Sir,
Tyrosine kinase inhibitors (TKI) are common group of drugs used in various malignancies including chronic myeloid leukemia (CML) and associated with various adverse effects. One novel adverse reaction in a patient on dasatinib was seen in our case, described herein.
A 61-year-old male presented to us with six months duration of progressive, painful, dry focal thickening of skin. He was a known case of CML with positive p210 fusion protein and received dasatinib 70 mg twice daily for five months for acute phase of CML. The dose was tapered to 70 mg once daily for last two months. There was no history of preexisting dermatosis and similar complains in family. On cutaneous examination, multiple, ill-defined areas of palmoplantar thickening were noted over both soles predominantly present over left sole (Fig. 1a) and plantar surface of left great toe extending up to hyponychium, leading to compact subungual hyperkeratosis (Fig. 1b). In addition, punctate keratotic lesions were seen over both palms and soles (Fig. 1a). Rest of the mucocutaneous and systemic examination was normal. KOH was negative from the lesions. Histopathological examination from the lesion over sole showed hyperkeratotic epidermis with hypergranulosis, acanthosis and papillomatosis without any dysplasia while dermis was unremarkable (Fig. 1c) consistent with palmoplantar keratoderma (PPK). Topical keratolytic containing 40% urea showed mild improvement in thickness at three months follow-up. Dasatinib was continued in view of ongoing acute phase CML.
Fig. 1.
A: Ill-defined diffuse areas of keratotic thickening over lateral aspect of left sole with punctate keratotic lesions over rest of the plantar surface. b: Similar plaque was present over plantar surface of left toe extending from lateral aspect of toe to hyponychium with compact subungual hyperkeratosis. c: Histopathological image of the lesion on left sole showing hyperkeratosis with parakeratosis, hyper-granulosis and regular acanthosis in epidermis and sparse lymphocytic infiltrate present in the dermis. (H and E stain, 80x)
Tyrosine kinase inhibitors are used in various malignancies and are not devoid of side effects which if severe, can warrant termination of therapy. Knowledge of newer non-lethal side-effects is vital for early recognition and management without interruption of life-saving chemotherapeutic drugs. The common reported cutaneous adverse effects of TKIs include superficial edema, morbilliform rash and hypo-and-hyperpigmentation, lichenoid reaction, psoriasis, pityriasis rosea-like eruption, ichthyosis-like rash, acute generalized exanthematous pustulosis, drug rash with eosinophilia and systemic symptoms, and Stevens-Johnson syndrome [1, 2]. Similar adverse effects have been reported with second generation TKIs such as dasatinib and nilotinib [3]. Adverse effects specific to dasatinib include localized and generalized vasculitis, mucositis and erythema, maculopapular eruption or exfoliative rash, pruritus, peripheral edema, alopecia, skin ulcers, xerosis, urticaria, photosensitivity, bullous eruptions, hypopigmentation, panniculitis, stomatitis, hyperhidrosis and palmoplantar erythrodysesthesia [3]. Prominent involvement of left sole with minimal involvement of palms and right sole can be explained by early detection of PPK (within six months) and presence of small punctate lesions suggest developing PPK. Temporal correlation of palmoplantar keratoderma with dasatinib as well as persistent PPK while CML improved suggests drug as possible etiology over paraneoplastic PPK. Among newer chemotherapeutic agents; sorafenib (multi-kinase inhibitors), vemurafenib (mitogen-activated protein kinase inhibitors), omlutinib (epidermal growth factor receptor inhibitors), capecitabine and tegafur are known to cause PPK [4]. The pathogenesis involves dysregulation of epidermal growth pathways secondary to inhibition of receptor tyrosine kinases leading to aberrant epidermal proliferation and differentiation [3]. Early identification allows for effective management without requirement of systemic immunosuppressants or treatment discontinuation. Topical keratolytics are mainstay of treatment while systemic retinoids can also be used.
To best of our knowledge and literature search this is first case of palmoplantar keratoderma seen in CML patient started on dasatinib. Further reports will add to the knowledge and further studies can be done to understand the pathogenesis of such adverse effects. The importance of observation lies in differentiation from paraneoplastic PPK and psoriatic keratoderma as seen with other tyrosine kinase inhibitors such as nilotinib [5].
Acknowledgements
We thank the patient for granting permission for clinical photography.
Author Contribution
Dr PG and Priyanka were involved in data collection and writing the draft of manuscript.
Dr Prabodha Kumar Das, Dr Biswanath Behera and Dr Vishal Thakur were involved in the guidance and supervision of the research. All three were involved in revision of the manuscript.
Dr Madhusmita Shetty provided the histopathological findings to confirm the diagnosis.
Funding
None.
Declarations
Conflict of Interest
None.
Footnotes
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