An eruption of basal cell carcinoma after ibrutinib

Abstract

Ibrutinib is a therapy targeting tyrosine kinase that has been used for various hematologic malignancies. It is associated with a variety of adverse effects, several of which are dermatologic. While there are few discussions of basal cell carcinoma as an adverse event, there have not yet been reports of a significantly increased incidence. Here, we present a patient with no dermatologic history who subsequently developed nearly 30 incidents of basal cell carcinoma after starting ibrutinib, leading to discontinuation of the therapy.

CASE SUMMARY

The patient was diagnosed with chronic lymphocytic leukemia and small lymphocytic leukemia (CLL/SLL) in 2017. In January of 2018, the patient began ibrutinib for treatment of CLL/SLL, which was effective in his disease management. He initially did not notice any significant side effects. A year later, the patient started developing basal cell carcinomas (BCCs) on his face, which were each treated with Mohs surgery. By late 2020, the patient continued to develop frequent and new BCCs, thus leading to the discussion between the dermatologist and the treating oncologist of discontinuing ibrutinib. The patient discontinued the medication soon thereafter after 34 months of therapy. The patient was then transitioned to venetoclax. The medical record noted a decreased incidence of BCC with 4 documented BCCs following this medication change. The patient had 27 BCCs since starting ibrutinib (Table 1), with 9 BCCs in the forehead area alone (Figure 1). The eruption of BCCs was a significant change to his dermatologic history, and it is expected that the incidence of BCCs will decrease now that he is no longer on ibrutinib therapy.

Table 1.

Timeline and locations of basal cell carcinomas following initiation of ibrutinib treatment in 2018

Year	Location
2019	Left alar crease, right ala, left chin, right inferior chin, left lateral cheek, left lateral forehead
2020	Center left forehead, right preauricular (superior and inferior), right lateral chin, right inferior cheek, right temple, right inferior cheek, left temple
2021	Right ala, dorsal nose, right preauricular
2022	Right inferior medial forehead, glabella, right inferior cheek, right middle cheek, right lower cheek, left lateral forehead, left temple, left nasal supratip
2023	Left inferior forehead, left chin

Figure 1.

Forehead with previous basal cell carcinoma incidences marked.

CLINICAL QUESTIONS

1. Which of the following is not a common dermatologic side effect of ibrutinib?

   1. Nail changes

   2. Skin atrophy

   3. Bleeding

   4. Rash

2. What has been the proposed mechanism by which CLL/SLL patients are at higher risk for BCC?

   1. Increased environmental exposures

   2. Reduced melanin synthesis

   3. Impaired immune surveillance

   4. Disrupted skin integrity

Answers are provided at the end of the article.

DISCUSSION

Ibrutinib is an emerging therapy targeting Bruton’s tyrosine kinase that gained Food and Drug Administration approval for various hematologic malignancies. It has been reported that 20% of patients taking ibrutinib will discontinue it due to intolerable adverse events.¹ To our knowledge, the development of numerous BCCs secondary to ibrutinib treatment has not been well established in the dermatology literature. There have been studies that note various dermatologic issues such as operative bleeding, photosensitivity, nail changes, and a slight increase in nonmelanoma skin cancer incidences.^1–3 Madronero et al reported two cases of BCC; however, both patients were able to continue ibrutinib after treatment with Mohs surgery.⁴ Bond et al evaluated the incidence of secondary malignancies after ibrutinib treatment and reported that 20% (137/691) of their patients were diagnosed with a nonmelanoma skin cancer, 44% (n = 60) of which were BCC.⁵

The mechanism by which ibrutinib leads to increased BCCs has not been confirmed or well elucidated, although there has been some discussion of possible theories. Sun et al conducted a pharmacovigilance study from the Food and Drug Administration Adverse Events Reporting System and noted that ibrutinib was significantly associated with a higher reporting of skin cancer compared with all other drugs to treat CLL.⁶ The authors proposed two potential mechanisms by which ibrutinib may be implicated in BCC development. Ibrutinib disrupts B-cell receptor signaling, leading to immune dysfunction, and the drug itself possesses a low target selectivity, altering the effects of endothelial growth factor receptors and resulting in photosensitivity.⁶ Both of these possible mechanisms correlate with an increased risk for BCC, and future studies are needed to explore the interplay of ibrutinib with immune dysregulation.

We present this patient in hopes to expand the discussion on potential nonmelanoma skin cancers associated with ibrutinib. Although we anticipate our patient will have reduced BCCs after discontinuing the therapy, he will remain under close surveillance for future incidences. We encourage physician reporting of such cases and further ongoing studies.

ANSWERS TO CLINICAL QUESTIONS

Question 1, b. Nail changes (a), bleeding (c), and rash (d) are all reported side effects of ibrutinib, while skin thinning (b) has not been reported. Nail changes include onychoschizia and onychorrhexis.¹ Increased risks of bleeding have been observed, and reported rashes include those that are vasculitic or pityriasiform.¹

Question 2, c. While the mechanism by which primary skin cancers occur secondary to ibrutinib therapy has not been determined, a theory that has been proposed postulates a potential alteration of CD4 and CD8 cell counts and possible impaired immune surveillance.⁵ This theory was described by Bond et al and has not yet been evaluated or validated but serves as a potential springboard that future studies may investigate.⁵

DISCLOSURE STATEMENT

The authors report no funding or conflicts of interest. The patient consented to publication of this case and photo.