Temsirolimus Plus R-CHOP Most Feasible of Chemotherapy Combinations in R/R Mantle Cell Lymphoma

August 12, 2020

Combining temsirolimus with a chemotherapy regimen as treatment of patients with relapsed or refractory mantle cell lymphoma is feasible, according to the phase 1b T3 clinical trial.

Combining temsirolimus (Torisel) with a chemotherapy regimen as treatment of patients with relapsed or refractory mantle cell lymphoma (MCL) is feasible, according to the phase 1b T3 clinical trial. The combination led to responses in all patients, but heavy hematologic toxicity prevented the study investigators from determining the maximum tolerated dose (MTD) of temsirolimus in 2 of the 3 study arms.

The goal of the study was to improve upon the limited efficacy observed with temsirolimus monotherapy by adding it to an active chemotherapy regimen.

T3 (NCT01389427) is a multicenter, dose-escalation study that evaluated temsirolimus in combination with 3 different chemotherapy regimens: R-CHOP (rituximab [Rituxan], cyclophosphamide, doxorubicin, vincristine, prednisone), R-DHA (rituximab, cisplatin, dexamethasone, high-dose cytarabine), and R-FC (rituximab, fludarabine, and cyclophosphamide). The primary end point was the incidence of dose-limiting toxicities, and the secondary end points included complete response (CR) rate, progression-free survival (PFS), duration of response (DOR), overall survival (OS), and the safety of temsirolimus.

In terms of dosing, intravenous temsirolimus could be administered at 15 mg, 25 mg, or 50 mg. However, only patients in the R-DHA arm received the 50-mg dose of temsirolimus. When added to R-CHOP, treatment was administered every 3 weeks for 6 cycles. With temsirolimus plus R-FC, treatment was administered every 4 weeks for 6 cycles, and for temsirolimus combined with R-DHA, patients also received treatment every 4 weeks for 6 cycles. Based on the study’s 3 + 3 design, all patients were enrolled for a minimum of 4 cycles, after which response was assessed by investigators. Patients also had 2 additional cycles of treatment following initial chemotherapy.

Forty-one patients were enrolled and treated in T3; 11 were placed into the temsirolimus plus R-CHOP arms, 15 were enrolled in the temsirolimus plus R-FC arm, and 17 were enrolled in the temsirolimus plus R-DHA arm. Following screening and treatment, 10 patients who received the R-CHOP regimen were evaluated for DLT and were evaluable for efficacy, as were 14 and 11 patients, respectively, in the R-FC arm. In addition, 17 patients from the R-DHA arm were evaluable for DLT, and 11 were evaluable for efficacy.

The objective response rate (ORR) observed with temsirolimus plus R-CHOP was 40%, which included CRs in 2 patients. The temsirolimus plus R-FC arm achieved an ORR of 43%, with CRs observed in 3 patients. The temsirolimus/R-DHA arm had the best response with an ORR of 47% and CRs observed in 6 patients.

Median follow-up in T3 was 30.5 months (range, 2-44) for all treatment arms. In the temsirolimus plus R-CHOP arm, the median PFS was 15.1 months, and the median OS was not reached. Among patients who received temsirolimus plus R-FC, the median PFS was 8.6 months and the median OS was 10.1 months. Finally, in the temsirolimus plus R-DHA arm, the median PFS was 13.9 months and the median OS was 24.2 months.

At the time of the final analysis, 20 patients were reported as alive. The median DOR observed in patients who achieved at least a partial response to therapy was 7.9 months in the R-CHOP combination, 13.5 months with the R-FC combination, and 16 months with temsirolimus/R-DHA. Notably, a total of 12 patients progressed on treatment, 1 while receiving temsirolimus plus R-CHOP, 6 while taking temsirolimus plus R-FC, and 5 in the temsirolimus plus R-DHA arm.

Overall, 58% of patients experienced DLTs in the study, and all patients experienced an adverse event (AE) of grade 3 or higher. In 5 patients, DLTs led to treatment discontinuation.

In the temsirolimus plus R-CHOP arm, grade 3 toxicities were seen in all patients who received the 25-mg dose of temsirolimus. These included 1 case each of gastrointestinal bleeding, febrile neutropenia, and dyspnea. Four patients also experienced grade 3 lymphopenia. Due to localized grade 3 neutropenia, patients receiving the 25-mg dose of temsirolimus plus R-CHOP had their treatment dose reduced to 15 mg, which was determined to be the MTD of temsirolimus when added to R-CHOP.

In the other 2 arms, the number of toxicities were high at both dose levels of temsirolimus and the MTD was not found in either arm. The largest number of toxicities were seen among patients who received 25 mg of temsirolimus plus R-FC as well as those who received the 50-mg dose of temsirolimus plus R-DHA, which led to the investigators lowering the dose in this arm.

The most common AEs were hematologic toxicities (thrombocytopenia, neutropenia, and febrile neutropenia), metabolism issues, biologic investigations, and infections. Serious AEs occurred in 68% of patients and the most frequently reported serious SAEs were infections and hematologic toxicities. Twenty-nine percent of AEs led to treatment discontinuation in the study.

Investigators led by Benoît Tessoulin, MD, PhD, concluded from these data that it is not easy to combine temsirolimus with a chemotherapy regimen because of the severe toxicity. The most feasible combination, according to the T3 study results, may be temsirolimus plus R-CHOP. Although Tessoulin et al did not demonstrate the MTD of temsirolimus in the study, they noted that response rates were positive and warrant further study of temsirolimus with a chemotherapy regimen.

Reference:

Tessoulin B, Bouabdallah K, Burroni B, et al. Safety and efficacy of temsirolimus in combination with three different immuno-chemotherapy regimens in relapse and refractory mantle cell lymphoma, final results of the T3 phase IB trial of the LYSA. Ann Hematol. 2020;99:1771-1778. doi:10.1007/s00277-020-04159-3