The mTOR Inhibitor Temsirolimus Added to Rituximab Combined With Dexamethasone, Cytarabine, and Cisplatinum (R-DHAP) for the Treatment of Patients With Relapsed or Refractory DLBCL – Results From the Phase-II STORM Trial

Abstract

There is a high need for novel treatment options in relapsed and refractory diffuse large B-cell lymphoma. Single agent mammalian target of rapamycin (mTOR) inhibitor treatment has shown promising efficacy in this entity. Here, we report on the results of the mTOR-inhibitor temsirolimus combined to standard rituximab-DHAP salvage regimen in a prospective, multicenter, phase II, open-label study. The STORM regimen consisted of rituximab 375 mg/m 2 (day 2) and DHAP (dexamethasone 40 mg day 3-6, cisplatinum 100 mg/m 2 day 3, cytarabine 2 × 2 g/m 2 day 4) with temsirolimus added on day 1 and 8 of a 21-day cycle, with 2 to 4 cycles planned. In part I, dose levels of 25, 50, 75, and 100 mg for temsirolimus were predefined. Based on the observed toxicity profile, a temsirolimus dose of 25 mg was defined as recommended dose for the part II extension cohort of the trial. The intention-to-treat cohort comprised 53 patients. Median age was 63 years and median number of prior regimen was 1. All but 1 patient had prior rituximab exposure. Temsirolimus dose was 50 mg on day 1 and 8 in 6 patients from the part I of the trial and 25 mg in the remaining 47 patients. In general, treatment was well tolerated with leucopenia and thrombocytopenia as most frequent severe adverse events. The overall response rate after the last cycle of temsirolimus R-DHAP was 66% with 24% complete responses. The ability to mobilize stem cells was not impaired by the treatment regimen. Twenty-eight patients received consolidation treatment with high-dose therapy (HDT) and stem cell transplantation. Median duration of response was not reached. The total 2-year progression-free survival (PFS) and overall survival (OS) were 53% and 59%. Patients who were consolidated with HDT achieved a 2-year PFS and a 2-year OS of 77.8% and 82.1%, respectively. We conclude that temsirolimus can be safely added to rituximab and DHAP with promising activity.

Advancements in cancer immunotherapies targeting CD20: from pioneering monoclonal antibodies to chimeric antigen receptor-modified T cells

“…A phase 3 study AUGUMENT confirmed the benefit of the addition of the immunomodulatory drug lenalidomide to the rituximab in r/r FL and MZL ( 45 ). Strategies involving the addition of mTOR inhibitors to rituximab combined with classic chemotherapeutics are also under investigation for the treatment of patients with r/r DLBCL, with promising results from phase 1 and 2 trials ( 46 , 47 ).…”

“…Several clinical trials have investigated the efficacy of other combination therapies involving CD20-targeting in patients with B-NHLs. Among these trials, the combination of R-DHAP regimen with temsirolimus, an mTOR inhibitor, has shown encouraging results, demonstrating improved outcomes in patients with r/r DLBCL ( 47 ). Temsirolimus has also demonstrated effectiveness in combination with rituximab alone in patients with r/r MCL in phase 2 clinical trial ( 177 ).…”

The progress of novel strategies on immune-based therapy in relapsed or refractory diffuse large B-cell lymphoma

“…However, vistusertib did not confer an advantage over mTORC1 inhibitors. The STORM study evaluated the safety and activity of temsirolimus plus R-DHAP as salvage therapy for patients with R/R DLBCL [ 166 ]. This treatment was well tolerated, and the most common AEs were leukopenia (75%), thrombocytopenia (83%), anemia (57%), and hypokalemia (25%) [ 166 ].…”

“…The STORM study evaluated the safety and activity of temsirolimus plus R-DHAP as salvage therapy for patients with R/R DLBCL [ 166 ]. This treatment was well tolerated, and the most common AEs were leukopenia (75%), thrombocytopenia (83%), anemia (57%), and hypokalemia (25%) [ 166 ]. At the end of the last follow-up, The ORR after the last cycle was 72% (36/50) with 42% (12/50) of CR.…”

“…The median DOR was not reached, and the 2-year PFS and OS were 53% and 59%. Patients who received auto-SCT achieved an ORR of 91% and a CR rate of 65% [ 166 ]. Everolimus combined with R-CHOP induced a high CR rate (96%, 23/24) in a phase-II trial of untreated DLBCL patients [ 167 ].…”