What is the management approach for a patient with Immune Thrombocytopenic Purpura (ITP)?

Management of Immune Thrombocytopenic Purpura (ITP)

The primary goal in ITP management is achieving a platelet count ≥30-50 × 10⁹/L to prevent major bleeding, not normalizing platelet counts, and treatment should only be initiated when thrombocytopenia severity and clinical condition increase bleeding risk. 1, 2

When to Treat vs. Observe

• Treatment is indicated when platelet count <30 × 10⁹/L with bleeding risk 2
• Treatment is also indicated for platelet counts between 30-50 × 10⁹/L if accompanied by substantial mucous membrane bleeding 1
• Patients with higher platelet counts without significant bleeding can be observed without treatment 1
• The decision to treat should be based on bleeding symptoms and bleeding risk, not platelet count alone 3

First-Line Treatment Strategy

Standard Corticosteroid Regimens

• Prednisone 0.5-2 mg/kg/day remains the standard initial therapy, continued until platelet count increases to 30-50 × 10⁹/L, which may require several days to several weeks 1
• Prednisone should be rapidly tapered and stopped in responders, and especially in non-responders after 4 weeks to avoid corticosteroid-related complications including weight gain, osteoporosis, cataracts, and infections 1, 3
• High-dose dexamethasone 40 mg/day for 4 days offers superior response rates compared to conventional prednisone, with initial response rates of 86-90% and sustained responses in 50-74% of patients 1, 2
• Dexamethasone can be given as a single cycle or up to 4 cycles given every 14 days 1

Emergency Treatment for Active Bleeding

• For uncontrolled bleeding or active CNS, GI, or genitourinary bleeding, combine prednisone with IVIg 1
• IVIg 1 g/kg single dose should be used with corticosteroids when rapid platelet increase is required within 24 hours 2
• IVIg 2 g/kg can be administered in divided doses per package insert 2
• High-dose methylprednisolone may also be useful in emergency settings 1
• Platelet transfusion at larger-than-usual doses, possibly in combination with IVIg, should be considered in life-threatening situations 1
• IV anti-D 50-75 μg/kg can be used for Rh(D) positive, non-splenectomized patients 2

Second-Line Treatment: The New Paradigm

Thrombopoietin Receptor Agonists (TPO-RAs) as Preferred Second-Line

TPO-RAs should be the initial second-line therapy for refractory ITP, offering sustained platelet responses with favorable long-term safety profiles and the potential for remission in up to 30% of patients after discontinuation. 3

Evidence Supporting TPO-RAs as First Choice

• Overall platelet response rates of 88% in non-splenectomized patients and 79% in splenectomized patients 1, 3
• Sustained responses documented for up to 4 years with continuous administration 1, 3
• Up to 30% of patients achieve long-term remission after tapering and discontinuation 4, 3
• TPO-RAs are the only therapy specifically developed to treat ITP, stably increasing platelet counts, reducing bleeding, reducing the need for rescue therapy, and improving quality of life 4, 3
• No increased risk of infections, thromboembolism, or malignancy compared to splenectomy 3
• Patients who fail one TPO-RA may still respond to the alternate agent 4, 3

Romiplostim (Nplate) Dosing

• Initial dose: 1 mcg/kg subcutaneous weekly injection 5
• Adjust weekly dose by increments of 1 mcg/kg until platelet count ≥50 × 10⁹/L 5
• Maximum weekly dose: 10 mcg/kg 5
• Most adult patients who respond achieve and maintain platelet counts ≥50 × 10⁹/L with a median dose of 2-3 mcg/kg 4
• If platelet count <50 × 10⁹/L, increase dose by 1 mcg/kg 5
• If platelet count >200 × 10⁹/L and ≤400 × 10⁹/L for 2 consecutive weeks, reduce dose by 1 mcg/kg 5
• If platelet count >400 × 10⁹/L, hold dose and assess platelet count weekly; resume at reduced dose when platelet count falls to <200 × 10⁹/L 5

Eltrombopag (Promacta/Alvaiz) Dosing

• Initial dose: 25-75 mg oral daily 1
• For ITP, initiate at 36 mg orally once daily for most adult and pediatric patients 6 years and older 6
• Maximum dose: 54 mg per day for ITP 6
• Must be taken without a meal or with a meal low in calcium (≤50 mg) 6
• Take at least 2 hours before or 4 hours after any medications or products containing polyvalent cations, such as antacids, calcium-rich foods, and mineral supplements 6

