Chronic Myeloid Leukaemia

 

Chronic Myeloid Leukemia: Current Understanding and Therapeutic Approaches

Dr Neeraj Manikath,Claude.ai

Abstract

Chronic myeloid leukemia (CML) represents a paradigm shift in cancer treatment, transforming from a fatal disease to a chronic condition with near-normal life expectancy. This review examines our current understanding of CML pathophysiology, the revolutionary impact of tyrosine kinase inhibitors (TKIs), challenges in disease management, and emerging therapeutic approaches. Recent developments in treatment-free remission strategies and novel targeted therapies highlight the evolving landscape of CML management. Understanding the molecular mechanisms of CML and advances in treatment modalities remains crucial for optimizing patient outcomes and addressing the remaining challenges in CML therapy.

Introduction

Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm characterized by the uncontrolled production and proliferation of mature and maturing granulocytes with normal differentiation.^1^ The disease accounts for approximately 15% of all adult leukemias, with an annual incidence of 1-2 cases per 100,000 adults.^2^ The median age at diagnosis is 57-60 years, although CML can occur in all age groups, including children.^3^

The identification of the Philadelphia chromosome, a reciprocal translocation between chromosomes 9 and 22 [t(9;22)(q34;q11)], and its molecular counterpart, the BCR-ABL1 fusion gene, has revolutionized our understanding of CML pathophysiology.^4^ This genetic abnormality results in the production of a constitutively active tyrosine kinase that drives the malignant transformation of hematopoietic stem cells.^5^

The development of tyrosine kinase inhibitors (TKIs) targeting the BCR-ABL1 oncoprotein has dramatically transformed CML from a fatal disease with a median survival of 3-5 years to a chronic condition with a life expectancy approaching that of the general population.^6^ This review examines our current understanding of CML pathophysiology, diagnostic approaches, therapeutic strategies, and future directions in CML management.

Pathophysiology

Molecular Basis

The hallmark genetic abnormality in CML is the Philadelphia chromosome, resulting from a reciprocal translocation between the long arms of chromosomes 9 and 22 [t(9;22)(q34;q11)]. This translocation juxtaposes the breakpoint cluster region (BCR) gene on chromosome 22 with the Abelson murine leukemia viral oncogene homolog 1 (ABL1) gene on chromosome 9, creating the fusion gene BCR-ABL1.^7^

The BCR-ABL1 fusion protein possesses constitutive tyrosine kinase activity that activates multiple downstream signaling pathways, including RAS/MAPK, PI3K/AKT, and STAT5, leading to increased cellular proliferation, reduced apoptosis, and altered cellular adhesion.^8^ The molecular weight of the BCR-ABL1 protein varies depending on the breakpoint in the BCR gene, with the 210-kDa protein (p210) being most commonly associated with CML.^9^

Recent studies have identified additional genetic alterations that may coexist with the BCR-ABL1 fusion gene, particularly in advanced phases of CML. These include mutations in tumor suppressor genes (TP53, CDKN2A), epigenetic regulators (ASXL1, TET2), and signaling molecules (RUNX1, NRAS).^10,11^ These additional genetic aberrations likely contribute to disease progression and therapy resistance.

Disease Progression

CML typically progresses through three clinical phases: chronic phase (CP), accelerated phase (AP), and blast phase (BP).^12^

The chronic phase is characterized by effective hematopoiesis with gradual myeloid expansion. Most patients (85-90%) are diagnosed in this phase, often incidentally during routine blood tests. Without effective treatment, CP-CML inevitably progresses to more advanced phases over a variable timeframe, typically 3-5 years.^13^

The accelerated phase represents an intermediate stage with features of increasing disease burden and genetic instability. Criteria for AP-CML include increased blasts (15-29%), persistent thrombocytopenia, clonal evolution with additional chromosomal abnormalities, and increasing splenomegaly despite therapy.^14^

The blast phase resembles acute leukemia, with >30% blasts in the bone marrow or peripheral blood, extramedullary blast proliferation, or large clusters of blasts in bone marrow biopsy.^15^ BP-CML may present as myeloid (~70%) or lymphoid (~30%) blast crisis, with lymphoid BP-CML having a somewhat better prognosis.^16^

