Ibrutinib‐related stellar hematomas of the palms and soles
Authors: Naia Oillarburu, Loic Ysebaert, Caroline Protin, Ariadna Ortiz‐Brugues, Sarah Baali, Estelle Parriel, Vincent Sibaud
Journal: American Journal of Hematology (2024)

Bruton's tyrosine kinase (BTK) inhibitors represent a major breakthrough in the treatment of chronic lymphocytic leukemia (CLL) or other B cell malignancies (e.g., mantle cell lymphoma, Waldenstrom's macroglobulinemia, marginal zone lymphoma), and graft versus host disease (GVHD). Ibrutinib is the first-in-class oral small-molecule BTK inhibitor that acts by covalent and irreversible binding to BTK, a Transient Erythroblastopenia of Childhood (TEC) family non-receptor tyrosine kinase. Although ibrutinib presents a favorable safety profile, it can be associated with adverse events, including dermatological toxicities which affect more than one third of patients.1 In this context, the progressive development of hematomas and bruising is clearly the most representative dermatological toxicity associated with BTK inhibitors, but a wide range of other skin manifestations have been also reported, including bacterial/fungal skin infections, folliculitis, maculopapular rash, eczema-like reactions, brittle nails with onychoschizia and onycholysis, paronychia, pruritus/xerosis, mild to moderate alopecia, stomatitis, or panniculitis.1-4 We describe here for the first time a new dermatological adverse event related to ibrutinib, with the occurrence in two patients of vascular lesions in the form of diffuse stellar hematomas involving the palms and soles exclusively. A 76-year-old female patient was diagnosed with CLL in January 2008. She was treated with a geno-identical allograft in July 2008 at the age of 59 years old, complicated by cutaneous graft versus host disease and sequellar hypogammaglobulinemia. Her CLL relapsed in 2017, with hyperlymphocytosis of approximately 100 G/L and no palpable tumor syndrome. The characteristics of her CLL showed a karyotype with a t(3; 12) translocation, no ATM or P53 gene deletion, negative molecular biology, and mutated IGVH status. BTK inhibitor ibrutinib was introduced at a total dose of 420 mg once a day. In December 2019, total dose was decreased to 280 mg/day due to atrial fibrillation. Then, ibrutinib was stopped in October 2020 for fungal sinusitis (mucormycosis) with secondary bacterial superinfection. Resumption of ibrutinib was decided in August 2021, 140 mg/d reduced to 1 dose every other day. Three years later, during a follow-up visit asymptomatic stellar vascular lesions on the palms and to a lesser extent to the soles were noticed. These punctiform hemorrhagic lesions were distributed bilaterally. On the hands, the lesions were predominantly located on the thenar and hypothenar eminences and the fingertips (Figure 1). A 73-year-old patient suffered from CLL since January 2014. CLL was characterized by a 17p deletion and non-mutated IGHV status. She was treated in first-line therapy with combination of rituximab and PI3k inhibitor idelalisib from January to September 2016 which had to be discontinued due to severe toxicity (i.e., grade IV neutropenia and colitis). Second-line therapy with ibrutinib was introduced on year later, at a dose of 420 mg/day, followed by a dose reduction (140 mg/day) after several episodes of skin and osteoarticular infections. In June 2024, similar vascular stellar lesions of the palms, localized to the thenar eminence of both hands were individualized. No vascular lesions were noted on soles (Figure 1). For these two patients, the lesions were totally asymptomatic and not associated with other hemorrhagic manifestations of the treatment except mild bruising on the arms. No other individualized clinical, biological, and pharmaceutical triggering factors (except BTK inhibitor exposure) were individualized. Dermoscopy revealed similar aspects in both cases with confluent petechial purpuric lesions and a glomerular appearance in some areas (Figure 2). Ibrutinib therapy was continued at the same dose. Petechiae and hematomas are the most common cutaneous adverse events of BTK inhibitors, affecting roughly a quarter of patients.1 These lesions tend to develop more frequently in elderly patients with epidermal atrophy and dermatoporis, with a privileged bilateral distribution in areas of repeated microtrauma and/or chronic UV exposure such as the lateral aspect of the forearms and less commonly the trunk.1, 2 They are possibly favored by concomitant use of systemic corticosteroids, antiplatelet agents, and oral anticoagulants. These lesions are promoted by a selective inhibition of platelet signaling and downstream functions of the glycoprotein VI receptor induced by ibrutinib, which strongly affects platelet adhesion on von Willebrand factor (VWF).5, 6 In the same way, patients exposed to ibrutinib present an increased risk of bleeding,6 particularly older men with lower platelet count and on multiple anticoagulant therapies. Low grade skin bleeding has shown a dose-dependent response3; therefore, transient discontinuation of ibrutinib should be considered for dermatologic surgery, for example, three days before and after surgery.7, 8 We can speculate that palmoplantar lesions developing in the two patients we have described are related to the same underlying vascular mechanism and are triggered by repeated localized microtraumas. The palmar predominance of these newly individualized hematomas could potentially be explained by the much greater plantar thickness of the stratum corneum with protective effects. Although its overall incidence has yet to be determined, it can be assumed that this newly described skin toxicity often goes unnoticed and is in practice fairly frequent. However, such stellar hematomas do not require specific treatment, only reassurance of the patients and their relatives. Finally, because next-generation BTK inhibitors such as acalabrutinib or zanubrutinib are able to interact with platelet aggregation9 and can also induce similar ecchymoses and bruising, we can speculate that development of such palmoplantar stellar hematomas may be also observed with these more selective targeted therapies.1, 10 The authors declare no conflicts of interest. The data support the findings on this study are available from the corresponding author upon reasonable request.