Imatinib

What is imatinib?

Imatinib mesylate (Gleevac®; USA and Glivec® Europe, New Zealand, from Novartis) is a small molecule inhibitor of ABL, KIT, and platelet-derived growth factor receptor (PDGFR) tyrosine kinases. It is an FDA-approved oral treatment for chronic myeloid leukaemia, acute lymphoblastic leukaemia, myelodysplastic/myeloproliferative disease, chronic eosinophilic leukaemia and metastatic/malignant gastrointestinal stromal tumours. Imatinib has also been used for the treatment of some skin conditions.

Indications of imatinib in dermatology

Reported uses of imatinib in dermatology include:

• Dermatofibrosarcoma protuberans (FDA approved)
• HIV-related Kaposi sarcoma
• Cutaneous manifestations of hypereosinophilic syndrome
• Sclerodermatous graft versus host disease
• Systemic sclerosis with/ without interstitial pneumonitis/ fibrosis
• Vitiligo
• Cutaneous mastocytosis
• Melanoma

Except for dermatofibrosarcoma protuberans, all other off-label dermatology indications are based on isolated case reports and small, uncontrolled series.

Dermatofibrosarcoma protuberans

• Dermatofibrosarcoma protuberans (DFSP) is a rare soft-tissue tumour with a tendency for subclinical extension and local recurrence.
• Surgical excision, even with tissue-sparing techniques, may cause significant deformity or disability because of the infiltrative nature of DFSP.
• Several case reports and at least one phase 2 multicentre open-label study in paediatric and adult patients have shown that neoadjuvant oral imatinib 400 or 800 mg/day (adults) and 40 mg/m²/day increased to 500 mg/m²/day (paediatric) is a well-tolerated, novel treatment approach to DFSP that reduces tumour burden and facilitates resection.
• An overall total response rate of 67% has been reported in a total population of 18 DFSP patients treated with imatinib.
• The median duration of response in the phase 2 study including 12 patients was 6.2 months, with a maximum period of 24.3 months.
• The rationale for the use of imatinib in the treatment of DFSP is based on its activity as a selective inhibitor of PDGFB tyrosinase kinase involved in DFSP generation and proliferation.
• The down-regulation of the kinase enzymatic activity through the binding of imatinib results in the down-regulation of DFSP proliferation and the induction of apoptosis.

HIV-related Kaposi sarcoma

• Kaposi sarcoma (KS) is a disease of multifocal vascular proliferation that requires infection with KS herpesvirus (KSHV/HHV-8).
• Activation of the c-kit and platelet-derived growth factor (PDGF) receptors by autocrine/paracrine mechanisms follows endothelial cell KSHV infection.
• Kaposi sarcoma presents as red to purplish spots (macules) and raised bumps (papules and nodules) anywhere on the skin or mucous membranes.
• In a pilot study, imatinib 300 mg twice daily, induced partial regression of AIDS-associated KS in five of 10 patients within four weeks.
• In a multicentre phase II study 30 patients with AIDS-related Kaposi sarcoma received imatinib 400 mg/day by mouth for up to 12 months with dose escalation up to 600 mg/day at three months if their disease was stable.
• Ten patients (33.3%) achieved a partial response, six (20%) had stable disease, and seven (23.3%) exhibited KS progression.
• Nine patients completed 52 weeks of imatinib therapy. The median treatment duration was 22.5 weeks.
• Only five patients (16.7%) discontinued therapy owing to adverse events. Antiretroviral regimens did not significantly alter imatinib metabolism.

