Chronic Myeloid Leukemia (CML)

What is Chronic Myeloid Leukemia (CML)?

Chronic myeloid leukemia (CML) is classified as a clonal hematopoietic stem cell disorder and is part of the broader group of myeloproliferative neoplasms (MPNs). The disease originates in a single, pluripotent hematopoietic stem cell that has undergone a critical genetic mutation. This cell gives rise to a massive, uncontrolled proliferation of progeny, primarily in the myeloid lineage.

The defining characteristic of chronic myeloid leukemia (CML) is the excessive production and accumulation of myeloid cells, granulocytes (neutrophils, eosinophils, and basophils), at all stages of maturation in the bone marrow and peripheral blood.

In its initial and most common presentation (Chronic Phase), chronic myeloid leukemia (CML) progresses slowly over months to years, which differentiates it from the aggressive course of Acute Leukemias.

Epidemiology and Incidence

Chronic myeloid leukemia (CML) is a relatively uncommon disease, accounting for approximately 15% of all leukemias in adults.

Age of Onset: While it can occur at any age, chronic myeloid leukemia (CML) is primarily a disease of older adults. The median age at diagnosis typically falls between 60 and 65 years. There is a slight male predominance.

Prevalence: The annual incidence is estimated to be around 1 to 2 cases per 100,000 adults.

What causes chronic myeloid leukemia (CML)?

The fundamental cause of chronic myeloid leukemia (CML) is a single, specific, recurrent genetic event: the formation of the BCR-ABL1 fusion oncogene. This aberrant gene product drives the malignant transformation of the hematopoietic stem cell.

The Philadelphia (Ph) Chromosome

The genetic abnormality that defines chronic myeloid leukemia (CML) is the Philadelphia (Ph) chromosome, named for the city where it was first discovered. The Ph chromosome is the result of a reciprocal translocation between the long arms of chromosome 9 and chromosome 22. This event is designated as t(9;22)(q34;q11).

The long arm of chromosome 9 (9q34) contains the ABL1 (Abelson murine leukemia viral oncogene homolog 1) gene, a proto-oncogene that is normally involved in cellular signaling and the long arm of chromosome 22 (22q11) contains the BCR (Breakpoint Cluster Region) gene, a gene with regulatory functions.

The Resulting Chromosomes

The smaller, derivative chromosome 22 (der(22)) that contains the fused BCR-ABL1 gene is the Ph chromosome. This is the pathogenic chromosome. The ABL1 gene encodes a non-receptor tyrosine kinase. In its normal state, its activity is tightly regulated and only switched on in response to specific growth signals. However, the BCR component causes the new BCR-ABL1 protein to spontaneously form homodimers or oligomers. This dimerization forces the ABL1 kinase domain into a permanent, “on” or activated conformation.

The result is a BCR-ABL1 protein that possesses constitutively active tyrosine kinase activity, meaning it constantly phosphorylates downstream targets, regardless of external signals.

A larger, derivative chromosome 9 (der(9)) is also formed, but this product is generally thought to be non-pathogenic in chronic myeloid leukemia (CML).

Mechanism of Leukemogenesis

The perpetually active BCR-ABL1 kinase acts as a master regulator, hijacking multiple intracellular signaling pathways to create a favorable environment for malignancy.

The genomic instability caused by BCR-ABL1 sets the stage for clonal evolution. Over time, the leukemic clone acquires additional mutations (e.g., trisomy 8, isochromosome 17q), leading to genetic instability, loss of differentiation capacity, and ultimately, progression from the indolent Chronic Phase (CP) to the highly aggressive Accelerated Phase (AP) and Blast Crisis (BC).

BCR-ABL1 activates key signaling cascades, including the RAS/MAPK, PI3K/AKT, and JAK/STAT pathways. These signals bypass normal growth controls, promoting rapid and sustained proliferation of the myeloid lineage cells. The activation of the PI3K/AKT pathway leads to the suppression of programmed cell death (apoptosis). This extends the lifespan of the chronic myeloid leukemia (CML) cells, allowing them to accumulate in the bone marrow and peripheral blood.

BCR-ABL1 disrupts normal cell adhesion mechanisms, allowing immature cells to spill out of the bone marrow into the circulation. It also contributes to genomic instability, impairing DNA repair and increasing the rate of secondary mutations.

