For:
Newly Diagnosed FLT3+ Acute Myeloid Leukemia (AML)
Important Safety Information:

CONTRAINDICATIONS
Do not use in patients with hypersensitivity to midostaurin or its excipients. Hypersensitivity reactions have included anaphylactic shock, dyspnea, flushing, chest pain, and angioed…

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Indication: RYDAPT is indicated, in combination with standard cytarabine and daunorubicin induction and cytarabine consolidation chemotherapy, for the treatment of adult patients with newly diagnosed acute myeloid leukemia (AML) who are FLT3 mutation–positive, as detected by an FDA-approved test.

Limitations of Use
RYDAPT is not indicated as a single-agent induction therapy for the treatment of patients with AML.

FLT3 Testing

FLT3 Mutation Testing

PROMPT, COMPREHENSIVE TESTING FOR FLT3 MUTATIONS MAKES A DIFFERENCE

Identifying FLT3 - Time Is of the Essence

 

 

FLT3+: prognosis and survival is poor

FLT3+: prognosis and survival is poor

  • Approximately 30% of all patients with AML are FLT3+1,2
  • Patients with FLT3+ ITD AML have a worse prognosis, with higher rates of relapse and lower rates of survival than the overall AML population3-5
  • FLT3+ TKD AML 5-year survival is 53%5
  • FLT3+ ITD AML 5-year survival rate is as low as 15%4,6

Get patients tested

Get patients tested

  • Complete FLT3 mutation testing is important to identify appropriate patients for targeted treatment options7-9
    • NCCN Guidelines® for AML recommend molecular genetic testing for AML mutations during the initial patient workup to establish the diagnosis7
  • LeukoStrat® CDx FLT3 Mutation Assay is the only FDA-approved FLT3 companion diagnostic test for AML*10,11

21,830 estimated new cases of AML in 201713

Approximately 41% of patients with AML did not receive FLT3 mutation testing, based on a 2016 survey of oncologists and pathologists (n=75) and 192 AML patient record.14†

  • These patients may not be identified for treatment with a FLT3 inhibitor.

Clinical recommendations for AML testing from the College of American Pathologists-American Society of Hematology (CAP-ASH) Guidelines and the NCCN Guidelines1,7

Genetic testing and screening recommendations from CAP-ASH and NCCN

aFor adult patients with confirmed core binding factor (CBF) AML (AML with t(8;21)(q22;q22.1); RUNX1-RUNX1T1 or inv(16)(p13.1q22) /t(16;16)(p13.1;q22); CBFB-MYH11), the pathologist or treating clinician should ensure that appropriate mutational analysis for KIT is performed. For patients other than those with confirmed CBF-AML, acute promyelocytic leukemia, or AML with myelodysplasia-related cytogenetic abnormalities, the pathologist or treating clinician should also ensure that mutational analysis for NPM1, CEBPA, and RUNX1 is also performed.

The CAP-ASH Guidelines represent the first joint recommendations produced by these two organizations for the initial diagnostic workup of acute leukemia.1

“The accurate classification of AML requires multidisciplinary diagnostic studies using immunohistochemistry, cytochemistry, or both, in addition to molecular genetics analysis.” 7

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.

WHY: FLT3 Is a Selective Marker

FLT3 receptor

Only patients newly diagnosed as FLT3 positive (FLT3+) with ITD or TKD mutations may be eligible to receive RYDAPT® (midostaurin) capsules. FLT3+ status is a prerequisite.10

In vitro, RYDAPT demonstrated the ability to inhibit FLT3 receptor signaling and cell proliferation, and it induced apoptosis in leukemic cells expressing ITD or TKD mutant FLT3 receptors or overexpressing wild-type FLT3 and PDGF receptors.10

WHO: Every Patient With Newly Diagnosed AML

Patient

All patients with newly diagnosed AML should have a FLT3 test because approximately 30% of all patients with AML are FLT3+.1,2

Patients newly diagnosed with FLT3+ AML with ITD or TKD mutations were enrolled in the RATIFY trial.10

WHEN: At Diagnosis

In parallel with cytogenetics.1 Results are needed at Day 8 after start of induction chemotherapy.10

At diagnosis, testing for FLT3 ITD or TKD should be performed in parallel with morphology evaluation, immunophenotyping (flow cytometry), cytogenetics FISH, and molecular studies (optional)

The LeukoStrat® CDx FLT3 Mutation Assay is selective and must be performed up front at diagnosis in parallel with cytogenetics to allow results in time for treatment decisions.1,10,12

HOW: Use the FDA-Approved FLT3 Mutation Test

The LeukoStrat® CDx FLT3 Mutation Assay* is used as an aid in the selection of patients with AML for RYDAPT treatment.10 Send out samples early to ensure fast and complete test results.

