Refractory TTP

Definitions

• International Working Group for Thrombotic Thrombocytopenic Purpura:
  • Refractory TTP is defined by the following findings despite five plasma exchanges and steroid treatment:
    • Persistent thrombocytopenia
    • Lack of a sustained platelet count increment, or platelet counts of < 50 x 10 ⁹/L
    • Persistently raised LDH level (> 1.5 ULN)
  • Severe refractory TTP is defined as refractory TTP in which the platelet count remains at < 30 x 10 ⁹/L.
  • During an acute presentation, the definition of refractory disease may require an escalation in therapy.
  • Patients failing to achieve remission or whose platelet count and LDH level initially improve but worsen despite ongoing treatment would also be considered to have refractory disease.
  • “The definition of refractory TTP can be challenging. Cases with an initial response, but then a reduced platelet count that is difficult to raise, may be considered to be refractory, and this may occur after five plasma exchange procedures. However, the clinical condition is likely to be more stable at this point.”
• UpToDate: Refractory disease is defined as TTP with thrombocytopenia, high LDH, or progressive or new ischemic organ injury that does not respond to initial treatment. Exacerbations (platelet count decrease to <150,000/microL that occurs within the first 30 days after stopping TPE or caplacizumab) are also considered to be refractory disease. This is becoming rare due to the routine incorporation of rituximab.
• Sukumar et al, 2021: Refractory TTP is defined as persistent thrombocytopenia (platelet count <50 × 109/L, without increment) and persistently elevated LDH (>1.5 × ULN) despite five plasma exchange treatments in conjunction with adequate steroid treatment. If platelet count remains <30 × 109/L, this is classified as severe refractory TTP.
• Laurence: “Refractory” disease, with no or only transient response in platelet count or continued clinical deterioration despite the use of PE and corticosteroids”.

Expert opinion

• Joly et al, 2023
  • “Rituximab might not be effective for the treatment of unresponsive TTP during the first 2 weeks, with a reported delay in the onset of its effect that may reach 27 days”.
  • “No consensus has been reached on the best approach to treat refractory, life-threatening TTP“.
  • If a patient does not respond to standard TPE and prednisone, options include:
    • Increase the intensity of the treatment sequentially, for example twice-daily TPE (1.5 volume plasma per session)
    • Add rituximab
    • Pulses of:
      • Cyclophosphamide
      • Bortezomib
    • Splenectomy (in the more severe cases)
• Sukumar et al, 2021
  • In patients with refractory TTP or evidence of progressive end organ damage, more intensive therapy, such as twice daily TPE, may be considered.
  • In patients with refractory disease, alternative immunosuppressive therapies may be considered:
    • Cyclosporine A
    • Mycophenolate mofetil
    • Vincristine (no longer preferred in rituximab era).
    • Bortezomib, as an alternative agent to rituximab
    • Cyclophosphamide
    • Splenectomy
• Sayani and Abrams, 2015
  • The reported incidence of patients who do not respond to PEX and corticosteroids and require additional therapy varies between 10% and 42%.¹
  • Treatment options include:
    • Increase corticosteroids (e.g., IV methylprednisolone 10 mg/kg per day for 3 days)
    • Twice-daily TPE
    • Rituximab
    • Splenectomy
    • Cyclosporine
    • Cyclophosphamide and vincristine
    • Bortezomib
    • Eculizumab
• Kubo and Matsumoto, 2023:
  • “Anti-tumor agents for multiple myeloma have been demonstrated to be effective for refractory, especially rituximab-resistant iTTP; these agents may possibly suppress antibody production by targeting plasma cells. Although limited to case reports, the efficacy of bortezomib, a proteasome inhibitor, and daratumumab, an anti-CD38 antibody agent, have been reported for rituximab-resistant iTTP”.
• UpToDate:
  • Reevaluate the diagnosis – e.g. sepsis related to the central venous catheter or medication effect.
  • Restart TPE if it has been stopped, same intensity and volume of plasma used.
  • Add caplacizumab and rituximab (if not already started), increase glucocorticoid dose
    • The first dose of caplacizumab is administered intravenously followed by daily subcutaneous doses.
    • Rituximab 375 mg/m² intravenously once a week for four consecutive weeks. administration should be timed to occur immediately after the day’s TPE because TPE will deplete rituximab from the circulation.
    • Methylprednisolone (e.g., Solumedrol) 1 gram intravenously daily for three days.
  • Other immunosuppression options for individuals who cannot receive caplacizumab or those who have persistent severe ADAMTS13 deficiency and are maintained in clinical remission with ongoing caplacizumab and rituximab include:
    • Cyclophosphamide 
    • Bortezomib 
    • Cyclosporin
    • Mycophenolate mofetil
    • Azathioprine 
    • Sirolimus 
    • Daratumumab 
  • Splenectomy
  • rADAMTS13²

Clinical practice guidelines

• Good practice statements (GPS) for the clinical care of patients with thrombotic thrombocytopenic purpura, 2017:
  • “Patients with refractory TTP unresponsive to standard treatments may be considered for other immunosuppressive treatments (with scant supporting evidence), such as:
  • Vincristine:
    • Vincristine (2 mg) is usually administered intravenously, at a slow rate of infusion. Typically, a single dose is used because additional doses can cause neurotoxicity and bone marrow suppression”.
  • Cyclosporine A:
    • Cyclosporine A is usually administered orally (300 mg/day) or intravenously (2-3 mg/kg/day, divided twice daily). The appropriate duration of therapy is unknown, although administration of this drug for several months, followed by tapering, has been reported
• British Society of Haematology, 2023.
  • In patients who have refractory iTTP or have severe ADAMTS13 deficiency despite anti-CD20 therapy, alternative immunosuppressive therapy should be considered. (2B)
  • Alternate immunomodulatory therapies, such as azathioprine, cyclophosphamide, splenectomy may be alternative options in patients with refractory or relapsing iTTP. (2C)
  • For pregnant women with iTTP refractory to PEX and steroids or who relapse, additional treatment options include ciclosporin, azathioprine and rituximab. (2C)
  • Plasma cell-directed therapy is considered in refractory iTTP despite anti-CD20 therapy, including:
    • Daratumumab
    • Bortezomib