Introduction:Acquired thrombotic thrombocytopenic purpura (TTP) is caused by autoantibodies against ADAMTS13 that prevent the cleavage of von Willebrand factor and allow the growth of microvascular thrombi, causing microangiopathic hemolysis and severe thrombocytopenia. Untreated TTP is almost always fatal but plasma exchange enables ~80% of patients to survive. Those who respond often have exacerbations or relapses that require more therapy. Exacerbations and refractory TTP usually can be treated effectively by combining plasma exchange, corticosteroids, and rituximab. A typical regimen for TTP is 4 weekly doses of rituximab 375 mg/m2, which is borrowed from protocols for B cell lymphomas. However, the pathogenic B cell mass in TTP is much less than in lymphoma and lower doses of rituximab may be enough. For example, case reports in TTP and studies in immune thrombocytopenia suggest that fixed doses of 100 mg and conventional doses of 375 mg/m2 have similar efficacy.

Methods:The ART study (Adjuvant Rituximab in TTP, NCT01554514) was designed as a pilot safety/efficacy study of low dose rituximab (100 mg/week x 4 doses) plus standard plasma exchange and corticosteroids for TTP. The study enrolled at Washington University, Beth-Israel Deaconess Medical Center, Emory University, and Duke University. Eligibility criteria include age ≥18 years with acute TTP and ADAMTS13 <10%. Exclusions include treatment for TTP within 2 months, severe infection, cancer, organ or stem cell transplant, pregnancy, hepatitis B, and use of calcineurin inhibitors within 6 months or rituximab within the past year. Treatment included daily 1.5 volume plasma exchanges, prednisone 1 mg/kg, and rituximab 100 mg weekly for 4 doses starting before the 5thplasma exchange. Treatment Response is defined as 2 consecutive days with a platelet count ≥150,000/µl. A Durable Treatment Response persists ≥30 days after stopping plasma exchange. The primary endpoint is a composite of Exacerbation or Refractory TTP, where Exacerbation is recurrence of TTP ≤30 days after a treatment response and Refractory TTP is failure to achieve a Treatment Response by day 28 or failure to achieve a Durable Treatment Response by day 60.Secondary endpoints include the relapse rate at 2 years.

Results:19 patients were enrolled. Two patients were subsequently excluded: 1 proved to have congenital TTP and was ineligible, 1 was withdrawn for protocol violations during the first week. The 17 evaluable patients have a median age of 48 years (range 30-71), 14 (82%) are African-American and 11 (65%) are female. All had a treatment response in a median of 5 days (range 3-16 days). 13 patients achieved normal ADAMTS13 levels after treatment, 2 had persistent severe ADAMTS13 deficiency, and 2 patients have yet to be assessed for ADAMTS13 responses. No patients had refractory disease and 2 had exacerbations; both achieved Durable Treatment Responses after 29 and 35 days. No patient died of TTP; 1 patient died of metastatic cancer. To date, 13 patients have completed 2 years of follow up and 3 (23%)have relapsed at 11, 19, and 22 months. For comparison, among 54 episodes of TTP at Washington University treated without rituximab, the primary endpoint occurred in 26 (48%). These included exacerbation in 23 (43%), refractory disease in 9 (17%), and both in 6 (11%). 6 patients died, and the incidence of relapse within 2 years was 51%. Treatment with low dose rituximab (100 mg) was associated with a significant decrease in the primary endpoint from 48% to 12% (P= 0.01, Fisher's exact test) and an encouraging decrease in 2-year relapse rate from 51% to 23% (P= 0.06).

Conclusions:These results with low dose rituximab (100 mg x 4 doses) are consistent with reports that immediate treatment of TTP with standard dose rituximab (375 mg/m2x 4 doses) reduces the incidence of exacerbation and refractory disease, and prevents or delays relapses. A direct comparison of these regimens would be useful to establish whether low dose rituximab has similar efficacy with greater ease of administration, less cost, and less risk of infusion reactions and late complications.


Sadler:Ablynx: Consultancy. Zwicker:Quercegen: Research Funding; Daiichi: Honoraria; Parexel: Consultancy; Incyte: Research Funding.

Author notes


Asterisk with author names denotes non-ASH members.

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