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| Year : 2012 | Volume
: 58
| Issue : 4 | Page : 331-334 |
A patient of chronic myelogenous leukemia developing painful rash on feet
P Kumar1, NK Das2, A Sil3, P Chakrabarti4
1 Department of Dermatology, Katihar Medical College and Hospital, Katihar, Bihar, India
2 Department of Dermatology, Medical College and Hospital, Kolkata, India
3 Department of Pharmacology, Burdwan Medical College and Hospital, Burdwan, West Bengal, India
4 Institute of Hematology and Transfusion Medicine, Medical College and Hospital, Kolkata, India
| Date of Web Publication | 4-Jan-2013 |
Correspondence Address:
P Kumar
Department of Dermatology, Katihar Medical College and Hospital, Katihar, Bihar
India
 Source of Support: None, Conflict of Interest: None  | Check |
DOI: 10.4103/0022-3859.105489
How to cite this article:
Kumar P, Das N K, Sil A, Chakrabarti P. A patient of chronic myelogenous leukemia developing painful rash on feet. J Postgrad Med 2012;58:331-4 |
Sir,
Hand foot disease (HFD), also known as palmoplantar erythrodysaesthesia (PPE), is a distinctive cutaneous adverse drug reaction to certain chemotherapeutic agents. 5-Fluorouracil by infusion, capecitabine, cytarabine, docetaxel, and doxorubicin are the commonly implicated agents. [1] Here, we are reporting a case of PPE in a patient receiving imatinib mesylate. PPE due to imatinib mesylate has been reported rarely; however, PPE due to other tyrosine kinase inhibitors are more common. [2]
A 29-year-old man, while being evaluated for spleenomegaly, showed leukocytosis on peripheral blood (28.15 × 109/L) with normal hemoglobin (13.6 g/dL), and normal platelet count (397 × 109/L). A differential count revealed a shift to the left (Neutrophil 40%, Lymphocyte 10%, Monocyte 4%, Eosinophil 4%, Basophil 6, % Myelocyte, 18%, and Metamyelocyte 18%). His provisional diagnosis was chronic myelogenous leukemia (CML), which was subsequently confirmed by the presence of Philadelphia (Ph) chromosome [Ph+ t (9;22) (q34;q11)] in 100% of the cells in metaphase. The patient belonged to economically under-privileged section of the society and could not afford costly drugs; hence he was initiated on cytoreduction with hydroxyurea (Hydrea®, Sarabhai Piramal Pharmaceuticals Limited, India 500 mg 3 caps once daily). Subsequently, he got access to imatinib mesylate (Glivec®, Novartis, India) 400 mg once daily free of cost through Glivec® International Patient Assistance Program (GIPAP). While on therapy, he developed painful erythema over palms and soles, which started with pain in feet while walking and pain in the hands while holding objects. Soon, he developed a few vesicles and presented to us. There was no history of application of/ contact with any irritant substance(s). On examination, palms and soles were edematous and erythematous. Few bullae also were noticed, some of which had ulcerated. Periungual area and sides of hands and feet also were involved with eczematous lesions [Figure 1]. Allergic contact dermatitis (ACD), id reaction, pompholyx, and PPE (HFD) were considered as differential diagnosis. Histopathology taken from pustule revealed full thickness necrosis of epidermis. There was an edema and mixed infiltration (mostly lymphocytes with few eosinophils and neutrophils) around blood vessels in upper dermis [Figure 2]. Based on the clinical presentation and histopathology findings, our case was diagnosed as Hand Foot disease due to imatinib mesylate. | Figure 1: (a,b) Presence of scaly plaques and pustules over palm and sole. (c,d) Note involvement of periungual area
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 | Figure 2: (a) Full thickness epidermal necrosis with mixed inflammatory infiltrate in upper dermis (H & E stain x40). (b,c) Full thickness epidermal necrosis- close up
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Imatinib mesylate was discontinued for 2 weeks, and the patient showed some improvement. The patient was treated with a short course of corticosteroids (prednisolone 1 mg/ kg) for 2 weeks along with topical clobetasol propionate, and all the lesions healed without any sequelae. As the patient could not afford alternative medicine (Dasatinib, a second generation Tyrosine Kinase Inhibitor), and the fact that dasatinib being a tyrosine kinase inhibitor may also be associated with PPE (HFD), [3] the decision of starting imatinib mesylate at a lower dose was made after discussion with the patient and with the treating physician. Imatinib was started at 100 mg once daily and gradually built-up to 300 mg once daily with occasional exacerbations (2 episodes since then). [Figure 3] These exacerbations, though severe, were not life-threatening and hence were managed with short course of systemic prednisolone and topical clobetasol propionate. | Figure 3: (a,b,c) Recurrence of lesions. (b) Note severe involvement of foot (c) as compared to hand
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The causality association was established by Naranjo scale [4] and WHO-UMC criteria. [5] The Naranjo scale showed a score of >9, which places the case in the category of "definite ADR."According to the WHO-UMC criteria, [4] the case qualifies in the "probable" causality category.The severity assessment of the case, as per Modified Hartwig Severity Scale, showed it to be of "moderate" (Level 3) severity. [6]
On further follow-up, he achieved complete cytogenetic response (no Ph chromosome positive cells on karyotyping) at 12 months but failed to achieve a major molecular response (BCR ABL transcript greater than 0.1%) at 18 months. He could not be shifted to a second line tyrosine kinase inhibitor for financial reasons as already stated. Dose escalation of imatinib mesylate (to 600 mg/day) was not possible because of PPE (HFD). Because he had achieved a complete cytogenetic response with imatinib mesylate which correlated with overall survival in CML, [7] our intent was to continue imatinib mesylate at least at a dose of 300 mg/day. Patient is still in complete hematological response and has not lost his cytogenetic response either.
