IDHIFA® OFFERS A DIFFERENT SAFETY PROFILE IN R/R AML
Adverse Reactions (ARs) Reported in ≥10% (Any Grade) or ≥3% (Grades 3-5) of Patients With R/R AML
Body system AR
All grades N=214 (%)
≥Grade 3 N=214 (%)
Metabolism and nutrition disorders
Tumor lysis syndrome (TLS)b
Blood and lymphatic system disorders
Nervous system disorders
aGastrointestinal disorders observed with IDHIFA® treatment can be associated with other commonly reported events, such as abdominal pain and weight decrease.
bTLS observed with IDHIFA® treatment can be associated with commonly reported uric acid increase.
cDifferentiation syndrome can be associated with other commonly reported events such as respiratory failure, dyspnea, hypoxia, pyrexia, peripheral edema, rash, or renal insufficiency.
Most Common (≥20%) New or Worsening Laboratory Abnormalities Reported in Patients with R/R Aml
All grades (%)
≥Grade 3 (%)
Total bilirubin increased
aIncludes abnormalities occurring up to 28 days after last IDHIFA® dose, if new or worsened by at least 1 grade from baseline, or if baseline was unknown. The denominator varies based on data collected for each parameter (N=213, except phosphorus [N=209]).
The median duration of exposure to IDHIFA® was 4.3 months (range, 0.3 to 23.6).
IDHIFA® demonstrated 30-day and 60-day mortality rates of 4.2% (9/214) and 11.7% (25/214), respectively.
Other clinically significant ARs occurring in ≤10% of patients included Respiratory, Thoracic, and Mediastinal Disorders (pulmonary edema, acute respiratory distress syndrome).
DOSE MODIFICATIONS IN THE CLINICAL TRIAL
43% of patients experienced an AR leading to a dose interruption
The most common ARs leading to interruption were differentiation syndrome (4%) and leukocytosis (3%)
5% of patients had a dose reduction due to an AR
No AR required dose reduction in more than 2 patients
17% of patients permanently discontinued therapy due to an AR
The most common reason for discontinuation was leukocytosis (1%)
ADDITIONAL ANALYSIS: The Frequency of ARs Over Time
ARs REPORTED IN ≥10% (ANY GRADE) OR ≥3% (GRADES 3-5) OF PATIENTS WITH R/R AML1
DIFFERENTIATION SYNDROME MAY OCCUR WITH IDHIFA®
Differentiation syndrome is associated with rapid proliferation and differentiation of myeloid cells. It may be life-threatening or fatal if not treated.
14% of patients experienced differentiation syndrome (n=29/214)
7% of patients experienced ≥Grade 3 differentiation syndrome (n=15/214)
4% of patients required dose interruption due to differentiation syndrome
For appropriate patient management,
IT IS IMPORTANT TO RECOGNIZE AND INITIATE TREATMENT FOR DIFFERENTIATION SYNDROME
Symptoms observed in patients treated with IDHIFA®
While there is no diagnostic test for differentiation syndrome, symptoms in patients treated with IDHIFA® included:
Acute respiratory distress represented by dyspnea and/or hypoxia, and need for supplemental oxygen
Pulmonary infiltrates and pleural effusion
Peripheral edema with rapid weight gain
Hepatic, renal, and multi-organ dysfunction
If differentiation syndrome is suspected, initiate oral or intravenous corticosteroids (eg, dexamethasone 10 mg every 12 hours) and hemodynamic monitoring until improvement
If severe pulmonary symptoms requiring intubation or ventilator support and/or renal dysfunction persist for more than 48 hours after initiation of corticosteroids, interrupt IDHIFA® until signs and symptoms are no longer severe
Taper corticosteroids only after resolution of symptoms
Symptoms of differentiation syndrome may recur with premature discontinuation of corticosteroid treatment
Hospitalization for close observation and monitoring of patients with pulmonary and/or renal manifestation is recommended
Differentiation syndrome has been observed with and without concomitant hyperleukocytosis in as early as 1 day and up to 5 months after IDHIFA® initiation
Initiate treatment with hydroxyurea, as per standard institutional practices
Interrupt IDHIFA® if leukocytosis is not improved with hydroxyurea
Then resume IDHIFA® at 100 mg daily when WBC is <30x109/L
WATCH AN AML EXPERT DISCUSS DIFFERENTIATION SYNDROME WITH IDHIFA®
Explore important topics in managing patients who have R/R AML with an IDH2 mutation receiving IDHIFA®, including diagnosing and treating differentiation syndrome and other adverse events.
Dr Harry Erba and Marilyn Pritchard, RN have been paid by Bristol Myers Squibb to participate in this video.
Additional Warnings, Precautions, & ARs
ADDITIONAL WARNINGS, PRECAUTIONS, AND ARs
SELECTED WARNINGS AND PRECAUTIONS
Based on animal embryo-fetal toxicity studies, IDHIFA® can cause embryo-fetal harm when administered to a pregnant woman.
