In a recent issue of Blood we reported that rituximab anti-CD20 monoclonal antibody is an active drug in adults with chronic idiopathic thrombocytopenic purpura (ITP), that it is able to induce long-lasting responses, and that in all responders a rise of the platelet count occurs early during treatment, usually right after the first antibody administration.1 We have now expanded our series with 7 additional cases, in whom we observed somewhat different patterns of response. Because patients with chronic ITP are being recruited for phase 2 clinical trials with rituximab (browse the web sites http://www.clinicaltrials.gov andhttp://www.itppeople.com/clinical.htm for more information), we would like to describe these cases.
Patients' pretreatment characteristics are reported in Table1. There were 6 women and 1 man, with a median age of 40 years (range, 20-66 years). All cases had ITP that had been resistant to between 2 and 6 different therapeutic regimens, including 3 patients who had already failed splenectomy. Rituximab schedule (375 mg/m2 intravenously once weekly for 4 consecutive weeks) and response criteria have been described before.1
All patients concluded the 4 doses of treatment and could be evaluated for response. As illustrated in Table 1, the platelet count rose to greater than 50 × 109/L in 6 patients, with 4 achieving a complete response (platelets > 100 × 109/L) and 2 a partial response (platelets > 50 × 109/L). In 5 of the responders (cases 1, 2, 4, 5, and 7) there was a marginal or no increase of the platelet count during rituximab administration, with responses appearing only 2 to 5 weeks after the last antibody infusion. Peak platelet counts occurred 10 to 16 weeks after the start of treatment, with a median peak count of 408 × 109/L (range, 92 × 109/L to 751 × 109/L). Two patients with complete remission (CR) have remained in remission with stable platelet counts during follow-up intervals of 7 to 12 or more months after the end of treatment. In the other 3 responders the follow-up is less than 6 months.
In one patient (case 6), we observed an early but transient rise of the platelet count after the first dose of rituximab, with a late response beginning to appear at week 8 from the start of treatment and lasting 7 weeks.
There were no significant changes of serum IgG, IgA, and IgM levels throughout the study, whereas peripheral blood B-cell counts sharply declined to near-zero values after the first dose of rituximab. Median absolute T-cell counts as well as natural-killer cell counts remained stable during the study period. No patient experienced adverse events during therapy.
Combining the results of our initial report with the present data, we can identify 2 patterns of response, early and late. In early responders there is an increase of the platelet count after the first or second antibody infusion. The platelet count continues to rise thereafter until a peak count, which is usually observed between week 6 and week 10. In late responders there is no rise of the platelet count during rituximab administration, or there is just a marginal and transient increase; in these cases platelets begin to rise at weeks 6 to 8 and very rapidly reach a peak count. How can one explain these 2 patterns of response? With the available data one can only speculate. It is possible that in early responders opsonized B cells block the macrophage system, a mechanism that reminds the mechanism of Fc receptor (FcR) blockade by opsonized red cells following anti-D immunoglobulin treatment.2 The decreased production of antiplatelet antibodies accounts for the late and sustained response. In late responders, the FcR blockade effect for some reason does not work, and we only see the late response.
In conclusion, our results confirm that rituximab is an active agent in patients with chronic ITP and that the side effects of this treatment are of mild entity. Contrary to our preliminary observations,1 responses can be expected not only early during treatment but also up to 6 weeks after the last rituximab infusion. Several issues about this agent, such as the optimum dose and treatment schedule, the exact mechanisms of action, and long-term side effects, are the objectives of current investigations.