Diagnosis and Classification

Diagnostic Criteria

The diagnosis of CML requires the demonstration of the Philadelphia chromosome by cytogenetic analysis or the BCR-ABL1 fusion gene by molecular techniques.^17^ According to the World Health Organization (WHO) criteria, CML diagnosis is established when the following elements are present:^18^

1. Persistent leukocytosis (≥15 × 10^9^/L) with granulocytic predominance and a characteristic differential showing all stages of granulocyte maturation
2. Basophilia often present
3. Thrombocytosis in 30-50% of cases
4. Splenomegaly in the majority of patients
5. Presence of the Philadelphia chromosome [t(9;22)(q34;q11)] or the BCR-ABL1 fusion gene

Laboratory Investigations

A comprehensive diagnostic workup for CML includes:^19^

Complete Blood Count (CBC): Typically shows leukocytosis (often >50 × 10^9^/L), with a full spectrum of myeloid cells at different maturation stages. Basophilia and eosinophilia are common, and platelet counts may be elevated or depressed.

Bone Marrow Examination: Reveals hypercellularity with granulocytic hyperplasia and a normal or increased number of megakaryocytes. The myeloid-to-erythroid ratio is markedly increased (often >10:1).

Cytogenetic Analysis: Conventional karyotyping remains the gold standard for detecting the Philadelphia chromosome. Additional chromosomal abnormalities may indicate disease progression.

Fluorescence In Situ Hybridization (FISH): Provides rapid detection of the BCR-ABL1 fusion with higher sensitivity compared to conventional cytogenetics, particularly useful when metaphases are inadequate for karyotyping.

Molecular Testing: Quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) for BCR-ABL1 transcripts is essential for diagnosis confirmation and subsequent monitoring of treatment response.

Disease Classification

The classification of CML into different phases aids in prognostication and therapeutic decision-making. The WHO and European LeukemiaNet (ELN) have established criteria for defining the chronic, accelerated, and blast phases of CML, with some differences between these classification systems.^20^

ELN criteria for accelerated phase include:^21^

• Blasts 15-29% in blood or bone marrow
• Blasts plus promyelocytes ≥30% in blood or bone marrow
• Basophils ≥20% in peripheral blood
• Persistent thrombocytopenia (<100 × 10^9^/L) unrelated to therapy
• Clonal chromosomal abnormalities in Ph+ cells (CCA/Ph+)

ELN criteria for blast phase include:

• Blasts ≥30% in blood or bone marrow
• Extramedullary blast proliferation
• Large clusters of blasts in bone marrow biopsy

Prognostic Factors

Several prognostic scoring systems have been developed to predict outcomes in CML patients, guiding treatment decisions and identifying high-risk patients who may benefit from more intensive monitoring or alternative therapeutic approaches.

Sokal and Hasford Scores

The Sokal score, developed in the pre-TKI era, incorporates age, spleen size, platelet count, and blast percentage to stratify patients into low, intermediate, and high-risk categories.^22^ The Hasford (or Euro) score additionally includes eosinophil and basophil percentages.^23^ Despite being developed before the TKI era, these scores maintain prognostic relevance in the context of TKI therapy, particularly for predicting cytogenetic and molecular responses.

EUTOS and ELTS Scores

The EUTOS (European Treatment and Outcome Study) score was specifically developed in the imatinib era, using basophil percentage and spleen size to predict complete cytogenetic response at 18 months.^24^ More recently, the EUTOS Long-Term Survival (ELTS) score was developed to predict long-term outcomes in CML patients treated with TKIs, incorporating age, spleen size, platelet count, and blast percentage.^25^ The ELTS score has demonstrated superior performance in predicting CML-related deaths compared to older scoring systems.

Molecular Response Kinetics

The depth and speed of molecular response to TKI therapy have emerged as important prognostic factors. Early molecular response (EMR), defined as BCR-ABL1 ≤10% on the International Scale (IS) at 3 months, is associated with improved long-term outcomes.^26^ Similarly, achieving a major molecular response (MMR, BCR-ABL1 ≤0.1% IS) by 12 months correlates with improved progression-free and overall survival.^27^

Recent studies suggest that the BCR-ABL1 halving time during the first months of therapy may provide additional prognostic information.^28^ Patients with a rapid decline in BCR-ABL1 transcripts typically have more favorable long-term outcomes and higher probabilities of achieving deep molecular responses.

