How to manage anemia in patients with Chronic Myeloid Leukemia (CML)?

Management of Anemia in Patients with Chronic Myeloid Leukemia

Anemia in CML patients on tyrosine kinase inhibitor (TKI) therapy should be managed primarily through dose modification and temporary treatment interruption, with erythropoiesis-stimulating agents (ESAs) reserved for persistent anemia after achieving stable cytogenetic response. 1

Understanding TKI-Induced Anemia

Myelosuppression during TKI treatment is extremely common and represents efficacy rather than true toxicity. 1 The mechanism involves:

• Combined suppression of the leukemic clone and inhibition of non-leukemic hematopoiesis, which is already reduced at diagnosis due to CML burden 1
• Time-limited phenomenon: Myelosuppression predominantly occurs in the first weeks to months of treatment and decreases substantially with longer TKI exposure 1
• Dose-dependent and reversible: Effects are reversible with treatment cessation or dose reduction 1

Normal stem and progenitor cells require time to recover from pre-existing suppression by the malignant clone and re-populate the bone marrow after TKI-induced reduction of leukemic hematopoiesis. 1

Initial Assessment and Monitoring

Blood counts should be monitored every 15 days until complete hematologic response without significant cytopenias has been achieved. 1

Key prognostic factors for developing anemia include:

• Starting hemoglobin level <12 g/dL 2
• Age ≥60 years 2
• Female gender 2
• Higher imatinib dose 2
• Intermediate or high Sokal risk group 2

Grade 3-4 Anemia Incidence by TKI

The frequency of severe anemia (grade 3-4) varies by agent and line of therapy: 1

First-line therapy:

• Imatinib 400 mg daily: 4.9% 1
• Nilotinib 300 mg twice daily: 3.4% 1
• Dasatinib 100 mg daily: 11.5% 1
• Bosutinib 500 mg daily: 6.0% 1

Second-line therapy:

• Nilotinib 400 mg twice daily: 10.9% 1
• Dasatinib 100 mg daily: 9.6% 1
• Bosutinib 500 mg daily: 13.9% 1

Primary Management Strategy: Dose Modification

The cornerstone of managing TKI-induced cytopenias is tight monitoring of blood counts with dose interruption and reduction as needed. 1 This approach recognizes that:

• Patients with chronic phase CML cannot be put at risk of dying from infection or bleeding 1
• Myelosuppression is rare once remission has been achieved 1
• Most patients restore normal hematopoiesis on TKI therapy, with transient cytopenias occurring due to delayed recovery of normal hematopoiesis despite good efficacy against leukemia 1

Role of Erythropoiesis-Stimulating Agents (ESAs)

ESAs should be considered for patients who develop persistent anemia while in stable complete cytogenetic response, particularly for late-onset chronic anemia. 2, 3

Evidence for ESA Efficacy:

Early anemia (during initial TKI therapy):

• Recombinant human erythropoietin 40,000 U subcutaneously once weekly achieved hemoglobin increase ≥2 g/dL in 68% of patients 2
• An additional 22% achieved hemoglobin increase of 1-1.9 g/dL 2
• ESA therapy is safe and effective in chronic-phase CML patients who develop anemia with imatinib therapy 2

Late chronic anemia (after ≥12 months of stable response):

• 82% of patients achieved erythroid response (defined as stable improvement >1.5 g/dL for >3 months) 3
• Median time from imatinib start to ESA treatment was 42.2 months 3
• No ESA-related toxicity was observed 3
• Among responders, 10 patients (24%) relapsed after median 20.7 months 3

ESA Dosing Regimens:

• Alpha-EPO: 40,000 IU weekly 3
• Beta-EPO: 30,000 IU weekly 3
• Darbepoetin: 150 mcg weekly 3

Prognostic Significance of Anemia

While moderate anemia (Hb ≤90 g/L) at diagnosis is associated with high-risk CML features, it does not affect long-term survival in the TKI era. 4

However, important caveats exist:

• Patients who develop anemia during TKI therapy show a trend toward lower probability of complete cytogenetic remission (68% vs. 77%, p=0.14) 2
• Patients with anemia combined with other manifestations of myelosuppression have significantly worse outcomes than those with isolated anemia 2
• Anemia reduces quality of life and can increase morbidity in chronic diseases 5

Critical Pitfalls to Avoid

Do not use blood transfusion as primary management for chronic anemia in CML patients. Blood transfusion elevates hemoglobin in the short term but does nothing to address the underlying disorder of failed red cell production. 5

Do not overlook rare but serious complications: Dasatinib can rarely cause aplastic anemia, which may require immunosuppression or allogeneic stem cell transplant if dose reduction fails. 6 This diagnosis should be considered in patients with CML who unexpectedly develop pancytopenia within the first year of dasatinib therapy. 6

Do not delay bone marrow evaluation when cytopenias are unexpectedly severe or persistent, as this may indicate disease progression or rare complications like aplastic anemia. 6

Consider intravenous iron supplementation in appropriate patients, as oral iron has limited efficacy in chronic anemia and intravenous iron can be given safely to patients with chronic diseases. 5