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 Table of Contents  
CASE REPORT
Year : 2022  |  Volume : 8  |  Issue : 2  |  Page : 83-85

Ponatinib-induced symmetric dermatitis


Department of Dermatology, Sri Ramachandra Institute of Higher Education & Research, Chennai, Tamil Nadu, India

Date of Submission26-Sep-2021
Date of Decision29-Mar-2022
Date of Acceptance29-Nov-2022
Date of Web Publication5-Jan-2023

Correspondence Address:
Anuradha Priyadarshini
Department of Dermatology, Sri Ramachandra Institute of Higher Education & Research, Porur, Chennai, Tamil Nadu 600116
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijdd.ijdd_39_21

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  Abstract 

Ponatinib is a third-generation tyrosine kinase inhibitor (TKI) which is used as a chemotherapeutic agent in the treatment of chronic myeloid leukemia. Despite being relatively less toxic than other older TKIs, it still has various adverse effects including skin rash. Cutaneous manifestations have varied presentations such as lichenoid, pityriasiform, ichthyosiform, and pityriasis rubra pilaris-like rash. We present here a 35-year-old male with chronic myeloid leukemia who developed a unique pattern of symmetrical rash to Ponatinib which was successfully treated with topical tacrolimus and reduction of dose of the drug.

Keywords: Cutaneous adverse drug reaction, symmetrical dermatitis, TKI


How to cite this article:
Lohani N, Rajesh G, Priyadarshini A, Sundaram M. Ponatinib-induced symmetric dermatitis. Indian J Drugs Dermatol 2022;8:83-5

How to cite this URL:
Lohani N, Rajesh G, Priyadarshini A, Sundaram M. Ponatinib-induced symmetric dermatitis. Indian J Drugs Dermatol [serial online] 2022 [cited 2023 May 28];8:83-5. Available from: https://www.ijdd.in/text.asp?2022/8/2/83/367125




  Key Message: Top


Ponatinib, a third-generation tyrosine kinase inhibitor (TKI) has varied patterns of cutaneous adverse drug reaction (CADR). The present case describes a new pattern of symmetrical dermatitis.


  Introduction Top


Tyrosine kinase inhibitors (TKIs) are a potent therapeutic weapon against signal transduction cascades triggered by tyrosine kinases. Ponatinib is a third-generation oral multi-tyrosine kinase inhibitor. It is effective against various cellular targets such as fibroblast growth factor receptor (FGFR) 1–4, platelet-derived growth factor receptor-a (PDGFR-a), vascular endothelial growth factor receptors-2 (VEGFR2), proto-oncogenes tyrosine-protein kinase c-SRC, c-KIT, FMS-related receptor tyrosine kinase 3 (FLT3), and RET proto-oncogene (RET).[1]

Ponatinib was approved in December 2012 by the US Food and Drug Administration and is indicated in adult patients with chronic phase (CP), accelerated phase (AP), or blast phase (BP) chronic myeloid leukemia (CML) who are resistant or intolerant to dasatinib or nilotinib and for whom subsequent treatment with imatinib is not clinically appropriate.[1]

Adverse effects of ponatinib include thrombocytopenia, abdominal pain, anemia, rash, pancreatitis, neutropenia, cardiac failure, and liver toxicity. The adverse reactions were more frequent in higher doses.[2] Ichthyosiform, lichenoid, and pityriasis rubra pilaris-like eruption have been reported due to ponatinib.[3],[4],[5] Ponatinib-induced symmetrical dermatitis has not been reported to the best of our knowledge. Here we present a case of CML with bilaterally symmetrical dermatitis due to ponatinib.


  Case Report Top


A 35-year-old man presented to our outpatient department with complaints of skin lesions over the trunk, back, bilateral axilla, thighs, legs, and feet for 1 month. He was a known case of CML on oral ponatinib. Previously the patient was treated with dasatinib and nilotinib which were discontinued due to hematological side effects. The patient was switched to ponatinib at 15 mg, which was raised to 30 mg 1 month prior to presentation to our outpatient department. The skin lesions developed after the dose was increased.

On examination, well-defined erythematous plaques with scaling were seen peripherally on the bilateral axillae, elbows, thighs, and legs, as well as centrally on the back and chest. The rash was in a symmetrical distribution [Figure 1].
Figure 1: Bilaterally symmetrical erythematous plaques with scaling seen over axilla, gluteal region, thighs, and abdomen

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The differential diagnosis was symmetrical drug-induced flexural exanthem, inverse psoriasis, contact dermatitis, Darier disease, Hailey-Hailey disease, and seborrheic dermatitis

Skin biopsy from right axilla region was done which showed thick compact hyperkeratosis with perivascular lymphocytic infiltrate. There was no spongiosis, necrotic keratinocyte, interface change, or eosinophilic infiltrate[[Figure 2]a, b]. Fungal hyphae were not seen.
Figure 2: Histopathological image of biopsy from rash on back showing compact hyperkeratosis with mild perivascular lymphocytic infiltrate. H&E stain, 100X

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The patient was diagnosed to have ponatinib-induced rash and was started on topical 0.1% tacrolimus and oral 5 mg levocetirizine. On consultation with the oncologist the dose was reverted to 15 mg, after which the lesion started resolving and was on maintenance.


