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IDH1 mutations can play a critical role in the development of AML1-4

IDH1 mutations are driver mutations that occur in 6 to 16% of patients with AML5

  • mIDH1 contributes to oncogenesis by catalyzing the production of 2-HG, which leads to disruption of cellular metabolism and epigenetic regulation6
  • Several studies have suggested that mIDH1 AML is associated with a poor prognosis6,7

IDH1 mutations block normal differentiation of myeloblasts1-3

IDH1 Mutations Blocking Differentiation of Myeloblasts IDH1 Mutations Blocking Differentiation of Myeloblasts

Test for mIDH1 before prescribing to optimize treatment

  • Both the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) and ASH‑CAP Guidelines recommend testing for actionable mutations, such as IDH1 mutations, in patients with AML8,9
    • “To appropriately stratify available intensive therapy options, expedite test results of molecular and cytogenetic analyses for immediately actionable mutations or chromosomal abnormalities.”
      - National Comprehensive Cancer Network® (NCCN®)
  • Evidence from a retrospective study showed that time from diagnosis to treatment does not appear to affect CR or OS rates in patients 60 years of age or older10,a
  • In newly diagnosed AML patients, further evidence showed that time from diagnosis to treatment does not affect the likelihood of response, early death, or long-term survival11,b
  • Waiting for genetic and laboratory test results prior to initiating treatment may ensure patients are given the best treatment option11
  • Give your AML patients the chance for improved survival—test and obtain mIDH1 results to inform prescribing options12

aMean SD for time from diagnosis to treatment in patients ≥60 years of age (n=664) was 7.5 ± 8.7 days.10

bPatients (N=2263) were subgrouped based on time from diagnosis to treatment (0-5 days, 6-10 days, 11-15 days, and >15 days). No difference in outcomes was observed between subgroups. Mean time from diagnosis to treatment was 5.65 days (SD ± 6.47 days) in the fully study population.11

2-HG, D-2-hydroxyglutarate; AML, acute myeloid leukemia; IDH1, isocitrate dehydrogenase-1.

Ivosidenib (TIBSOVO) is recommended by the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) as a category 1 preferred treatment option8

NCCN Guidelines® recommends ivosidenib (TIBSOVO) + azacitidine as a category 1 preferred treatment option for newly diagnosed patients ≥18 years of age with mIDH1 AML who are not candidates for intensive remission induction therapy8

NCCN Guidelines recommends ivosidenib (TIBSOVO) monotherapy as a category 2A treatment option for IC-ineligible, newly diagnosed and R/R AML patients with an IDH1 mutation8

AML, acute myeloid leukemia; ASH, American Society of Hematology; CAP, College of American Pathologists; IC, induction chemotherapy; IDH1, isocitrate dehydrogenase-1; R/R, relapsed/refractory.

TIBSOVO (ivosidenib tablets) targets the mutant IDH1 enzyme to restore myeloid differentiation12,13

TIBSOVO restores differentiation of myeloblasts12,13

TIBSOVO® Restoring Differentiation of Myeloblasts TIBSOVO® Restoring Differentiation of Myeloblasts
  • In blood samples from patients with AML with mutated IDH1, ivosidenib decreased 2‑HG levels ex vivo, reduced blast counts, and increased percentages of mature myeloid cells12
  • Ivosidenib was shown to inhibit selected IDH1 R132 mutants at much lower concentrations than wild-type IDH1 in vitro12
  • Susceptible IDH1 mutations are defined as those leading to increased levels of 2‑HG in the leukemia cells and where efficacy is predicted by (1) clinically meaningful remissions with the recommended dose of ivosidenib and/or (2) inhibition of mutant IDH1 enzymatic activity at concentrations of ivosidenib sustainable at the recommended dosage according to validated methods12
    • Susceptible IDH1 mutations are R132C and R132H

2-HG, D-2-hydroxyglutarate; AML, acute myeloid leukemia; IDH1, isocitrate dehydrogenase‑1.

