Raynaud‐like phenomenon in two patients on nilotinib

Abstract

A previously healthy 20-year-old woman was diagnosed with chronic myeloid leukaemia (CML) in chronic phase in November 2010. She participated in a multi-centre, singlearm study of nilotinib 300 mg twice daily as frontline treatment of patients with Philadelphia-positive CML in chronic phase.Within 1 week of initiation of nilotinib she reported episodes of cold, white hands and blue discoloration of the nails. The image shows the hands of our patient (on the right) and her mother (on the left) during these episodes, which occurred several times per week and were characterized by a sudden onset and recovery within 5-10 min. There was no obvious provocation, especially no association with changes in temperature, position of the arm, physical activity or time after intake of nilotinib. The symptoms were completely reversible. There were no signs of arterial insufficiency of the upper extremities and sensation was found to be intact. No antinuclear antibody or cryoglobulin was present.After consultation with the principal investigator, nilotinib was stopped and imatinib 400 mg once daily was started. Within 2 weeks of initiation of imatinib she reported a diminishing frequency of occurrence of these episodes. However, imatinib resulted in side effects, especially disabling (grade 3) bone pain, arthralgia and nausea. Nilotinib was restarted and continued in an adjusted dose of 150 mg twice daily. The episodes of cold, white fingers and blue nails reappeared in a non-disabling and low frequency. She achieved a major molecular response within 3 months of re-starting nilotinib.The second patient, a 40-year-old female with CML who participated in the same trial, reported, immediately after starting nilotinib 300 mg twice daily, the sudden onset of cold fingers in association with sharply demarcated color changes of skin pallor or sometimes cyanotic skin discoloration. With rewarming, the ischaemic phase usually lasted for about 15 min. The attacks were exaggerated by cold but also occurred spontaneously and no other manifestations of vascular insufficiency were detected, either clinically or serologically. She decided not to stop her medication and these Raynaud-like complaints are occurring much less frequently after 18 months of treatment. She has achieved a major molecular response.Nilotinib is an oral ATP-competitive inhibitor of protein kinase activity of BCR-ABL1. Nilotinib also inhibits FIP1L1-PDGFRA tyrosine kinase and the stem cell factor receptor, KIT-kinase. Side effects resembling peripheral arterial insufficiency as described in these two patients have not previously been reported with nilotinib, although similar features occur with imatinib.The exact pathogenesis of the cold, white hands and blue discoloration of the nails in these patients is not clear. In the second patient the findings resembled Raynaud's phenomenon at first sight, while in the first patient they lacked the typical triphasic course of Raynaud's syndrome. The clinical presentation does seem to suggest an arterial cause, possibly transient ...

Drug‐induced Raynaud's phenomenon: beyond β‐adrenoceptor blockers

“…On the other hand, exactly the opposite reaction has been described with other TKIs. Emergence of RP during the first week of treatment with nilotinib has been described in two patients . One of them experienced improvement after the treatment was switched to imatinib, with recurrence of RP on the reintroduction of nilotinib.…”

Cross Skin Reactivity to Tyrosine Kinase Inhibitors in a Patient with Chronic Myelogenous Leukemia

“…Lower incidence of skin rash (11% and 15%) was found in patients with blast crisis (myeloid and lymphoid, respectively), compared with 22% and 27% of the patients with accelerated and chronic phases of CML [16]. Two cases of Raynaud-like phenomenon induced by nilotinib have been recently reported [17]. No pigmentary skin changes induced by nilotimib have yet been described.…”

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