Aldesleukin

Use in patients with HIV infection

The use, benefits, and adverse effects of aldesleukin in HIV-infected patients have been extensively reviewed [ ]. 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 [ ].

In two randomized, controlled studies (44 patients given subcutaneous aldesleukin, 58 given a modified-release polyethylene glycol-modified formulation, 27 given continuous intravenous aldesleukin, and 50 controls), aldesleukin was well tolerated and a minority of patients required drug withdrawal because of adverse events [ , ]. The overall adverse effects profile of both routes of administration was very similar, but was substantially less severe than previously described with high-dose aldesleukin. It consisted mostly of fatigue, nasal/sinus congestion, fever above 38 °C, headache, gastrointestinal disorders, stomatitis, somnolence, and mood change. Increased bilirubin and alanine transaminase activities were more frequent than in the control group. None of the patients developed the capillary leak syndrome or significant hypertension, but cardiomyopathy, attempted suicide, ulcerative colitis, and exacerbation of hepatitis B were identified in one patient each among 85 patients treated with aldesleukin [ ]. Erythema and injection site reactions were observed in 66–69% of patients who received subcutaneous aldesleukin, and skin biopsies showed a perivascular infiltrate with lymphocytes and some eosinophils.

Use in patients with metastatic melanoma

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 [ ]. 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.

In a randomized trial, 102 patients with metastatic melanoma had more frequent treatment-related adverse effects, particularly hematological suppression in patients treated with tamoxifen, cisplatin, and dacarbazine followed by interferon alfa and aldesleukin, than in patients treated with chemotherapy alone, but there was no increase in survival [ ].

General adverse effects and adverse reactions

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

High-dose aldesleukin is associated with a wide range of adverse effects, and practical guidelines for their avoidance and management have been detailed [ ]. Constitutional symptoms (malaise, fever, chills and asthenia) are universal in patients treated with high-dose aldesleukin [ ]. Although they are usually suppressed by paracetamol (acetaminophen), indometacin, or pethidine, they are one of the major reasons for stopping treatment. Myalgia and arthralgia are sometimes associated with the flu-like symptoms.

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 [ ]. This results in a third-space clinical syndrome, generalized or peripheral edema, weight gain, cardiovascular and pulmonary complications 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 endothelial cells, release of secondary cytokines, and activation of the complement cascade [ ].

Denileukin diftitox

Denileukin diftitox is a fusion protein formed by binding human aldesleukin to the cytotoxic A chain of diphtheria toxin. This product binds to the aldesleukin receptor and inhibits protein synthesis, resulting in cell death. It has been approved for treatment of persistent or recurrent cutaneous T cell lymphoma and is being evaluated in patients with severe psoriasis.

In 71 patients with cutaneous T cell lymphomas randomized to denileukin diftitox 9 or 18 μg/kg/day, flu-like and gastrointestinal symptoms were observed in 92% [ ]. About 60% had an acute hypersensitivity reaction, with dyspnea, back pain, hypotension, and chest pain or tightness within 24 hours of infusion. A vascular leak syndrome, as defined by the presence of at least two of edema, hypoalbuminemia, and hypotension, occurred in 25%.

A dose-escalation study in 35 patients with psoriasis confirmed that constitutional symptoms in response to denileukin diftitox were dose-related and less frequent at lower doses (below 5 micrograms/kg/day) [ ]. There was only one case of mild vascular leak syndrome. Skin reactions compatible with delayed hypersensitivity reactions were noted in three patients, including one case of exfoliative dermatitis.

The more severe adverse effects of denileukin diftitox consisted of acute hypersensitivity reactions during or within 24 hours of infusion in 69% of patients, and a vascular leak syndrome in 27% of patients, which was severe in 6%. In contrast to acute hypersensitivity reactions, the vascular leak syndrome was typically delayed and occurred within the first 2 weeks of infusion [ ]. Whether this was due to a direct action of denileukin diftitox or to tumor lysis syndrome is unknown.

Cardiovascular

Hemodynamic and cardiac complications are the major limitations of high-dose aldesleukin and have been described in both adults [ ] and children [ ]. Significant hypotension requiring meticulous maintenance therapy with intravenous fluids or low-dose vasopressors was observed in most patients [ ]. The clinical findings were very similar to the hemodynamic pattern seen in early septic shock. Aldesleukin-induced increases in plasma nitrate and nitrite concentrations correlated with the severity of hypotension [ ].

