NEW ORLEANS—A study designed to determine the optimal duration of rituximab maintenance in patients with follicular lymphoma has found median progression-free survival (PFS) doubles when treatment is continued to a maximum of 5 years, according to results presented at the 55th American Society of Hematology Annual Meeting and Exposition.
This advance comes without “increased undue toxicity,” said Christian J. Taverna, MD, of Kantonsspital, Munsterlingen, Switzerland.
In the randomized phase 3 SAKK 35/03 trial, 270 patients with untreated, relapsed, stable, or chemotherapy-resistant follicular lymphoma (all grades) received four weekly doses of rituximab 375 mg/m². Median age was 57 years (range, 25- 82 years).
From October 2004 to November 2007, 165 patients who had a complete or partial response to this induction regimen were randomly assigned to receive rituximab 375 mg/m² short-term maintenance, either four administrations every 2 months (arm A; n = 82), or long-term maintenance every 2 months for a maximum of 5 years or until disease progression or unacceptable toxicity (arm B; n = 83). A total of 124 patients were chemotherapy-naïve.
Primary end point was event-free survival (EFS) from randomization. Events included disease progression or relapse, unacceptable toxicity, death from any cause, initiation of non-protocol or concomitant steroids or radiotherapy, or secondary malignancy.
Results showed median EFS to be 3.4 years (95% CI: 2.1-5.3 years) in arm A, and 5.3 years (95% CI: 3.5 years-NA) in arm B. However, “using the prespecified log-rank test, this difference is statistically not significant (P = 0.14),” Dr. Taverna said. “We observed an unexplained difference in disease progression and relapse during the first 8 months after randomization (3 in arm A vs. 10 in arm B) when treatment in both arms was the same, which led to an early crossing of the EFS curves at 18 months.”
In arm A, three events occurred in the first 8 months, all disease progression or relapse. In arm B, 14 events occurred: one patient died, 10 had disease progression or relapse, two had secondary malignancy, and one, unacceptable toxicity.
When only patients at risk after 8 months from randomization were evaluated, median EFS in arm B was significantly prolonged: 7.1 years (95% CI: 4.4 years–NA) compared with 2.9 years (95% CI: 1.8-4.8 years) in arm A (log-rank test P = 0.004).
Median PFS was also significantly longer in arm B, at 7.4 years (95% CI: 5.1 years-not achieved) compared with 3.5 years (95% CI: 2.1-5.9 years; hazard ratio, 0.63; 95% CI: 0.41-0.99; log-rank test P = 0.04). No significant difference in overall survival or best response was observed.
Maintenance treatment was stopped due to unacceptable toxicity in three patients in arm B, but none of the patients in arm A. “Six subsequent cancers developed in arm A and eight in arm B. One infection grade 3 [or higher] was reported in arm A, whereas seven infections grade 3 or higher occurred in five patients in arm B,” Dr. Taverna said.
Response following restaging of 164 patients (62.8%) in both arms was 35 complete responses (CR; 13.4%), nine CR unconfirmed (3.4%), and 120 partial responses.
In arm A, the short-term maintenance group, 41 patients (50%) experienced at least one adverse event (AE). Only one patient had infection grade 3 or higher and six had secondary malignancy. In arm B, the long-term maintenance group, 63 patients (76%) had at least one AE; 12 with grade 3 and two with grade 4, with five patients having infection grade 3 or higher. Secondary malignancy occurred in eight patients.