Survival, Transformation and Causes of Death of Follicular Lymphoma: A Finnish Nationwide Population-Based Study

Background Follicular lymphoma (FL) represents the most common indolent B-cell lymphoma (BCL), comprising approximately 25% of all BCL cases in the Western countries. Histologically, FL is subdivided into low-grade (grade 1−2) and high-grade (grade 3A and 3B). Low-grade FL is generally indolent, whereas there is less certainty about the course of FL grade 3A. FL grade 3B is considered an aggressive lymphoma. FL is generally associated with long survival, however, a substantial proportion of FLs undergo transformation to large B-cell lymphoma characterized by aggressive clinical behavior and increased mortality. Population-based long-term data on survival, transformation and causes of death of FL is limited.

Aims We estimated overall survival (OS) and the risk of transformation to large B-cell lymphoma in patients diagnosed with FL in Finland in 1995−2018. We also compared mortality rates between the patients with or without transformation.

Methods Patients diagnosed with incident FL (ICD-O-3 morphology codes 9690/3, 9691/3, 9695/3 and 9698/3) and lymphoma not otherwise specified (NOS) (9590/3, 9591/3) in Finland between 1995 and 2018 were retrieved from the Finnish Cancer Registry (FCR). The diagnosis of FL and possible transformation were confirmed from the pathology reports. Transformation was defined as the diagnosis of morphologically verified large B-cell lymphoma at least 3 months after the primary diagnosis of FL.

For all patients with histologically verified FL, we collected data on histological grade, gender, date of birth, FL diagnosis and last follow-up (f-up), vital status at the end of f-up, date of transformation and cause of death if applicable. Patients for whom the pathology report did not state a specific histological grade were termed unclassifiable. F-up for OS was completed on December 31, 2018. The patients with FL histological grade 3B, incorrect diagnostic or FL diagnosis/transformation recorded by death certificate or autopsy only were excluded. No patients were lost to f-up before the end of the study period.

OS was estimated by the Kaplan-Meier method. The cumulative incidence of transformation was estimated by the Aalen-Johansen method, considering death before transformation as a competing event. Analysis of total mortality was performed using Cox regression. Transformation was treated as a time-varying covariate. All statistical analyses were performed using R, version 4.2.0.

Results We identified 4014 patients diagnosed with FL after above mentioned exclusions. Baseline characteristics, as well as grade-specific rates of transformation and death, are shown in the Table 1. Median age at diagnosis was 64 years (IQR, 55−72; range, 14−94 years), with a slight female predominance (55%). Low-grade FL was the most frequent, followed by unclassifiable and grade 3A. There were no clinically significant differences in the age at diagnosis between the males and females, nor across the histological grades. Median follow-up time was 6.1 years (IQR, 2.4−10.9; range 0−24 years).

Transformation occurred in 294 patients during 28466 person-years of follow-up (crude transformation rate, 10.3 per 1000). The cumulative incidence of transformation for the whole cohort was 4.6% (95% CI, 3.9-5.3) at 5 years and 8.4% (95% CI, 7.5-9.5) at 10 years from diagnosis (Fig. 1), with no apparent plateau.

Overall, 1260 (31%) patients died during a total f-up of 29361 person-years (crude mortality rate, 42.9 per 1000). In comparison, the crude mortality rate following transformation was 181.1 per 1000. Lymphoma was the most common cause of death (55%), followed by non-malignant cause (31%) and secondary malignant neoplasm (14%). OS was 80.3% (95% CI, 79.0−81.7) at 5 years and 65.0% (95% CI, 63.2−66.8) at 10 years from diagnosis. After adjusting for potential confounders (age at diagnosis, gender and year of diagnosis), transformation (HR 5.01; 95% CI, 4.21−5.96) and Grade 3A (HR 1.42; 95% CI, 1.13−1.78; low-grade as reference) were associated with a substantial increase in mortality.

Conclusions In this large nationwide population-based study, the risk of transformation to large B-cell lymphoma was 8.4% at 10 years. Grade 3A and transformation were associated with a substantially increased risk of death. Lymphoma was the leading cause of death. Long-term OS and baseline characteristics were in accordance with previously published data for FL.

Leppä:Incyte: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Research Funding; Gilead Sciences: Consultancy, Honoraria; BMS: Consultancy, Research Funding; Bayer: Research Funding; Orion Pharma: Consultancy; Pfizer: Consultancy; Beigene: Consultancy; Genmab: Research Funding; Nordic Nanovector: Research Funding.