Rhabdomyolysis in patients taking isocitrate dehydrogenase inhibitors for R/R Acute Myeloid Leukemia Free

Mutations in isocitrate dehydrogenase (IDH1, IDH2) are present in ~20% of adult patients with acute myeloid leukemia (AML) (Im, 2014). Gain of function mutations in these genes result in production of the R-enantiomer of 2-hydroxyglutarate (2-HG), a competitive inhibitor of α-ketoglutarate dependent enzymes which are critical for DNA repair and demethylation; targeted small molecule inhibitors reverse these leukemogenic effects by binding to mutated IDH at an allosteric site, thereby decreasing production of 2-HG and allowing for the differentiation of hematopoietic stem cells (Nassereddine, 2018).

Common all-grade adverse events associated with IDH inhibitors include fatigue, nausea, arthralgia, myalgia, vomiting, diarrhea, constipation, hyperbilirubinemia, anemia, thrombocytopenia, QT prolongation, and differentiation syndrome (Chen, 2023). A small phase I study on the safety of off-label ivosidenib in patients with IDH-mutated glioma has previously demonstrated creatine kinase (CK) elevation to be a common adverse effect, occurring in 1/3 of patients (Peters, 2023). Additionally, the FDA package insert for ivosidenib recommends monitoring serum CK weekly for the first month of therapy. Here, we highlight two cases of rhabdomyolysis in patients taking IDH inhibitor therapy.

Patient A is an 81 y.o. white female with dual IDH1/IDH2 mutated AML. She was started on treatment with azacitidine, venetoclax, and magrolimab and achieved MRD-negative CR after cycle 1, then went on to complete 6 cycles of therapy, followed by 4 cycles of maintenance therapy with combination decitabine/cedazuridine and venetoclax prior to relapse. She was then treated with combination decitabine/cedazuridine, venetoclax, and ivosidenib. On C1D43, the patient presented to the emergency room with complaints of bilateral lower extremity pain; her CK was 5.3K, and she unfortunately left against medical advice. On C1D44, the patient was brought back to the emergency with complaints of severe weakness and difficulty walking; her CK was elevated to 6.6K. She was started on continuous intravenous (IV) fluids and her rosuvastatin home medication was discontinued. Her CK peaked at 7.3K on hospital day #5 before normalizing.

Patient B is an 82 y.o. white female with IDH2 mutated AML. She was started on treatment with azacitidine and enasidenib and achieved MRD-positive CR with persistent cytogenetic abnormalities. Azacitidine was discontinued after C33, at which time she continued on enasidenib monotherapy. On C71D11, she presented to the emergency room with bilateral lower extremity weakness; her CK was 10.7k and she was started on continuous IV fluids. She was on a stable dose of atorvastatin at the time of this event and had recently started azithromycin for symptoms of upper respiratory tract infection.

Two additional cases of IDH-associated CK elevation were reviewed but did not reach rigor of inclusion due to either (a) the presence of confounding factors or (b) elevations in CK < 5K. One such example was a 68 y.o. male with high-risk myelodysplastic syndrome (MDS) whose CK was 5.8k in the setting of Stenotrophomonas myonecrosis approximately 2 weeks after beginning enasidenib; this was likely secondary to a leg wound sustained from a recent fall. Another instance was a 70 y.o male with AML whose CK was 640 within 3 weeks of starting enasidenib, however the patient was asymptomatic and his CK improved without intervention.

CK elevation is a well-described potential side effect of IDH inhibitors, however there is no current literature describing the significant complication of rhabdomyolysis in patients taking such medications. While the second case represents the additional impact of presumed drug-drug interaction given the addition of another weak CYP450 inhibitor (azithromycin), the first case illustrates the risk for rhabdomyolysis, which may last beyond the FDA-recommended 1-month monitoring period. Study limitations include sample size and sampling bias.

In IDHm cells, 2-HG inhibits ATP synthase, disrupting mitochondrial ATP production and increasing reliance on glutaminolysis and oxidative phosphorylation (Fu, et. al 2015). We hypothesize that rhabdomyolysis observed with IDH inhibitors may reflect a convergence of metabolic stressors, particularly in susceptible populations such as elderly patients with low muscle mass, and those on concomitant statins.