Chronic Myeloid Leukemia (CML) Clinical Presentation & Phases

Chronic myeloid leukemia (CML) is characterized by its natural history of a relatively indolent, chronic phase that invariably progresses to a fatal acute phase (Blast Crisis) if left untreated. Modern therapy with Tyrosine Kinase Inhibitors (TKIs) aims to keep the patient permanently in the Chronic Phase.

Chronic Phase (CP)

The Chronic Phase is the most common presentation, with 85−90% of patients diagnosed at this stage. It is characterized by the uncontrolled, yet well-differentiated, proliferation of myeloid cells.

Symptoms

Symptoms are often nonspecific, mild, or absent entirely (incidental finding on routine blood work).

• Constitutional Symptoms: Fatigue, low-grade fever, night sweats, and unintentional weight loss (common symptoms related to high cellular turnover and metabolic demand).
• Abdominal Fullness/Pain: Due to massive splenomegaly.
• Bleeding/Bruising: Due to functional platelet defects, even when platelet counts are high.
• Gout/Arthralgia: Related to increased uric acid production (hyperuricemia) from high cell turnover.

Physical Examination

• Splenomegaly: The most consistent and important physical finding. The spleen is often significantly enlarged, firm, and palpable below the costal margin.
• Hepatomegaly: Mild to moderate liver enlargement may be present.
• Signs of Hyperviscosity: Rarely, very high white blood cell (WBC) counts (≥200×10⁹/L) can lead to hyperviscosity symptoms (priapism, visual disturbances, or central nervous system signs), requiring urgent management.

Accelerated Phase (AP)

The Accelerated Phase represents a phase of clonal evolution and disease instability, serving as a biological bridge between the Chronic Phase and Blast Crisis. The disease becomes more difficult to control with standard therapy. The specific criteria for defining the AP often vary slightly across organizations (e.g., WHO, ELN), but generally include the following features:

• Increasing Blasts: Peripheral blood or bone marrow blasts between 10% and 19%.
• Persistent Cytopenias: Unexplained, persistent thrombocytopenia (≤100×10⁹/L) or persistent thrombocytopoiesis, unresponsive to therapy.
• Persistent Leukocytosis: Increasing WBC count despite treatment.
• Increasing Basophils: Peripheral blood basophils ≥20%.
• New Clonal Evolution: The development of new cytogenetic abnormalities (e.g., trisomy 8, isochromosome 17q, second Ph chromosome) in Ph-positive cells.
• Extramedullary Disease: New or enlarging soft tissue masses (granulocytic sarcomas).

Blast Crisis (BC)

Blast Crisis is the final and most aggressive stage of chronic myeloid leukemia (CML), representing transformation to acute leukemia. It carries a grave prognosis and is much harder to treat than the initial Chronic Phase.

• Defining Criteria: The most critical criterion for blast crisis is:
  • Blasts ≥20% in the peripheral blood or bone marrow.
  • Presence of extramedullary blast proliferation (granulocytic sarcoma).
• Lineage of Transformation: The transformation can follow two main paths:
  • Myeloid Blast Crisis (MBC): The malignant clone differentiates into acute myeloid leukemia (AML). This is the most common form (60−70% of cases).
  • Lymphoid Blast Crisis (LBC): The malignant clone differentiates into B-cell or T-cell acute lymphoblastic leukemia (ALL). This occurs in about 20−30% of cases and may respond better to ALL-specific chemotherapy regimens in conjunction with TKIs.
• Clinical Implications: Symptoms often resemble aggressive acute leukemia (severe cytopenias, infection, bleeding) and require immediate, intensive therapy.

How is chronic myeloid leukemia (CML) investigated?

The diagnosis of chronic myeloid leukemia (CML) requires a multi-modal approach, combining standard hematology tests with advanced molecular and cytogenetic studies to confirm the presence of the BCR-ABL1 oncogene.

Peripheral Blood Smear (PBF) and Complete Blood Count (CBC)

The initial findings from a routine blood test are often highly suggestive of CML.