Cutaneous manifestations of hypereosinophilic syndrome

• The hypereosinophilic syndrome (HES) is a rare haematological disorder with sustained overproduction of eosinophils in the bone marrow, eosinophilia, tissue infiltration and organ damage.
• Skin symptoms consist of angioedema, unusual urticarial lesions and eczematous, therapy-resistant, prurigo papules and nodules.
• There are at least eight reports in the literature describing the efficacy of imatinib in the treatment of HES.
• In a subpopulation of HES patients with the FIP1L1-PDGFRA fusion gene (giving rise to a new constitutively active fusion tyrosine kinase) imatinib is first-line therapy.
• Previously, corticosteroids were the first line of therapy.
• For HES patients with demonstrated FIP1L1-PDGFRα fusion kinase, a starting dose of 100 mg/day is recommended.
• Dose increase from 100 mg to 400 mg for these patients may be considered in the absence of adverse drug reactions if assessments demonstrate an inadequate response to therapy.

Sclerodermatous chronic graft vs host disease

• Sclerodermatous graft versus host disease (sGVHD) is a rare, late complication of haematopoietic cell transplantation, thought to be an immune-mediated response characterised by abnormal T-cell function and dysregulation of tyrosine kinase cascades.
• Manifestations include severe skin and subcutaneous fibrosis with contractures leading to reduced joint mobility.
• The profibrotic cytokine transforming growth factor-β and stimulatory autoantibodies against the platelet-derived growth factor receptor has been implicated in the pathogenesis of sGVHD.
• Imatinib mesylate has been shown to selectively inhibit both the platelet-derived growth factor receptor and transforming growth factor-β signalling pathways.
• At least two case reports of severe sclerodermatous chronic GVHD that were successfully treated with imatinib have been reported in the literature.

Systemic sclerosis

• Systemic sclerosis (also called scleroderma) results from an overproduction of collagen in body tissues.
• It is a fibrotic disease that affects the skin, and also visceral organs.
• What prompts this abnormal collagen production is uncertain, but the body's immune system appears to play a role.
• Imatinib mesylate is a potent inhibitor of platelet-derived growth factor and transforming growth factor-β signalling pathways which may play a role in systemic sclerosis (SSc)-associated skin changes.
• A phase II double-blind trial in 28 patients with systemic sclerosis failed to demonstrate the efficacy of imatinib 400 mg daily to improve skin fibrosis of diffuse scleroderma after six months of treatment based on validated outcome measurements.
• In another phase IIa, randomised, open-label single arm clinical trial, 30 patients with diffuse systemic sclerosis were treated with imatinib 400 mg daily.
• In this open-label experience, improvements in skin thickening were observed as assessed by Modified Rodnan skin scores (MRSS) every three months.
• Further investigation of tyrosine kinase inhibition for diffuse cutaneous systemic sclerosis in a double-blind randomised placebo-controlled trial is warranted.

Imatinib has also been used in generalised morphoea.

Vitiligo

• Vitiligo is a common autoimmune skin disorder that results in partial loss of skin pigmentation with white patches of skin.
• There are at least 2 case reports in the literature where imatinib has been used to treat vitiligo in an adult and a paediatric patient.
• The suggested mechanism of action is that imatinib mesylate interferes in the production of melanin.

Cutaneous mastocytosis

• Mastocytosis is an uncommon disorder defined by increased and abnormal mast cells in one or more tissues.
• Cutaneous mastocytosis is limited to the skin, with varying degrees of rash, pruritus (itch), and disfigurement.
• Mastocytosis has been associated with somatic mutations in the gene encoding the tyrosine kinase KIT, leading to the identification of KIT as a therapeutic target.
• The KIT inhibitor imatinib mesylate is approved for aggressive systemic mastocytosis without the D816V c-kit mutation or with c-kit mutational status unknown.
• A recent case report describes the successful treatment of a female patient with disabling pruritus due to cutaneous mastocytosis, with no evidence of systemic mastocytosis, with imatinib mesylate 400 mg daily, achieving symptomatic improvement at two weeks and durable response at 23 months.

Melanoma

Imatinib has been suggested as a suitable for melanoma carrying certain c-kit mutations. These include:

• Advanced malignant melanoma
• Acral melanoma
• Mucosal melanoma
• Uveal melanoma
• Melanoma associated with chronic sun damage, lentigo maligna melanoma and lentiginous melanoma.

