AHFS Class:

• Antineoplastic Agents 10:00

Generic Name(s):

• Aldesleukin

Chemical Name:

• 125-l-Serine-2-133-Interleukin 2 (human reduced)

Molecular Formula:

• C₆₉₀H₁₁₁₅N₁₇₇O₂₀₃S₆

Aldesleukin, a human interleukin-2 derivative, is a biosynthetic (recombinant DNA origin) cytokine (i.e., lymphokine) with antineoplastic and immunomodulating activities.1,2

Renal Cell Cancer

Overview

Aldesleukin, alone or in combination therapy, is used for the treatment of metastatic renal cell carcinoma in selected patients.1,5,22 There is no generally accepted standard therapy for metastatic renal cell carcinoma.22,52,64,109

Surgery

Because of the poor response to systemic therapy, surgical resection often is included in the management of metastatic renal cell carcinoma.144 Nephrectomy may be performed in selected patients for palliation of symptoms and improvement in the quality of life.22,109,116,117,135 Selected patients with a solitary metastasis or a limited number of metastases occurring at a long interval following initial nephrectomy for renal cell carcinoma may achieve prolonged survival with surgical resection of metastases.22,109,117,144 The benefit of aggressive surgical management in patients with a solitary metastasis found at the time of diagnosis of the primary tumor is less clear;52 some experts state that nephrectomy and surgical resection of the metastasis provide benefit110,117 whereas others observe that outcome is poor in such patients despite surgery.109,117

Although routine surgery to debulk tumors before systemic drug therapy generally is not advised,109,135 some evidence suggests that nephrectomy may remove immunosuppressive factors associated with tumor growth, and primary nephrectomy followed by biologic therapy may offer benefit in selected patients with metastatic renal cell carcinoma.116,117,144,163,185,186,187,188,189 In 2 randomized trials, median survival was prolonged in patients with metastatic renal cell cancer who underwent radical nephrectomy followed by interferon alfa compared with patients who received interferon alfa alone.185,188 Retrospective analysis of cases from a registry of patients with metastatic renal cell cancer suggests that nephrectomy followed by aldesleukin may achieve similarly prolonged survival.187 Aldesleukin also has been used prior to surgery in patients with metastatic renal cell cancer; complete responses to therapy have been reported in patients with metastatic renal cell carcinoma undergoing adjunctive nephrectomy (i.e., resection of primary tumor) and/or aggressive surgical resection of residual disease following major response to aldesleukin-based regimens.109,113,132,139,154

Drug Therapy

Various forms of systemic drug therapy, including cytotoxic agents, hormonal agents, and biologic agents (e.g., aldesleukin, interferon alfa), have been studied in patients with metastatic renal cell carcinoma.22,109,144 Response rates with cytotoxic chemotherapy generally have been poor for any regimen that has been studied in adequate numbers of patients with metastatic renal cell carcinoma.15,19,20,22,52,64,99,109,144,157,158,159 Although hormonal therapy (e.g., medroxyprogesterone acetate, tamoxifen) has been studied in the treatment of metastatic renal cell carcinoma, results have been disappointing, and these agents are no longer used.22,52,109,117,145,146,147

Immunotherapy with cytokines, such as aldesleukin or interferon alfa, is used for the systemic treatment of metastatic renal cell carcinoma20,22,109,111,115,117,144 despite low response rates. Both the likelihood and duration of response, including durable complete regression in some cases, appear to be improved compared with those observed with conventional chemotherapy.15,20,21,22,52,101 In addition, a survival benefit has been associated with interferon-alfa-containing regimens in patients with metastatic renal cell carcinoma.179,180 Thus, while response rates for this advanced cancer remain disappointing with currently employed therapy, including current aldesleukin regimens, evidence to date indicates that therapy that includes biologic response modifiers such as aldesleukin may provide an option for systemic treatment in some patients.5,15,20,21,22,144 In carefully selected patients with a major response to aldesleukin therapy, nephrectomy and/or surgical resection of residual disease following immunotherapy may prolong disease-free survival.109,113,132,139

Whether higher response rates or more durable responses are observed in patients with metastatic renal cell carcinoma receiving immunotherapy with cytokines, such as aldesleukin, than in those receiving supportive care only has not been fully established.52,135,136 Results from a randomized, placebo-controlled trial showed no benefit in overall response rate, rate of durable complete response, time to disease progression, or duration of survival with use of the cytokine interferon gamma-1b for metastatic renal cell carcinoma.134

Aldesleukin is labeled for use in the treatment of metastatic renal cell carcinoma based on evidence from noncomparative, phase 2 studies;111 aldesleukin has not been studied in placebo-controlled trials, and evidence from randomized trials comparing aldesleukin monotherapy or aldesleukin-containing regimens with other agents is limited.115,134,135,136 Antiangiogenic agents (e.g., sorafenib, sunitinib) are labeled for use in the treatment of advanced renal cell cancer.22 Studies are under way to establish the role of these agents in the first-line treatment of metastatic renal cell cancer.22 Because the current prognosis for patients with metastatic renal cell carcinoma is poor and conventional cytokine therapy has minimal activity with substantial toxicity, all patients with this cancer should be considered for inclusion in clinical trials at the time of diagnosis.22,52,109,110,135,144,149 Supportive care (e.g., adequate analgesia for pain management, surgery for solitary brain metastasis or spinal cord compression, radiation therapy for palliation of metastases, particularly painful bone metastases) remains a mainstay of therapy for patients with metastatic renal cell cancer.52,109,110,162

In a phase 3 randomized, controlled trial, the use of aldesleukin as adjuvant therapy following surgical resection of stage III or IV renal cell carcinoma did not affect disease-free or overall survival.150 Currently, no systemic therapy has been shown to reduce the risk of relapse or prolong survival in patients with localized renal cell carcinoma at high risk of recurrence;109,110,144,151,152,153 preliminary results from a small randomized trial suggest that adjuvant therapy with ex vivo activated T cells (ALT) and high-dose cimetidine delays disease recurrence.164

Monotherapy for Metastatic Renal Cell Cancer

Aldesleukin is used as monotherapy for the treatment of metastatic renal cell carcinoma.1,22,109,111,116,117,144 During 7 phase 2 clinical trials in which 255 patients with metastatic renal cell carcinoma received courses of therapy consisting of two 5-day cycles of aldesleukin 600,000 units/kg (5 studies) or 720,000 units/kg (2 studies) given as a 15-minute IV infusion every 8 hours for up to 14 doses per cycle, objective response was observed in 15% (7% complete and 8% partial responses);1,111 all patients in these studies were asymptomatic or symptomatic but fully ambulatory (ECOG performance status 0 or 1, respectively).1,111 The 95% confidence interval for the objective response rate was 11-20%.1 Onset of tumor regression has been observed as early as 4 weeks after completion of the first course of treatment, and tumor regression may continue for up to 12 months following initiation of aldesleukin therapy.1 The median duration of objective response with aldesleukin therapy for those with partial responses is 20 months.1 The minimum median duration of objective response for those with complete responses is 80 months.1 The median duration of overall objective response (partial or complete) currently is 54 months (range: 3-131+ months).1 Continued follow-up shows that complete responses to aldesleukin for metastatic renal cell cancer are durable.193 Tumor regression was observed in both pulmonary and extrapulmonary sites (e.g., liver, lymph node, renal bed recurrences, soft tissue).1,111 Responses also were observed in patients with individual bulky lesions and large cumulative tumor burden.1,111

Objective response rates of 0-50% have been observed in other studies of patients receiving aldesleukin alone or in combination with other agents for metastatic renal cell carcinoma;15,23,24,26,27,28,29,30,31,32,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,53,54,55,97,98 variability in response rates with aldesleukin therapy is influenced by the small number of patients in many of these studies, study selection criteria (e.g., ECOG performance status), prognostic factors (e.g., prior treatment, site of metastases), dosage schedules, and mode of administration.15,23,28,31,36

Good performance status (i.e., ECOG performance status of 0 corresponding to asymptomatic patients) is associated with higher rates of response and a lower frequency of adverse effects with aldesleukin therapy in patients with metastatic renal cell carcinoma.1,111,112 Although reliable criteria for selecting patients most likely to benefit from cytokine therapy have not been established, prognostic factors have been identified that are associated with poor outcome despite treatment with aldesleukin and/or interferon alfa (e.g., multiple sites of metastasis, metastasis to the liver, metastasis within 1 year following diagnosis of primary tumor).115

Evidence from controlled, comparative studies evaluating the efficacy of aldesleukin versus other agents in the treatment of metastatic renal cell carcinoma is limited.15,52,101,115 Although the overall response rates associated with either aldesleukin or interferon alfa monotherapy appear to be similar at about 15 and 10-15%, respectively, current evidence suggests that the incidence of complete or durable response is greater with aldesleukin therapy (5 versus 1%).15,22,52,115,117 However, interferon alfa therapy is less toxic than high-dose aldesleukin therapy,52,115,149 and 2 large randomized trials have demonstrated a survival benefit associated with interferon-alfa-containing regimens in patients with metastatic renal cell carcinoma179,180 whereas such data are lacking for aldesleukin.52

Combination Therapy for Metastatic Renal Cell Cancer

Aldesleukin has been used in various combination regimens with other agents, such as biologic response modifiers (e.g., interferon alfa), 37,42,43,44,45,46,49,53,115,117,119,120,121,122,123,124,125,126,136,138,161 or adoptive immunotherapy (e.g., lymphokine-activated killer [LAK] cells, tumor-infiltrating lymphocytes [TILs]),26,27,29,30,31,32,37,38,47,48,49,51,98,105,127,128,156 for the treatment of metastatic renal cell carcinoma.

