TIBSOVO in combination with azacitidine for treatment of newly diagnosed IC-ineligible mIDH1 AML
Adverse reactions
Adverse reactions (≥10%) in patients with AML who received TIBSOVO + azacitidine with a difference of ≥2% between arms compared with placebo + azacitidine1 | ||||
---|---|---|---|---|
TIBSOVO + azacitidine (N=71) |
Placebo + azacitidine (N=73) |
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Body system Adverse reaction |
All grades | Grade ≥3 | All grades | Grade ≥3 |
Gastrointestinal disorders | ||||
Nausea | 42% | 3% | 38% | 4% |
Vomiting | 41% | 0 | 27% | 1% |
Investigations | ||||
Electrocardiogram QT prolonged | 20% | 10% | 7% | 3% |
Psychiatric disorders | ||||
Insomnia | 18% | 1% | 12% | 0 |
Blood system and lymphatic system disorders | ||||
Differentiation syndromea |
15% | 10% | 8% | 8% |
Leukocytosis | 13% | 0 | 1% | 0 |
Vascular disorders | ||||
Hematoma | 15% | 0 | 4% | 0 |
Hypertension | 13% | 4% | 8% | 5% |
Musculoskeletal and connective tissue disorder | ||||
Arthralgia | 30% | 4% | 8% | 1% |
Respiratory, thoracic, and mediastinal disorders | ||||
Dyspnea | 20% | 3% | 15% | 5% |
Nervous system disorders | ||||
Headache | 11% | 0% | 3% | 0% |
Adverse reactions (≥10%) in patients with AML who received TIBSOVO + azacitidine with a difference of ≥2% between arms compared with placebo + azacitidine | ||||
---|---|---|---|---|
TIBSOVO + azacitidine (N=71) |
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Body system Adverse reaction |
All grades | Grade ≥3 | ||
Gastrointestinal disorders | ||||
Nausea | 42% | 3% | ||
Vomiting | 41% | 0 | ||
Investigations | ||||
Electrocardiogram QT prolonged | 20% | 10% | ||
Psychiatric disorders | ||||
Insomnia | 18% | 1% | ||
Blood system and lymphatic system disorders | ||||
Differentiation syndromea |
15% | 10% | ||
Leukocytosis | 13% | 0 | ||
Vascular disorders | ||||
Hematoma | 15% | 0 | ||
Hypertension | 13% | 4% | ||
Musculoskeletal and connective tissue disorders | ||||
Arthralgia | 30% | 4% | ||
Respiratory, thoracic, and mediastinal disorders | ||||
Dyspnea | 20% | 3% | ||
Nervous system disorders | ||||
Headache | 11% | 0 |
Placebo + azacitidine (N=73) |
||||
Body system Adverse reaction |
All grades | Grade ≥3 | ||
Gastrointestinal disorders | ||||
Nausea | 38% | 4% | ||
Vomiting | 27% | 1% | ||
Investigations | ||||
Electrocardiogram QT prolonged | 7% | 3% | ||
Psychiatric disorders | ||||
Insomnia | 12% | 0 | ||
Blood system and lymphatic system disorders | ||||
Differentiation syndromea |
8% | 8% | ||
Leukocytosis | 1% | 0 | ||
Vascular disorders | ||||
Hematoma | 4% | 0 | ||
Hypertension | 8% | 5% | ||
Musculoskeletal and connective tissue disorders | ||||
Arthralgia | 8% | 1% | ||
Respiratory, thoracic, and mediastinal disorders | ||||
Dyspnea | 15% | 5% | ||
Nervous system disorders | ||||
Headache | 3% | 0 |
IC, induction chemotherapy; mIDH1, mutated isocitrate dehydrogenase-1.
a Grade 1 is mild, Grade 2 is moderate, Grade 3 is severe, Grade 4 is life-threatening.
b Differentiation syndrome can be associated with other commonly reported events such as peripheral edema, leukocytosis, pyrexia, dyspnea, pleural effusion, hypotension, hypoxia, pulmonary edema, pneumonia, pericardial effusion, rash, fluid overload, tumor lysis syndrome, and creatinine increased.
