Early Rituximab Intensification Generates No Differences in Outcomes as Treatment of DLBCL

Early rituximab (Rituxan) intensification during treatment with rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone (R-CHOP) demonstrated no difference in outcomes as treatment of patients with diffuse large B-cell lymphoma (DLBCL) compared with the standard R-CHOP regimen, according to a randomized phase 3 clinical trial.

“In DLBCL, rapid tumor control is critical to improve outcome by avoiding development of refractory disease on or after R-CHOP, because patients with refractory disease have poor prognosis,” the study authors wrote. “In this study, 4 additional rituximab administrations were added during the first 3 weeks. Compared with a historical control population (RICOVER-60 population), no differences in outcome were observed for the whole population.”

A subgroup analysis demonstrated that patients with high-intermediate and high International Prognostic Index (IPI) scores had higher complete response (CR) rates after intensification of rituximab, but this did not generate improved survival outcomes.

There was no statistically significant difference between the 2 treatment arms for the primary end point of complete response (CR) rate on induction therapy. CRs were achieved by 254 (89%) patients in the R-CHOP-14 arm and 249 (86%) in the RR-CHOP-14 arm (HR, 0.82; 95% CI, 0.50-1.36; P =.44). The CR rates in the R-CHOP-14 and RR-CHOP-14 arms for patients younger than 66 years were 90% and 85% compared with 88% and 88% in those aged 66 or older, respectively.

After a median follow-up of 92 months (range, 1-131), 364 patients were alive, and the median failure-free survival (FFS) and progression-free survival (PFS) were not reached in the R-CHOP-14 arm compared with 101 months for both in the RR-CHOP-14 arm. The median disease-free survival and overall survival had also not been reached in either arm. The 3-year FFS rate was 74% in the R-CHOP-14 arm (95% CI, 68%-78%) versus 69% (95% CI, 63%-74%) in the RR-CHOP-14 arm (HR, 1.26; 95% CI, 0.98-1.61; P =.07). The 5-year FFS rate was 68% in the R-CHOP-14 arm (95% CI, 62%-73%) and 62% in the RR-CHOP-14 arm (95% CI, 56%-67%).

The 3-year PFS rate was 74% in the R-CHOP-14 arm (95% CI, 69%-79%) versus 71% (95% CI, 66%-76%) in the RR-CHOP-14 arm (HR, 1.20; 95% CI, 0.94-1.55; P =.15), and the 5-year PFS rate was 69% (95% CI, 63%-64%) versus 64% (95% CI, 58%-69%), respectively.

The 3-year DFS rate from date of CR among patients who achieved a CR on protocol treatment was 81% in the R-CHOP-14 arm (95% CI, 76%-85%) versus 76% (95% CI, 70%-81%) in the RR-CHOP-14 arm (HR, 1.24; 95% CI, 0.93-1.65; P=.15), and the 5-year DFS rates were 75% (95% CI, 69% to 80%) and 70% (95% CI, 64% to 75%), respectively.

At 3-years, the OS rate was 81% in the R-CHOP-14 arm (95% CI, 76%-85%) versus 76% (95% CI, 70%-80%) in the RR-CHOP-14 arm (HR, 1.27; 95% CI, 0.97-1.67; P =.09), while the 5-year OS rates were 77% (95% CI, 71% to 81%) and 69% (95% CI, 63% to 74%), respectively.

According to the planned subgroup analyses, the impact of treatment on FFS, DFS, and OS was not different between patients aged 65 and younger versus 66 and older, male versus female, or low versus low-intermediate versus high-intermediate versus high age-adjusted IPI scores. These findings were similar for subgroups of patients with different DLBCL phenotypes.

Overall, 210 patients died, which included 96 in the R-CHOP-14 arm and 114 in the RR-CHOP-14 arm. In the R-CHOP-14 arm, the cause of death was lymphoma-related in 41 patients, treatment-related in 9, intercurrent death in 8, secondary malignancy in 11, other reasons in 15, and unknown in 12. In the RR-CHOP-14 arm, the causes of death were lymphoma-related in 56 patients, treatment-related in 10, intercurrent death in 10, secondary malignancy in 11, other reasons in 11, and unknown in 16.

The proportion of patients with at least 1 adverse event (AE) did not differ between the 2 treatment arms. The most common grade 3/4 AEs included cytopenia and infections. Patients between the ages of 66- and 80-years experienced toxicity more significantly in the RR-CHOP-14 arm, particularly neutropenia and infections.

In the R-CHOP-14 and RR-CHOP-14 arms, grade 3 AEs occurred in 70 patients (25%) and 70 patients (24%), respectively, including neutropenia (8% v. 10%), anemia (15% v. 17%), thrombocytopenia (5% v. 7%), infection (20% v. 22%), neurologic toxicity (13% v. 13%), gastrointestinal (13% v. 11%), and cardiac toxicity (4% v. 4%). Grade 4 AEs in the R-CHOP-14 and RR-CHOP-14 arms included neutropenia (32% v. 37%), febrile neutropenia (1% v. 0%), anemia (4% v. 2%), thrombocytopenia (7% v. 6%), infection (5% v. 2%), neurologic toxicity (1% v. 1%), gastrointestinal (1% v. 2%), and cardiac toxicity (none v. 1%), respectively.

A total of 17 grade 5 AEs were reported during induction, which included 9 in the R-CHOP-14 arm and 8 in the RR-CHOP-14 arm. The main cause of death in both arms was infection, which occurred in 4 patients from each arm. Other causes in the R-CHOP-14 arm included small-bowel perforation in 2, sudden death in 2, and progressive multifocal leukoencephalopathy in 1. In the RR-CHOP-14 arm, the other causes of death included myocardial infarction in 1, gastrointestinal bleeding in 1, small-bowel perforation in 1, and cardiac arrhythmia in 1.

A total of 600 patients were enrolled to the study between November 14, 2017 and April 6, 2012, and 574 patients were eligible, in which 286 were allocated to the R-CHOP-14 arm and 288 to the RR-CHOP-14 arm. Overall, 269 patients in the R-CHOP-14 arm received at least 6 cycles of treatment and 261 in the RR-CHOP-14 arm, while 151 patients (53%) received 7 or 8 cycles of treatment in the R-CHOP-14 arm and 158 (55%) in RR-CHOP-14 arm.

_Reference

_{Lugtenburg PJ, de Nully Brown P, van der Holt B, et al. Rituximab-CHOP with early rituximab intensification for diffuse large B-cell lymphoma: a randomized phase III trial of the HOVON and the nordic lymphoma group (HOVON-84). J Clin Oncol. doi: 10.1200/JCO.19.03418}