• Leukocytosis: There is typically a marked and persistent elevation of the White Blood Cell (WBC) count, often ranging from 25×10⁹/L to over 500×10⁹/L.
• Myeloid Left Shift: The blood smear shows a characteristic full spectrum of myeloid maturation (the myeloid bulge). This means that cells at almost every stage of granulocyte development are present, including myeloblasts, promyelocytes, myelocytes, metamyelocytes, bands, and segmented neutrophils. The number of myelocytes and neutrophils usually dominates.
• Key Morphological Clues:
  • Basophilia: An absolute increase in basophils is a highly characteristic and important finding in chronic myeloid leukemia (CML).
  • Eosinophilia: Eosinophil counts are also frequently elevated.
  • Thrombocytosis: Platelet counts are often normal or elevated (thrombocytosis) in the Chronic Phase, though they can become low (thrombocytopenia) in the Accelerated Phase.
• Leukocyte Alkaline Phosphatase (LAP) Score: The LAP score, which measures an enzyme present in mature neutrophils, is characteristically low or absent in CML. This contrasts sharply with other causes of leukocytosis (like infection or leukemoid reaction), where the LAP score is high.

Bone marrow aspiration and biopsy

While the diagnosis is molecular, bone marrow examination provides information on cellularity, maturation, and ruling out progression.

• Cellularity: The marrow is usually markedly hypercellular (>80% cellularity).
• Granulocytic Hyperplasia: The primary feature is extreme hyperplasia of the granulocytic lineage, with an increased myeloid-to-erythroid (M:E) ratio, typically 10:1 to 30:1 (normal is 2:1 to 4:1).
• Megakaryocytes: Small, dysplastic megakaryocytes are often increased in number.
• Fibrosis: Reticulin fibrosis may be present, which can indicate a poorer prognosis or progression to the Accelerated Phase.
• Blast Count: The percentage of blasts is determined here to classify the disease phase:
  • Chronic Phase (CP): Blasts <10%
  • Accelerated Phase (AP): Blasts 10% to 19%
  • Blast Crisis (BC): Blasts ≥20%

Molecular and Cytogenetic Confirmation (Crucial for Definitive Diagnosis)

The definitive diagnosis relies on confirming the t(9;22) translocation and the presence of the BCR-ABL1 fusion gene.

Conventional Karyotyping (Cytogenetics)

Cytogenetics is essential for the initial diagnosis, as it can detect the primary Ph chromosome, t(9;22)(q34;q11), and any additional chromosomal abnormalities (clonal evolution) that signal progression (e.g., trisomy 8).

Fluorescence in situ Hybridization (FISH)

FISH technique uses fluorescently labeled DNA probes specific to the BCR and ABL1 regions by to detect the fusion signal (one red and one green signal merge to form a yellow fusion signal). This technique is useful for rapid confirmation in peripheral blood or when bone marrow cells fail to grow in culture for karyotyping. It is sensitive enough to detect the BCR-ABL1 fusion in up to 95% of CML cases.

Quantitative Polymerase Chain Reaction (qPCR)

This is the gold standard for monitoring treatment response. qPCR measures the reduction in the leukemic burden relative to a control gene and is reported on the International Scale (IS). This allows comparison of results globally and guides treatment decisions, particularly regarding goals like Major Molecular Response (MMR) and Treatment-Free Remission (TFR).

Prognostic Scoring and Risk Stratification

Prognostic scoring systems in chronic myeloid leukemia (CML) are designed to predict a patient’s long-term outcome before they start Tyrosine Kinase Inhibitor (TKI) therapy. These scores, based on easily obtainable clinical and hematological parameters at the time of diagnosis, help clinicians stratify patients into risk groups (low, intermediate, or high) to guide the selection of the most appropriate initial TKI.

The Traditional Sokal Risk Score

The Sokal Score was the first widely used prognostic tool for chronic myeloid leukemia (CML). It was developed in the pre-TKI era (when Interferon-alpha and chemotherapy were the standard treatments) to predict the median survival time for patients. While still sometimes mentioned, its use has largely been superseded by modern scores that are more accurate in the context of TKI therapy.

Parameter	Contribution
Age	Older age is associated with worse prognosis.
Spleen Size	Significant splenomegaly indicates higher disease burden.
Platelet Count	Very high or very low platelet counts predict poorer outcomes.
Peripheral Blood Blasts	Higher blast percentage is the strongest negative predictor.

