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Chronic Leukemia

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Notes on Chronic Myeloid Leukemia (CML)

  • chronic myeloid leukemia
  • CML
  • hematological malignancy
  • leukemia
  • disease progression

By Dr. Ayesha Fatima

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  1. Slide 1. CHRONIC LEUKEMIA Prepared by Dr. Ayesha Fatima Pharm D Assistant Professor Dept of Pharmacy Practice
  2. Slide 2. • Chronic leukemias are • Slow onset, indolent course • Cells involved are more differentiated • Often detected incidentally during routine blood work Common chronic leukemias include: 1. Chronic Myeloid Leukemia (CML) 2. Chronic Lymphocytic Leukemia (CLL) 3. Hairy Cell Leukemia 4. Prolymphocytic Leukemia • Chronic leukemias are slowly progressing cancers of the blood and bone marrow that involve mature or maturing hematopoietic cells. • OR • Chronic leukemias are clonal hematologic malignancies characterized by the slow proliferation of mature or maturing cells from either the myeloid or lymphoid lineage.
  3. Slide 3. • CML is a clonal myeloproliferative disorder characterized by the uncontrolled proliferation of mature and maturing granulocytic cells (neutrophils, basophils, eosinophils) in the bone marrow and peripheral blood. • It arises from the malignant transformation of a pluripotent hematopoietic stem cell. • The disease is cytogenetically defined by the Philadelphia chromosome (Ph), which produces the BCR-ABL fusion oncogene. Epidemiology • Accounts for 15–20% of adult leukemias • More common in men than women • Median age at diagnosis: 67 years • Rare in children; more common in adults Chronic Myeloid Leukemia (CML)
  4. Slide 4. • CML is mainly caused by a specific genetic mutation rather than environmental or inherited factors. • Philadelphia chromosome (Ph) formation causes CML This chromosome is produced by a translocation between: Chromosome 9 (ABL gene) Chromosome 22 (BCR gene) • No association with: 1. Heredity or family history 2. Geography 3. Ethnicity or race 4. Socioeconomic status • Associated Risk Factor: • Exposure to ionizing radiation • Seen in atomic bomb survivors (Hiroshima and Nagasaki) • Higher incidence in patients exposed to therapeutic radiation Etiology
  5. Slide 5. 1. Philadelphia Chromosome (Ph) and BCR-ABL formation • Ph results from a reciprocal translocation between: • Chromosome 9 (region q34) carrying the ABL gene • Chromosome 22 (region q11) carrying the BCR gene • Symbolized as t(9;22)(q34;q11) • This creates the BCR-ABL fusion gene on the shortened chromosome 22 (Philadelphia chromosome) 2. Formation of BCR-ABL Protein • The BCR-ABL gene codes for a fusion protein with constitutive tyrosine kinase activity • Promotes uncontrolled cell division • Inhibits apoptosis (via Fas pathway) • Alters cell adhesion and DNA repair Pathophysiology
  6. Slide 6. Normal ABL Function BCR-ABL Abnormality Controlled cell growth Uncontrolled proliferation Regulated by cell signals Escape from normal control mechanisms Promotes apoptosis Inhibits apoptosis (anti-Fas signaling) Mechanism: 3. Clonal Hematopoiesis • CML arises from one pluripotent hematopoietic stem cell • This transformed clone expands abnormally, displacing normal hematopoiesis • Hyperproliferation of granulocytes and their precursors • Affected lineages include: • Myeloid (granulocytes, monocytes, erythrocytes, megakaryocytes) • Sometimes lymphoid (T and B cells) ➤ Thus, Ph+ cells are found in multiple hematopoietic lineages
