In the JournalsPerspective

Low-dose rituximab induces high response rates in acquired thrombotic thrombocytopenic purpura

Jeffrey I. Zwicker
Jeffrey I. Zwicker

Adjuvant low-dose rituximab in combination with plasma exchange and steroids appeared effective for the treatment of acquired thrombotic thrombocytopenic purpura, according to results of a prospective, single-arm phase 2 study published in Blood.

“Some of the potential benefits of lower-dose rituximab are shorter infusion times, cost and infusion-related toxicity,” Jeffrey I. Zwicker, MD, associate professor of medicine at Beth Israel Deaconess Medical Center and Harvard Medical School, told HemOnc Today. “However, we did observe a case of respiratory failure during infusion which was attributed to rituximab infusion.”

The survival rate for patients with thrombotic thrombocytopenic purpura (TTP), a blood disorder caused by autoantibodies against the ADAMTS13 gene, increased from less than 10% to 80% with the introduction of plasmapheresis with plasma exchange. However, more than 30% of patients with TTP have at least one relapse within 2 years, according to study background.

Rituximab (Rituxan; Genentech, Biogen) has been shown to normalize ADAMTS13 and induce durable remissions among more than 90% of patients with relapsed or refractory TTP. Researchers also observed evidence of improved rates of remission and DFS with rituximab in the first-line setting. However, no prospective clinical trial has evaluated the safety and efficacy of low-dose rituximab for this patient population.

A previous retrospective study showed rituximab doses between 200 mg/m2 to 500 mg/m2 produced no differences in outcomes.

For the current study, Zwicker and colleagues enrolled 19 patients (median age, 49 years; 12 women; median BMI, 33.5 kg/m2) with TTP, including seven after initial diagnosis and 11 at the time of relapse. They omitted one patient later diagnosed with congenital TTP from the analyses.

All but one patient had undetectable ADAMTS13 at baseline.

Treatment consisted of 100 mg rituximab every 5 to 9 days for 4 weeks plus plasma exchange and 1 mg/kg prednisone daily until response.

The composite outcome of TTP exacerbation or refractory disease served as the study’s primary endpoint.

Median time to treatment response was 5 days.

Results showed no cases of primary refractory TTP after 30 days. However, two cases of exacerbation required re-initiation of plasma exchange.

One patient relapsed within 12 months of enrollment and two more relapsed after 2 years of follow-up.

Researchers observed no differences in 6-month CD19-positive lymphocyte counts among patients who relapsed vs. those who did not (median, 4% vs. 4.6%).

Thirteen patients achieved normal ADAMTS13 levels, defined as 60% or higher (median response, 36 days), whereas three patients achieved a partial response (levels 30%) and two had ADAMTS13 levels below 5%.

Several severe adverse events may have been related to rituximab, including one case of grade 4 respiratory failure, researchers noted.

“Following lower-dose rituximab, the circulating B lymphocyte population was essentially zero with sustained response seen at 1 year. I suspect that the lower-dose rituximab achieves a maximal B lymphocyte response such that additional rituximab would not alter long term outcomes,” Zwicker said. “However, we did not perform a comparative study so [we] cannot definitively conclude that long term outcomes are influenced by using a reduced rituximab dose.” – by John DeRosier

For more information:

Jeffrey I. Zwicker, MD, can be reached at jzwicker@bidmc.harvard.edu.

Disclosures: Zwicker reports research funding from Incyte and Quercegen Pharma, as well as advisory roles with Bayer, Pfizer, Portola Pharmaceuticals and Seattle Genetics. Two other authors report a patent related to fluorogenic substrate for ADAMTS13 issued to Washington University.

Jeffrey I. Zwicker
Jeffrey I. Zwicker

Adjuvant low-dose rituximab in combination with plasma exchange and steroids appeared effective for the treatment of acquired thrombotic thrombocytopenic purpura, according to results of a prospective, single-arm phase 2 study published in Blood.

“Some of the potential benefits of lower-dose rituximab are shorter infusion times, cost and infusion-related toxicity,” Jeffrey I. Zwicker, MD, associate professor of medicine at Beth Israel Deaconess Medical Center and Harvard Medical School, told HemOnc Today. “However, we did observe a case of respiratory failure during infusion which was attributed to rituximab infusion.”

The survival rate for patients with thrombotic thrombocytopenic purpura (TTP), a blood disorder caused by autoantibodies against the ADAMTS13 gene, increased from less than 10% to 80% with the introduction of plasmapheresis with plasma exchange. However, more than 30% of patients with TTP have at least one relapse within 2 years, according to study background.

Rituximab (Rituxan; Genentech, Biogen) has been shown to normalize ADAMTS13 and induce durable remissions among more than 90% of patients with relapsed or refractory TTP. Researchers also observed evidence of improved rates of remission and DFS with rituximab in the first-line setting. However, no prospective clinical trial has evaluated the safety and efficacy of low-dose rituximab for this patient population.

A previous retrospective study showed rituximab doses between 200 mg/m2 to 500 mg/m2 produced no differences in outcomes.

