Genomic analyses of cutaneous melanoma (CM) have yielded biological and therapeutic insights, but understanding of non-ultraviolet (UV)-derived CMs remains limited.,Deeper analysis of acral lentiginous melanoma (ALM), a rare sun-shielded melanoma subtype associated with worse survival than CM, is needed to delineate non-UV oncogenic mechanisms.,We thus performed comprehensive genomic and transcriptomic analysis of 34 ALM patients.,Unlike CM, somatic alterations were dominated by structural variation and absence of UV-derived mutation signatures.,Only 38% of patients demonstrated driver BRAF/NRAS/NF1 mutations.,In contrast with CM, we observed PAK1 copy gains in 15% of patients, and somatic TERT translocations, copy gains, and missense and promoter mutations, or germline events, in 41% of patients.,We further show that in vitro TERT inhibition has cytotoxic effects on primary ALM cells.,These findings provide insight into the role of TERT in ALM tumorigenesis and reveal preliminary evidence that TERT inhibition represents a potential therapeutic strategy in ALM.
Ipilimumab is a monoclonal antibody that antagonizes cytotoxic T lymphocyte antigen-4, a negative regulator of the immune system.,The authors report on advanced refractory melanoma patients treated in a compassionate use trial of ipilimumab at the Memorial Sloan-Kettering Cancer Center.,Patients with advanced refractory melanoma were treated in a compassionate use trial with ipilimumab 10 mg/kg every 3 weeks for 4 doses.,Those with evidence of clinical benefit at Week 24 (complete response [CR], partial response [PR], or stable disease [SD]) then received ipilimumab every 12 weeks.,A total of 53 patients were enrolled, with 51 evaluable.,Grade 3/4 immune-related adverse events were noted in 29% of patients, with the most common immune-related adverse events being pruritus (43%), rash (37%), and diarrhea (33%).,On the basis of immune-related response criteria, the response rate (CR + PR) was 12% (95% confidence interval [CI], 5%-25%), whereas 29% had SD (95% CI, 18%-44%).,The median progression-free survival was 2.6 months (95% CI, 2.3-5.2 months), whereas the median overall survival (OS) was 7.2 months (95% CI, 4.0-13.3 months).,Patients with an absolute lymphocyte count (ALC) ≥1000/μL after 2 ipilimumab treatments (Week 7) had a significantly improved clinical benefit rate (51% vs 0%; P = .01) and median OS (11.9 vs 1.4 months; P < .001) compared with those with an ALC <1000/μL.,The results confirm that ipilimumab is clinically active in patients with advanced refractory melanoma.,The ALC after 2 ipilimumab treatments appears to correlate with clinical benefit and OS, and should be prospectively validated.,Cancer 2010.,© 2010 American Cancer Society.,This description of 51 patients with advanced, treatment-refractory melanoma who were enrolled in a compassionate use trial of ipilimumab at Memorial Sloan-Kettering Cancer Center confirms that ipilimumab is active in this disease setting.,In addition, the results suggest that the absolute lymphocyte count after 2 ipilimumab treatments (at Week 7) highly correlates with the rate of clinical benefit at Week 24 and overall survival.