© 2007 European Society for Medical Oncology
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Sunitinib induced hypertension, thrombotic microangiopathy and reversible posterior leukencephalopathy syndrome
A 54-year-old female with suboptimally controlled hypertension (RR 150/90) and an imatinib-resistant gastrointestinal stromal cell tumor, had been on treatment with sunitinib malate (Sutent, previously known as SU011248; Pfizer, NY), a vascular endothelial growth factor receptor (VEGFR)/c-kit/platelet-derived growth factor receptor (PDGFR)/Flt3 tyrosine kinase inhibitor. The drug was given orally daily 50 mg for a 4-week-on, 2-week-off schedule since November 2005. During the 4-week-on cycles, thrombocytopenia was present, but the platelet counts restored to normal values in the 2-week-off schedule (Figure 1). On treatment with sunitinib, 20% regression of the tumor was seen. On 22 June 2006, in her last week of her 6th 4-week-on cycle, she experienced loss of vision and epileptical insults. Her blood pressure was 210/110 mmHg, papilledema was absent. Significant laboratory findings included a hemoglobin of 7.5 mmol/l, a platelet count of 26 x 109/l, a serum creatinine of 220 µmol/l and a lactate dehydrogenase (LD) of 6505 U/l. Peripheral smear showed 18% schistocytes. D-dimers were increased (>5000 ng/ml), PT 12.7 s, INR 1.1, APTT 24 s, fibrinogen 4.3 g/l and ADAMTS13 (A Disintegrin And Metalloprotease domain, with ThromboSpondin type 1 motif 13) activity measured on day 2 was 40% (normal value 30%–200%). Magnetic resonance imaging (MRI) of the brain showed features of posterior leukencephalopathy with occipital and parietal high-intensity lesions on a T2-weighed scan (Figure 2).
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Management of the hypertension was initiated with labetalol and nitroprusside i.v., while sunitinib was stopped. Later on, labetalol, enalapril and hydrochlorothiazide were given orally. Six units of fresh frozen plasma were administered in the first 4 days, awaiting the ADAMTS13 results. During the next 6 days, her platelets returned to baseline (247 x 109/l), serum creatinin nearly normalized (95 µmol/l) and LD declined to 1036 U/l. The patient was without insults under phenytoine treatment and recovered completely. After discharge, patient was treated with imatinib again at the, for her, maximum tolerated dose of 600 mg daily. Four months later, she progressed again and was treated with nilotinib in a phase III study.
Thrombotic microangiopathy (TMA) can be caused by malignant hypertension, sepsis, disseminated cancer, pregnancy with or without preeclampsia or the HELPP (hemolysis, elevated liver enzyme levels and a low platelet count) syndrome. Thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS) are also characterized by TMA. TMA is thought to be due to excess fragmentation of erythrocytes passing through the narrowed vascular lumen with fibrinoid necrosis and perivascular edema, and an excess consumption of platelets activated by the injured endothelium [1–5]. Plasma levels of ADAMTS13 have been shown to be very low in familial or some of the sporadic cases of TTP and reports have shown that patients with such low plasma levels respond very well to plasmapheresis. In patients with TMA from other etiologies, symptomatic treatment seems most effective [6, 7].
Angiogenesis inhibitors aim at partly blocking the extracellular binding of vascular endothelial growth factor (VEGF) to its receptor by anti-VEGF antibodies (i.e. bevacizumab), and partly blocking the intracellular signaling pathway of VEGFR by inhibitors of receptor tyrosine kinases (i.e. sunitinib). Sunitinib is a tyrosine kinase inhibitor that targets VEGFR-2 and PDGFR-ß, which are both the major expression subtypes of VEGFR/PDGFR in capillary vasculature. It is hypothesized that sunitinib acts via direct anti-VEGFR and anti-PDGFR effects that results in damage of the capillary endothelium.
Recent case reports describe TMA during treatment with anti-VEGF agents [8, 9]. Frangie et al. [8] report TMA occurring during treatment with bevacizumab and sunitinib for a metastatic renal carcinoma. Lesions of TMA and mesangiolysis (as confirmed by renal biopsy in this case report) were likely associated with the inhibition of VEGFR activation by anti-VEGF antibodies and by the inhibition of the VEGFR intracellular signaling pathway. Furthermore, the study of Sugimoto et al. [10] suggests that down-regulation or neutralization of circulating VEGF may play an important role in the induction of hypertension and proteinuria in various kidney diseases, patients on anti-VEGF agents and in women with preeclampsia.
Reversible posterior leukencephalopathy syndrome (RPLS) is a MRI-based diagnosis that can be associated with clinical symptoms as presented by our patient. RPLS is triggered most often by hypertensive emergency, associated with toxemia of pregnancy and immunosuppressive or cytotoxic agents [11, 12], but has been described to be associated with hypercoagulable state in normotensive individuals [13] and in TTP and HUS [14]. RPLS is most likely due to disruption of cerebral vascular endothelial cells and impaired cerebrovascular autoregulation leading to edema [11]. Renal dysfunction also appears to predispose the brain to RPLS, possibly because of chronic uremia or fluid overload. T2 weighted MR images, at the height of symptoms, characteristically show diffuse hyperintensity selectively involving the parieto-occipital white matter [12]. An important characteristic of RPLS is the reversibility of the imaging abnormalities [11]. If appropriate management (such as initiation of antihypertensive treatment or discontinuation of immunosuppressive drugs) is delayed, however, there is a great risk of permanent neurological damage because of ensuing cerebral infarction or hemorrhages [15, 16].
In the patient presented, several predisposing factors for RPLS were present such as hypertension, hypercoagulopathy, TMA and renal failure. Therefore, the contribution of drug withdrawal, antihypertensive treatment and fresh frozen plasma leading to the prompt recovery of all signs and symptoms cannot be exactly unraveled.
RPLS has been described in relation to bevacizumab (Avastin) in combination with hypertension [17–19]. It was speculated that this may have resulted from effects of this VEGF inhibitor on the blood–brain barrier or from bevacizumab induced vasospasm, which coupled with hypertension, led to RPLS. Furthermore, RPLS has been shown to be induced by RAF kinase inhibitor BAY 43-9006 (sorafenib) [20].
Our case report shows that sunitinib can cause multiple manifestations of endothelial damage, with hypertension, TMA and RPLS. Because of the increasing use of anti-VEGF agents in the treatment of cancer patients, oncologists should be aware of these potential associations, as early recognition and prompt therapeutic intervention can be beneficial.
Department of Clinical Oncology and Immunohematology, Leiden University Medical Center, Leiden, The Netherlands
* (E-mail: h.w.kapiteijn{at}lumc.nl)
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