Primary Treatment for Patients in Chronic Phase

There are 4 TKIs licensed for use in patients with newly diagnosed CML in the United Kingdom, including:

  • Imatinib (first generation TKI)
  • Bosutinib (second generation TKI)
  • Dasatinib (second generation TKI)
  • Nilotinib (second generation TKI)

Large randomized phase 3 trials have compared the second-generation agents to imatinib and have demonstrated similar results. Most patients diagnosed with CML will have a life expectancy similar to that of the normal population and will likely die of non-CML related causes. Certain patient populations in chronic phase may particularly benefit from second-generation TKIs as frontline therapy (Table 3), including:


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  • Those with high or intermediate ELTS or Sokal scores in whom a reduction in disease progression has been demonstrated with a first-line second-generation TKI
  • Women who wish to have children, where the more rapid molecular response achieved with a second-generation agent is desirable
  • ‘Younger’ patients, nominally the under 30s, and children, who are excellent candidates for stem cell transplantation if the need arises, and in whom concerns have been raised regarding more aggressive disease at presentation

However, early use of a second-generation TKI should be balanced against the risk of exacerbating comorbid conditions, particularly in older patients who exhibit a greater number of comorbidities.

Table 3. Selected Recommendations by the BSH Guideline Panel on Primary Therapy for Patients in Chronic Phase1

RecommendationGRADE Criteria
Imatinib is the recommended first-line treatment for the majority of adults and children with CML presenting in CPGrade 1A
All patients should have baseline assessment with an ECG, lipid profile, fasting glucose or HbA1c, CVD risk assessment, and hepatitis B and C screeningGrade 2B
Comorbidities should be assessed to help in the choice of second-generation TKIGrade 2B
Abbreviations: BSH, British Society for Haematology; CML, chronic myeloid leukemia; CP, chronic phase; CVD, cardiovascular disease; ECG, electrocardiogram; GRADE, Grading of Recommendations Assessment; HbA1c, glycated hemoglobin A1c; TKI, tyrosine kinase inhibitor.

Resistance or Intolerance to First-Line Therapy

In cases of primary resistance or intolerance to imatinib, any of the second-generation TKIs may be used (Table 4). There are no studies directly comparing second-generation agents in this setting, but all 3 available agents have demonstrated efficacy in the absence of specific mutations, with up to 40% of patients achieving durable complete cytogenetic response.

Table 4. Selected Recommendations by the BSH Guideline Panel on Management of Patients Who Are Resistant to or Intolerant of First-Line Therapy1

RecommendationGRADE Criteria
Change to an alternative TKI should be considered if treatment failure on first-line therapy is documentedGrade 1A
The choice of second-line therapy in resistant patients is initially guided by BCR-ABL1 KD mutational analysisGrade 1B
Dose escalation to 600 mg/d of imatinib is reasonable for patients with a suboptimal response meeting the ELN ‘warning’ criteria and with good tolerance of the standard doseGrade 2B
In the absence of specific mutations the patients pre-existing comorbidities and the known side effect profiles of the second-generation TKIs should inform the treatment choiceGrade 2B
Abbreviations: ELN, European LeukemiaNet; GRADE, Grading of Recommendations Assessment; KD, kinase domain; TKI, tyrosine kinase inhibitor.

Other Recommendations and Concluding Remarks

The guideline authors also included recommendations on the management of patients with advanced-phase disease (accelerated phase and blast crisis), side effects of TKIs and their management, allogeneic stem cell transplantation in CML, CML and parenting, and the possibility for discontinuing treatment in some patients.

In an interview, Jane Apperley, MD, of Imperial College, London, and co-author of the guidelines explained that “[Currently], we’re using virtual educational meetings, internationally, nationally and locally to help explain and update colleagues [on the new guidelines], and an additional very important voice belongs to our patients.”

She concluded, “They too should be asking for their physicians to be performing to the highest standards.”

To read the comprehensive list of recommendations containing qualifying remarks, readers should refer to the full publication in the British Journal of Haematology.

References

1. Smith G, Apperley J, Milojkovic D, et al. A British Society for Haematology Guideline on the diagnosis and management of chronic myeloid leukaemia. Br J Haematol. Published online July 30, 2020. doi: 10.1111/bjh.16971

2. Bhatia R. Novel approaches to therapy in CML. Hematology Am Soc Hematol Educ Program. 2017(1):115-120. doi:10.1182/asheducation-2017.1.115