Isolated knuckle hyperpigmentation associated with bosutinib

Description

We present a case involving a man in his early 50s, employed as a shopkeeper, who received a diagnosis of chronic myeloid leukaemia-chronic phase in 2019. At the time of diagnosis, the p210 BCR-ABL transcript level was measured at 15.73%. Initially, imatinib was prescribed, but the patient failed to achieve a major molecular response (MMR) within the first 12 months of treatment (BCR-ABL 1.76%). No tyrosine kinase domain mutation was detected through next-generation sequencing, leading to the patient’s transition to dasatinib (100 mg/day).

After 1 year of dasatinib treatment, the patient achieved MMR (0.098%). However, he developed bilateral pleural effusion, necessitating a change of medication. The patient was switched to bosutinib (500 mg once daily), which exhibited a positive response with subsequent visits showing normal blood counts and an undetectable BCR-ABL level (after 18 months).

Remarkably, after 8 months of bosutinib therapy, a distinctive change in pigmentation emerged over the knuckles. Hyperpigmentary alterations surfaced on both hands, spreading asymmetrically across the metacarpophalangeal and distal interphalangeal joints, as depicted in figure 1. These changes were confined solely to the hands, sparing other body areas. Despite maintaining normal vitamin B12 levels (table 1), attempts were made with oral vitamin B12 supplementation, yielding no improvement in the observed lesions. A thorough exploration of occupational factors, considering the patient’s role as a shopkeeper and his limited exposure to pigmentary substances, ruled out external influences. A dermatological consultation ensued, revealing no specific cause for the hyperpigmentation. Although a prescribed moisturiser cream proved ineffective in alleviating the skin patches, the prevailing consensus attributed this occurrence to drug-induced hyperpigmentation, with bosutinib as a probable causative agent.

Figure 1.

Hyperpigmented macules over metacarpophalangeal and distal interphalangeal joints on both hands.

Table 1.

Patient’s laboratory investigations

Lab findings	Reference range	Patient results
Haemoglobin (g/L)	120–155	125
Haematocrit (%)	34.9–44.5	36.8
MCV (fL)	82–100	92
MCH (pg)	27–34	29
MCHC (g/L)	316–354	332
Red blood cell count (per mm3)	4.3–5.8	4.9
White cell count (× 109/L)	3.5–10.5	5.6
Platelet count (per mm3)	150 000–450 000	148 000
BUN (mg/dL)	12–21	24
Creatinine (mg/dL)	0.7–1.2	0.9
Methylmalonic acid (µmol/L)	0.07–0.27	0.10
Homocysteine (µmol/L)	<15	6
Folic acid (nmol/L)	7–40	20
Vitamin B12 (pg/mL)	160–950	450

BUN, blood urea nitrogen; MCH, mean corpuscular haemoglobin; MCHC, mean corpuscular haemoglobin concentration; MCV, mean corpuscular volume.

Cutaneous adverse reactions are commonly associated with tyrosine kinase inhibitors (TKIs) and often manifest as pigmentary disorders, skin exfoliation and non-specific rashes.¹ While imatinib is commonly associated with these reactions, pigmentary changes are relatively rare with bosutinib and dasatinib. Despite both drugs targeting tyrosine kinase activity, bosutinib focuses primarily on the STE family of kinases, specifically the STE20 subfamilies. In contrast, dasatinib inhibits KIT (KIT proto-oncogene receptor tyrosine kinase) or PDGFR (platelet-derived growth factor receptor) activity.² The skin manifestations attributed to dasatinib are believed to stem from the inhibition of the c-KIT/SCF (c-KIT/stem cell factor) signal transduction pathway, a crucial player in melanocyte physiology.³ On the other hand, bosutinib exhibits non-specific inhibition on SIKs (salt-inducible kinases). This family of kinases typically restrains the GPCR/cAMP/PKA axis, which induces melanogenesis, ultimately resulting in hypopigmentation. Conversely, bosutinib, through its non-specific inhibition, leads to hyperpigmentation.⁴

Typically, skin-related issues associated with bosutinib involve mild rashes.¹ The most frequently reported side effects include nausea, diarrhoea, myelosuppression, hepatotoxicity, renal toxicity,⁵ lung disorders⁶ and fluid retention. However, data on skin manifestations due to bosutinib are limited and necessitate further exploration.

Skin changes with TKIs, particularly dasatinib, can occur anywhere between 1 and 61 months after initiation, as reported by Tarantini et al.⁷ In our case, they were noted 8 months after initiation of bosutinib.

It is important to note that knuckle hyperpigmentation is commonly associated with megaloblastic anaemia due to vitamin B12 deficiency, occurring in approximately 19.0% of patients. However, in this case, the patient’s normal B12 levels along with normal MCV and methylmalonic acid levels and vitamin B12 administration despite normal levels not yielding any change ruled out this condition.⁸

Learning points.

• Hyperpigmentary skin changes can be seen as a side effect of bosutinib, a second-generation tyrosine kinase inhibitor.

• Tyrosine kinase inhibitors need to be extensively studied for side effects involving skin lesions.

Ethics statements

Patient consent for publication

Consent obtained directly from patient(s).