A woman in her 80s presented for investigation into a non-healing right lower leg ulcer and new neutropenia (0.7x109/L) lead to a diagnosis of AML. An IDH2 c.515 G>A (p.Arg172Lys) variant was detected by digital droplet PCR. She was given low dose cytarabine and thioguanine but discontinued therapy after two cycles due to non-healing ulcers. Therapy was switched to enasidenib 100mg daily. She had been commenced on rosuvastatin 40mg daily and dabigatran 110mg twice-a-day 4 years prior due to an ischemic stroke.
After 10 months of enasidenib, she experienced 3 days of lethargy, nausea and bilateral lower limb weakness. Weakness improved over a 3 week period, but worsened precipitously after enasidenib reintroduction (figure 1).
At worst, examination demonstrated symmetrically reduced 2/5 hip flexion and inability to walk. Creatine kinase (CK) values were elevated alongside Creatinine. Cerebral computed tomography demonstrated evidence of prior ischemic infarction, and spinal cord magnetic resonance imaging (MRI) was unremarkable. Electromyography was consistent with myopathy, and anti-HMG-CoA reductase antibodies were not detected. MRI of the legs demonstrated abnormal proximal muscle hyperintensity (figure 2). She recommenced Enasidenib two weeks after recovery without recurrent biochemical derrangement or weakness. She passed away of AML 16 months from diagnosis.
Enasidenib is an oral IDH2 inhibitor approved by the FDA for use in elderly patients with relapse or refractory IDH2 mutated AML. Oral monotherapy is aimed at achieving a balance of disease control and minimising toxicity associated with cytotoxic regimens. Enasidenib efficacy was demonstrated in a Phase 3 study [1] for patients with relapsed or refractory AML over 60 years of age, with 9% of patients over the age of 80. Our patient was intolerant of low-intensity cytotoxic therapy and enasidenib provided a targeted option for her IDH2 mutated AML given her age and comorbidities.
As exhibited by this case, drug-drug interactions need to be considered as a contributor to the toxicity-benefit estimation. An off-target effect of enasidenib is inhibition of the clearance of BCRP/ABCG2 substrates [2]. Rosuvastatin is a substrate of BCRP [3], a property in which it differs notably from other commonly prescribed statins such as atorvastatin. Exclusion of other causes including HMG-CoA-directed antibody mediated necrotizing myositis and time-course of myositis resolution (figure 1) are consistent with statin toxic myopathy.
Statins are ubiquitous in the older population most likely to receive oral monotherapy for AML, yet there is controversy in this age group regarding the purported benefit of statins. Indeed guidelines recommend statin use should only be considered in patients with at least 3 years life expectancy [4] due to the treatment duration required to establish benefit.
This is the first published report that enasidenib can lead to overt statin toxic myopathy. Therefore initiation of enasidenib monotherapy should trigger discontinuation of rosuvastatin specifically, and potentially statin therapy altogether.