TPO-RA Management Pearls

• Use the minimum TPO-RA dose necessary to maintain target platelet count and prevent bleeding 4
• If a patient achieves target platelet count at the lowest recommended dose, hold the TPO-RA and monitor closely for potential remissions 4
• Abrupt interruptions of TPO-RAs or excessive dose adjustments may cause platelet fluctuations and should be avoided 4
• Platelet fluctuations are more common with romiplostim and may be resolved by switching to eltrombopag 4
• Platelet fluctuations may also be more common in splenectomized patients 4

Splenectomy: Now a Later Option

Splenectomy should now be considered after TPO-RAs given the availability of effective medical therapy. 3

When to Consider Splenectomy

• Typically defer splenectomy for at least 6 months to allow for potential spontaneous remission 1
• For ITP <12 months duration, prefer TPO-RAs over rituximab due to greater durability of response with ongoing use 2
• For ITP >12 months duration, prefer rituximab over splenectomy despite splenectomy's superior durable response rates, due to operative risks and irreversible nature with long-term infection and thrombosis risks 2
• Splenectomy may be the most desirable option for patients who want to minimize their medication and monitoring needs 4

Splenectomy Outcomes and Risks

• Initial response rate of 80-85% 1, 2, 3
• Long-term durable response in 60-70% of patients (approximately two-thirds achieving lasting remission over 5-10 years) 1, 3
• Up to 30% of initial responders relapse within 10 years, typically within 2 years 3
• 10% surgical complication rate within 30 days, even with laparoscopic approaches 3
• 3- to 4-fold increased risk of death from septicemia, pulmonary embolism, and non-Hodgkin lymphoma that persists for >10 years 3
• Vaccination before splenectomy is essential to prevent overwhelming post-splenectomy infection 1
• Long-term risks include delayed relapse, infection, thromboembolism, and possibly cancer 4

Rituximab as Alternative Second-Line

• Initial response rates of 60% with complete responses in 40% 1, 3
• Can be dosed at 100 mg or 375 mg/m² weekly for 4 weeks 1
• Response typically occurs within 1-8 weeks 3
• Long-term sustained responses in only 20-30% of cases (15-20% of responders maintain response >3-5 years) 2, 3
• The lack of significant benefit with long-term use of rituximab should be considered 4
• Effects of age, sex, and duration of ITP on efficacy should limit use in male patients and in those who have had ITP for >1 year 4

Third-Line Immunosuppressive Options for Truly Refractory Cases

Individual Agents and Response Rates

• Azathioprine 1-2 mg/kg/day (maximum 150 mg/day): response rates up to 45-67% 1, 3
• Cyclosporin A 5 mg/kg/day for 6 days, then 2.5-3 mg/kg/day (titrate to blood levels 100-200 ng/mL): response rates of 50-80% with 42% complete response 1, 3
• Mycophenolate mofetil 1000 mg twice daily for at least 3-4 weeks: response rates up to 75% with complete response in up to 45% 1, 3
• Danazol 200 mg 2-4 times daily: response rates of 40-67% complete or partial response 1, 3
• Cyclophosphamide: response rates of 24-85% but carries a risk of acute myeloid leukemia 1, 3
• Dapsone 75-100 mg/day: response rates up to 50% within 3 weeks, but requires screening for G6PD deficiency before starting 1, 3

Monitoring Requirements

• Weekly CBC with platelet counts during dose adjustment phase 1
• Monthly CBC monitoring after stable dose achieved 1
• Weekly CBC for at least 2 weeks following discontinuation of treatment 1
• For pediatric patients on TPO-RAs, reassessment of body weight is recommended every 12 weeks 5
• Monitor for bone marrow reticulin formation with TPO-RAs 2

Critical Pitfalls to Avoid

• Prolonged corticosteroid use (>6-8 weeks) must be avoided due to risks of weight gain, osteoporosis, cataracts, infections, and increased bleeding risk 1, 3
• Do not use plasmapheresis, as there is no evidence of efficacy in chronic ITP 1
• Do not delay TPO-RA initiation in favor of splenectomy based on outdated treatment paradigms 3
• Do not attempt to normalize platelet counts—the goal is maintaining hemostatic platelet counts (30-50 × 10⁹/L) 3, 5
• Discontinue TPO-RAs if platelet count does not increase to a level sufficient to avoid clinically important bleeding after 4 weeks at maximum weekly dose of 10 mcg/kg 5
• Monitor for thrombotic/thromboembolic complications, particularly portal vein thrombosis in patients with chronic liver disease receiving eltrombopag 6
• Abrupt interruptions of TPO-RAs or excessive dose adjustments may cause dangerous platelet fluctuations 4