Diffuse plate-like sheets of desquamation.

A 69-year-old woman with a history of relapsed acute lymphocytic leukemia presented for evaluation of a diffuse, asymptomatic scaly rash appearing 15 days after initiating inotuzumab ozogamicin 0.5 mg/m2 infusions and ponatinib 45 mg daily, which were started 2 months previously. Review of systems, including pruritus and flu-like symptoms, was negative. The patient received prednisone 20 mg daily and triamcinolone 1% topical treatment without improvement of the rash. The rash only improved upon cessation of ponatinib, while inotuzumab ozogamicin was continued. Examination revealed thick plate-like sheets of desquamation to the scalp, upper portion of the chest, dorsal aspect of the forearms, and distal parts of both legs (Fig 1). Punch biopsies of the upper portion of the chest and lateral aspect of the shin were performed (Figs 2 and 3).

Fig 1

Fig 2

Fig 3

Question 1: Based on the clinical presentation and histopathologic findings, what is the most likely diagnosis?

Acquired ichthyosis

Pityriasis rotunda

Eczema craquelé (asteatotic eczema)

Progressive symmetric erythrokeratoderma (PSEK)

Atopic dermatitis

Answers:

Acquired ichthyosis – Correct. This is a drug-induced acquired ichthyosis secondary to ponatinib therapy. Acquired ichthyosis is a rare condition with onset in adulthood and can be associated with underlying malignancies, infections, inflammatory disorders, or medications. Ichthyotic scaling commonly presents on the trunks, limbs, and scalp. Scales can be white, brown, or gray and vary in size from 1 mm to 1 cm.1, 2, 3 It has been reported that third-generation tyrosine kinase inhibitors, such as ponatinib, are associated with ichthyosiform eruptions.2, 3, 4 Histopathology, which is nonspecific, may show compact ortho- and/or parakeratotic hyperkeratosis and inflammatory infiltrate in the papillary dermis. The granular layer may be absent (similar to ichthyosis vulgaris), normal, or thickened.1, 2, 3

Pityriasis rotunda – Incorrect. Pityriasis rotunda is characterized by hypopigmented or hyperpigmened, well-demarcated, scaly, round patches or thick plaques, often 10 cm in size. Microscopic features resemble ichthyosis vulgaris with a diminished granular cell layer along with hyperkeratosis and no parakeratosis.

Eczema craquelé (asteatotic eczema) – Incorrect. Xerosis is the predisposing factor for eczema craquelé and has an indolent course over years. Eczema craquelé is characterized by pruritic skin with fine scale and interconnected fissures.

PSEK – Incorrect. Also known as Darier-Gottron syndrome, PSEK presents during infancy, extending into puberty but rarely into adulthood. PSEK is characterized by symmetric, well-demarcated, fixed, erythematous, hyperkeratotic plaques involving the cheeks, the extensor surfaces of the upper and lower extremities, and the buttocks. Histopathology demonstrates acanthosis, basket-weave and patchy parakeratotic hyperkeratosis, and a prominent granular layer.

Atopic dermatitis – Incorrect. Atopic dermatitis is a relapsing, pruritic condition commonly affecting infants and children. It is characterized by scaly, erythematous papules and plaques involving flexural areas with lichenification in chronic cases.

Question 2: Which of the following eruptions is

Pityriasis rubra pilaris-like

Seborrheic

Lichen planopilaris-like

Folliculocentric

Psoriasiform

Answers:

Pityriasis rubra pilaris-like – Incorrect. Reported pityriasis rubra pilaris-like cases describe asymptomatic, red-orange papules coalescing to plaques with islands of sparing progressively developing over 2 to 12 weeks after ponatinib initiation.2, 3, 4

Seborrheic – Incorrect. A case of ponatinib-induced seborrheic eruption has been reported presenting with follicular prominence with hyperkeratotic spicules over the beard area and eyebrows with lateral eyebrow alopecia 10 days after drug initiation.

Lichen planopilaris-like – Incorrect. Few cases of lichen planopilaris-like eruptions associated with ponatinib have been reported. These have been characterized by follicular erythematous papules with perifollicular scale and loss of hair follicles along the scalp. Additionally, erythematous papules of the eyebrows with nonscarring alopecia were present.

Folliculocentric – Incorrect. There are reported cases of ponatinib causing a folliculocentric eruption presenting as asymptomatic perifollicular erythema with prominent follicular hyperkeratotic spicules and dyskeratosis over the chest and abdomen.

Psoriasiform – Correct. BCR-ABL inhibitors, including imatinib and nilotinib, angiogenesis inhibitors, immune checkpoint inhibitors, and anti-CD20 monoclonal antibodies are anticancer therapies associated with psoriasis hyperkeratotic reactions. There are no reports thus far of ponatinib causing psoriasiform eruptions.

Question 3: What is the reported appropriate next step in management for these refractory lesions?

Topical retinoid

Systemic retinoid

Ammonium lactate

Mycophenolate mofetil

Urea

Answers:

Topical retinoid – Incorrect. Traditionally, topical retinoid therapy has been used as first-line agents along with topical steroids and anti-seborrheic agents in mild cases.2, 3, 4

Systemic retinoid – Correct. Refractory cases have been treated successfully with oral acitretin 10 mg daily. Systemic retinoids should be considered with caution, as liver enzyme abnormalities can occur. The mechanism behind retinoids as effective therapy is unknown. One proposed theory involves retinoids causing upregulation of heparin-binding epidermal growth factor-like growth factor leading to local chemotherapeutic resistance in keratinocytes. Another theory describes the role of retinoids in aiding to terminally differentiate epidermal cells leading to reduced uptake of chemotherapy within keratinocytes.2, 3, 4

Ammonium lactate – Incorrect. Ammonium lactate is not used for severe, refractory cases. It has previously been used for mild-to-moderate hyperkeratotic lesions secondary to ponatinib.

Mycophenolate mofetil – Incorrect. Mycophenolate mofetil can be considered as a steroid-sparing agent for psoriasiform and erythrodermic eruptions secondary to tyrosine kinase inhibitors; however, it is contraindicated in the setting of this patient’s leukemia.

Urea – Incorrect. Keratolytics, such as urea, have been used as initial therapy for mild-to-moderate ponatinib-induced rashes alongside high-potency topical steroids. Urea has not been used as a first-line agent in severe, refractory cases.

Conflicts of interest

None disclosed.