Sample Types
Collection Tubes
Storage and Shipment

*FLT3 mutation testing is performed by The Laboratory for Personalized Molecular Medicine (LabPMM), a subsidiary of Invivoscribe Technologies, Inc., which has gained FDA approval for its FLT3 test as a companion diagnostic for RYDAPT in newly diagnosed FLT3+ AML. Laboratory for Personalized Molecular Medicine® is a registered trademark of Invivoscribe Technologies, Inc.

Derived from an Ipsos Oncology MDx Biomarker testing in AML study (October-November 2016).

Samples must be received by LabPMM within a maximum of 4 days after collection. LabPMM usually delivers results in 2 to 3 days after the sample is received.

ATP, adenosine triphosphate; EDTA, ethylenediaminetetraacetic acid; FISH, fluorescence in situ hybridization; FLT3, FMS-like tyrosine kinase 3; ITD, internal tandem duplication; PDGF, platelet-derived growth factor receptor; TKD, tyrosine kinase domain.

 

References:
 
  1. 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.
  2. Levis M. FLT3 mutations in acute myeloid leukemia: what is the best approach in 2013? Hematology Am Soc Hematol Educ Program. 2013;2013:220-226.
  3. Ferrara F, Schiffer CA. Acute myeloid leukaemia in adults. Lancet. 2013;381(9865):484-495.
  4. Gale RE, Green C, Allen C, et al. The impact of FLT3 internal tandem duplication mutant level, number, size, and interaction with NPM1 mutations in a large cohort of young adult patients with acute myeloid leukemia. Blood. 2008;111(5):2776-2784.
  5. Mead AJ, Linch DC, Hills RK, Wheatley K, Burnett AK, Gale RE. FLT3 tyrosine kinase domain mutations are biologically distinct from and have a significantly more favorable prognosis than FLT3 internal tandem duplications in patients with acute myeloid leukemia. Blood. 2007;110(4):1262-1270.
  6. Fathi AT, Chabner BA. FLT3 inhibition as therapy in acute myeloid leukemia: a record of trials and tribulations. Oncologist. 2011;16(8):1162-1174.
  7. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Acute Myeloid Leukemia V.3.2021. © National Comprehensive Cancer Network, Inc. 2021. All rights reserved. Accessed May 15, 2021. To view the most recent and complete version of the guideline, go online to NCCN.org.
  8. Patel JP, Gönen M, Figueroa ME, et al. Prognostic relevance of integrated genetic profiling in acute myeloid leukemia. N Engl J Med. 2012;366(12):1079-1089.
  9. De Kouchkovsky I, Abdul-Hay M. Acute myeloid leukemia: a comprehensive review and 2016 update. Blood Cancer J. 2016;6(7):e441.
  10. Rydapt [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corp; 2021.
  11. U.S. Food and Drug Administration. List of Cleared or Approved Companion Diagnostic Devices (In Vitro and Imaging Tools). Available at: http://www.fda.gov/CompanionDiagnostics. Accessed November 1, 2019.
  12. Leukostrat® CDx FLT3 Mutation Assay technical flyer. Invivoscribe website. https://www.invivoscribe.com/uploads/products/informationalDownloads/LabPMM-Flyer_Leukostrat-CDx_FLT3_8.5x11_20170420.pdf. Accessed November 6, 2017.
  13. National Cancer Institute. SEER Cancer Stat Facts: Acute Myeloid Leukemia (AML). http://seer.cancer.gov/statfacts/html/amyl.html. Accessed November 6, 2017.
  14. Data on file. Ipsos Oncology MDx: biomarker testing in AML: US 2016 Q4. Novartis Pharmaceuticals Corp; 2016.

INDICATION for RYDAPT® (midostaurin) capsules

Acute Myeloid Leukemia
RYDAPT is indicated, in combination with standard cytarabine and daunorubicin induction and cytarabine consolidation chemotherapy, for the treatment of adult patients with newly diagnosed acute myeloid leukemia (AML) who are FLT3 mutation–positive, as detected by an FDA-approved test.

