Ivosidenib for Relapsed/Refractory Acute Myeloid Leukemia

On July 20, 2018, the FDA approved ivosidenib (Tibsovo) as a treatment option for adult patients with relapsed/refractory acute myeloid leukemia, specifically with a mutation in the IDH1 gene. The FDA granted the application both fast track and priority review designations, and ivosidenib also received orphan drug designation from the agency. The drug is the first wholly owned product from Agios to receive FDA approval and follows the manufacturer’s 2017 release of enasidenib (Idhifa), which was codeveloped and cocommercialized with Celgene for the treatment of AML with an IDH2 mutation.

IDH Mutations in AML
IDH mutations are associated with increased age and occur in approximately 20% of adult patients with AML. IDH1 mutations are slightly less common than IDH2 mutations, occurring in approximately 7% to 14% of AML cases. Mutations in IDH1 and IDH2 together are the most common AML mutations, causing an oncometabolite, (R)-2-hydroxyglutarate (2-HG), to increase in concentration, seen both in vitro and in vivo. The result is direct inhibition of epigenetic regulators, such as chromatin-modifying histone and DNA demethylases, leading to a hypermethylation signature, in which gene expression is altered. Affected cells lose their ability to progress from immature progenitors to a fully differentiated state.1

Patient Selection
Eligible patients are identified by the presence of IDH1 mutations in the blood or the bone marrow. An FDA-approved test, the RealTime IDH1 Assay, sponsored by Abbott Laboratories, is available for IDH1 mutation detection. Patients with relapsed disease who had no IDH1 gene mutation at initial diagnosis should be retested because the mutation can emerge during treatment and at relapse.2

Mechanism of Action
Ivosidenib, a small molecule inhibitor, targets mutant IDH1. Susceptible IDH1 mutations are defined as those leading to increased levels of 2-HG in leukemia cells and where efficacy is predicted by clinically meaningful remissions with the recommended dose of ivosidenib and/or inhibition of mutant IDH1 enzymatic activity at concentrations of ivosidenib sustainable at the recommended dosage according to validated methods. The most common of such mutations are R132H and R132C substitutions.3

Dosage and Administration 
Ivosidenib is available in 250-mg tablets. The recommended dose is 2 tablets (500 mg) taken orally at the same time each day with or without food. Administration with a high-fat meal should be avoided because of increased ivosidenib concentration. Unless patients encounter disease progression or unacceptable toxicity, treatment should continue for at least 6 months to allow for adequate clinical response time.3

Warnings and Precautions
Differentiation Syndrome
Nineteen percent of patients with relapsed/refractory AML treated with ivosidenib in clinical trials experienced differentiation syndrome (34 of 179 patients). Differentiation syndrome may be life-threatening or fatal if not treated and is associated with rapid proliferation and differentiation of myeloid cells.

Symptoms noted during clinical trials included noninfectious leukocytosis, peripheral edema, pyrexia, dyspnea, pleural effusion, hypotension, hypoxia, pulmonary edema, pneumonitis, pericardial effusion, rash, fluid overload, tumor lysis syndrome, and increased creatinine clearance. Seventy-nine percent of patients who experienced differentiation syndrome recovered after treatment or after ivosidenib dose interruption.3

Suspected differentiation syndrome should be treated with intravenous (IV) dexamethasone 10 mg every 12 hours, or an alternative oral or IV corticosteroid, along with hemodynamic monitoring until improvement. Treatment with hydroxyurea or leukapheresis should be initiated, when clinically indicated, for concomitant noninfectious leukocytosis. Corticosteroids and hydroxyurea should be tapered after symptom resolution, but corticosteroids should be continued for at least 3 days to avoid recurrence of differentiation syndrome symptoms associated with premature discontinuation. Additionally, if symptoms are severe despite 48 hours of corticosteroid treatment, ivosidenib treatment should be paused until signs and symptoms are no longer severe in nature.3

Cardiovascular Issues
Patients treated with ivosidenib can develop corrected QT (QTc) interval prolongation and ventricular arrhythmias. Nine percent of patients treated with ivosidenib had a QTc interval greater than 500 milliseconds, and 14% had an increase from baseline QTc greater than 60 milliseconds. Risk of QTc interval prolongation would be expected to increase with concomitant use of medications known to prolong QTc interval, such as antiarrhythmics, fluoroquinolones, triazole antifungals, 5-hydroxytryptamine-3 receptor antagonists, and cytochrome P450 (CYP) 3A4 inhibitors.

