Salvage Blinatumomab Therapy Generates Durable Responses in Relapsed/Refractory DLBCL

August 3, 2020

Blinatumomab as salvage therapy for patients with relapsed/refractory diffuse large B-cell lymphoma may induce durable complete responses and a survival benefit, according to a pooled analysis of 3 clinical trials.

Blinatumomab (Blincyto) as salvage therapy for patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) may induce durable complete responses (CRs) and a survival benefit, according to a pooled analysis of 3 clinical trials.

Patients with relapsed/refractory DLBCL are associated with a poor prognosis, in which 50% to 74% of patients fail to achieve a response to their next line of therapy. The median overall survival (OS) is expected to be 6 to 10 months. Among those who achieve disease remission with salvage therapies, 30% to 50% of patients will relapse within 1 year of treatment. This underscores the importance of developing salvage therapies that can induce more durable responses.

The 3 studies used for the pooled analysis were open-label, multicenter, single-arm clinical trials, including the phase 1 study of relapsed/refractory B-cell non-Hodgkin lymphoma (B-NHL; NCT00274742; n = 14), the phase 2 of relapsed/refractory DLBCL (NCT01741792; n = 25), and the phase 2 of relapsed/refractory B-NHL (NCT02910063; n = 34). According to the findings from the phase 1 of B-NHL and phase 2 trials of DLBCL and B-NHL, blinatumomab generated activity in patients with relapsed/refractory DLBCL, in which the CR rates were 26%, 16%, and 29%, respectively. The duration of CR, OS, and safety of the CD19/CD3 bispecific T-cell engager (BiTE) were evaluated.

The objective response rate (ORR) was an end point for both the phase 1 study of B-NHL and the phase 2 of DLBCL, while complete metabolic response (CMR) was the primary end point for the phase 2 B-NHL study. Overall, 17 of the 73 patients (23%) in the pooled analysis achieved a CMR or CR within 12 weeks of treatment with blinatumomab and were included in the assessment of duration of CR (DOCR).

Overall, 83% of patients in the phase 2 -B-NHL study and 100% of those in the phase 2 DLBCL study had DLBCL, while 68% in the phase 1 had DLBCL. A total of 11 patients (65%) had relapsed disease, 6 (35%) had primary refractory disease, 16 (94%) had at least 2 lines of prior therapy, and 4 (24%) had received prior hematopoietic stem cell transplantation (HSCT).

Sixteen of the 17 patients with relapsed/refractory DLBCL who achieved a CR/CMR had completed 1 cycle of blinatumomab and 11 had received at least 80% of their total intended dose for cycle 1. Sixteen patients (94%) had treatment interruptions, which was due to adverse events (AEs) in 5 patients (29%). Three patients who had completed cycle 1 of blinatumomab were able to complete cycle 2, and 2 patients achieved at least 80% of cycle 2’s intended dose. During cycle 2, treatment discontinuation was due to an AE in 2 patients (12%) and technical reasons in 1 patient.

The median DOCR had not been reached (95% CI, 6.0-not estimable [NE]) after a median follow-up of 15.6 months. Overall, 79.0% of patients remained in response at 6 months, 62.2% at 12 months, 62.2% at 18 months, and 62.2% at 21 months. Among 17 patients who had achieved a CR/CMR, 4 (23.5%) had relapsed while 1 (5.9%) had died during follow-up. Three patients of the 7 who were still in CR at 12 months received an autologous HSCT.

Thirteen patients had achieved a partial response (PR), and the median duration of a PR was 2.1 months (95% CI, 0.9-NE) after a median follow-up of 7.6 months. Additionally, 32.7% were estimated to remain in response at 6 months, 21.8% at 12 months, 21.8% at 18 months, and NE at 24 months. Six of the 13 patients (46.2%) relapsed, 2 (15.4%) had died, and 4 (30.8%) received an HSCT.

The median OS was not reached after a median follow-up of 16.4 months (95% CI, 13.1-NE) The OS probability was 100% at 6 months, 86.5% at 12 months, 77.9% at 18 months, and 77.9% at 24 months.

Three of the 17 patients who responded after treatment (17.6%) died during follow-up and 9 (52.9%) went on to receive HSCT.

All 17 patients had experienced any-grade treatment-emergent AEs (TEAEs), 14 (82.4%) of which experienced grade 3 or greater TEAEs and 8 (47.1%) of which had serious AEs. Three patients (17.6%) discontinued treatment due to TEAEs. The most common grade 3 TEAEs included neurologic events (5.3%), infections (35.3%), cytopenias (29.4%), and elevated liver enzymes (17.6%).

Treatment-related AEs (TRAEs) occurred in 16 patients (94.1%), and 11 patients (64.7%) had grade 3 or greater TRAEs, 1 (5.9%) of which experienced grade 4 or greater TRAEs. Four of the TRAEs were considered serious. Eleven patients (64.7%) developed TRAEs of grade 3 or greater in severity, and 2 patients (11.8%) discontinued treatment. However, no life-threatening or fatal AEs were observed.

Out of the 17 patients, 15 (88.2%) had neurologic AEs of any grade, which included tremor (52.9%), headache (47.1%), and paresthesia (23.5%). Neurologic AEs of grade 3 or greater in severity were observed in 6 patients (35.3%), which led to treatment interruptions in 4 patients (23.5%) and treatment discontinuation in 2 patients (11.8%). No grade 4 or fatal neurologic AEs were observed, but 1 patient experienced grade 3 cytokine release syndrome.

Despite the median DOCR and OS not being reached at the time of analysis, a total of 62.2% of patients were responding, and 86.5% were alive at 12 months of follow-up. Three patients in the phase 2 DLBCL trial also achieved late CRs that were not included in this analysis, and those patients also had longer DOCRs.

Reference:

Viardot A, Hess G, Bargou RC, et al. Durability of complete response after blinatumomab therapy for relapsed/refractory diffuse large B-cell lymphoma. Leukemia & Lymphoma. [Published Online July 7, 2020]. doi: 10.1080/10428194.2020.1783442