Aldesleukin has been used in combination with interferon alfa, another biologic response modifier, for the treatment of metastatic renal cell carcinoma.37,42,43,44,45,46,49,53,115,117,119,120,121,122,123,124,125,138 A collective response rate of about 20% (5% complete responses, 15% partial responses), similar to the overall response rate of 15% observed with aldesleukin monotherapy,111,117,122 has been observed in patients with metastatic renal cell carcinoma receiving aldesleukin—administered by IV bolus injection,46,53,138 continuous IV infusion,37,42,43,44,45,49,115,124 or subcutaneous injection119,120,121,122,123,125 —in combination with interferon alfa. Current evidence has not established whether the combination of aldesleukin and interferon alfa is superior to aldesleukin alone in patients with this cancer.46,115,117,123,124,125 A retrospective analysis indicates that similar efficacy and less toxicity are observed in patients receiving subcutaneous aldesleukin and subcutaneous interferon alfa compared with continuous IV infusion of aldesleukin alone for advanced renal cell carcinoma.119 In a large, randomized trial, patients receiving continuous IV infusion of aldesleukin combined with subcutaneous interferon alfa-2a had a higher response rate and higher rate of event-free survival at 1 year but no difference in overall survival compared with those receiving either agent alone; greater toxicity was observed in patients receiving aldesleukin, either alone or in combination therapy, than in those receiving interferon alfa.115 The low response rates observed for monotherapy with aldesleukin or interferon alfa in this trial may have contributed to the differences observed in comparison with the combination therapy.52,116,124

Limited evidence from a randomized, phase 2 trial suggests that the addition of interferon alfa-2b to a high-dose, intermittent IV infusion regimen of aldesleukin did not improve response rate, and incidence of complete response and duration of response appeared to be more favorable for patients receiving high-dose aldesleukin monotherapy for advanced renal cell carcinoma.46 At a median follow-up of 72 months in another randomized phase 2 trial, median duration of response was longer (53 versus 14 months) and the rate of progression-free survival at 3 years was higher (13 versus 3%) for patients receiving high-dose IV aldesleukin alone compared with those receiving high-dose IV aldesleukin and IV interferon alfa-2b.132 In a phase 3 randomized trial, response rates were higher but there was no difference in progression-free survival or overall survival for patients receiving high-dose IV aldesleukin alone versus those receiving an outpatient regimen of subcutaneous aldesleukin and subcutaneous interferon alfa.190 A phase 2 randomized trial indicates that toxicity is greater but overall survival is not improved when subcutaneous interferon alfa is added to a regimen of subcutaneous aldesleukin.125 In a randomized trial, no survival difference was observed in patients receiving subcutaneous aldesleukin, subcutaneous interferon alfa, and oral tamoxifen versus oral tamoxifen alone.136 Large randomized trials comparing various regimens are needed to establish the role of combination therapy with aldesleukin and interferon alfa in patients with metastatic renal cell carcinoma.46,115,117,123,124,125

Aldesleukin also has been used in combination with other biologic response modifiers (e.g., interferon beta),126 or adoptive immunotherapy (e.g., LAK cells, TILs),26,27,29,30,31,32,37,38,47,48,49,51,98,105,127,128,156 for the treatment of metastatic renal cell carcinoma. Current evidence suggests that the addition of interferon beta does not improve response rate or survival in patients receiving aldesleukin for advanced disease.126 Concomitant administration of aldesleukin and LAK cells15,26,27,29,30,31,32,37,38,51,98,105 does not provide greater benefit than aldesleukin monotherapy.29,30,31,38,105,156 Although durable antitumor responses127,128 have been reported in some patients receiving aldesleukin combined with TILs, with or without interferon alfa,15,37,47,48,49,99,127,128 a randomized, phase 3 trial did not show any benefit in response rate or survival duration with the addition of CD8⁺-selected TILs to low-dose continuous IV infusion of aldesleukin administered following nephrectomy.163 Further study is needed to establish the role of combination therapy with aldesleukin and adoptive immunotherapy in patients with metastatic renal cell carcinoma.163

Further study also is needed to establish the benefit of aldesleukin-containing combination regimens versus aldesleukin monotherapy.116,120,122,123 Randomized trials are needed to determine the comparative efficacy and safety of an outpatient regimen of subcutaneous aldesleukin and interferon alfa versus high-dose intravenous aldesleukin alone.52,116,122

Other Considerations

Despite initial response to aldesleukin, tumor relapse is common in patients with metastatic renal cell carcinoma, particularly following partial response to therapy.113 Treatment of relapsed disease with the same aldesleukin-based therapy that produced the initial response rarely is effective.113,114 Some secondary responses have been observed in patients receiving an aldesleukin-based regimen different from the regimen that produced the initial response.113

Melanoma

Overview

Aldesleukin is used for the palliative treatment of metastatic melanoma in selected patients.1,5,68,165,168,170,178 Durable complete responses have been observed in a small percentage of patients receiving aldesleukin for metastatic melanoma, including some who have disease with poor prognostic factors (e.g., visceral metastases, ECOG performance status).1,168,170,178 Because of low response rates and substantial toxicity, use of high-dose aldesleukin therapy is restricted to carefully selected patients receiving treatment from experienced clinicians at established cancer treatment centers.5,52,165,166,170,178 Another established treatment option for patients with metastatic melanoma is dacarbazine monotherapy (see Dacarbazine 10:00).5,165,166 In contrast to other agents or regimens used for the treatment of metastatic melanoma, therapy with aldesleukin appears to offer more complete and durable responses,170 but comparative studies are lacking.52 Aldesleukin has been used alone and in combination† with other agents in the palliative treatment of metastatic melanoma.1,5,68

Monotherapy for Metastatic Melanoma

Aldesleukin is used as monotherapy for the treatment of metastatic melanoma.1,20,31,170,178 The indication for use of aldesleukin monotherapy for metastatic melanoma is based on evidence from uncontrolled, phase 2 studies;20,170 response rates average 16% for aldesleukin as a single agent with a complete response rate of about 6%.1,20,68,169,170,178

The current indication for use of aldesleukin in the treatment of metastatic melanoma is based on evidence from phase 2 clinical trials in which 270 patients received courses consisting of two 5-day cycles of aldesleukin 600,000 units/kg (4 studies) or 720,000 units/kg (3 studies) given as a 15-minute IV infusion every 8 hours for up to 14 doses per cycle; additional data from a manufacturer-sponsored study involving 5 patients also were included.1,170 Objective response was observed in 16% (6% complete and 10% partial responses);1,170 all patients in these studies were asymptomatic or symptomatic but fully ambulatory (ECOG performance status 0 or 1, respectively).1,170 The 95% confidence interval for the objective response rate was 12-21%.1

The median duration of objective response with aldesleukin therapy for those with partial responses is 6 months.1,170 The minimum median duration of objective response for those with complete responses is 59 months.1 The median duration of overall objective response (partial or complete) currently is 9 months (range: 1-122+ months).1,170 Tumor regression was observed in both visceral (e.g., lung, liver) and nonvisceral (e.g., lymph nodes, soft tissue, adrenal gland, subcutaneous tissue) sites.1,170 Responses also were observed in patients with individual bulky lesions and large cumulative tumor burden.1 Good performance status (i.e., ECOG performance status of 0 corresponding to asymptomatic patients) is associated with higher rates of response and a lower frequency of adverse effects with aldesleukin therapy in patients with metastatic melanoma.1,170

Combination Therapy for Metastatic Melanoma

Aldesleukin has been used in various combination regimens with other agents including biologic response modifiers (e.g., interferon alfa),43,53,55,79,80,81,173 adoptive immunotherapy (e.g., LAK cells, TILs),30,31,47,51,65,66,70,71,74,75,76,78 and/or conventional chemotherapeutic agents (e.g., cisplatin, dacarbazine)82,171,172 for the treatment of metastatic melanoma. Although higher response rates have been observed with some aldesleukin-containing combination regimens for the treatment of metastatic melanoma,15,52,65,68,85,100,101,172,176 improvement in survival has not been demonstrated and toxicity often is greater.30,52,65,66,81,101,171,172,174,175,176 The use of aldesleukin in combination with vaccines containing antigens from melanoma cells is being investigated.181 The role of aldesleukin in combination regimens for the treatment of metastatic melanoma remains to be established.52,165,170,174,175,176

Regimens combining aldesleukin with other biologic response modifiers (e.g., interferon alfa) and/or conventional chemotherapeutic agents (cisplatin, dacarbazine) have been studied in randomized trials.68,81,171,172 Aldesleukin has been used in combination with interferon alfa for the treatment of metastatic melanoma.43,53,55,79,80,81,173 The addition of interferon alfa did not increase response rate or prolong survival in patients receiving high-dose IV aldesleukin81 or continuous IV infusion aldesleukin and IV cisplatin.171 Although favorable response rates have been reported in patients with advanced melanoma receiving aldesleukin and cisplatin in phase 2 studies,52,82 the benefit of cisplatin has not been confirmed in randomized trials.68,172 A phase 3 randomized trial showed that the addition of cisplatin increased response rate and prolonged progression-free survival but did not prolong overall survival in patients receiving aldesleukin and interferon alfa.172

Aldesleukin also has been used, with or without interferon alfa, as a component of biochemotherapy regimens for metastatic melanoma.83,84,85,86,87,88,174,175,176 Although higher objective response rates have been reported in patients who received sequential administration of conventional chemotherapeutic agents (e.g., cisplatin alone; cisplatin and dacarbazine; carmustine, cisplatin, and dacarbazine) followed by aldesleukin with or without interferon alfa,83,84,85,86,87,88 the use of combination therapy with chemotherapy and biologic therapy has not been shown to improve survival and has been associated with substantial toxicity.174,175,176,191 Analysis of pooled data194 from randomized studies indicates that the addition of aldesleukin and/or interferon alfa to chemotherapy increases response rates but does not prolong survival in patients with metastatic melanoma. In a phase 3 randomized trial in patients with metastatic melanoma, the addition of biotherapy with IV aldesleukin and subcutaneous interferon alfa following chemotherapy with cisplatin, vincristine, and dacarbazine resulted in high response rates and prolonged time to progression, but there was no difference in survival and toxicity was greater with the biochemotherapy regimen.191 In a randomized trial, patients receiving combination chemotherapy (cisplatin, dacarbazine, and tamoxifen) followed by high-dose IV aldesleukin and subcutaneous interferon alfa-2b had increased toxicity but no improvement in survival compared with patients receiving chemotherapy alone for metastatic melanoma.174 In a randomized, phase 2 trial, the addition of immunotherapy with subcutaneous aldesleukin and subcutaneous interferon alfa caused immune activation but greater toxicity and no apparent difference in response rate, progression-free survival, or overall survival in patients receiving chemotherapy with carmustine, cisplatin, dacarbazine, and tamoxifen.175 Similarly, evidence from uncontrolled studies suggests that concomitant administration of aldesleukin and either cyclophosphamide (as an immunomodulator)89,90,104 or dacarbazine91,92,93 does not offer substantial improvement compared with aldesleukin monotherapy, although toxicity may be reduced with lower doses of aldesleukin used in these regimens.52,89,90,91,101,104

The timing and sequence of administration of chemotherapy and biotherapy appears to affect efficacy and toxicity, and other regimens (e.g., concurrent biochemotherapy) are being investigated.176,182,183 In a randomized trial in patients with metastatic melanoma, there was no difference in survival for concurrent biochemotherapy with cisplatin, vinblastine, dacarbazine, aldesleukin, and interferon alfa-2b versus combination chemotherapy with cisplatin, vinblastine, and dacarbazine.183 In another randomized trial in patients with metastatic melanoma, there was no difference in response rates or survival when IV aldesleukin was added following a regimen of dacarbazine, cisplatin, and subcutaneous interferon alfa.192

Aldesleukin also has been used in combination with adoptive immunotherapy, such as lymphokine-activated killer (LAK) cells30,31,51,65,66 and tumor-infiltrating lymphocytes (TILs),47,70,71,74,75,76,78 for the management of metastatic melanoma. Evidence to date indicates that, as in metastatic renal cell carcinoma,15,29,30,31,64,99,105 the efficacy of aldesleukin generally is not improved by the addition of LAK cells to the regimen.30,31,52,65,66,101,156 The addition of other types of adoptive immunotherapy (e.g., autologous lymphocytes activated by interleukin-2 ex vivo, tumor-infiltrating lymphocytes [TIL]) to aldesleukin for the treatment of metastatic melanoma does not substantially increase response rate or prolong survival,68 and these methods are associated with considerable complexity and cost compared with other aldesleukin regimens.52,72,78,101 Additional well-controlled studies are needed to define the role of aldesleukin in the management of metastatic melanoma;15,52,57,58,59,60,61,62,170 response rates, duration of response, toxicity, and careful study of biologic and immunologic mechanisms must be considered in establishing the optimum regimen of the drug in this disease.15,52

