A phase II study of the survivin suppressant YM155 in patients with refractory diffuse large B‐cell lymphoma

Abstract

BACKGROUND: Few effective therapeutic options exist for patients with refractory diffuse large B-cell lymphoma (DLBCL). YM155 is a survivin suppressant with activity against DLBCL in a phase I trial. This phase II study was conducted to better characterize the toxicity and efficacy of this small molecule in patients with refractory DLBCL. METHODS: Forty-one patients with a median age of 66 years and 3 prior regimens were enrolled and treated with a YM155 dose of 5 mg/m 2 /d by continuous infusion for 168 hours every 21 days for up to 15 cycles of treatment. The median number of completed cycles was 3. RESULTS: One patient had a complete remission (CR) (2.4%) with an additional 2 patients (5.9%) responding, with a median progression-free survival of 58 days. CONCLUSIONS: YM155 was well tolerated with major toxicities including anemia and fatigue. Whereas YM155 had limited single-agent activity, preclinical data suggest its role in combination with other agents, including rituximab, and a study of that combination in ongoing. Cancer 2012;118:3128-

Prognostic and biological significance of survivin expression in patients with diffuse large B-cell lymphoma treated with rituximab-CHOP therapy

“…Although the drug's safety and tolerability have been confirmed, single-agent YM155, as monotherapy regimen, demonstrated only limited activity in patients with refractory diffuse large B-cell lymphoma in a phase II clinical study. 69 In contrast, preclinical studies have demonstrated that YM155 plus rituximab, bendamustine, or a STAT3 inhibitor has obvious inhibitory effects on diffuse large B-cell lymphoma. 70,71 Taking into account the negative prognostic impact of survivin expression in activated B cell-like diffuse large B-cell lymphoma patients, assessment of clinical benefits should include stratification into different subgroups when evaluating survivin suppressants, especially when it combines with rituximab.…”

Combination of YM155, a Survivin Suppressant, with Bendamustine and Rituximab: A New Combination Therapy to Treat Relapsed/Refractory Diffuse Large B-cell Lymphoma

“…Despite its clinical benefits, the high-dose bendamustine treatment was often limited because of the development of hematologic toxicity, primarily lymphopenia, neutropenia, leukopenia, and thrombocytopenia (12). YM155 monotherapy demonstrated modest anticancer activity with no serious hematologic events in patients with refractory DLBCL (26). These data suggest that the combination of YM155 with bendamsutine and rituximab may be beneficial.…”

“…In a phase I study, three of five patients with NHL, including one with DLBCL refractory to R-CHOP, showed an objective response to single-agent YM155 (25). A phase II trial confirmed the safety and tolerability of YM155 in patients with refractory DLBCL (26). In another phase II trial, the combination of YM155 with rituximab also showed clinical activity [interim data: overall response rate 9/16 (56.3%), with 2/16 (12.5%) CR, 7/16 (43.8%) PR, and 4/16 (25%) stable disease; ref.…”

Survivin is highly expressed in CD34+38− leukemic stem/progenitor cells and predicts poor clinical outcomes in AML

“…YM155, 45 developed as a smallmolecule suppressor of survivin, has entered phase 2 clinical trials in various cancers and showed limited single-agent activity; combination trials are ongoing. [46][47][48][49] However, the effect of YM155 and its combination with chemotherapies on AML cells and AML stem/progenitor cells has not been investigated. Interestingly, survivin levels were shown to correlate with various catenins.…”