What is the recommended treatment for anemia in a patient with myelodysplastic syndrome (MDS) who is JAK2 (Janus kinase 2) positive?

Treatment of Anemia in JAK2+ Myelodysplastic Syndrome

Erythropoiesis-stimulating agents (ESAs) are the first-line treatment for anemia in MDS patients, including those with JAK2 positivity, when baseline serum erythropoietin levels are <500 mU/mL and transfusion requirements are limited. 1

Initial Assessment and Risk Stratification

Before initiating treatment, perform:

• Complete blood count with differential
• Serum erythropoietin (sEpo) level measurement
• Bone marrow aspiration with iron stain and cytogenetics
• Assessment for del(5q) status
• Verification of iron status (treat deficiency if present)

First-Line Treatment Algorithm

For JAK2+ MDS without del(5q):

1. Measure serum erythropoietin level

   • If sEpo ≤500 mU/mL:

     • Start ESA therapy: Epoetin 40,000-60,000 units SC 1-3 times weekly or Darbepoetin 150-300 μg SC weekly 2, 1
     • Assess response after 6-8 weeks
     • Response rates are approximately 60% when baseline EPO level is low and transfusion requirement is absent or limited 2

   • If sEpo >500 mU/mL:

     • ESAs are unlikely to be effective (poor response rate) 2
     • Consider alternative approaches (see second-line options)

2. If partial response to ESA alone:

   • Add G-CSF 1-2 μg/kg SC daily or 1-3 times weekly 2
   • This combination is particularly effective in patients with ≥15% ringed sideroblasts 2

For JAK2+ MDS with del(5q):

• Lenalidomide is the treatment of choice at 10 mg/day for 3 weeks every 4 weeks 2
• Response rates of 60-65% with median duration of RBC transfusion independence of 2-2.5 years 2
• Monitor for neutropenia and thrombocytopenia, which occur in ~60% of patients during initial weeks 2

Second-Line Treatment Options

If no response to first-line therapy after 8 weeks:

1. For patients without del(5q):

   • Immunosuppressive therapy (ATG ± cyclosporine) if patient has favorable features:

     • Age <65 years
     • Transfusion history <2 years
     • Normal karyotype
     • HLA-DR15 positive
     • Hypocellular marrow 2

   • Hypomethylating agents (Azacitidine or Decitabine)

     • Can achieve RBC transfusion independence in 30-40% of patients 2
     • Consider for patients unlikely to respond to immunosuppressive therapy

   • Lenalidomide

     • 25-30% response rate in non-del(5q) MDS resistant to ESAs 2
     • Can be combined with ESAs if initial ESA response was lost 2

2. For patients with del(5q) resistant to lenalidomide:

   • Consider hypomethylating agents
   • Test for TP53 mutations (associated with poor outcomes) 2
   • Consider allogeneic stem cell transplantation for eligible patients 2

Monitoring and Follow-up

• Evaluate response after 6-8 weeks of treatment
• For ESA responders, continue treatment but attempt to decrease dose to lowest effective dose
• Monitor complete blood counts regularly
• Target hemoglobin ≤12 g/dL to avoid thromboembolic complications 2
• For lenalidomide patients, monitor for cytopenias weekly during first 8 weeks

Transfusion Support

• Use leukopoor RBC products for symptomatic anemia when specific treatments fail 2
• Consider iron chelation therapy for patients requiring chronic transfusions 2
• For transplant candidates, consider CMV-negative and irradiated products 2

Clinical Pearls and Pitfalls

• Predictors of good response to ESAs: Low baseline sEpo (<500 mU/mL), limited transfusion history, <5% marrow blasts, and no multi-lineage dysplasia 1
• Avoid targeting hemoglobin >12 g/dL due to increased risk of thromboembolic events 2
• ESAs have shown no negative impact on AML progression and may improve survival in lower-risk MDS 2
• JAK2 positivity in MDS may indicate overlapping features with myeloproliferative neoplasms, but the core treatment approach for anemia remains similar
• Always verify iron repletion before starting ESA therapy 2
• If no response is seen within 8 weeks, treatment should be considered a failure and discontinued 2