Advise females of reproductive potential and males with female partners of reproductive potential to use effective contraception during treatment with IDHIFA® and for at least 2 months after the last dose
Advise pregnant women of the potential risk to the fetus
IDHIFA® may interfere with bilirubin metabolism through inhibition of UGT1A1.
Total bilirubin elevations (≥2x upper limit of normal [ULN] at least one time) were observed in 37% of patients (80/214)
Of these patients, 35% had elevations within the first month of treatment, and 89% had no concomitant elevation of transaminases or other severe adverse events related to liver disorders
No patients required a dose reduction for hyperbilirubinemia, and treatment was interrupted in 3.7% of patients for a median of 6 days
Additionally, 1.4% of patients (3/214) discontinued IDHIFA® permanently due to hyperbilirubinemia
IDHIFA® can induce myeloid proliferation resulting in a rapid increase in WBC count
12% of patients experienced leukocytosis
Tumor lysis syndrome
IDHIFA® can induce myeloid proliferation resulting in a rapid reduction in tumor cells, which may pose a risk for TLS
IDHIFA® (enasidenib) is indicated for the treatment of adult patients with relapsed or refractory (R/R) acute myeloid leukemia (AML) with an isocitrate dehydrogenase-2 (IDH2) mutation as detected by an FDA-approved test.
Patients treated with IDHIFA have experienced symptoms of differentiation syndrome, which can be fatal if not treated. Symptoms may include fever, dyspnea, acute respiratory distress, pulmonary infiltrates, pleural or pericardial effusions, rapid weight gain or peripheral edema, lymphadenopathy, bone pain, and hepatic, renal, or multi-organ dysfunction. If differentiation syndrome is suspected, initiate corticosteroid therapy and hemodynamic monitoring until symptom resolution.
Differentiation Syndrome: See Boxed WARNING. In the clinical trial, 14% of patients treated with IDHIFA experienced differentiation syndrome, which may be life-threatening or fatal if not treated. Differentiation syndrome has been observed with and without concomitant hyperleukocytosis, in as early as 1 day and up to 5 months after IDHIFA initiation. Symptoms in patients treated with IDHIFA included acute respiratory distress represented by dyspnea and/or hypoxia and need for supplemental oxygen; pulmonary infiltrates and pleural effusion; renal impairment; fever; lymphadenopathy; bone pain; peripheral edema with rapid weight gain; and pericardial effusion. Hepatic, renal, and multi-organ dysfunction have also been observed. If differentiation syndrome is suspected, initiate systemic corticosteroids and hemodynamic monitoring until improvement. Taper corticosteroids only after resolution of symptoms. Differentiation syndrome symptoms may recur with premature discontinuation of corticosteroids. If severe pulmonary symptoms requiring intubation or ventilator support and/or renal dysfunction persist for more than 48 hours after initiation of corticosteroids, interrupt IDHIFA until signs and symptoms are no longer severe. Hospitalization for close observation and monitoring of patients with pulmonary and/or renal manifestation is recommended.
Embryo-Fetal Toxicity: Based on animal embryo-fetal toxicity studies, IDHIFA can cause embryo-fetal harm when administered to a pregnant woman. Advise females of reproductive potential and males with female partners of reproductive potential to use effective contraception during treatment with IDHIFA and for at least 2 months after the last dose. Advise pregnant women of the potential risk to the fetus.
The most common adverse reactions (≥20%) included total bilirubin increased (81%), calcium decreased (74%), nausea (50%), diarrhea (43%), potassium decreased (41%), vomiting (34%), decreased appetite (34%), and phosphorus decreased (27%)
The most frequently reported ≥Grade 3 adverse reactions (≥5%) included total bilirubin increased (15%), potassium decreased (15%), phosphorus decreased (8%), calcium decreased (8%), diarrhea (8%), differentiation syndrome (7%), non-infectious leukocytosis (6%), tumor lysis syndrome (6%), and nausea (5%)
Serious adverse reactions were reported in 77.1% of patients. The most frequent serious adverse reactions (≥2%) were leukocytosis (10%), diarrhea (6%), nausea (5%), vomiting (3%), decreased appetite (3%), tumor lysis syndrome (5%), and differentiation syndrome (8%). Differentiation syndrome events characterized as serious included pyrexia, renal failure acute, hypoxia, respiratory failure, and multi-organ failure
Coadministration of IDHIFA increases the exposure of OATP1B1, OATP1B3, BCRP, and P‑glycoprotein (P‑gp) substrates, which may increase the incidence and severity of adverse reactions of these substrates. If coadministered, decrease the dosage of the substrate as recommended in the respective prescribing information and as clinically indicated.
Because of the potential for adverse reactions in the breastfed child, advise women not to breastfeed during treatment with IDHIFA and for at least 2 months after the last dose.
Data on file, Celgene Corporation. Summit, New Jersey.
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