Long term follow-up supports R-CHOP and rituximab maintenance for the treatment of mantle cell lymphoma in elderly patients

In recent decades, the prognosis of patients with mantle cell lymphoma (MCL) has improved significantly.¹ This is, in part, due to the use of high-dose cytarabine induction immunotherapy and autologous stem cell transplantation in younger, fit patients. However, the majority of elderly patients with MCL are not considered suitable for intensive chemoimmunotherapy and are transplant ineligible for high-dose therapy. Therefore, efforts have been made to determine effective induction regimens and post-induction maintenance strategies.²

The 2012 3.5 year follow-up of the phase III randomized MCL Elderly trial (NCT00209209) demonstrated the enhanced clinical activity of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) compared to rituximab, fludarabine, and cyclophosphamide (R-FC) chemotherapy.³ The study analysis also highlighted the benefit of rituximab (R) over interferon alpha (IFN) maintenance following R-CHOP in elderly patients with MCL.³ The Lymphoma Hub covered the 6.7 year follow-up presented at the  59^th Annual Meeting & Exposition of the American Society of Hematology (ASH), which can be accessed here. The 7.6-year follow-up of the study was recently published by Hanneke C. Kluin-Nelemans, University of Groningen, Groningen, NL, and colleagues.⁴

Study aim: To confirm long-term results of the MCL Elderly trial investigating the efficacy of R maintenance after induction chemotherapy (R-CHOP vs R-FC) for elderly patients with MCL not suitable for autologous stem cell transplant (auto-SCT)

Study design

• Patients (N= 560) aged ≥65 years with newly diagnosed stage II-IV MCL were recruited
• Induction therapy: patients were randomly allocated to receive either eight cycles of R-CHOP every three weeks (n= 280) or six cycles of R-FC every four weeks (n= 280)
• Maintenance therapy: responders to induction therapy (n= 316) were then 1:1 randomized to receive either R (375 mg/m² every 2 months) or IFN (three million units subcutaneously three times a week and pegylated IFN 1μg/kg once a week)
• The primary outcomes for induction and maintenance therapies were complete response (CR) rate and progression-free survival (PFS) from the end of induction respectively

Results

• Median age at induction was 70 years in the R-CHOP (range, 61—87) and the R-FC (range, 60—85) cohorts

Outcomes of induction therapy

• Median follow-up time: 7.6 years
• The outcomes of induction therapy are illustrated in Table 1

Table 1. Response rates to induction R-CHOP and R-FC therapies

NS, not significant; ORR, overall response rate; OS, overall survival; R-CHOP, rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone; R-FC, rituximab, fludarabine, and cyclophosphamide
	R-CHOP	R-FC	P
ORR, %	84	78	NS
Median OS, years	6.4	3.9	0.0054
Cumulative incidences of death at five years, %	9	19	0.0043
OS after first treatment failure, years	2.3	1.0	0.0012

Outcomes of maintenance therapy

• Median follow-up time of responders: 8 years
• The outcomes of maintenance therapy are illustrated in Table 2
• Responders to R-CHOP elicited the greatest benefit from R maintenance

Table 2. Response rates to R and IFN maintenance therapies 

IFN, interferon alpha; OS, overall survival; PFS, progression free survival; R, rituximab; R-CHOP, rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone; R-FC, rituximab, fludarabine, and cyclophosphamide
	R	IFN	P
Median PFS, years	5.2	2.0	0.0109
Median OS, years	9.8	6.4	0.009
Responders to R-CHOP Median PFS, years Median OS, years	5.4 9.8	1.9 7.1	0.001 0.0026
Responders to R-FC Median PFS, years	5.0	2.6	0.0315

Conclusion

Consistent with the 2012 observation, R-CHOP induction with R maintenance prolonged PFS and OS in elderly patients with MCL. This long-term follow-up indicated the superiority of R maintenance on OS when compared to IFN maintenance. Additionally, the study showed that even patients receiving R-FC induction benefitted from R maintenance as indicated by a longer PFS. Although initiation with R-FC has produced disappointing outcomes throughout the MCL elderly study, the regimen performed extremely well in a small subgroup of patients that tolerated R-FC toxicity with a higher proportion of patients presented as MRD negative in the R-FC-tolerating subgroup. Duration of R maintenance was touched on in this follow-up and data indicated that patients terminating R therapy after 2 years elicited significantly poorer PFS compared with those who continued R treatment beyond 2 and 3 years.