Et tu, Ibrutinib?

By Warren R. Heymann, MD
July 8, 2020
Vol. 2, No. 27

When it comes to medications that I never prescribe, I learn from my patients who present with findings that compel me to do my homework. Such was the case of a middle-aged woman with chronic lymphocytic leukemia (CLL) who developed a peculiar macular ecchymotic eruption on her extensor extremities. That was my introduction to ibrutinib (Imbruvica) associated adverse reactions. Tyrosine kinase is a cytoplasmic enzyme essential for B-lymphocyte survival, by regulating tracking, homing, and adhesion of CLL cells. (1) Ibrutinib is a Bruton tyrosine kinase inhibitor utilized for CLL, mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), Waldenstom macroglobulinemia (WM), and refractory, chronic graft-versus-host disease. If you have not yet seen any adverse reactions to ibrutinib, it will not be long before you do.

From a dermatologist’s vantage point, there are several presentations, related to unique aspects of ibrutinib’s mechanism and the underlying condition for which it is being prescribed.

Certainly, patients with B-cell lymphoproliferative disorders have immunodysregulation that puts them at risk for increased infection and more aggressive keratinocytic carcinomas. Invasive aspergillosis is increasingly recognized in patients treated with ibrutinib. McCarter et al reported the case of a 79-year-old man with splenic B-cell lymphoma/leukemia who developed a fatal case of disseminated A. fumigatus infection, manifesting as widely distributed subcutaneous nodules (demonstrating a focal neutrophilic infiltrate histologically), and systemic abscesses of the central nervous system, heart, lung, and muscle. (2) Staphylococcal scalded skin syndrome, due to methiciliin-sensitive S. aureus producing exfoliative toxin-A, has been reported in a 63-year-old woman being treated with ibrutinib for B-cell CLL. (3)

The immunodysregulation can be fascinatingly paradoxical. A 77-year-old Chinese man developed indurated plaques that proved to be a T-cell cutaneous pseudolymphoma, while on ibrutinib for his CLL. The pseudolymphoma resolved within a week of discontinuation of ibrutinib, only to reappear with readministration of the drug. (4)

Drug rashes, such as the “maculopapular” (I prefer morbilliform) rash, as depicted in the case of a 79-year-old man on ibrutinib for WM, may be appreciated in 3-27% of cases with ibrutinib as monotherapy. Further research will need to determine if this is true allergy or due to viral reactivation (5), (such as HHV-6 or HHV-7). Interestingly, in this context, Bitar et al reported the case of a pityriasiform eruption observed in a 62-year-old man with relapsed CLL who had been on ibrutinib for 6 months. He was not tested for viral reactivation; a biopsy demonstrated spongiotic dermatitis with eosinophils. He was treated with topical triamcinolone — the eruption resolved within 3 months without discontinuation of ibrutinib. (6)

There have been several reports of neutrophilic dermatoses secondary to ibrutinib, presenting as tender, subcutaneous nodules. Histologically these demonstrate a mixed lobular and septal picture with prominent leukocytoclasis, and possible vasculitis. Some pannicultic lesions may resolve spontaneously, while others require prednisone to suppress the inflammation without discontinuation of ibrutinib, although discontinuation of the drug may lead to a rapid resolution of these lesions. (7,8,9) Although pyoderma gangrenosum (PG) may complicate lymphoproliferative malignancies (notably monoclonal gammopathy), Giovanni et al presented the case of a 55-year-old man with CLL who developed PG after 5 months of ibrutinib. The lesions were treated with prednisone and dapsone, along with tapering and ultimately discontinuing ibrutinib. (10)

Although specific for inhibiting Bruton tyrosine kinase, ibrutinib may display concomitant epidermal growth factor (EGFR) inhibition. This could have profound effects on keratin, resulting in deep palmo-plantar fissures (11), brittle nails, and hair changes of texture, curling/straightening, and softening. Ibrutinib covalently binds to the cysteine moieties near the active site of the tyrosione kinase enzyme. It has been speculated, but not proven, that ibrutinib’s effect on keratin may be secondary to disruption of the disulfide bonds between cysteine residues. These are not drug-limiting toxicities. Biotin has been reported to improve nail findings (I will save my comments regarding biotin supplementation for a future commentary!). (1,11, 12) Aphthous-like mucosal ulcerations may also be attributed to ibrutinib in a dose-dependent manner. These may be treated by short courses of prednisone and/or a reduction of the ibrutinib dose. (13)

Of all ibrutinib’s cutaneous adverse effects, the most urgent are bleeding complications. This is especially true for those undergoing cutaneous surgery. As noted, patients with CLL are at an increased risk for keratinocytic carcinomas, and hence, more likely to have cutaneous oncologic surgery — by standard excision or Mohs micrographic surgery. As noted by Parra et al, two TEC family kinases, Bruton tyrosine kinase and TEC are involved in platelet activation. Ibrutinib’s inhibition of platelet-expressed BTK and TEC are likely responsible for the associated bleeding risk. The authors detail two cases of elderly men with WM and CLL, respectively, with hemorrhagic complications attributed to ibrutinib. As opposed to standard anticoagulants, which are not discontinued for routine dermatologic surgery, the authors recommend that surgeons consult with the hematologist-oncologist to consider withholding ibrutinib prior to surgery. (14)

I’d like to end on a reasonably high note. Lee et al reported the case of a 51-year-old man with paraneoplastic pemphigus (PNP) associated with CLL. He had responded minimally to rituximab, cyclosporine, prednisone, mycophenolate mofetil, and plasmapheresis. Because his CLL was progressive, ibrutinib was administered — his CLL demonstrated marked improvement, as did his PNP over 4 to 6 weeks, with complete resolution of his blisters, balanitis, and conjunctivitis over the ensuing few months. Unfortunately, ibrutinib needed to be discontinued because of florid ecchymoses and purpura, probably secondary to elevated levels of the drug due to concurrent administration of antifungal agents.