  Discussion Top


TKIs are specifically designed to target the overexpressed tyrosine kinase receptors and subsequent downstream molecules in several cancer types.[6] TKIs have been used effectively in the treatment of CML and Philadelphia chromosome positive acute lymphocytic leukemia (Ph+ ALL).[7]

Resistance to TKI occurs due to point mutations of tyrosine protein kinase ABL1 domain. The T315I or gatekeeper mutation is characterized by the replacement of a wildtype threonine with a hydrophobic isoleucine in the adenosine triphosphate (ATP)-binding pocket, causing steric hindrance.[1]

There have been various cutaneous manifestations reported due to TKIs. First-generation TKI imatinib has been known to cause nonspecific skin rash, pruritus, superficial edema, lichen planus, hypopigmentation, and hyperpigmentation.[8] Second-generation TKIs such as dasatinib and nilotinib have been associated with xerosis, alopecia, edema, pruritus, keratosis, and pilaris.[9] Ponatinib has been shown to cause various CADRs including pityriasis rubra pilaris (PRP)-like hyperkeratotic folliculocentric eruption which develop 1–4 weeks into treatment and ichythyosiform eruptions developing after one month of treatment.[10] Other lesions reported include lamellar ichthyosis-like, keratosis pilaris-like, lichen plano pilaris-like, and lichenoid eruption.[5] The rash in the present case showed symmetrical dermatitis without lichenoid or folliculocentric features.

The pathogenesis for the cutaneous adverse effects is not clear yet. However, it has been suggested that it occurs due to inhibitory activity against cellular targets such as FGFR, PDGFR, VEGFR, KIT, and SRC.[3]

In the above-mentioned skin lesions, histopathological features include subacute spongiotic dermatitis, thickened cornified layer, and alternating orthokeratosis and parakeratosis in PRP like rash.[7] Perifollicular fibrosis, hyperkeratosis with varying orthokeratosis and parakeratosis, and scant perivascular lymphocytic infiltrate have been reported in other cases.[3]

Treatment for the cutaneous lesions mainly comprises of emollients, topical corticosteroids, topical keratolytics such as urea and ammonium lactate, antifungals, retinoids (both systemic and topical), ultraviolet (UV) B-therapy, and topical tacrolimus as seen in our patient.[10]

A potential causal relationship between ponatinib dose intensity and its adverse events has been proposed. Thus, effective management of patients receiving ponatinib can possibly be achieved with dose modification, while balancing both safety and efficacy. For advanced stage patients in whom dose reduction is not practical, alternate regimens such as retinoids can be used to alleviate the skin lesions.[6]


  Conclusion Top


Cutaneous adverse events to TKI are not uncommon. Ponatinib, a third-generation TKI, albeit essential for TKI-resistant leukemia, has significant CADR with varied patterns of presentation. The present case describes a ponatinib-induced symmetrical dermatitis which is easily managed by dose alteration and topical therapy.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Molica M, Scalzulli E, Colafigli G, Foà R, Breccia M. Insights into the optimal use of ponatinib in patients with chronic phase chronic myeloid leukaemia. Ther Adv Hematol 2019;10:2040620719826444.  Back to cited text no. 1
    
2.
Chan O, Talati C, Isenalumhe L, Shams S, Nodzon L, Fradley M, et al. Side-effects profile and outcomes of ponatinib in the treatment of chronic myeloid leukemia. Blood Adv 2020;4:530-8.  Back to cited text no. 2
    
3.
Eber AE, Rosen A, Oberlin KE, Giubellino A, Romanelli P. Ichthyosiform pityriasis rubra pilaris-like eruption secondary to ponatinib therapy: Case report and literature review. Drug Saf Case Rep 2017;4:19.  Back to cited text no. 3
    
4.
Kamat D, Chatterjee D, Mahajan R. Ponatinib-induced atypical pityriasis rubra pilaris-like rash. Indian J Dermatol Venereol Leprol 2020;86:688-90.  Back to cited text no. 4
[PUBMED]  [Full text]  
5.
Teigen IA, Sæle AKM, Reikvam H. A patient with maculopapular rash and lichenoid skin damage caused by ponatinib. J Int Med Res 2020;48:300060520903660.  Back to cited text no. 5
    
6.
Tan FH, Putoczki TL, Stylli SS, Luwor RB. Ponatinib: A novel multi-tyrosine kinase inhibitor against human malignancies. Onco Targets Ther 2019;12:635-45.  Back to cited text no. 6
    
7.
Dorer DJ, Knickerbocker RK, Baccarani M, Cortes JE, Hochhaus A, Talpaz M, et al. Impact of dose intensity of ponatinib on selected adverse events: Multivariate analyses from a pooled population of clinical trial patients. Leuk Res 2016;48:84-91.  Back to cited text no. 7
    
8.
Brazzelli V, Grasso V, Borroni G. Imatinib, dasatinib and nilotinib: A review of adverse cutaneous reactions with emphasis on our clinical experience. J Eur Acad Dermatol Venereol 2013;27:1471-80.  Back to cited text no. 8
    
9.
Delgado L, Giraudier S, Ortonne N, Zehou O, Cordonnier C, Hulin A, et al. Adverse cutaneous reactions to the new second-generation tyrosine kinase inhibitors (dasatinib, nilotinib) in chronic myeloid leukemia. J Am Acad Dermatol 2013;69:839-40.  Back to cited text no. 9
    
10.
Ransohoff JD, Kwong BY. Cutaneous adverse events of targeted therapies for hematolymphoid malignancies. Clin Lymphoma Myeloma Leuk 2017;17:834-51.  Back to cited text no. 10
    


    Figures

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