Among other cardiovascular complications, cardiac dysrhythmias were reported in 6–10% of patients, angina pectoris or documented myocardial infarction in 3–4%, and mortality due to myocardial infarction in 1–2% [ ]. Severe myocardial dysfunction, myocarditis, and cardiomyopathy have been seldom reported [ , ].

The cardiopulmonary toxicity of high-dose intravenous bolus aldesleukin has been analysed in 199 metastatic melanoma or renal cell carcinoma patients without underlying cardiac disease [ ]. Cardiovascular events occurred within hours after starting infusion, persisted throughout aldesleukin therapy, and normalized within 1–3 days after treatment withdrawal. Hypotension was the most frequent adverse effect (53% of treatment courses) and resolved promptly with vasopressor treatment. Unexpectedly, the response to treatment was significantly better in patients with melanoma who had hypotension. There were cardiac dysrhythmias in 9% of patients; they mostly consisted of easily manageable atrial fibrillation or supraventricular tachycardia. Further courses of aldesleukin in 11 of these patients produced recurrent dysrhythmias in only two, and long-term treatment of dysrhythmias was never required. High-degree atrioventricular block and repetitive episodes of ventricular tachycardia were each observed once. Although 11% of patients had raised creatine kinase activity before or during treatment, only 2.5% had a documented rise in the MB isoenzyme fraction.

At-risk patients include those with pre-existing cardiac disease, whereas age, performance status, and sex are not significantly associated with cardiopulmonary toxicity. In view of this risk, it is reasonable to monitor cardiac function and creatine kinase activity closely in all patients, or to exclude those with significant underlying coronary or cardiorespiratory disease. Pretreatment cardiac screening has greatly reduced the incidence of myocardial infarction, ischemia, and related dysrhythmias, and two-dimensional and Doppler echocardiography was suggested to be helpful to anticipate cardiovascular toxicity [ ]. A reduction in systemic vascular resistance, stroke work index, and left ventricular ejection fraction are usually involved in the pathophysiology of cardiac dysfunction. Clinical, electrocardiographic, and radionuclide ventriculography monitoring in 22 patients undergoing a 5-day continuous intravenous infusion of aldesleukin for various cancers showed that reversible left ventricular dysfunction accounted for most of the observed hemodynamic changes [ ]. Indeed, significant coronary disease was usually not observed in patients undergoing cardiac catheterization, which argues for direct myocardial damage [ ]. In isolated reports, clinical and histological findings of eosinophilic, lymphocytic, or mixed lymphocytic–eosinophilic myocarditis also suggested an immune-mediated drug reaction [ ].

Aldesleukin-induced cardiac eosinophilic infiltration has been reported [ ].

• After 25 days of treatment with continuous aldesleukin infusion (up to 150 000 units/kg/day) for stage IV Hodgkin’s disease, a 26-year-old woman had increased fatigue, tachycardia, hypotension, and hypothermia. Echocardiography showed bilateral intraventricular masses. Her maximal absolute eosinophil count was 11.4 × 10 ⁹ /l and the platelet count was 17 × 10 ⁹ /l. Despite aldesleukin withdrawal, her condition deteriorated and she died. Postmortem examination showed biventricular thrombi and prominent eosinophilic infiltration of the endomyocardium.

Of 10 subsequent patients who received prolonged infusions of aldesleukin and were monitored by echocardiography, one developed asymptomatic changes in cardiac function, with features suggestive of early thrombus formation and a reduced ejection fraction during weeks 6–8. The maximal absolute eosinophil count was 5 × 10 ⁹ /l. These abnormalities resolved on aldesleukin withdrawal.

Conjugates of aldesleukin with polyethylene glycol produce less cardiovascular toxicity [SEDA-20, 333].

Respiratory

Dose-related cough has been reported as the most frequent adverse effect of inhaled aldesleukin [ ].

