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Maintenance rituximab prolongs PFS in patients with CLL
Rituximab maintenance therapy prolonged PFS and appeared safe for patients who responded to rituximab plus chemotherapy induction therapy, according to the final, event-triggered analysis of a phase 3 trial.
This benefit persisted among patients with minimum residual disease (MRD) positivity in blood or bone marrow.
“Our findings suggest a role for rituximab (Rituxan; Genentech, Biogen) maintenance therapy in first-line and second-line treatment of chronic lymphocytic leukemia over a broad range of disease characteristics, with different chemotherapy induction regimens and particularly in patients [who are] still not MRD negative,” Richard Greil, MD, of the third medical department at Paracelsus Medical University Salzburg in Salzburg, Austria, and colleagues wrote. “Under a worldwide view of the CLL population and the affordability of the drug, rituximab might allow large numbers of adequately selected patients to access the beneficial effects of a maintenance approach.”
Greil and colleagues investigated how rituximab maintenance therapy impacted outcomes among 263 patients aged 18 years or older who had achieved complete response or complete response with incomplete bone marrow recovery (56%), or partial response to first-line or second-line rituximab-containing chemotherapy.
After induction, 56% of evaluable patients were negative for MRD in peripheral blood and 32% were negative for MRD in bone marrow.
Researchers randomly assigned patients to 375 mg/m2 IV rituximab every 3 months (n = 134; median age, 63 years; range, 35-83) or observation (n = 129; median age, 63 years; range, 58-71) for 2 years.
Researchers stratified for chemotherapy type and the degree of remission following induction therapy.
PFS served as the study’s primary endpoint. Secondary endpoints included conversion to complete response, complete response with incomplete bone marrow recovery or MRD negativity; median MRD in peripheral blood; and MRD PFS, which was added as a secondary endpoint following trial design.
The median observation time was 33.4 months (interquartile range [IQR], 25.7-42.8) for the rituximab group and 34 months (IQR, 25.4-41.9) for the observation group.
Thirty-seven patients discontinued prematurely for a reason other than progression.
Patients in the rituximab group demonstrated a median PFS of 47 months, whereas median PFS was 35.5 months in the observation arm (HR = 0.5; 95% CI, 0.33-0.75). After only 25 deaths, median OS was not reached in either arm and did not appear to differ between the groups (HR = 0.77; 95% CI, 0.35-1.72).
Eight (13%) patients assigned rituximab experienced a transition from partial response to complete response or complete response with incomplete bone marrow recovery, compared with one (2%) patient in the observational arm.
Rituximab maintenance therapy also appeared to increase the time to next treatment (median not reached vs. 47.3 months; 95% CI, 36.4-incalculable).
Data from 131 patients in the rituximab arm and 127 patients in the observation arm showed more patients in the observation arm experienced MRD progression (n = 94 vs. 62, P < .0001). Further, conversion to MRD negativity occurred more frequently in the rituximab arm (n = 12 vs. 1, P = .0028).
Median MRD PFS appeared longer among patients assigned rituximab than those assigned observation (31.3 months vs. 12 months; HR = 0.4; 95% CI, 0.29-0.56).
Grade 3 to grade 4 neutropenia occurred in 28 (21%) patients in the rituximab group and 14 (11%) in the observation group. Infections of all grades were more frequent in the rituximab group (66% vs. 50%).
Greil and colleagues acknowledged patient selection may have limited the findings and that these results may not be as applicable for elderly or frail patient populations.
“Continuous assessment of MRD status, as done in our trial, could inform the design of future trials to determine the optimal timing, duration and surveillance of rituximab maintenance,” the researchers wrote.
The benefit of maintenance treatment for CLL may vary from patient to patient, Constantine S. Tam, MD, MBBS, consultant hematologist at the Peter MacCallum Cancer Centre at University of Melbourne in Australia, wrote in an accompanying editorial.
“Some patients who carry a mutated IGHV gene and who are MRD negative after fludarabine, cyclophosphamide, and rituximab might be functionally cured of their leukaemia, and thus have no disease to treat,” Tam wrote. “... For the remaining patients, the clinician must weigh up the costs and risks of 2 years of antibody maintenance, for a gain in time to next treatment of 1 year or less, and no discernable benefit in OS. In the era before the kinase inhibitors, this gain might have been worthwhile, particularly for older or infirm patients with few options for salvage therapy.
“Whether this benefit is still relevant today depends on the clinician’s access to novel drugs, and whether the safety of these agents hold up with longer-term follow-up,” Tam wrote. – by Nick Andrews
Disclos ure: Greil reports grants and personal fees from Amgen, Bristol-Myers Squibb, Celgene, Novartis, Roche and Takeda. Tam reports honoraria from AbbVie, Janssen, Novartis and Roche. Please see the full study for a list of all other researchers’ relevant financial disclosures.