Risk of Secondary Hematological Malignancies in Patients with Follicular Lymphoma: A Retrospective Analysis of 1045 Patients Treated in the Rituximab Era
Authors: Prusila Roosa Enni Inkeri , Sorigue Marc , Postila Aleksi , Salmi Petteri , Tanhua Taru , Tikkanen Susanna , Kakko Sakari , Kuitunen Hanne , Pollari Marjukka , Nystrand Ilja , Kuusisto Milla , Vasala Kaija , Jantunen Esa , Korkeila Eija , Karihtala Peeter , Turpeenniemi-Hujanen Taina , Kuittinen Outi 
Published: October 2019

Abstract
Introduction
Follicular lymphoma (FL) is the most common indolent lymphoma. Majority of the patients with FL have a good respond to first-line treatment. Relapses are common and many patients need to be re-treated (Izutsu K. J Clin Exp Hematop 2014).
Treatment results of indolent non-Hodgkin lymphomas have improved vastly in last decades. This is resulting from the use of therapeutic antibodies such as rituximab (Friedberg JW. Haematologica 2008). With improved survival the risk of secondary malignancies may be higher.
Some of the regimens used in the treatment of FL, especially alkylating agents, have been associated with the risk of secondary hematological malignancies such as myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Incidence of secondary MDS/AML peaks 4-6 years after the initial treatment. Secondary MDS/AML have poor prognosis. The incidence of secondary hematological malignancies and the impact of various treatment regimens among different lymphomas is still largely unknown (Friedberg JW. Haematologica 2008).
Data of 1045 patients with FL was collected to find out the incidence of secondary hematological malignancies. We also wanted to know if the incidence is related to certain types of treatment or chemotherapy regimens.
Methods
This is a retrospective registry study. Clinical data was collected from six hospitals in Finland and two hospitals in Spain. We analyzed clinical data from hospital records of all patients with FL diagnosed between 1997 and 2016. Information such as age, stage, details of treatment, possible relapses, current status and details about secondary hematological malignancy were investigated.
Results
Median follow-up time was 5.6 years. Baseline characteristics and treatment-related data are presented in Table 1. Altogether 984 of all patients received treatment for lymphoma and from all patients 80.1% received rituximab during treatment.
In all patients the 1-year PFS was 92.1% and the 5-year PFS 59.8%. The 5-year DSS was 91.6% and the 5-year OS was 84.1%. The incidence of secondary hematological malignancies is presented in Figure 1a. From all patients 15 (1.4%) developed secondary hematological malignancy. There were 5 cases of MDS, 4 AML, 1 acute promyelosytic leukemia, 1 acute lymphoblastic leukemia, 1 chronic lymphosytic leukemia, 1 chronic myelosytic leukemia, 1 large granular lymphosytic leukemia and 1 myeloma. The 5-year risk for secondary hematological malignancy was 1.3% and the approximated 10-year risk was 3.0%.
The risk of secondary hematological malignancy was associated with the number of treatment lines (p=0.039), Figure 1b. There was no statistically significant difference between different first-line chemotherapy regimens. However, there was a trend presenting higher risk, when using alkylating regimens in the first line. With CHOP-like treatment the 5-year risk was 1.1% and the approximated 10-year risk was 3.6%.
Conclusions
This is a retrospective study from rituximab era. The prognosis of follicular lymphoma is good with the current treatment methods and the risk of secondary hematological malignancy seems to be low. Due to low incidence, it seems, that it is not necessary to avoid chemotherapy in the fear of secondary hematological malignancies. However, multiple lines of treatment are associated with higher risk for secondary hematological malignancies. Therefore, the use of regimens with long remission, like rituximab maintenance, would probably reduce the risk of secondary hematological malignancies.

Disclosures
No relevant conflicts of interest to declare.