Ibrutinib Plus R-Mini-CHOP Misses OS End Point but Shows Improved PFS in Newly Diagnosed DLBCL

Ibrutinib (Imbruvica) plus rituximab (Rituxan) and mini-CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone [R-mini-CHOP]) failed to demonstrate a statistically significant improvement in overall survival (OS) at 2 years but led to an improvement in progression-free survival (PFS), quality of life (QOL), and function in elderly patients with diffuse large B-cell lymphoma (DLBCL), according to findings from the Australasian Leukaemia & Lymphoma Group NHL29 Study that were presented at the 2021 ASH Annual Meeting and Exposition.

“The 2-year overall survival [OS] in the [standard of care group] is 59%, and the 2-year progression-free survival was 47%. We also know that the addition of ibrutinib to full dose R-CHOP in younger patients has efficacy…however, significant toxicity limits the ability to complete therapy in patients 60 years and above,” Emma Verner, MBBS, Department of Haematology, Concord Repatriation General Hospital in Australia, said during a presentation of the findings.

“We therefore hypothesized that the addition of ibrutinib to mini-CHOP in elderly patients with diffuse large B-cell lymphoma would be both tolerable and efficacious, improving the 2-year overall survival.”

Following data cutoff of June 6, 2021, median follow-up in 79 patients aged 75 or older was 34.3 months (range, 0.2-66.3). In total, 80% completed 6 cycles of R-mini-CHOP and 71% completed 8 cycles.

The overall response rate was 76%, including 56 complete responses (70%), 5 partial responses (6%), a single patients with stable disease (1%), and 9 with progressive disease (11%). Seven patients (9%) were not evaluable and 2 (2.5%) were missing end of trial response assessments. Response rates did not differ by cell of origin (COO; non-Germinal Centre B [GCB], 82% vs GCB, 71%; P = .24).

Although there was a trend toward improved OS, a target of a 15% increase from 59% with the current standard of care was not seen. The 2-year OS with the combination was 68% (95% CI, 57%-78%; P = .11). Median OS was not reached (NR; 95% CI, 35-NR); however, this was longer in those with a lower International Prognostic Index (IPI) of 1 to 3 (not reached [NR]) compared with an IPI of 4 (35 months) or 5 (19 months).

Of note, the 2-year PFS with the addition of ibrutinib was 60% (95% CI, 49%-72%; P < .03), a significant different from 47% with the standard of care. Median PFS was 53 months (95% CI, 20-NR).

The COO had no impact on 2-year OS, with the median in GCB (95% CI, 29-NR) and the non-GCB (95% CI, 24-NR) groups not reached (P = .99). The same was seen with 2-year PFS, with a median in GCB of 30 months (95% CI, 17-NR) and not reached in non-GCB (95% CI, 19-NR) (P = .97).

Lastly, according to the primary analysis, 2-year disease-free survival (DFS) was 85% (95% CI, 60%-95%), with the median NR (95% CI, 32-NR).

Twenty-eight deaths occurred (35%): 16 due to progressive lymphoma, 5 from infection, 2 from respiratory failure, 2 from other malignancy, 1 from cardiac arrest, 1 from intra-abdominal hemorrhage, and 1 due to gastric hemorrhage.

Almost all patients (99%) experienced at least 1 adverse event (AE), with 24 (30%) reporting with grade 1 to 2, 49 (64%) with grade 3 to 4, and 5 (6%) with grade 5 AEs. The most common grade 3 or greater AEs were lung infection (13%), other infections (11%), anemia (11%), febrile neutropenia (9%), thrombocytopenia (9%), and atrial fibrillation (8%). Serious AEs occurred in 67%, the most common being lung infection (11%), atrial fibrillation (9%), fever (9%), and other infection (9%).

Investigators temporarily stopped treatment with ibrutinib in 62% of patients and permanently stopped treatment in 25%. Treatment discontinuation occurred due to toxicity (11%), progressive disease (6%), patient choice (4%), death (4%), or consent withdrawal (3%).

The study also found that EORTC-QLQ-C30 global health status among patients significantly improved between screening (n = 78; mean [standard deviation], 58 [25]), end of treatment (n = 57; 63 [23]), and 18-month post-treatment (n = 29; 74 [19]) (P = .007). Patients reported significant reductions in fatigue, nausea and vomiting, pain, insomnia, appetite loss, constipation, and diarrhea. However, the investigators noted that there was no impact of Cumulative Illness Rating Scale-Geriatric score on disease response rate or risk of death.

In the prospective, multicenter, single-arm, phase 2 study, investigators administered six 21-day cycles of ibrutinib at 560 mg plus R-mini-CHOP, comprised of 375mg/m2 rituximab, 400 mg/m2 cyclophosphamide, 25 mg/m2 doxorubicin, 1 mg vincristine on day 1, and prednisone at either 40mg/m2 or 100mg/day for 5 days. Treatment was followed by 2 additional 21-day cycles of rituximab plus ibrutinib.

To be eligible for the trial, patients had to be 75 years or older, have newly diagnosed de novo DLBCL, have an ECOG performance status of 2 or less, and have stage I to IV disease. Patients were excluded if they had central nervous system involvement, required coagulation with warfarin, required dual antiplatelet therapy with aspirin and a P2Y12 antagonist, or a malignancy within 3 years.

Two-year OS served as the primary end point. Secondary end points included response rates, PFS, DFS, and toxicity.

Median age was 81.5 years (range, 75-95). The majority of patients were female (51%), had stage III or IV (81%) disease, and had an IPI risk score of 3 to 5 (63%). On centralized immunohistochemistry (IHC), 57% were non-GCB cell-like subtype and 43% were GCB.

“To conclude, the addition of ibrutinib to mini-CHOP was deliverable, with a respectable 2-year overall survival [rate] of 68%. However, our ambitious target of the 15% increase was not reached in a small sample size,” Verner said. “We are encouraged by our significantly improved progression-free survival of 60%. And despite the considerable, but not unexpected, toxicity in this elderly cohort, the quality of life and functioning improvements in survivors are also promising. This data supports further study of adding Bruton tyrosine kinase inhibitors to mini-CHOP in elderly patients with diffuse large B-cell lymphoma.”

Reference

1. Verner E, Johnston A, Pati N, et al. Efficacy of Ibrutinib, Rituximab and Mini-CHOP in Very Elderly Patients with Newly Diagnosed Diffuse Large B Cell Lymphoma: Primary Analysis of the Australasian Leukaemia & Lymphoma Group NHL29 Study. Presented at: 2021 ASH Annual Meeting and Exposition; December 11-14, 2021; Atlanta, Georgia. Abstract 304. https://bit.ly/3DIfFuR