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Looking beyond the blast percentage threshold in MDS and AML1

Fixed blast cutoffs are suboptimal in distinguishing MDS from AML1

  • Clinical classifications systems continue to evolve to de-emphasize morphologic features and fixed blast cutoffs in categorizing MDS and AML2
  • Updated 2022 WHO and ICC guidelines focus heavily on molecular and genetic features when characterizing MDS and AML2

ICC, International Consensus Classification; WHO, World Health Organization.

CLASSIFICATIONS HAVE EVOLVED BASED ON THE RECOGNITION THAT MDS EXISTS ON A BIOLOGIC CONTINUUM WITH AML3,4

Updated classifications redefined the blast count cutoff in the absence of genetic abnormalities3,4

WHO 2022 guidance for MDS-IB23,a
10% 19% to
blasts in the bone marrow
According to WHO 2022, MDS-IB2 may
be regarded as AML-equivalent from
a clinical trial design when appropriate
ICC 2022 guidance for MDS/AML4
10% 19% to
blasts in the blood or bone marrow
According to ICC 2022, MDS/AML should
be considered for both MDS and AML
trials to help optimize management options

Patients classified as MDS-IB2 or MDS/AML may have poorer outcomes5-9

  • Approximately 1 in 5 MDS patients classify as MDS/AML and may have poorer overall survival outcomes and a greater possibility of progressing to AML5-9

aThe WHO 2022 guidance for MDS-IB2 includes 5% to 19% blasts in the peripheral blood or Auer rods.3

ICC, International Consensus Classification; MDS-EB2, MDS with excess blasts 2; RAEB, refractory anemia with excess blasts; RAEB-T, RAEB in transformation; WHO, World Health Organization.

CONSIDER HOW UPDATED CLASSIFICATIONS MAY IMPACT HOW YOUR PATIENTS ARE DIAGNOSED AND MANAGED3

Certain genetic abnormalities determine a diagnosis of AML3,4

Updated classifications redefined the diagnosis of AML in the presence of genetic abnormalities3,4

WHO 2022 guidance
AML with defining genetic abnormalities3
AML can be diagnosed in the presence of certain mutations and/or defined genetic abnormalities such as NPM1, irrespective of blast countb
ICC 2022 guidance
AML with recurrent genetic abnormalities4
All entities defined by the presence of certain recurrent genetic abnormalities such as NPM1 and other genetically related entities can be diagnosed as AML if ≥10% blasts are presentc
  • The National Comprehensive Cancer Network® (NCCN®) recognizes that patients with certain genetic abnormalities are considered to have AML even if the marrow blast count is less than 20%10,d
  • IDH1 mutations frequently co-occur in up to 60% of patients with NPM1 mutations11
  • Conduct molecular testing to determine if your patients have an AML-defining genetic abnormality or an IDH1 mutation3,12

Consider using TIBSOVO + AZA for patients with newly diagnosed mIDH1 AML12

Learn more

bRUNX1::RUNX1T1 fusion, CBFB::MYH11 fusion, DEK::NUP214 fusion, RBM15::MRTFA fusion, BCR::ABL1 fusion, KMT2A rearrangement, MECOM rearrangement, NUP98 rearrangement, NPM1 mutation, CEBPA mutation, myelodysplasia-related genetic abnormalities, and other defined genetic alterations.3

ct(8;21) (q22;q22.1)/RUNX1::RUNX1T1), inv(16)(p13.1q22) or t(16;16)(p13.1;q22)/CBFB::MYH11, t(6;9)(p22.3;q34.1)/DEK::NUP214, t(9;11)(p21.3;q23.3)/MLLT3::KMT2A, other KMT2A rearrangements, inv(3)(q21.3q26.2) or t(3;3)(q21.3;q26.2)/GATA2; MECOM(EVI1), other MECOM rearrangements, other rare recurring translocations, mutated NPM1, and in-frame bZIP CEBPA mutations.4

