In Newly Diagnosed CML, Missed or Reduced Doses of Imatinib or Dasatinib Within First 3 Months Associated With Poorer Molecular Response and More Treatment Discontinuation

 

In Newly Diagnosed CML, Missed or Reduced Doses of Imatinib or Dasatinib Within First 3 Months Associated With Poorer Molecular Response and More Treatment Discontinuation



• Subanalysis of SPIRIT2: open-label, randomized phase III trial[1]
Summary of Key Conclusions
• Treatment interruption or dose reductions within first 3 months of treatment with the tyrosine kinase inhibitors (TKIs) dasatinib or imatinib affect outcomes in patients with newly diagnosed chronic myeloid leukemia (CML)
o Reduced likelihood of achieving molecular responses at 3 and 12 months
o Higher chance of ongoing dose reductions
o Increased likelihood of discontinuing treatment
• Molecular response to dasatinib or imatinib at 3 months associated with increased likelihood of deeper molecular responses (BCR-ABL < 1% on International Scale [IS] or BCR-ABL < .1%IS) at 12 months
• Dasatinib induces higher rate of molecular response than imatinib at 3 and 12 months but also associated with higher rate of missed or reduced doses
• Results will inform study design of SPIRIT3 trial studying switch to ponatinib following imatinib or nilotinib
Background
• In patients with CML receiving TKI treatment, tumor load reductions within first 3 months of treatment (MR1: BCR-ABL < 10%IS) associated with better outcomes[2]
• Treatment interruptions or dose reductions used to manage cytopenias in 15% to 20% of newly diagnosed patients receiving TKI
• Current analysis investigated effect on molecular response of missed treatment days and average dosing during first 3 months of treatment in patients with newly diagnosed CML randomized to receive imatinib or dasatinib[1]
Schematic of Study Design

 


Eligibility
• Newly diagnosed CML (N = 814)
• Completed 3 months of therapy
Description of Current Analysis
• Intent-to-treat (ITT) analysis of 12-month molecular responses based on 3-month BCR-ABL levels
o MR1 (BCR-ABL < 10%IS) at 3 months
o MR2 (BCR-ABL < 1%IS) at 12 months
o MR3 (BCR-ABL < .1%IS) at 12 months
• Dosing parameters
o Imatinib or dasatinib
o 0, 1-14, or > 14 missed treatment days during first 3 months
o Average dose received during first 3 or 12 months
• Primary endpoint: 5-year event-free survival
• Secondary endpoints
o 3-month BCR-ABL < 10%[IS] by real-time quantitative polymerase chain reaction (RQ-PCR)
o Complete cytogenetic response at 12 months, using BCR-ABL <1%IS by RQ-PCR as proxy
o Adverse events
Main Findings
• BCR-ABL transcripts < 10% at 3 months associated with increased likelihood of deeper molecular responses (BCR-ABL < 1% and BCR-ABL < .1%) at 12 months in ITT population
o BCR-ABL < 10% at 3 months higher in patients receiving dasatinib (91%) than imatinib (75%)


• Reduced or missed TKI doses during first 3 months of treatment decrease likelihood of achieving molecular response
o Dasatinib associated with more missed or reduced doses than imatinib but also achieved higher rate of molecular response at both time points
o Higher potency of dasatinib may compensate for missed doses
• Molecular response at 3 months


• Molecular response at 12 months


• Missed doses during first 3 months increase likelihood of treatment discontinuation and reduce ability to take the medicine consistently for Months 3-12


References
1. Apperley JF, Szydlo RM, Gerrard G, et al. Dose interruption/reduction of tyrosine kinase inhibitors in the first 3 months of treatment of CML is associated with inferior early molecular responses and predicts for an increased likelihood of discontinuation of the first line agent. Program and abstracts of the 55th American Society of Hematology Annual Meeting and Exposition; December 7-10, 2013; New Orleans, Louisiana. Abstract 93.
2. Marin D, Ibrahim AR, Lucas C, et al. Assessment of BCR-ABL 1 transcript levels at 3 months is the only requirement for predicting outcome for patients with chronic myeloid leukemia treated with tyrosine kinase inhibitors. J Clin Oncol. 2012;30:232-238.

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