Outpatient Intravenous Interleukin-2 with Famotidine Has Activity in Metastatic Melanoma

Abstract

Daily short intravenous interleukin-2 (IL-2) infusions have been developed to decrease toxicity while maintaining the anticancer activity of this agent against melanoma. Such IL-2 schedules have previously been shown to promote lymphokine-activated killer cell (LAK) activity. Famotidine may increase LAK activity by increasing IL-2 internalization by the IL-2 receptor on lymphocytes. Twenty-one patients with metastatic melanoma were treated with IL-2 18 million IU/m² intravenously (i.v.) over 15–30 minutes and famotidine 20 mg i.v. daily for 3 days for 6 consecutive weeks on an outpatient basis. Cycles were repeated every 8 weeks. Patient characteristics: 13 males/8 females, median age, 51 (range: 26–79), and median Eastern Cooperative Oncology Group performance status, 1; common metastatic sites: lymph nodes (16), lungs (14), subcutaneous (8), liver (7), and bone (7). Prior systemic therapy: chemotherapy (7); IL-2 (7); and interferon (5). Most common toxicities were myalgia/arthralgia, rigors, nausea/emesis, and mild elevation of liver function tests. No patients required hospitalization for toxicity of therapy. One patient (5%) has had a complete response (ongoing at 29+ months), while 4 other patients (19%) had partial responses (total response rate: 24%; 95% confidence interval: 9%–48%). Responses occurred in lung, spleen, bones, lymph nodes, and subcutaneous sites. Median response duration=20+ months. Outpatient intravenous IL-2 and famotidine has activity in melanoma.

Introduction

The cytokine interleukin-2 (IL-2) is able to activate lymphocytes to mediate the destruction of natural killer cell-resistant tumor lines.¹ These activated lymphocytes are called lymphokine-activated killer cells (LAKs), are primarily CD56-positive by flow cytometry, and are generated by high IL-2 doses.^2,3

IL-2 is able to induce LAKs to mediate antitumor responses in patients with metastatic melanoma. Schedules using high-dose bolus doses (600,000 IU/kg every 8 hours) yield complete response rates of ∼6% and partial response rates of an additional 10%.⁴ The complete responses achieved with this agent can be very durable, with the median duration of such responses over 4½ years.

Unfortunately, high-dose bolus IL-2 may lead to various toxicities, the most serious of which includes a capillary leak syndrome that can be manifested by hypotension, fluid retention, and pulmonary edema.^5,6 Therefore, this schedule requires administration in the hospital and, in some instances, intensive care admission and monitoring.

Daily short infusions of IL-2 at doses of 18–21.6 million IU/m² have been developed to attempt to decrease toxicity, while maintaining the anticancer activity. Response rates of 15%–26% have been described in kidney cancer and melanoma.^7,8 LAK activity is elicited in vitro by such doses.⁷

Famotidine has been associated with both increased lymphocytic infiltration of tumors in vivo and increased tumor cell cytotoxicity by lymphocytes in vitro.^9,10 The latter effect is postulated to be due to increased internalization of IL-2 by IL-2 receptors on natural killer cells. The serum famotidine level needed for this effect corresponds to what is achievable clinically with intravenous administration.

We tested the combination of outpatient intravenous IL-2 with famotidine to determine the response rate, median duration of response, and median survival of patients with metastatic melanoma treated with this regimen.

Patients and Methods

In this retrospective study from 2008 to 2012, 21 patients with measurable evidence of histologically confirmed metastatic melanoma were treated (Table 1). Patients were required to have Eastern Cooperative Oncology Group performance status <1, estimated survival of at least 3 months, white blood cell count >3500/mm³, platelets>100,000/mm³, hemoglobin>9.0 g/dL, total bilirubin, ALT, AST<3×upper limit of normal, and serum creatinine <2.0 mg/dL. Patients were excluded for autoimmune diseases such as inflammatory arthritis, which could potentially be exacerbated by IL-2, any medical illness requiring corticosteroids or other immunosuppressive agents such as methotrexate, current untreated brain metastases, history of significant cardiovascular disease, such as myocardial infarction, congestive heart failure, primary cardiac arrhythmias, angina pectoris, or cerebrovascular accident. Informed consent was obtained from all patients before study.

