The results of a recent pilot study suggest that low-dose rituximab provides similar efficacy to standard-dose rituximab for the treatment of acquired thrombotic thrombocytopenic purpura (TTP), a finding that could point to potential cost savings for patients in the nonlymphoma setting.

According to data presented at the 2018 American Society of Hematology (ASH) Annual Meeting & Exposition,¹ adjuvant low-dose rituximab and plasma exchange in patients with acquired TTP and severe ADAMTS13 deficiency was associated with low rates of early exacerbation or refractory disease, the study’s primary endpoint. In the open-label study led by J. Evan Sadler, MD,* Chief of Division of Hematology at Washington University in St. Louis, the incidence of early exacerbations or refractory TTP was 12% at 30 days, and the relapse rate was 28% at 2 years—both favorable outcomes compared to historical controls. According to the authors of the study, however, adverse events were observed with the reduced dose, suggesting that the likely benefit to lower-dose rituximab will be cost savings rather than decreased toxicity.

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.

— Jeffrey I. Zwicker, MD

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“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,” said 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, Boston. “But the principal benefit of lower-dose rituximab would be savings of thousands upon thousands of dollars.”

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.

Study Methodology

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.

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.

Early Exacerbations and Refractory Disease

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.

Adverse Events

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.

“Based on these data, low-dose rituximab appears to make sense in patients who don’t have lymphoma,” said one member of the audience. “Were relapse rates based on clinical relapse or ADAMTS13 activity levels?”

“Relapse wasn’t based on ADAMTS13 activity levels,” Dr. Zwicker replied. “All patients who relapsed had low ADAMTS13 levels, but a fair number of patients with low levels never relapsed. Relapse was always clinically defined, meaning thrombocytopenia was present and plasma exchange was reinitiated.”

“Similarly, not all patients who went into remission had normalized ADAMTS13 activity levels,” Dr. Zwicker continued. “There were patients who remained relapse-free without normalization, just like you would see with full-dose 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.

REFERENCE

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.