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Despite advancements in treating cutaneous melanoma, patients with acral and mucosal (A/M) melanomas still have limited therapeutic options and poor prognoses. We analyzed 156 melanomas (101 cutaneous, 28 acral, and 27 mucosal) using the Foundation One cancer-gene specific clinical testing platform and identified new, potentially targetable genomic alterations (GAs) in specific anatomic sites of A/M melanomas. Using novel pre-clinical models of A/M melanoma, we demonstrate that several GAs and corresponding oncogenic pathways associated with cutaneous melanomas are similarly targetable in A/M melanomas. Other alterations, including MYC and CRKL amplifications, were unique to A/M melanomas and susceptible to indirect targeting using the BRD4 inhibitor JQ1 or Src/ABL inhibitor dasatinib, respectively. We further identified new, actionable A/M-specific alterations, including an inactivating NF2 fusion in a mucosal melanoma responsive to dasatinib in vivo. Our study highlights new molecular differences between cutaneous and A/M melanomas, and across different anatomic sites within A/M, which may change clinical testing and treatment paradigms for these rare melanomas., (© 2024 UICC.)

A total of 65 patients with advanced cutaneous malignant melanoma (MM) have now been treated with interferon alpha-2b (Intron A) at a dose of 10 million IU/m2 administered subcutaneously thrice weekly. Fifty-one patients were evaluable for response, and 4 of these (7.8%) achieved complete remission; 2 of these 4 remain so at 37 + and 54 + months. Six additional patients achieved a partial remission. All responders had subcutaneous, lymph node and/or pulmonary metastases only. In all responders, therapy was continued for a total of 12 months. The vast majority of patients experienced side effects, largely flu-like symptoms, mild leukopenia and mild hepatocellular dysfunction. No evidence of cumulative toxicity was observed. Our experience indicates that interferon alpha-2b is active in patients with advanced cutaneous MM.

Sixteen patients with advanced (stage III) malignant melanoma were treated with escalating doses of intravenous BCNU and melphalan starting at 400 and 35 mg/m2, respectively, and escalating to 1,000 and 110 mg/m2, respectively, combined with autologous marrow transplantation. The duration of granulocytopenia and time to granulocyte recovery was similar in all groups regardless of chemotherapy dose. Platelet recovery was delayed in patients receiving the highest doses of chemotherapy. This study showed that bone marrow colony-forming units in culture took as long as 6 months to recover. This was adequate to bring peripheral blood counts to normal but not to pretreatment levels. These studies indicate that autologous bone marrow transplantation is beneficial in enhancing short-term recovery, but may not be beneficial in the long-term hematopoietic recovery.

Following recent reports suggesting that the addition of cimetidine to interferon may enhance response rates in patients with metastatic malignant melanoma, we have completed a Phase II study of the use of recombinant alpha 2 interferon and cimetidine in patients with advanced malignant melanoma and who had progressive disease following interferon therapy alone. We observed two partial responses, no complete responses, and two patients had stable disease. Toxicity encountered was analogous to that of interferon alone. We conclude that the additional of cimetidine to alpha interferon is not beneficial in the treatment of advanced metastatic malignant melanoma.

Cutaneous malignant melanoma is occurring in epidemic proportions in the United States. To provide a profile of persons at risk and the epidemiologic features of malignant melanoma, we reviewed the records of 325 patients with cutaneous malignant melanoma seen at the University of Colorado Health Sciences Center between 1973 and 1983. Most patients had fair skin, brown or blonde hair, blue or green eyes, and had difficulty in suntanning. The majority of melanomas (72%) developed in preexisting nevi. In women, melanomas were most common on the extremities, and in men they occurred most frequently on the trunk, head or neck. The most frequently noted depth of invasion was Clark's level IV. At diagnosis, most of the patients (77%) were at stage I. We conclude that malignant melanoma constitutes a major disease problem in the western United States that is largely preventable with appropriate physician and patient education.

Fifty-nine patients with metastatic malignant melanoma were entered into a phase II trial of recombinant alpha-2 interferon given in a dosage of 10 million IU/M2 subcutaneously three times per week for one year. Forty-five of these were evaluable for response. Of five evaluable patients with ocular primaries, none responded to interferon treatment. Four of 40 patients (10%) with cutaneous primaries achieved complete remission, and 6 further patients (15%) had partial remissions for a combined response rate of 25%. Two patients remain in complete remission 15+ and 32+ months after starting treatment. Responses were limited to subcutaneous, lymph node and lung metastases. The treatment schedule was well tolerated with the majority of patients receiving more than 70% of their predicted doses. Flu-like symptoms were the most common side effect. No evidence of cumulative toxicity was seen. We conclude that interferon is an active agent in metastatic malignant melanoma of cutaneous origin and that further trials are indicated.