Phase 1 study of lenalidomide plus dose‐adjusted EPOCH‐R in patients with aggressive B‐cell lymphomas with deregulated MYC and BCL2

Abstract

Background Dual translocation of MYC and BCL2 or the dual overexpression of these proteins in patients with aggressive B‐cell lymphomas (termed double‐hit lymphoma [DHL] and double‐expressor lymphoma [DEL], respectively) have poor outcomes after chemoimmunotherapy with the combination of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R‐CHOP). Retrospective reports have suggested improved outcomes with dose‐intensified regimens. In the current study, the authors conducted a phase 1 study to evaluate the feasibility, toxicity, and preliminary efficacy of adding lenalidomide to dose‐adjusted etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin with rituximab (DA‐EPOCH‐R) in patients with DHL and DEL. Methods The primary objective of the current study was to determine the maximum tolerated dose of lenalidomide in combination with DA‐EPOCH‐R. A standard 3+3 design was used with lenalidomide administered on days 1 to 14 of each 21‐day cycle (dose levels of 10 mg, 15 mg, and 20 mg). Patients attaining a complete response after 6 cycles of induction therapy proceeded to maintenance lenalidomide (10 mg daily for 14 days every 21 days) for 12 additional cycles. Results A total of 15 patients were enrolled, 10 of whom had DEL and 5 of whom had DHL. Two patients experienced dose‐limiting toxicities at a lenalidomide dose of 20 mg, consisting of grade 4 sepsis. The maximum tolerated dose of lenalidomide was determined to be 15 mg. The most common nonhematologic grade ≥3 adverse events included thromboembolism (4 patients; 27%) and hypokalemia (2 patients; 13%) (toxicities were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events [version 4.0]). The preliminary efficacy of the regimen was encouraging, especially in the DEL cohort, in which all 10 patients achieved durable and complete metabolic responses with a median follow‐up of 24 months. Conclusions The combination of lenalidomide with DA‐EPOCH‐R appears to be safe and feasible in patients with DHL and DEL. These encouraging results have prompted an ongoing phase 2 multicenter study.

Altered pathways and targeted therapy in double hit lymphoma

“…In clinical studies, lenalidomide exhibited promising efficacy in DLBCLs, especially in non-GCB subtype, with significantly prolonged PFS and OS, either as a single agent [ 293 ] or in combination with chemotherapies (R-CHOP and similar therapies) [ 293 , 294 ] or other regiments(rituximab or ibrutinib) [ 295 , 296 ], as well as being maintenance strategy [ 297 ]. For DHL, the response to lenalidomide plus DA-EPOCH-R is less satisfied compared to DELs in terms of disease remission, PFS, and CNS involvement [ 292 ]. The difference may be attributed to the small DHL patient group or the higher correlation between DEL and non-GCB lymphoma, which respond better to lenalidomide-based therapies [ 292 , 329 ].…”

“…For DHL, the response to lenalidomide plus DA-EPOCH-R is less satisfied compared to DELs in terms of disease remission, PFS, and CNS involvement [ 292 ]. The difference may be attributed to the small DHL patient group or the higher correlation between DEL and non-GCB lymphoma, which respond better to lenalidomide-based therapies [ 292 , 329 ]. Durable remission was observed in a DHL-BCL6 case when treated with lenalidomide following salvage chemotherapy [ 330 ].…”

DA-EPOCH-R improves the prognosis of patients with double-expressor lymphoma: A single-center retrospective study and meta-analysis

“…Innovative strategies are urgently needed to improve the outcomes of DEL patients. Several innovative targeted drugs, such as ABT-199 [ 39 , 40 ] (a BCL2 inhibitor that was associated with a high CR rate in patients with DEL after combination with the CHOP-based regimen in a phase I trial), lenalidomide (a targeted drug for drivers of MYC expression that was demonstrated to exhibit the safety and feasibility of lenalidomide when combined with the DA-EPOCH-R regimen in patients with DHL and DEL in a phase I study), [ 41 ] ibrutinib (a BTK inhibitor that was confirmed to improve the PFS and OS in DEL patients) [ 42 ] and several advanced immunotherapies, such as checkpoint inhibitors and cellular immunotherapies, [ 43 ] have provided a framework for future therapeutic strategies. The combination of new targeted drugs with the R-CHOP or DA-EPOCH-R regimen may show additional superiority over the conventional DA-EPOCH-R regimen in terms of survival in the future and may provide more treatment opportunities for patients with DEL.…”

Hypokalemia After Rituximab Administration in Steroid-Dependent Nephrotic Syndrome: A Case Report

“…Hypokalemia caused by rituximab administration has never been reported in the literature so far. Hypokalemia was reported as a rare adverse event of complex chemo-immunotherapy combinations for lymphoma treatment (Polprasert et al, 2011;Budde et al, 2013;Johnston et al, 2016;Godfrey et al, 2019;Shimada et al, 2020). However, none of these reports suggested a direct link between rituximab administration and hypokalemia.…”