  7. Slide 7. Phase Features Chronic Phase (CP) Increased mature granulocytes; often asymptomatic Accelerat ed Phase (AP) Increased blasts, cytogenetic abnormalities, worsening symptoms Blast Crisis (BC) ≥20% blasts in blood or marrow; resembles acute leukemia 4. Disease Phases of CML
  8. Slide 8. 5. Molecular Targeting of BCR-ABL Tyrosine Kinase • The BCR-ABL protein is a tyrosine kinase, and targeting this enzyme was a major breakthrough. • BCR-ABL creates a constitutively active tyrosine kinase, critical for disease pathogenesis Mechanism of TKI (e.g., Imatinib • Binds to the ATP-binding site of the tyrosine kinase domain • Prevents phosphorylation of downstream targets • Stops cell signaling required for proliferation • ATP binds to BCR-ABL's kinase domain and activates signaling for: • Proliferation, Survival, Anti-apoptosis 6. Second-Generation TKIs • Used when resistance or intolerance to imatinib occurs or as frontline therapy: 1. Dasatinib 2. Nilotinib 3. Bosutinib • Third-generation TKI: • Ponatinib (active against T315I mutation)
  9. Slide 9. • Chronic Myeloid Leukemia (CML) progresses through three distinct clinical phases: Chronic Phase (CP), Accelerated Phase (AP), and Blast Crisis (BC). • Most patients are diagnosed in the Chronic Phase, which typically has an indolent course and favorable prognosis with treatment. Clinical Presentation of CML Symptom Mechanism Fatigue, weight loss, night sweats Cytokine-mediated effects of leukemia Left upper quadrant pain, early satiety Splenomegaly Bone pain Marrow expansion Abdominal pain, priapism, visual changes, confusion Leukostasis from extreme leukocytosis Gout, uric acid stones Hyperuricemia from high cell turnover Common Signs and Symptoms
  10. Slide 10. 1. Physical Examination Findings • Splenomegaly (common) • Hepatomegaly • Occasionally lymphadenopathy Test Typical Findings Complete Blood Count (CBC) Leukocytosis (WBC often >100,000/mm³), thrombocytosis, basophilia Peripheral Blood Smear Left shift with all stages of granulocyte maturation Serum Biochemistry ↑ Uric acid, ↑ LDH Leukocyte Alkaline Phosphatase (LAP) Score Typically low or absent DIAGNOSIS of CML 2. Laboratory test
  11. Slide 11. Parameter Finding Cellularity Markedly hypercellular (75– 90%) Myeloid: Erythroid Ratio Increased (10– 30:1) Blasts <10% in CP Megakaryocytes Increased but normal morphology Fibrosis Typically absent or minimal Test Purpose Karyotyping Detect Philadelphia chromosome (t[9;22][q34;q11]) FISH (Fluorescence In Situ Hybridization) Detect BCR-ABL fusion gene RT-PCR (Quantitative PCR) Measure BCR-ABL1 transcript levels using International Scale (IS) for monitoring response to treatment 3. Bone Marrow Biopsy 4. Cytogenetics and Molecular Diagnostics
  12. Slide 13. 1. Treatment Goals in CML 1. Eradicate the leukemic clone from the bone marrow. 2. Maintain chronic phase (CP) as long as possible. 3. Minimize treatment-related toxicity. 4. Achieve and maintain deep molecular response. 5. Prevent or delay progression to accelerated phase (AP) or blast crisis (BC). TREATMENT AND MANAGEMENT OF CML
  13. Slide 14. 2. Tyrosine Kinase Inhibitors (TKIs) – Mainstay of Therapy First-Generation TKI: Imatinib • Standard initial dose: 400 mg orally once daily. • Binds ATP-binding site of BCR-ABL tyrosine kinase. • Proven to induce high rates of complete hematologic, cytogenetic, and molecular responses. • IRIS trial: 10-year survival ~83%. Response Monitoring Timelines : 3 months: Complete hematologic response. 6 months: Partial cytogenetic response. 12 months: Complete cytogenetic response. 18 months: Major molecular response (MMR). Imatinib Toxicities : • Myelosuppression (most common). • GI upset, edema, rash, hepatotoxicity. • Interacts with CYP3A4 metabolized drugs.