Limitations of Use
RYDAPT is not indicated as a single-agent induction therapy for the treatment of patients with AML.

IMPORTANT SAFETY INFORMATION for RYDAPT® (midostaurin) capsules

CONTRAINDICATIONS
  • Do not use in patients with hypersensitivity to midostaurin or its excipients. Hypersensitivity reactions have included anaphylactic shock, dyspnea, flushing, chest pain, and angioedema
WARNINGS AND PRECAUTIONS
Embryo-Fetal Toxicity
  • Do not use during pregnancy. Midostaurin caused severe embryo-fetal abnormalities and death in animal studies
  • Verify pregnancy status of females of reproductive potential within 7 days prior to initiating RYDAPT
  • Advise females of reproductive potential to use effective contraception during treatment and for at least 4 months after the last dose
  • Males taking RYDAPT should use effective contraception with females of reproductive potential and pregnant women and for at least 4 months after the last dose
  • Pregnancy exposure registry to monitor pregnancy outcomes: Females who may have been exposed to RYDAPT during pregnancy, directly or through a male partner receiving RYDAPT, should contact Novartis Pharmaceuticals Corporation at 1-888-669-6682 and/or at https://report.novartis.com/
Pulmonary Toxicity
  • Cases of interstitial lung disease and pneumonitis, some fatal, have occurred in patients treated with RYDAPT as monotherapy or with chemotherapy
  • Monitor patients for pulmonary symptoms. Discontinue RYDAPT in patients who experience signs or symptoms of interstitial lung disease or pneumonitis without an infectious etiology
Risk of Prolonged Severe Neutropenia and Thrombocytopenia in Pediatric Patients Treated With Combination Chemotherapy
  • Prolonged (≥44 days) grade 4 neutropenia and thrombocytopenia were reported in 2 pediatric patients with FLT3 mutation-positive AML treated with midostaurin and combination chemotherapy. An azole antifungal (a strong CYP3A4 inhibitor) was coadministered which may increase midostaurin concentrations and risk of toxicity
  • The safety and effectiveness of RYDAPT in pediatric patients have not been established
ADDITIONAL CONSIDERATIONS
Lactation
  • Because of the potential for serious adverse reactions in breastfed infants from RYDAPT, advise women not to breastfeed during treatment with RYDAPT and for at least 4 months after the last dose
Infertility
  • Based on findings in animals, RYDAPT may impair fertility in females and males of reproductive potential. It is unknown whether these effects on fertility are reversible
Drug Interactions
  • Strong CYP3A Inducers: Avoid concomitant use as strong CYP3A4 inducers decrease exposure to midostaurin and may reduce efficacy
  • Strong CYP3A Inhibitors: Coadministration with strong CYP3A4 inhibitors may increase midostaurin concentrations and may increase the risk of toxicity. Monitor patients for increased risk of adverse reactions, especially during the first week of RYDAPT use in each chemotherapy cycle and the first week of consecutive RYDAPT administration. Consider alternative therapies that do not strongly inhibit CYP3A4 activity
  • CYP2B6, BCRP, OATP1B1 Substrates: RYDAPT decreased the systemic exposure of a sensitive CYP2B6 substrate. Coadministration of RYDAPT increased the exposure of a breast cancer resistance protein (BCRP) and organic anion transporter polypeptide (OATP)1B1 substrate. Dose adjustments for coadministered CYP2B6, BCRP, or OATP1B1 substrates may be necessary with RYDAPT
ADVERSE REACTIONS
Acute Myeloid Leukemia
  • Most common adverse reactions (≥20%) were febrile neutropenia (83%), nausea (83%), mucositis (66%), vomiting (61%), headache (46%), petechiae (36%), musculoskeletal pain (33%), epistaxis (28%), device-related infection (24%), hyperglycemia (20%), upper respiratory tract infection (20%), and electrocardiogram QT prolonged (20%)
  • Most frequent grade 3/4 adverse reactions (≥10%) were febrile neutropenia (84%), device-related infection (16%), and mucositis (11%)
  • Most common (≥10%) laboratory abnormalities were hypolcalcemia (74%), alanine aminotransferase increase (71%), and hypernatremia (21%)

Please see full Prescribing Information for RYDAPT® (midostaurin) capsules.

*Aggressive systemic mastocytosis (ASM), systemic mastocytosis with an associated hematological neoplasm (SM-AHN), and mast cell leukemia (MCL) are collectively referred to as advanced systemic mastocytosis (SM).