Risk of Acute Myeloid Leukemia in Adults with Primary Immune Thrombocytopenia Treated with Thrombopoietin Receptor Agonists: A French Nationwide Population-Based Study

Introduction

Immune thrombocytopenia (ITP) is a rare autoimmune disease due to platelet destruction and impaired megacaryopoiesis. Thrombopoietin receptor agonists (TPO-RAs) are widely used as second-line treatment in ITP. Due to the presence of the thrombopoietin receptor on megakaryocytes but also on hematopoietic stem cells, the question of a leukemogenic risk with TPO-RAs is a concern. In 2013, 62 reports of acute myeloid leukemia (AML) were detected in ITP patients treated with TPO-RA in the Food and Drug Administration Adverse Event Reporting System, a pharmacovigilance database. An association between AML reports and TPO-RA exposure among all adverse drug reaction reports in ITP patients was found with a reporting odds-ratio (OR) of 3.70 (95% CI: 1.18-11.16) for romiplostim and 1.92 (95% CI: 0.65-5.70) for eltrombopag. Because many factors influence the spontaneous reporting of adverse reactions, this safety signal must be confirmed or invalidated in a large cohort of ITP patients. This was the aim of the present study.

Methods

Due to the expected rarity of AML, we designed a nested case-control study in a nationwide cohort of adult patients with a new diagnosis of primary ITP. Adult patients were selected from January 2011 to December 2018 in the FAITH (French Adult Immune Thrombocytopenia) cohort. The FAITH cohort was built in the French National Health Insurance System Database, linking socio-demographic, outpatient and hospitalization data in the entire French population (67 million individuals). ITP patients were identified through an accurate algorithm (positive predictive value of 95.8% – 95% CI: 92.8 to 98.8 – in a previous validation study) using the International Classification of Diseases, tenth version (ICD-10) D69.3 code recorded as hospital discharge diagnosis or long-term disease diagnosis (the latter allows full reimbursement of health care and is coded by general practitioners). Secondary ITP and prevalent cases were excluded using a prior observation period of ≥1 year. The occurrence of AML was identified using appropriate ICD-10 diagnosis codes (C92.0, C92.4-C92.9) recorded as hospital discharge diagnosis or long-term disease diagnosis. The exposure to romiplostim and eltrombopag (the two TPO-RAs available in France) was identified using community pharmacy dispensing in the whole country. We described the cases of AML and measured the association between AML diagnosis and previous exposure to TPO-RAs (ever vs never exposed) using a logistic regression model.

Results

During the study period, 8,172 adults with primary ITP were selected. The median age was 63.2 years (Q1-Q3: 42.1-77.3) and 4,437 (54.3%) patients were women. The total follow-up time was 31,410 person-years. In total, 1,637 (20.0%) patients were exposed at least once to a TPO-RA: 1,241 (15.2%) to eltrombopag with a median cumulative exposure time of 5.7 months (Q1-Q3: 2.3-15.2), and 785 (9.6%) to romiplostim with a median cumulative exposure time of 6.6 months (Q1-Q3: 2.8-18.1). The follow-up time was similar between the 1,637 patients ever exposed to TPO-RAs and the 6,535 patients never exposed to TPO-RA (median: 3.7 and 3.8 years, respectively).

In total, 46 (0.6%) patients developed an AML (median age of 74.8 years, 60.9% of men). The median time between ITP diagnosis and AML was 1.3 years (Q1-Q3: 0.5-2.8). We identified 36 AML in patients never exposed to TPO-RAs (0.6%; 95% CI: 0.4-0.8) and 10 in patients ever exposed to TPO-RAs (0.6%; 95% CI: 0.3-1.1): 10 patients have been exposed to eltrombopag, and 3 to eltrombopag and romiplostim sequentially.

Among these 10 patients, the median age was 72.3 years (Q1-Q3: 67.8-80.0) and 7 were men. The median time between ITP diagnosis and AML was 1.1 years (Q1-Q3: 0.4-2.3; min-max: 0.4-5.4). The median time between the first dispensing of TPO-RA and AML diagnosis was 8.9 months (Q1-Q3: 4.2-16.0; min-max: 1.7-62.8). The median cumulated duration of exposure to TPO-RAs before AML was 3.9 months (Q1-Q3: 2.1-5.7; min-max: 1.7-12.7).

In the case-control analysis evaluating the association between the exposure to TPO-RAs (ever/never exposed model) and the subsequent occurrence of AML, the unadjusted OR was 1.1 (95% CI: 0.6-2.2) and the age- and sex-adjusted OR was 1.0 (95% CI: 0.5-2.1).

Conclusion

In this nationwide population-based study, the exposure to TPO-RAs was not associated with an increased incidence of AML in adult patients with primary ITP (primary at diagnosis).