- TIBSOVO + azacitidine was associated with a lower rate of infection of any grade compared with azacitidine (28% vs 49%)2
Select laboratory abnormalities
Select laboratory abnormalities (≥10%) that worsened from baseline in patients with newly diagnosed AML who received TIBSOVO + azacitidine1,a,b | ||||
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TIBSOVO + azacitidine (N=71) |
Placebo + azacitidine (N=73) |
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Parameter | All grades | Grade ≥3 | All grades | Grade ≥3 |
Hematology parameters | ||||
Leukocytes decreased | 65% | 55% | 64% | 58% |
Platelets decreased | 58% | 42% | 71% | 58% |
Hemoglobin decreased | 56% | 46% | 66% | 58% |
Neutrophils decreased | 25% | 23% | 35% | 32% |
Lymphocytes increased | 24% | 1% | 10% | 1% |
Chemistry parameters | ||||
Glucose increased | 56% | 13% | 47% | 11% |
Phosphate decreased | 41% | 10% | 34% | 12% |
Aspartate aminotransferase increased | 37% | 0 | 23% | 0 |
Magnesium decreased | 35% | 0 | 26% | 0 |
Alkaline phosphatase increased | 32% | 0 | 29% | 0 |
Potassium increased | 24% | 3% | 12% | 1% |
Select laboratory abnormalities (≥10%) that worsened from baseline in patients with newly diagnosed AML who received TIBSOVO + azacitidinea,b | ||||
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TIBSOVO + azacitidine (N=71) |
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Paramater | All grades | Grade ≥3 | ||
Hematology parameters | ||||
Leukocytes decreased | 65% | 55% | ||
Platelets decreased | 58% | 42% | ||
Hemoglobin decreased | 56% | 46% | ||
Neutrophils decreased | 25% | 23% | ||
Lymphocytes decreased | 24% | 1% | ||
Chemistry parameters | ||||
Glucose increased | 56% | 13% | ||
Phosphate decreased | 41% | 10% | ||
Aspartate aminotransferase increased | 37% | 0 | ||
Magnesium decreased | 35% | 0 | ||
Alkaline phosphatase increased | 32% | 0 | ||
Potassium increased | 24% | 3% |
Placebo + azacitidine (N=73) |
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Paramater | All grades | Grade ≥3 | ||
Hematology parameters | ||||
Leukocytes decreased | 64% | 58% | ||
Platelets decreased | 71% | 58% | ||
Hemoglobin decreased | 66% | 58% | ||
Neutrophils decreased | 35% | 32% | ||
Lymphocytes increased | 10% | 1% | ||
Chemistry parameters | ||||
Glucose increased | 47% | 11% | ||
Phosphate decreased | 34% | 12% | ||
Aspartate aminotransferase increased | 23% | 0 | ||
Magnesium decreased | 26% | 0 | ||
Alkaline phosphatase increased | 29% | 0 | ||
Potassium increased | 12% | 1% |
aLaboratory abnormality was defined as new or worsened by at least one grade from baseline or if baseline was unknown.
bThe denominator used to calculate percentages is the number of treated subjects who can be evaluated for Common Terminology for Adverse Events (CTCAE) criteria for each parameter in each arm.
