Indicated for the treatment of adult patients with chronic or accelerated phase chronic myeloid leukemia (CML) with resistance and/or intolerance to two or more tyrosine kinase inhibitors (TKI). Learn about Important Safety Information including Warnings and Precautions regarding Myelosuppression, Bleeding, Hyperglycemia, and Embryo-Fetal Toxicity.

SEQUENTIAL TKI USE | IDENTIFYING TKI FAILURE

CML THERAPY AFTER 2 OR MORE TKI FAILURES
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EFFECTIVENESS IN CHRONIC PHASE CML

See the response rates achieved in chronic phase patients   

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EFFECTIVENESS IN ACCELERATED PHASE CML

See the response rates achieved in accelerated phase patients   

Recognize the many roads that may lead to TKI failure

Resistance can lead to discontinuation1

  • If an adequate response is never achieved
  • If response is lost as the disease changes over time

Resistance can be caused by multiple factors1

  • Mutations of the BCR-ABL gene
  • Increased BCR-ABL gene expression
  • Poor treatment adherence
  • Limited bioavailability of medication
  • Quiescent CML stem cells
  • Clonal evolution

Intolerance can also lead to discontinuation2

Monitoring patient response to treatment

  • NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) recommend monitoring patients with CML with quantitative reverse transcriptase polymerase chain reaction (qPCR) every 3 months for all patients after initiating TKI therapy, including those who meet response milestones at 3, 6, and 12 months.
  • After complete cytogenetic response (CCyR) has been achieved, molecular monitoring is recommended every 3 months for 2 years and every 3 to 6 months thereafter.

Monitoring response to TKI therapy and mutational analysis
qPCR = quantitative reverse transcriptase polymerase chain reaction; IS = International Scale
*FISH has seen inadequately studied for monitoring response to treatment.
**NCCN Guidelines® recommend mutational analysis for patients who do not achieve response milestones, any sign of loss of response (hematologic or cytogenetic relapse), and if there is a 1-log increase in BCR-ABL1 level with loss of MMR. Currently there are no specific guidelines for changing therapy based on rising BCR-ABL1 levels as detected by qPCR. Changes of therapy based solely on rising BCR-ABL1 levels should be done only in the context of a clinical trial.


Response criteria
aFaderl S et al: Chronic myelogenous leukemia: Biology and therapy. Ann Intern Med 1999;131:207-219. The American College of Physicians-American Society of Internal Medicine is not responsible for the accuracy of the translation.
bA minimum of 20 metaphases should be examined.
cO'Brien SG, Guilhot F, Larson RA, et al. Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med 2003;348:994-1004.
dCCyR typically correlates with BCR-ABL1 (IS) ≤1% (>0.1%–1%).
eHughes TP, Kaeda J, Branford S, et al. Frequency of major molecular responses to imatinib or interferon alfa plus cytarabine in newly diagnosed chronic myeloid leukemia. NEngl J Med 2003;349:1423-1432.
fHughes T, Deininger M, Hochhaus A, et al. Monitoring CML patients responding to treatment with tyrosine kinase inhibitors: review and recommendations for harmonizing current methodology for detecting BCR-ABL transcripts and kinase domain mutations and for expressing results. Blood 2006;108:28-37.


Response milestones
aPatients with BCR-ABL1 only slightly >10% at 3 months and/or with a steep decline from baseline, may achieve <10% at 6 months and have generally favorable outcomes. Therefore, it is important to interpret the value at 3 months in this context, before making drastic changes to the treatment strategy.


Clinical considerations and treatment options
Adapted with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Chronic Myeloid Leukemia V.4.2018. © 2018 National Comprehensive Cancer Network, Inc. All rights reserved. The NCCN Guidelines® and illustrations herein may not be reproduced in any form for any purpose without the express written permission of NCCN. To view the most recent and complete version of the NCCN Guidelines, go online to NCCN.org. The NCCN Guidelines are a work in progress that may be refined as often as new significant data becomes available.

aAchievement of response milestones must be interpreted within the clinical context. Patients with more than 50% reduction compared to baseline or minimally above the 10% cutoff can continue the same dose of TKI for another 3 months.
bDiscontinuation of TKI with careful monitoring is feasible in selected patients.

Consider a protein synthesis inhibitor after resistance or intolerance to 2 or more TKIs

While SYNRIBO®, a protein synthesis inhibitor, was studied in patients with resistance, the effectiveness was not evaluated at the level of underlying causes of resistance

Omacetaxine mepesuccinate (SYNRIBO®) is a recommended treatment option by the NCCN Guidelines for patients with disease that is resistant and/or intolerant to 2 or more TKIs.2

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.

Indication

  • SYNRIBO®® (omacetaxine mepesuccinate) for injection, for subcutaneous use, is indicated for the treatment of adult patients with chronic or accelerated phase chronic myeloid leukemia (CML) with resistance and/or intolerance to two or more tyrosine kinase inhibitors (TKI)

Important Safety Information

Warnings and Precautions

  • Myelosuppression: Patients with chronic phase and accelerated phase CML who used SYNRIBO experienced severe and fatal myelosuppression including thrombocytopenia, neutropenia, and anemia. Patients with neutropenia are at increased risk for infections, and should be monitored frequently and advised to contact a physician if they have symptoms of infection or fever. Monitor complete blood counts weekly during induction and initial maintenance cycles and every two weeks during later maintenance cycles, as clinically indicated
  • Bleeding: SYNRIBO causes severe thrombocytopenia which increases the risk of hemorrhage. Fatalities from cerebral hemorrhage have occurred. Severe, non-fatal gastrointestinal hemorrhages have also occurred. Monitor platelet counts as part of the complete blood count (CBC) monitoring as recommended. Avoid anticoagulants, aspirin, and non-steroidal anti-inflammatory drugs (NSAIDs) when the platelet count is <50,000/µL as they may increase the risk of bleeding
  • Hyperglycemia: SYNRIBO can induce glucose intolerance. Monitor blood glucose levels frequently, especially in patients with diabetes or risk factors for diabetes. Avoid SYNRIBO in patients with poorly controlled diabetes mellitus until good glycemic control has been established
  • Embryo-Fetal Toxicity: SYNRIBO can cause fetal harm when administered to a pregnant woman. Women should be advised to avoid becoming pregnant while using SYNRIBO

Adverse Reactions

  • Serious adverse reactions (frequency ≥5%) in chronic phase patients: bone marrow failure, thrombocytopenia, febrile neutropenia, and infections
  • Serious adverse reactions (frequency ≥5%) in accelerated phase patients: febrile neutropenia, thrombocytopenia, anemia, diarrhea, and infections
  • Most common adverse reactions (frequency ≥20%) in chronic and accelerated phase patients: thrombocytopenia, anemia, neutropenia, diarrhea, nausea, fatigue, asthenia, injection site reaction, pyrexia, infection, and lymphopenia
TO REPORT SIDE EFFECTS: Contact us at 1-800-896-5855 or USMedInfo@tevapharm.com
References
  1. Karvela M, Helgason GV, Holyoake TL. Mechanisms and novel approaches in overriding tyrosine kinase inhibitor resistance in chronic myeloid leukemia. Expert Rev Anticancer Ther. 2012;12:381-392.
  2. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Chronic Myeloid Leukemia V.4.2018 – January 28, 2018. ©National Comprehensive Cancer Network, Inc. 2018. All rights reserved. Accessed April 17, 2018. To view the most recent and complete version of the guideline, go online to NCCN.org.