What causes a rash in patients with myeloproliferative disorders or cancer?

Mechanisms of Rash in Myeloproliferative Disorders and Cancer

Rashes in myeloproliferative disorders and cancer occur through three distinct mechanisms: direct infiltration of malignant cells into the skin (specific cutaneous manifestations), paraneoplastic phenomena from the disease itself, or as adverse effects from anticancer therapies including tyrosine kinase inhibitors and immunomodulatory drugs. 1, 2

Direct Malignant Cell Infiltration (Specific Cutaneous Manifestations)

• Leukemia cutis represents direct invasion of the dermis by malignant hematopoietic cells, which can be the first indication of underlying hematologic malignancy 2
• Myelodysplastic syndromes can present as widespread granulomatous dermatitis that may precede the diagnosis by up to 2 years, manifesting as generalized, mildly pruritic eruptions 3
• In primary myelofibrosis, cutaneous involvement occurs in 20-30% of patients, with xanthelasma being the most common manifestation, appearing as yellowish plaques around the eyelids or yellowish-brown papules on the face, neck, axilla, trunk or groin 1
• Subcutaneous nodules or granuloma annulare-like lesions can also represent direct disease involvement 1

Paraneoplastic Dermatoses from the Disease Itself

• Myeloproliferative neoplasms have complex pathogenesis involving systemic inflammation and clonal hematopoiesis that can manifest cutaneously without direct cell infiltration 4
• These non-specific cutaneous findings reflect the immune status and stage of disease 2
• Granulomatous dermatitis associated with myelodysplasia demonstrates interstitial dermal granulomatous inflammation on biopsy, representing an immune-mediated phenomenon rather than direct infiltration 3

Treatment-Related Rashes (Most Common in Clinical Practice)

Tyrosine Kinase Inhibitors for Myeloproliferative Disorders

• Rash occurs in 20-43% of patients treated with TKIs for chronic myeloid leukemia, with bosutinib causing rash in 43% (6% grade 3-4) in second-line use and 20% in first-line use 1
• Nilotinib and dasatinib also cause rash, with higher doses, CYP3A4 drug interactions, dehydration, salty food, sunburn and skin contusions predisposing to development 1
• Most cutaneous adverse events are dose-related, mild to moderate, and self-limiting 1
• Patients who develop rash on imatinib typically do not experience recurrence when switched to dasatinib or other TKIs 1

Immunomodulatory Drugs (Lenalidomide, Thalidomide, Pomalidomide)

• Lenalidomide-associated rash occurs at a median of 3 weeks after exposure, with nearly all rashes being morbilliform in pattern 5
• 45% of evaluable lenalidomide rashes are grade 3-4 by NCI-CTCAE criteria, making this a significant cause of treatment discontinuation 5, 6
• Rash presents as patchy, raised, macular skin lesions, sometimes with localized urticaria and associated pruritus 6
• Nonserious rash is the leading cause of permanent early discontinuation of lenalidomide in postmarketing surveillance, despite being uncommon in registration trials 6

Targeted Therapies for Solid Tumors

• EGFR inhibitors cause acneiform rash in 75-90% of patients (all grades) and 10-20% (grade 3-4), typically developing within the first days to weeks of therapy 1
• MEK inhibitors cause papulopustular eruption in 74-85% (all grades) and 5-10% (grade 3-4) of patients 1
• The rash presents as follicular papules and pustules in areas with high density of sebaceous glands (face, scalp, upper chest and back) 1
• Bacterial colonization or superinfection develops in up to 38% of cases, requiring vigilant monitoring 1
• Paradoxically, occurrence and severity of rash correlate positively with therapy response and improved survival 1

Pathophysiology of Treatment-Related Rashes

• EGFR inhibitor rashes result from dense periadnexal leucohistiocytic inflammatory infiltrate with clustering of macrophages, Langerhans cells, T cells, mast cells and neutrophils 1
• The inflammatory infiltrate is caused by EGFR inhibitor-induced secretion of chemokines and cytokines by epidermal keratinocytes 1
• EGFR is most abundantly expressed in keratinocytes of the basal and suprabasal layers of the epidermis and hair follicle, explaining the distribution pattern 1

Critical Clinical Pitfalls

• Do not confuse drug-induced rash with life-threatening conditions like Stevens-Johnson syndrome or toxic epidermal necrolysis, which require immediate hospitalization and discontinuation of all suspected agents 7
• Skin sloughing exceeding 30% body surface area with epidermal detachment represents grade 4 toxicity requiring emergency intervention 7
• Avoid prophylactic topical antibiotics; reserve them only for documented superinfection 7
• The negative effect on quality of life from dermatological adverse events is significant and greater with targeted therapies than cytotoxic agents, leading to dose interruptions in 76% and discontinuations in 32% of cases 1