- TIBSOVO + azacitidine was associated with fewer severe cytopenias compared with azacitidine1,2
- Median duration of exposure to TIBSOVO was 6 months (range, 0 to 33)1
- 34 patients (48%) were exposed to TIBSOVO for at least 6 months
- 22 patients (31%) were exposed to TIBSOVO for at least 1 year
- Fatal adverse reactions occurred in 4% of patients due to differentiation syndrome (3%) and one case of cerebral ischemia1
TIBSOVO + azacitidine: Dose discontinuations, interruptions, and reductions1
TIBSOVO + azacitidine for newly diagnosed AML (N=71) | |
Adverse reactions that lead to permanent discontinuation in ≥2% of patients | Differentiation syndrome (3%), pulmonary embolism (3%) |
Most common (>5%) adverse reactions that lead to dose interruption | Neutropenia (25%), electrocardiogram QT prolonged (7%), thrombocytopenia (7%) |
Adverse reactions that lead to dose reduction | Electrocardiogram QT prolonged (8%), neutropenia (8%), thrombocytopenia (1%) |
Safety profile: TIBSOVO monotherapy
Adverse reactions common to both the newly diagnosed and R/R settings reported in ≥10% (any grade) or ≥5% (Grade ≥3) of patients who received TIBSOVO monotherapy1 |
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Newly diagnosed AML (N=28) |
R/R AML (N=179) |
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Body system Adverse reaction |
All grades | Grade ≥3 | All grades | Grade ≥3 |
Gastrointestinal disorders | ||||
Diarrhea | 61% | 7% | 34% | 2% |
Nausea | 36% | 7% | 31% | 1% |
Abdominal pain | 29% | 4% | 16% | 1% |
Constipation | 21% | 4% | 20% | 1% |
Vomiting | 21% | 4% | 18% | 1% |
Mucositis | 21% | 0% | 28% | 3% |
General disorders and administration site conditions | ||||
Fatigue | 50% | 14% | 39% | 3% |
Edema | 43% | 0% | 32% | 1% |
Metabolism and nutrition disorders | ||||
Decreased appetite | 39% | 4% | 18% | 2% |
Blood system and lymphatic system disorders | ||||
Leukocytosis | 36% | 7% | 38% | 8% |
Differentiation syndromea |
25% | 11% | 19% | 13% |
Musculoskeletal and connective tissue disorders | ||||
Arthralgia | 32% | 4% | 36% | 4% |
Myalgia | 25% | 4% | 18% | 1% |
Respiratory, thoracic, and mediastinal disorders | ||||
Dyspnea | 29% | 4% | 33% | 9% |
Cough | 14% | 0% | 22% | <1% |
Investigations | ||||
Electrocardiogram QT prolonged | 21% | 11% | 26% | 10% |
Nervous system disorders | ||||
Neuropathy | 14% | 0% | 12% | 1% |
Headache | 11% | 0% | 16% | 0% |
Skin and subcutaneous tissue disorders | ||||
Rash | 14% | 4% | 26% | 2% |
Adverse reactions common to both the newly diagnosed and R/R settings reported in ≥10% (any grade) or ≥5% (Grade ≥3) of patients who received TIBSOVO monotherapy1 |
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Newly diagnosed AML (N=28) |
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Body system Adverse reaction |
All grades | Grade ≥3 | ||
Gastrointestinal disorders | ||||
Diarrhea | 61% | 7% | ||
Nausea | 36% | 7% | ||
Abdominal pain | 29% | 4% | ||
Constipation | 21% | 4% | ||
Vomiting | 21% | 4% | ||
Mucositis | 21% | 0% | ||
General disorders and administration site conditions | ||||
Fatigue | 50% | 14% | ||
Edema | 43% | 0% | ||
