Rapid Step-up Dosing Schedule of Glofitamab Is Feasible for Relapsed/Refractory Diffuse Large B Cell Lymphoma Patients
Authors: Yang Jing , Wang Liang 
Published: December 2024

Background:
Glofitamab, a bispecific CD20-directed CD3 T-cell engager, was approved to treat relapsed or refractory diffuse large B-cell lymphoma, not otherwise specified (DLBCL, NOS) or large B-cell lymphoma (LBCL) arising from follicular lymphoma, after two or more lines of systemic therapy. Following a single 1,000 mg dose of obinutuzumab on Cycle 1 Day 1 to deplete circulating and lymphoid tissue B cells, glofitamab is administered by intravenous infusion according to a step-up dosing schedule (2.5 mg on Day 8 of Cycle 1 and 10 mg on Day 15 of Cycle 1), then 30 mg on Day 1 of each subsequent cycle for a maximum of 12 cycles. This step-up dosing schedule was meant to reduce cytokine release syndrome (CRS) and tumor flare, which was reported to occur in 70% and 12% of patients, respectively. However, patients with rapid progressing or highly-aggressive disease might not be capable of waiting for the standard yet slow step-up dosing schedule, thus, a relatively rapid step-up dosing schedule is worth investigation concerning the safety profiles.
Methods:
Patients of DLBCL who failed prior two or more lines of therapy were given glofitamab alone or combined with other targeted agents using a rapid step-up dosing schedule as following: a single 1,000 mg dose of obinutuzumab on Cycle 1 Day 0, then 2.5 mg of glofitamab on Day 3 of Cycle 1, 10 mg on Day 8 of Cycle 1, and 30 mg on Day 15 of Cycle 1). Treatment responses were evaluated on Day 28 of Cycle1. For patients responding to glofitamab, 30 mg of glofitamab was given on Day 1 of each subsequent cycle for a maximum of 10 cycles (21 days each cycle).
Results:
Six consecutive patients treated with at least one cycle of glofitamab using this rapid step-up dosing schedule were included in this analysis for safety profiles. The median age was 60 years old (47-70), and all had stage IV disease. The median number of prior lines of therapy was 3 (2-9), with four patients failing previous CAR-T cell therapy. All patients had progressing disease at the time of glofitamab treatment, and three of them had bulky disease. Five patients received glofitamab monotherapy, and one patient were treated with glofitamab and polatuzumab vedotin. All six patients completed the rapid step-up dosing schedule, and were evaluable for both safety and efficacy. Among these six patients, CRS occurred in two patients during Cycle 1 (one with grade 1 CRS, and one with grade 2 CRS), both recovered after supportive care and dexamethasone administration. One patient with baseline ICE (Immune Effector Cell Encephalopathy) score of 5 and secondary central nervous system lymphoma developed grade 4 Immune effector cell-associated neurotoxicity syndrome (ICANS) during Cycle 1 and gave up subsequent treatments due to rapid disease progression. One patient suffered from grade 2 skin rash, which relieved after use of dexamethasone. One patient complained the whole-body bone pain, and lab test revealed grade two hypercalcemia, which was correlated with rapid disease progression, confirmed by CT scan, and this adverse event was recovered after use of denosumab. At Day 28 of Cycle 1, efficacy was evaluated using PET-CT or CT scan, and three patients responded to glofitamab (two with partial remission, and one with complete remission), and the other three patients got disease progression.
Conclusions:
Glofitamab given with a rapid step-up dosing schedule was tolerable in patients with relapsed/refractory DLBCL, and should be used with caution in patients with CNS lymphoma. The efficacy and safety profiles of this rapid step-up schedule needs to be verified in prospective clinical trials.