How to manage anemia in a patient with myeloproliferative disease on hydroxyurea and iron supplements?

Management of Anemia in Myeloproliferative Disease on Hydroxyurea

Evaluate whether the anemia is due to hydroxyurea toxicity (hemoglobin <10 g/dL at the lowest effective dose) or hemolytic anemia, as both scenarios require immediate discontinuation of hydroxyurea and transition to alternative cytoreductive therapy such as interferon-alpha or ruxolitinib. 1, 2

Immediate Assessment Required

Check for hydroxyurea intolerance criteria:

• If hemoglobin has dropped below 10 g/dL at any dose of hydroxyurea required to maintain disease control, this meets European LeukemiaNet criteria for hydroxyurea intolerance 1, 3
• Obtain urgent laboratory evaluation for hemolytic anemia: serum LDH, haptoglobin, reticulocyte count, unconjugated bilirubin, urinalysis, and direct/indirect Coombs tests 2
• Look specifically for acute jaundice or hematuria, which signal hemolytic anemia requiring immediate hydroxyurea discontinuation 2, 4

Critical Decision Point: Is This Hydroxyurea Toxicity?

If hemoglobin <10 g/dL represents hydroxyurea-induced myelosuppression:

• Stop hydroxyurea immediately - do not attempt dose reduction, as the patient has already demonstrated intolerance 1, 2
• Transition to second-line cytoreductive therapy with interferon-alpha (preferred as non-leukemogenic) or consider ruxolitinib if the patient has failed multiple agents 1
• The FDA label explicitly warns that bone marrow suppression with anemia is a recognized toxicity requiring drug discontinuation 2

If hemolytic anemia is confirmed:

• Discontinue hydroxyurea permanently - this is a recognized adverse effect in myeloproliferative disorders 2, 4
• Hemolysis has been specifically reported in patients with essential thrombocythemia and other MPDs on hydroxyurea, requiring multiple transfusions until drug cessation 4
• Do not rechallenge with hydroxyurea after confirmed hemolytic anemia 2

Common Pitfall to Avoid

Do not continue iron supplementation alone while maintaining hydroxyurea - iron deficiency is not the primary issue if the patient meets intolerance criteria. The European LeukemiaNet specifically defines hemoglobin <10 g/dL at the lowest effective hydroxyurea dose as treatment failure requiring drug change, not supportive care escalation 1, 3

Alternative Cytoreductive Options After Hydroxyurea Failure

Interferon-alpha is the preferred second-line agent:

• Non-leukemogenic, unlike sequential cytotoxic agents 1
• Particularly appropriate for younger patients (<40 years) 1
• Can be effective even in late-phase refractory disease 5

Ruxolitinib may be considered:

• Especially if splenomegaly or constitutional symptoms are prominent 1
• Requires baseline platelet count ≥50 × 10⁹/L for safe initiation 1

Anagrelide is an option for essential thrombocythemia specifically:

• Non-leukemogenic alternative 1
• Less appropriate if anemia is the dominant concern 1

Supportive Care During Transition

• Provide RBC transfusions for symptomatic anemia during the transition period 1
• Consider erythropoiesis-stimulating agents (ESAs) only if serum erythropoietin ≤500 mU/dL and the patient is not transfusion-dependent 1
• ESAs are ineffective for transfusion-dependent anemia in myelofibrosis 1

Leukemogenic Risk Context

The decision to stop hydroxyurea is further supported by leukemogenic concerns:

• Hydroxyurea carries approximately 14% risk of AML/MDS when used alone, increasing to 30% when preceded by other cytotoxic agents like busulfan 6
• Patients receiving multiple cytotoxic agents have significantly higher leukemic transformation risk 1, 6
• This reinforces the importance of switching to non-leukemogenic agents like interferon-alpha rather than adding additional cytotoxic therapy 1