Aldesleukin adverse effects

The use, benefits, and adverse effects of aldesleukin in HIV-infected patients have been extensively reviewed (8). Aldesleukin significantly increased the CD4+ cell count without an increase in viral load. However, many questions remain unanswered. In particular, it is still not known whether immunological improvements translate into clinical benefit. Regardless of how aldesleukin is administered—intravenously, subcutaneously, or as polyethylene glycol-modified (pegylated) aldesleukin— adverse effects are generally not treatment-limiting. As the duration of adverse effects was shorter with the subcutaneous route, these patients may be treated as outpatients (9). 

Non-steroidal anti-inflammatory agents used to reduce fever and other aldesleukin adverse effects can theoretically potentiate aldesleukin nephrotoxicity by inhibiting prostaglandin synthesis. However this effect was deemed unhkely by several authors (85). 

Aldesleukin is with recombinant technology prepared interleukin-2 (IL-2). IL-2 binds to the IL-2 receptor and so stimulates proliferation of T-helper cells and cytotoxic T-cells. It also activates macrophages and stimulates B-cell activity. It is used in metastasized renal carcinoma. Life threatening car-diotoxicity may occur. Other adverse effects include bone marrow depression and neurotoxicity with manifestations varying from somnolence to delirium. 

Several serious toxicities have been observed, with a fatahty rate of 5% in the initial studies. The major adverse effect is severe hypotension in as many as 85% of patients, which may lead to myocardial infarctions, pulmonary edema, and strokes. This hypotension is thought to be due to a capillary leak syndrome resulting from extravasation of plasma proteins and fluid into ex-travascular space and a loss of vascular tone. Patients with significant cardiac, pulmonary, renal, hepatic, or CNS conditions should not receive therapy with aldesleukin. Other adverse reactions include nausea and vomiting, diarrhea, stomatitis, anorexia, altered mental status, fevers, and fatigue. 

The adverse effects of aldesleukin include fever, chills, malaise, skin rash, nausea, vomiting (often resistant to antiemetics), diarrhea, fluid retention, myalgia, insomnia, disorientation, life-threatening hypotension, and the capillary leak syndrome (which can be preceded by weight gain) (SEDA-15, 491) (2). 

In an analysis of data from 270 patients with metastatic melanoma in eight clinical trials, high-dose aldesleukin (8.4-9.8 MU/kg during each cycle) produced an overall objective response rate of 16%, with 17 complete responses and 26 partial responses (12). Although the response rate was low, there was a durable response for at least 24 months in 10 of 17 complete responders. Adverse effects were primarily the same as those previously described in patients with metastatic renal cell carcinoma, and severe hypotension (64%) was the most frequent. Six patients died from bacterial sepsis, but none was taking prophylactic antibiotics. 

The frequencies of severe adverse effects of aldesleukin (7) are listed in Table 1 and the most frequent reasons for withdrawal of high-dose intravenous aldesleukin in Table 2. 

Table 1 The frequencies of severe adverse effects of aldesleukin...

A wide range of aldesleukin-induced adverse effects is associated with the capillary leak syndrome, which is characterized by an increase in vascular permeability with subsequent leakage of fluids and proteins into the extravascular space (4). This results in a third-space clinical syndrome, generalized or peripheral edema, weight gain, cardiovascular and pulmonary comphcations with hypotension, pericardial, and pleural effusions, ascites, oliguria, and prerenal azotemia. Symptoms usually resolve in a few days after aldesleukin withdrawal. Studies on the mechanism have raised a number of hypotheses, such as damage to the endothehal cells, release of secondary cytokines, and activation of the complement cascade (15). 

Dose-related cough has been reported as the most frequent adverse effect of inhaled aldesleukin (28). 

Pulmonary features of the adverse effects of aldesleukin include lung opacities, diffuse pulmonary interstitial edema, pleural effusions, alveolar edema, and hypoxemia, with full and rapid recovery after treatment withdrawal (29,30). 

Aldesleukin-induced increase in lung capillary permeability or direct cardiac dysfunction is thought to be a likely mechanism of this adverse effect, and a localized vascular leak syndrome, attributed to activation of eosinophils in the lung and subsequent deposition of the eosinophil major basic protein, has also been suggested, as reported in a 49-year-old woman with breast cancer (31). 

Hematological adverse effects of aldesleukin typically included transient anemia, thrombocytopenia, eosinophi-lia, neutropenia, extreme lymphopenia, and rebound lymphocytosis (4,59). Transient suppression of hemopoiesis by secondary cytokines, peripheral platelet destruction, and increased endothelium margination of lymphocytes are possible mechanisms. 

In a phase III trial in 190 patients with metastatic melanoma, sequential chemotherapy with dacarbazine, cisplatin, and vinblastine plus interferon alfa and aldesleukin modestly increased the response rates and produced considerably more frequent and severe adverse effects than chemotherapy alone (128). In particular, severe episodes of anemia and thrombocytopenia that required blood or platelet transfusions were 2-6 times more frequent in the chemotherapy group. 

The primary indication for aldesleukin is in the irealment of adult mclaslalic renal carcinoma. Il is administered via intravenous infusion in doses of 10.0(X) to 50.000 U/kg every 8 hours for 12 days. Il is primarily metabolized by the kidneys. with no active form found in the urine. Aldesleukin causes serious adverse effects in patients, including fever, hypotension, pulmonary congestion and dyspnea. coma.gav iroinleslinal bleeding, respiratory failure, renal failure, arrhythmias.. seizures, and death. 

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