Refractory Idiopathic Thrombocytopenic PurpuraNEW MODALITIES IN TREATMENT

Background

Splenectomy• Nearly 85% immediate platelet response , 70% will maintain them at 5 years• Risk for relapse the first 2 years after splenectomy: accessory spleen.

• Underlying disease giving rise to secondary ITP: “primary immunodeficiency”

• High rates of spontaneous remission in children• Overwhelming infection from encapsulated organisms “vaccines &

prophylactic penicillin”• Two weeks before surgery: Vaccines, Penicillin

Safety

• Irreversible procedure• Laparoscopic splenectomy is considered safe “Not less than 20 × 109 at

the time of surgery”

• Portal vein thrombosis: has been reported in children• long-term risk of sepsis: monitoring for late thrombotic events

• Rate of venous thrombosis, atherosclerosis, and pulmonary hypertension is unknown, BUT described after splenectomy in other hematologic diseases

Splenectomy

Rituximab• Rituximab depletes B cells by binding to the CD20 antigen surface markers.

(refer to Pathophysiology)

• Rituximab has been shown to increase numbers of T-regulatory cells and prevent the activity of Th1-autoreactive cells specifically against GPIIb/IIIa.

• Not FDA approved for the treatment of ITP.

• American Hematology Association have more than 5 years of experience in the use of rituximab as a second-line.

• Initial response rate approximately 60%• Germinal centers and the BM theory. In addition, the majority of plasma cells are

preserved in patients receiving anti-CD20 Ab therapy.

• No “standard” dose for rituximab in children, most frequently administered dose remains 375 mg/m2 for 4 consecutive weeks, Single 375 mg/m2, similar response100 mg/dose for 4 weeks

• Late relapses are possible• Previous splenectomy NO

• Corticosteroids and secondary

Rituximab

• Serum sickness

• Hypogammaglobulinemia: 1) Check baseline Igs before administration.2) Supplemental IVIg is indicated yearly.

Comparing Rituximab with Splenectomy • No RCT• Two randomized trials• Rituximab + Dexamethasone to Dexamethasone AND Rituximab with Placebo• Surgery could be delayed Meta analysis

Safety

Rituximab

TPO• Endogenous TPO regulates platelet production by increasing the number, ploidy, and

maturation of BM megakaryocytes• TPO is made in the liver, and its synthesis is consistent over time unless there are

reductions in the number of functioning hepatocytes• Recombinant human TPO agents• Half-lives of 40 hours and increased platelet counts in humans.• Abs to endogenous TPO

Two new TPO receptor agonists (Romiplostim and Eltrombopag) have been studied extensively and are approved for the treatment of chronic ITP in adults who have had an insufficient response to corticosteroids, IVIg, and splenectomy.

• It has no homology to TPO, the risk of immunogenicity seen with early agents is diminished.

• Dose dependent response• On day 5 and diminishes by day 28 after a single subcutaneous dose.• Romiplostim has been FDA approved since 2008• Initial dose of 1 μg/kg given subcutaneously each week• Third trial patients had a platelet count > 50 × 109/L

• Elalfy et al denoteedd that 50% of patients in both romiplostim and placebo arms had at least one adverse event; none was serious

• Ten patients on romiplostim (83.3%) maintained the efficacy endpoint

• Mokhtar et al, Results revealed that four out of the seven patients achieved variable response

Romiplostim

• Small, nonpeptide TPO mimetic, NO homology to endogenous TPO NOT immunogenic

• It binds to the transmembrane region of the TPO receptor rather than the TPO-binding site, NOT compete with endogenous TPO = additive

• Dose dependent, half-life being 21-30 hr• Oral, starting dose of 50 mg daily• Polyvalent cations such as calcium, aluminum, magnesium, and zinc also reduce the

absorption of eltrombopag• A trial demonstrated a 59% response rate for platelet counts > 50 × 109/L at 6 weeks

compared with 16% in the placebo group.

Eltrombopag

• Myelofibrosis formation after prolonged stimulation of megakaryocytes with TPO receptor agonists “mouse models”

• Reports in humans: development or worsening of cataracts and lens changes “Eltrombopag”

• Neither TPO agents should be given to pregnant or nursing teens

Safety

TPO

Comparing Rituximab alone with Rituximab+ TPO (2015 mar)

• Response was achieved in 79.2% of patients in the combination group vs 71.1% in the monotherapy group

• Complete response rate was 45.4% in the combination group compared with 23.7% in the monotherapy group

• The combination group had significantly shorter time to response compared with the monotherapy group

• Failed to show a beneficial effect on the long-lasting response

References1. American society Of Hematology Childhood immune thrombocytopenia: role of

rituximab, recombinant thrombopoietin, and other new therapeutics, Janna M. Journeycake, December 8, 2012

2. Annals of Hematology, Romiplostim in children with chronic refractory ITP: randomized placebo controlled study, Mohsen Saleh Elalfy, 12 February 2011

3. Platelets, Volume 23, Issue 4, 2012, Romiplostim therapy in children with unresponsive chronic immune thrombocytopenia, Mokhtar GM, 2012 Apr 3.

4. American society Of Hematology, A multicenter randomized open-label study of rituximab plus rhTPO vs rituximab in corticosteroid-resistant or relapsed ITP, Zhou H et al, Epub 2015 Jan 9.