Long-Term Follow-up Study of Patients Aged 80 Years or Older Treated By Attenuated Chemotherapy Mini-CHOP Plus Anti-CD20 for DLBCL, Update of the LNH03-7B and LNH09-7B Lysa Trials

Background.

The aging of the population and the increased risk of lymphoma with age are two concordant factors to consider an increased frequency of B lymphomas in the coming years. Continuous effort are required to optimize tolerability and efficacy of treatments for the frail elderly population over 80 years of age not eligible for standard chemotherapy doses regimens. LNH03-7B (NCT01087424; Peyrade F et al, Lancet Oncol 2011) and LNH09-7B (NCT01195714; Peyrade F et al, Lancet Haematol 2017) clinical trials studies conducted in patients (pts) over 80 years of age, demonstrated attenuated doses of chemotherapy (mini-CHOP) associated with an anti-CD20 antibody provide a satisfactory safety and efficacy profile. In the population 80 years and higher, long-term follow-up including the causes of mortality remains unknown. This long-term follow-up study of the LNH03-7B and LNH09-7B clinical trials investigate outcome of pts after more than 10 years after inclusion.

Methods.

We estimated PFS and OS survival probabilities on the global population and separately in studies LNH03-7B and LNH09-7B respectively. At the cut-off time of this long-term analysis (January 2024), the median follow-up time since inclusion was 12.2 years. From the global population (n=269 pts), 65 pts were alive and eligible for follow-up. Causes of deaths and secondary malignancies were recorded. In order to estimate the excess mortality hazard on the survivorship population studied in long-term follow-up, the overall mortality hazard was compared with the expected mortality hazard using the French lifetable database provided by INSEE (Institut National de la Statistique et des Etudes Economiques). This lifetable provides mortality rate by year, age and sex.

Results.

The median age of the global population at inclusion was 83 years (range, 79 to 86). 75.8% of the pts had a disseminated disease and 69.5% had an IPI score from 3 to 5. In the global population, we observed 211 events for the PFS (97 progressions and 114 deaths without progression). Median PFS was 2.4 years (95% CI: [1.6-4.1]). The PFS at 5 years was estimated at 38.0% (95% CI: [31.8-44.2]) and at 10 years estimated at 13.7% (95% CI: [9.1- 19.3]). We observe 204 deaths for OS analysis. Median OS was 4.1 years (95% CI: [2.5-5.3]). The 5-year OS was 44.4% (95% CI: [37.9-50.6]) and 10-year OS was 15.8% (95% CI: [10.9-21.6]).

The leading identified cause of death was lymphoma (35.8% [n=73/269 pts]) and deaths related to treatment reach 4.9% (10/269) of pts. The cause of death of 75 (36.8%) pts could not be determined. Second primary malignancies was recorded in 17 (6.3%) pts from the 269 pts included. PFS were not significantly different between LNH-03-7B and LNH-09-7B studies (median 1.8 year [95% CI: 1.1-3.5] and 3.7 years [95% CI: 1.7-4.9], respectively; p=0.3158). OS were not significantly different between LNH-03-7B and LNH-09-7B studies (median 2.9 years [95% CI: 2.1-5.3] and 4.2 years [95% CI: 3.2-6.4], respectively; p=0.3212). Deaths related to treatments during treatment period seems to be reduced by introduction of prephase in LNH-09-7B protocol (8.3% [10/149] in LNH-03-7B versus 0% [0/120] in LNH-09-7B. No delayed treatment-related deaths were recorded in both clinical trials.

Considering a flexible parametric model for the excess mortality hazard, we estimated in survivorship long term follow-up population studied that 1-year increase of age was associated with a hazard ratio of 1.039 [95%CI: 0.943-1.114] on the excess mortality.

Conclusion.

Attenuated mini-CHOP chemotherapy plus anti-CD20 continues to demonstrate benefit without excess of mortality related to treatment in long-term survivorship follow-up studies. Introduction of prephase treatment appears to reduce the risk of treatment-related deaths during therapy period.

In this elderly population, while a significant proportion of causes of death was not determined, the leading identified cause of death was lymphoma, prompting the search for future therapeutic regimens improving control of the disease.