The addition of rituximab to chemotherapy improves overall survival in mantle cell lymphoma-a pooled trials analysis

Abstract

Mantle cell lymphoma (MCL) is a distinct subtype of B-cell lymphoma and commonly used induction immunochemotherapies include the anti-CD20 antibody rituximab. However, efficacy data for rituximab regarding overall survival (OS) in first line MCL therapy remain conflicting.We report long-term outcomes of a pooled trials analysis comparing Cyclophosphamide, Doxorubicine, Vincristine, Prednisone (CHOP) to R-CHOP in MCL to confirm efficacy on failure free survival (FFS) and OS in relevant subgroups. Untreated, adult MCL patients of two prospective trials assigned to CHOP or R-CHOP were included. Primary endpoints were FFS and OS, secondary endpoints included duration of response (DOR), secondary malignancies and OS after relapse. Between 1996 and 2003, 385 MCL patients were assigned to CHOP (201) or R-CHOP (184). After a median follow-up of 13.4 years, the addition of Rituximab significantly improved FFS (1.36 vs. 2.07 years, HR 0.62 (0.50-0.77)), OS (4.84 vs. 5.81 years, HR 0.78 (0.61-0.99)) and DOR (1.48 vs. 2.08 years, HR 0.67 (0.53-0.86)). Furthermore, Rituximab improved survival across different MCL risk groups. In a post-hoc analysis of OS after relapse comparing patients receiving chemotherapy with / without rituximab, rituximab maintained efficacy with a median OS of 3.10 vs. 2.11 years (HR 0.70, 0.54-0.91). The rate of secondary malignancies was 0.5 and 3.9% for hematological and 7 and 8% for non-hematological malignancies for CHOP and R-CHOP patients, respectively. We present mature results of a pooled MCL cohort, demonstrating prolonged FFS, OS and DOR for the combined immuno-chemotherapy, confirming the standard of care in first line treatment.

Keywords: Immuno-chemotherapy; Long-term outcome; Mantle cell lymphoma; Rituximab.

Fig. 1

Consort diagram

Fig. 2

Kaplan–Meier Analysis of Patients treated with CHOP versus R-CHOP. a Failure free Survival for patients treated with CHOP versus R-CHOP. Median FFS 1.36 (1.18 – 1.66) vs. 2.07 (1.78 – 2.65) years; 5 year FFS probability 0.11 (0.07 – 0.16) vs. 0.23 (0.17 – 0.30). MIPI-adjusted HR 0.62 (0.50 – 0.77). b Overall Survival for patients treated with CHOP versus R-CHOP. Median OS 4.84 (4.10–5.97) vs. 5.81 (4.89–6.94) years; 5 year OS probability 0.48 (0.41–0.55) vs. 0.55 (0.48–0.63); 10-year OS probability 0.23 (0.18–0.30) vs. 0.31 (0.24–0.39). MIPI-adjusted HR 0.78 (0.61 – 0.99). c Duration of response for patients treated with CHOP versus R-CHOP. Median DOR 1.48 (1.19 – 1.85) vs. 2.08 (1.65 – 2.65) years; 5-year DOR probability 0.14 (0.09 – 0.20) vs. 0.25 (0.19 – 0.33). MIPI-adjusted HR 0.67 (0.53 – 0.86)

Fig. 3

Subgroup analysis for failure free and overall survival. a Forest plots for failure free and overall survival. b CHOP versus R-CHOP in male patients (n = 291). MIPI-adjusted HR for FFS 0.56 (0.44 – 0.72) and for OS 0.69 (95% CI: 0.53 – 0.91). c CHOP versus R-CHOP in female patients (n = 94), MIPI-adjusted HR for FFS 0.73 (0.46 – 1.16) and for OS 1.02 (0.60 – 1.72)

Fig. 4

Overall survival after first treatment failure. a OS stratified by first line treatment. No significant difference is observed for patients pre-treated with CHOP versus R-CHOP, HR (ref. CHOP) 1.09 (0.83 – 1.41)*, p = 0.54*. b OS stratified by second line treatment with or without rituximab. HR (ref. no rituximab) 0.70 (0.54—0.91)*, p = 0.0077*. c OS after first treatment failure stratified by second line treatment for all patients and d) for patients < 65 years. *adjusted for MIPI continuous score, time from registration to first treatment failure, first line treatment