Every treatment with rituximab is dosed as though it were for lymphoma, but the B-cell mass in nonmalignant disease is likely to be much less than that in a lympho­proliferative disorder.
As Dr. Zwicker reported, the standard-of-care treatment for TTP is plasma exchange and corticosteroids, which has been shown to reduce mortality, although upfront rituximab has gained broader acceptance. When administered at 4 weekly doses of 375 mg/m2, rituximab has demonstrated potential efficacy for preemptive therapy with less relapse and higher response rates, but the high dose, which is borrowed from protocols for B-cell lymphomas, has been questioned for the treatment of nonmalignant disease.
"Every treatment with rituximab is dosed as though it were for lymphoma, but the B-cell mass in nonmalignant disease is likely to be much less than that in a lymphoproliferative disorder," said Dr. Zwicker. He noted that a recently published retrospective analysis examining low-dose rituximab in other autoimmune cytopenias such as idiopathic thrombocytopenic purpura and pure red cell aplasia showed similar outcomes when compared to standard-dose rituximab.
The ART study (Adjuvant Rituximab in TTP, ClinicalTrials.gov identifier NCT01554514) was designed as a pilot safety/efficacy study of low-dose rituximab (100 mg/wk for 4 doses) plus standard plasma exchange and corticosteroids for TTP. Dr. Sadler and colleagues enrolled patients at Washington University, Beth Israel Deaconess Medical Center, Emory University, and Duke University.
In patients with acquired thrombotic thrombocytopenic purpura, low-dose rituximab (100 mg/wk for 4 doses) and plasma exchange reduced the incidence of exacerbation and refractory disease at rates comparable to standard-dose rituximab (375 mg/m2 for 4 doses).
The pilot study also demonstrated a low rate of relapse at 2 years (28%) with low-dose rituximab.
The key inclusion criterion was thrombocytopenia, defined as a platelet count less than 80,000/μL for newly diagnosed patients and a platelet count less than 120,000/µL for relapsed patients. In addition, enrolled patients had to be receiving plasma exchange for TTP and needed to have evidence of red cell fragmentation on smear and elevated levels of lactate dehydrogenase. They also required documentation of low ADAMTS13 activity (< 10%) before study entry. Patients with active infection, stem cell transplant, congenital TTP, or prior rituximab therapy were excluded from the study.
Treatment included daily 1.5 plasma volume exchange, prednisone at 1 mg/kg, and rituximab at 100 mg weekly for 4 doses starting before the fifth plasma exchange. Plasma exchange was continued until a response was achieved.
The study's primary endpoint was lowering the incidence of exacerbations or refractory TTP. Exacerbation was defined as a recurrence of TTP within 30 days of a treatment response, and refractory TTP was defined as failure to achieve a treatment response by day 28 or failure to achieve a durable treatment response by day 60. Secondary endpoints included treatment response (defined as 2 consecutive days with a platelet count greater than 150,000/μL) and relapse at 2 years.
As Dr. Zwicker reported at the ASH meeting, a total of 18 patients (median age, 48 years) were included in the final analysis. The majority of patients were African American (n = 13), and the cohort was evenly split in terms of initial diagnosis and relapsed TTP. Of note, said Dr. Zwicker, the median value of ADAMTS13 activity was 0%, which indicates severe deficiency.
With respect to the primary endpoint, there were two exacerbations, and no patients demonstrated refractory disease. The cumulative incidence of exacerbations or refractory TTP was 12% at 30 days.
In terms of initial treatment response, all patients achieved a platelet count greater than 150,000/μL for 2 consecutive days. The median time to response was 5 days, and all patients achieved an initial response within 3 weeks. At 2 years, the relapse rate was 28%, Dr. Zwicker reported.
Researchers observed variable responses to initial therapy with respect to ADAMSTS13 activity, ranging from undetectable to normalization, and that pattern persisted over the ensuing year. Although 13 patients (76.4%) ultimately achieved normal ADAMTS13 levels after treatment, 2 had persistent, severe ADAMTS13 deficiency.
Levels of CD19-positive B lymphocytes responded more predictably, said Dr. Zwicker. He noted that decreased levels of B lymphocytes only started to recover approximately 6 to 12 months after rituximab therapy. "The recovery pattern of B lymphocytes seems to be very similar to what you would observe with full-dose rituximab," he added.
Finally, Dr. Zwicker highlighted an episode of acute respiratory failure suffered by a patient during a third infusion of rituximab that required intubation and ultimately extracorporeal membrane oxygenation. Although this patient survived, said Dr. Zwicker, the event is a reminder that there are potential side effects with rituximab, even with lower doses. Other adverse events were reported, Dr. Zwicker added, but they were more likely related to the plasma exchange than the rituximab.
*Dr. Sadler passed away on December 13, 2018, after a brief illness. For more about Dr. Sadler's life, see related article below.
DISCLOSURE: Dr. Zwicker has received honoraria from Daiichi Sankyo and research funding from Incyte and Quercegen and is a consultant for Parexel.
1. Zwicker JI, Sadler E, Muia J, et al: Efficacy of adjuvant low dose rituximab and plasma exchange for acquired TTP with severe ADAMTS13 deficiency. 2018 ASH Annual Meeting & Exposition. Abstract 374. Presented December 2, 2018.