Rituximab

Rituximab in thrombotic thrombocytopenic purpura (TTP)

Overview:

  • Rituximab is a humanized monoclonal antibody that targets CD20 antigen present on B lymphocytes, leading to depletion of B lymphocytes.
  • Rituximab has been used in the treatment of a wide variety of autoimmune diseases, including immune thrombocytopenia and autoimmune hemolytic anemia.
  • Rationale for considering treatment with rituximab is that > 95% of adult patients with immune thrombocytopenia (ITP) reported to have autoantibodies against ADAMTS13.
  • Prospective studies have shown that rituximab is effective and safe in immune TTP. There is no evidence of increased infection risk.
  • Rituximab was first used to treat TTP in relapsed or refractory cases, where it was found to be effective in attaining remission and reducing relapse rates.
  • Rituximab was subsequently used:
    • In acute de novo TTP cases, leading to reduced relapse rates and an increase in time to relapse.
    • On a prophylactic basis to patients deemed to be at high risk of an acute TTP relapse.

Suggested dosing:

  • 375 mg/m2 IV weekly for 4 weeks.
  • Therapeutic plasma exchange (TPE) should be discontinued for ≥ 4 hours after rituximab infusion, to minimize removal of rituximab during exchange.
  • Giving rituximab more frequently than weekly, e.g. every 3–4 days, may overcome removal during TPE.

Notes:

  • Rule out hepatitis B infection before giving rituximab, which may delay use in emergency settings.

First-line therapy:

  • Phase 2 clinical trial
    • Phase 2, nonrandomized trial.
    • Forty patients with acquired TTP (34 de novo, 6 relapse) received rituximab 375 mg/m2 intravenously within the first 3 days of admission and diagnosis. A total of 4 treatments, 1 per week for 4 weeks, were given.
    • Clinical outcomes were compared to historical controls (n = 40) who had not received rituximab.
    • All patients received corticosteroids and TPE continued daily from admission and until a sustained platelet count of > 150 x 109/L was reached for 2 consecutive days.
    • As compared with historical controls, patients receiving rituximab showed:
      • No overall difference in length of stay
      • Fewer TPE episodes (in whites compared to nonwhite in the rituximab group)
      • Significant reduction in relapse risk
      • Decrease in anti-ADAMTS13 IgG and a rise in ADAMTS13 activity
      • No excess infections or serious adverse events with rituximab
  • Retrospective analysis
    • Rituximab given in 104 episodes of acute TTP, 86 patients who had never been previously treated with rituximab (rituximab-naïve patients).
    • Of the rituximab-naïve patients, rituximab was given within 3 days of admission in 54, and after 3 days in 32.
    • In rituximab-naïve patients:
      • Administration of rituximab early (< or equal to 3 days) rather than late (> 3 days) was associated with:
        • A significant reduction in the number of TPE.
        • Faster attainment of remission
        • Shorter hospital stay
      • Complete remission was achieved in 82/86 (95%) patients. All four patients who did not achieve remission died during the acute episode.
      • The overall time to remission was 14 days (range 4–52 days).

Second-line therapy:

Guideline recommendations:

  • ISTH guidelines:
    • For patients with iTTP experiencing their first acute event, the panel suggests the addition of rituximab to corticosteroids and TPE over corticosteroids and TPE alone. (A conditional recommendation in the context of very low certainty evidence.)
    • The panel notes that the primary effect of rituximab appears to be the prevention of relapses; however, many patients with iTTP may not experience a relapse, regardless of the initial treatment regimen. Given such low certainty evidence, a fairly narrowed range of outcomes affected by rituximab, and issues related to drug cost, the panel choose to make conditional recommendation for the use of rituximab.
    • Practitioners may consider among the conditions in favor of rituximab use, the presence of a known comorbid autoimmune disorder, albeit with scant supportive evidence.
    • For patients with iTTP experiencing a relapse, the panel suggests the addition of rituximab to corticosteroids and TPE over corticosteroids and TPE alone. (A conditional recommendation in the context of very low certainty evidence.)
    • For patients with iTTP who are in remission, but still have low plasma ADAMTS13 activity with no clinical signs/symptoms, the panel suggests the use of rituximab over nonuse of rituximab for prophylaxis.
  • British Committee for Standards in Haematology:
    • In acute idiopathic TTP with neurological/cardiac pathology, which are associated with a high mortality, rituximab should be considered on admission, in conjunction with PEX and steroids (1B).
    • Patients with refractory or relapsing immune-mediated TTP should be offered rituximab (1B).
  • Guidelines on the Use of Therapeutic Apheresis in Clinical Practice:
    • Rituximab is commonly used to treat refractory or relapsing TTP.
    • Studies have also described the incorporation of rituximab as adjunctive agent with initial TPE.
    • Since rituximab immediately binds to CD20-bearing lymphocytes, an 18-24-hour interval between its infusion and TPE is used in practice.