What are the main side effects of JAK (Janus Kinase) 1 and 2 inhibitors, such as ruxolitinib (Ruxolitinib) and baricitinib (Baricitinib), compared to JAK3 inhibitors, like tofacitinib (Tofacitinib) and ritlecitinib (Ritlecitinib), in terms of neutropenia and lymphopenia?

JAK Inhibitor Side Effects: Neutropenia with JAK1/2 vs Lymphopenia with JAK3

JAK1/2 inhibitors primarily cause neutropenia while JAK3 inhibitors are more associated with lymphopenia due to their different signaling pathway effects on hematopoiesis. This distinction is important for monitoring and managing patients on these medications.

Mechanism of Hematologic Side Effects

JAK1/2 Inhibitors (Ruxolitinib, Baricitinib)

• Neutropenia mechanism: JAK2 plays a crucial role in hematopoiesis, particularly in granulocyte colony-stimulating factor (G-CSF) signaling which is essential for neutrophil production 1
• Hematologic profile:
  • Neutropenia (0.5-1.0 × 10⁹/L) is common but rarely associated with infections 1
  • Anemia is especially prominent due to JAK2 inhibition (erythropoietin signals via JAK2 homodimers) 1
  • Thrombocytopenia can also occur 1

JAK3 Inhibitors (Tofacitinib, Ritlecitinib)

• Lymphopenia mechanism: JAK3 is predominantly expressed in lymphocytes and mediates signaling through the common gamma chain cytokine receptors (IL-2, IL-4, IL-7, IL-9, IL-15, IL-21) that are critical for lymphocyte development and function 1
• Hematologic profile:
  • Lymphopenia is more common, with counts <0.5 × 10⁹/L associated with increased risk of serious and opportunistic infections 1
  • Less impact on erythropoiesis and thrombopoiesis compared to JAK1/2 inhibitors 1

Clinical Implications and Monitoring

For JAK1/2 Inhibitors

• Monitoring focus:
  • Complete blood count with differential, particularly watching neutrophil counts
  • Hemoglobin levels (anemia management may be required)
  • Platelet counts 1
• Clinical concerns:
  • Ruxolitinib commonly causes thrombocytopenia and anemia as main adverse events 1
  • Worsening anemia is often seen at the beginning of therapy 1
  • Dose adjustments may be needed for cytopenias 2

For JAK3 Inhibitors

• Monitoring focus:
  • Lymphocyte counts (particularly CD4+ T cells)
  • Signs of opportunistic infections 1
• Clinical concerns:
  • Increased risk of herpes zoster reactivation 1
  • Higher risk of serious and opportunistic infections with profound lymphopenia 1

Practical Management Approach

1. Pre-treatment assessment:

   • Complete blood count with differential
   • Infectious disease screening (TB, HBV, HCV)
   • Vaccination status (consider recombinant zoster vaccine before JAK3 inhibitors) 3

2. Monitoring schedule:

   • For JAK1/2 inhibitors: CBC with differential every 4 weeks initially, then every 3 months; more frequent monitoring if cytopenias develop 1
   • For JAK3 inhibitors: CBC with differential at baseline, 4-8 weeks after starting, and every 3 months thereafter 1

3. Dose adjustments:

   • For neutropenia with JAK1/2 inhibitors: Consider dose reduction if ANC <1.0 × 10⁹/L
   • For lymphopenia with JAK3 inhibitors: Consider interruption if lymphocyte count <0.5 × 10⁹/L 1

Important Considerations and Pitfalls

• Infection risk: Despite different cytopenia profiles, both classes increase infection risk, with herpes zoster being particularly common 1

• Combination therapy: Avoid combining with other immunosuppressants that may compound cytopenias 3

• Patient selection: For patients with pre-existing cytopenias, consider:

  • For anemic patients: Avoid JAK1/2 inhibitors or consider momelotinib (less myelosuppressive) 4
  • For patients with lymphopenia: JAK1/2 inhibitors may be preferred over JAK3 inhibitors
  • For thrombocytopenic patients: Consider pacritinib (less myelosuppressive) 4

• Recovery pattern: Cytopenias are generally reversible upon dose reduction or treatment discontinuation 2, 5

By understanding these differential hematologic effects, clinicians can better select appropriate JAK inhibitors based on patients' baseline hematologic parameters and monitor for the most likely adverse effects during treatment.