dt(8;21)(q22;q22.1)/RUNX1::RUNX1T1, inv(16)(p13.1q22) or t(16;16) (p13.1;q22)/CBFB::MYH11, t(9;11)(p21.3;q23.3)/MLLT3::KMT2A, other KMT2A rearrangements, t(6;9)(p22.3;q34.1)/DEK::NUP214, inv(3)(q21.3q26.2), t(3;3)(q21.3;q26.2)/GATA2; MECOM(EVI1), other MECOM rearrangements, mutated NPM1, in-frame bZIP CEBPA mutations (ICC only), RBM15::MRTFA fusion (WHO only), NUP98 rearrangement (WHO only).10

AML, acute myeloid leukemia; ICC, International Consensus Classification; NCCN, National Comprehensive Cancer Network® (NCCN®); WHO, World Health Organization.

See TIBSOVO access information

References: 1. Estey E, Hasserjian RP, Döhner H. Distinguishing AML from MDS: A fixed blast percentage may no longer be optimal. Blood. 2022;139(3):323-332. doi:10.1182/blood.2021011304 2. 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 3. Khoury JD, Solary E, Abla O, et al. The 5th edition of the World Health Organization Classification of Haematolymphoid Tumours: Myeloid and Histiocytic/Dendritic Neoplasms. Leukemia. 2022;36(7):1703-1719. doi:10.1038/s41375-022-01613-1 4. 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 5. Cazzola M. Risk stratifying MDS in the time of precision medicine. Hematology Am Soc Hematol Educ Program. 2022;2022(1):375-381. doi:10.1182/hematology.2022000349 6. Huber S, Haferlach T, Müller H, et al. MDS subclassification–do we still have to count blasts?: supplementary materials. Leukemia. 2023;37(4):942-945. doi:10.1038/s41375-023-01855-7 7. Chaudhuri D, Khan KI, Al Shouli R, et al. Secondary acute myeloid leukemia in myelodysplastic syndrome patients aged over 60 years. Cureus. 2023;15(6):e40124. doi:10.7759/cureus.40124 8. IPSS-M Risk Calculator. mds-risk-model.com. Accessed March 17, 2024. https://mds-risk-model.com/ 9. Nachtkamp K, Strupp C, Vukelja M, et al. The new WHO 2022 and ICC proposals for the classification of myelodysplastic neoplasms. Validation based on the Düsseldorf MDS Registry and proposals for a merged classification. Leukemia. 2024;38(2):442-445. doi:10.1038/s41375-024-02157-2 10. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Myelodysplastic Syndromes V.1.2024. © National Comprehensive Cancer Network, Inc. 2024. All rights reserved. Accessed February 20, 2024. To view the most 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. 11. Patel KP, Ravandi F, Ma D, et al. Acute myeloid leukemia with IDH1 or IDH2 mutation: frequency and clinicopathologic features. Am J Clin Pathol. 2011;135(1):35-45. doi:10.1309/AJCPD7NR2RMNQDVF 12. Tibsovo. Package insert. Servier Pharmaceuticals LLC; 2023.

 

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

Relapsed or Refractory Myelodysplastic Syndromes (MDS)

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

IMPORTANT SAFETY INFORMATION

WARNING: DIFFERENTIATION SYNDROME IN AML AND MDS
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 and MDS: 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 common 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
  • In patients with MDS, the most common adverse reactions including laboratory abnormalities (≥25%) are creatinine increased, arthralgia, albumin decreased, aspartate aminotransferase increased, fatigue, diarrhea, cough, sodium decreased, decreased appetite, myalgia, phosphate decreased, pruritus, and rash

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 and MDS 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 use of intensive induction chemotherapy
Indications & Important Safety Information

IMPORTANT SAFETY INFORMATION

WARNING: DIFFERENTIATION SYNDROME IN AML AND MDS

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.