The prolong trial: A two Phase randomized placebo-controlled trial to optimize rituximab response with dexamethasone and maintenance therapy with low dose rituximab in immune thrombocytopenia (ITP) patients

Abstract

Abstract Background ITP is an autoimmune bleeding disorder characterized by thrombocytopenia and increased bleeding risk. Corticosteroids (CS) are the standard 1st-line treatment of ITP. Most adults respond to CS initially, but < 1/3 achieve durable responses; the remaining require a 2nd-line therapy. Rituximab, a chimeric anti-CD20 monoclonal antibody that targets B cells is a widely used 2nd-line treatment in ITP. It induces durable responses in about 40% of patients; however, half of these will relapse over time. The primary objective was to determine if rituximab (R)maintenance therapy is superior to placebo in prolonging responses among ITP patients who respond initially to R. Secondary objectives investigated if the initial response to R could be improved by adding dexamethasone (DXM), as well safety, bleeding and patient reported outcomes. Methods PROLONG was a prospective multi-center, international, two-phase, double-randomized study (NCT03010202), started Jan 2017 and completed Dec 2024. Patients were recruited from 17 centers in 5 countries (Norway, Tunisia, Egypt, France, Denmark). The 1st (induction) phase was an open-label with 1:1 randomization into: R 1000 mg on day 1 and 15 versus R + 2 cycles of DXM (20 mg daily for 4 days) on days 1 and 15. The 2nd (maintenance) phase was a double-blind, 1:1 randomization of those who responded in the induction phase, to maintenance with rituximab 500 mg or placebo (equivalent volume of iv NaCl 0.9%) on weeks 0 and 24 after randomization. Inclusion criteria were: primary ITP of < one-year duration, platelet count of <30X109/L measured within 4 weeks prior to inclusion, and failure to respond or response with relapse after one or more 4-day cycles of DXM or after > 3 weeks of prednisolone. Patients who responded (platelet count >50X109/L) at week 24 after induction were randomized to maintenance with R or placebo. The primary endpoint was sustained response during the maintenance phase with loss of response defined as: 2 consecutive measurements with platelet counts <50X109/L at a 1-8-week interval, and/or, use of any ITP-directed therapies due to bleeding or thrombocytopenia. Main secondary endpoints were; response to R versus R+DXM (defined as mean platelet count >50X109/L at week 24 (± 2 weeks) after randomization without use of any other ITP-directed therapies after week 18 following randomization), bleeding measured by WHO bleeding criteria, and number of advers events. Results In total 130 patients were randomized. Of these, 3 did not receive study medication. The intent-to-treat population included 127 patients (mean age 44 years, 57% females) randomized to R monotherapy (n=64) or R+DXM (n=63). Median duration of ITP prior to randomization was 3 months and median platelet count was 15X109/L. Four patients received less than 2 full-dose R infusions and 2 received less than 2 full-dose DXM cycles, mainly due to intolerance. At week 24, 24 (37.5%) patients achieved response to R vs 38 (60.3%) to R+DXM (p-value =0.01). Seventeen (26%) patients in the R group and 8 (13%) in the R+DXM discontinued prematurely due to lack of response, death or intolerance. Median (Q1;Q3) platelet counts at week 24 in those who completed the 1st phase were in the R/R-DXM groups 80X109/L (19;177) vs 97X109/L (46;181). Time to first bleeding episode was significantly longer in the R+DXM group (p-value =0.03). No difference in use of rescue therapy was observed between the groups. Median (Q1;Q3) levels of IgG (g/L) at week 24 in the R/R+DXM groups were 8.8 (7;13) and 11 (7;13) and IgM were 0.9 (0.6-1.2) and 0.9 (0.4;1.5) respectively. During the 1st phase 33 serious adverse events were reported in 25 patients, including: 4 covid infections, 2 venous thrombosis, 7 serious bleeding events (2 fatal) and 2 bacterial infections (1 fatal). 59 out of 127 patients (46%) who responded to induction therapy, entered the maintenance phase, and were randomized to maintenance with R or placebo. No SAEs were reported during this phase. Analysis of response to maintenece with R/placebo is ongoing but full results should be available by ASH. Conclusions In ITP patients of less than 1 year duration, who had inadequatel response to CS, adding a moderate dose DXM to R substantially improved the initial response compared to R alone and delayed the time to first bleeding. Results of the maintenance phase will be presented at ASH. The study was funded by the Norwegian Regional Health Authority South-East