PPE (HFD) is a distinctive cutaneous reaction and is clinically characterized by painful symmetric erythema of palm and sole. [1] A prodrome of dysesthesia, usually tingling sensation or burning sensation, is usually noticed. Apart from classical presentation, various other clinical presentations are well-known. Some patients may present with fine desquamation with or without erythema. A bullous variant has been described, specifically associated with cytarabine and methotrexate. [1] Rarely, patients may present with painful hyperkeratotic areas on pressure points, surrounded by rings of erythema and edema. Non-white patients have presented with progressive hyperpigmentation of palm, sole and rarely, entire body. [8] PPE seems to be dose-dependent. The exact pathogenesis is not known; however, it is postulated that these drugs are excreted in the sweat from the eccrine sweat glands, which are numerous on palms and soles. [1] The diagnosis is mainly clinical. Histopathology may be helpful in atypical cases. The common histopathological findings are interface dermatitis with a cell-poor infiltrate and a variable degree of epidermal necrosis. [1] PPE is usually managed by wound care, cold compresses, emollients, elevation of extremities, and analgesics. Potent topical steroids have been used with variable success. Pyridoxine in a dose of 100-300 mg per day is very effective in treating and preventing PPE. More severe cases may require systemic corticosteroid and dose modification of agent (dose reduction or increase in dosing interval).
Our case had the lesions of bullous PPE, which is a very rare and severe PPE. Similar bullous lesions may be seen in other common disorders like pompholyx and irritant contact dermatitis. Hence, recognition of various presentations of PPE is very important as it can be a dose limiting adverse effect or may necessitate the discontinuation of implicated agent altogether in severe cases. [1] In our case, the patient tolerated the bouts of exacerbation (which were managed with corticosteroids) and continued the medicine albeit at a lower dose.
| :: Acknowledgment | |  |
Prof. (Dr.) Pijush Kanti Datta, HOD Dermatology, Medical College & Hospital, Kolkata. Authors would love to thank him for his valuable inputs in review of histopathology slides.
| :: References | | |
| 1. | Nagore E, Insa A, Sanmartín A. Antineoplastic therapy-induced palmar plantar erythrodysesthesia (′Hand-Foot′) syndrome incidence, recognition and management. Am J Clin Dermatol 2000;1:225-34. 
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| 2. | Battistella M, Frémont G, Vignon-Pennamen MD, Gornet JM, Dubertret L, Viguier M. Imatinib-induced hand-foot syndrome in a patient with metastatic gastrointestinal stromal tumor. Arch Dermatol 2008;144:1400-2.
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| 3. | Amitay-Laish I, Stemmer SM, Lacouture ME. Adverse cutaneous reactions secondary to tyrosine kinase inhibitors including imatinib mesylate, nilotinib and dasatinib. Dermatol Ther 2011;24:386-95.
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| 4. | Naranjo CA, Busto U, Sellers EM, Sandor P, Ruiz I, Roberts EA, et al. A method of estimating the probability of adverse drug reactions. Clin Pharmacol Ther 1981;30:239-45.
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| 5. | The use of the WHO-UMC system for standardized case causality assessment [monograph on the Internet]. Uppsala: The Uppsala Monitoring Centre; 2005. Available from: http://www.who-umc.org/graphics/4409.pdf
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| 6. | Hartwig SC, Siegel J, Schneider PJ. Preventability and severity assessment in reporting adverse drug reactions. Am J Hosp Pharm 1992;49:2229-32.
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| 7. | de Lavallade H, Apperley JF, Khorashad JS, Milojkovic D, Reid AG, Bua M, et al. Imatinib for newly diagnosed patients with chronic myeloid leukemia: Incidence of sustained responses in an intention-to-treat analysis. J Clin Oncol 2008;26:3358-63.
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| 8. | Saif MW, Elkify AA. Identifying and treating fluoropyrimidine-associated Hand-and-Foot syndrome in white and non-white patients. J Support Oncol 2007;5:337-43.
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[Figure 1], [Figure 2], [Figure 3]
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