Hair and Nail Changes During Long-term Therapy With Ibrutinib for Chronic Lymphocytic Leukemia

Abstract

Importance Ibrutinib (Imbruvica®), a Bruton tyrosine kinase (BTK) inhibitor, is a new targeted agent approved by the US Food and Drug Administration for the treatment of chronic lymphocytic leukemia (CLL), mantle cell lymphoma, and Waldenström macroglobulinemia. Ibrutinib is overall well-tolerated but requires long-term treatment until disease progression or intolerable toxicity occurs. Little is known regarding its cutaneous adverse effects. Objective To describe the hair and nail manifestations associated with the long-term use of ibrutinib for the treatment of CLL. Design Prospective study of patients enrolled in a single-arm phase II clinical trial of ibrutinib for CLL between March 2014 and October 2015 Setting A single institution study at the National Institutes of Health. Participants The study evaluated 66 patients with CLL. Main outcomes and measures The primary outcome, nail and hair changes associated with ibrutinib therapy, was assessed by an 11question survey. In addition, the severity of nail changes was determined from a 0–3 rating scale for both onychoschizia and onychorrhexis. Results Among 66 patients, 44 (66.6%) reported brittle fingernails at a median of 6.5 months after starting ibrutinib (95% CI 6–12 months). 15 patients (22.7%) developed brittle toenails after a median of 9 months of ibrutinib therapy (95% CI 6–15). Textural hair changes were reported in 17 patients (25.7%), at a median of 9 months of ibrutinib treatment (95% CI 6–12). Conclusion and relevance Hair and nail abnormalities are commonly associated with ibrutinib and appear several months after initiating therapy. Ibrutinib inhibits BTK by covalently binding to cysteine 481.Whether ibrutinib affects the hair and nails by binding and altering cysteine rich proteins of hair and nails or due to other off-target remains unknown.

Cell‐of‐origin in diffuse large B‐cell lymphoma: findings from the UK's population‐based Haematological Malignancy Research Network

“…Dermatological toxicities have also been reported in 2-27% of treated patients (Ransohoff & Kwong, 2017;Iberri et al, 2018), mainly mild-to-moderate rash, neutrophilic panniculitis, progressive hair and nail changes, skin infections, bruising, petechiae and purpuric eruption (Fabbro et al, 2015;Bitar et al, 2016;Ransohoff & Kwong, 2017;Iberri et al, 2018). In contrast, oral toxicity with ibrutinib has rarely been described.…”

Dose‐limiting stomatitis associated with ibrutinib therapy: a case series

“…In contrast, oral toxicity with ibrutinib has rarely been described. A prospective dermatological survey did not observe any mucosal involvement in a cohort of 66 consecutive patients (Bitar et al , ). However, a recent pivotal study reported all‐grade and high‐grade stomatitis in 11% and 1% of treated patients, respectively, but the clinical aspects were not documented (Byrd et al , ).…”

“…However, the rate of grade ≥3 adverse events remains low and treatment discontinuation due to toxicity (Byrd et al , , ) is uncommon and mostly related to infections (Byrd et al , , ; Burger et al , ; Puła et al , ; Tran & O'Brien, ). Dermatological toxicities have also been reported in 2–27% of treated patients (Ransohoff & Kwong, ; Iberri et al , ), mainly mild‐to‐moderate rash, neutrophilic panniculitis, progressive hair and nail changes, skin infections, bruising, petechiae and purpuric eruption (Fabbro et al , ; Bitar et al , ; Ransohoff & Kwong, ; Iberri et al , ). In contrast, oral toxicity with ibrutinib has rarely been described.…”

“…It would be reminiscent of a localized adaptive cellular immune response where ibrutinib‐conjugated peptides would be presented to host immune cells via a major histocompatibility complex, leading to a T‐cell‐driven immune response and bystander tissue destruction (Fabbro et al , ). Moreover, although ibrutinib demonstrates high selectivity for BTK, it also exerts off‐target effects on other kinases, including irreversible binding to epidermal growth factor receptor (EGFR) or HER2 (Bitar et al , ). This mechanism could partly explain the pathogenesis of ibrutinib‐associated oral ulcers, even though anti‐EGFR‐related mucositis mostly occurs in the first weeks of treatment, solely involves nonkeratinized mucosae (similar to other kinase inhibitors, including mTOR inhibitors) and remains of low grade (Vigarios et al , ).…”

Pharmacokinetic and pharmacodynamic evaluation of ibrutinib for the treatment of chronic lymphocytic leukemia: rationale for lower doses

“…[35] Brittle nails and textural hair changes have been reported during long-term therapy of CLL with ibrutinib, but the underlying mechanisms remain unknown. [86]…”