  14. Slide 15. Dasatinib • Dose: 100 mg once daily (CP), 140 mg daily (AP/BC). • Active against many imatinib-resistant mutations except T315I. • Can cause pleural effusions, cytopenias, rash. Nilotinib • Dose: 300-400 mg twice daily. • More potent than imatinib. • Risk of QTc prolongation, hyperbilirubinemia. Bosutinib • Dose: 500 mg daily. • Fewer off-target effects. • Common side effects: diarrhea, rash. Ponatinib • Dose: 45 mg daily, effective against T315I mutation. • Black box warning: vascular occlusion, liver failure. • Reserved for T315I-positive or TKI-refractory CML. 3. Advanced-Generation TKIs
  15. Slide 16. 4. Response Assessment Types of Responses : • Hematologic: Normal blood counts. • Cytogenetic: % of Ph+ cells in marrow. • Molecular: BCR-ABL mRNA by RT-PCR (on International Scale). Molecular Response Milestones: • Early molecular response (EMR): BCR-ABL <10% at 3–6 months. • Major molecular response (MMR): BCR-ABL <0.1% (3-log reduction). • Complete molecular response (CMR): Undetectable BCR-ABL. Monitoring: • RT-PCR for BCR-ABL every 3 months. • Bone marrow cytogenetics if molecular targets not met.
  16. Slide 17. 5. Resistance to TKIs • Mechanisms: • BCR-ABL point mutations (e.g., T315I). • Gene amplification. • P-glycoprotein overexpression, clonal evolution. • Mutation analysis is done if: • Loss of response. • Failure to meet milestones. • Progression to AP/BC. 6. Conventional Cytotoxic Chemotherapy (For Leukoreduction) • Hydroxyurea: Rapidly lowers WBC count in newly diagnosed CP-CML. • Dose: 40–50 mg/kg/day until WBCs <10,000/mm³. • Discontinue once TKIs are started. • Busulfan is obsolete due to pulmonary toxicity.
  17. Slide 18. 7. Interferon-Alpha (IFN-α) ● Previously standard before TKIs. ● Now limited to: ○ Patients intolerant or resistant to TKIs. ○ Post-HSCT relapse. ● Combined with TKIs in clinical trials. ● Significant toxicity: flu-like symptoms, depression, autoimmune issues. 8. Omacetaxine Mepesuccinate ● Approved for CML resistant to ≥2 TKIs or with T315I mutation. ● SC injection: 1.25 mg/m² BID × 14 days induction. ● MOA: Inhibits protein synthesis → reduces BCR-ABL and Mcl-1. ● Used in CP or AP CML.
  18. Slide 19. 9. Hematopoietic Stem Cell Transplantation (HSCT) ● Allogeneic HSCT: Only curative option. ● Best outcomes in younger patients with early CP. ● 5-year survival: ○ Matched sibling donor: ~70–80%. ○ Matched unrelated donor: ~40–70%. ● Limitations: ○ Only ~30% of patients have sibling donors. ○ Transplant-related mortality increases with age (>50 years). ○ GVL effect plays a key role in long-term remission.
  19. Slide 20. ● Chronic Lymphocytic Leukemia (CLL) is a lymphoproliferative disorder characterized by a progressive accumulation of functionally incompetent, clonal B lymphocytes in the blood, bone marrow, and lymphoid tissues. ● These abnormal B cells typically co-express CD5, CD19, and CD23 and have low levels of surface immunoglobulins (IgM and IgD). Chronic Lymphocytic Leukemia (CLL)
  20. Slide 21. Epidemiology 1. Most common leukemia in Western countries, particularly the United States. 2. Incidence (US): Approximately 20,720 new cases in 2019. 3. Age: a. Median age at diagnosis: 71 years. b. Around 20–30% of cases occur in patients younger than 55 years. 4. Sex: Male predominance (about 2:1 male-to-female ratio). 5. Ethnicity: Higher incidence among White populations. 6. Familial risk: a. First-degree relatives of CLL patients have a 3-fold increased risk of developing CLL or other lymphoid malignancies.
  21. Slide 22. Etiology (Risk Factors) The exact cause of CLL is unknown, but several risk factors have been identified: 1. Genetic predisposition: Family history of CLL or lymphoid malignancies. 2. Male sex 3. Advanced age 4. White race 5. Environmental and occupational exposures 6. Monoclonal B-cell lymphocytosis (MBL): a. Considered a precursor condition. b. Patients with MBL have clonal B cells in their blood with CLL-like immunophenotype. c. MBL precedes the development of CLL in almost all cases and can be detected 6 months to 6.4 years before diagnosis.