When confronted with new dermatoses, astute (and/or compulsive) dermatologists will carefully consider every administered medication to determine if it could be the culprit. When asking “et tu, ibrutinib?” (and you, ibrutinib?), the appropriate answer may be “sane quidem” (no doubt). While Julius Caesar’s demise by Brutus’ knife (among 60 other assassins) was tragic, use of ibrutinib should not be. Conscii (be aware) of ibrutinib’s manifold cutaneous adverse reactions.

Point to Remember: Ibrutinib is increasingly being used for patients with CLL and other B-cell lymphoproliferative disorders. Dermatologists need to be vigilant for multiple cutaneous adverse reactions, and surgeons may wish to consider discontinuing the drug prior to surgery to avoid hemorrhagic complications.

Our expert's viewpoint

Sylvia Hsu, MD
Professor and Chair, Department of Dermatology
Lewis Katz School of Medicine
Temple University

With the expanding use of ibrutinib, dermatologists should be aware of the different presentations of ibrutinib-associated cutaneous reactions, which can occur in up to a quarter of patients. The association between the drug and the cutaneous side effect may not be obvious, since the skin manifestations are variable and the onset of the cutaneous toxicity can range from one week to more than a year after beginning the culprit drug. Fortunately, the majority of ibrutinib-induced cutaneous side effects can be treated symptomatically with topical corticosteroids and oral antihistamines. The skin toxicity usually resolves without discontinuation of the drug.

Dr. Hsu had disclosed financial relationships with the following to the AAD at the time of publication: AbbVie, Amgen, Celgene, Centocor, Corrona, Dr. Reddy, Eli Lilly, Genentech, Janssen, Novartis, Promius, Ranbaxy, Sanofi/Regeneron, Valeant. Full disclosure information is available at coi.aad.org.

1. Heldt Manica LA, Cohen PR. Ibrutinib-associated nail plate abnormalities: Case reports and review. Drug Saf Case Rep 2017; 4: 15.

2. McCarter SJ, Vijayvargiya P, Sidana S, Nault AM, et al. A case of ibrutinib-associated aspergillosis presenting with central nervous system, myocardial, pulmonary, intramuscular, and subcutaneous abscesses. Leuk Lymphoma 2019; 60: 559-561.

3. Saluzzo S, Layer F, Stingl G, Stary G. Staphylococcal scalded skin syndrome caused by a rare variant of exfoliative-toxin-A+ S. aureus in an adult immunocompromised patient. Acta Derm Venereol 2018; 98: 138-139.

4. Ho AKH, Koh XQ, Liau MMQ, Tan KB, Tan, CL. Ibrutinib-associated T-cell pseudolymphoma. Clin Exp Dermatol 2019; 44: 828-830.

5. Jensen AB, Stausbøl-Gron B, Riber-Hansen R. d’Amore F. Ibrutinib-associated skin toxicity: A case of maculopapular rash in a 79-yeard old Caucasian male patient with Waldenstrom’s macroglobulinemia and review of the literature. Dermatol Reports 2017; 9: 6976.

6. Bitar C, Sadeghian A, Sullivan L, Murina A. Ibrutinib-associated pityriasis rosea-like rash. JAAD Case Rep 2018; 4: 55-57.

7. Fabbro SK, Smith SM, Dubrovsky JA, Gru AA, Jones JA. Panniculitis in patients undergoing treatment with the Bruton tyrosine kinase inhibitor ibrutinib for lymphoid leukemias. JAMA Oncol 2015; 1: 684-686.

8. Hammel JA, Roth GM, Ferguson N, Fairley JA. Lower extremity ecchymotic nodules in a patient being treated with ibrutinib for chronic lymphocytic leukemia. JAAD Case Rep 2017; 3: 178-179.

9. Stewart J, Bayers S, Vandergriff T. Self-limiting ibrutinib-induced neutrophilic panniculitis. Am J Dermatopathol 2018; 40: e28-e29.

10. Giovanni B, Ibatici A, Sola S, Brunasso AMG, Massone C. Ibrutinib and pyoderma gangrenosum in a patient with B-cell chronic lymphocytic leukemia. Am J Dermatopathol 2019; Feb 27 [Epub ahead of print].

11. Sollena P, Mannino M, Laurenti L, DeSimone C, Peris K. Ibrutinib-associated palmo-plantar fissures in a patient with chronic lymphocytic leukaemia: A novel cutaneous adverse event. J Eur Acad Dermatol Venereol 2019; 33: e332-e334.

12. Bitar C, Farooqui MZH, Valdez J, Saba NS, et al. Hair and nail changes during long-term therapy with ibrutinib for chronic lymphocytic leukemia. JAMA Dermatol 2016; 153; 698-701.

13. Oberic L, Yseaert L, Sibaud V. Dose-limiting stomatitis associated with ibrutinib therapy: A case series. Br J Haematol 2019: 185: 784-788.

14. Parra CE, Newsom E, Lee EH, Allan JN, Minkis K. Association of ibrutinib treatment with bleeding complications in cutaneous surgery. JAMA Dermatol 2017; 153: 1069-1070.

15. Lee A, Sandhu S, Imaly-Gillespie L, Mulligan S, Shumack. Successful use of Bruton’s kinase inhibitor, ibrutinib, to control paraneoplastic pemphigus in a patient with paraneoplastic autoimmune mutiorgan syndrome and chronic lymphocytic leukaemia. Australas J Dermatol 2017; 58: e240-e242.

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