per physician discretion where patient is still responding and has not refused follow-up or gone to other treatment, follow in observation. Patients with macroglobulinemia and who obtain a minor response should follow the schema as a partial response (PR). One cycle = 4 weeks. MR, minimal remission.

Fig 2.

Kaplan and Meier curve of progression free-survival (PFS) and overall survival (OS) in 50 patients with relapsed Waldenström macroglobulinemia treated with single-agent everolimus.

Fig 3.

(A) Maximum percent decrease from baseline in immunoglobulin M (IgM) over all cycles in response to everolimus per patient. (B) Median and interquartile range for IgM values in response to everolimus per each cycle.

Fig 4.

Median and interquartile range for hemoglobin values in response to everolimus per each cycle. The lowest hemoglobin value per patient for each cycle was used for this analysis.

Fig 5.

Computed tomography scan before and after two cycles of everolimus showing a significant decrease in the retroperitoneal lymph nodes after therapy. The patient also had a more than 60% reduction in the immunoglobulin M paraprotein after two cycles of therapy.