Other Considerations

Despite initial response to aldesleukin, tumor relapse is common in patients with metastatic melanoma, particularly following partial response to therapy.113 Treatment of relapsed disease with the same aldesleukin-based therapy that produced the initial response rarely is effective.113,114 Some secondary responses have been observed in patients receiving an aldesleukin-based regimen different from the regimen that produced the initial response (e.g., aldesleukin combined with tumor-infiltrating lymphocytes following initial treatment with aldesleukin monotherapy).113

Reconstitution and Administration

Aldesleukin is administered by IV infusion;1,3 the drug also is administered subcutaneously†.15,40,55

Aldesleukin powder for injection is reconstituted by adding 1.2 mL of sterile water for injection to a vial labeled as containing 22 million units (1.3 mg) of the drug; the resultant solution contains 18 million units (1.1 mg)/mL.1 Because aldesleukin is not compatible with bacteriostatic water for injection or sodium chloride injection, use of these diluents should be avoided when preparing aldesleukin solutions.1,96,101 During reconstitution, the water should be directed toward the side of the vial with gentle swirling, not shaking, to avoid excessive foaming of the solution.1 For rapid IV infusion, the appropriate dose of aldesleukin should then be withdrawn and diluted in 50 mL of 5% dextrose injection, preferably in a plastic (PVC) container, and infused over 15 minutes.1,101

Dilution and delivery of aldesleukin solutions outside the concentration range of 30-70 mcg/mL result in decreased stability and activity of the drug, and use of such solutions for short-duration IV infusion should be avoided.101 The manufacturer states that a larger or smaller volume of 5% dextrose injection may be used to maintain an aldesleukin concentration of 30-70 mcg/mL.1,101

The use of plastic rather than glass containers reportedly results in more consistent drug delivery because aldesleukin may adhere to glass.1,52 Aldesleukin solution should be brought to room temperature prior to IV infusion.1 Aldesleukin should not be coadministered with other drugs in the same container.1 The manufacturer recommends that an inline filter not be used during IV administration of the drug.1,101

Aldesleukin solutions should be inspected visually for discoloration and particulate matter prior to administration whenever solution and container permit.1

Dosage

The frequency and severity of adverse effects of aldesleukin generally are dose related.1 Administration of doses in excess of the recommended dose has been associated with a more rapid onset of anticipated dose-limiting toxicities.1 Adverse effects of aldesleukin that persist following discontinuance of the drug should be monitored and managed with supportive treatment.1 Life-threatening toxicities of aldesleukin may be ameliorated by IV administration of dexamethasone, which also may reduce the therapeutic effect of aldesleukin.1,52,101

Dosage of aldesleukin should be adjusted carefully according to patient tolerance and response.1 Potency of aldesleukin usually is expressed in international units (IU);1,3 because other units also have been reported (e.g., Cetus Units [CU], Roche Units [RU], Biologic Response Modifiers Program Units [BRMPU]) and are not equivalent (e.g., 1 RU = 3 IU, 1 CU = 6 IU), care should be exercised in interpreting published dosages and concentrations.3,101 In the dosage section, international units are stated as units rather than as IU in order to minimize medication errors that could have resulted from misinterpretation of written orders employing IU.

When a vial labeled as containing 22 million units of the drug is reconstituted by adding 1.2 mL of sterile water for injection, each mL contains 18 million units of aldesleukin, which is equivalent to 1.1 mg of the drug.1

Renal Cell Cancer

The optimum dosage and regimen for aldesleukin in the treatment of metastatic renal cell carcinoma have not been established.15,31,34,39,40,49,52,54,55,99,101,103,111,116,143 The course of therapy currently suggested by the manufacturer consists of two 5-day cycles of aldesleukin treatment separated by a 9-day rest period; in each cycle, aldesleukin 600,000 units/kg is given as a 15-minute IV infusion every 8 hours for 14 doses (maximum of 28 doses per course) or until intolerable adverse effects develop.1,23,38,52,111

In clinical trials of high-dose intermittent IV infusion therapy with aldesleukin, individual doses frequently were withheld because of toxicity, with a median of 20 out of 28 doses per course of therapy being administered during the initial course of therapy in patients with metastatic renal cell carcinoma.1 In practice, greater than 90% of patients had doses of aldesleukin withheld during a course of therapy.1 Modification of aldesleukin dosage for toxicity should involve withholding or interrupting a dose or doses rather than reducing individual doses.1 The decision whether to stop, withhold, or restart aldesleukin therapy must be made after global assessment of the patient according to the guidelines outlined in the manufacturer's labeling.1

Other dosage schedules and modes of administration for aldesleukin therapy, including administration by continuous IV infusion† over 24 hours29,32,33,35,36,37,38,39,97,98,105,115,119,143 and by subcutaneous injection†,15,40,55,112,121,137 have been used in patients with metastatic renal cell carcinoma. Aldesleukin frequently has been administered by continuous IV infusion† in a dosage of 18 million units/m² daily for two 5-day cycles, with a drug-free interval of about 5-8 days between cycles.15,32,35,36,37,38,97,115,119 The drug also has been administered by subcutaneousinjection† in a dosage of 18 million units daily for 5 days, followed by a 2-day rest period.15,40 For additional cycles, a dosage of 9 million units is given on days 1 and 2, followed by 18 million units daily for the next 3 days.15,40,52,101 Treatment cycles with subcutaneous therapy have been administered for 6 consecutive weeks separated by a 3-week drug-free period.40 Additional study is needed to determine the optimum regimen of aldesleukin for patients with metastatic renal cell carcinoma.31,34,37,38,39,40,49,54,64,98,99,103,111,116,143

Because of errors in dosage calculation and reconstitution,52 some clinicians have used an aldesleukin dosage of 720,000 units/kg, given as a 15-minute IV infusion every 8 hours for a maximum of 15 doses per cycle, with a rest period of 10 days between the 2 cycles.20,31 Alternatively, a low-dose intermittent IV infusion regimen of aldesleukin 72,000 units/kg may be as effective as, and less toxic than, a high-dose intermittent IV infusion regimen of 720,000 units/kg in patients with metastatic renal cell carcinoma.103 In a randomized trial, higher response rates and trends toward more complete responses and more durable complete responses occurred with high-dose versus low-dose aldesleukin therapy, but there was no difference in overall survival.103 Limited evidence from a phase 2 study suggests that aldesleukin exhibits a dose-response relationship when used as a single agent for the treatment of metastatic renal cell carcinoma;46 longer follow-up and further study are needed to establish the effect of dose when aldesleukin is used alone or in combination regimens.46,118

Patients should be evaluated approximately 4 weeks after completion of the initial course of high-dose intermittent IV infusion therapy with aldesleukin and again immediately prior to the scheduled start of the next course.1 The manufacturer states that further therapy with the drug should be undertaken only if there is some evidence of tumor regression following the last course and the patient has not developed serious toxicity that would contraindicate continuation of therapy.1 However, some clinicians believe that stabilization of disease alone in the absence of serious toxicity warrants continued therapy with aldesleukin.52,101 The manufacturer states that each treatment course should be separated by a drug-free interval of at least 7 weeks from the date of previous hospital dischar 1 however, some clinicians report use of shorter rest periods (i.e., 2-4 weeks) between courses of treatment with aldesleukin.52 While the optimum duration of aldesleukin therapy remains to be established, the manufacturer reports that tumor regression has continued for up to at least 12 months after administration of one or more courses of therapy with the drug.3

Some evidence suggests that administration of aldesleukin by continuous infusion using a controlled-delivery system results in reduced potency of the drug, and some experts state that aldesleukin should not be administered by continuous IV infusion;144,160 manufacturer studies demonstrate that the physical and chemical stability of aldesleukin solutions administered by continuous IV infusion depend on specific conditions including temperature, the concentration of the solution, and the infusion device environment.101 Subcutaneous administration of aldesleukin, generally in dosages lower than those administered IV, may produce similar response rates but less toxicity than IV infusion;15,40,52,55,103,118,137,154 however, additional study and longer follow-up with comparative analysis of overall survival and durability of responses is needed to determine the optimum regimen of aldesleukin for patients with metastatic renal cell carcinoma.15,31,34,37,38,39,40,49,52,54,64,98,99,103,117,118,122,144,154

Melanoma

The optimum dosage and regimen for aldesleukin in the treatment of metastatic melanoma have not been established.15,52,66,101,170 The usual course of therapy consists of two 5-day cycles of aldesleukin treatment separated by a 6- to 9-day rest period; in each cycle, aldesleukin 600,000 units/kg is given as a 15-minute IV infusion every 8 hours for 14 doses (maximum of 28 doses per course) or until intolerable adverse effects develop.1,170 Because of errors in dosage calculation and reconstitution,52 some clinicians used an aldesleukin dosage of 720,000 units/kg, given as a 15-minute IV infusion every 8 hours for a maximum of 15 doses per cycle, with a rest period of 10 days between the 2 cycles.20,31

In clinical trials of high-dose intermittent IV infusion therapy with aldesleukin, individual doses frequently were withheld because of toxicity, with a median of 18 doses out of 28 doses per course of therapy being administered during the initial course of therapy in patients with metastatic melanoma.1 In practice, greater than 90% of patients had doses of aldesleukin withheld during a course of therapy.1 Modification of aldesleukin dosage for toxicity should involve withholding or interrupting a dose or doses rather than reducing individual doses.1 The decision whether to stop, withhold, or restart aldesleukin therapy must be made after global assessment of the patient according to the guidelines outlined in the manufacturer's labeling.1

Other aldesleukin dosage regimens, including continuous IV infusion†32,33,36,37,177 and subcutaneous administration†15,55,79,83 of aldesleukin, have been used in patients with metastatic melanoma. Some clinicians report similar efficacy but less toxicity with a low-dose intermittent IV infusion regimen of aldesleukin,89,90,104,107 but comparative studies are lacking.15 Therapy with lower doses of aldesleukin also is being investigated in studies of combination regimens including chemotherapy, other biologic agents, or vaccine therapy.168,170 Although these alternative methods of administering aldesleukin have been associated with reduced toxicity, further study with comparative analysis of overall survival and durability of responses is needed to establish the comparative efficacy of such regimens in patients with metastatic melanoma.15,52,79

Patients should be evaluated approximately 4 weeks after completion of the initial aldesleukin course and again immediately prior to the scheduled start of the next course.1 The manufacturer states that further therapy with the drug should be undertaken only if there is some evidence of tumor regression following the last course and the patient has not developed serious toxicity that would contraindicate continuation of therapy.1 However, some clinicians believe that stabilization of disease alone in the absence of serious toxicity warrants continued therapy with aldesleukin.52,101 The manufacturer states that each treatment course should be separated by a drug-free interval of at least 7 weeks from the date of previous hospital dischar 1 clinicians report rest periods of 6-12 weeks between courses of treatment with aldesleukin.170 In clinical trials of aldesleukin used as a single agent for the treatment of metastatic melanoma, therapy typically was limited to 2 or 3 courses in patients experiencing a major response, and a maximum of 5 treatment courses was permitted.170 While the optimum duration of aldesleukin therapy remains to be established, the manufacturer reports that tumor regression has continued for up to at least 12 months after administration of one or more courses of therapy with the drug.3