Metabolism and nutrition disorders | ||||
Decreased appetite | 39% | 4% | ||
Blood system and lymphatic system disorders | ||||
Leukocytosis | 36% | 7% | ||
Differentiation syndromea |
25% | 11% | ||
Musculoskeletal and connective tissue disorders | ||||
Arthralgia | 32% | 4% | ||
Myalgia | 25% | 4% | ||
Respiratory, thoracic, and mediastinal disorders | ||||
Dyspnea | 29% | 4% | ||
Cough | 14% | 0% | ||
Investigations | ||||
Electrocardiogram QT prolonged | 21% | 11% | ||
Nervous system disorders | ||||
Neuropathy | 14% | 0% | ||
Headache | 11% | 0% | ||
Skin and subcutaneous tissue disorders | ||||
Rash | 14% | 4% |
R/R AML (N=179) |
||||
Body system Adverse reaction |
All grades | Grade ≥3 | ||
Gastrointestinal disorders | ||||
Diarrhea | 34% | 2% | ||
Nausea | 31% | 1% | ||
Abdominal pain | 16% | 1% | ||
Constipation | 20% | 1% | ||
Vomiting | 18% | 1% | ||
Mucositis | 28% | 3% | ||
General disorders and administration site conditions | ||||
Fatigue | 39% | 3% | ||
Edema | 32% | 1% | ||
Metabolism and nutrition disorders | ||||
Decreased appetite | 18% | 2% | ||
Blood system and lymphatic system disorders | ||||
Leukocytosis | 38% | 8% | ||
Differentiation syndromea |
19% | 13% | ||
Musculoskeletal and connective tissue disorders | ||||
Arthralgia | 36% | 4% | ||
Myalgia | 18% | 1% | ||
Respiratory, thoracic, and mediastinal disorders | ||||
Dyspnea | 33% | 9% | ||
Cough | 22% | <1% | ||
Investigations | ||||
Electrocardiogram QT prolonged | 26% | 10% | ||
Nervous system disorders | ||||
Neuropathy | 12% | 1% | ||
Headache | 16% | 0% | ||
Skin and subcutaneous tissue disorders | ||||
Rash | 26% | 2% |
R/R, relapsed or refractory.
aDifferentiation syndrome can be associated with other commonly reported events such as peripheral edema, leukocytosis, pyrexia, dyspnea, pleural effusion, hypotension, hypoxia, pulmonary edema, pneumonia, pericardial effusion, rash, fluid overload, tumor lysis syndrome, and creatinine increased.1
Additional adverse reactions in the newly diagnosed monotherapy setting
Additional adverse reactions in the newly diagnosed setting reported in ≥10% (any grade) or ≥5% (Grade ≥3) of patients who received TIBSOVO monotherapy1 | ||
Newly diagnosed AML (N=28) |
||
Adverse reaction | All grades | Grade ≥3 |
Dizziness | 21% | 0% |
Pruritus | 14% | 4% |
Dyspepsia | 11% | 0% |
Weight decreased | 11% | 0% |
- Common (≥5%) serious adverse events included differentiation syndrome (18%), electrocardiogram QT prolonged (7%), and fatigue (7%). There was one case of posterior reversible encephalopathy syndrome (PRES)1
-
Median duration of exposure to TIBSOVO: 4.3 months (range, 0.3-40.9)1
- 10 patients (36%) were exposed to TIBSOVO for ≥6 months and 6 patients (21%) for ≥1 year
Additional adverse reactions in the R/R monotherapy setting
Additional adverse reactions in the R/R setting reported in ≥10% (any grade) or ≥5% (Grade ≥3) of patients who received TIBSOVO monotherapy1 | ||
R/R AML (N=179) |
||
Adverse reaction | All grades | Grade ≥3 |
Pyrexia | 23% | 1% |
Chest pain | 16% | 3% |
Pleural effusion | 13% | 3% |
Hypotension | 12% | 4% |
Tumor lysis syndrome | 8% | 6% |
R/R, relapsed or refractory.
