• Many patients experience resistance to TKI treatment, requiring a switch to an alternative TKI.1,2
  • According to European LeukemiaNet (ELN) recommendations, resistance is the failure to achieve BCR-ABL1 ≤1% (complete cytogenetic response [CCyR]) at 12 months of 1L or 2L treatment.1,3
  • Resistance rates remain high during 2L treatment also:

 

60_70 percent

60–70% of patients fail to achieve MMR4

50–56 percent

50–56% of patients fail to achieve CCyR4

Image: Illustration of a patient and doctor standing side-by-side, the doctor placing a reassuring hand on the patient.
 
  • Existing guidelines from the ELN, National Comprehensive Cancer Network (NCCN), and British Society for Haematology (BSH) provide important information on treatment and monitoring of response for 1L and 2L therapies.1,5,6

Icon 1: Patient.

Patients on TKI therapy should be monitored every 3 months until achieving a stable MMR and at 3–6-monthly intervals afterwards1,5,6

Icon 2: Tablets.

Tolerance to treatment should also be regularly monitored1,5,6

Icon 3: Doctor.

Close monitoring of both response and tolerance to treatment is essential to avoid giving patients suboptimal/ inappropriate treatment1,5,6

 

Optimal Treatment Response Milestones

Table 1: Optimal treatment response milestones for 1L and 2L TKI therapy as per ELN recommendations1 

  OPTIMAL
BCR-ABL1 IS LEVEL
WARNING
BCR-ABL1 IS LEVEL
WARNING
BCR-ABL1 IS LEVEL
BASELINE NA High-risk ACA, high-risk ELTS score NA
3 MONTHS ≤10% >10% >10% if confirmed within 1–3 months
6 MONTHS ≤1% >1%–10% >10%
12 MONTHS ≤0.1% (MMR) >0.1%–1% >1%
ANY TIME ≤0.1% >0.1%–1%

Loss of MMRa
>1%, resistance mutations, high-risk ACA

ACA, additional chromosome abnormalities in Ph+ cells; ELTS, EUTOS long-term survival score; IS, international scale; MMR, major molecular response; NA, not applicable; TFR, treatment-free remission.
For patients aiming at TFR, the optimal response (at any time) is BCR-ABL1 ≤ 0.01% (MR4).
A change of treatment may be considered if MMR is not reached by 36–48 months.
aLoss of MMR (BCR-ABL1 > 0.1%) indicates failure after TFR
Table adapted from Hochhaus A, et al. Leukemia. 2020;34:966–84.

Click here for more information on optimal molecular response monitoring

 

Emergence of new mutations can be problematic

  • Sequential treatment with TKIs can result in the emergence of new mutations, which in turn can decrease patient sensitivity to other TKIs.4
  • More than 100 different BCR-ABL1 kinase domain mutations that affect TKI binding have been reported.7     
  • The BCR-ABL1 T315I gate-keeper mutation is resistant to all approved ATP binding site-targeting TKIs, except ponatinib.4 
  • Patients who develop new mutations in later lines of therapy have fewer treatment options due to limited sensitivity to remaining TKIs.4

 

Guidelines are key for better treatment outcomes

  • It is possible that ELN and BSH monitoring recommendations may not be consistently implemented.8,9
    • Patients did not have assessments at recommended intervals     
    • Monitoring was conducted less frequently than recommended
    • Real-world evidence showed that although sensitivity monitoring is recommended, it is not always performed10
  • Patients without frequent molecular monitoring are at higher risk of disease progression,8,9 so it is crucial to follow ELN and BSH monitoring and treatment recommendations.
  • There is a lack of precise treatment guidelines for patients failing 2L therapy.4

 

Important considerations for personalised care

  • Several factors affect the choice of TKI for treatment, including line of treatment (frontline vs later lines), Sokal risk score, additional mutations/aberrations, age, co-morbidities, and cardiovascular risk factors.
  • Treatment should be tailored to each patient’s specific profile to increase the likelihood of response and minimise AEs.7     
  • In addition, since several different mutations result in treatment resistance, selecting the right drug for a particular patient is imperative.

 

Guidelines and recommendations

ELN 2020 guidelines: https://www.nature.com/articles/s41375-020-0776-2

BSH 2020 guidelines: https://onlinelibrary.wiley.com/doi/full/10.1111/bjh.16971

 

References:

  1. Hochhaus A, et al. Leukemia. 2020;34:966–84.
  2. Hochhaus A, et al. Leukemia. 2020;34:1495–1502. 
  3. Baccarani M, et al. Blood. 2013;122(6):872–884. 
  4. Cortes J, et al. J Hematol Oncol. 2021;14(1):44.
  5. National Comprehensive Cancer Network. NCCN: Clinical practice guidelines in oncology. Chronic Myeloid Leukemia V2.2021.
  6. Smith G, et al. Br J Haematol. 191:171–193.
  7. Hochhaus A, et al. Ann Oncol. 2017;28(Suppl 4):iv41–iv51.
  8. Milojkovic D, et al. Br J Haematol. 2021;192:62–74.
  9. Goldberg S, et al. J Oncol Pract. 2015;11. 10.1200/JOP.2014.001099.
  10. Atallah EL, et al. J Clin Oncol. 2020;38(15):7548.
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