Differentiation syndrome is caused by rapid proliferation and differentiation of myeloid cells.
14% of patients (29/214) treated with IDHIFA experienced differentiation syndrome.
Differentiation syndrome has been observed with and without concomitant hyperleukocytosis, and as early as 10 days and at up to 5 months after IDHIFA initiation.
If untreated, differentiation syndrome may be life-threatening or fatal.
At first suspicion of differentiation syndrome:
If severe pulmonary symptoms requiring intubation or ventilator support, and/or renal dysfunction persist for more than 48 hours after initiation of corticosteroids:
Based on animal embryo-fetal toxicity studies, IDHIFA can cause embryo-fetal harm when administered to a pregnant woman.
The safety evaluation of single-agent IDHIFA is based on 214 patients with R/R AML who were assigned to receive 100 mg daily.
The most common adverse reactions (ARs) (≥20%) of any grade were nausea, vomiting, diarrhea, elevated bilirubin, and decreased appetite.
Overall, 43% of patients (92/214) required a dose interruption due to an AR.
5% of patients (10/214) required a dose reduction due to an AR.
17% of patients (36/214) permanently discontinued IDHIFA due to an AR.
|Nausea||107 (50)||11 (5)|
|Diarrhea||91 (43)||17 (8)|
|Vomiting||73 (34)||4 (2)|
|Metabolism and nutrition disorders|
|Decreased appetite||73 (34)||9 (4)|
|Tumor lysis syndromeb||13 (6)||12 (6)|
|Blood and lymphatic system disorders|
|Differentiation syndromec||29 (14)||15 (7)|
|Noninfectious leukocytosis||26 (12)||12 (6)|
|Nervous system disorders|
|Dysgeusia||25 (12)||0 (0)|
aGastrointestinal disorders observed with IDHIFA treatment can be associated with other commonly reported events such as abdominal pain and weight decrease.
bTumor lysis syndrome 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.
Other clinically significant ARs occurring in ≤10% of patients included Respiratory, Thoracic, and Mediastinal Disorders (pulmonary edema, acute respiratory distress syndrome).
|Parametera||All grades (%)||≥Grade 3 (%)|
|Total bilirubin increased||81||15|
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 phosphorous N=209).
IDHIFA may interfere with bilirubin metabolism through inhibition of UGT1A1.
IDHIFA 100 mg once daily
Swallow whole with a cup of water.
Do not split or crush the tablets.
Administer IDHIFA tablets orally about the same time each day with or without food.
For patients without disease progression or unacceptable toxicity, treat for a minimum of 6 months to allow time for clinical response
|Adverse reaction||Recommended action|
|Noninfectious leukocytosis (WBC count greater than 30 x 109/L)|
|Elevation of bilirubin greater than 3x ULN sustained for ≥2 weeks without elevated transaminases or other hepatic disorders|
|Other Grade 3a or higher toxicity considered related to treatment including TLS|
a Grade 1 is mild, Grade 2 is moderate, Grade 3 is serious, Grade 4 is life-threatening.
There are no contraindications to IDHIFA.
Patients must meet the following criteria to enroll:
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