- Serious adverse reactions (≥5%) were differentiation syndrome (10%), leukocytosis (10%), and electrocardiogram QT prolonged (7%). There was one case of progressive multifocal leukoencephalopathy (PML)1
-
Median duration of exposure to TIBSOVO: 3.9 months (range, 0.1-39.5)1
- 65 patients (36%) were exposed to TIBSOVO for ≥6 months and 16 patients (9%) for ≥1 year
Laboratory abnormalities reported in patients who received TIBSOVO monotherapy1
Laboratory abnormalities common to both the newly diagnosed and R/R settings reported in ≥10% (any grade) or ≥5% (Grade ≥3) of patients who received TIBSOVO monotherapy1,b | ||||
Newly diagnosed AML (N=28) |
R/R AML (N=179) |
|||
Parameter | All grades | Grade ≥3 | All grades | Grade ≥3 |
Hemoglobin decreased | 54% | 43% | 60% | 46% |
Alkaline phosphatase increased | 46% | 0% | 27% | 1% |
Potassium decreased | 43% | 11% | 31% | 6% |
Sodium decreased | 39% | 4% | 39% | 4% |
Uric acid increased | 29% | 4% | 32% | 6% |
Aspartate aminotransferase increased | 29% | 4% | 27% | 1% |
Creatinine increased | 29% | 0% | 23% | 1% |
Magnesium decreased | 25% | 0% | 38% | 0% |
Phosphate decreased | 21% | 7% | 25% | 8% |
Alanine aminotransferase increased | 14% | 4% | 15% | 1% |
Laboratory abnormalities common to both the newly diagnosed and R/R settings reported in ≥10% (any grade) or ≥5% (Grade ≥3) of patients who received TIBSOVO monotherapy1,b | ||||
Newly diagnosed AML (N=28) |
||||
Parameter | All grades | Grade ≥3 | ||
Hemoglobin decreased | 54% | 43% | ||
Alkaline phosphatase increased | 46% | 0% | ||
Potassium decreased | 43% | 11% | ||
Sodium decreased | 39% | 4% | ||
Uric acid increased | 29% | 4% | ||
Aspartate aminotransferase increased | 29% | 4% | ||
Creatinine increased | 29% | 0% | ||
Magnesium decreased | 25% | 0% | ||
Phosphate decreased | 21% | 7% | ||
Alanine aminotransferase increased | 14% | 4% |
R/R AML (N=179) |
||
Parameter | All grades | Grade ≥3 |
Hemoglobin decreased | 60% | 46% |
Alkaline phosphatase increased | 27% | 1% |
Potassium decreased | 31% | 6% |
Sodium decreased | 39% | 4% |
Uric acid increased | 32% | 6% |
Aspartate aminotransferase increased | 27% | 1% |
Creatinine increased | 23% | 1% |
Magnesium decreased | 38% | 0% |
Phosphate decreased | 25% | 8% |
Alanine aminotransferase increased | 15% | 1% |
R/R, relapsed or refractory.
bLaboratory abnormality was defined as new or worsened by at least one grade from baseline or if baseline is unknown.1
Additional laboratory abnormalities reported in ≥10% (any grade) or ≥5% (Grade ≥3) of patients1:
- In patients with newly diagnosed AML: calcium decreased (all grades, 25%; Grade ≥3, 4%)
- In patients with R/R AML: bilirubin increased (all grades, 16%; Grade ≥3, 1%)
Monotherapy: Dose discontinuations, interruptions, and reductions1
Newly diagnosed AML (N=28) | R/R AML (N=179) | |
Adverse reactions that led to permanent discontinuation | Diarrhea (4%), PRES (4%) | Guillain-Barré syndrome (1%), rash (1%), stomatitis (1%), creatinine increased (1%) |
Most common adverse reactions that led to dose interruption | Electrocardiogram QT prolonged (14%), differentiation syndrome (11%) | Electrocardiogram QT prolonged (7%), differentiation syndrome (3%), leukocytosis (3%), dyspnea (3%) |
Adverse reactions that led to dose reduction | Electrocardiogram QT prolonged (7%) |
3% of patients required a dose reduction due to an adverse reaction
- Adverse reactions leading to dose reduction included electrocardiogram QT prolonged (1%), diarrhea (1%), nausea (1%), decreased hemoglobin (1%), increased transaminases (1%) |
Newly diagnosed AML (N=28) |
|
Adverse reactions that led to permanent discontinuation | Diarrhea (4%), PRES (4%) |
Most common adverse reactions that led to dose interruption | Electrocardiogram QT prolonged (14%), differentiation syndrome (11%) |
Adverse reactions that led to dose reduction | Electrocardiogram QT prolonged (7%) |
R/R AML (N=179) |
|
Adverse reactions that led to permanent discontinuation | Guillain-Barré syndrome (1%), rash (1%), stomatitis (1%), creatinine increased (1%) |
Most common adverse reactions that led to dose interruption | Electrocardiogram QT prolonged (7%), differentiation syndrome (3%), leukocytosis (3%), dyspnea (3%) |
Adverse reactions that led to dose reduction |
3% of patients required a dose reduction due to an adverse reaction
|
PRES, posterior reversible encephalopathy syndrome.