For the current study, Zwicker and colleagues enrolled 19 patients (median age, 49 years; 12 women; median BMI, 33.5 kg/m2) with TTP, including seven after initial diagnosis and 11 at the time of relapse. They omitted one patient later diagnosed with congenital TTP from the analyses.

All but one patient had undetectable ADAMTS13 at baseline.

Treatment consisted of 100 mg rituximab every 5 to 9 days for 4 weeks plus plasma exchange and 1 mg/kg prednisone daily until response.

The composite outcome of TTP exacerbation or refractory disease served as the study’s primary endpoint.

Median time to treatment response was 5 days.

Results showed no cases of primary refractory TTP after 30 days. However, two cases of exacerbation required re-initiation of plasma exchange.

One patient relapsed within 12 months of enrollment and two more relapsed after 2 years of follow-up.

Researchers observed no differences in 6-month CD19-positive lymphocyte counts among patients who relapsed vs. those who did not (median, 4% vs. 4.6%).

Thirteen patients achieved normal ADAMTS13 levels, defined as 60% or higher (median response, 36 days), whereas three patients achieved a partial response (levels 30%) and two had ADAMTS13 levels below 5%.

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Several severe adverse events may have been related to rituximab, including one case of grade 4 respiratory failure, researchers noted.

“Following lower-dose rituximab, the circulating B lymphocyte population was essentially zero with sustained response seen at 1 year. I suspect that the lower-dose rituximab achieves a maximal B lymphocyte response such that additional rituximab would not alter long term outcomes,” Zwicker said. “However, we did not perform a comparative study so [we] cannot definitively conclude that long term outcomes are influenced by using a reduced rituximab dose.” – by John DeRosier

For more information:

Jeffrey I. Zwicker, MD, can be reached at jzwicker@bidmc.harvard.edu.

Disclosures: Zwicker reports research funding from Incyte and Quercegen Pharma, as well as advisory roles with Bayer, Pfizer, Portola Pharmaceuticals and Seattle Genetics. Two other authors report a patent related to fluorogenic substrate for ADAMTS13 issued to Washington University.

    Perspective
    A. Koneti Rao

    A. Koneti Rao

    Acquired TTP is a rare, antibody-mediated disorder associated with high morbidity and mortality rates. The introduction of plasma exchange has had a major impact on clinical outcomes. FDA-approved treatment strategies include removal of the pathogenic antibodies with replacement of the deficient ADAMTS13 activity by plasma exchange, suppression of the aberrant immune mechanisms and, more recently, modulating platelet-von Willebrand factor interactions with caplacizumab (Cablivi, Ablynx). Corticosteroids and rituximab have been the most widely used immunosuppressive agents.

    Rituximab administration is associated with favorable outcomes in acute TTP and is increasingly becoming part of front-line treatment upon initial diagnosis. This is based on strong evidence from observational studies in which patients received plasma exchange and corticosteroids, as well. The widely used rituximab dosage for patients with TTP patients has been 375 mg/m2, administered weekly for 4 weeks. This dosage has been adopted from other disorders, namely non-Hodgkin lymphoma.

    The optimal rituximab dosage for TTP remains unclear. Studies of patients with other immune, non-neoplastic disorders — such as autoimmune hemolytic anemia and primary immune thrombocytopenia — indicate that lower doses of rituximab (100 mg/week) are effective. The efficacy of low-dose rituximab has not been studied in TTP. The current study by Zwicker and colleagues addresses this issue.

    The findings in this study are similar to those of previous published studies among patients with acute TTP treated with rituximab at the 375 mg/m2 dose and plasma exchange. The response rate for recovery of ADAMTS13 was 89%, comparable to that of previous studies.

    This study represents a major contribution to the evolving treatment strategies for acute TTP. Despite the limitations inherent to small studies, the evidence from this prospective, multicenter trial is compelling regarding the efficacy of low-dose rituximab in acute TTP.  This is supported by the efficacy of a similar dose in primary immune thrombocytopenic purpura and autoimmune hemolytic anemia. The effects on ADAMTS13 and the CD19 lymphocyte numbers at 12 months are encouraging. The low-dose rituximab regimen would be expected to confer benefits in terms of drug costs and the duration of infusion. Adverse events possibly related to rituximab were observed among some patients, including severe grade 4 respiratory failure for one patient. Further studies would need to define whether the advantages of low-dose rituximab translate to adverse events, as well.

    Still to be established is the impact of dose reduction on long-term durability of response; follow-up was up to 2 years in this study. The study provides a strong impetus for a multicenter trial comparing the low-dose regimen with the currently used dose.

    This landmark trial is another feather in the cap of J. Evan Sadler, MD, PhD, whose accomplishments and immense contributions in the basic and clinical aspects of von Willebrand factor, von Willebrand disease, TTP, ADAMTS13 and many other areas constitute his legacy. It, too, will have an impact for years to come.

    • A. Koneti Rao, MD, FACP, FAHA
    • HemOnc Today Editorial Board Member
      Temple University

    Disclosures: Rao reports no relevant financial disclosures.