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Low-dose rituximab reduces exacerbation, refractory disease in acquired thrombotic thrombocytopenic purpura
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SAN DIEGO — Use of adjuvant low-dose rituximab with plasma exchange reduced incidence of exacerbation and refractory disease among patients with acquired thrombotic thrombocytopenic purpura and severe ADAMTS13 deficiency, according to study results presented at ASH Annual Meeting and Exposition.
The low-dose rituximab (Rituxan; Genentech, Biogen) regimen also appeared associated with low relapse rates.
The findings are consistent with the benefits previously reported with standard-dose rituximab, according to Jeffrey I. Zwicker, MD, chief of the section of benign hematology at Beth Israel Deaconess Medical Center and associate professor of medicine at Harvard Medical School.
“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,” Zwicker and colleagues wrote.
Acquired thrombotic thrombocytopenic purpura (TTP) is a blood disorder caused by autoantibodies against the ADAMTS13 gene. The autoantibodies prevent cleavage of von Willebrand factor and allow growth of microvascular thrombi, according to study background. This process leads to microangiopathic hemolysis and severe thrombocytopenia.
The condition is almost always fatal if left untreated. Approximately 80% of patients who undergo plasma exchange survive, but those who respond often experience exacerbations or relapses that require additional treatment.
The combination of plasma exchange, corticosteroids and rituximab often effectively treat TTP exacerbations and refractory disease.
The standard regimen consists of four weekly rituximab doses, with the 375 mg/m2 dose determined from B-cell lymphoma protocols.
“The thing with rituximab is ... everything is dosed as if it were lymphoma,” Zwicker said during a presentation. “However, the B-cell mass in nonmalignant disease is likely to be much less than that in a myeloproliferative disorder. The benefit of lower-dose rituximab is the savings of thousands upon thousands of dollars.”
Case reports in TTP and immune thrombocytopenia suggest that fixed doses of 100 mg and conventional doses of 375 mg/m2 have similar efficacy.
In the ART study, Zwicker and colleagues assessed the efficacy and safety of low-dose rituximab —100 mg/week for 4 weeks — plus standard plasma exchange and corticosteroids for adults with acute TTP and ADAMTS13 less than 10%.
Exclusion criteria included TTP treatment within the prior 2 months, severe infection, receipt of organ or stem cell transplant, cancer, pregnancy, hepatitis B infection, use of calcineurin inhibitors within 6 months and receipt of rituximab within the past year.
Treatment consisted of daily 1.5-volume plasma exchanges and prednisone 1 mg/kg. Low-dose rituximab started prior to the fifth plasma exchange.
Researchers defined treatment response as two consecutive days with platelet count of at least 150,000/µl, and they defined durable treatment response as persisting at least 30 days after stopping plasma exchange.
A composite of exacerbation — defined as TTP recurrence less than 30 days after treatment response — and refractory TTP, defined as failure to achieve treatment response by day 28 or failure to achieve durable treatment response by day 60, served as the primary endpoint.
Treatment response — defined as two consecutive days with platelet count greater than 150,000 — and relapse, defined as TTP recurrence more than 30 days after initial response, served as secondary objectives.
Inclusion criteria included platelet count less than 80,000 for newly diagnosed disease or less than 120,000 for relapsed disease; plasma exchange for TTP; and ADAMTS13 activity less than 10%.
The analysis included 17 evaluable patients (median age, 48 years; range, 30-73; 72% black; 56% women). Eight patients (44%) had initial TTP and 10 (56%) had relapsed disease.
All patients achieved treatment response (median time to response, 5 days; range, 3-16).
Thirteen patients (76.4%) achieved normal ADAMTS13 levels after treatment, whereas two had persistent severe ADAMTS13 deficiency and two had not been assessed for ADAMTS13 response at the time of analysis.
No patients developed refractory disease. Two patients had exacerbations but achieved durable treatment response, one after 29 days and the other after 35 days.
No patients died of TTP. One patient died of metastatic cancer.
Researchers reported three possibly related severe adverse events. They included one case each of acute respiratory failure, one central line infection and bacteremia, and one case of atrial fibrillation.
Thirteen patients completed 2 years of follow-up. Three (23%) of them relapsed — one at 11 months, one at 19 months and one at 22 months.
Researchers compared the outcomes from the low-dose rituximab cohort with results from a series of 54 TTP episodes treated without rituximab at Washington University.
In that comparison cohort, 23 patients (43%) had exacerbation, nine (17%) developed refractory disease and six (11%) had both. Six patients died.
An evaluation of the primary endpoint showed a significantly lower percentage of patients who received low-dose rituximab experienced exacerbation or refractory TTP (12% vs. 48%; P = .01). The 2-year relapse rate in the no-rituximab cohort was more than double that of the low-dose rituximab cohort (51% vs. 23%). The difference did not reach statistical significance, but Zwicker and colleagues described this result as encouraging. – by Mark Leiser
Reference:
Zwicker JI, et al. Abstract 374. Presented at: ASH Annual Meeting and Exposition; Dec. 1-4, 2018; San Diego.
Disclosures: Zwicker reports honoraria from Daiichi Sankyo, research funding from Incyte and Quercegen, and a consultant role with Parexel. Please see the abstract for all other authors’ relevant financial disclosures.