Certain patients may require more frequent monitoring, such as those with congenital long QTc syndrome, congestive heart failure, and electrolyte imbalances, as well as those taking medications in the categories noted above. Therapy adjustments should be evaluated against severity of QTc prolongation. Patients with QTc interval prolongation along with signs or symptoms of life-threatening arrhythmia should permanently discontinue ivosidenib. For QTc increases greater than 500 milliseconds, treatment should be interrupted and ivosidenib subsequently reduced. For QTc increases greater than 480 milliseconds but less than 500 milliseconds, treatment should be interrupted.3

Guillain-Barré Syndrome
Although neuropathies are rare, patients should be monitored for their onset, such as that of unilateral/bilateral weakness, sensory alterations, paresthesia, and difficulty breathing. Patients with Guillain-Barré syndrome should permanently discontinue ivosidenib.3

Adverse Reactions
The most serious adverse reactions noted during clinical trials included differentiation syndrome (10%), leukocytosis (10%), and electrocardiogram QT prolongation (7%). One case of progressive multifocal leukoencephalopathy was documented. Adverse reactions leading to dose interruption were electrocardiogram QT prolongation (7%), differentiation syndrome (3%), leukocytosis (3%), and dyspnea (3%). Three percent of patients (5 of 179) required a dose reduction after experiencing an adverse event (AE).3 These AEs were categorized as electrocardiogram QT prolongation (1%), diarrhea (1%), nausea (1%), decreased hemoglobin (1%), and increased transaminases (1%). Guillain-Barré syndrome, rash, stomatitis, and increased creatinine clearance (1% each) were cause for permanent discontinuation of therapy during clinical studies. Fatigue, leukocytosis, arthralgia, diarrhea, dyspnea, edema, nausea, mucositis, electrocardiogram QT prolongation, rash, pyrexia, cough, and constipation were the most common AEs (>20%) of any grade.3

Drug Interactions

CYP3A4 Inhibitors/Inducers
Plasma concentrations of ivosidenib can be increased when coadministered with CYP3A4 inhibitors, thus increasing the risk of QTc interval prolongation. Avoidance of moderate to strong CYP3A4 inhibitors is ideal, but if coadministration is unavoidable, reducing the ivosidenib dose to 250 mg once daily is advised. Alternatively, coadministration of strong CYP3A4 inducers can decrease ivosidenib plasma concentrations. CYP3A4 inducers should be avoided during treatment with ivosidenib.3

QTc-Prolonging Drugs
The risk of QTc interval prolongation is heightened when QTc-prolonging drugs are coadministered with ivosidenib. Avoidance is also recommended, but if unavoidable, patients must be monitored closely for signs and symptoms of QTc interval prolongation.

Effect of Ivosidenib on Other Drugs
Ivosidenib has been shown to induce CYP3A4 and may induce CYP2C9. Reduction of drug concentrations for sensitive substrates would be expected; therefore, alternative therapies should be considered. For example, ivosidenib should not be coadministered with itraconazole or ketoconazole (CYP3A4 substrates) because of a loss of antifungal efficacy. If coadministration is unavoidable, patients should be monitored for a reduction of clinical effect for affected medications.

Pharmacokinetics 
The median time to maximum plasma concentration (Cmax) is approximately 3 hours. A high-fat meal increased ivosidenib Cmax by 98% and area under the curve 0 to infinity by approximately 25%. The mean apparent volume of distribution of ivosidenib at steady state is 234 L, and protein binding ranges from 92% to 96% in vitro. The terminal half-life is 93 hours, and clearance is 4.3 L/hour. Ivosidenib is the predominant component (>92%) of total radioactivity in plasma and primarily metabolized by CYP3A4 with minor N-dealkylation and hydrolytic pathways. After a single oral administration, 77% of ivosidenib was eliminated in the feces (67% unchanged) and 17% in the urine (10% unchanged).3

Pharmacokinetics evaluated in specific populations regarding age, sex, race, body weight, ECOG performance status, mild-to-moderate renal impairment, or mild hepatic impairment were not affected with any clinical significance. In patients with severe renal impairment, renal impairment requiring dialysis, or moderate-to-severe hepatic impairment, pharmacokinetic impacts are unknown.3

Clinical Studies  
The efficacy of ivosidenib was studied in a single-arm, open-label, multicenter clinical trial of 174 adult patients with relapsed/refractory AML with an IDH1 mutation. Patients were identified first by a local or central diagnostic test, which was confirmed retrospectively using the RealTime IDH1 Assay. Patients were started on a dose of 500 mg daily and continued untileither disease progression, unacceptable toxicity, or hematopoietic stem cell transplantation. The trial measured the percentage of patients with no evidence of disease and full recovery of blood counts after treatment (complete remission [CR]), as well as patients with no evidence of disease and partial recovery of blood counts after treatment (complete remission with partial hematologic recovery [CRh]).4

With a median follow-up of 8.3 months and median treatment duration of 4.1 months, approximately one-third of patients experienced a CR or a CRh that lasted a median 8.2 months. Of the 110 patients who required transfusions of blood or platelets because of AML at the start of the study, 41 (37%) did not require a transfusion for at least 56 days after treatment with ivosidenib.4

References
  1. Isocitrate dehydrogenase mutations in myeloid malignancies. Leukemia. 2017;31:272-281. nature.com/articles/leu2016275.pdf. Accessed August 2, 2018. 
  1. List of cleared or approved companion diagnostic devices (in vitro and imaging tools).  FDA website. www.fda.gov/CompanionDiagnostics. Accessed August 2, 2018.
  1. Tibsovo [package insert]. Cambridge, MA: Agios Pharmaceuticals Inc.; 2018.
  1. FDA approves first targeted treatment for patients with relapsed or refractory acute myeloid leukemia who have a certain genetic mutation [news release]. Silver Spring, MD: FDA; July 20, 2018. www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm614115.htm.  Accessed August 2, 2018.





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