Meghan Rourke

Phase II Trial of the Oral Mammalian Target of Rapamycin Inhibitor Everolimus in Relapsed or Refractory Waldenström Macroglobulinemia

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 trials 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.

Phase II Trial of Weekly Bortezomib in Combination With Rituximab in Relapsed or Relapsed and Refractory Waldenström Macroglobulinemia

PURPOSE This study aimed to determine activity and safety of weekly bortezomib and rituximab in patients with relapsed/refractory Waldenström macroglobulinemia (WM). PATIENTS AND METHODS Patients who had at least one previous therapy were eligible. All patients received bortezomib intravenously weekly at 1.6 mg/m(2) on days 1, 8, and 15, every 28 days for six cycles and rituximab 375 mg/m(2) weekly on cycles 1 and 4. The primary end point was the percentage of patients with at least a minor response. RESULTS Thirty-seven patients were treated. The majority of patients (78%) completed treatment per protocol. At least minimal response (MR) or better was observed in 81% (95% CI, 65% to 92%), with two patients (5%) in complete remission (CR)/near CR, 17 patients (46%) in partial response, and 11 patients (30%) in MR. The median time to progression was 16.4 months (95% CI, 11.4 to 21.1 months). Death occurred in one patient due to viral pneumonia. The most common grade 3 and 4 therapy-related adverse events included reversible neutropenia in 16%, anemia in 11%, and thrombocytopenia in 14%. Grade 3 peripheral neuropathy occurred in only two patients (5%). The median progression-free (PFS) is 15.6 months (95% CI, 11 to 21 months), with estimated 12-month and 18-month PFS of 57% (95% CI, 39% to 75%) and 45% (95% CI, 27% to 63%), respectively. The median overall survival has not been reached. CONCLUSION The combination of weekly bortezomib and rituximab showed significant activity and minimal neurologic toxicity in patients with relapsed WM.

Clinical and Translational Studies of a Phase II Trial of the Novel Oral Akt Inhibitor Perifosine in Relapsed or Relapsed/Refractory Waldenstrom's Macroglobulinemia

Background: Waldenströms macroglobulinemia (WM) is a rare, low-grade lymphoproliferative disorder. Based on preclinical studies, we conducted a phase II clinical trial testing the efficacy and safety of the Akt inhibitor perifosine in patients with relapsed/refractory WM. Patients and Methods: Thirty-seven patients were treated with oral perifosine (150 mg daily) for six cycles. Stable or responding patients were allowed to continue therapy until progression. Results: The median age was 65 years (range, 44-82). The median number of prior therapy lines was two (range, one to five). Of the 37 patients, 4 achieved partial response (11%), 9 minimal response (24%), and 20 showed stable disease (54%). The median progression-free survival was 12.6 months. Additionally, β2 microglobulin of >3.5 mg/dL was associated with poor event-free survival (P = 0.002). Perifosine was generally well tolerated; adverse events related to therapy were cytopenias (grade 3-4, 13%), gastrointestinal symptoms (grade 1-2, 81%), and arthritis flare (all grades, 11%). Translational studies using gene expression profiling and immunohistochemistry showed that perifosine inhibited pGSK activity downstream of Akt, and inhibited nuclear factor κB activity. Conclusion: Perifosine resulted in at least a minimal response in 35% of patients and a median progression-free survival of 12.6 months in patients with relapsed or relapsed/refractory WM, as well as in vivo inhibition of pGSK activity. The results of this study warrant further evaluation of perifosine in combination with rituximab or other active agents in patients with WM. Clin Cancer Res; 16(3); 1033–41

Phase II trial of weekly bortezomib in combination with rituximab in untreated patients with Waldenström Macroglobulinemia

This study aimed to determine the activity and safety of weekly bortezomib and rituximab in patients with untreated Waldenström Macroglobulinemia (WM). Patients with no prior therapy and symptomatic disease were eligible. Patients received bortezomib IV weekly at 1.6 mg/m2 on days 1, 8, 15, q 28 days × 6 cycles, and rituximab 375 mg/m2 weekly on cycles 1 and 4. Primary endpoint was the percent of patients with at least a minor response (MR). Twenty‐six patients were treated. At least MR was observed in 23/26 patients (88%) (95% CI: 70–98%) with 1 complete response (4%), 1 near‐complete response (4%), 15 partial remission (58%), and 6 MR (23%). Using IgM response evaluated by nephlometry, all 26 patients (100%) achieved at least MR or better. The median time to progression has not been reached, with an estimated 1‐year event free rate of 79% (95% CI: 53, 91%). Common grade 3 and 4 therapy related adverse events included reversible neutropenia in 12%, anemia in 8%, and thrombocytopenia in 8%. No grade 3 or 4 neuropathy occurred. The combination of weekly bortezomib and rituximab exhibited significant activity and minimal neurological toxicity in patients with untreated WM. Am. J. Hematol., 2010.

Review of clinical trials conducted in Waldenstrom macroglobulinemia and recommendations for reporting clinical trial responses in these patients

Many novel therapeutic agents are being tested in clinical trials for Waldenstrom macroglobulinemia (WM). However, given the paucity of large clinical trials in WM, the establishment of a standard treatment regimen that can be used for comparison of response has become challenging. We therefore performed a review of published clinical trials in WM. Systematic searches of the PubMed and Medline databases, including The Cochrane Library, were performed for the search terms: clinical trials, Waldenstrom, macroglobulinemia, and lymphoplasmacytic lymphoma. Studies of transplant in WM are beyond the scope of this review and were excluded. A total of 44 clinical trials were found in this search (38 full articles, six abstracts). Of these, 11 were performed in patients with untreated WM, 14 in patients with relapsed or refractory WM, 17 in both upfront and relapsed or refractory WM, and two studies did not provide this information. Based on this review, we recommend new response criteria and definitions of time to event analysis to be used in future clinical trials of WM. This review of the published literature would serve as a reference for comparison of response and survival analysis in current clinical trials.