Educational theme | Treatment of elderly patients with follicular lymphoma

Our educational theme on the Lymphoma Hub this quarter has aimed to explore the management of elderly patients with lymphoma. The previous article in this series investigated the recent advances in prognostic assessment and treatment of elderly patients, and can be found here.

Follicular lymphoma (FL) is a form of indolent non-Hodgkin lymphoma that is more common in older patients; however, due to the increased likelihood of comorbidities, these patients are less frequently included in chemotherapy trials. More data is required to understand the impact of age on treatment efficacy and disease progression. There has been some indication that older age is not associated with higher-risk disease in FL, therefore, investigation of a large cohort of patients is necessary.

Carla Casulo and colleagues described the results of older patients with FL across 18 randomized controlled trials, in an article recently published in Blood Advances.¹

Study design

The Follicular Lymphoma Analysis of Surrogacy Hypothesis (FLASH) group carried out pooled analysis of individual patient data from first-line randomized controlled chemotherapy trials to investigate the association between age, clinical characteristics, and outcomes. A total of 18 trials were included with 5,922 patients enrolled. A subgroup of 3,450 patients who were treated with rituximab were also analyzed.

Patients with untreated FL were eligible if enrolled in 1 out of 21 studies included in the FLASH database. Studies with all patients ≤70 years were excluded.

The primary endpoints of the study were:

• Complete response (CR) at 24 and 30 months (CR24 and CR30, respectively)
• Progression-free survival (PFS) at 24 months

Secondary endpoints were:

• PFS
• Overall survival (OS)

Results

The majority of patients were ≤60 years old (63.0%); 27.9% were between 61−70 years, 8.8% were between 71−80 years, and only 0.3% were >80 years. Elevated hemoglobin and β-2 levels were more common in patients >70 years (both p<0.0001). Over 90% of patients included had Eastern Cooperative Oncology Group performance scores of 0−1 (Table 1).

Table 1. Baseline patient characteristics*

ECOG-PS, Eastern Cooperative Oncology Group-performance status; FLIPI, Follicular Lymphoma International Prognostic Index; Hb, hemoglobin; ULN, upper limit of normal. *Adapted from Casulo et al.1
Characteristic		Age ≤70 y n = 5,380	Age >70 y n = 542	Total N = 5,922	p value
Age, years	Mean (SD)	53.7 (10.10)	74.0 (3.00)	55.6 (11.29)	< 0.0001
Median (range)	55.0 (17.8, 70.0)	73.2 (70.0, 90.1)	56.3 (17.8, 90.1)
Sex (%)	Female	49.5	55.9	50.1	0.0042
ECOG-PS	0−1, %	95.0	91.2	94.6	0.0004
≥2, %	5.0	8.8	5.4
Missing, n	854	55	909
FLIPI (%)	Low, %	21.8	2.6	20.0	< 0.0001
Intermediate, %	38.7	26.7	37.5
High, %	39.5	70.8	42.4
Missing, n	846	77	923
Nodal sites	<5, %	35.0	45.6	36.0	< 0.0001
≥5, %	65.0	54.4	64.0
Missing, n	1,818	167	1,985
Hb at baseline	≥12 g/dL, %	81.4	72.8	80.6	< 0.0001
<12 g/dL, %	18.6	27.2	19.4
Missing, n	1,315	130	1,445
β-2 at baseline	> ULN, %	48.5	67.8	50.2	< 0.0001
≤ ULN, %	51.5	32.2	49.8
Missing, n	3,468	365	3,833

CR24 and CR30 rates were similar between the two age groups (Table 2). With a median follow-up of 5.1 and 5.6 years, the OS of patients was significantly decreased in the >70 group compared with patients ≤70 years (p < 0.001). OS remained significantly reduced in the group of patients >70 years old (p < 0.001) following analysis that considered death after progression as the event of interest, with death without progression as a competing risk.

PFS was reduced in patients >70 years old compared with those ≤70 years (p < 0.001), however when considering death without disease progression as a competing risk, the difference between ages groups was no longer significant (p = 0.965). Therefore, while patients >70 were more likely to die than the younger group, this was not a result of disease progression.

Table 2. Survival outcomes*

PFS, progression-free survival; OS, overall survival; CR, complete response. *Adapted from Casulo et al.1
Outcome	≤70 years	>70 years
CR24, %	32.3	29.6
CR30, %	34.3	31.8
PFS, years	3.8	3.1
OS, years	15.7	7.4

In the rituximab treated subgroup (n = 4,564) the CR24 (38.5% vs 39.9%, >70 and ≤70 years, respectively) and CR30 (41.6% vs 43.2%%, >70 and ≤70 years, respectively) results were comparable between age groups.

Conclusion

PFS was shown to be similar between adult and elderly (>70 years) patients with FL in this analysis, indicating that age should not automatically disqualify patients from standard treatment or clinical trials. It should be noted that while this data is promising, only 9.2% of patients in this study were >70 years old. A prospective study in patients >70 years old with FL is needed to confirm these findings.