Additional Prognostic Factors

Several additional factors may influence prognosis in CML:

Clonal Chromosomal Abnormalities: The presence of additional chromosomal abnormalities at diagnosis (particularly trisomy 8, isochromosome 17q, or an extra Ph chromosome) is associated with poorer outcomes.^29^

BCR-ABL1 Transcript Type: Most CML patients express e13a2 (b2a2) or e14a2 (b3a2) transcripts. Some studies suggest that e14a2 transcripts may be associated with deeper molecular responses and better outcomes.^30^

Comorbidities: The presence of significant comorbidities can impact treatment tolerance and overall survival, particularly in older patients.^31^

Age: Advanced age remains an adverse prognostic factor, even in the TKI era, partly due to reduced treatment tolerance and increased comorbidities.^32^

Therapeutic Approaches

Tyrosine Kinase Inhibitors

The advent of tyrosine kinase inhibitors (TKIs) has revolutionized CML treatment, transforming it from a fatal disease to a chronic condition with a near-normal life expectancy for most patients.^33^ Currently, five TKIs are approved for CML treatment:

Imatinib (Gleevec/Glivec): The first-generation TKI that binds to the inactive conformation of the BCR-ABL1 kinase domain, preventing ATP binding and inhibiting tyrosine kinase activity.^34^ The landmark IRIS trial demonstrated the remarkable efficacy of imatinib with a 10-year overall survival rate of 83.3%.^35^

Dasatinib (Sprycel): A second-generation TKI with 325-fold greater potency against BCR-ABL1 compared to imatinib. Dasatinib binds to both active and inactive conformations of BCR-ABL1 and inhibits SRC family kinases.^36^ The DASISION trial showed faster and deeper responses with dasatinib compared to imatinib in newly diagnosed CML.^37^

Nilotinib (Tasigna): Another second-generation TKI with 20-30 fold higher potency than imatinib, binding exclusively to the inactive conformation of BCR-ABL1.^38^ The ENESTnd trial demonstrated superior efficacy of nilotinib over imatinib, with higher rates of major molecular response and reduced disease progression.^39^

Bosutinib (Bosulif): A dual SRC/ABL kinase inhibitor with activity against most imatinib-resistant BCR-ABL1 mutations except T315I.^40^ The BELA and BFORE trials established the efficacy of bosutinib in both first-line and subsequent-line settings.^41,42^

Ponatinib (Iclusig): A third-generation TKI designed specifically to overcome the T315I mutation, which confers resistance to all other approved TKIs.^43^ The PACE trial demonstrated efficacy in heavily pretreated patients, including those with the T315I mutation.^44^ However, ponatinib is associated with significant cardiovascular adverse events, necessitating careful patient selection and monitoring.

Response Monitoring and Definitions

The monitoring of treatment response in CML primarily relies on hematologic, cytogenetic, and molecular assessments, with internationally standardized definitions:^45^

Hematologic Response:

• Complete Hematologic Response (CHR): Normalization of blood counts with absence of immature cells, resolution of splenomegaly

Cytogenetic Response:

• Complete Cytogenetic Response (CCyR): No Ph+ metaphases
• Partial Cytogenetic Response (PCyR): 1-35% Ph+ metaphases
• Minor Cytogenetic Response: 36-65% Ph+ metaphases
• Minimal Cytogenetic Response: 66-95% Ph+ metaphases

Molecular Response:

• Early Molecular Response (EMR): BCR-ABL1 ≤10% IS at 3 months
• Major Molecular Response (MMR or MR3.0): BCR-ABL1 ≤0.1% IS
• Deep Molecular Response:
  • MR4.0: BCR-ABL1 ≤0.01% IS
  • MR4.5: BCR-ABL1 ≤0.0032% IS
  • MR5.0: BCR-ABL1 ≤0.001% IS

Regular monitoring of BCR-ABL1 transcript levels by qRT-PCR is recommended every 3 months until MMR is achieved, then every 3-6 months.^46^ Failure to achieve time-dependent molecular milestones or loss of previously achieved responses should prompt investigation for treatment adherence issues, drug interactions, and BCR-ABL1 kinase domain mutations.