Table 1.

Patient Characteristics

Patient characteristics
Male/female	13/8
Median age (range)	51 (26–79)
Performance status (median)	1
Most common sites of metastases
LN	16 (76%)
Lung	14 (67%)
Subcutaneous/soft tissue	8 (38%)
Liver	7 (33%)
Bone	7 (33%)
M1a	2 (9.5%)
M1b	4 (19%)
M1c	15 (71%)
Prior systemic therapy
Chemotherapy	7 (33%)
None	8 (38%)
IL-2	7 (33%)
IFN	5 (24%)

LN, lymph nodes; IL-2, interleukin-2; IFN, interferon.

Before treatment on this regimen, all patients had to have undergone a low-level cardiac stress test and/or cardiac evaluation to exclude occult atherosclerotic heart disease.

All patients underwent complete history and physical examination, complete blood count with differential (CBC), hepatic profile, serum creatinine, chest X-ray, tumor measurements, and evaluation of performance status. Blood studies, including CBC, liver enzymes, electrolytes, and creatinine were obtained before the start of each week of IL-2 therapy. Radiographic studies to evaluate for a response were done after every cycle. Standard RECIST response criteria were utilized.¹¹ Partial responses were measured from the date that the response was determined by tumor measurements.

Treatment regimen

Patients received famotidine 20 mg intravenously (i.v.) followed immediately by IL-2 18 million IU/m²/day in 50 cc 5% dextrose (or 0.9 normal saline) IVPB over 15–30 min daily for 3 days per week for a total of 6 weeks (18 total doses). Patients then rested for 2 weeks. Cycles were repeated therefore every 8 weeks in the absence of disease progression or intolerable toxicity.

Supportive care

Therapy was administered by oncology-trained nurses in an outpatient oncology setting. Patients were typically premedicated with ondansetron 16 mg i.v. per day, meperidine 25 mg i.v., acetaminophen 650 mg orally, and ibuprofen 400 mg. Patients were examined daily to determine their tolerance of therapy. For systolic blood pressures <90 mm Hg, patients were treated with normal saline infusions to keep systolic blood pressure >90 mm Hg. Patients were observed for 4–6 hours after IL-2 administration. During the observation phase, additional doses of meperidine were given for the control of rigors; acetaminophen and/or ibuprofen were utilized for fever and muscle or joint pain; and ondansetron and prochlorperazine were administered for nausea.

Those patients experiencing grade III toxicity unresponsive to standard measures had doses omitted.¹² Repeated grade III toxicity resulted in patients being treated using a 50% reduction of their daily IL-2 dose.

Results

The median number of cycles received=1 (range: 1–10). The median number of IL-2 doses received per cycle was 18.^{6

–18} The most common toxicities are listed in Table 2. Overall, this regimen was well tolerated.

Table 2.

Most Common Toxicities

Toxicity	Patients	%
Arthralgia/myalgia	14	67
Rigors	14	67
Nausea/emesis	13	62
Elevated LFT's	11	52
Pruritus	11	52
Fever	10	48
Hypotension	10	48
Decreased appetite	7	33
Constipation	6	29

Reversible episodes of hypotension requiring transient administration of intravenous fluids occurred in 10 patients. No patients required hospitalization for hypotension or other treatment-related toxicity. Three patients were treated at 50% daily dosing due to hypotension. All of the toxicities above have been described with IL-2-based therapies.

