Identifying and Managing TKI Resistance in CP-CML

Failure to meet and maintain key response milestones may indicate TKI resistance

According to the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®), there are critical molecular response milestones in CP-CML that indicate the likelihood of TKI resistance in patients.1

Early treatment response milestones from NCCN.

aBCR::ABL1 ≤0.1% at 12 months is associated with a very low probability of subsequent loss of response and a high likelihood of achieving a subsequent deep molecular response (DMR MR4.0; ≤0.01% BCR::ABL1IS), which is a prerequisite for a trial of treatment-free remission.

bIf treatment goal is long-term survival: BCR::ABL1≤1% at 12 months is optimal; if treatment goal is treatment-free remission: BCR::ABL1≤0.1% at 12 months is optimal.

cPatients 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.

Adapted with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Chronic Myeloid Leukemia V.1.2023. ©2022 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 The NCCN Guidelines are a work in progress that may be refined as often as new significant data becomes available. 

These milestones are roughly based on BCR::ABL1IS levels over treatment time2

  • In primary TKI resistance, patients fail to achieve an initial response and their BCR::ABL1IS levels remain high or continue to rise within 3-12 months
  • Secondary TKI resistance can occur at any point when a previous effective regimen loses its therapeutic effect and BCR::ABL1IS levels rise above acceptable levels

An expert perspective

Managing TKI Resistance in CP-CML

Javier Pinilla-Ibarz,* MD, PhD, the Head of the Lymphoma Section at the Moffitt Cancer Center, defines and discusses TKI resistance.d

dDisclaimer: This is a promotional non-CME program intended only for healthcare professionals involved in the treatment of CP-CML.

Javier Pinilla-Ibarz, MD, PhD is a paid consultant of Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited (Takeda Oncology). This video is intended for informational purposes only and is not a substitute for your clinical knowledge or professional judgment. The views and opinions expressed in this video are those of the presenter and Takeda Oncology and do not necessarily reflect the opinions of the Lymphoma Section at the Moffitt Cancer Center.

Status of TKI-resistance should inform treatment selection — NCCN Guidelines Recommendations1

For TKI-resistant disease  

Switch to an alternate TKI and evaluate patient for allogeneic hematopoietic cell transplantation.

For possible TKI resistance

Switch to another TKI or continue the same TKI (with the exception of imatinib) and consider allogeneic hematopoietic cell transplantation.

For TKI-sensitive disease and non-optimal BCR::ABL1IS levels

Doctors may share decision-making with the patient to determine a treatment plan.e,f

For TKI-sensitive disease and optimal BCR::ABL1IS levels

Stay on current TKI.

eSwitching from imatinib to a 2G TKI improves response, but is associated with increased toxicity.
fConsider referral to a specialized CML center and/or enrollment in a clinical trial.

A patient's CP-CML mutational status should inform TKI selection1  

Single-point mutations in BCR::ABL1 can impair a TKI’s functionality and lead to resistance.1-3 All TKIs, except ponatinib,g have known mutations that can impair their ability to inhibit BCR::ABL11

gBrand name is ICLUSIG®

Response-based efficacy data for ICLUSIG

The impact of the T315I mutation on survival and more

Which CP-CML patients are appropriate for ICLUSIG?