Treatment Resistance and Mutations

Despite the remarkable efficacy of TKI therapy, approximately 20-30% of CML patients experience treatment failure or intolerance.^47^ Primary resistance refers to the failure to achieve appropriate response milestones, while secondary resistance involves loss of previously achieved responses.

BCR-ABL1 kinase domain mutations represent a major mechanism of TKI resistance, affecting the binding of TKIs to their target.^48^ Over 100 different mutations have been identified, with varying degrees of impact on TKI sensitivity. The T315I mutation, often described as the "gatekeeper" mutation, confers resistance to all approved TKIs except ponatinib.^49^

Mutation analysis should be performed in cases of treatment failure, suboptimal response, or loss of response. The identification of specific mutations can guide TKI selection:^50^

• V299L, T315A, F317L/V/I/C: Consider nilotinib or bosutinib
• Y253H, E255K/V, F359V/C/I: Consider dasatinib or bosutinib
• T315I: Consider ponatinib or experimental agents
• E255K/V, F359C/V, Y253H plus T315I: Consider ponatinib

Treatment-Free Remission

Treatment-free remission (TFR), the ability to discontinue TKI therapy without disease recurrence, has emerged as an important goal in CML management.^51^ Several studies have demonstrated that approximately 40-60% of patients with sustained deep molecular responses can successfully discontinue TKI therapy without molecular relapse.^52,53^

Key factors associated with successful TFR include:^54^

• Duration of TKI therapy (≥5-6 years)
• Duration of deep molecular response (≥2 years)
• Prior treatment with interferon
• Deeper molecular responses (MR4.5 or better)
• Low Sokal risk score
• Digital PCR negativity

The EURO-SKI trial, one of the largest TFR studies, reported a 6-month TFR rate of 61% among patients with at least MR4.0 and ≥3 years of TKI therapy.^55^ The duration of TKI therapy and deep molecular response were identified as the most important predictors of successful TFR.

Current guidelines recommend considering TFR attempts only in optimal candidates with at least MR4.0 for ≥2 years, ≥5 years of TKI therapy, no prior treatment failure, and access to frequent high-quality molecular monitoring.^56^ Monthly molecular monitoring is recommended during the first 6 months after TKI discontinuation, followed by monitoring every 2 months for the next 6 months, and every 3 months thereafter.

Advanced Phase CML

The management of accelerated phase (AP) and blast phase (BP) CML remains challenging, with less favorable outcomes compared to chronic phase disease.^57^

For patients presenting in AP-CML, TKI monotherapy (preferably second-generation TKIs) can induce complete hematologic responses in 70-80% and complete cytogenetic responses in 40-60%.^58^ However, responses tend to be less durable than in CP-CML.

BP-CML management typically involves combination approaches with TKIs and intensive chemotherapy regimens, tailored according to the myeloid or lymphoid phenotype.^59^ For myeloid BP, TKIs combined with AML-type chemotherapy (cytarabine plus an anthracycline) may be used, while lymphoid BP may benefit from TKIs plus ALL-type regimens.

Allogeneic hematopoietic stem cell transplantation (HSCT) should be considered in eligible patients with AP or BP-CML who achieve return to chronic phase, as it represents the only potentially curative option for advanced disease.^60^

Emerging Therapies and Future Directions

Novel TKIs and BCR-ABL1 Inhibitors

Several next-generation TKIs are in various stages of development:

Asciminib (ABL001): The first-in-class STAMP (Specifically Targeting the ABL Myristoyl Pocket) inhibitor that binds to the myristoyl pocket of BCR-ABL1 rather than the ATP-binding site, offering a mechanism distinct from conventional TKIs.^61^ The ASCEMBL trial demonstrated superior efficacy of asciminib compared to bosutinib in heavily pretreated patients, including those with resistance to multiple prior TKIs.^62^ Asciminib received FDA approval in 2021 for patients with resistance or intolerance to at least two prior TKIs.

