A Phase II Study Evaluating the Efficacy of Rituximab in the Management of Patients with Relapsed or Refractory TTP
Authors: Foley Stephen Ronan , Rock Gail , Barth David , Arnold Donald M. , Webert Kathryn E , Yenson Paul R. , Kelton John G. , Clark William Foster , Li Lihua 
Published: October 2019

Abstract
Background: As many as 30-50% of patients diagnosed with Thrombotic Thrombocytopenic Purpura (TTP) either relapse or become refractory to therapeutic plasma exchange (TPE). There remains a pressing need to evaluate novel treatments for these patients. Rituximab is a chimeric anti-CD20 monoclonal antibody that has demonstrated efficacy potentially by eliminating active B-lymphocytes and production of ADAMTS 13 inhibitor considered central to the pathogenesis of TTP.
Intervention: We conducted a prospective multi-center phase II open-label trial in Canadian hospital-based apheresis units to evaluate the efficacy of rituximab in the management of adult patients with relapsed or refractory TTP. Functional and antigenic ADAMTS13 enzyme, inhibitor levels and anti-CD 20 were measured at initiation, 8, 12, 24 and 52-weeks as well as routine hematologic parameters, complete remission, rate of relapse, overall mortality and adverse events. Rituximab was administered intravenously once weekly for a total of 4 doses at 375 mg/m2 in eligible consenting patients.
Results: Twenty refractory and 20 relapsing TTP patients were enrolled (N=40). A complete response (CR) was defined by a platelet count >150 x 109/L, an LDH <1.5 times the upper limit of normal, absence of progressive neurologic symptoms and no further need for TPE. At week 8, 77% of refractory patients and 90% of relapsed patients were in CR. At week 52, 15/20 refractory patients (3 deaths, 1 lost to follow-up) and 18/20 of relapsed patients (1 withdrew, 1 lost to follow-up) were alive and in CR. Of the 40 patients enrolled a total of 3 patients died; all in the refractory arm: two with functional ADAMTS13 <10% and detectable inhibitor. Two deaths were related to fungal infection (week 2) and active TTP (week 8). A third death was attributed to thrombotic complications at week 29. All refractory patients with normal ADAMTS13 enzyme at baseline had a complete response at week 8 and remained in remission for the remainder of follow-up (52 weeks). Despite being in complete hematological and clinical remission, relapsing TTP patients still had a positive inhibitor at 24 (50% of patients) and 52 weeks (10% of patients). All patients had < 3% CD 20+ B-lymphocytes at 8 and 12 weeks post rituximab. Median platelet counts in the refractory group recovered more slowly than in the relapsing TTP patients. By week 8 refractory TTP patients received a median of 26 plasma exchanges and relapsed patients received a median of 11(P<0.001).
Conclusion: At the conclusion of this study the overall mortality rate was 8%, 15% (95% CI: 5% to 36%) for the refractory group and 0% (95% CI: 0% to 16%) for the relapsed group. Nine refractory patients were dialysis-dependent at baseline and only 2 had a serum creatinine >250 µmol/L and remained on dialysis at week 52. These patients had normal ADAMTS13 enzyme measurements throughout the time period of the study. Results of this study indicate that TPE and rituximab is an effective combination in patients with relapsed or refractory TTP.

Disclosures
Foley: Novartis: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Lundbeck: Consultancy, Honoraria; Hoffman-LaRoche: Consultancy, Honoraria, Research Funding; Jansen: Consultancy, Honoraria; Alexion: Consultancy, Honoraria. Off Label Use: Rituxan is a CD20-directed cytolytic antibody indicated for the treatment of patients with: Non-Hodgkin's Lymphoma (NHL) (1.1) Chronic Lymphocytic Leukemia (CLL) (1.2)  Rheumatoid Arthritis (RA) in combination with methotrexate in adult patients with moderately-to severely-active RA who have inadequate response to one or more TNF antagonist therapies (1.3) . Arnold:GSK: Honoraria, Research Funding; Hoffman-LaRoche: Research Funding; Bristol Myers Squibb: Consultancy; Amgen: Consultancy, Honoraria, Research Funding. Clark:Alexion: Honoraria; CSN: Honoraria; ASN: Honoraria; Octapharm: Honoraria; Danone Research: Honoraria.