Dosage Modification for Toxicity and Contraindications for Continued Therapy

Toxicities requiring dosage modification should involve withholding or interrupting a dose rather than reducing the individual dose to be given.1 Most adverse effects are self-limiting and usually reversible after discontinuance of aldesleukin, but adverse effects that persist should be managed with supportive treatment.1 While glucocorticoids (e.g., IV dexamethasone) have been shown to ameliorate adverse effects of aldesleukin, including fever, renal insufficiency, hyperbilirubinemia, confusion, and dyspnea, concomitant use may reduce the therapeutic effect of aldesleukin and should be avoided1,101 except under life-threatening circumstances.52

Cardiac Toxicity

Aldesleukin doses should be withheld if atrial fibrillation, supraventricular tachycardia, or bradycardia requiring treatment occurs or is recurrent or persistent; doses of the drug may be administered subsequently if the patient is asymptomatic with complete recovery to normal sinus rhythm.1

Aldesleukin doses should be withheld if systolic blood pressure is less than 90 mm Hg with increasing vasopressor requirements; doses of the drug may be administered subsequently if the systolic blood pressure equals or exceeds 90 mm Hg and the requirement for vasopressor therapy is stable or improving.1

Aldesleukin doses should be withheld if ECG changes consistent with myocardial infarction, ischemia, or myocarditis, with or without chest pain, occur or if there is suspicion of cardiac ischemia; doses of the drug may be reinstituted subsequently if the patient is asymptomatic, myocardial infarction and myocarditis have been ruled out, the clinical suspicion of angina is minimal, or there is no evidence of ventricular hypokinesia.1

Retreatment with aldesleukin is contraindicated in patients who developed any of the following cardiac toxicities during a previous course of therapy with the drug: sustained ventricular tachycardia (at least 5 consecutive ventricular beats) or other uncontrolled or treatment-resistant cardiac arrhythmia; chest pain with ECG abnormalities, consistent with angina or myocardial infarction; or cardiac tamponade.1

Respiratory Toxicity

Aldesleukin doses should be withheld if oxygen saturation is less than 90%; doses of the drug may be administered subsequently if oxygen saturation equals or exceeds 90%.1

Retreatment with aldesleukin is contraindicated in patients who developed respiratory dysfunction requiring intubation for longer than 72 hours during a previous course of therapy with the drug.1 Some clinicians advise that retreatment with aldesleukin not be undertaken in any patient who, during a previous course of therapy, developed respiratory dysfunction requiring intubation, without regard to the duration required for this treatment intervention.52

Neurologic Toxicity

Aldesleukin doses should be withheld if changes in mental status, including moderate confusion or agitation, occur; doses of the drug may be administered subsequently if mental status changes resolve completely.1

Retreatment with aldesleukin is contraindicated in patients who developed repetitive or treatment-resistant seizures, coma, or toxic psychosis persisting longer than 48 hours during a previous course of therapy with the drug.1

Renal Toxicity

Aldesleukin doses should be withheld if the serum creatinine concentration equals or exceeds 4.5 mg/dL or is 4 mg/dL or greater in the presence of severe volume overload, acidosis, or hyperkalemia; doses of the drug may be administered subsequently if serum creatinine concentration is less than 4 mg/dL and fluid and electrolyte status is stable.1

Aldesleukin doses should be withheld if persistent oliguria is present with urine output of less than 10 mL/hour for 16-24 hours with an increasing serum creatinine concentration; doses of the drug may be administered subsequently if urine output exceeds 10 mL/hour with a decrease in serum creatinine concentration of greater than 1.5 mg/dL or normalization of serum creatinine concentration.1

Retreatment with aldesleukin is contraindicated in patients who developed renal dysfunction requiring dialysis for longer than 72 hours during a previous course of therapy with the drug.1 Some clinicians advise that retreatment with aldesleukin not be undertaken in any patient who, during a previous course of therapy, developed renal dysfunction requiring dialysis, without regard to the duration required for this treatment intervention.52

Hepatic Toxicity

If signs of hepatic failure occur, including encephalopathy, increasing ascites, liver pain, or hypoglycemia, further treatment with aldesleukin for that course of therapy should be discontinued; consideration may be given to starting a new course of treatment at least 7 weeks after cessation of adverse effects (if all signs of hepatic failure have resolved) and discharge from the hospital.1 Some clinicians report shorter rest periods (i.e., 2-4 weeks) between courses of treatment with aldesleukin.52

GI Toxicity

Aldesleukin doses should be withheld if GI bleeding demonstrated by stool guaiac test is repeatedly positive with a result greater than 3+ or 4+; doses of the drug may be administered subsequently when stool guaiac test results are negative.1

Retreatment with aldesleukin is contraindicated in patients who developed bowel ischemia or perforation or GI bleeding requiring surgery during a previous course of therapy with the drug.1

Infectious Complications

Aldesleukin doses should be withheld if sepsis syndrome occurs and the patient is clinically unstable; doses of the drug may be administered subsequently if sepsis syndrome has resolved, the patient is clinically stable, and the infection is being treated.1

Dermatologic Toxicity

Aldesleukin doses should be withheld if bullous dermatitis or marked worsening of preexisting skin condition (topical steroid therapy should be avoided) occurs; doses of the drug may be administered subsequently if all signs of bullous dermatitis resolve.1

Aldesleukin is a highly toxic drug.1,15,20 The adverse effects of aldesleukin are frequent, often serious, and sometimes fatal.1,6,15,20 The rate of drug-related death in patients receiving single-agent therapy with aldesleukin for metastatic renal cell carcinoma or metastatic melanoma is 4% (11/255)1,111 or 2% (6/270),1,170 respectively. The frequency and severity of adverse effects generally are dose related and schedule dependent.1,140 Aldesleukin-associated adverse effects appear to be more frequent and severe with high-dose, relatively rapid IV infusion of the drug compared with low-dose, subcutaneous† administration or continuous IV infusion†.15,52,101 Administration of doses in excess of the recommended dose has been associated with a more rapid onset of anticipated dose-limiting toxicities.1 Most adverse effects of aldesleukin are self-limiting and usually (but not invariably) reverse or improve within 2 or 3 days of discontinuance of the drug because of its short half-life;1,15,20,170 adverse effects that persist should be monitored and managed with supportive treatment.1 Adverse effects of aldesleukin resulting in permanent sequelae include myocardial infarction, bowel perforation/infarction, and gangrene.1

Data on common adverse effects of aldesleukin are derived from experience with 525 patients receiving the drug as a single agent in clinical trials, including 255 patients with metastatic renal cell carcinoma and 270 patients with metastatic melanoma.1,111,170 The most common adverse effects of aldesleukin include hypotension, diarrhea, renal dysfunction with oliguria, chills, and vomiting.1 The most frequently reported life-threatening or grade 4 adverse effects of aldesleukin include renal dysfunction with oliguria/anuria, hypotension, respiratory disorder (i.e., ARDS, respiratory failure, intubation), coma, and bilirubinemia.1 Many adverse effects of aldesleukin, including the most serious, are related to or result from the capillary leak syndrome caused by the drug.1,6,15,111 Additional adverse effects associated with aldesleukin have been reported in a population of 1800 patients receiving various dosing regimens of the drug (e.g., subcutaneous administration, continuous infusion, administration with LAK cells) and in patients receiving various treatment regimens that included the drug.1

Morbidity and mortality associated with aldesleukin treatment of metastatic renal cell carcinoma or metastatic melanoma in clinical trials were related to the ECOG performance status of the patients.1,15,111 Compared with patients who had a performance status of 0, those with a performance status of 1 or higher had a higher rate of aldesleukin-related mortality and a higher incidence of serious adverse effects.1,111,170 Careful patient selection and evaluation and appropriate management of adverse effects can reduce the morbidity and mortality associated with aldesleukin therapy.6,10,15,20

Flu-like Syndrome

A flu-like syndrome, including fever and/or chills and rigors, develops to some degree in many patients receiving aldesleukin.1,6,13,15 Chills1,6,15,20 or fever1,6,15,20 occurred in 52 or 29%, respectively, of patients with metastatic renal cell carcinoma or metastatic melanoma receiving the recommended dosing regimen of aldesleukin in clinical trials; fever was life-threatening or grade 4 in 1% of patients receiving the drug in clinical trials.1 Since these signs and symptoms do not occur for a few hours after administration of aldesleukin, they are believed to result from release of pyrogenic factors and/or cytokines.6,15 Chills and rigors and/or fever may be accompanied by other symptoms.1,6 Pain or abdominal pain occurred in 12 or 11% of patients, respectively;1 malaise or asthenia (i.e., weakness) occurred in 27 or 23%, respectively, of patients receiving the recommended dosing regimen of aldesleukin in clinical trials.1 Arthralgia and/or myalgia also may be associated with the syndrome.6,15,140 Chest pain,140 back pain,140 and fatigue140 have been reported in patients receiving aldesleukin.

Treatment with an antipyretic agent or a nonsteroidal anti-inflammatory agent (e.g., ibuprofen, indomethacin), beginning immediately before the initiation of aldesleukin therapy and continuing for 12 hours after the last dose of the drug, may minimize the risk of developing fever and/or its severity,1,7 as well as some of the other flu-like symptoms or acute adverse effects.7 In clinical trials, meperidine was administered to control the rigors associated with fever.1

Capillary Leak Syndrome

Aldesleukin administration, particularly at dosages currently recommended by the manufacturer, is associated with capillary leak syndrome, which results in hypotension and reduced organ perfusion that may be severe and can result in death.1,6,8,11,15,101 The capillary leak syndrome begins immediately after aldesleukin treatment is initiated and is characterized by increased vascular permeability to proteins and fluids and reduction of vascular tone.1,6,15

The exact mechanism of increased vascular permeability remains to be established.6,15 In most patients, a decrease in mean arterial blood pressure occurs within 2-12 hours after initiation of therapy.1 With continued aldesleukin treatment, patients will develop clinically important hypotension (i.e., systolic blood pressure less than 90 mm Hg or a decrease of 20 mm Hg from baseline systolic blood pressure) and hypoperfusion.1 In addition, extravasation of plasma proteins and fluids into the extravascular space leads to formation of edema and, in some patients, development of ascites and/or pleural or pericardial effusions.1,6,11

Hypotension occurred in 71% of patients with metastatic renal cell carcinoma or metastatic melanoma receiving the recommended dosing regimen of aldesleukin in clinical trials and was life-threatening (grade 4) in 3% of patients.1 Peripheral edema1 and edema1 occurred in 28 and 15%, respectively, of patients receiving the recommended dosing regimen of the drug in clinical trials.1 Fluid retention associated with capillary leak syndrome can result in substantial increases in body weight;1,11,20,142 weight gain occurred in 16% of patients receiving the recommended dosing regimen of aldesleukin in clinical trials.1 Capillary leak syndrome also may be associated with cardiac arrhythmias (supraventricular and ventricular), angina, myocardial infarction, respiratory insufficiency requiring intubation, GI bleeding or infarction, renal insufficiency, and mental status changes.1,142

