Ibrutinib-Associated Nail Plate Abnormalities: Case Reports and Review
Drug Saf - Case Rep
Ibrutinib-Associated Nail Plate Abnormalities: Case Reports and Review
Lucas A. Heldt Manica 0 1 2
Philip R. Cohen 0 1 2
0 Department of Dermatology, University of California San Diego, La Jolla , 10991 Twinleaf Court, San Diego, CA 92131-3643 , USA
1 & Philip R. Cohen
2 & Lucas A. Heldt Manica
Chronic lymphocytic leukemia is a lymphoproliferative disorder characterized by a gradual accumulation of neoplastic B-lymphocytes. Ibrutinib is a novel therapy for chronic lymphocytic leukemia. Ibrutinib therapy has been associated with nail plate abnormalities. Other common cutaneous adverse events caused by ibrutinib appear to be bruising, hair changes, pruritus, and rashes. We describe the clinical features of two patients with chronic lymphocytic leukemia: a 79-year-old woman and a 53-year-old man who developed nail plate abnormalities approximately 6 and 4 months, respectively, after beginning ibrutinib therapy. We also review the characteristics of other patients with chronic lymphocytic leukemia with ibrutinib-associated nail plate abnormalities. The PubMed database was used to search the following terms: abnormal, abnormalities, adverse, brittle, chronic, cutaneous, dystrophy, events, effects, ibrutinib, lymphocytic, leukemia, nail, plate, and side. The relevant referenced papers generated by the search were reviewed. In conclusion, ibrutinib is used to treat chronic lymphocytic leukemia. It is usually
John A. Burns School of Medicine, University of Hawaii,
5737 Kalanianaole hwy, Honolulu, HI 96821-1741, USA
well-tolerated. Many patients receiving ibrutinib will
develop nail plate abnormalities. This adverse event is not
a drug-limiting toxicity.
Ibrutinib, a tyrosine kinase inhibitor, is a novel therapy for chronic lymphocytic leukemia that has been associated with nail plate abnormalities.
The brittle nails in ibrutinib-treated patients may result from the drug’s ability to disrupt the disulfide bonds between the cysteine residues in the nail.
The ibrutinib-associated nail changes that occur in patients with chronic lymphocytic leukemia are not a drug-limiting toxicity.
Chronic lymphocytic leukemia is a lymphoproliferative
disorder characterized by a gradual accumulation of
neoplastic B-lymphocytes. Ibrutinib, a tyrosine kinase
inhibitor, is a novel therapy for chronic lymphocytic leukemia;
it is typically dosed at 420 mg orally once daily. Tyrosine
kinase is a cytoplasmic enzyme that is essential for
B-lymphocyte survival; it is involved in the regulation of
trafficking, homing and adhesion of chronic lymphocytic
leukemia cells [
]. We describe two patients with
chronic lymphocytic leukemia who developed nail plate
abnormalities after initiating therapy with ibrutinib.
A 79-year-old woman with chronic lymphocytic leukemia
was referred by her oncologist for a skin check. The patient
noted changes in the appearance and texture of her nails
within 6 months of starting systemic treatment for chronic
lymphocytic leukemia with ibrutinib at an oral daily dose
of 420 mg. She was not receiving any other chronic
lymphocytic leukemia-directed therapy.
Cutaneous skin examination was significant for changes
of her toenails (Figs. 1, 2, 3) and fingernails, which
appeared fragile and brittle; biotin 2.5 mg daily was
prescribed. In addition, she had ecchymoses on her arms and
legs. Ten actinic keratosis were discovered and treated with
cryotherapy. No cutaneous malignancies were diagnosed.
At follow-up evaluation 3 months after starting biotin,
her toenails were less brittle. New ecchymoses on her
extremities continued to develop.
A 53-year-old man with chronic lymphocytic leukemia was
referred by his oncologist for a skin check. The patient
noted that the appearance of his nails had changed within 4
months of starting systemic treatment for chronic
lymphocytic leukemia with ibrutinib at an oral daily dose of
420 mg. ABT199 (Venetoclax), a Bcl-2 inhibitor, had been
added 3 months after the initiation of ibrutinib. He was not
receiving any other chronic lymphocytic leukemia-directed
Fig. 1 Distant view of ibrutinib-induced nail changes on the toes of a
79-year-old woman with chronic lymphocytic leukemia. The toenails
are fragile and brittle. There is distal shedding of the right great
toenail and horizontal splitting of the left great toenail.
Drugassociated erosion of the distal left third toe is also present
Fig. 3 Ibrutinib-associated changes of the distal right great toe and
toenail in a woman with chronic lymphocytic leukemia. There is
erythema of the proximal nailfold. The surface of the nail is rough and
there are horizontal ridges. The distal nail shows fissures and splitting;
the lateral portion has shed
Cutaneous skin examination was significant for changes
to the nails on his thumb (Fig. 4), finger (Figs. 5 and 6) and
toe (Fig. 7); they appeared fragile and brittle. Biotin
2.5 mg daily was prescribed. In addition, desquamative
dermatitis with red-brown macules and petechiae was
present on the tip of the left great toe (Fig. 8). No
cutaneous malignancies were observed.
