Scanning electron microscopy of ibrutinib-induced hair shaft changes^☆

Dear Editor,

Bruton’s tyrosine kinase (BTK) is essential for the development and maturation of B-lymphocytes. These cells do not mature in individuals with mutations in this enzyme, and they have X-linked agammaglobulinemia, the most common type of congenital agammaglobulinemia.¹

BTK is also expressed in tumor cells, and its inhibition is gaining increasing importance in the treatment of B-lineage neoplasms.² BTK participates in the activation of these cells, being important for the survival of malignant B cells and, therefore, its inhibition decreases their proliferation and survival.

Ibrutinib is a potent irreversible BTK inhibitor and was the first inhibitor of this enzyme approved by the FDA for the treatment of the following diseases in adults: 1) Chronic graft-versus-host disease, after the failure of one or more systemic therapy lines; 2) Chronic lymphocytic leukemia/small cell lymphocytic lymphoma (CLL/SCLL); 3) CLL/SCLL in adults with 17p deletion; 4) Mantle-cell lymphoma in adults who have received at least one prior therapy; 5) Relapsed/refractory marginal zone lymphoma, in adults who require systemic therapy and have received at least one prior anti-CD20-based therapy; and 6) In Waldenström’s macroglobulinemia.³

The described side effects are fatigue, diarrhea, peripheral edema, cardiac arrhythmia (atrial fibrillation), bleeding, and infections (respiratory tract).⁴,⁵,⁶

Ibrutinib can have cutaneous adverse effects, with a peak incidence in the first year of treatment. The most common manifestations are skin rash, petechiae and ecchymosis. Also, urticaria, herpes simplex and herpes zoster reactivation, panniculitis, and Stevens-Johnson syndrome may occur.⁶,⁷

Despite the specificity for BTK, some skin effects are similar to those produced by EGF (epidermal growth factor) inhibitors,⁸ such as the described acneiform rash, changes in hair/eyelashes,⁹ and longitudinal grooves on nails.

A 72-year-old patient who had received ibrutinib for six months to treat mantle lymphoma unresponsive to conventional therapy was assessed. The patient reported a slight alteration in his hair, with a change in its curling (Fig. 1). Some hair shafts were cut and examined in natura with scanning electron microscopy. At medium magnification, discreet longitudinal channels were observed in the hair shafts (Fig. 2A and B), which are not seen in normal hair (Fig. 2C). At high magnification, these channels were very evident (Figs. 3 4).

Figure 1
Modification in hair curl pattern.

Figure 2
Scanning electron microscopy. (A. and B) Medium magnification showing discreet hair shaft channels (x300 and 270). (C) normal control (×300).

Figure 3
Scanning electron microscopy. High magnification revealing a channel in the hair shaft (×550).

Figure 4
Scanning electron microscopy. High magnification showing a channel in the hair shaft (×650).

The authors did not find any reports in the literature of an examination of hairs shafts with scanning electron microscopy showing alterations caused by ibrutinib. There are some reports with EGF inhibitors, in which channels were also described in the hair shafts,⁹ in this case with greater clinical consequences, making the hair frizzy and the eyelashes elongated (trichomegaly) and without curvature. The channels seen in these drug-induced cases are similar to those seen in families with uncombable hair, and in a syndromic type of pili canaliculi associated with a central nervous system degeneration called giant axonal neuropathy.¹¹

The findings of this patient demonstrate, on ultrastructural examination, a similarity between the alterations of EGF and BTK inhibitors.

BTK inhibition is an expanding concept in the treatment of hematologic malignancies, with 22 drugs under development, and the emergence of drugs with less systemic and cutaneous toxicity is possible in the near future.¹⁰,¹²

• ☆
  Study conducted at the Graduate Program in Health and Behavior, Universidade Católica de Pelotas, Pelotas, RS, Brazil.
• Financial support
  None declared.

References

• ¹
  Cardenas-Morales M, Hernandez-Trujillo VP. Agammaglobulinemia: from X-linked to Autosomal Forms of Disease. Clin Rev Allergy Immunol. 2022;63:22-35.
• ²
  Pal Singh S, Dammeijer F, Hendriks RW. Role of Bruton’s tyrosine kinase in B cells and malignancies. Mol Cancer. 2018;17:57.
• ³
  update.com [Internet]. Ibrutinibe: informa¸cões sobre medicamentos. UpToDate. [cited 2022 Aug 08]. Available from: https://www.uptodate.com/contents/ibrutinib-drug-information.
  » https://www.uptodate.com/contents/ibrutinib-drug-information.
• ⁴
  Paydas S. Management of adverse effects/toxicity of ibrutinib. Crit Rev Oncol Hematol. 2019;136:56-63.
• ⁵
  Lasica M, Tam CS. Management of Ibrutinib Toxicities: a Practical Guide. Curr Hematol Malig Rep. 2020;15:177-86.
• ⁶
  Lipsky A, Lamanna N. Managing toxicities of Bruton tyrosine kinase inhibitors. Hematology Am Soc Hematol Educ Program. 2020;2020:336-45.
• ⁷
  Sibaud V, Beylot-Barry M, Protin C, Vigarios E, Recher C, Ysebaert L. Dermatological Toxicities of Bruton’s Tyrosine Kinase Inhibitors. Am J Clin Dermatol. 2020;21:799-812.
• ⁸
  Singer S, Tan SY, Dewan AK, Davids M, LaCasce AS, Treon SP, et al. Cutaneous Eruptions from Ibrutinib Resembling EGFR Inhibitor-Induced Dermatologic Adverse Events. J Am Acad Dermatol. 2019;20:S0190-962233308-0.
• ⁹
  Sartori DS, Almeida AL, Oliveira GSP, Almeida Jr HL. Scanning electron microscopy of panitumumab-induced eyelash and hair alterations - Pili canaliculi. An Bras Dermatol. 2022;97:240-2.
• ¹⁰
  Cunha Filho RR, Almeida Jr HL, Rocha NM, Castro LAS. Uncombable hair syndrome (pili trianguli et canaliculi): clinical variation in 12 members of one family. An Bras Dermatol. 2008;83:53-5.
• ¹¹
  Almeida HL Jr, Garcias G, Silva RM, Batista SL, Pasetto F. Pili canaliculi as manifestation of giant axonal neuropathy. An Bras Dermatol. 2016;91:125-7.
• ¹²
  Estupiñán HY, Berglöf A, Zain R, Smith CIE. Comparative Analysis of BTK Inhibitors and Mechanisms Underlying Adverse Effects. Front Cell Dev Biol. 2021;9:630942.

Publication Dates

• Publication in this collection
  04 Aug 2023
• Date of issue
  2023

History

• Received
  04 Sept 2022
• Accepted
  18 Oct 2022
• Published
  02 Mar 2023