What is the recommended second-line therapy for patients with chronic immune thrombocytopenia (ITP) who have had an insufficient response to first-line treatments, specifically using a Thrombopoietin (TPO) receptor agonist?

Thrombopoietin Receptor Agonists for Chronic ITP After First-Line Treatment Failure

For patients with chronic immune thrombocytopenia (ITP) who have had an insufficient response to first-line treatments, thrombopoietin receptor agonists (TPO-RAs) are the recommended second-line therapy due to their superior efficacy and safety profile compared to other options. 1

TPO-RA Options and Efficacy

TPO-RAs are specifically approved for patients with chronic ITP who had an insufficient response to either first-line therapy or splenectomy. The available agents include:

• Eltrombopag: Oral tablet, taken once daily without food or with a low-calcium meal 2
• Romiplostim: Subcutaneous injection, administered once weekly 3
• Avatrombopag: Oral tablet (newer agent, mentioned in 2022 guidelines) 1

These agents have demonstrated impressive response rates:

• 70-80% of patients respond to TPO-RAs in clinical trials 1
• 85-95% of patients respond at least once in long-term extension studies 1
• Initial responses typically occur within 1-2 weeks of treatment initiation 1

Mechanism of Action

TPO-RAs work by:

• Binding to and activating the thrombopoietin receptor on hematopoietic stem cells 4
• Directly stimulating platelet production in the bone marrow 1
• Unlike earlier thrombopoietin mimetics, modern TPO-RAs do not induce formation of anti-TPO antibodies 1

Clinical Benefits Beyond Platelet Count

TPO-RAs offer several advantages:

• Reduce bleeding events and need for emergency treatments 1
• Improve quality of life in patients with chronic ITP 1
• May induce long-term remissions in approximately 30% of patients, even after discontinuation 1
• Real-world experience confirms the efficacy seen in clinical trials 1

Choosing Between TPO-RAs

The 2022 update to the American Society of Hematology guidelines suggests that any of the available TPO-RAs (avatrombopag, eltrombopag, hetrombopag, or romiplostim) can be used, as there are no substantial differences among them that would change recommendations regarding TPO-RAs as a drug class 1.

If a patient fails to respond to one TPO-RA, switching to another may be beneficial:

• In one study, 83% of patients who didn't respond to eltrombopag subsequently responded to romiplostim 5
• 60% of patients who didn't respond to romiplostim subsequently responded to eltrombopag 5

Monitoring and Safety Considerations

When using TPO-RAs, monitor for:

• Hepatotoxicity: Regular liver function tests are required, especially with eltrombopag 2
• Thrombotic/thromboembolic complications, particularly in patients with chronic liver disease 2, 3
• Development of neutralizing antibodies if severe thrombocytopenia develops during treatment 3
• Weekly complete blood counts during dose adjustment, then monthly after stable dose 6

Comparison with Other Second-Line Options

TPO-RAs are generally preferred over other second-line options:

• Splenectomy: While effective (85% initial response), it carries significant risks including infections, thromboembolism, and possibly increased malignancy risk that persists for >10 years after surgery 1
• Rituximab: Lower sustained response rates compared to TPO-RAs 7
• Fostamatinib: Newer option, but primarily investigated in highly refractory patients failing multiple agents 1

Treatment Algorithm for Chronic ITP

1. First-line treatment failure (insufficient response to corticosteroids, IVIg, or anti-D immunoglobulin)
2. Initiate TPO-RA therapy:
   • Eltrombopag: Start at 36 mg once daily (lower dose for patients with hepatic impairment or East-/Southeast-Asian ancestry) 2
   • Romiplostim: Start at 1 mcg/kg once weekly subcutaneously 3
3. Adjust dose to maintain platelet count ≥50 × 10⁹/L
4. If inadequate response to one TPO-RA, consider switching to another TPO-RA
5. If TPO-RAs fail, consider rituximab, splenectomy, or other immunosuppressive agents 7

Special Considerations

• TPO-RAs were traditionally considered lifelong therapies, but evidence suggests some patients may achieve sustained remissions after discontinuation 1
• Approximately 20% of patients develop adverse reactions that may necessitate switching to a different TPO-RA 5
• The goal of treatment is to achieve a safe platelet count (>30 × 10⁹/L) to prevent bleeding, not to normalize platelet counts 6

TPO-RAs represent a significant advancement in ITP management, offering effective platelet count improvement with a favorable safety profile compared to more invasive options like splenectomy.