Response to therapy

One complete (5%) and four (19%) partial responses were seen (24% response rate; 95% confidence interval [CI]: 9%–48%). Median response duration=20+ months (range: 1–35.5+ months). Responses were seen in lung, liver, lymph nodes, bones, and subcutaneous sites as noted in Table 3. One patient who had been in a partial response for 6.5 months was taken to surgery for resection of a remaining hypermetabolic lymph node noted on positron emission tomography/computed tomography scan. Only inflammatory cells and no viable tumor cells were identified at that time. He is therefore considered to be in a pathologic complete response, since his surgery (29+ months). This patient had previously experienced progressive disease while on multiple prior therapies, including interferon-α-2b, continuous infusion IL-2, and temozolomide.

Table 3.

Response to Therapy

Patient age (years)	Prior systemic therapy	Disease site	Type/duration of response (months)
26	Chemo^a	Spleen, LN, soft tissue	PR 6.5→CR 29+
	IFN, IL-2
79	IFN	Lung	PR 23+
70	None	LN, SQ	PR 20+
49	None	LN	PR 3+
50	None	Bone, LN	PR 1

Temozolomide.

SQ, subcutaneous.

Median survival for all patients is 6.5 months. The median survival of responding patients is 24.5 months (range: 21.25–37+ months). Six patients are alive at a median of 27.8+ months.

Discussion

High-dose bolus schedules of IL-2 (600,000 IU/kg every 8 hours) are active in metastatic melanoma. The toxicities of thrice-daily dosing schedules, including pulmonary edema, cardiac arrhythmia, and hypotension requiring vasopressor support can be daunting.^4
–6

Also, since the majority of patients treated with high-dose bolus IL-2 do not achieve any response of their tumors, other methods to improve this therapy are in order. Famotidine may be able to augment the immune response against cancer. Cytotoxicity of both LAK and tumor infiltrating lymphocytes may be enhanced by increased IL-2 internalization in the presence of famotidine.⁹ Also, famotidine may increase the infiltration of cytotoxic lymphocytes into tumors.¹⁰ Third, our group has described that patients with metastatic melanoma responding to famotidine and continuous infusion followed by a bolus dose of IL-2 have increased numbers of CD56+ cells at subcutaneous and lymph node sites.¹³

Mitchell et al. have examined the use of outpatient intravenous IL-2 with the daily dose being 21.6 million IU/m² for 5 days for 2 consecutive weeks.⁷ Low-dose cyclophosphamide was administered in this regimen in an attempt to lessen suppressive aspects of the immune system, including regulatory T-cells, and thereby further augment an immune response. This regimen has been shown to yield the LAK activity against melanoma cell lines in-vitro.⁷

The 24% response rate in our current study is comparable to other IL-2 regimens. Most IL-2 regimens, including those using ex vivo-activated cytotoxic T-cells or LAKs, have response rates in the 15%–22% range.^{4,14

–19}

A prior phase II study of single daily intravenous IL-2 without famotidine reported a response rate of 10% (95% CI: 3%–23%).²⁰ Our group has previously seen two responses in 7 patients with melanoma treated with outpatient intravenous IL-2.⁸ We and other investigators have combined such daily intravenous IL-2 infusions with low-dose cyclophosphamide. Response rates in these studies have ranged from 4% to 36%.^7,21
–23

Our approach in the current study allowed for the treatment of patients on an outpatient basis. While some degree of hypotension was common in this cohort of patients, all instances resolved with intravenous saline infusions. No patients required hospitalization for vasopressor support. Indeed, no patients required hospitalization due to toxicity of therapy.

This relative lack of serious toxicity allowed for the treatment of older patients not typically considered for IL-2-based therapy.^15,24,25 On this study, 4 patients 70 years or older were able to receive this therapy. In fact, 2 of these are among our responding patients, both achieving partial responses lasting over 20 months in duration.

Longer term survival in selected patients remains a particularly appealing aspect of IL-2-based therapy. Six patients (29%) on this study are alive at >2 years. Our group has previously described that 25% of patients treated with continuous infusion IL-2 plus famotidine survived at least 24 months.²⁶

Conclusions

This combination of outpatient intravenous IL-2 and famotidine has activity in metastatic melanoma. Long-term even disease-free survival may be seen.

Footnotes

Disclosure Statement

There are no existing financial conflicts.

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