Dasatinib: A novel therapeutic option for xanthoma disseminatum with moderate efficacy

Dear Editor,

Xanthoma disseminatum (XD) is a multisystem, non-langerhans cell histiocytosis characterised by proliferation of CD68 and factor ⅫⅠ expressing histiocytes in the skin, mucosa, and internal organs. It is difficult to treat, with various treatment options being tried.^1-3 Herein, we report a patient with XD and diabetes insipidus (DI), showing a moderate response to dasatinib, an oral tyrosine kinase inhibitor.

A 29-year-old male presented with an 8-year history of asymptomatic, slowly progressive, reddish-brown swellings all over his body, associated with increased thirst and frequency of urination for 5 years. There were no other systemic symptoms or relevant personal and family history. Examination revealed multiple discrete and coalescent, flat-topped, firm, reddish-brown papules and plaques distributed over the body, with a flexural predilection [Figure 1a]. Similar papules involved the soft palate, penile shaft, and scrotum.

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Figure 1:

(a) Multiple well-defined reddish brown papules coalescing to form plaques over the face, trunk, and upper limbs, with a predilection for axillae, (b) Diffuse infiltration of foamy and spindled histiocytes admixed with giant cells in the dermis (Haematoxylin and eosin, 400x), (c) Moderate flattening and softening of the papules and plaques after 6 months of dasatinib treatmen.

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Baseline investigations, including complete hemogram, liver and renal function tests, and serum electrolytes (sodium 143 meq/L), were within normal limits. His baseline urine and serum osmolality were {131 mosmol/kg (300-1200)} and {305 mosmol/kg (285-300)}, respectively. The water deprivation test was suggestive of vasopressin deficiency (VD). The hormonal profile demonstrated low free T4 levels {4.22 ng/dl (4.8-12.7)}. The serum levels of parathyroid hormone {29.7 pg/ml (15-65)}, testosterone {11.5 nmol/ml (9.9-27.8)}, follicle stimulating hormone {3.2 mIU/ml (1.5-12.4)}, luteinising hormone {7.59 mIU/ml (1.7-8.6)}, growth hormone {0.923 ng/ml (0-2.5)}, adrenocorticotropic hormone {10.1 pg/ml (7.2-63.3)}, prolactin {10.9 ng/ml (4-15.2)}, and cortisol {301 nmol/ml (171-536)} were within normal limits. Whole-body low-dose computed tomography (CT) for bony lytic lesions, fasting lipid profile, serum, and urine protein electrophoresis were unremarkable. Magnetic resonance imaging (MRI) of the brain revealed absence of the posterior pituitary bright spot. Skin biopsy demonstrated diffuse dense dermal infiltrate composed of foamy and spindled histiocytes and multinucleate giant cells [Figure 1b]. On immunohistochemistry, these cells stained positive for CD68 and were negative for CD1a and CD117. XD with central DI was diagnosed, and oral dasatinib (50 mg) twice daily was initiated, along with thyroxine (75 μg) and oral desmopressin (0.1 mg). After 6 months, there was moderate flattening and softening of papules and plaques over the face, limbs, and trunk [Figure 1c]. However, improvement was less marked over thicker coalescent plaques. No new skin lesions appeared, and urinary symptoms were controlled. The patient’s quality of life also significantly improved. Examination for fluid retention and blood pressure monitoring were done at each visit. Chest X-ray and electrocardiogram (ECG) were repeated after 1 month of treatment. Complete hemogram and liver and renal biochemistries were performed monthly for 3 months, followed by once every 3 months. Dasatinib was well-tolerated with no significant adverse effects, including haematological effects, bleeding tendencies, fluid retention, and QT prolongation. We plan to continue therapy until the treatment response plateaus.

XD is a histiocytic proliferative disorder having multiple treatments options including cyclophosphamide, azathioprine, cladribine, vinblastine, and a combination of rosiglitazone, simvastatin, and fenofibrate.^1-3 Sawatkar et al., demonstrated significant improvement of skin lesions in XD to imatinib over 24 months.⁴

Dasatinib is a second-generation oral tyrosine kinase inhibitor acting on multiple targets, including SRC family kinases, breakpoint cluster region-Abelson (BCR-ABL), KIT, platelet-derived growth factor receptor β (PDGFRβ), and Ephrin type-A receptor 2 (EPHA2). Dasatinib is used for treating chronic myeloid leukaemia (CML) in adults, demonstrating efficacy and better safety in patients refractory to imatinib.⁵ It has also demonstrated an inhibitory effect on aggressive histiocytic sarcoma cells both in vitro and xenograft mouse models, possibly by targeting the EPHA2 receptor.⁶ Eissa et al., demonstrated dramatic response of dasatinib in a child with treatment-refractory juvenile xanthogranuloma.⁷ The effect of dasatinib can be attributed to its inhibitory effect on multiple tyrosine kinase pathways, thereby causing arrest of dendritic cell proliferation. Dasatinib worked better in the recent-onset soft plaques compared to the thick fibrotic plaques, possibly due to greater inhibition of early dendritic cell proliferation, indicating that earlier initiation favors better clinical outcome.

Despite the partial response, dasatinib could be a valuable second-line agent for treating XD. The efficacy and response-time in our case is comparable to a few existing therapies, including cladribine and lipid-lowering agents.^1,2,4 Dasatinib was chosen over imatinib owing to its superior affinity to BCR-ABL kinase and broader spectrum of activity against multiple kinases. ⁵ With respect to safety, pleural effusion and sporadic haematological adverse effects are more common with dasatinib. Cladribine, despite its efficacy,¹ requires monthly hospitalisation for infusion and is associated with a significant risk of adverse effects, including immune suppression and opportunistic infections.

Our case lacked an objective assessment scale for therapeutic response, and further studies are required to establish the efficacy of dasatinib in XD. However, the promising efficacy with a good safety profile suggests its addition to the therapeutic armamentarium for XD.