The management of aldesleukin-induced capillary leak syndrome involves careful monitoring of fluid and organ perfusion status through frequent monitoring of blood pressure, heart rate, and organ function, including assessment of the patient's mental status and urine output.1 Hypovolemia should be assessed by catheterization and central venous pressure monitoring;1 administration of IV fluids (e.g., colloid replacement fluids) is recommended for the treatment of hypovolemia.1 While large volumes of IV fluids may be required to correct hypovolemia, caution is necessary since unrestrained fluid administration may exacerbate complications associated with edema or effusions.1 Flexibility in fluid and vasopressor management is essential for maintaining organ perfusion and blood pressure; therefore, extreme caution should be used when treating patients with fixed requirements for large volumes of fluid (e.g., those with hypercalcemia).1,101 Management of edema and ascites and/or effusions depends on careful balancing of fluid shifts so that the consequences of hypovolemia (e.g., impaired organ perfusion) or fluid accumulation (e.g., pulmonary edema) do not exceed the patient's tolerance.1

Based on clinical experience, early administration of IV dopamine 1-5 mcg/kg per minute to patients with manifestations of capillary leak syndrome, before the onset of hypotension, can help maintain organ perfusion, particularly renal perfusion, and thereby preserve urine output.1 Body weight and urine output should be closely monitored.1 If blood pressure and organ perfusion are not sustained by the initial dosage of IV dopamine, an increase in the dosage to 6-10 mcg/kg per minute may be beneficial;1 alternatively, IV phenylephrine hydrochloride 1-5 mcg/kg per minute may be added to the low-dose dopamine infusion.1 However, caution is required since the prolonged use of vasopressors, alone or in combination, at relatively high doses may be associated with cardiac rhythm disturbances.1 If adequate organ perfusion is not maintained, as demonstrated by altered mental status, decreased urine output, a decrease in systolic blood pressure to less than 90 mm Hg, or the onset of cardiac arrhythmias, subsequent doses of aldesleukin should be withheld until recovery of organ perfusion and an increase in systolic blood pressure to greater than 90 mm Hg are observed.1

Recovery from capillary leak syndrome begins soon after discontinuance of aldesleukin therapy.1 Usually within a few hours, blood pressure increases, organ perfusion is restored, and reabsorption of extravasated fluid and protein begins.1 After blood pressure normalizes, administration of diuretics may hasten recovery in patients who experienced excessive weight gain or edema, particularly if these signs are associated with shortness of breath from pulmonary congestion.1

Cardiovascular Effects

Hypotension as a consequence of the capillary leak syndrome is among the most frequent serious adverse effects of aldesleukin, particularly at dosages currently recommended by the manufacturer, and occurs in most patients receiving the drug.1,6,11,20,101,111,170 (See Cautions: Capillary Leak Syndrome.) Aldesleukin also is associated with a variety of adverse cardiac effects including arrhythmias,1,6,15 myocardial ischemia or infarction,1,6,8,15,20 myocarditis,1,6,15 and angina,1 which appear to result at least in part from the capillary leak syndrome.1,6,8,15

Among patients with metastatic renal cell carcinoma or metastatic melanoma receiving the recommended dosing regimen of aldesleukin, tachycardia,1 occurred in 23% of patients;1 vasodilation,1 supraventricular tachycardia,1,142 cardiovascular disorder (i.e., fluctuations in blood pressure, asymptomatic ECG changes, congestive heart failure),1 and arrhythmia1,6,15 occurred in 13, 12, 11, and 10% of patients, respectively.1 Myocardial infarction1,6,8,20 and cardiac arrest1 each occurred in 1% of patients with metastatic renal cell carcinoma or metastatic melanoma1 receiving the recommended dosing regimen of aldesleukin in clinical trials, and myocardial ischemia1,6 occurred in less than 1% of patients.1 In an additional population of more than 1800 patients receiving various dosing regimens of aldesleukin, fatal myocardial infarction or fatal cardiac arrest occurred in less than 1% of patients.1 Life-threatening (or grade 4) supraventricular tachycardia, cardiovascular disorder (i.e., fluctuations in blood pressure), or ventricular tachycardia, occurred in 1% of patients with metastatic renal cell carcinoma or metastatic melanoma receiving the recommended dosing regimen of aldesleukin;1 other adverse cardiovascular effects described as grade 4 or life-threatening in severity, including shock, bradycardia, ventricular extrasystoles, syncope, atrial arrhythmia, phlebitis, second-degree AV block, endocarditis, pericardial effusion, peripheral gangrene, thrombosis, and coronary artery disorder, each were reported in less than 1% of such patients.1

Other serious adverse cardiovascular effects, including pericarditis and myocarditis, have been reported in patients receiving various dosing regimens of aldesleukin.1 Hypertension1 , cardiomyopathy,1 and fatal endocarditis1 each has been reported in patients receiving various treatment regimens that included aldesleukin. Other adverse cardiovascular effects that have been reported in patients receiving aldesleukin include ventricular premature complexes,140,142 and atrial premature complexes.140

Respiratory Effects

Dyspnea1,6,15 and lung disorder (i.e., physical findings associated with pulmonary congestion, rales, and rhonchi) 1,6,15 are among the most frequent serious adverse effects of aldesleukin, occurring in 43 and 24%, respectively, of patients with metastatic renal cell carcinoma or metastatic melanoma receiving the recommended dosing regimen of the drug in clinical trials.1 Respiratory disorder, including acute respiratory distress syndrome (ARDS),1 infiltrates on chest radiograph,1 or unspecified pulmonary changes,1 occurred in 11% of patients.1 These and other adverse respiratory effects of the drug are often associated with the capillary leak syndrome.1,6,15 Pleural effusion may result from accumulation of extravascular fluid caused by aldesleukin-induced capillary leak syndrome.1

Life-threatening (or grade 4) respiratory disorder (i.e., ARDS, respiratory failure, intubation),1,15,20 dyspnea,1 and apnea,1 have been reported in 3, 1, and 1%, respectively, of patients with metastatic renal cell carcinoma or metastatic melanoma receiving the recommended dosing regimen of aldesleukin;1 other adverse respiratory effects described as grade 4 or life-threatening in severity, including respiratory acidosis,1 pulmonary edema,1,6,142 hyperventilation,1 hypoxia,1 hemoptysis,1 hypoventilation,1 or pneumothorax,1 each have been reported in less than 1% of such patients.1 In an additional population of more than 1800 patients receiving various dosing regimens of aldesleukin, fatal pulmonary effects, including pulmonary edema, respiratory arrest, respiratory failure, or pulmonary emboli resulting in death, occurred in less than 1% of patients.1

Cough increase1 and rhinitis1 occurred in 11 and 10%, respectively, of patients receiving the recommended dosing regimen of aldesleukin in clinical trials.1 Other serious adverse respiratory effects include tracheoesophageal fistula,1 reported in patients receiving various dosing regimens of aldesleukin, and pneumonia (bacterial, fungal, viral),1 reported in patients receiving various treatment regimens that included aldesleukin. Other adverse respiratory effects reported in patients receiving aldesleukin include tachypnea140 and wheezing.140

Nervous System Effects

Onset of neurologic effects, including changes in mental status1 , speech difficulties,1 cortical blindness,1 limb or gait ataxia,1 hallucinations,1 agitation,1 obtundation,1 and coma,1 has been reported following aldesleukin therapy in patients without CNS metastases.1 Radiologic findings in patients receiving aldesleukin include multiple and, less commonly, single cortical lesions on MRI and evidence of demyelination.1 Neurologic manifestations associated with aldesleukin usually are reversible with discontinuance of the drug; however, permanent neurologic defects have been reported.1 At least one case of possible cerebral vasculitis, responsive to dexamethasone, has been reported in a patient receiving aldesleukin.1

Changes in mental status (e.g., lethargy, somnolence, confusion, agitation),1,6,8,9,15,20 which are among the most frequent and serious adverse effects of aldesleukin, may be associated with capillary leak syndrome.1 Confusion occurred in 34% of patients with metastatic renal cell carcinoma or metastatic melanoma receiving the recommended dosing regimen of aldesleukin in clinical trials and was life-threatening or grade 4 in 1% of patients;1 somnolence was reported in 22% of patients and was life-threatening or grade 4 in less than 1% of patients.1 Life-threatening or grade 4 adverse nervous system effects, such as coma,1 stupor,1 and psychosis,1 occurred in 2, 1, and 1% of patients, respectively.1 Life-threatening (or grade 4) agitation,1 neuropathy,1 paranoid reaction,1 seizure,1 tonic-clonic (grand mal) seizure,1 or delirium1 each occurred in less than 1% of patients receiving aldesleukin in clinical trials.1 Limited data in patients receiving aldesleukin concomitantly with lymphokine-activated killer (LAK) cells suggest that changes in mental status appear to be dose related and tend to occur toward the end of a treatment course.9 These changes generally are reversible within several days after aldesleukin treatment is discontinued,1,15 but occasionally may worsen immediately after cessation of therapy;15,101 severe changes may persist longer and require temporary treatment with antipsychotic drugs.9

Anxiety1 and dizziness1 occurred in 12 and 11%, respectively, of patients with metastatic renal cell carcinoma or metastatic melanoma receiving the recommended dosing regimen of aldesleukin in clinical trials.1 In an additional population of more than 1800 patients receiving various dosing regimens of aldesleukin, fatal stroke occurred in less than 1% of patients.1 Other serious adverse nervous system effects reported in patients receiving various dosing regimens of aldesleukin include transient ischemic attacks,1 meningitis,1 and cerebral edema;1 severe depression leading to suicide occurred in less than 1% of patients.1

Cerebral lesions,1 cerebral hemorrhage,1 encephalopathy,1 extrapyramidal syndrome,1 neuralgia,1 neuritis,1 neuropathy (i.e., demyelination),1 and insomnia1 have been reported in patients receiving various treatment regimens that included aldesleukin. Other adverse neurologic effects reported in patients receiving aldesleukin include headache,140 sensory dysfunction,140 and motor dysfunction.140

Renal and Electrolyte Effects

Renal dysfunction with oliguria1,6,10,11,15,20 is one of the most frequent serious adverse effects of aldesleukin, occurring in 63% of patients with metastatic renal cell carcinoma or metastatic melanoma receiving the recommended dosing regimen of the drug in clinical trials; life-threatening or grade 4 oliguria occurred in 6% of patients.1 Anuria1 occurred in less than 10% of patients receiving aldesleukin in clinical trials, and life-threatening or grade 4 anuria occurred in 5% of patients.1 Renal insufficiency may be associated with capillary leak syndrome in patients receiving aldesleukin.1 Increased serum creatinine concentrations1,10,11,20 occurred in 33% of patients1 receiving the recommended dosing regimen of the drug in clinical trials and were life-threatening or grade 4 in 1% of all patients.1 Grade 4 or life-threatening acute kidney failure occurred in 1% of patients receiving aldesleukin in clinical trials.1 Increased BUN,1,6,11 increased nonprotein nitrogen (NPN),1 abnormal kidney function,1 kidney failure,1 or acute tubular necrosis1 was reported as life-threatening or grade 4 in less than 1% of patients receiving aldesleukin in clinical trials.1 In an additional population of more than 1800 patients receiving various dosing regimens of aldesleukin, renal failure resulting in death occurred in less than 1% of patients.1

Other adverse renal effects reported in patients receiving aldesleukin include proteinuria,140 hematuria,140 dysuria,140 renal impairment requiring dialysis,140 urinary retention,140 and urinary frequency.140 Allergic interstitial nephritis has been reported in patients receiving various dosing regimens of aldesleukin.1

