Toxicity and Activity of a Twice Daily High-dose Bolus Interleukin 2 Regimen in Patients With Metastatic Melanoma and Metastatic Renal Cell Cancer

Abstract

The standard q8h high-dose interleukin-2 (IL-2) regimen produces clear benefit for a subset of patients, but has limited acceptance because of its substantial acute toxicity including hypotension requiring pressors in 30% to 50%, the schedule is inconvenient for medical staff who must assess patients before each dose, and in some hospitals, the limited availability of monitored beds. We initiated a high-dose IL-2 program with a modified twice daily dosing schedule, limited the total number of doses per course to 8, and treated patients in an oncology ward without cardiac monitoring. Hypotension was managed preferentially with normal saline fluid boluses and/or delay in treatment. We conducted a retrospective chart review of 41 consecutive metastatic melanoma (n=33) and renal cancer (n=8) patients treated with the modified high-dose IL-2 regimen. The median number of IL-2 doses administered in the first cycle was 15. Overall toxicity was similar to published data for the q8h schedule, but only 9.79% of patients required pressors. Twenty-four percent of patients were transferred electively or emergently to the intensive care unit. There were no treatment-related deaths. The objective response rate was 12.5% and 0% in melanoma and renal cancer, respectively. Responses were durable, and 2 additional melanoma patients with mixed responses remain disease-free after resection of residual or recurrent sites of disease. In summary, the twice-daily IL-2 regimen has meaningful activity, may be more convenient to administer, reduces the need for elective monitored beds, and may be preferable for development of combinations with newer immune modulators.

Stimulation of natural killer cells with a CD137-specific antibody enhances trastuzumab efficacy in xenotransplant models of breast cancer

“…This may translate to a clinical benefit in reduced toxicity of the combination antibody approach, as systemic NK cell stimulation should not be expected. Current therapies such as high-dose IL-2, though clinically beneficial, are limited by systemic toxicity (36,37). Other approaches, such as IL-12 or blockade of inhibitory KIR receptors, similarly are unable to selectively target NK cells implicated in trastuzumab-mediated tumor cell killing (36, 38, 39).…”

High dose interleukin-2 (Aldesleukin) - expert consensus on best management practices-2014

“…The interval between courses may vary considerably for a variety of other reasons including patient recovery and logistics. The standard dose of HD IL-2 remains 600,000 IU/kg (based on initial studies), although higher and lower approaches have been described in the literature [1][2][3][4][5][6][7][8][9][10][11][12][13]43]. The NCI and some sites use 720,000 IU/kg [1].…”

“…Some institutions have adopted schedules that continue to use the standard amount of IL-2 per dose but offer variations in dosing interval and number of dosing cycles [12,44]. These approaches indicate that interest remains in optimizing IL-2 therapy in ways which maintain efficacy but improve the safety profile for patients.…”

“…At the same time, the number of doses of IL-2 being administered per course has decreased, reducing toxicity without an apparent impact on efficacy [1,2,[7][8][9][10][12][13][14]. These trials have stipulated the standard dose and schedule of HD IL-2, but this delivery and management could vary according to each site's tolerance for specific toxicities and approach to managing them.…”

miR-155 augments CD8 + T-cell antitumor activity in lymphoreplete hosts by enhancing responsiveness to homeostatic γ c cytokines

“…Similar to lymphodepleting regimens, high-dose IL-2 is associated with substantial toxicities mainly as a result of a capillary leak syndrome, which results in a hypovolemic state and fluid accumulation in the tissues (13).…”