Maintenance therapy with the anti-CD20 monoclonal antibody rituximab after autologous hematopoietic cell transplantation (AHCT) prolonged event-free, progression-free, and overall survival in patients with mantle cell lymphoma (MCL), compared with those who did not receive maintenance therapy, according to a study published in the New England Journal of Medicine.
In an unblinded, prospective, randomized, phase III trial, Steven Le Gouill, MD, PhD, from the University Hospital Hôtel-Dieu in Nantes, France, and co-authors investigated whether rituximab maintenance therapy would prolong response in patients who had received a transplant conditioning regimen without total-body irradiation and induction therapy without alkylating and anthracycline agents.
Between September 2008 and August 2012, the researchers enrolled 279 adult patients (median age = 57 years; range = 27-65 years) who were younger than 66 years of age and had untreated MCL. Patients included in the study were eligible to undergo AHCT, had Ann Arbor stage II-IV disease, and had an Eastern Cooperative Oncology Group performance status score of <3. Patients with other major coexisting conditions were excluded.
All patients received induction therapy with four courses of R-DHAP (rituximab, dexamethasone, high-dose cytarabine, and cisplatin).
Twenty patients who had a partial response or whose tumor was reduced by <75 percent then received rescue induction therapy with four courses of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone).
A total of 257 patients underwent AHCT (14 R-DHAP–treated patients and 8 R-CHOP–treated patients were excluded, mainly for disease progression or ineligibility to receive AHCT). Prior to transplant, patients received conditioning therapy with R-BEAM (rituximab, carmustine, etoposide, cytarabine, melphalan).
For as long as three months after transplant, patients were randomized to either the maintenance arm (rituximab 375 mg/m2 administered intravenously every 2 months for 3 years; n=120) or the observation arm (n=120).
At data cutoff (July 1, 2015), the median follow-up from randomization was 50.2 months (range = 46.4-54.2 months). Eighty-three patients in the rituximab cohort had received the scheduled three-year course of therapy; among patients who stopped rituximab, the most common reasons were disease progression (n=16) or neutropenia (n=9).
Serious infections following AHCT were reported in four patients in each cohort (related to spondylitis, pyelonephritis, septicemia, and varicella in the rituximab cohort and septicemia, cellulitis, meningitis, and severe pneumonia in both lungs in the observation group). The most frequent grade 3/4 adverse event in both cohorts was neutropenia.
Incidence of progressive disease and death appeared to be lower in the rituximab group (16 and 13 patients, respectively) than in the observation group (37 and 24 patients). Lymphoma was the major cause of death in each group (8 in the rituximab cohort and 16 in the observation cohort), whereas the development of a secondary cancer led to three patient deaths in the rituximab cohort and one patient death in the observation group.
After four courses of R-DHAP induction, the overall response rate was 89 percent, with a complete response rate of 77 percent. Starting from randomization, the median event-free survival (EFS; primary endpoint) was not reached in either cohort. The median progression-free survival (PFS) and overall survival (OS) were also not reached in either group.
Four-year EFS, PFS, and OS rates for patients who received maintenance therapy versus those who did not were:
- EFS: 79% (95% CI 70-86) vs. 61% (95% CI 50-70; p=0.001)
- PFS: 83% (95% CI 73-88) vs. 64% (95% CI 55-73; p<0.001)
- OS: 89% (95% CI 81-94) vs. 80% (95% CI 72-88; p=0.04)
Patients who received rituximab maintenance had a significantly lower risk of disease progression, relapse, death, rituximab allergy, or severe infection, compared with patients receiving no maintenance therapy (hazard ratio = 0.46; 95% CI 0.28-0.74; p=0.002).
Among the 11 patients who received R-CHOP prior to randomization, four were assigned to the rituximab group: One had disease progression and died, and three were alive at the time of analysis. The other seven were randomized to the observation cohort: Four relapsed but were alive at analysis, and three died.
For the 59 patients who did not undergo randomization, the median PFS was 11 months (95% CI 6.4-28.0), and the median OS was 30.6 months (95% CI 12.3-44.6).
“Maintenance therapy with rituximab after R-DHAP induction therapy, followed by R-BEAM consolidation therapy, prevented relapses and was associated with a low risk of major infection,” the authors concluded, adding that the study results “show the efficacy of a cytarabine-based induction regimen free of anthracycline or alkylating agents in patients with this condition.”
Because the study included only patients who received rituximab maintenance therapy after R-DHAP induction therapy, followed by R-BEAM consolidation therapy, the study’s findings are limited to this population, the authors noted. “Whether maintenance therapy with rituximab improves outcomes in patients who are treated with other regimens is unknown.” The study also did not measure immunoglobulin levels to determine the degree and duration of immunosuppression with this treatment approach.
The study was supported by Roche and Amgen.
The authors report no financial conflicts.
Le Gouill S, Thieblemont C, Oberic L. Rituximab after autologous stem-cell transplantation in mantle-cell lymphoma. N Engl J Med. 2017;377:1250-60.