Abstract
Standard-dose intravenous recombinant interleukin-2 (rIL-2) is indicated for the treatment of some subtypes of cancer; however, severe adverse events, including venous thromboembolism (VTE), may complicate its administration. Low-dose subcutaneous rIL-2 is being studied for the management of immune-mediated diseases, since it can modulate the immunological response by specifically targeting T regulatory (Treg) cells; importantly, it is supposed to cause fewer or no complications. In this systematic review and meta-analysis of phase II-III randomized controlled trials (RCTs), we investigated the safety of low-dose (<6 Million International Unit [MIU]/day) and ultra-low-dose (≤1 MIU/day) rIL-2 for severe adverse events (grade III-V) with a focus on VTE. Data of 1,321 patients from 24 RCTs were analysed: 661 patients were randomized to the rIL-2 arm (on top of standard of care) and 660 patients to standard of care alone or placebo. Two studies reported higher rates of thrombocytopenia in the low-dose rIL-2 arm. Ultra-low-dose rIL-2 was reported to be well tolerated in 6 studies with a negligible rate of severe adverse events. Symptomatic VTE events were not reported in any of the study arms (absolute risk difference 0% [95%CI −0.1%; +0.1%]). Our results may facilitate the study and introduction in clinical practice of low-dose rIL-2 for potentially new indications.
Highlights
Interleukin 2 (IL-2) is required for the activation, growth, and differentiation of several families of immune cells, including T lymphocytes, B lymphocytes, and natural killer (NK) cells[1,2]
The search for unpublished randomized clinical trials on the topic resulted in the evaluation of 79 additional studies that were registered on the database: none of them met the inclusion criteria, since they were single-arm studies (n = 45), non-randomized (n = 10), used a high dose of recombinant interleukin-2 (rIL-2) (n = 11), studied another exposure (n = 4), or already published and included in our study (n = 9)
The safety profile of rIL-2 appeared favourable when rIL-2 was given at ultra-low dose
Summary
Interleukin 2 (IL-2) is required for the activation, growth, and differentiation of several families of immune cells, including T lymphocytes, B lymphocytes, and natural killer (NK) cells[1,2]. Serious safety concerns have been raised around the use of high-dose IL-2, which has been reported to potentially cause acute thromboembolic events, including VTE15,16, as well as cardiac, cerebral, and hepatic venous thrombosis[17,18,19], as reported in the product monograph[20]. Other severe adverse events (AE) reported in patients administered high-dose rIL-2 include capillary leak syndrome, sepsis, and autoimmune reactions[20]. In the absence of any comprehensive assessment of its safety, the administration of rIL-2 for research purposes to patients diagnosed with conditions characterized by an intrinsic high risk of severe adverse events and venous thromboembolism should be cautious[26]. In our systematic review and meta-analysis, we investigated the safety of low- or ultra-low-dose subcutaneous rIL-2 administration in humans
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