What is the management of pancytopenia in an adult patient with a history of chronic myeloid leukemia or sickle cell disease taking hydroxyurea?

Management of Hydroxyurea-Induced Pancytopenia

Immediately discontinue hydroxyurea when pancytopenia develops, and do not resume until blood counts recover to safe thresholds (ANC ≥1,500/mm³, platelets ≥75,000/mm³, hemoglobin ≥10 g/dL), then restart at a reduced dose only if hydroxyurea remains clinically indicated. 1

Context-Specific Management Algorithms

For Chronic Myeloid Leukemia (CML)

Hydroxyurea should never be continued as definitive therapy for CML—it serves only as temporary cytoreduction before tyrosine kinase inhibitor (TKI) initiation. 2

If pancytopenia develops during the brief pre-TKI hydroxyurea period:

• Stop hydroxyurea immediately 1
• Initiate TKI therapy (imatinib 400 mg daily, nilotinib 300 mg twice daily, or dasatinib 100 mg once daily) as soon as BCR-ABL1 is confirmed, regardless of blood counts 2
• For symptomatic leukocytosis while awaiting count recovery, consider leukapheresis instead of restarting hydroxyurea 1
• Monitor CBC every 2-4 weeks until counts stabilize on TKI therapy 2

The critical error is delaying TKI initiation due to hydroxyurea-induced cytopenias—every day without TKI therapy represents lost opportunity for achieving optimal molecular responses. 2

For Myeloproliferative Neoplasms (Polycythemia Vera/Essential Thrombocythemia)

Hydroxyurea-induced pancytopenia in PV/ET patients defines resistance/intolerance to the drug and mandates switching to alternative cytoreductive therapy. 1, 3

European LeukemiaNet criteria for hydroxyurea resistance/intolerance include:

• ANC <1.0 × 10⁹/L, platelets <100 × 10⁹/L, or hemoglobin <10 g/dL at the lowest dose required to achieve disease control 1, 3
• This occurs in approximately 10-15% of patients on hydroxyurea therapy 1

Management algorithm when pancytopenia develops:

1. Discontinue hydroxyurea immediately 1, 3
2. For PV: Continue phlebotomy to maintain hematocrit <45% and low-dose aspirin (81-100 mg daily) 1, 4
3. For ET: Continue low-dose aspirin if high-risk patient 3, 4
4. Switch to second-line cytoreductive therapy:
   • Interferon-alpha (preferred for younger patients <40 years or pregnant patients) 1, 3, 4
   • Ruxolitinib (for PV patients resistant/intolerant to hydroxyurea) 3
   • Anagrelide (for ET patients, though primarily affects platelets) 3
   • Busulfan (only for elderly patients >70 years with PV) 1

For Sickle Cell Disease

The evidence for hydroxyurea in sickle cell disease shows it reduces pain crises and acute chest syndrome, but pancytopenia represents a serious toxicity requiring dose modification or discontinuation. 5

Management approach:

• Hold hydroxyurea until ANC ≥1,500/mm³, platelets ≥75,000/mm³, and hemoglobin recovers 6
• Consider filgrastim (G-CSF) for persistent severe neutropenia (ANC <500/mm³ for >7 days) 7
• When restarting, reduce dose by 25-50% from the dose that caused pancytopenia 6
• Monitor CBC weekly for 4 weeks after restart, then every 2-4 weeks 5
• If pancytopenia recurs at reduced dose, discontinue hydroxyurea permanently 6, 8

Critical Monitoring Parameters

During hydroxyurea therapy, monitor CBC every 2-4 weeks initially, then every 4-8 weeks once stable. 3, 4

Dose reduction thresholds (before frank pancytopenia develops):

• ANC 1,000-1,500/mm³: Hold drug until ANC ≥1,500/mm³, restart at reduced dose 1
• Platelets 50,000-75,000/mm³: Hold drug until platelets ≥75,000/mm³, restart at reduced dose 1
• Hemoglobin approaching 10 g/dL with declining trend: Consider dose reduction 1

Special Populations Requiring Dose Adjustment

Renal impairment significantly increases hydroxyurea exposure and pancytopenia risk. 6

For CrCl <60 mL/min or ESRD on hemodialysis:

• Reduce initial hydroxyurea dose by 50% 6
• Exposure (AUC) increases by 64% in patients with renal impairment 6
• Monitor CBC weekly for first month, then every 2 weeks 6

Common Pitfalls to Avoid

Do not continue hydroxyurea at the same dose hoping counts will spontaneously recover—this leads to prolonged, severe pancytopenia requiring transfusion support and growth factors. 7

Do not restart hydroxyurea at the original dose after count recovery—this invariably causes recurrent pancytopenia. 6, 7

Do not use hydroxyurea as long-term monotherapy for CML—this represents substandard care given the availability of curative TKI therapy. 2

In patients with prior exposure to multiple cytotoxic agents (busulfan, other alkylators), hydroxyurea-induced pancytopenia may be more severe and prolonged (>3 months recovery time documented). 7

Supportive Care During Recovery

For severe neutropenia (ANC <500/mm³):

• Consider filgrastim 5 mcg/kg/day subcutaneously until ANC >1,000/mm³ 1, 7
• Implement neutropenic precautions and consider prophylactic antibiotics if fever develops 1

For severe thrombocytopenia (platelets <10,000/mm³ or bleeding):

• Platelet transfusions to maintain count >10,000/mm³ (>50,000/mm³ if bleeding) 1

For severe anemia (hemoglobin <7-8 g/dL or symptomatic):

• RBC transfusions as needed 1
• In transplant candidates, use leukocyte-reduced blood products 2