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

Abstract

Interleukin-2 (IL-2) was historically one of the few treatments for adults with stage IV solid tumors that could produce complete responses (CRs) that were often durable for decades without further therapy. The majority of complete responders with metastatic renal cell carcinoma (mRCC) and metastatic melanoma (mM) could probably be classified as "cures". Recent publications have suggested improved efficacy, perhaps due to improved patient selection based on a better understanding of clinical features predicting outcomes. Guidelines for clinical management were established from experience at the National Cancer Institute (NCI) and an affiliation of institutions known as the Cytokine Working Group (CWG), who were among the first to utilize HD IL-2 treatment outside of the NCI. As new centers have opened, further management variations have emerged based upon center-specific experience, to optimize administration of IL-2 and provide high quality care for patients at each individual site. Twenty years of evolution in differing environments has led to a plethora of clinical experience and effective management approaches. The goal of this review is to summarize the spectrum of HD IL-2 treatment approaches, describing various effective strategies that incorporate newer adjunctive treatments for managing the side effects of IL-2 in patients with mRCC and mM. The goal for IL-2 therapy is typically to administer the maximum number of doses of IL-2 without putting the patient at unacceptable risk for severe, irreversible toxicity. This review is based upon a consensus meeting and includes guidelines on pre-treatment screening, criteria for administration and withholding doses, and defines consensus criteria for safe administration and toxicity management. The somewhat heterogeneous best practices of 2014 will be compared and contrasted with the guidelines provided in 2001 and the package inserts from 1992 and 1998.

Keywords: Clinical management; Cytokines; Interleukin-2; Melanoma; Renal cell carcinoma; Treatment guidelines.

Figure 1

Timing of the administration of the 4th and 5th IV boluses of IL-2 is plotted versus systolic and diastolic blood pressure and heart rate. This patient shows characteristic exacerbation of hypertension 3-4 hours after infusion responsive to fluid boluses.

Figure 2

Timing of the administration of the 6th and 7th IV boluses of IL-2 is plotted versus systolic and diastolic blood pressure and heart rate. This patient is unresponsive to a fluid bolus and phenylephrine is begun at 50 mcg per minute with good effects permitting administration of the 7th dose. The resulting hypotension and tachycardia are treated with an increase in the phenylephrine dose and another bolus of fluid. The late night dose will likely be held.

Figure 3

Shows a week of HD IL-2 administration with typical evolution of daily serum BUN, creatinine, potassium and bicarbonate values. In this patient the 1st and 2nd doses on day 3 are held. Spontaneous improvement occurs with conclusion of dosing on day 5.

Figure 4

Plots weight (actual and ideal curve), fluid support (IV rate and boluses) during a cycle of HD IL-2. As the week progresses, weight gain falls behind ideal and increasing fluid and bolus support is necessary. Finally, vasopressor support is added before the final dose is administered.

Figure 5

A logarithmic plot of blood lymphocyte, eosinophil, platelet and granulocyte absolute counts and hemoglobin during a cycle of HD IL-2 administration. Platelet and lymphocyte counts fall rapidly to very low levels. Eosinophils progressively rise during administration. After cessation of treatment, platelets and lymphocytes quickly return to normal and often rebound to 2-5 times their baseline levels. Eosinophilia may persist for weeks.