Enhanced survival associated with vitiligo expression during maintenance biotherapy for metastatic melanoma.

Vitiligo, an autoimmune skin disorder, was evaluated in 49 metastatic melanoma patients treated with an immunotherapy regimen of maintenance biotherapy (mBT) following induction concurrent biochemotherapy (cBCT). Patients receiving mBT demonstrated a stable or better response to cBCT. The mBT regimen consisted of outpatient subcutaneous injections of low-dose IL-2 (1 MIU/m(2)) 5/7 days weekly, GM-CSF (125 mcg/m(2)) 14 days monthly, and high-dose pulses of in-patient continuous infusion decrescendo IL-2 (54 MIU/m(2)) over 48 hours monthly for the first 6 months and every 2 months thereafter. The majority of patients had poor prognostic features. Forty-nine patients were without evidence of vitiligo at the start of mBT. Of these, 21 patients (43%) developed vitiligo during mBT and had a median overall survival from the start of mBT of 18.2 months (95% CI, 12.3-N/A) compared to 8.5 months (95%CI <6.7-12.7) for 28 non-vitiligo patients (P=0.027). Six of 21 vitiligo patients (29%) expressed IgG antibody titers to tyrosinase-related protein-2 compared to four of 28 non-vitiligo patients (14%) (P=NS). The development of vitiligo in metastatic melanoma patients on cBCT/mBT immunotherapy correlates with a better therapeutic outcome.

Low-dose outpatient chemobiotherapy with temozolomide, granulocyte-macrophage colony stimulating factor, interferon-alpha2b, and recombinant interleukin-2 for the treatment of metastatic melanoma.

PURPOSE: The objective of this study was to further investigate the efficacy and safety of low-dose outpatient chemobiotherapy in patients with unresectable metastatic melanoma. PATIENTS AND METHODS: Thirty-one patients with histologically confirmed unresectable measurable metastatic melanoma were enrolled onto an open-label, multicenter phase II study. The treatment regimen consisted of oral temozolomide followed by subcutaneous biotherapy with granulocyte macrophage colony-stimulating factor, interferon-alfa, and recombinant interleukin-2 (rIL-2). RESULTS: Twenty-eight patients (90%) had M1c disease, and 58% had three or more sites of metastasis. Four patients (13%), all with M1c disease, had a complete response, and four patients had a partial response. The median progression-free survival was 4.9 months and the median overall survival was 13.1 months. Two patients (6%) developed CNS metastasis as the first site of disease progression, and 7 (23%) of 30 experienced CNS progression after receiving chemobiotherapy. A total of 112 cycles of therapy were administered. Toxicity occurred in 78% of the cycles and was grade 1 or 2 in the majority of cases and easily managed. Grade 4 toxicity occurred in 3% of the cycles. CONCLUSION: This low-dose chemobiotherapy combination produces clinical responses in patients with metastatic melanoma, even in those with M1c disease, is well tolerated, and allows home dosing. It offers a reasonable alternative to high-dose regimens, such as high-dose biochemotherapy or rIL-2 requiring prolonged periods of hospitalization, or single agent outpatient regimens, such as dacarbazine, which is usually not effective in patients with M1c disease. Furthermore, it may protect against the development of brain metastases.

Biochemotherapy for metastatic melanoma with limited central nervous system involvement.

OBJECTIVES: Biochemotherapy outcomes were examined in stage IV melanoma patients with previously treated or active central nervous system (CNS) metastases prior to systemic therapy. PATIENTS AND METHODS: Patients who received biochemotherapy for metastatic melanoma with active or pretreated CNS metastases were compared to patients without evidence of CNS metastases in terms of response, time to progression (TTP), overall survival (OS), and treatment toxicity. RESULTS: Twenty-six (16%) of 159 total patients began biochemotherapy with previously treated or active CNS metastases (group I), compared to 133 (84%) who were radiographically free of CNS involvement (group II). A partial or complete response to biochemotherapy was seen in 13 (50%) group I patients, compared to 56 (42%) group II patients (p = 0.243). The median TTP and median survival were 5.5 and 7.0 months, respectively, for group I patients and 6.0 and 9.9 months, respectively, for group II patients (p = 0.222 and 0.434 for TTP and OS, respectively). Five (19%) group I patients survived longer than 24 months. Gamma Knife radiosurgery or surgical resection of CNS disease prior to biochemotherapy improved survival versus delayed treatment (p = 0.017 and 0.005, respectively). CONCLUSION: Patients with limited CNS metastases and widespread systemic disease can achieve prolonged survival with targeted treatment of CNS lesions and aggressive systemic therapy.

Maintenance biotherapy for metastatic melanoma with interleukin-2 and granulocyte macrophage-colony stimulating factor improves survival for patients responding to induction concurrent biochemotherapy.

PURPOSE: A prospective Phase II study of a novel maintenance biotherapy regimen after induction biochemotherapy was conducted in patients with metastatic melanoma in efforts to maintain responses and improve survival. EXPERIMENTAL DESIGN: Thirty-three patients with poor prognosis metastatic melanoma who achieved a partial response (PR) or stable disease (SD) to induction concurrent biochemotherapy were treated with chronic low-dose interleukin (IL)-2 and granulocyte macrophage-colony stimulating factor, and intermittent pulses of intermediate/high-dose decrescendo IL-2 over a 12-month period. The outcome of these patients was compared with a control group of patients at our institution who were treated recently with induction biochemotherapy and achieved a PR or SD. RESULTS: Five patients (15%) achieved a complete response, and 4 patients (12%) maintained SD for at least 6 months on maintenance biotherapy. The median progression-free survival (PFS) and overall survival (OS) were 8.1 months and 18.5 months, respectively, compared with historical controls, which were PFS 5.9 months (P = 0.0015) and OS 9.3 months (P = 0.0004). Administration of maintenance biotherapy was a significant predictor of PFS (P = 0.0008) and OS (P = 0.0001) in multivariate and matched-pair analyses (P = 0.002). The maintenance biotherapy regimen was well tolerated with no dose-limiting acute or cumulative toxicities. CONCLUSION: In this single institution study, maintenance biotherapy with IL-2 and granulocyte macrophage colony-stimulating factor in patients achieving PR or SD to induction biochemotherapy improved PFS and OS compared with historical controls. A larger multicenter Phase II trial has been initiated in an effort to confirm these results.