Other

Imatinib has also been reported to have been used successfully for:

• Nephrogenic fibrosing dermopathy
• Merkel cell carcinoma
• Mycosis fungoides
• Plexiform neurofibromas

Drug interactions with imatinib

• CYP3A4 inducers (carbamazepine, oxcarbamazepine, phenytoin, fosphenytoin, phenobarbital, and primidone) may decrease the plasma concentration of imatinib. Imatinib doses up to 1200 mg/day (600 mg twice daily) have been given to patients receiving concomitant potent CYP3A4 inducers.
• CYP3A4 inhibitors (eg, ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, and voriconazole) may increase the plasma concentration of imatinib.
• Imatinib is an inhibitor of CYP3A4 and may increase the plasma concentration of other CYP3A4 metabolised drugs (eg alfentanil, ciclosporin, diergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus or tacrolimus).
• Because warfarin is metabolised by CYP2C9 and CYP3A4, patients who require anticoagulation, low-molecular weight or standard heparin should be considered instead of warfarin if imatinib is to be administered concurrently.
• Interactions with drugs metabolised by CYP2D6 – Imatinib increased the plasma concentration of metoprolol by approximately 23% suggesting that imatinib has a weak inhibitory effect on CYP2D6-mediated metabolism.
• No dose adjustment is necessary; however, caution is recommended when administering imatinib with CYP2D6 substrates that have a narrow therapeutic window.

Adverse effects with imatinib

The most frequently reported adverse reactions (>30%) are:

• Oedema
• Nausea
• Vomiting
• Muscle cramps
• Musculoskeletal pain
• Diarrhoea
• Fatigue
• Abdominal pain

Skin changes

Skin changes that often occur during treatment with imatinib include:

• Postoperative periorbital purpura
• Periorbital oedema and epiphora
• Hypopigmented macules (depigmentation)
• Lichen planus-like reactions affecting skin, nails, oral mucosa
• Psoriasiform dermatitis
• Pityriasis rosea and pityriasiform reactions
• Photosensitivity including drug-induced photosensitive dermatitis

Less common reactions include:

• Multiple eruptive dermatofibromas
• Pseudoporphyria
• Hyperpigmentation (greying) – very rare
• Halo naevi
• Lymphomatoid granulomatosis
• Severe cutaneous drug reactions (AGEP, SJS/ TEN, DRESS)
• Livedoid skin reaction
• Panniculitis (erythema nodosum)
• Follicular mucinosis

Some skin changes may be related to underlying haematological conditions, their treatment and immunosuppression:

• Keratoacanthoma
• Squamous cell carcinoma
• Sweets syndrome
• Eccrine squamous syringometaplasia
• Neutrophilic eccrine hidradenitis
• Herpes zoster

Use of imatinib in specific populations

Pregnancy

• Imatinib can cause fetal harm when administered to a pregnant woman. There have been post-market reports of spontaneous abortions and infant congenital anomalies in women who have taken imatinib.
• If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, it should be withdrawn.

Nursing mothers

• Imatinib and its active metabolite are excreted into human milk.
• Because of the potential for serious adverse reactions in nursing infants from imatinib, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Paediatric use

• There are no data in children under one year of age.

Geriatric use

• The efficacy of imatinib is similar in older and younger patients.
• In clinical trials, no difference was observed in the safety profile in patients older than 65 years as compared to younger patients.

Hepatic impairment

• Patients with severe hepatic impairment tend to have higher exposure to both imatinib and its metabolite than patients with normal hepatic function.
• At steady state, the mean C_max (maximum concentration in plasma)/dose and AUC (area under the curve)/dose for imatinib increased by about 63% and 45%, respectively, in patients with severe hepatic impairment compared to patients with normal hepatic function.

Renal impairment

• Dose reductions are necessary for patients with moderate and severe renal impairment.

Contraindications

• The use of imatinib in patients with a hypersensitivity to the active substance or any of the excipients is contraindicated.