Aldesleukin-induced renal dysfunction resolves in most patients within 1-2 weeks after discontinuance of the drug, but in some patients recovery may be more prolonged and/or incomplete.10,11,15 Preexisting renal impairment appears to be associated with an increased risk of more severe and prolonged renal dysfunction.10,15

Various electrolyte disturbances may occur in patients receiving aldesleukin.1,11 Hypomagnesemia1 and hypocalcemia1,141 occurred in 12 and 11%, respectively, of patients with metastatic renal cell carcinoma or metastatic melanoma receiving the recommended dosing regimen of the drug in clinical trials;1 grade 4 or life-threatening hypocalcemia occurred in less than 1% of patients.1 Although intravenous administration of calcium chloride to correct low serum concentrations of ionized calcium has been reported in several patients receiving high-dose intravenous aldesleukin, the intended effects of such treatment on hemodynamic parameters (i.e., mean arterial pressure, systemic vascular resistance) were inconsistent; low serum concentrations of calcium are associated with elevated serum concentrations of parathyroid hormone, which may contribute to the hypotensive effect of aldesleukin therapy.141 Other electrolyte disturbances reported in patients receiving aldesleukin include hypophosphatemia,11,140 hypokalemia,140 hyponatremia,140 hyperkalemia,140 hypercalcemia,140 hypernatremia,140 and hyperphosphatemia.140

GI Effects

Diarrhea1,6,15,20 and vomiting1,6,15 occurred in 67 and 50%, respectively, of patients with metastatic renal cell carcinoma or metastatic melanoma receiving the recommended dosing regimen of aldesleukin in clinical trials;1 grade 4 or life-threatening diarrhea or vomiting were reported in 2 or 1% of all patients, respectively.1 Nausea1,6,15,20 or nausea and vomiting1 occurred in 35 or 19%, respectively, of patients in clinical trials;1 nausea and vomiting were described as grade 4 or life-threatening in less than 1% of all patients in clinical trials.1 Stomatitis1,6 and anorexia1,6,15 have been reported in 22 and 20%, respectively, of patients receiving the recommended dosing regimen of aldesleukin in clinical trials;1 stomatitis was described as grade 4 or life-threatening in less than 1% of patients.1

GI bleeding or infarction may be associated with capillary leak syndrome in patients receiving aldesleukin;1 grade 4 or life-threatening GI hemorrhage occurred in less than 1% of patients receiving the recommended dosing regimen of aldesleukin in clinical trials.1 Adverse GI effects described as grade 4 or life-threatening in severity, including hematemesis,1 bloody diarrhea,1 GI disorder,1 intestinal perforation,1 or pancreatitis,1 each were reported in less than 1% of patients receiving aldesleukin in clinical trials.1 In an additional population of more than 1800 patients receiving various dosing regimens of aldesleukin, other serious adverse GI effects, including duodenal ulceration,1 and bowel necrosis,1 have been reported.1 Intestinal perforation resulting in death has occurred in less than 1% of patients receiving various dosing regimens of aldesleukin.1

Other adverse GI effects reported in patients receiving aldesleukin include taste disorders,140 dyspepsia,140 and constipation.140 Colitis,1 gastritis,1 intestinal obstruction,1 and retroperitoneal hemorrhage1 have been reported in patients receiving various treatment regimens that included aldesleukin. Exacerbation of quiescent Crohn's disease, requiring surgical intervention, has been reported rarely in patients with metastatic renal cell carcinoma following treatment with aldesleukin.12

Enlarged abdomen1 occurred in 10% of patients with metastatic renal cell carcinoma or metastatic melanoma receiving the recommended dosing regimen of aldesleukin in clinical trials.1

Hepatic and Biliary Effects

Adverse hepatic effects occur in many patients receiving aldesleukin,1,6,13,15 perhaps in part because the drug causes substantial, reversible intrahepatic cholestasis.6,13,15 Increased serum concentrations of bilirubin1,6,13,15 and AST1,6,13,15 have been reported in 40 and 23%, respectively, of patients with metastatic renal cell carcinoma or metastatic melanoma receiving recommended dosing regimens of aldesleukin in clinical trials;1 bilirubinemia and increased serum AST concentrations were described as grade 4 or life-threatening in 2 and 1%, respectively, of patients receiving aldesleukin in clinical trials.1 Increased serum alkaline phosphatase concentration1,6,13 was reported in 10% and described as grade 4 or life-threatening in less than 1% of patients receiving the recommended dosing regimen of aldesleukin in clinical trials.1 Ascites may result from accumulation of extravascular fluid caused by aldesleukin-induced capillary leak syndrome.1 Abnormal liver function tests1 have been reported in less than 1% of patients with metastatic renal cell carcinoma or metastatic melanoma receiving the recommended dosing regimen of the drug in clinical trials.1

Adverse hepatic effects generally have been reversible within 5-7 days after discontinuance of aldesleukin therapy.6,13 Liver failure resulting in death was reported in less than 1% of patients receiving the drug in various dosing regimens.1 Jaundice also has been reported in patients receiving aldesleukin.140 Cholecystitis,1 hepatitis,1 and hepatosplenomegaly1 have been reported in patients receiving various treatment regimens that included aldesleukin.1

Dermatologic Effects

The most common adverse dermatologic effects of aldesleukin are rash1 and pruritus1,6,14,15 , which occurred in 42 and 24%, respectively, of patients with metastatic renal cell carcinoma or metastatic melanoma receiving the recommended dosing regimen of the drug in clinical trials.1 Exfoliative dermatitis1 has been reported in 18% of patients receiving the recommended dosing regimen of the drug in clinical trials.1

Erythema has been reported in patients receiving aldesleukin.6,14,15,140 Aldesleukin-induced dermatologic toxicity commonly is manifested as macular erythema and usually is localized to the head and neck, but occasionally may be generalized.14,15 Generalized erythroderma, which has been reported to be dose dependent,15 may be followed by desquamation within 48-72 hours after drug discontinuance;14,15 resolution of these skin changes may require several weeks.15,16 Erythrodermic psoriatic exacerbation and localized flare of psoriasis in patients with a history of the disease have been reported during aldesleukin therapy.16 Persistent but nonprogressive vitiligo has occurred in patients with malignant melanoma treated with the drug.1 Other adverse dermatologic effects reported in patients receiving aldesleukin include dry skin,140 purpura or petechiae,140 and alopecia.140 Urticaria1,140 has been reported in patients receiving aldesleukin or various treatment regimens that included aldesleukin. See Cautions: Sensitivity, Immunologic, and Inflammatory Reactions.

Local Effects

Injection site reactions have been reported in patients receiving the recommended dosing regimen of aldesleukin in clinical trials.140 Subcutaneous administration of aldesleukin has been commonly associated with the development of nodules or indurations at the injection site.101 These nodules reportedly are transient and usually disappear within a few months following discontinuance of therapy.101 The manufacturer states that application of cold compresses to the injection site prior to and following subcutaneous administration of the drug may be used to help reduce pain and swelling.101 If cold compresses are not effective, moist heat or warm packs may be applied to the injection site before subcutaneous administration of the drug.101 Cellulitis1 and injection site necrosis1 have been reported in patients receiving various treatment regimens that included aldesleukin.1

Sensitivity, Immunologic, and Inflammatory Reactions

Sensitivity Reactions

Nonanaphylactic allergic reactions have been reported in patients receiving the recommended dosing regimen of aldesleukin in clinical trials.140 Treatment with aldesleukin or other interleukin-2 preparations may predispose individuals to acute, atypical adverse reactions to iodinated radiographic contrast media.1 Approximately 13% of patients (range: 11-28%) receiving various treatment regimens containing interleukin-2 (e.g., aldesleukin) experienced reactions with subsequent administration of iodinated radiographic contrast media, including fever, chills, nausea, vomiting, diarrhea, pruritus, rash, hypotension, edema, and oliguria.1 (See Drug Interactions: Roentgenographic Agents.) Anaphylaxis1 has been reported in patients receiving various treatment regimens that included aldesleukin.

Autoimmunity and Inflammatory Reactions

Aldesleukin, used alone or in combination with interferon alfa (see Drug Interactions: Interferon Alfa), has been associated with the development or exacerbation of autoimmune disease and inflammatory disorders.1 Exacerbation of Crohn's disease,1 scleroderma,1 thyroiditis,1 inflammatory arthritis,1 diabetes mellitus,1 oculo-bulbar myasthenia gravis,1 crescentic IgA glomerulonephritis,1 cholecystitis,1 cerebral vasculitis,1 Stevens-Johnson syndrome,1 or bullous pemphigoid1 has been reported following aldesleukin therapy.1 Onset of symptomatic hyperglycemia and/or diabetes has been reported during aldesleukin therapy.1

Hypothyroidism, sometimes preceded by hyperthyroidism, has been reported following treatment with aldesleukin, and some patients required thyroid hormone replacement therapy.1 Hyperthyroidism also has been reported in patients receiving various treatment regimens that included aldesleukin.1 Aldesleukin-associated changes in thyroid function may be a manifestation of autoimmunity.1 (See Cautions: Precautions and Contraindications.)

Antibody Formation

In patients with metastatic renal cell carcinoma or metastatic melanoma who received the recommended dosing regimen of aldesleukin in clinical trials, 74 or 66%, respectively, developed low titers of non-neutralizing anti-interleukin-2 antibodies.1 Although neutralizing antibodies were not detected in these patients, they have been detected in 1/106 patients (less than 1%) treated with IV aldesleukin in a wide variety of dosing regimens.1 The clinical importance of anti-interleukin-2 antibodies is not known.1

Infectious Complications

Aldesleukin therapy is associated with impaired neutrophil function (decreased chemotaxis)1,6,20 and an increased risk of disseminated infection (most frequently Staphylococcus aureus infection),6,15 including sepsis1,6,15,17,20 and bacterial endocarditis.1,15 (See Cautions: Precautions and Contraindications.) Infections, including infections involving the urinary tract, injection site, indwelling catheter tips, or phlebitis or sepsis,140 occurred in 13% of patients receiving the recommended dosing regimen of the drug for metastatic renal cell carcinoma or metastatic melanoma in clinical trials and were life-threatening or grade 4 in 1% of patients.1 Life-threatening sepsis has been reported in 1% of patients receiving aldesleukin in clinical trials.1 Disseminated infections acquired during aldesleukin therapy contribute substantially to treatment-related morbidity.15 Antibiotic prophylaxis and aggressive treatment of suspected and documented infections may reduce the morbidity of aldesleukin treatment.15,20

Hematologic Effects

Thrombocytopenia1,6,15,20 occurred in 37% of patients and was described as grade 4 or life-threatening in severity in 1% of patients with metastatic renal cell carcinoma or metastatic melanoma receiving the recommended dosing regimen of aldesleukin in clinical trials.1 Anemia1,6,15,20 and leukopenia1,15 occurred in 29 and 16%, respectively, of patients receiving the drug in clinical trials;1 grade 4 or life-threatening anemia or leukopenia were each reported in less than 1% of patients.1 Grade 4 or life-threatening coagulation disorder (i.e., intravascular coagulopathy)1,15 has been reported in 1% of patients receiving the recommended dosing regimen of aldesleukin in clinical trials.1 Packed red blood cell and/or platelet transfusions may be necessary in patients receiving the drug.6,15,20 Grade 4 or life-threatening hemorrhage has been reported in less than 1% of patients receiving the recommended dosing regimen of aldesleukin in clinical trials.1

Grade 4 or life-threatening leukocytosis1 occurred in less than 1% of patients receiving the recommended dosing regimen of aldesleukin in clinical trials.1 Eosinophilia has been reported in patients receiving aldesleukin.140 Neutropenia1 has been reported in patients receiving various treatment regimens that included aldesleukin.