TIBSOVO monotherapy was associated with a low rate of severe cytopenias3,4
Warnings and Precautions
Differentiation Syndrome in AML: In the clinical trial, 25% (7/28) of patients with newly diagnosed AML and 19% (34/179) of patients with relapsed or refractory AML treated with TIBSOVO experienced differentiation syndrome. Differentiation syndrome is associated with rapid proliferation and differentiation of myeloid cells and may be life-threatening or fatal if not treated. Symptoms of differentiation syndrome in patients treated with TIBSOVO included noninfectious leukocytosis, peripheral edema, pyrexia, dyspnea, pleural effusion, hypotension, hypoxia, pulmonary edema, pneumonitis, pericardial effusion, rash, fluid overload, tumor lysis syndrome, and creatinine increased. Of the 7 patients with newly diagnosed AML who experienced differentiation syndrome, 6 (86%) patients recovered. Of the 34 patients with relapsed or refractory AML who experienced differentiation syndrome, 27 (79%) patients recovered after treatment or after dose interruption of TIBSOVO. Differentiation syndrome occurred as early as 1 day and up to 3 months after TIBSOVO initiation and has been observed with or without concomitant leukocytosis.
If differentiation syndrome is suspected, initiate dexamethasone 10 mg IV every 12 hours (or an equivalent dose of an alternative oral or IV corticosteroid) and hemodynamic monitoring until improvement. If concomitant noninfectious leukocytosis is observed, initiate treatment with hydroxyurea or leukapheresis, as clinically indicated. Taper corticosteroids and hydroxyurea after resolution of symptoms and administer corticosteroids for a minimum of 3 days. Symptoms of differentiation syndrome may recur with premature discontinuation of corticosteroid and/or hydroxyurea treatment. If severe signs and/or symptoms persist for more than 48 hours after initiation of corticosteroids, interrupt TIBSOVO until signs and symptoms are no longer severe.
QTc Interval Prolongation: Patients treated with TIBSOVO can develop QT (QTc) prolongation and ventricular arrhythmias. One patient developed ventricular fibrillation attributed to TIBSOVO. Concomitant use of TIBSOVO with drugs known to prolong the QTc interval (eg, anti-arrhythmic medicines, fluoroquinolones, triazole anti-fungals, 5-HT3 receptor antagonists) and CYP3A4 inhibitors may increase the risk of QTc interval prolongation. Conduct monitoring of electrocardiograms (ECGs) and electrolytes. In patients with congenital long QTc syndrome, congestive heart failure, or electrolyte abnormalities, or in those who are taking medications known to prolong the QTc interval, more frequent monitoring may be necessary.
Interrupt TIBSOVO if QTc increases to greater than 480 msec and less than 500 msec. Interrupt and reduce TIBSOVO if QTc increases to greater than 500 msec. Permanently discontinue TIBSOVO in patients who develop QTc interval prolongation with signs or symptoms of life-threatening arrhythmia.
Guillain-Barré Syndrome: Guillain-Barré syndrome can develop in patients treated with TIBSOVO. Monitor patients taking TIBSOVO for onset of new signs or symptoms of motor and/or sensory neuropathy such as unilateral or bilateral weakness, sensory alterations, paresthesias, or difficulty breathing. Permanently discontinue TIBSOVO in patients who are diagnosed with Guillain-Barré syndrome.