On September 13, 2018, the Food and Drug Administration (FDA) approved a new drug for the treatment of Acute Myelocytic Leukemia (AML) –ivosidenib (trade name Tibsovo, manufactured by Agios Pharmaceuticals, Inc.). It is an oral drug for the treatment of AML that is relapsed or refractory after at least 1 prior systemic antitumor therapy and carries a mutation in the isocitrate dehydrogenase-1 (IDH1) gene.
In parallel, the FDA approved the real-time IDH1 test (manufactured by Abbott) as a companion diagnostic to screen patients with AML for treatment with ivosidenib by detecting IDH1 gene-specific mutations in blood or bone marrow samples from patients with AML.
Ivosidenib is also the only approved small molecule targeted agent for IDH1 that has been granted Fast Track and Priority Review designation by the FDA and has also received Orphan Drug Designation.
What is relapsed or refractory acute myeloid leukemia?
Acute myeloid leukemia is a rapidly progressive cancer in which a large number of abnormal white blood cells appear in the patient’s blood and bone marrow (with reference to the WHO classification criteria for tumors of the hematopoietic and lymphoid tissues, a ratio of more than 0.200 peripheral blood or bone marrow primitive cells is seen in the development of acute myeloid leukemia). The rapid proliferation of these abnormal cells can prevent the production of normal blood cells, leading to anemia, bleeding, fever, and several other symptoms in patients.
Acute myeloid leukemia is the most common acute leukemia in adults, and the National Institutes of Health (NCI) predicts that in 2018, 19,520 people in the United States will be diagnosed with AML and 10,670 people with AML will die. For adult patients younger than 60 years of age, the standard treatment for AML is erythromycin combined with cytarabine (also known as 7+3) induction chemotherapy, followed by consolidation chemotherapy, autologous hematopoietic stem cell transplantation (Auto HSCT), and allogeneic hematopoietic stem cell transplantation (Allo- HSCT).
A subset of patients with AML who do not go into remission after 2 courses of standard regimens or who relapse within 12 months (reappearance of leukemic cells in peripheral blood or primitive cells in bone marrow>0.050 or extramedullary The prognosis for such patients is poor and they are collectively referred to as relapsed or refractory AML. The main reason for relapse or refractory is that the leukemia cells are resistant to chemotherapy drugs.
The incidence of IDH1 gene mutations in patients with acute myeloid leukemia is 6% to 10%. In 2009, researchers identified the IDH gene in acute myeloid leukemia and found that IDH mutations accelerate the growth of myeloid cancer cells, are associated with cancer development, and may also lead to poor prognosis. IDH genes include IDH1, IDH2, and NAD+ coenzyme genes (IDH-α, IDH-β, IDH-γ) in mitochondria.
In 2017, enasidenib (trade name: Idhifa, manufactured by Celgene) was the first to receive FDA approval for the treatment of relapsed or refractory acute myeloid leukemia carrying IDH2 mutations, and likewise, approval for the concomitant diagnosis of this treatment –the real-time IDH2 test (manufactured by Abbott).
What is ivosidenib?
Unlike traditional chemotherapy drugs that work by killing cancer cells, ivosidenib is a small molecule orally targeted drug that works by blocking the enzymatic response of cancer cells caused by mutations in the IDH1 gene to reduce the abnormal metabolites of 2-hydroxyglutaric acid (2-HG), thereby promoting cancer cell differentiation and exerting an anti-cancer The effect of this drug is to promote the differentiation of cancer cells and exert anti-cancer effects.
It is well known that one of the hallmarks of cancer cells is their uncontrolled division and low degree of differentiation. It has been clinically found that the less differentiated the cancer cells are, the more malignant the cancer is. The success of Ivosidenib provides support for this theory.
Evidence of efficacy: 32.8% achieved complete remission and also reduced transfusion dependence
Ivosidenib was approved primarily based on the results of a single-arm trial. The trial included 174 adult patients (18 to 87 years of age) with relapsed or refractory acute myeloid leukemia who carried the IDH1 mutation. With a median follow-up of 8.3 months, 32.8% (57) of patients experienced complete remission or partial hematologic recovery with a complete remission rate (CRh) lasting an average of 8.2 months. The complete remission rate was 24.7% (43 patients) and the complete remission rate with partial hematologic recovery was 8% (14 patients).
The complete remission rate for partial hematologic recovery is the percentage of patients whose blood counts have partially recovered, meaning that no signs of leukemia have been detected in these patients, but some blood counts (or just platelet counts) have not returned to normal levels.
Of the 110 patients who required red blood cell and/or platelet transfusions at entry into the trial, 37.3% (41 patients) no longer required transfusions within 56 days. Of the 64 patients who did not require a transfusion at entry into the trial, more than half (38 patients) did not have a transfusion within 56 days.
Black box warning: be alert for differentiation syndrome
Common adverse reactions to Ivosidenib include fatigue, leukocytosis, arthralgia, diarrhea, dyspnea, edema, nausea, mucositis, prolonged QT on ECG, rash, fever, cough, and constipation.
It is important to note that the instructions for ivosidenib include a black box warning that the drug may cause a lethal differentiation syndrome with symptoms including fever, dyspnea, acute respiratory distress, pneumonia, pleural effusion or pericardial effusion, a rapid weight gain, peripheral edema, or multiple organ failure such as liver and kidney failure.
The FDA requires physicians to treat the symptoms of differentiation syndrome with glucocorticoids as soon as they are identified and to monitor the patient closely until the symptoms resolve.
Some other serious warnings include prolonged QT interval (a dangerous cardiac arrhythmia) and Guillain-Barré syndrome (a dangerous neuropathy). In addition, ivosidenib may cause harm to newborns, and women who are breastfeeding should not take the drug.
How do I use ivosidenib?
According to the approved product insert, the recommended use and dosage of ivosidenib is as follows:
- The recommended dose of ivosidenib is 500 mg orally daily until disease progression or unacceptable toxicity occurs. For patients without disease progression or unacceptable toxicity, the drug needs to be taken for at least 6 months.
- Avoid a high-fat diet while taking the drug.
- Blood tests and blood biochemistry are required prior to dosing, at least weekly for the first month, every other week for the second month, and monthly during treatment.
- Blood creatine phosphokinase is monitored weekly during the first month of treatment. Monitor electrocardiogram (ECG) at least once a week for the first 3 weeks of treatment and then at least once a month for the duration of treatment.
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IVOSIDENIB has not yet been approved by the State Food and Drug Administration, but the phase III trial (AGILE) that included Chinese patients has been approved, and hopefully the efficacy of the drug will be reflected in our patients as well.