Chronic lymphocytic leukemia is hematologic malignancy
of B-lymphocytes. It is one of the most common leukemias
diagnosed in adults [
]. It primarily presents in older
individuals; 70% of patients are aged[ 65 years at the time
of diagnosis [
A diagnosis of chronic lymphocytic leukemia should be
considered in the presence of unexplained absolute or
relative lymphocytosis [
]. The clinical course of chronic
lymphocytic leukemia is variable. In some patients, the
disease can progress rapidly and lead to death a few years
after diagnosis [
], whereas in other patients the disease
has an indolent course and the patients may never need
The first-line treatment for patients with chronic
lymphocytic leukemia often includes a combination of
chemotherapy agents and immunotherapy (anti-CD20
monoclonal antibody) [
1–3, 5–7, 9, 10
]. However, the age
and comorbidities of the individuals being treated often
limit the applicability of these standard treatments.
1, 2, 5–7, 11
]. Ibrutinib is a new drug for the treatment of
patients with chronic lymphocytic leukemia.
Ibrutinib is an oral, irreversible tyrosine kinase inhibitor.
It affects neoplastic cells by covalently binding in the
cysteine moiety in the active site of tyrosine kinase,
resulting in subsequent inhibition of neoplastic cell
proliferation, substrate adhesion, migration and survival
1, 3, 4
Ibrutinib is generally well tolerated. Significant side
effects of the medication include anemia, atrial fibrillation,
bleeding, diarrhea, fatigue, fever, hypertension, muscle and
bone pain, nausea, neutropenia, pneumonia,
thrombocytopenia and tumor lysis syndrome [
1–6, 10, 12
hair changes and nail plate abnormalities, pruritus and
rashes are the most common cutaneous side effects of
2–4, 10, 12–14
]; less common skin adverse
events include purpuric painful nodules and pyoderma
]. Hair changes associated with the
use of ibrutinib include straightening and softening;
increased curliness has also been reported [
Earlier studies reported by Farooqui et al. [
] and Bitar
et al. [
] have noted nail changes associated with the use
of ibrutinib. Farooqui et al. [
] described 51 patients with
chronic lymphocytic leukemia treated with ibrutinib. In
total, 22 (43%) of the patients developed nail ridging.
Bitar et al. [
] described 66 patients with chronic
lymphocytic leukemia treated with ibrutinib. Brittle
fingernails were noted in 44 (67%) patients, and toenail
changes were observed in 15 (23%) patients. The median
time for onset of changes after initiating treatment with
ibrutinib was 6.5 months for fingernails and 9 months for
toenails. As with these individuals, both of our patients
showed nail plate abnormalities within 6 months of
initiating therapy with ibrutinib. The nail plate abnormalities
were not a drug-limiting toxicity for any of these patients.
The pathogenesis of ibrutinib-induced nail changes has
been postulated [
]. The integrity of the keratin-associated
fibrous proteins is preserved by disulfide bonds between
cysteine residues [
13, 17, 18
]. Ibrutinib covalently binds to
the cysteine moieties near the active site of the tyrosine
kinase enzyme [
2, 4, 13
]. Since cysteines are crucial for
nail integrity, it is speculated that ibrutinib disrupts the
disulfide bonds between the cysteine residues, causing nail
brittleness to develop [
Fingernails typically grow 3 mm per month and toenails
grow 1 mm per month. Therefore, the complete growth
cycle is 3–6 months for fingernails and 12–18 months for
]. Hence, the appearance of ibrutinib-associated
nail changes may not be noted until the nail has completed
its growth cycle.
In most patients, treatment of the ibrutinib-induced nail
brittleness or other drug-associated nail changes is not
necessary. We recommended that our patients keep their
nails short. We also prescribed daily biotin and
recommended that the patients apply nail polish once a week.
One of our patients noted significant improvement of her
nails at follow-up examination 3 months after starting daily
Ibrutinib is used to treat chronic lymphocytic leukemia. It
is usually well tolerated. Bruising, hair changes, nail plate
abnormalities, pruritus and rashes are the most common
cutaneous adverse events caused by ibrutinib. Similar to
the individuals described in this report, many patients
treated with ibrutinib develop nail plate abnormalities.
However, this adverse event is not a drug-limiting toxicity.
Compliance with Ethical Standards
Funding No funding or sponsorship was received for this study or
publication of this article.
Authorship All named authors meet the International Committee of
Medical Journal Editors (ICMJE) criteria for authorship for this
manuscript, take responsibility for the integrity of the work as a
whole, and have given final approval for the version to be published.
Conflict of interest Lucas A. Heldt Manica, BS, and Philip R.
Cohen, MD, have nothing to disclose.
Informed consent Informed consent was obtained from the patients
for being included in the study.
Open Access This article is distributed under the terms of the
Creative Commons Attribution-NonCommercial 4.0 International
License (http://creativecommons.org/licenses/by-nc/4.0/), which
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author(s) and the source, provide a link to the Creative Commons
license, and indicate if changes were made.
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