Patients are categorized into low, intermediate, or high-risk groups based on a derived score calculated using a complex formula incorporating these four variables.

The EUTOS Long-Term Survival (ELTS) Score

The ELTS Score is the preferred modern risk stratification tool for chronic myeloid leukemia (CML) patients starting first-line TKI therapy (specifically, Imatinib). It was developed and validated using data from patients treated with Imatinib and is considered a better predictor of long-term outcomes in the modern treatment landscape, particularly Failure-Free Survival (FFS).

Components of the ELTS Score

The ELTS score uses the same four clinical parameters as the Sokal score but assigns them different weightings, reflecting the understanding that age is a more dominant factor in the TKI era.

Parameter	Weighting/Threshold
Age	Scored differently for patients <50, 50−60, and >60 years.
Spleen Size	Scored by the number of cm below the costal margin.
Platelet Count	Scored based on absolute values (e.g., <67.5 or >434×109/L).
Peripheral Blood Blasts	Score assigned based on the percentage of blasts.

ELTS Risk Groups and Interpretation

The final ELTS score places the patient into one of three risk categories:

• Low Risk (LR): Predicts excellent prognosis and high rate of long-term molecular response.
• Intermediate Risk (IR): Suggests a slightly increased risk of failing to achieve optimal response.
• High Risk (HR): Predicts the highest rate of treatment failure and progression.

Clinical Application of Risk Stratification

The primary utility of these scores is in guiding the initial selection of the TKI.

• Low/Intermediate Risk Patients: These patients generally have excellent outcomes with first-generation TKIs (Imatinib), which is often preferred due to its lower cost, established safety profile, and minimal non-hematological toxicities.
• High-Risk Patients: For patients classified as High Risk by ELTS, starting treatment with a second-generation TKI (e.g., Dasatinib or Nilotinib) is generally recommended. These agents are more potent and achieve deep molecular response (DMR) faster, which may mitigate the initial poor prognostic factors and improve FFS.
• Monitoring: Regardless of the initial score, strict adherence to the 3-month benchmark (achieving BCR-ABL1≤10% IS) remains the most crucial predictor of long-term success. If this benchmark is missed, treatment must be escalated, even in a previously low-risk patient.

Current treatment and management for CML

The current treatment and management of chronic myeloid leukemia (CML) is focused on targeting the BCR-ABL protein with tyrosine kinase inhibitors (TKIs). TKIs are oral medications that block the BCR-ABL protein from signaling, which prevents the leukemia cells from growing and dividing.

There are six TKIs that are currently approved for the chronic myeloid leukemia (CML) treatment:

• Imatinib (Gleevec)
• Nilotinib (Tasigna)
• Dasatinib (Sprycel)
• Bosutinib (Bosulif)
• Ponatinib (Iclusig)
• Asciminib (Scemblix)

Imatinib was the first TKI to be developed for the chronic myeloid leukemia (CML) treatment, and it remains the first-line treatment for most patients. However, some patients may not respond to imatinib, or they may develop resistance to it over time. In these cases, a second- or third-generation TKI may be used.

TKIs have revolutionized the treatment of chronic myeloid leukemia (CML), and they have led to significant improvements in survival rates. In fact, most patients with chronic myeloid leukemia (CML) who are treated with TKIs can now expect to live a normal lifespan.

Treatment goals

The primary goal of treatment for chronic myeloid leukemia (CML) is to achieve complete molecular remission (CMR). CMR is defined as the absence of detectable BCR-ABL transcripts in the blood.

Achieving CMR is important because it is associated with the best long-term outcomes for patients with chronic myeloid leukemia (CML). Patients who achieve CMR have a very low risk of relapse and progression to the more aggressive blastic phase of chronic myeloid leukemia (CML).

Treatment options

The specific chronic myeloid leukemia (CML) treatment options will depend on the patient’s individual disease characteristics, such as the phase of chronic myeloid leukemia (CML) and their response to previous treatments.

For most patients with newly diagnosed chronic phase chronic myeloid leukemia (CML), the first-line treatment is imatinib. Imatinib is a very effective TKI, and it can achieve CMR in up to 90% of patients.

