Phase 1–2 study of vorinostat (SAHA), cladribine and rituximab (SCR) in relapsed B‐cell non‐Hodgkin lymphoma and previously untreated mantle cell lymphoma

Abstract

Summary Altered DNA methylation and histone acetylation in lymphoma provided the rationale for using vorinostat (SAHA), cladribine and rituximab (SCR) in non‐Hodgkin lymphomas (NHL) in this phase 1–2 study (NCT00764517). Treatment included cladribine 5 mg/m2 intravenously (IV) (days 1–5), rituximab 375 mg/m2 IV (weekly 4× for cycle 1 and 1×/month) and vorinostat orally once daily (days 1–14) every 28 days for up to six cycles. Phase 1 included relapsed patients (n = 10) in a standard 3 + 3 dose escalation design (vorinostat: 200, 300 and 400 mg). No dose‐limiting toxicities were seen. The phase 2 dose for vorinostat was 400 mg po (days 1–14). The majority of phase 2 patients had mantle cell lymphoma (MCL) (n = 57; 39 previously untreated, 10 relapsed). The primary objective was objective response rate [complete response (CR) + partial response] which was 39% (7/18) in relapsed patients and 97% (38/39) with 80% (31/39) attaining a CR in previously untreated MCL. At a median follow‐up of 42 months, median progression‐free survival (PFS) and overall survival (OS) for relapsed NHL were 19·5 [95% confidence interval (CI): 2·0–33·0] and 25·0 (95% CI: 12·0–45·0) months respectively. Median PFS for previously untreated MCL was 84·0 months; OS could not be estimated. Toxicities were primarily haematological.

Management of Drug Resistance in Mantle Cell Lymphoma

“…This triple combination reached an ORR of 97%, including 80% CR, with a 2-year PFS of 70.7% and OS of 86.9%, in previously untreated MCL patients. However, the ORR dropped to 39% in R/R MCL patients [163]. Improved results were reported in another trial using cladribine-rituximab combination in association with BTZ in B-NHL patients, including 24 MCL cases: the ORR and CR for both new and relapsed/refractory MCL cases were 85% and 77%, respectively [164].…”

Epigenetic targeting in lymphoma

“…Although outcomes from singleagent HDIs in mantle cell lymphoma (MCL) have been disappointing, a Phase II study evaluating the combination of vorinostat with six cycles of cladribine and rituximab in untreated MCL has reported a striking median PFS of 84 months, with acceptable toxicity. 82 In R/R MCL, the combination of vorinostat, fludarabine and mitoxantrone and dexamethasone has been evaluated in a Phase II study; although the ORR was 77Á8% the regimen was not well tolerated with only 15% of patients completing the planned treatment course. 81 The EZH2 inhibitor, tazometostat, has shown promise in early phase studies, particularly for those 10-25% of patients with FL with activating EZH2 mutations.…”

Cladribine Induces ATF4 Mediated Apoptosis and Synergizes with SAHA in Diffuse Large B-Cell Lymphoma Cells

“…Cladribine and SAHA, in combination with gemcitabine and busulfan, also provided synergistic cytotoxicity in lymphoma cell lines [25]. Stephen E. Spurgeon showed a phase 1/2 study, which using SAHA, cladribine, and rituximab in relapsed B-cell non-Hodgkin lymphoma (NHL) and previously untreated MCL resulted in a high complete response rate [26]. In this study, we also tried to investigate whether combined SAHA and cladribine have a synergistic effect in DLBCL cells.…”