  22. Slide 23. Pathophysiology CLL is characterized by: 1. Clonal expansion of B cells a. Derived from CD5+ B lymphocytes (unusual because CD5 is typically a T-cell marker). b. These cells express low levels of surface IgM and IgD, and co-express CD5, CD19, and CD23. c. Functionally incompetent – poor antibody production and impaired immune function. 2. Defective apoptosis a. CLL cells accumulate due to impaired programmed cell death rather than high proliferation. b. Overexpression of anti-apoptotic genes, such as: i. BCL-2 ii. BCL-1 c. Loss of tumor suppressor genes, such as: i. RB1
  23. Slide 24. 3. Role of B-cell receptor (BCR) signaling ● BCR signaling is a key driver of CLL cell survival. ● Bruton’s tyrosine kinase (BTK) plays a crucial role: ○ Activates downstream pathways ○ Promotes survival, proliferation, chemokine signaling, and cell migration. 4. PI3K Pathway • Phosphatidylinositol 3-kinase (PI3K), especially the delta (δ) isoform, is hyperactive. • Regulates: ■ Cell motility ■ Survival ■ Proliferation
  24. Slide 25. 6. Transformation to aggressive lymphoma (Richter’s Syndrome) ● Occurs in 4–10% of CLL patients. ● Transformation to diffuse large B- cell lymphoma (DLBCL). ● Triggered by: ○ Additional cytogenetic mutations ○ Epstein-Barr virus (EBV) infection 5. Genetic abnormalities ● Cytogenetic changes are observed in about 80% of patients: ○ Common abnormalities: Deletions on chromosomes 11q, 12, 13q, and 17p ○ 17p deletion (TP53) is associated with poor prognosis and treatment resistance. ● Somatic mutations in genes involved in: ○ Cell cycle/DNA repair ○ Intracellular signalin ○ RNA splicing ● These mutations can guide prognosis and therapy selection
  25. Slide 26. Staging Rai Stage Clinical Features Risk Median Survival 0 Lymphocytosis only Low >10 years I Lymphocytosis + lymphadenopathy Intermediate ~7 years II + Organomegaly (hepatomegaly and/or splenomegaly) Intermediate ~7 years III + Anemia (Hb <11 g/dL) High 2–4 years IV + Thrombocytopenia (platelets <100,000/μL) High 2–4 years Rai Staging System (used in the U.S.)
  26. Slide 27. Clinical Presentation of CLL A. Constitutional (Systemic) Symptoms 1. These are nonspecific and may indicate disease progression: 2. Fever (unexplained) 3. Fatigue (most common symptom affecting quality of life) 4. Unintentional weight loss 5. Night sweats 6. These symptoms often reflect disease burden or cytokine release. B. Physical Examination Findings 1. Lymphadenopathy Commonly involves cervical, axillary, and inguinal nodes. 2. Splenomegaly a. May cause early satiety or abdominal discomfort. 3. Hepatomegaly
  27. Slide 28. C. Laboratory Findings 1. Peripheral Blood a. Absolute lymphocytosis: Lymphocyte count often >5,000/μL b. Anemia: can be due to: Autoimmune hemolytic anemia (Coombs +) c. Thrombocytopenia: due to marrow suppression d. Hypo- or hypergammaglobulinemia: e. Monoclonal gammopathy (rare, <5% of cases) 1. Bone Marrow a. Hypercellular marrow b. Increased mature lymphocytes c. Increased megakaryocytes i. May indicate compensatory response to thrombocytopenia
  28. Slide 29. Treatment Goals in CLL 1.Achieve and maintain prolonged remission. 2.Minimize treatment-related toxicity. 3.Delay disease progression. 4.Preserve the patient’s quality of life 5.Cure is not the primary goal in most patients. TREATMENT AND MANAGEMENT OF CLL
  29. Slide 30. Indications for initiating therapy : 1. Symptomatic disease: B symptoms (fever, night sweats, fatigue, weight loss). 2. Threatened organ function (e.g., organomegaly causing dysfunction). 3. Bone marrow failure: anemia (Hb < 11 g/dL), thrombocytopenia (platelets < 100,000/mm³). 4. Bulky disease (massive splenomegaly or lymphadenopathy). 5. Rapid lymphocyte doubling time (< 6 months). 6. High-risk cytogenetics (e.g., del(17p), TP53 mutations). 7. Asymptomatic early-stage CLL (Rai 0 or Binet A) is observed , not treated ("watch and wait").
