The Impact of Rituximab Resistance on Overall Survival Rate in Low-Grade Follicular Lymphoma

Background: Recent studies have prospectively established that concurrent or sequential addition of rituximab (R) to conventional therapies improves the overall survival rate (OS) for patients with low-grade follicular lymphoma (FL).  However, there is little information regarding the prognosis of patients considered R-resistant.  

Subjects/Methods: We examined the records of 305 subjects with a diagnosis of FL seen at our institution between 1995 and 2007.  To better define the prognosis for R-resistant subjects, we identified 133 subjects (grade 1, N=75; grade 2, N=41; grade 1 or 2, N=17) who completed an R-containing treatment (R alone, N=61; R combination, N=72) and had at least six months of follow-up from start of R-containing therapy.  For the purposes of our study, we define R-resistance as progression of lymphoma within 6 months of the first R dose (i.e., the dose defining R-resistance) of the R-containing regimen followed by progression.  Overall survival rates were evaluated for all subjects from first dose of R to last follow-up or death and, for R-resistant subjects, from the dose defining R-resistance to last follow-up or death.  R-resistant subjects (N=62 [47%]) were subdivided into primary refractory (R-resistant after first R-containing treatment; N=30) or acquired resistant (R-resistant after at least one prior R-containing treatment without progression within 6 months; N=32).  Median age at first treatment with R was 55 years (range: 21-87) for all subjects and 54 years (range: 21-87) for R-resistant subjects (for primary refractory, median=54 years [range: 28-87]; for acquired resistant, median=55 years [range 30-81]).  The median number of prior non-R-containing treatment regimens was 1 (range: 0-4) for resistant subjects, and 0 (range: 0-3) for non resistant subjects.  The median number of R-containing regimens for subjects with acquired resistance was 2 (range: 2-4).  The frequency of large cell transformation did not differ between R-resistant and non R-resistant cohorts (N=7/71 [10%] and N=8/62 [13%], respectively). 

Results: Of 20 deaths observed for all subjects with FL receiving R or R containing regimens, 19 deaths occurred after R-resistance.  At a median follow-up of 56 months (range 6-115) for all subjects receiving R, the median OS was not reached with 5-year Kaplan-Meier OS estimate = 81%.  For R-resistant subjects, median OS from first dose of R defining R-resistance was 64 months (range: 6-100) with 5-year Kaplan-Meier OS estimate = 58%.  Median rates of OS from R dose defining R-resistance were not significantly different between primary refractory and acquired resistant subjects.  For subjects with acquired R-resistance, median time from first dose of R to first dose of R defining R-resistance was 10.4 months (range: 9-83). 

Conclusion: The OS estimate for subjects with R-resistant FL (5-year estimate OS = 58%) appears worse than survival estimates reported for unselected subjects with FL (5 year estimate OS = 80% for grade 1; 76% for grade 2 [SEER Survival Monograph, Non-Hodgkin Lymphoma]).  This inferior prognosis seems unrelated to large cell transformation.  Survival is similar for subjects with primary refractory and acquired resistance when survival is measured from the R dose used to define R-resistance.