What is ivosidenib and how does it work?
Ivosidenib is an oral inhibitor of mutated isocitrate dehydrogenase-1 (IDH1) enzymes. IDH1 mutations occur in ~10 percent of acute myeloid leukemia (AML) cases and lead to impaired hematopoietic differentiation. Ivosidenib inhibits IDH1 enzymes, which leads to a reduction in blast counts and an increase in the proportion of mature cells.
What is this approved for?
Ivosidenib is approved for the treatment of patients with relapsed or refractory AML which harbor an IDH1 mutation. Ivosidenib was studied in 258 patients with IDH1-mutated relapsed or refractory AML (N Engl JMed 2018;378:2386-2398). Patients were treated with ivosidenib 500 mg PO daily until disease progression or unacceptable toxicity. The median time to response was 1.9 months, with a median time to complete response (CR) of 2.8 months (range 0.9-8.3 months). The median duration of response was 6.5 months and the median duration of complete response was 9.3 months. In the relapsed/refractory AML subset, the rate of CR was 21.8 percent and the OR was 39.1 percent. There were serious (grade >=3) treatment-related adverse effects in 20.7 percent of patients. In addition, QTc prolongation was seen in 7.8 percent and IDH differentiation syndrome in 3.9 percent of patients.
How do you administer this drug?
Ivosidenib is taken orally once daily, with or without food at a starting dose of 500 mg (2 x 250 mg tablets). High-fat meals should be avoided as it significantly increases the ivosidenib levels. Missed doses should be taken as soon as possible, unless within 12 hours before the next dose. A vomited dose should not be repeated.
Are there any premedications needed?
No antiemetics or other premedications are necessary.
What are the common side effects associated with ivosidenib (> or =10%)?
* Cardiovascular: edema, QTc prolongation, chest pain, hypotension
* Neurologic: headache, neuropathy
* General: fatigue, arthralgia, myalgia, fever
* Dermatologic: rash
* Metabolic/Renal: hyponatremia, hypomagnesemia, hyperuricemia, hypokalemia, hypophosphatemia, increased serum creatinine
* Pulmonary: dyspnea, cough, pleural effusion
* GI: diarrhea, nausea, mucositis, constipation, decreased appetite, vomiting, abdominal pain
* Hematologic: decreased hemoglobin, leukocytosis, differentiation syndrome
* Hepatic: increased alkaline phosphatase, increased AST, increased ALT
What are the uncommon side effects associated with ivosidenib (less than 10%?)
Tumor lysis syndrome, differentiation syndrome, Guillain-Barre syndrome, progressive multifocal leukoencephalopathy, ventricular arrhythmia, and ventricular fibrillation.
Are there any important drug interactions?
Ivosidenib is a substrate of CYP3A4 and P-gp/ABCB1. Concomitant treatment with strong CYP3A4 inducers should be avoided. If moderate/strong CYP3A4 inhibitors are required, the dose of ivosidenib should be reduced to 250 mg daily. Caution should be taken for medications with a risk of QTc prolongation, and with patients with a congenital long QT syndrome.
How do I adjust the dose in the setting of renal or hepatic insufficiency?
There are no dose adjustments in patients with mild/moderate (CrCl > 30 mL/min) renal impairment, nor in those with mild hepatic impairment. Ivosidenib has not been studied in people with severe (CrCl < 30 mL/min) renal dysfunction, ESRD on dialysis, or moderate/severe hepatic impairment.
Practical tips
* Treatment should continue for at least 6 months to see the maximum clinical effects, unless the patient has unacceptable side effects, if there is disease progression, or undergoing hematopoietic stem cell transplantation.
* The patient's medication list should be screened for agents that can prolong the QTc interval, with steps taken to mitigate the risk.
* For the first month, weekly labs should include CBC/diff, CMP, and CPK. ECGs should be done weekly for the first 3 weeks, then monthly. During the second month, the CBC/diff and CMP should be done every other week, then monthly thereafter.
* Monitor for differentiation syndrome, as well as for infectious leukocytosis. If differentiation syndrome is suspected, initiate dexamethasone 10 mg IV every 12 hours (or equivalent steroid) and hemodynamic monitoring until improvement.
What should my patients know about ivosidenib?
Patients should not stop ivosidenib or change the dose without direction from their oncologist. Patients should contact their oncology team if they have any moderate-severe adverse effects as well as the following:
* Differentiation syndrome symptoms can include fever, cough, difficulty breathing, rash, decreased urine output, low blood pressure, rapid weight gain, swelling of arms or legs.
What useful links are available?
* https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/211192s000lbl.pdf
* https://www.nejm.org/doi/full/10.1056/NEJMoa1716984
Any ongoing clinical trials related to ivosidenib?
Ivosidenib is being studied in combination with venetoclax in mutated IDH1 hematologic malignancies, with azacitidine in previously untreated AML with the IDH1 mutation and as maintenance treatment after allo-HSCT in myeloid neoplasms with the IDH1 mutation. More information is available at https://clinicaltrials.gov.
LISA LOHR, PHARMD, BCOP, BCPS, is Clinical Oncology Specialist/MTM provider at Masonic Cancer Clinic Fairview/University of Minnesota Health, Minneapolis. RAMASWAMY GOVINDAN, MD, Professor of Medicine; Anheuser Busch Chair in Medical Oncology; Director, Section of Medical Oncology, Division of Oncology, Washington University School of Medicine, serves as the Pharmacy Forum column physician advisor. SARA K. BUTLER, PHARMD, BCPS, BCOP, is Clinical Oncology Pharmacy Supervisor, Barnes-Jewish Hospital, St. Louis, Mo., and also serves as a Pharmacy Forum column co-editor. JANELLE E. MANN, PHARMD, BCOP, is Clinical Oncology Pharmacist, Washington University School of Medicine, Alvin J. Siteman Cancer Center, St. Louis, Mo., and serves as a Pharmacy Forum column co-editor.