  30. Slide 31. a. Alkylating Agents 1. Chlorambucil a. Historical agent; still used in frail or elderly patients. b. No OS benefit over observation in early-stage disease. c. Often used in elderly or frail patients. d. Dose : 15–40 mg/m² orally every 28 days or 4–8 mg/m²/day. 2. Cyclophosphamide a. Given orally (1–3 mg/kg/day). b. Risk: hemorrhagic cystitis, bladder cancer with prolonged use. Therapeutic Approaches 1. Cytotoxic Chemotherapy
  31. Slide 32. B. Purine Analogs • Fludarabine • Highly active against CLL. • Dose : 25–30 mg/m² IV daily for 5 days. • Greater CR rates than chlorambucil but more immunosuppression . • Risk of neutropenia , viral reactivations (HSV, VZV). • Others : Cladribine and Pentostatin (less commonly used) C. Bendamustine ● Has properties of both alkylating agents and purine analogs. ● Higher response rates than chlorambucil (CR: 31% vs 2%). ● Toxicities: myelosuppression , GI , rash .
  32. Slide 33. 2. Monoclonal Antibody-Based Biologic Therapy 1. Anti-CD20 Antibodies ● Rituximab : Chimeric anti-CD20 ○ Limited efficacy as monotherapy due to low CD20 expression in CLL. ● Ofatumumab : Fully human anti-CD20 ○ Active in fludarabine- and alemtuzumab-refractory disease. ● Obinutuzumab : Glycoengineered, type II anti-CD20 ○ Stronger direct cell killing. ○ Superior PFS when combined with chlorambucil or venetoclax vs rituximab. 1. Anti-CD52 Antibody a. Alemtuzumab i. Active in del(17p) or fludarabine-refractory CLL. ii. High risk of pancytopenia, opportunistic infections (requires prophylaxis).
  33. Slide 34. 3. Targeted Therapy a. BTK Inhibitors • Ibrutinib • Irreversibly inhibits Bruton's tyrosine kinase (BTK). • Highly effective even in del(17p)/TP53-mutated disease. • Toxicities: Atrial fibrillation, bleeding, tumor lysis syndrome, lymphocytosis (benign). • Resistance: BTK C481S or PLCγ2 mutations. • Acalabrutinib ■ More selective BTK inhibitor (fewer off-target effects). ■ Better tolerated (fewer cardiac side effects). ■ Not effective in BTK-resistant cases.
  34. Slide 35. b. PI3K Inhibitors • Idelalisib (PI3Kδ) • Duvelisib (PI3Kδ/γ) • Used with rituximab in relapsed/refractory CLL. • Serious toxicities: hepatotoxicity, colitis, pneumonitis, infection. • Requires infection prophylaxis (PJP, CMV monitoring). c. BCL-2 Inhibitor • Venetoclax • Induces apoptosis by inhibiting BCL-2. • Effective in del(17p) and refractory CLL. • Tumor lysis syndrome (TLS) risk: requires slow dose ramp-up. • Combination with rituximab or obinutuzumab is highly effective.
  35. Slide 36. Role of Hematopoietic Stem Cell Transplantation (HSCT) ● Allogeneic HSCT: Potentially curative but limited to younger patients with high-risk, refractory disease. ● Risks: GVHD, high treatment-related mortality. ● Not commonly used now due to availability of effective targeted therapies. ● I ndications: ○ Young, fit patients with TP53 mutations or refractory disease ○ Consider non-myeloablative transplant in elderly
  36. Slide 37. Regimen Components Use Key Notes FCR Fludarabine + Cyclophosphamide + Rituximab Fit, younger patients High CR rate; risk of infections, cytopenias BR Bendamustine + Rituximab Alternative to FCR in elderly Better tolerated, slightly lower PFS Ibrutinib + Obinutuzumab For elderly or unfit Longer PFS vs Obinutuzumab + Chlorambucil Venetoclax + Rituximab (VR) Relapsed/refractory CLL Superior to BR (longer PFS, OS benefit) Venetoclax + Obinutuzumab (VO) First-line therapy Approved for treatment- naïve CLL Combination Regimens

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