What is Chronic Myeloid Leukemia (CML)?

From the Guidelines

Chronic Myeloid Leukemia (CML) is a type of blood cancer that begins in the bone marrow and involves excessive production of abnormal white blood cells, and the primary treatment involves tyrosine kinase inhibitors (TKIs) such as imatinib, nilotinib, dasatinib, bosutinib, or ponatinib, which target the BCR-ABL protein to stop abnormal cell growth, as recommended by the European LeukemiaNet 2020 guidelines 1.

Overview of CML

CML develops when a genetic change occurs in the DNA of a single bone marrow cell, creating the BCR-ABL fusion gene (Philadelphia chromosome) through a translocation between chromosomes 9 and 22, as described in the European Leukemianet laboratory recommendations for the diagnosis and management of CML 1. This abnormal gene produces a protein that signals cells to divide continuously without regulation. CML typically progresses slowly through three phases: chronic, accelerated, and blast phases.

Symptoms and Diagnosis

Common symptoms of CML include fatigue, weight loss, night sweats, enlarged spleen, and easy bleeding or bruising. Diagnosis is typically made through blood and bone marrow tests, including molecular assessment of the BCR-ABL rearrangement, which enables diagnosis in the remaining 5% of patients without the Philadelphia chromosome, as noted in the ESMO clinical recommendations for diagnosis, treatment, and follow-up of CML 1.

Treatment and Management

Treatment primarily involves TKIs, which are typically taken daily and indefinitely to control the disease. Regular blood tests and bone marrow examinations are necessary to monitor treatment response. With proper treatment, many patients with CML can achieve long-term remission and have a near-normal life expectancy, though they typically require lifelong medication management, as stated in the European LeukemiaNet 2020 recommendations for treating CML 1. The goal of CML treatment is normal survival and good quality of life without life-long treatment, and specialty care for complications of chronic TKI therapy is required for optimal management, as highlighted in the European LeukemiaNet 2020 recommendations 1.

Key Points

• CML is a type of blood cancer that begins in the bone marrow and involves excessive production of abnormal white blood cells.
• The primary treatment involves TKIs such as imatinib, nilotinib, dasatinib, bosutinib, or ponatinib.
• Regular blood tests and bone marrow examinations are necessary to monitor treatment response.
• With proper treatment, many patients with CML can achieve long-term remission and have a near-normal life expectancy.
• Specialty care for complications of chronic TKI therapy is required for optimal management, as recommended by the European LeukemiaNet 2020 guidelines 1.

From the FDA Drug Label

The primary efficacy endpoint in chronic phase CML was MCyR, defined as elimination (CCyR) or substantial diminution (by at least 65%, partial cytogenetic response) of Ph+ hematopoietic cells. Chronic Phase CML Dose-Optimization Trial: A randomized, open-label trial (NCT00123474) was conducted in adult patients with chronic phase CML to evaluate the efficacy and safety of dasatinib administered once daily compared with dasatinib administered twice daily Table 17: Efficacy of Dasatinib in Adult Patients with Imatinib-Resistant or -Intolerant Chronic Phase CML (minimum of 24 months follow-up) Table 18: Long-Term MMR of Dasatinib in the Dose Optimization Trial: Adult Patients with Imatinib-Resistant or -Intolerant Chronic Phase CMLa

Chronic Myeloid Leukemia (CML) is a type of cancer that affects the blood and bone marrow. It is characterized by the uncontrolled growth of myeloid cells in the bone marrow, leading to an overproduction of immature white blood cells.

• Key points about CML include:
  • It is a type of leukemia that progresses slowly over time
  • It is often treated with targeted therapies, such as dasatinib, which inhibit the growth of cancer cells
  • The primary efficacy endpoint in chronic phase CML is MCyR, which is defined as the elimination or substantial diminution of Ph+ hematopoietic cells
  • Dasatinib has been shown to be effective in achieving MCyR in adult patients with imatinib-resistant or -intolerant chronic phase CML 2 The treatment of CML typically involves the use of targeted therapies, such as dasatinib, which have been shown to be effective in achieving MCyR and improving survival rates in patients with CML 2.

From the Research

Definition and Characteristics of Chronic Myeloid Leukemia (CML)

• Chronic Myeloid Leukemia (CML) is a myeloproliferative neoplasm with an annual incidence of 1-2 cases per 100,000 adults 3, 4, 5.
• It accounts for approximately 15% of newly diagnosed cases of leukemia in adults 3, 4, 5.
• CML is characterized by a balanced genetic translocation, t(9;22)(q34;q11.2), involving a fusion of the Abelson gene (ABL1) from chromosome 9q34 with the breakpoint cluster region (BCR) gene on chromosome 22q11.2, known as the Philadelphia chromosome 3, 4, 5.

Treatment Options for CML

• Four tyrosine kinase inhibitors (TKIs), imatinib, dasatinib, bosutinib, and nilotinib, are approved by the United States Food and Drug Administration for first-line treatment of newly diagnosed CML in chronic phase (CML-CP) 3, 4, 5.
• Clinical trials with second and third-generation TKIs reported significantly deeper and faster responses, but had no impact on survival prolongation 3, 4, 5.
• For CML post-failure on frontline therapy, second-line options include second and third-generation TKIs 3, 4, 5.
• Allogeneic stem cell transplantation remains an important therapeutic option for patients with CML-CP and failure (due to resistance) of at least two TKIs, and for all patients in advanced phase disease 3, 4, 5.

Considerations for Treatment Decision-Making

• The selection of a first-line TKI should consider parameters such as disease risk, potency, and toxicity profile of each TKI, as well as each patient's unique comorbidities and preferences 6, 7.
• Comorbidities of the patient, side effect profile, and cost of the TKI should be important considerations in decision-making 7.
• Noncompliance or treatment failure should be recognized early, and prompt intervention increases the chance of achieving the best possible response 7.