Musculoskeletal Effects

Arthralgia and myalgia may be associated with a flu-like syndrome (see Cautions: Flu-like Syndrome) that occurs in patients receiving aldesleukin.6,15,140 Exacerbation or initial presentation of inflammatory arthritis has been reported in patients receiving aldesleukin.1 Rhabdomyolysis,1 myopathy,1 and myositis1 have been reported in patients receiving various treatment regimens that included aldesleukin. Muscle spasm140 also has been reported in patients receiving aldesleukin.

Ocular Effects

Optic neuritis resulting in transient or permanent blindness has been reported in patients receiving various dosing regimens of the drug in clinical trials.1 Mydriasis1 and pupillary disorder1 described as grade 4 in severity occurred in less than 1% of patients with metastatic renal cell carcinoma or metastatic melanoma receiving the recommended dosing regimen of aldesleukin in clinical trials.1 Conjunctivitis has been reported in patients receiving aldesleukin.140

Endocrine and Metabolic Effects

Thyroid dysfunction, usually hypothyroidism, sometimes preceded by hyperthyroidism, has been reported in patients receiving aldesleukin.1,6,15 Symptoms of thyroid dysfunction usually have developed within 2 months of initiation of aldesleukin treatment.15 Some patients have required thyroid hormone replacement therapy.1 Aldesleukin-associated changes in thyroid function may be a manifestation of autoimmunity. (See Cautions: Precautions and Contraindications.)

Plasma concentrations of cortisol, corticotropin, β-endorphin, epinephrine, and norepinephrine have been reported to be increased during aldesleukin treatment.6,15 Adrenal hemorrhage leading to acute adrenal insufficiency during aldesleukin therapy was reported in a patient with renal cell carcinoma with preexisting adrenal metastases.6,15

Metabolic disturbances may occur in patients receiving aldesleukin.1 Onset of symptomatic hyperglycemia and/or diabetes has been reported during aldesleukin therapy and may be a manifestation of autoimmunity.1 Acidosis1,11 occurred in 12% and was described as grade 4 or life-threatening in severity in 1% of patients with metastatic renal cell carcinoma or metastatic melanoma receiving the recommended dosing regimen of aldesleukin in clinical trials.1 Grade 4 or life-threatening hyperuricemia1 has been reported in less than 1% of patients receiving aldesleukin in clinical trials.1 Other metabolic disturbances reported in patients receiving aldesleukin include hypoalbuminemia,140 hypoproteinemia,140 alkalosis,11,140 hypoglycemia,140 and hypocholesterolemia.140 Rapid and marked reductions in plasma concentrations of ascorbic acid, which appears to be required for optimum cell-mediated immunity, have been reported during adoptive immunotherapy with aldesleukin and lymphokine-activated killer (LAK) cells; ascorbic acid concentrations became undetectable in some patients, and return of these values toward normal was more rapid in patients who had higher baseline ascorbic acid concentrations and who responded to aldesleukin-LAK therapy.18

Weight loss of 10% of body weight or greater has been reported in patients receiving the recommended dosing regimen of aldesleukin in clinical trials.140 Grade 4 or life-threatening hypothermia1 occurred in less than 1% of patients with metastatic renal cell carcinoma or metastatic melanoma receiving the recommended dosing regimen of aldesleukin in clinical trials.1 Fatal malignant hyperthermia was reported in less than 1% of patients receiving various dosing regimens of the drug.1

Precautions and Contraindications

Because the adverse effects of aldesleukin are frequent, often serious, and sometimes fatal,1,15,20 the potential benefit of the drug to the patient must be weighed carefully against the possible risks involved.1,15,20 The manufacturer states that aldesleukin should be administered in a hospital setting under the supervision of a qualified physician who is experienced in the use of this agent and only when the possible benefits are thought to outweigh the possible risks.1 In addition, intensive care facilities and specialists in cardiopulmonary or intensive care medicine must be readily available in case certain serious aldesleukin-induced toxicities develop (e.g., capillary leak syndrome and associated cardiac, cardiovascular, pulmonary, and other effects).1

Because aldesleukin is a highly toxic drug, careful patient selection, including assessment of cardiac and pulmonary functions, blood chemistry, and blood cell counts, is mandatory prior to initiation of therapy with the drug.1 Serious, life-threatening, or fatal adverse effects associated with aldesleukin therapy may occur in patients with normal cardiovascular, pulmonary, hepatic, or CNS function.1 The use of aldesleukin is contraindicated in patients with substantial cardiac, pulmonary, hepatic, renal, or CNS impairment.1 Treatment with the drug should be limited to patients with normal cardiac and pulmonary functions as determined by thallium stress test and pulmonary function tests, respectively.1 Patients are eligible for treatment with the drug if their serum creatinine concentration does not exceed 1.5 mg/dL.1 The performance status of patients also should be considered; experience with aldesleukin in patients with a relatively poor performance status (i.e., an ECOG performance status greater than 1) is extremely limited.1 Prior to the initiation of aldesleukin therapy and at daily intervals during administration of the drug, hematologic tests (including complete blood count and differential and platelet counts), blood chemistries (including serum electrolyte concentrations and renal and hepatic function tests), and chest radiographs should be performed.1

During aldesleukin therapy, vital signs (i.e., temperature, pulse, blood pressure, respiration rate) should be monitored at least every 4 hours1,52 and the patient's weight and fluid intake and output should be monitored daily.1,52 If systolic blood pressure is decreased, especially to less than 90 mm Hg, constant cardiac rhythm monitoring should be performed.1 If an abnormal complex or cardiac rhythm occurs, an ECG should be performed.1 In hypotensive patients, vital signs should be monitored hourly.1

Because renal and hepatic function are impaired with aldesleukin therapy, concomitant administration of known nephrotoxic (e.g., aminoglycosides, indomethacin) or hepatotoxic (e.g., methotrexate, asparaginase) drugs may further increase renal or hepatic toxicity, respectively.1 In addition, decreased renal or hepatic function resulting from aldesleukin therapy may result in delayed elimination of concomitantly administered drugs and increase the risk of toxicity from such drugs.1 Similarly, concomitant administration of drugs with known cardiotoxic or myelotoxic effects may increase the risk of cardiotoxicity or myelotoxicity, respectively.1 Safety and efficacy of aldesleukin used in combination with chemotherapeutic agents have not been established.1 Concomitant administration of β-blocking agents or other antihypertensive agents may potentiate aldesleukin-induced hypotension.1

All patients should be thoroughly evaluated and treated for CNS metastases and have a negative CT scan prior to receiving therapy with aldesleukin.1 New neurologic manifestations and anatomic lesions have been reported following aldesleukin therapy in patients without evidence of CNS metastases.1 (See Cautions: Nervous System Effects.) Neurologic manifestations associated with aldesleukin usually are reversible with discontinuation of the drug; however, permanent neurologic defects have been reported.1 In addition, since aldesleukin may cause seizures, the drug should be used with extreme caution in patients with a history of seizure disorder.1

Clinicians should keep in mind that mental status changes occurring in patients receiving aldesleukin may be a direct result of CNS toxicity caused by the drug or may be indicative of bacteremia or early bacterial sepsis, hypoperfusion, or occult CNS malignancy.1 If mental status changes are caused by aldesleukin, they generally reverse within several days after discontinuance of the drug,15 although they may progress for several days before recovery begins.1,15,101 Rarely, patients have experienced permanent neurologic deficits associated with use of aldesleukin.1 Aldesleukin therapy should be withheld in patients developing moderate to severe lethargy or somnolence; continued administration of the drug may result in coma.1 Because aldesleukin can affect CNS function, concomitant administration of drugs that affect the CNS (e.g., opioids, antiemetics, anxiolytics) may increase the risk of CNS effects.1

The manufacturer recommends that baseline pulmonary function tests with measurement of arterial blood gases be performed in patients receiving aldesleukin.1 Adequate pulmonary function (FEV₁ greater than 2 L or exceeding 75% of the predicted value based on height and age) should be documented prior to initiation of therapy with the drug.1 During treatment, pulmonary function should be monitored regularly by clinical examination, assessment of vital signs, and pulse oximetry.1 Patients with dyspnea or clinical signs of respiratory impairment (i.e., tachypnea or rales) should be further evaluated with arterial blood gas determinations performed as often as is clinically indicated.1

According to the manufacturer, a stress thallium study should be performed in all patients prior to initiation of aldesleukin therapy to document that cardiac ejection fraction is normal and myocardial wall motion is unimpaired.1,101 If results of the stress thallium test suggest minor wall motion abnormalities, further testing is suggested to exclude clinically important coronary artery disease.1 During therapy with aldesleukin, cardiac function should be assessed daily by clinical examination and evaluation of vital signs.1 Patients with signs or symptoms of chest pain, murmurs, gallops, irregular cardiac rhythm, or palpitation should be further assessed with an ECG examination and evaluation of cardiac enzymes (e.g., determination of serum creatine phosphokinase [CPK] concentration).1 Evidence of myocardial injury, including findings compatible with myocardial infarction or myocarditis, has been reported in patients receiving aldesleukin.1 Ventricular hypokinesia caused by myocarditis may persist for several months.1 If there is evidence of cardiac ischemia or congestive heart failure, aldesleukin therapy should be withheld, and a repeat thallium study should be performed.1 Aldesleukin should be used with extreme caution in patients with normal thallium stress tests and pulmonary function tests who have a history of prior cardiac or pulmonary disease.1

Because aldesleukin treatment is associated with impaired neutrophil function and an increased risk of disseminated infection, including sepsis and bacterial endocarditis, preexisting bacterial infections should be adequately treated prior to initiation of therapy with the drug.1 In addition, patients with indwelling central catheters should receive prophylaxis with anti-infectives effective against gram-positive microorganisms, particularly Staphylococcus aureus (e.g., oxacillin, nafcillin, ciprofloxacin, vancomycin).1,6,15 Such prophylactic regimens have been associated with a reduced incidence of staphylococcal infections in aldesleukin-treated patients.1 Anti-infective prophylaxis and aggressive treatment of suspected and documented infections may reduce the morbidity of aldesleukin treatment.15,20

Use of aldesleukin, alone or in combination with interferon, may exacerbate preexisting autoimmune disease or inflammatory disorder and also has been associated with the initial presentation of such conditions.1 (See Autoimmunity and Inflammatory Reactions in Cautions: Sensitivity, Immunologic, and Inflammatory Reactions.) Hypothyroidism, sometimes preceded by hyperthyroidism, has been reported following treatment with aldesleukin, and some patients required thyroid hormone replacement therapy.1 Changes in thyroid function may be a manifestation of autoimmunity.1

Because aldesleukin enhances cellular immune function, the drug may increase the risk of allograft rejection in transplant patients.1

Patients receiving aldesleukin experience fever, chills, rigors, pruritus, and/or adverse GI effects, and medical intervention and management of these effects may be beneficial.1 Administration of standard antipyretic therapy, including a nonsteroidal anti-inflammatory agent (NSAIA), beginning immediately prior to initiation of aldesleukin therapy may reduce fever.1 Meperidine has been used to control rigors.1 Histamine H₂-receptor antagonists have been administered for prophylaxis of GI irritation and bleeding, and antiemetics and antidiarrheals have been administered as needed for nausea and diarrhea, respectively.1 In clinical trials, these medications generally were discontinued 12 hours after the last dose of aldesleukin.1 Antipruritics (e.g., hydroxyzine) or histamine H₁-receptor antagonists (e.g., diphenhydramine) have been used to control symptoms from pruritic rash and were continued until the condition resolved.1 Topical creams and ointments may be applied as needed for the symptomatic treatment of aldesleukin-associated skin manifestations; preparations containing a steroid (e.g., hydrocortisone) should be avoided.1

Toxicities requiring dosage modification should involve withholding or interrupting a dose of aldesleukin rather than reducing the individual dose to be given.1 Further therapy with aldesleukin is contraindicated in patients who developed certain toxicities during a previous course of therapy with the drug.1 (See Dosage Modification for Toxicity and Contraindications for Continued Therapy in Dosage under Dosage and Administration.)

