Anticoagulation with Factor Xa Inhibitors Is Associated with Improved Overall Response and Progression-Free Survival in Patients with Metastatic Malignant Melanoma Receiving Immune Checkpoint Inhibitors-A Retrospective, Real-World Cohort Study.

Immune checkpoint inhibitors (ICI) significantly improved the prognosis of advanced melanoma patients. However, many patients do not derive long-term benefit from ICI therapy due to primary and acquired resistance. In this regard, it has been shown that coagulation factors contribute to cancer immune evasion and might therefore promote resistance to ICI. In particular, recent observations in murine systems demonstrated that myeloid-derived factor Xa (FXa) impedes anti-tumor immunity in the tumor microenvironment and that the oral FXa inhibitor (FXa-i) rivaroxaban synergizes with ICI. The synergistic effect of FXa inhibitors with clinical ICI therapy is unknown. We performed a retrospective study of 280 metastatic melanoma patients who were treated with ICI and stratified them for concomitant anticoagulation (AC) by medical chart review. Data on baseline patient characteristics, specific AC treatment, ICI therapy, other tumor-targeting therapies, and clinical outcomes were analyzed. Of 280 patients who received ICI, 76 received concomitant AC during initial ICI therapy. Patients on AC were treated either with heparins (n = 29), vitamin K antagonists (VKA) (n = 20), or FXa-i (n = 27). Patients requiring AC during ICI therapy showed no significantly reduced objective response rate (ORR) (p = 0.27), or progression-free (PFS; median PFS 4 vs. 4 months; p = 0.71) or overall survival (OS; median OS: 39 vs. 51 months; p = 0.31). Furthermore, patients who underwent AC did not show significantly more bleeding complications (p = 0.605) than those who were not anticoagulated. Remarkably, stratification of patients by the class of AC revealed that patients receiving FXa-i were more likely to obtain CR (26.9 vs. 12.6%, p = 0.037), and showed better ORR (69.2 vs. 36.4%, p = 0.005), PFS (median PFS: 12 months vs. 3 months; p = 0.006), and OS (median OS not reached vs. 42 months; p = 0.09) compared to patients not receiving FXa-i. Patient demographics and tumor characteristics in this patient subcohort did not significantly differ from patients not on FXa-i. In summary, our study provides first clinical evidence that the clinical application of FXa-i may enhance the efficacy of ICI therapy via the restoration of anti-tumor immunity, while patients who received FXa-i were not more likely to encounter bleeding complications.

The Status of Adjuvant and Neoadjuvant Melanoma Therapy, New Developments and Upcoming Challenges.

The global incidence of malignant melanoma, the leading cause of skin cancer death, has steadily increased in recent years. Surgical excision is the treatment of choice for early-stage melanoma. However, 40-60% of patients with high-risk melanoma or with nodal involvement eventually experience loco-regional relapse or tumor progression. Adjuvant therapy aims to reduce the rate of recurrence in radically operated high-risk patients with melanoma and thus improves survival. Interferon-α has long been the only approved drug for adjuvant melanoma therapy, despite an unclear survival benefit. The landmark success of immune-checkpoint inhibitors and BRAF/MEK-directed targeted therapies in the treatment of patients with stage IV melanoma led to the initiation of clinical trials in the adjuvant setting. These trials demonstrated the efficacy of immune-checkpoint inhibitors and targeted therapies for the adjuvant treatment of high-risk patients with melanoma, as shown both by an increase in recurrence-free survival and the emergence of long-term survivors, finally resulting in the approval of the cytotoxic T-lymphocyte antigen 4 inhibitor ipilimumab, PD1 inhibitors (nivolumab, pembrolizumab), and BRAF/MEK inhibitors for adjuvant melanoma therapy. This review aims to delineate the advances in adjuvant melanoma therapy, issuing particularly recent results from clinical trials. Moreover, we also discuss pending issues and future challenges, which comprise the adequate selection of adjuvant regimens for patient subgroups and the identification of markers likely to predict the individual response to adjuvant treatments. Last, we outline the role of emerging neoadjuvant approaches, which may complement adjuvant strategies and are currently investigated in clinical trials.

Hemophagocytic lymphohistiocytosis of a melanoma patient under BRAF/MEK-inhibitor therapy following anti-PD1 inhibitor treatment: a case report and review to the literature.

Hemophagocytic lymphohistiocytosis (HLH) is a rare but life-threatening condition. HLH in infants and young children is usually inherited, which is then classified as primary HLH. Secondary HLH, in contrast, is caused by many different conditions such as infections, cancer or medication and affects mostly adults. HLH is a hyperinflammatory condition, which may mimic an acute septic shock. We report on a 68-year-old patient with malignant melanoma with lymph node metastases. Due to the lymphogenic progression, treatment was switched from nivolumab to dabrafenib and trametinib. Twenty-one days after initiation of BRAF/MEK inhibitor therapy, the patient presented to our emergency department with clinical signs of infection such as fever and fatigue. Laboratory tests showed excessive inflammation levels without identifying an underlying pathogen. Two days later, the patient developed an increasing pancytopenia. After extending the diagnosis, we found very high ferritin levels, hypertriglyceridemia, hypofibrinogenemia and a soluble CD25 receptor. Based on the laboratory results, prolonged fever and splenomegaly, we were able to diagnose HLH as the underlying condition. We immediately initiated treatment with intravenous prednisone, which remarkably improved the clinical symptoms. After full recovery, we reinitiated anti-tumor treatment with vemurafenib and cobimetinib, which was tolerated without side effects. Due to the relatively nonspecific nature of the clinical signs and symptoms and the significant overlap with other diseases such as sepsis, the diagnosis of HLH is often delayed. This explains, in part, the high morbidity and mortality rate. Our case shows that early treatment with steroids is effective. However, much work remains in order to raise awareness and improve the understanding of the pathophysiology of this condition.