However, some patients may not respond to imatinib, or they may develop resistance to it over time. In these cases, a second- or third-generation TKI may be used.

Second-generation TKIs, such as nilotinib and dasatinib, are more potent than imatinib and can achieve CMR in a higher percentage of patients. Third-generation TKIs, such as ponatinib and asciminib, are even more potent than second-generation TKIs and can be used to treat patients with chronic myeloid leukemia (CML) who are resistant to other TKIs.

In addition to TKIs, other chronic myeloid leukemia (CML) treatment options include:

• Stem cell transplant: A stem cell transplant is a procedure in which the patient’s own stem cells are harvested and then reinfused into the body after high-dose chemotherapy. Stem cell transplants can be curative, but they are associated with significant risks.
• Chemotherapy: Chemotherapy is a type of medication that kills cancer cells. Chemotherapy is not curative, but it can be used to control the disease in patients who are not responding to TKIs or who are not eligible for a stem cell transplant.

Management of chronic myeloid leukemia (CML)

Once a patient with chronic myeloid leukemia (CML) has achieved CMR, they need to continue taking their TKI indefinitely. This is because the BCR-ABL gene fusion is still present in the patient’s body, even if they are in remission. If the patient stops taking their TKI, the leukemia cells can return.

In addition to taking their TKI, patients with chronic myeloid leukemia (CML) also need to be monitored closely for any signs of relapse. This typically involves regular blood tests and bone marrow biopsies.

Frequently Asked Questions (FAQs)

What is CML life expectancy?

CML life expectancy has significantly improved due to advancements in treatment, particularly tyrosine kinase inhibitors (TKIs). With effective treatment, many patients with CML can live long, near-normal lives. However, factors such as the stage of the disease at diagnosis, response to treatment, and the development of resistance can influence individual outcomes. Regular monitoring and adherence to treatment plans are crucial for managing CML and maximizing life expectancy.

Can CML be cured?

While there is no definitive cure for chronic myeloid leukemia (CML), modern treatments, particularly tyrosine kinase inhibitors (TKIs), have significantly improved outcomes. Many patients with CML can live long, near-normal lives. With ongoing advancements in research and treatment, the goal of curing CML remains a focus for medical professionals.

What are the three stages of CML?

Chronic myeloid leukemia (CML) is typically divided into three phases.

1. Chronic phase: This is the initial stage, characterized by a gradual increase in abnormal white blood cells. Symptoms may be mild or absent during this phase.
2. Accelerated phase: As the disease progresses, the number of abnormal white blood cells increases rapidly. Symptoms may become more severe, including fatigue, weight loss, and easy bleeding or bruising.
3. Blast crisis: This is the most advanced stage, characterized by a high number of immature white blood cells (blasts) in the blood and bone marrow. Symptoms can be severe and life-threatening, including fever, infections, and bleeding.

What happens if CML is not treated?

If chronic myeloid leukemia (CML) is not treated, the disease can progress through three phases: chronic, accelerated, and blast crisis. As the disease advances, symptoms become more severe, including fatigue, weight loss, easy bleeding, and infections. In the blast crisis stage, the disease can be life-threatening. Early diagnosis and treatment with tyrosine kinase inhibitors (TKIs) are crucial for managing CML and improving outcomes.

Does CML run in families?

CML is not typically inherited. While a small number of cases may be linked to inherited genetic factors, most cases of CML occur spontaneously. However, certain genetic mutations, such as the Philadelphia chromosome, are common in CML and can be detected through genetic testing.

Can CML spread to other organs?

Yes, CML can spread to other organs. As the disease progresses, abnormal white blood cells can accumulate in various organs, including the liver, spleen, and lymph nodes. This can lead to organ enlargement, pain, and dysfunction. However, with effective treatment, the spread of CML can be controlled, and complications can be minimized.

Disclaimer: This article is intended for informational purposes only and is specifically targeted towards medical students. It is not intended to be a substitute for informed professional medical advice, diagnosis, or treatment. While the information presented here is derived from credible medical sources and is believed to be accurate and up-to-date, it is not guaranteed to be complete or error-free. See additional information.

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