Results from 20-year retrospective study in MCL: R-CHOP/HD-ASCT strong choice as first-line therapy in physically fit adult MCL patients

On November 16, 2017, Fabienne Widmer of University Hospital Zurich, Zurich, Switzerland and colleagues published online in Annals of Hematology, results from a retrospective analysis of the outcome and therapy tolerance in patients with mantle cell lymphoma (MCL) treated with rituximab plus cyclophosphamide, doxorubicin, vincristine and prednisone induction followed by consolidating high-dose chemotherapy and autologous stem cell support (R-CHOP/HD-ASCT) or rituximab plus fractionated cyclophosphamide, vincristine, doxorubicin and dexamethasone alternating with high-dose methotrexate-cytarabine (R-hyper-CVAD/MTX-AraC) at University Hospital Zurich from January 1996 - January 2016. Primary endpoints were remission rate (RR), progression-free survival (PFS) and overall survival (OS). Secondary endpoints were an impact of baseline patient and disease characteristics on OS and PFS; toxicity and adverse events from the start of chemotherapy until 1 month after therapy termination.

Key Highlights:

• Both first-line therapies showed similar outcome with a median OS longer than 10 years
• All patients responded and 97% achieved CR
• R-CHOP/HD-ASCT associated with significantly lower hematological toxicity and economic burden

Treatment:

• No institutional standard existed for the choice of a single treatment protocol
• Treating physicians were free to choose between the options considered to be equivalent with respect to efficacy
• Therapy regimens were administered according to the published protocols for:
  • R-CHOP alone followed by HD-ASCT
  • R-CHOP with alternating cycles of rituximab plus dexamethasone, high-dose cytarabine and cisplatin (R-DHAP) followed by HD-ASCT
  • R-Maxi-CHOP alternated with high-dose cytarabine and followed by HD-ASCT, as well as R-hyper-CVAD/ MTX-AraC without consolidating HD-ASCT
• Primary endpoints were remission rate (RR), PFS and OS
• Secondary endpoints were impact of baseline patient and disease characteristics on OS and PFS, and toxicity and adverse events from the start of chemotherapy until 1 month after therapy termination

Efficacy:

• R-CHOP-based induction chemotherapy led to an overall response rate (ORR) of 100%
  • 16 (66%) patients achieved a complete response (CR), and 8 (33%) patients a partial response (PR)
  • R-hyper-CVAD/MTX-AraC CR rate was 100% (n = 11)
• Estimated median OS for the entire cohort was not reached after a follow-up of 10 years with a 10-year OS rate of 76%
  • There was no significant difference in OS between both therapy groups
  • Five-year and 10-year OS rates in the RCHOP/HD-ASCT-based group and the R-hyper-CVAD group were 88.7 versus 76.9% (P = 0.54)
• Median PFS in the R-CHOP/HD-ASCT-based group and the R-hyper-CVAD group was 5.4 versus 3.1 years, and the 5-year and 10-year PFS rates were 56.9 vs. 33.1% (P = 0.15) and 36.9 vs. 22.3% (P = 0.24), respectively

Safety:

• The number of required erythrocyte concentrates was significantly lower in the R-CHOP/HD-ASCT-based group, when compared to the R-hyper-CVAD group (1.3 vs. 14.8; P = 0.010)
• The number of required thrombocyte concentrates was increased by a factor 2 in the R-hyper-CVAD group (6.1 vs. 3.2, P = 0.104)
• Twenty-six of 35 patients developed febrile neutropenia CTCAE grade IV
• Febrile neutropenia CTCAE grade IV appeared equally often in both groups, but patients in R-hyper-CVAD group developed more than one febrile neutropenia episode during first-line therapy
• In all patients of the R-CHOP/HD-ASCT-based group except one, febrile neutropenia appeared after high-dose chemotherapy and autologous stem cell support

The final analysis of these data showed that OS and PFS outcomes of both first-line therapies in advanced MCL are nearly identical. What’s more, both first-line therapies were associated with an estimated OS longer than 10 years. Therapy tolerance was superior in the R-CHOP/HD-ASCT-based therapy group with respect to complication-induced hospitalizations, hematological toxicity and economic burden, while R-hyper-CVAD/MTX-AraC proved superior with respect to quality of life measures. Based on these outcomes, the investigators concluded that R-CHOP/cytarabine with high-dose chemotherapy and autologous stem cell support is the preferred, first-line treatment regimen in qualified, fit patients with advanced MCL.

Abstract 

Standard of care for untreated mantle cell lymphoma (MCL) is still debated. At the University Hospital Zurich, advanced MCL in physically fit patients is treated either with rituximab plus cyclophosphamide, doxorubicin, vincristine and prednisone induction followed by consolidating high-dose chemotherapy and autologous stem cell support (R-CHOP/HD-ASCT), or with rituximab plus fractionated cyclophosphamide, vincristine, doxorubicin and dexamethasone alternating with high-dose methotrexate cytarabine (R-hyper-CVAD/MTX-AraC) without consolidating HD-ASCT upon physicians’ and patients’ choice. We retrospectively analysed the outcome and therapy tolerance in patients with MCL treated with R-CHOP/HD-ASCT or R-hyper-CVAD/ MTX-AraC at the University Hospital Zurich between January 1996 and January 2016. Forty-three patients were included; 29 patients received R-CHOP/HD-ASCT and 14 patients R-hyper-CVAD/MTX-AraC. Mean age at diagnosis was 54.4 years (range 38–68 years). Thirty-five patients (81.4%) completed the entire first-line therapy (n = 24 in the R-CHOP/HD-ASCT group, n = 11 in the R-hyper-CVAD group). Of those, all patients responded and 97% achieved a complete remission (CR). With a mean follow-up of 5.7 years 10-year progression-free survival (PFS) for all patients was 32% and overall survival (OS) was 76%, with no difference between the two therapy groups. Complication-induced hospitalisation rate, haematological toxicity and economic burden were significantly higher in the R-hyper-CVAD therapy group. In contrast, quality of life and global health state were better in the R-hyper-CVAD therapy group. Both first-line therapies showed similar outcome with a median OS longer than 10 years. Due to significantly lower haematological toxicity and lower economic burden, we recommend R-CHOP/HD-ASCT as first-line therapy in fit adult patients with advanced MCL.