Among 199 patients with metastatic melanoma or renal cell carcinoma treated with high-dose intravenous bolus aldesleukin, there was severe respiratory distress in 3.2% of treatment courses, but intubation was required in only one [ ]. This is far less common than earlier estimates that 10–30% of patients develop respiratory distress severe enough to warrant mechanical ventilation in 5–20% of cases [ ]. The improvement may be related to the current strict selection criteria for the evaluation of pulmonary function, limited fluid management strategy, prophylactic antibiotics, and prompt withdrawal of treatment in patients presenting with shortness of breath, rales, or persistent hypoxemia.

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 [ , ].

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 [ ].

There is no significant association between pre-existing clinical dysfunction and radiological interstitial edema [ ]. Very severe adult respiratory distress syndrome requiring double lung transplantation has been reported in one patient [ ].

Inhaled aldesleukin in three cycles of 36 MIU/day for 5 days/week or for 3 out of 4 weeks for 12 weeks has been investigated in 51 patients with pulmonary metastases from renal cell carcinoma [ ]. In 40% of the cycles inhalation of aldesleukin was associated with cough and 7% had fatigue.

Nervous system

Severe pain resulting from a previously asymptomatic thoracic spine metastasis has been attributed to aldesleukin in a 64-year-old man with metastatic renal cell carcinoma [ ].

Fatal acute leukoencephalopathy with brain perivascular foci demyelination [ ] and delayed progressive cognitive dysfunction [ ] have been reported in isolated cases.

The neurotoxicity of aldesleukin is usually dose-related and can be treatment-limiting [ ].

Sensory systems

Transient episodes of amaurosis or scotomata, both of which recurred after aldesleukin rechallenge, have been described [ ]. Three other patients had visual phenomena, including diplopia, scotomata, and palinopsia during treatment, which resolved on withdrawal of aldesleukin [ ].

Psychological, psychiatric

Aldesleukin can cause moderate impairment of cognitive function, with disorientation, confusion, hallucinations, sleep disturbances, and sometimes severe behavioral changes requiring transient neuroleptic drug administration [ ]. Some of the cognitive deficits mimicked those observed in dementias, such as Alzheimer’s disease. Several studies have also shown increased latency and reduced amplitude of event-related evoked potentials in patients with cognitive impairment [ , ]. Other infrequent adverse effects included paranoid delusions, hallucinations, loss of interest, sleep disturbances or drowsiness, reduced energy, fatigue, anorexia, and malaise. Coma and seizures were exceptionally noted. Symptoms occurred within 1 week of treatment and complete recovery was usually noted after aldesleukin withdrawal.

In 10 patients with advanced tumors, low-dose subcutaneous aldesleukin produced significant psychological changes; increased depression scores, psychasthenia, and conversion hysteria were the most common findings [ ].

The short-term occurrence of depressive symptoms has been investigated by using the Montgomery and Asberg Depression Rating Scale (MADRS) before and after 3 and 5 days of treatment in 48 patients without a previous psychiatric history and treated for renal cell carcinoma or melanoma with aldesleukin alone (n = 20), aldesleukin plus interferon alfa-2b (n = 6), or interferon alfa-2b alone (n = 22) [ ]. On day 5, patients in the aldesleukin groups had significantly higher MADRS scores, whereas there were no significant changes in the patients who received interferon alfa-2b alone. Eight of 26 patients given aldesleukin and only three of 22 given interferon alfa-2b alone had severe depressive symptoms. Depressive symptoms occurred as early as the second day of aldesleukin treatment and were more severe in the patients who received both cytokines. Early detection of mood changes can be useful in pinpointing patients at risk of subsequent severe neuropsychiatric complications.

Neuropsychiatric symptoms are less frequent with subcutaneous aldesleukin [ ]. No predictive or predisposing factors have been clearly identified. Whether a direct effect of aldesleukin on neuronal tissues, an increased vascular brain permeability with a subsequent increased brain water content, or an aldesleukin-induced release of neuroendocrine hormones (beta-endorphin, ACTH, or cortisol), accounted for these effects, is unknown. A possible immune-mediated cerebral vasculitis has also been reported in one patient [ ].

Endocrine

Various hormonal and metabolic effects of aldesleukin are temporally related to hypotension. Transient serum rises in ACTH, cortisol, beta-endorphin, adrenaline and noradrenaline have been found, whereas there were no significant changes in the plasma concentrations of several other hormones [ ].

An acute episode of adrenal insufficiency secondary to adrenal hemorrhage occurred in one patient receiving aldesleukin [ ].