Long‐term results of the phase II trial of the oral mTOR inhibitor everolimus (RAD001) in relapsed or refractory Waldenstrom Macroglobulinemia

Abstract

Everolimus is an oral raptor mTOR inhibitor and has shown activity in patients with Waldenstrom's macroglobulinemia (WM). This study examines a large cohort of patients with relapsed/refractory WM with long-term follow up for survival. Patients were eligible if they had measurable disease, a platelet count >75,000 3 10 6 /L, an absolute neutrophil count >1,000 3 10 6 /L. Patients received everolimus 10 mg PO daily and were evaluated monthly. A success was defined as a complete or partial response (PR); minor responses (MR) were recorded and considered to be of clinical benefit. Sixty patients were enrolled and treated. The overall response rate (ORR) was 50% (all PR); the clinical benefit rate including MR or better was 73% (95% CI: 60-84%) with 23% MR. The median time to response for patients who achieved PR was 2 months (range, 1-26). The median duration of response has not been reached and median progression-free survival (PFS) was 21 months. Grade 3 or higher toxicities (at least possibly related to everolimus) were observed in 67% of patients. The most common grade 3 or 4 toxicities were anemia (27%), leukopenia (22%), and thrombocytopenia (20%). Other nonhematological toxicities were diarrhea (5%), fatigue (8%), stomatitis (8%) and pulmonary toxicity (5%). Everolimus has a high single-agent activity of 73% including MR, with a progression free survival of 21 months, indicating that this agent is active in relapsed/refractory WM.

The mTORC1 inhibitor everolimus has antitumor activity in vitro and produces tumor responses in patients with relapsed T-cell lymphoma

“…The study allowed the accrual of uncommon lymphomas on an exploratory basis. The results of the trial for other major lymphoma subtypes (diffuse large B-cell lymphoma [DLBCL], mantle cell lymphoma [MCL], and Waldenström macroglobulinemia) have been reported [13][14][15][16][17] ; however, the results for the TCL patients have never been reported. This study was conducted through the Mayo Clinic Cancer Center and was approved by the Mayo Clinic Institutional Review Board.…”

“…This ORR is similar to the experience with everolimus in relapsed HL 15 ; higher than what we observed in relapsed DLBCL and MCL 16 and lower than that found for relapsed Waldenström macroglobulinemia. 13,14 Everolimus in this study and others 31,32 has a reasonable toxicity profile as a single agent at Figure 6. Change in plasma cytokine levels in 8 patients after 2 cycles of everolimus therapy.…”

“…We have reported that the PI3K/mTOR pathway is activated in NHL cells 12 and that mTORC1 inhibitors have activity in relapsed B-cell NHL. [13][14][15][16][17][18][19][20][21] TCLs account for approximately 10% of all NHL in the United States. 22 Just as in B-cell NHL, there are a number of clinicopathological types that vary in presentation and outcome.…”

Treatment recommendations for patients with Waldenström macroglobulinemia (WM) and related disorders: IWWM-7 consensus

“…Responses were rapid, occurring at a median of 2 months, and the median PFS was 21 months. 33 Grade $ 3 toxicities occurred in 67% of patients. Among previously untreated patients (N 5 33), everolimus induced at least PR in 61% (plus 12% MRs), 20 although discordance between serum IgM levels and bone marrow disease burden was commonly observed.…”

Post‐remission intensive treatment after induction chemotherapy is feasible in selected elderly patients with acute myeloid leukemia and age ≥75 years: A retrospective analysis of the Rete Ematologica Lombarda

“…New therapeutic options such as ibrutinib or everolimus maybe used more frequently in patients with WM in the near future. However, these agents do not always induce a significant bone marrow response in comparison to the IgM response observed in the serum [7,8]. However, the significant bone marrow response in many patients with CyBorD can make it an attractive option for achieving complete remissions in patients who do not achieve adequate bone marrow responses with other agents.…”