Whether to give rituximab pre- or post-splenectomy is also uncertain. An advantage of presplenectomy rituximab is that many patients will achieve remission, delaying the need for surgery. Also, rituximab is a good option for patients whose medical conditions put them at high risk for complications with splenectomy. However, it is unknown whether rituximab poses any long-term risks, while the long-term risks of splenectomy are well-defined. Rituximab is the only curative option left for patients who have failed splenectomy and is a reasonable option for these patients.
There is an intriguing trial in which patients were randomly assigned to dexamethasone alone versus dexamethasone plus rituximab upon presentation with ITP; those who were refractory to dexamethasone alone received salvage therapy with dexamethasone plus rituximab.43 The dexamethasone plus rituximab group had an overall higher rate of sustained remission at 6 months than the dexamethasone group, 63% versus 36%. Interestingly, patients who failed their first course of dexamethasone but then were “salvaged” with dexamethasone/rituximab had a similar overall response rate of 56%, suggesting that saving the addition of rituximab for steroid failures may be an effective option.
Although not “chemotherapy,” rituximab is not without risks. Patients can develop infusion reactions, which can be severe in 1% to 2% of patients. In a meta-analysis the fatal reaction rate was 2.9%.40 Patients with chronic hepatitis B infections can experience reactivation with rituximab, and thus all patients should be screened before treatment. Finally, the very rare but devastating complication of progressive multifocal leukoencephalopathy has been reported.
Thrombopoietin Receptor Agonists
Although patients with ITP have low platelet counts, studies starting with Dameshek have shown that these patients also have reduced production of platelets.44 Despite the very low circulating platelet count, levels of the platelet growth factor thrombopoietin (TPO) are not raised.45 Seminal studies with recombinant TPO in the 1990s showed that ITP patients responded to thrombopoietin-stimulating protein, but the formation of anti-TPO antibodies halted trials with the first generation of these agents. Two TPO receptor agonists (TPO-RA) are approved for use in patients with ITP.
Romiplostim. Romiplostim is a peptibody, a combination of a peptide that binds and stimulates the TPO receptor and an Fc domain to extend its half-life.46 It is administered in a weekly subcutaneous dose starting at 1 to 3 µg/kg. Use of romiplostim in ITP patients produces a response rate of 80% to 88%, with 87% of patients being able to wean off or decrease other anti-ITP medications.47 In a long-term extension study, the response was again high at 87%.48 These studies have also shown a reduced incidence of bleeding.
The major side effect of romiplostim seen in clinical trials was marrow reticulin formation, which occurred in up to 5.6% of patients.47,48 The clinical course in these patients is the development of anemia and a myelophthisic blood smear with teardrop cells and nucleated red cells. These changes appear to reverse with cessation of the drug. The bone marrow shows increased reticulin formation but rarely, if ever, shows the collagen deposition seen with primary myelofibrosis.
Thrombosis has also been seen, with a rate of 0.08 to 0.1 cases per 100 patient-weeks,49 but it remains unclear if this is due to the drug, part of the natural history of ITP, or expected complications in older patients undergoing any type of medical therapy. Surprisingly, despite the low platelet counts, patients with ITP in one study had double the risk of venous thrombosis, demonstrating that ITP itself can be a risk factor for thrombosis.50 These trials have shown no long-term concerns for other clinical problems such as liver disease.
Eltrombopag. The other available TPO-RA is eltrombopag,51 an oral agent that stimulates the TPO receptor by binding the transmembrane domain and activating it. The drug is given orally starting at 50 mg/day (25 mg for patients of Asian ancestry or with liver disease) and can be dose escalated to 75 mg/day. The drug needs to be taken on an empty stomach. Eltrombopag has been shown to be effective in chronic ITP, with response rates of 59% to 80% and reduction in use of rescue medications.47,51,52 As with romiplostim, the incidence of bleeding was also decreased with eltrombopag in these trials.47,51
Clinical trials demonstrated that eltrombopag shares with romiplostim the risk for marrow fibrosis. A side effect unique to eltrombopag observed in these trials was a 3% to 7% incidence of elevated liver function tests.21,52 These abnormal findings appeared to resolve in most patients, but liver function tests need to be monitored in patients receiving eltrombopag.
Clinical use. The clearest indication for the use of TPO-RAs is in patients who have failed several therapies and remain symptomatic or are on intolerable doses of other medications such as prednisone. The clear benefits are their relative safety and high rates of success. The main drawback of TPO-RAs is the need for continuing therapy as the platelet count will return to baseline shortly after these agents are stopped. Currently there is no clear indication for one medication over the other. The advantages of romiplostim are great flexibility in dosing (1–10 µg/kg week) and no concerns about drug interaction. The current drawback of romiplostim is the Food and Drug Administration’s requirement for patients to receive the drug from a clinic and not at home. Eltrombopag offers the advantage of oral use, but it has a limited dose range and potential for drug interactions. Both agents have been associated with marrow reticulin formation, although in clinical use this risk appears to be very low.53