Rituximab and three dexamethasone cycles provide responses similar to splenectomy in women and those with immune thrombocytopenia of less than two years duration

Abstract

Adults with newly diagnosed or persistent immunothrombocytopenia frequently relapse upon tapering steroids; adults and children with chronic disease have an even lower likelihood of lasting response. In adults with newly-diagnosed immunothrombocytopenia, two studies showed that dexamethasone 40 mg/day × four days and 4 rituximab infusions were superior to dexamethasone alone. Studies have also shown three cycles of dexamethasone are better than one and patients with persistent/chronic immunothrombocytopenia respond less well to either dexamethasone or rituximab. Therefore, 375 mg/m(2) × 4 rituximab was combined with three 4-day cycles of 28 mg/m(2) (max. 40 mg) dexamethasone at 2-week intervals and explored in 67 ITP patients. Best long-term response was assessed as complete (platelet count ≥ 100 × 10(9)/L) or partial (50-99 × 10(9)/L). Only 5 patients had not been previously treated. Fifty achieved complete (n=43, 64%) or partial (n=7, 10%) responses. Thirty-five of 50 responders maintained treatment-free platelet counts over 50 × 10(9)/L at a median 17 months (range 4-67) projecting 44% event-free survival. Duration of immunothrombocytopenia less than 24 months, achieving complete responses, and being female were associated with better long-term response (P<0.01). Adverse events were generally mild-moderate, but 3 patients developed serum sickness and 2 colitis; there were no sequelae. Dexamethasone could be difficult to tolerate. Fourteen patients became hypogammaglobulinemic and half had increased frequency of minor infections; 9 of 12 evaluable patients recovered their IgG levels. Rituximab combined with three cycles of dexamethasone provides apparently better results to reported findings with rituximab alone, dexamethasone alone, or the combination with one cycle of dexamethasone. The results suggest medical cure may be achievable in immunothrombocytopenia, especially in women and in patients within two years of diagnosis. (clinicaltrials.gov identifier:02050581).

Trial registration: ClinicalTrials.gov NCT02050581.

Copyright© Ferrata Storti Foundation.

Figures

Figure 1.

Dosing of R+Dex combination therapy. (A) 53 patients received the intended dosage of 4 weekly infusions of standard dose (375 mg/m2) rituximab and three × 4-day cycles of 28 mg/m2 dexamethasone (maximum 40 mg) at 2-week intervals. Four patients either received their dexamethasone before the rituximab (1), after the rituximab (1), had 1 cycle of dexamethasone and 2–3-infusion replacement treatments with high-dose methylprednisolone (1) or had 3 infusions of high-dose methylprednisolone with each rituximab (1). (B) 8 patients had deviations in their dexamethasone dosing including one patient who received 5 cycles of low-dose dexamethasone by choice of the referring physician. (C) 5 patients had side effects (2 colitis and 3 serum sickness) which resulted in their receiving a reduced number of infusions of rituximab and of dexamethasone. (D) one patient discontinued rituximab after the 3rd infusion due to allergic reactions but received 3 courses of dexamethasone.

Figure 2.

Long-term analysis of all patients treated with R+3Dex. Kaplan-Meier analysis estimates the long-term response to R+3Dex. Vertical marks indicate the last follow up of an ongoing response. 44% of the 67 patients treated were estimated to have a long-term response at more than five years from treatment. Eight responders maintain their treatment-free response a median of nine months past the last relapse.

Figure 3.

Kaplan-Meier analysis of variables related to response to R+3Dex: (A) Duration of ITP ≤ 24 months vs. > 24 months. Vertical tick marks (Duration of ITP ≤ 24 months) and square markers (Duration of ITP > 24 months) indicate the last follow up of a response. In comparing shorter and longer durations of ITP (≤ and > 24 months), patients with shorter duration (solid lines) project better long-term responses (59%) than those with a longer history of disease (dotted lines; 19%) (log-rank P = 0.002). (B) Sex: females vs. males. Of 37 females, 31 responded and 25 had long-term treatment-free responses. Of 30 males, 19 responded and 10 had ongoing responses. Females had a better projected long-term outcome than males (females 61% vs. males 17%) (log-rank P = 0.0078). (C) Quality of Response: CR vs. PR CRs (solid line) projected a better long-term response than PRs (dotted line) (log-rank P = 0.0002). (D) Patient age: children vs. adults. Adults had a significantly higher initial response but responding children had a lower rate of relapse than responding adults so by 30 months from initial treatment there was no longer a significant difference in the projected long-term outcome of adults (47%) and children (41%).

Figure 4.

Response vs. age (18 years). There was no relationship between age of adult patients and best response achieved. Median age in the adult population (18 years) was 36 years (range 18–64 years).