See TIBSOVO access information

References: 1. Data on file. Servier Pharmaceuticals LLC. 2. Molenaar RJ, Maciejewski JP, Wilmink JW, van Noorden CJF. Wild-type and mutated IDH1/2 enzymes and therapy responses. Oncogene. 2018;37(15):1949-1960. 3. Figueroa ME, Abdel-Wahab O, Lu C, et al. Leukemic IDH1 and IDH2 mutations result in a hypermethylation phenotype, disrupt TET2 function, and impair hematopoietic differentiation. Cancer Cell. 2010;18(6):553-567. 4. Megías-Vericat JE, Ballesta-López O, Barragán E, Montesinos P. IDH1-mutated relapsed or refractory AML: current challenges and future prospects. Blood Lymphat Cancer. 2019;9:19-32. doi:10.2147/BLCTT.S177913 5. DiNardo CD, Ravandi F, Agresta S, et al. Characteristics, clinical outcome, and prognostic significance of IDH mutations in AML. Am J Hematol. 2015;90(8):732-736. doi:10.1002/ajh.24072 6. Roboz GJ, DiNardo CD, Stein EM, et al. Ivosidenib induces deep durable remissions in patients with newly diagnosed IDH1-mutant acute myeloid leukemia. Blood. 2020;135(7):463-471. 7. Xu Q, Li Y, Lv N, et al. Correlation between isocitrate dehydrogenase gene aberrations and prognosis of patients with acute myeloid leukemia: a systemic review and meta-analysis. Clin Cancer Res. 2017;23(15):4511-4522. 8. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Acute Myeloid Leukemia V.1.2024. © National Comprehensive Cancer Network, Inc. 2024. All rights reserved. Accessed March 1, 2024. To view the more recent and complete version of the guideline, go online to NCCN.org. NCCN makes no warranties of any kind whatsoever regarding their content, use, or application and disclaims any responsibility for their application or use in any way. 9. Arber DA, Borowitz MJ, Cessna M, et al. Initial diagnostic workup of acute leukemia: Guideline from the College of American Pathologists and the American Society of Hematology. Arch Pathol Lab Med. 2017;141(10):1342-1393. 10. Sekeres MA, Elson P, Kalaycio ME, et al. Time from diagnosis to treatment initiation predicts survival in younger, but not older, acute myeloid leukemia patients. Blood. 2009;113(1):28-36. doi:10.1182/blood-2008-05-157065 11. Röllig C, Kramer M, Schliemann C, et al. Does time from diagnosis to treatment affect the prognosis of patients with newly diagnosed acute myeloid leukemia? Blood. 2020;136(7):823-830. doi:10.1182/blood.2019004583 12. Tibsovo. Package insert. Servier Pharmaceuticals LLC; 2023. 13. Data on file. Servier Pharmaceuticals LLC. 14. Arber DA, Orazi A, Hasserjian RP, et al. International Consensus Classification of Myeloid Neoplasms and Acute Leukemias: integrating morphologic, clinical, and genomic data. Blood. 2022;140(11):1200-1228. doi:10.1182/blood.2022015850 15. Falini B, Martelli MP. Comparison of the International Consensus and 5th WHO edition classifications of adult myelodysplastic syndromes and acute myeloid leukemia. Am J Hematol. 2023;98(3):481-492. doi:10.1002/ajh.26812

 

Indications

TIBSOVO is indicated for patients with a susceptible isocitrate dehydrogenase-1 (IDH1) mutation as detected by an FDA-approved test with:

Newly Diagnosed Acute Myeloid Leukemia (AML)

  • In combination with azacitidine or as monotherapy for the treatment of newly diagnosed AML in adults 75 years or older, or who have comorbidities that preclude use of intensive induction chemotherapy

Relapsed or Refractory AML

  • For the treatment of adult patients with relapsed or refractory AML

IMPORTANT SAFETY INFORMATION

WARNING: DIFFERENTIATION SYNDROME IN AML
Patients treated with TIBSOVO have experienced symptoms of differentiation syndrome, which can be fatal. Symptoms may include fever, dyspnea, hypoxia, pulmonary infiltrates, pleural or pericardial effusions, rapid weight gain or peripheral edema, hypotension, and hepatic, renal, or multi-organ dysfunction. If differentiation syndrome is suspected, initiate corticosteroid therapy and hemodynamic monitoring until symptom resolution.

WARNINGS AND PRECAUTIONS

Differentiation Syndrome in AML: Differentiation syndrome is associated with rapid proliferation and differentiation of myeloid cells and may be life-threatening or fatal. 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.

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. 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, electrolyte abnormalities, or 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.

ADVERSE REACTIONS

  • In patients with AML, the most adverse reactions including laboratory abnormalities (≥25%) are leukocytes decreased, diarrhea, hemoglobin decreased, platelets decreased, glucose increased, fatigue, alkaline phosphatase increased, edema, potassium decreased, nausea, vomiting, phosphate decreased, decreased appetite, sodium decreased, leukocytosis, magnesium decreased, aspartate aminotransferase increased, arthralgia, dyspnea, uric acid increased, abdominal pain, creatinine increased, mucositis, rash, electrocardiogram QT prolonged, differentiation syndrome, calcium decreased, neutrophils decreased, and myalgia

DRUG INTERACTIONS

Strong or Moderate CYP3A4 Inhibitors: Reduce TIBSOVO dose with strong CYP3A4 inhibitors. Monitor patients for increased risk of QTc interval prolongation.

Strong CYP3A4 Inducers: Avoid concomitant use with TIBSOVO.

Sensitive CYP3A4 substrates: Avoid concomitant use with TIBSOVO.

QTc Prolonging Drugs: Avoid concomitant use with TIBSOVO. If co-administration is unavoidable, monitor patients for increased risk of QTc interval prolongation.

LACTATION

Advise women not to breastfeed.

Please see Full Prescribing Information, including BOXED WARNING for AML patients.

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INDICATIONS

TIBSOVO is indicated for patients with a susceptible isocitrate dehydrogenase-1 (IDH1) mutation as detected by an FDA-approved test with:

Newly Diagnosed Acute Myeloid Leukemia (AML)

  • In combination with azacitidine or as monotherapy for the treatment of newly diagnosed AML in adults 75 years or older, or who have comorbidities that preclude the use of intensive induction chemotherapy
Indications & Important Safety Information

IMPORTANT SAFETY INFORMATION

WARNING: DIFFERENTIATION SYNDROME IN AML

Patients treated with TIBSOVO have experienced symptoms of differentiation syndrome, which can be fatal. Symptoms may include fever, dyspnea, hypoxia, pulmonary infiltrates, pleural or pericardial effusions, rapid weight gain or peripheral edema, hypotension, and hepatic, renal, or multi-organ dysfunction. If differentiation syndrome is suspected, initiate corticosteroid therapy and hemodynamic monitoring until symptom resolution.