ivosidenib and Syndrome

The isocitrate dehydrogenases enzymes, IDH1 and IDH2, catalyze the conversion of isocitrate to α-ketoglutarate (αKG) in the cell cytoplasm and mitochondria, respectively, and contribute to generating the dihydronicotinamide-adenine dinucleotide phosphate (NADPH) as reductive potential in different cellular processes. Mutations in IDH1 and IDH2 genes are found collectively in about 20-25% of acute myeloid leukemia (AML) patients. Mutant IDH enzymes have neomorphic activity and convert αKG to the oncometabolite R-2-hydroxyglutarate (R-2-HG) which accumulates at high levels in the cell and hampers the function of αKG-dependent enzymes, including epigenetic regulators, thus leading to altered gene expression and block of differentiation and contributing to leukemia development. Inhibition of the neomorphic mutants induces marked decrease in R-2-HG levels and restores myeloid differentiation. Enasidenib and ivosidenib are potent and selective inhibitors of mutant IDH2 and IDH1, respectively, act as differentiating agents and showed clinical activity in relapsed/refractory (R/R) AML harboring the specific mutation. As single agents, both drugs have been approved by the Food and Drug Administration (FDA) for the treatment of R/R AML. The relevance of IDH targeting within either single agent approach or, most importantly, combinatorial treatments in AML will be discussed.

Topics: Aminopyridines; Antineoplastic Agents; Cell Differentiation; Clinical Trials as Topic; Glutarates; Glycine; Humans; Isocitrate Dehydrogenase; Isocitrates; Ketoglutaric Acids; Leukemia, Myeloid, Acute; Multicenter Studies as Topic; Mutation, Missense; NADP; Pyridines; Syndrome; Triazines

Ivosidenib is a novel oral inhibitor of mutated isocitrate dehydrogenase 1 approved for the treatment of refractory or relapsed acute myeloid leukemia in patients with isocitrate dehydrogenase 1 mutations or as first-line agent in patients unable to tolerate chemotherapy. It is known to commonly cause differentiation syndrome, but an association with cardiovascular complications is not well established.. We present the case of a 34-year-old female with relapsed acute myeloid leukemia post-allogeneic transplant who developed ivosidenib-induced differentiation syndrome complicated by myopericarditis and cardiogenic shock.. Ivosidenib was discontinued, and aggressive management was pursued with high-dose steroids, ventilatory and pressure support and diuresis. She had significant improvement and later tolerated reintroduction of ivosidenib without recurrent episodes of differentiation syndrome or cardiac complications.. To the best of our knowledge, this is the first reported case of myopericarditis and cardiogenic shock related to ivosidenib use. This case highlights the high index of suspicion required to recognize early signs of targeted therapy-related complications and exemplifies the beneficial collaborative role a cardio-oncology team provides in improving patient care.

Topics: Adult; Female; Glycine; Humans; Leukemia, Myeloid, Acute; Mutation; Myocarditis; Pyridines; Recurrence; Shock, Cardiogenic; Syndrome

We report a case of differentiation syndrome in a patient receiving the IDH1 inhibitor ivosidenib, with skin biopsy showing isocitrate dehydrogenase (IDH) R132H-mutated leukemia cutis. A 72-year-old man with IDH1-mutated acute myeloid leukemia (AML), status-post allogeneic cell transplantation, on ivosidenib for 6 months, was admitted for culture-negative neutropenic fever, pink and purpuric plaques and patches on the legs, abdomen and back, edema, hypotension, and shortness of breath. Skin biopsy revealed an infiltrate of atypical, immature, myeloperoxidase-positive mononuclear cells compatible with leukemia cutis or Sweet syndrome. Although dermal edema and interstitial neutrophilic infiltrate with karyorrhexis characteristic of Sweet syndrome were not seen, the atypical cells lacked expression of CD117 and CD34, which were expressed in the original leukemia. Additional immunohistochemical staining of suspected blasts was strongly positive for IDH1 R132H, suggesting a diagnosis of leukemia cutis. As the immunophenotype of blasts in skin infiltrates can significantly differ from the immunophenotype seen in blood and bone marrow, this case shows that mutation-specific antibodies such as anti-IDH1 R132H may be useful to help distinguish malignant from non-malignant infiltrates in the skin. Furthermore, differentiation syndrome may show histopathologic features of leukemia cutis on skin biopsy.

Topics: Aged; Antineoplastic Agents; Diagnosis, Differential; Glycine; Humans; Immunohistochemistry; Isocitrate Dehydrogenase; Leukemia, Myeloid, Acute; Leukemic Infiltration; Male; Mutation; Pyridines; Skin; Syndrome