IDHIFA A Novel Precision Medicine for Acute Myeloid Leukemia

FDA Approves Precision Medicine Enasidenib as new Targeted Treatment for individuals with AML and IDH2 genetic mutation

by Dr. C.H. Weaver updated 1/2019

According to clinical trial results published in the journal Blood, some patients with relapsed or treatment-resistant acute myeloid leukemia (AML) may achieve remission with the precision medicine IDHIFA (enasidenib).

AML is the most lethal of the blood cancers, which together are the third leading cause of cancer deaths in the U.S.; AML is responsible for more than 10,000 deaths each year. Despite advances in treating other blood cancers, the standard of treatment for AML – a combination of toxic chemotherapies – has remained the same for more than 40 years. Overall prognosis remains poor, with a five-year survival rate below 20 percent for patients over age 60.

Up to 15 percent of people with AML have a mutation in the IDH2 gene, which prevents their white blood cells from maturing into neutrophils, an integral part of the body’s immune system. Instead, these white blood cells become leukemia cells.

Unlike standard AML therapies, which aggressively target all white blood cells, enasidenib inhibits the mutated IDH2 gene, allowing immature white blood cells to naturally mature into neutrophils.

Of the 239 IDH2 mutation positive AML patients included in a clinical trial evaluating enasidenib, 74 percent had treatment-resistant disease with few or no remaining therapy options available. Of those 176 patients, 71 (40.3%) responded to treatment, with 34 (19.3%) achieving a complete remission.

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Overall survival for these patients nearly tripled compared to previous studies evaluating other treatments in this patient population, up from 3.3 months to 9.3 months.

The U.S. Food and Drug Administration approved IDHIFA for the treatment of adult patients with relapsed or refractory acute myeloid leukemia (AML) who have a specific genetic mutation. The drug is approved for use with a companion diagnostic, the Real Time IDH2 Assay, which is used to detect specific mutations in the IDH2 gene in patients with AML.

“IDHIFA is a targeted therapy that fills an unmet need for patients with relapsed or refractory AML who have an IDH2 mutation,” said Richard Pazdur, M.D., director of the FDA’s Oncology Center of Excellence and acting director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. “The use of Idhifa was associated with a complete remission in some patients and a reduction in the need for both red cell and platelet transfusions.”

AML is a rapidly progressing cancer that forms in the bone marrow and results in an increased number of abnormal white blood cells in the bloodstream and bone marrow. The National Cancer Institute at the National Institutes of Health estimates that approximately 21,380 people will be diagnosed with AML this year; approximately 10,590 patients with AML will die of the disease in 2017.

IDHIFA is an isocitrate dehydrogenase-2 inhibitor that works by blocking several enzymes that promote cell growth. If the IDH2 mutation is detected in blood or bone marrow samples using the RealTime IDH2 Assay, the patient may be eligible for treatment with Idhifa.

The efficacy of Idhifa was studied in a single-arm trial of 199 patients with relapsed or refractory AML who had IDH2 mutations as detected by the RealTime IDH2 Assay. The trial measured the percentage of patients with no evidence of disease and full recovery of blood counts after treatment (complete remission or CR), as well as patients with no evidence of disease and partial recovery of blood counts after treatment (complete remission with partial hematologic recovery or CRh). With a minimum of six months of treatment, 19 percent of patients experienced CR for a median 8.2 months, and 4 percent of patients experienced CRh for a median 9.6 months. Of the 157 patients who required transfusions of blood or platelets due to AML at the start of the study, 34 percent no longer required transfusions after treatment with Idhifa.

Side effects of IDHIFA (enasidenib):

Nausea, vomiting, diarrhea, increased levels of bilirubin (substance found in bile) and decreased appetite are common. Women who are pregnant or breastfeeding should not take Idhifa because it may cause harm to a developing fetus or a newborn baby.

The prescribing information for IDHIFA includes a boxed warning that an adverse reaction known as differentiation syndrome can occur and can be fatal if not treated. Sign and symptoms of differentiation syndrome may include fever, difficulty breathing (dyspnea), acute respiratory distress, inflammation in the lungs (radiographic pulmonary infiltrates), fluid around the lungs or heart (pleural or pericardial effusions), rapid weight gain, swelling (peripheral edema) or liver (hepatic), kidney (renal) or multi-organ dysfunction. At first suspicion of symptoms, doctors should treat patients with corticosteroids and monitor patients closely until symptoms go away.

IDHIFA was granted Priority Review designation, under which the FDA’s goal is to take action on an application within six months where the agency determines that the drug, if approved, would significantly improve the safety or effectiveness of treating, diagnosing or preventing a serious condition. Idhifa also received Orphan Drug designation, which provides incentives to assist and encourage the development of drugs for rare diseases.

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