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.

Efficacy

Trial Design

Confidence from the Largest Phase 3 Trial in FLT3+ AML

RATIFY was a phase 3, randomized, double-blind, placebo-controlled study performed in partnership with the Alliance for Clinical Trials in Oncology1,2

Efficacy Trial Design

*Transplantation was allowed but not specifically mandated per study protocol. Patients who proceeded to hematopoietic stem cell transplantation (SCT) stopped receiving study treatment, but all patients were followed for survival.1

Efficacy and safety were evaluated through all phases of the study1,2
  • Included in the study were 717 adults with newly diagnosed FLT3+ AML1
  • RYDAPT® (midostaurin) capsules plus standard cytarabine and daunorubicin induction and high-dose cytarabine consolidation chemotherapy (n=360) was compared with standard chemotherapy plus placebo (n=357), followed by continuous RYDAPT or placebo treatment according to initial assignment for up to 12 additional 28-day cycles1
    • A second course of induction was administered to 25% of patients, 62% initiated at least 1 cycle of consolidation, 29% initiated maintenance, and 17% completed all 12 planned cycles of maintenance; 21% of patients underwent SCT in first CR
  • The primary end point in RATIFY was OS, which was measured from the date of randomization until death by any cause. There was no re-randomization at the start of postconsolidation therapy and, therefore, there was no assessment of the efficacy of RYDAPT in this stage alone1
  • The primary analysis was conducted after a minimum follow-up of approximately 3.5 years following randomization of the last patient1
  • Secondary end points included EFS and the toxicity of RYDAPT plus chemotherapy1,2
  • Patients with acute promyelocytic leukemia or therapy-related AML were not eligible1
  • Patents who proceeded to hematopoietic stem cell transplantation (SCT) stopped receiving study treatment1
  • All patients were followed for survival1

Overall Survival

Prescribe the Only Treatment With Significant and Sustained Survival Benefits vs Standard Chemotherapy.

Significant efficacy demonstrated in combination with standard cytarabine and daunorubicin induction and cytarabine consolidation vs standard chemotherapy with placebo.

Overall Survival
  • Because survival curves plateaued before reaching the median, median survival could not be reliably estimated1
  • OS was measured from the date of randomization until death by any cause1

Event-Free Survival

Greater EFS with RYDAPT plus standard chemotherapy vs standard chemotherapy plus placebo1
Event-Free Survival 60 days
  • An EFS event was defined as a failure to obtain a complete remission (CR) within 60 days of initiation of protocol therapy, relapse, or death from any cause1
Event-Free Survival Anytime
  • An exploratory analysis of EFS, defined as a failure to obtain a CR anytime during induction, relapse, or death from any cause, with failures assigned as an event on study day 11

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+4,5
  • Patients with FLT3+ ITD AML have a worse prognosis, with higher rates of relapse and lower rates of survival than the overall AML population6-9
  • FLT3+ TKD AML 5-year survival is 53%8
  • FLT3+ ITD AML 5-year survival rate is as low as 15%7,9

Get patients tested

Get patients tested

  • Complete FLT3 mutation testing is important to identify appropriate patients for targeted treatment options10,11
    • NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for AML recommend molecular genetic testing for AML mutations during the initial patient workup to establish the diagnosis3
  • LeukoStrat® CDx FLT3 Mutation Assay is the only FDA-approved FLT3 companion diagnostic test for AML*1,12
Prompt, comprehensive testing makes a difference.

 

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.

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.

bid, twice daily; EFS, event-free survival; FLT3, FMS-like tyrosine kinase 3; ITD, internal tandem duplication; OS, overall survival; TKD, tyrosine kinase domain; National Comprehensive Cancer Network® (NCCN®).

References:
  1. Rydapt [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corp; 2021.
  2. Date on file. Study no. CPKC412A2301. Novartis Pharmaceuticals Corp; 2016.
  3. 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.
  4. 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.
  5. 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.
  6. Ferrara F, Schiffer CA. Acute myeloid leukaemia in adults. Lancet.2013;381(9865):484-495.
  7. 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.
  8. 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.
  9. Fathi AT, Chabner BA. FLT3 inhibition as therapy in acute myeloid leukemia: a record of trials and tribulations. Oncologist. 2011;16(8):1162-1174.
  10. 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.
  11. De Kouchkovsky I, Abdul-Hay M. Acute myeloid leukemia: a comprehensive review and 2016 update. Blood Cancer J. 2016;6(7):e441.
  12. 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.

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).