Aldesleukin is contraindicated in patients with a known history of hypersensitivity to interleukin-2 or any component of the formulation.1 The drug also is contraindicated in patients with an abnormal thallium stress test or pulmonary function test results and in those with organ allografts.1

Pediatric Precautions

Safety and efficacy of aldesleukin in children younger than 18 years of age have not been established.1

Geriatric Precautions

Safety and efficacy of aldesleukin in geriatric patients have not been studied specifically to date.1 Twenty-seven patients aged 65 years and older participated in clinical trials of aldesleukin (19 with metastatic renal cell carcinoma and 8 with melanoma).1 Response rates and median number of courses of therapy were similar between geriatric and younger patients; a trend toward an increased incidence of severe urogenital toxicity and dyspnea was observed among geriatric patients.1

Aldesleukin is metabolized principally in the kidney; because geriatric patients may have decreased renal function and because patients with renal impairment may be at increased risk of aldesleukin-induced toxicity, patients in this age group should be monitored closely and dosage adjusted accordingly (see Dosage Modification for Toxicity and Contraindications for Continued Therapy in Dosage under Dosage and Administration).1

Mutagenicity and Carcinogenicity

Studies to determine the mutagenic or carcinogenic potential of aldesleukin have not been performed to date.1

Pregnancy, Fertility, and Lactation

Pregnancy

Although there are no adequate and controlled studies to date in humans, aldesleukin has been shown to have embryolethal effects in rats when given in doses 27 to 36 times the usual human dose.1 Significant maternal toxicity was observed in pregnant rats receiving aldesleukin by IV injection during a critical period of organogenesis at doses 2.1 to 36 times higher than the usual human dose; no evidence of teratogenicity was observed other than that attributed to maternal toxicity.1 Aldesleukin should be used during pregnancy only when the potential benefits justify the possible risks to the fetus.1

Fertility

Studies to determine the effects of aldesleukin on fertility have not been performed to date, and it also is not known whether the drug can affect reproductive capacity.1 It is recommended that aldesleukin not be administered to fertile individuals of either gender who are not practicing effective contraception.1

Lactation

It is not known whether aldesleukin is distributed into human milk.1 Because of the potential for serious adverse effects in nursing infants if the drug were distributed into milk, a decision should be make whether to discontinue nursing or the drug, taking into account the importance of the drug to the woman.1

CNS-Active Drugs

Because aldesleukin may affect CNS function, interactions may occur following concomitant administration with CNS-active drugs, such as opiate, analgesic, antiemetic, sedative, or tranquilizing agents.1

Nephrotoxic and Hepatotoxic Drugs

Because renal and hepatic function are impaired with aldesleukin therapy, concomitant administration of known nephrotoxic (e.g., aminoglycosides, indomethacin) or hepatotoxic (e.g., methotrexate, asparaginase) drugs may further increase renal or hepatic toxicity, respectively.1

Cardiotoxic Drugs

Concomitant administration of known cardiotoxic drugs (e.g., anthracyclines such as doxorubicin) with aldesleukin may increase cardiotoxicity.1

Antineoplastic Agents

Concurrent administration of cytotoxic agents that cause myelotoxicity with aldesleukin may increase such toxicity.1 The safety and efficacy of aldesleukin administered in combination with any chemotherapeutic agent have not been established.1

Hypersensitivity reactions, consisting of erythema, pruritus, and hypotension, have been reported in patients receiving combination regimens with sequential administration of high-dose aldesleukin and antineoplastic agents, specifically, dacarbazine, cisplatin, tamoxifen, and interferon alfa.1 These hypersensitivity reactions occurred within hours of administration of chemotherapy, and medical intervention was required in some patients.1

Interferon Alfa

Aldesleukin used in combination with interferon alfa has been associated with the development or exacerbation of autoimmune disease and inflammatory disorders.1 Development or exacerbation of thyroiditis,1 inflammatory arthritis,1 oculo-bulbar myasthenia gravis,1 crescentic IgA glomerulonephritis,1,155 Stevens-Johnson syndrome,1 or bullous pemphigoid1 has been reported following concurrent use of aldesleukin and interferon alfa. In one patient who developed rapidly progressive renal failure following combination therapy with aldesleukin and interferon alfa for metastatic renal cell carcinoma, renal biopsy revealed crescentic glomerulonephritis.155

The incidence of myocardial injury, including myocardial infarction,1 myocarditis,1 ventricular hypokinesia,1 and severe rhabdomyolysis,1 appears to be increased in patients receiving concurrent aldesleukin and interferon alfa.1

See Drug Interactions: Antineoplastic Agents.

Corticosteroids

Although corticosteroids (i.e., glucocorticoids) have been shown to ameliorate aldesleukin-induced adverse effects, including fever, renal insufficiency, hyperbilirubinemia, confusion, and dyspnea, concomitant use of such agents may reduce the antitumor effectiveness of aldesleukin and should be avoided.1

Hypotensive Agents

Concomitant administration of antihypertensive agents (e.g., β-blocking agents) may potentiate aldesleukin-induced hypotension.1

Roentgenographic Agents

Treatment with aldesleukin or other interleukin-2 preparations may predispose individuals to acute, atypical adverse reactions to iodinated radiographic contrast media.1 In a review of reports involving several hundred patients receiving various treatment regimens containing interleukin-2, approximately 13% of patients (range: 11-28%) experienced such reactions with subsequent administration of iodinated radiographic contrast media.1 The reactions included fever, chills, nausea, vomiting, diarrhea, pruritus, rash, hypotension, edema, and oliguria.1 The onset of symptoms usually occurred within hours (most often 1-4 hours) after administration of the contrast media.1 The cause of these reactions is not known, but they are similar to immediate adverse effects caused by interleukin-2.1 Although most of these reactions were reported to occur when the radiographic contrast media was administered within 4 weeks after the last dose of interleukin-2, some have occurred when the contrast media was administered several months after interleukin-2 treatment.1

Pharmacology

Aldesleukin, a biologic response modifier, is a human recombinant interleukin-2 (IL-2) that possesses the biologic activities of endogenous IL-2.1 Aldesleukin exerts a wide range of regulatory actions on the immune system, including enhancement of lymphocyte mitogenesis and stimulation of long-term growth of human IL-2 dependent cell lines, enhancement of lymphocyte cytotoxicity, induction of lymphokine-activated killer (LAK) cell and natural killer (NK) cell activity, and induction of interferon-gamma production.1 Administration of aldesleukin in animals and humans produces immune effects in a dose-dependent manner, including activation of cellular immunity with profound lymphocytosis, eosinophilia, and thrombocytopenia; and production of cytokines including tumor necrosis factor, IL-1, and interferon gamma.1 The precise mechanism of action of aldesleukin is unknown, and how the effects of aldesleukin on the immune system contribute to the antineoplastic activity of the drug have not been established.1

Pharmacokinetics

Absorption

Upon completion of IV infusion of aldesleukin, approximately 30% of an administered dose is detectable in plasma.1

Distribution

Following IV infusion over short periods, aldesleukin is rapidly distributed into the extravascular space; studies of radiolabeled aldesleukin in rats indicate rapid (less than 1 minute) uptake of the drug into lung, liver, kidney, and spleen.1

It is not known whether aldesleukin is distributed into milk.1

Elimination

Aldesleukin is cleared from plasma relatively rapidly following IV infusion over a short period.1 Following a 5-minute IV infusion in cancer patients, the elimination half-life of aldesleukin remaining in plasma was 85 minutes.1 In cancer patients, clearance of the drug from plasma averaged 268 mL/minute.1

Aldesleukin is metabolized principally in the kidney, and the active drug generally is undetectable or present in only trace quantities in the urine.1 Both glomerular filtration and peritubular extraction contribute to delivery of the drug to the proximal tubule, and clearance of the drug is preserved in patients with rising serum creatinine concentrations.1 Greater than 80% of the amount of aldesleukin distributed to plasma, cleared from the circulation, and presented to the kidney is metabolized to amino acids in the cells lining the proximal convoluted tubules.1

Chemistry and Stability

Chemistry

Aldesleukin, a human interleukin-2 derivative, is a biosynthetic (recombinant DNA origin) cytokine (i.e., lymphokine) that possesses complex antineoplastic and immunomodulating activities.1,2 The drug is a biologic response modifier.1,2 Aldesleukin, a protein of 132 amino acids, has an amino acid sequence closely related to endogenous human interleukin-2 (HuIL-2), differing from the endogenous glycoprotein only by the absence of an N -terminal alanine, the replacement of cysteine with serine at position 125 of the sequence, and the absence of glycosylation.1,2,4

Potency of aldesleukin is determined by a lymphocyte proliferation bioassay and is expressed in international units (IU) as established by the World Health Organization 1^st International Standard for Interleukin-2 (human);1 because other units also have been reported (e.g., CU, RU, BRMPU) and are not equivalent, care should be exercised in interpreting published dosages and concentrations.3

Aldesleukin is commercially available as a sterile, white to off-white, lyophilized cake for injection that contains dibasic and monobasic sodium phosphate as a buffer.1 Following reconstitution with sterile water for injection, the injection has a pH of about 7.5 (range: 7.2-7.8).1

Stability

Aldesleukin lyophilized cake for injection should be refrigerated at 2-8°C with protection from light and should not be used beyond the expiration date printed on the vial.1 Aldesleukin lyophilized cake for injection or reconstituted or diluted solutions of the drug should not be frozen.1 Reconstituted or diluted solutions of the drug are stable for up to 48 hours under refrigeration or at room temperature (2-25°C).1 Reconstituted or diluted solutions of the drug contain no preservative and should be stored in the refrigerator at 2-8°C; the solution should be brought to room temperature prior to infusion.1 Unused portions of aldesleukin solution should be discarded.1

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care. For further information on the handling of antineoplastic agents, see the ASHP Guidelines on Handling Hazardous Drugs at [Web].

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