What is the optimal first‑line therapy for a 43‑year‑old man with chronic‑phase chronic myeloid leukemia presenting with marked leukocytosis, normal hematocrit, and thrombocytosis?

Treatment of Chronic-Phase CML with Marked Leukocytosis and Thrombocytosis

This 43-year-old man should receive immediate cytoreduction with hydroxyurea to rapidly control his marked leukocytosis (WBC 71,860) and thrombocytosis (platelets 573,000), followed by definitive first-line therapy with a tyrosine kinase inhibitor—either imatinib 400 mg daily or a second-generation TKI (nilotinib or dasatinib). 1

Immediate Management: Cytoreduction Phase

Hydroxyurea should be initiated immediately to achieve rapid cytoreduction before starting definitive TKI therapy, as this patient presents with marked leukocytosis and thrombocytosis that require quick control. 1 This short pretreatment phase prevents potential complications from extreme cell counts, including leukostasis and thrombotic events. 2, 3, 4

• Monitor for tumor lysis syndrome and implement prophylaxis according to institutional standards during cytoreduction. 5
• The goal is to reduce WBC below 10 × 10⁹/L and platelets below 450,000/mm³ before initiating TKI therapy. 1

Definitive First-Line TKI Therapy

Standard Option: Imatinib 400 mg Daily

Imatinib 400 mg once daily remains the established gold standard for first-line treatment of chronic-phase CML worldwide. 1 The landmark IRIS study demonstrated progression-free survival of 84% and overall survival of 88% at 6 years. 1

• There is no indication to use higher imatinib doses (600-800 mg) outside clinical trials, as randomized studies failed to show superiority of 800 mg over 400 mg. 1
• At 12 months, imatinib achieves major molecular response (MMR) in 22% and complete cytogenetic response (CCyR) in 65% of patients. 6

Alternative Option: Second-Generation TKIs

Second-generation TKIs (nilotinib 300 mg twice daily or dasatinib) may be considered as first-line therapy, particularly for patients seeking faster and deeper molecular responses. 1

Nilotinib 300 mg twice daily demonstrates superior efficacy compared to imatinib: 6

• MMR at 12 months: 44% (nilotinib) vs 22% (imatinib), p<0.0001
• CCyR by 12 months: 80% vs 65%
• MR4.5 at 60 months: 53.5% vs 31.4%

However, second-generation TKIs carry specific toxicity profiles that must be considered: 7

• Nilotinib: increased risk of vaso-occlusive events (ischemic heart disease, cerebrovascular events, peripheral arterial disease)—requires caution in patients with diabetes or pre-existing vascular disease
• Dasatinib: pulmonary arterial hypertension, pleural effusions (33% in some populations), and platelet dysfunction increasing hemorrhagic risk

Risk Stratification

Calculate prognostic risk score using the EUTOS system (preferred for TKI-treated patients) or Sokal/EURO scores before initiating therapy. 1 For this 43-year-old patient with platelets 573,000:

• EUTOS score = (4 × spleen size in cm below costal margin) + (7 × basophil percentage)
• Risk categories: Low ≤87, High >87

The patient's age (43 years) and platelet count (573,000) factor into Sokal and EURO calculations but not EUTOS. 1 Risk stratification helps predict response rates and progression-free survival, though it does not change initial TKI selection in standard practice.

Baseline Diagnostic Requirements

Before initiating TKI therapy, ensure completion of: 1

• Bone marrow aspirate and biopsy with chromosome banding analysis (CBA) to confirm t(9;22)(q34;q11.2) and detect additional chromosomal abnormalities
• Qualitative RT-PCR to identify BCR-ABL transcript type (e14a2 or e13a2)
• Baseline BCR-ABL quantitative PCR is not required but will be essential for monitoring

Response Monitoring Schedule

Establish rigorous monitoring to detect treatment failure early: 1

• At 3 months: Assess complete hematologic response (CHR)—WBC <10 × 10⁹/L, platelets <450,000/mm³, no immature granulocytes, basophils <5%, non-palpable spleen
• At 6 months: Bone marrow cytogenetics—target Ph+ ≤35% metaphases
• At 12 months: Target complete cytogenetic response (0% Ph+ metaphases) or BCR-ABL ≤1% on International Scale
• Every 3 months: Quantitative RT-PCR for BCR-ABL transcripts

Treatment Failure Definitions

Switch to second-generation TKI if: 1

• Ph+ >95% or BCR-ABL >10% at 3 months
• Ph+ >65% or BCR-ABL >10% at 6 months
• Ph+ ≥1% or BCR-ABL >1% at 12 months
• Loss of complete cytogenetic response or major molecular response at any time

Perform BCR-ABL kinase domain mutation analysis if inadequate response occurs, as mutations are the most common mechanism of TKI resistance (present in 42% of chronic-phase patients after imatinib failure). 6

Critical Pitfalls to Avoid

Do not delay hydroxyurea initiation in patients with marked leukocytosis and thrombocytosis, as extreme thrombocytosis (>1,000 × 10⁹/L) paradoxically causes both bleeding and thrombosis through acquired platelet dysfunction. 3, 4, 8 This patient's platelet count of 573,000 approaches this threshold.

Do not use busulfan for cytoreduction—it should no longer be used in CML management. 1

Do not recommend upfront allogeneic stem cell transplantation as first-line therapy due to transplant-related mortality; drug treatment is superior. 1 Transplantation is reserved for patients who fail multiple TKIs or progress to blast phase.

Ensure electrolyte repletion (potassium and magnesium) before starting any TKI, as all agents may prolong QT interval. 7