Olverembatinib (HQP1351): A third-generation TKI with activity against multiple BCR-ABL1 mutations, including T315I. Phase 2 trials have shown promising results in patients with T315I mutations or resistance to multiple TKIs.^63^

PF-114: Another third-generation TKI designed to target BCR-ABL1 with the T315I mutation, currently in clinical development.^64^

Targeting CML Stem Cells

CML stem cells demonstrate relative insensitivity to TKIs through various mechanisms, including quiescence, altered signaling pathways, and microenvironmental interactions.^65^ This persistence of leukemic stem cells likely explains why most patients require indefinite TKI therapy.

Several approaches to target CML stem cells are under investigation:^66^

Peroxisome Proliferator-Activated Receptor γ (PPARγ) Agonists: Pioglitazone has been shown to reduce CML stem cell quiescence through activation of the tumor suppressor protein PP2A, enhancing TKI efficacy.^67^

JAK2 Inhibitors: Ruxolitinib and other JAK2 inhibitors may target the JAK/STAT pathway, which remains active in CML stem cells despite BCR-ABL1 inhibition.^68^

Venetoclax: This selective BCL-2 inhibitor has shown promising activity against CML stem cells in preclinical models, particularly when combined with TKIs.^69^

PROTAC-Based Approaches: Proteolysis-targeting chimeras (PROTACs) that degrade BCR-ABL1 protein represent a novel therapeutic strategy potentially capable of overcoming TKI resistance.^70^

Immunotherapeutic Approaches

Harnessing the immune system to target residual CML cells may complement the direct anti-leukemic effects of TKIs:^71^

Immune Checkpoint Inhibitors: PD-1/PD-L1 and CTLA-4 inhibitors are being evaluated in combination with TKIs to enhance immune surveillance against CML cells.^72^

Therapeutic Vaccines: Various vaccine strategies, including peptide vaccines targeting BCR-ABL1 junctional peptides and dendritic cell vaccines, are under investigation to stimulate anti-leukemic immune responses.^73^

CAR-T Cell Therapy: Although less developed in CML compared to acute leukemias, chimeric antigen receptor T-cell therapies targeting CML-specific antigens represent a potentially promising approach, particularly for advanced disease.^74^

Challenges and Future Perspectives

Despite the remarkable success of TKI therapy in CML, several challenges remain:

Treatment Discontinuation

While treatment-free remission represents an important goal, predictive biomarkers to identify optimal candidates for TKI discontinuation remain limited.^75^ Ongoing research focuses on identifying molecular, immunological, and microenvironmental factors associated with successful TFR.^76^ Digital PCR and next-generation sequencing approaches may provide more sensitive detection of residual disease, potentially improving patient selection for TFR attempts.^77^

Long-Term Safety and Quality of Life

The necessity for lifelong TKI therapy in many patients raises concerns about long-term safety and quality of life.^78^ Cardiovascular complications, metabolic abnormalities, endocrine dysfunction, and musculoskeletal issues have been reported with various TKIs.^79,80^ Optimizing TKI selection based on individual patient characteristics, comorbidities, and potential drug interactions represents an important aspect of personalized CML management.

Advanced Disease

Despite progress in CP-CML management, outcomes for BP-CML remain poor, with median survival typically less than one year.^81^ Novel approaches combining TKIs with targeted agents addressing specific pathways involved in disease progression (e.g., WNT/β-catenin, Hedgehog) or immunotherapeutic strategies may improve outcomes for these patients.^82^

Access to Optimal Care

Global disparities in access to TKIs, molecular monitoring, and specialized hematology care remain significant challenges.^83^ The availability of generic imatinib has improved access in many regions, but comprehensive CML management, including regular molecular monitoring and access to second/third-generation TKIs for resistant disease, remains limited in resource-constrained settings.^84^

Conclusion

The management of chronic myeloid leukemia represents one of the most remarkable success stories in modern oncology. The development of targeted therapies based on a deep understanding of disease pathophysiology has transformed CML from a fatal disease to a chronic condition with a near-normal life expectancy for most patients.

Current research focuses on refining treatment strategies to maximize efficacy while minimizing toxicity, identifying optimal candidates for treatment discontinuation, developing novel approaches to target resistant disease and leukemic stem cells, and addressing the remaining challenges in advanced disease management.

As our understanding of CML biology continues to evolve and new therapeutic options emerge, the goal of functional cure or true disease eradication appears increasingly achievable for a growing proportion of CML patients.

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