Acral Lentiginous Melanoma

1. Disease Summary:

Acral lentiginous melanoma (ALM) is a rare subtype of cutaneous melanoma that primarily occurs on non-hair-bearing surfaces, such as the palms of the hands, soles of the feet, and under the nails. It is characterized by a slow-growing, pigmented lesion that can be mistaken for benign conditions, leading to delayed diagnosis. ALM is the most common melanoma subtype in individuals with darker skin tones, particularly among Asian and Hispanic populations. This subtype is associated with a poorer prognosis compared to other melanoma types, largely due to its late presentation and unique biological characteristics.

2. Global Prevalence and Disease Burden:

ALM accounts for approximately 2-3% of all melanoma cases in Western countries but represents a significantly higher proportion (up to 55-65%) in populations of color. In the United States, around 2,000 to 3,000 new cases of ALM are diagnosed annually (PMID: 19380664). The disease burden is exacerbated by its aggressive nature and the challenges associated with early detection. The 5-year melanoma-specific survival rates for ALM are approximately 80.3%, significantly lower than the rates for other melanoma subtypes (91.3%) (PMID: 19380664). The economic impact of ALM includes healthcare costs related to treatment, management of complications, and loss of productivity due to illness.

3. Unmet Medical Need:

The unmet medical needs for patients with acral lentiginous melanoma are multifaceted:

Delayed Diagnosis: ALM often presents in areas that are not routinely examined, leading to late-stage diagnosis. This delay contributes to poorer outcomes and higher mortality rates. The difficulty in recognizing early lesions due to their atypical appearance further complicates timely intervention (PMID: 29951919).
Limited Treatment Efficacy: Current treatment options, including immune checkpoint inhibitors (ICIs) and targeted therapies, have shown limited effectiveness in ALM patients. The poor immunogenicity of ALM tumors results in lower response rates to ICIs compared to other melanoma types (PMID: 39438074). Additionally, the infrequent occurrence of BRAF mutations in ALM limits the applicability of BRAF/MEK inhibitors, which are effective in other melanoma subtypes (PMID: 29951919).
Lack of Targeted Therapies: There is a significant gap in the development of targeted therapies specifically for ALM. While some patients may have mutations in genes such as KIT and NRAS, the overall understanding of the genetic landscape of ALM is still evolving, and targeted treatment options remain scarce (PMID: 34562816).
Racial Disparities: ALM disproportionately affects individuals of color, who may face additional barriers to accessing care, including socioeconomic factors and healthcare disparities. This contributes to worse outcomes and highlights the need for tailored approaches to treatment and management in these populations (PMID: 37659614).

4. Current Treatment Options:

Current treatment options for acral lentiginous melanoma include:

Surgical Intervention: The primary treatment for localized ALM is surgical excision. However, the effectiveness of surgery diminishes significantly for advanced stages (PMID: 29951919).
Immune Checkpoint Inhibitors: Drugs such as pembrolizumab (anti-PD-1) and nivolumab (anti-PD-1) have been used, but their efficacy in ALM is lower than in other melanoma types. A study reported an objective response rate (ORR) of only 18.3% for patients treated with a combination of PD-1 and CTLA-4 inhibitors (PMID: 39438074).
Targeted Therapies: While BRAF/MEK inhibitors are standard for BRAF-mutant melanoma, their effectiveness is limited in ALM due to the low mutation rates. Some studies have explored c-KIT inhibitors, which have shown a modest ORR of 22% in ALM patients (PMID: 34562816).
Adjuvant Therapies: There is ongoing research into the use of adjuvant therapies, including radiation and systemic therapies, but these approaches require further validation through clinical trials (PMID: 29951919).

5. Current Clinical Trials:

Several clinical trials are currently investigating new treatment options for ALM. These include:

Combination Therapies: Trials are exploring the efficacy of combining immune checkpoint inhibitors with other agents to enhance treatment responses in ALM patients (PMID: 39438074).
Targeted Therapy Trials: Research is ongoing to evaluate the effectiveness of targeted therapies for patients with specific genetic mutations associated with ALM (PMID: 34562816).
Novel Agents: New agents and combinations are being tested in clinical settings to determine their safety and efficacy in treating ALM, particularly in advanced stages (PMID: 29951919).

6. Additional Context:

The management of acral lentiginous melanoma requires a multidisciplinary approach, including dermatologists, oncologists, and surgical specialists. Increased awareness and education about ALM among healthcare providers and the public are crucial for improving early detection and outcomes. Furthermore, addressing the socioeconomic barriers faced by patients, particularly those from racial and ethnic minority groups, is essential for equitable access to care and treatment.