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IDHIFA for R/R AML

AML IS A COMPLEX, HETEROGENEOUS DISEASE DRIVEN BY MULTIPLE GENE MUTATIONS, INCLUDING IDH21,2

In a recent analysis of 200 patients with de novo AML:

>99%

More than 99% had at least 1 mutation associated with the disease, and the majority had multiple mutations3

8%-19%

8% to 19% of people with
AML have an IDH2 mutation4

Despite progress in the understanding of the pathophysiology of AML, prognosis following relapse remains poor.5

  • There is no generally accepted standard of care for patients with R/R AML, and additional approaches for the treatment of these patients are needed6

Testing for IDH2 Mutations

In R/R AML, Targeted Therapy Begins with a Test

THE 2017 CAP-ASH GUIDELINES
recommend testing for IDH2 mutations during diagnostic workup.7

IDH2 is a driver mutation of AML and can be readily detected by molecular profiling.8,9

  • Testing can be performed at diagnosis and relapse in parallel with cytogenetics6
  • Molecular profiling of IDH2 mutations can be performed on bone marrow or peripheral blood using an FDA-approved test

Talk to your pathologist about including IDH2 in your profiling panel

HCP Testing Overview

IDHIFA Mechanism of Action

TAKE A DIFFERENT APPROACH—RELEASE THE BLOCK ON MYELOID DIFFERENTIATION

IDHIFA, the only non-cytotoxic, targeted inhibitor of the mutant IDH2 enzyme, releases the block on myeloid differentiation.

myeloblast
Myeloblast
white blood cell
White blood cell (WBC)
red blood cell
Red blood cell (RBC)
platelet
Platelet

normal IDH2 enzyme The normal IDH2 enzyme converts isocitrate to alpha-ketoglutarate (α-KG), a substrate for enzymes essential to gene expression and myeloid differentiation.10-14

mutated idh2 enzyme Mutated IDH2 converts α-KG to 2-hydroxyglutarate (2-HG), an oncometabolite that leads to a block on myeloid differentiation and results in myeloblast proliferation.10-14

idhifa blocked the conversion of alpha-ketoglutarate to 2-HG In preclinical studies, IDHIFA blocked the conversion of α-KG to 2-HG. In patient blood samples, IDHIFA decreased 2-HG levels and induced myeloid differentiation.15

NORMAL MARROW
DIFFERENTIATION BLOCKED
DIFFERENTIATION RESTORED
myeloblastMyeloblast
white blood cellWhite blood cell (WBC)
red blood cellRed blood cell (RBC)
plateletPlatelet

NORMAL MARROW

normal IDH2 enzyme The normal IDH2 enzyme converts isocitrate to alpha-ketoglutarate (α-KG), a substrate for enzymes essential to gene expression and myeloid differentiation.10-14

DIFFERENTIATION BLOCKED

mutated idh2 enzyme Mutated IDH2 converts α-KG to 2-hydroxyglutarate (2-HG), an oncometabolite that leads to a block on myeloid differentiation and results in myeloblast proliferation.10-14

DIFFERENTIATION RESTORED

idhifa blocked the conversion of alpha-ketoglutarate to 2-HG In preclinical studies, IDHIFA blocked the conversion of α-KG to 2-HG. In patient blood samples, IDHIFA decreased 2-HG levels and induced myeloid differentiation.15

NORMAL MARROW
DIFFERENTIATION BLOCKED
DIFFERENTIATION RESTORED

References:

  1. Estey E, Döhner H. Acute myeloid leukaemia. Lancet. 2006;368(9550):1894-1907.
  2. Burnett A, Wetzler M. Löwenberg B, Therapeutic advances in acute myeloid leukemia. J Clin Oncol. 2011;29(5):487-494.
  3. The Cancer Genome Atlas Research Network. Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia. N Engl J Med. 2013;368(22):2059-2074.
  4. Döhner H, Weisdorf DJ, Bloomfield CD. Acute myeloid leukemia. N Engl J Med. 2015;373(12):1136-1152.
  5. Breems DA, Van Putten WL, Huijgens PC, et al. Prognostic index for adult patients with acute myeloid leukemia in first relapse. J Clin Oncol. 2005;23(9):1969-1978.
  6. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Acute Myeloid Leukemia V.3.2017. © National Comprehensive Cancer Network, Inc. 2017. All rights reserved. Accessed August 25, 2017. To view the most recent and complete version of the guideline, go online to NCCN.org. The National Comprehensive Cancer Network 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.
  7. 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 [published online on February 22, 2017]. Arch Pathol Lab Med. 2017. doi:10.5858/arpa.2016-0504-CP.
  8. Papaemmanuil E, Gerstung M, Bullinger L, et al. Genomic classification and prognosis in acute myeloid leukemia. N Engl J Med. 2016;374(23):2209-2221.
  9. Patel K, 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.
  10. McKenney AS, Levine RL. Isocitrate dehydrogenase mutations in leukemia. J Clin Invest. 2013;123(9):3672-3677.
  11. Su X, Wellen KE, Rabinowitz JD. Metabolic control of methylation and acetylation. Curr Opin Chem Biol. 2016;30:52-60.
  12. Yang H, Ye D, Guan K, et al. IDH1 and IDH2 mutations in tumorigenesis: mechanistic insights and clinical perspectives. Clin Cancer Res. 2012;18(20):5562-5571.
  13. Genetics Home Reference. Your guide to understanding genetic conditions: IDH2 gene. NIH US National Library of Medicine website. https://ghr.nlm.nih.gov/gene/IDH2. Published February 2016. Accessed May 10, 2017.
  14. 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;18:553-567.
  15. Data on file, Celgene Corporation. Summit, New Jersey.

Indication

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.

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Important Safety Information

WARNING: DIFFERENTIATION SYNDROME

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.

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WARNINGS AND PRECAUTIONS

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, as early as 10 days and at 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 1 month after the last dose. Pregnant women, patients becoming pregnant while receiving IDHIFA, or male patients with pregnant female partners should be apprised of the potential risk to the fetus.

ADVERSE REACTIONS

  • 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

LACTATION

Many drugs are excreted in human milk and because of the potential for adverse reactions in breastfed infants, advise women not to breastfeed during treatment with IDHIFA and for at least 1 month after the last dose.

Please see full Prescribing Information, including Boxed WARNING.

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Celgene Commercial Co-pay Program Terms and Conditions

Eligibility

Patients must meet the following criteria to enroll:

  • Covered by commercial or private insurance
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Program Benefits

  • For Celgene oral hematology products, Celgene provides assistance to reduce the co-pay of eligible patients to $25 per prescription with a maximum benefit of $10,000 per enrollment period
  • For Celgene IV products, the Program will cover the co-pay for each prescription of a Celgene product up to a maximum of $10,000 per enrollment period
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