Journal Club – TTP

Scully M, McDonald V, Cavenagh J, et al. A phase 2 study of the safety and efficacy of rituximab with plasma exchange in acute acquired thrombotic thrombocytopenic purpura. Blood. 2011;118(7):1746-1753.

Clinical Question

In patients with immune thrombotic thrombocytopenic purpura (TTP) is the addition or rituximab to plasma exchange and steroids safe and effective to shorten the time to remission?

Background

TTP is a life-threatening illness characterized by the presence of autoantibodies against ADAMTS13 resulting in severe deficiency of ADAMTS13. Subsequently ultralarge-vWF multimers are unable to be cleared leading to microvascular thrombi formation, thrombocytopenia, microangiopathic hemolytic anemia and ultimately organ damage and death. The use of corticosteroids along with plasma exchange has significantly improved outcomes for patients with TTP. These interventions act two-fold by clearing or reducing production of the autoantibody and replacing normal ADAMTS13. Nevertheless, despite improvements in the acute management of TTP, some patients require prolonged plasma exchange to achieve remission and 30-50% of patients experienced relapse. In these patients, further immunosuppressive therapies including cyclosporine, cyclophosphamide, vincristine, and others were often used in the past. Rituximab, an anti-CD20 antibody, had been used in case series with the rationale of B-cell depletion to decrease production of the pathogenic autoantibody. This phase 2 study was designed to evaluate the efficacy and safety prospectively in a larger cohort of patients with acquired TTP.

Guidelines

The International Society on Thrombosis and Hemostasis (ISTH) 2020 guidelines suggest the addition of rituximab to plasma exchange in corticosteroids for index presentations (Recommendation 2: a conditional recommendation in the context of very low certainty of evidence) as well as the addition of rituximab to plasma exchange and corticosteroids for patients experiencing a relapse of TTP (Recommendation 4: a conditional recommendation in the context of very low certainty of evidence).¹

The British Society for Haematology (BSH) recommends pre-emptive therapy with Rituximab should be given to patients with immune TTP when ADAMTS13 activity <20 IU/dL or higher levels associated with clinical symptoms. (1B)²

Study Design:

• Multicentered, non-randomized Phase 2 study
• Setting: United Kingdom (Southeast England TTP Study Group)
• N = 80:
  • 40 patients enrolled in the interventional arm
  • 40 patients matched from historical controls
• Follow-up period: at least 12 months
• Primary efficacy outcome: number of plasma exchange treatments to remission as defined by the number of procedures per admission compared with historical controls.
• Key secondary outcomes:
  • Efficacy Outcomes
    • Length of stay
    • Mortality at 3 months
    • B cell depletion as measured by CD19 count
    • Effect on ADAMTS13 activity and anti-ADAMTS13 IgG
    • Time to relapse
  • Safety Outcomes
    • Infusion-related reactions
    • Allergic reactions
    • Immunoglobulin levels
    • Frequency of infections in 12 months of follow up

Population:

Inclusion Criteria:

• Patients > 18 years and < 65 years who present with an acute episode of TTP
• Evidence of microangiopathic hemolytic anemia
• Thrombocytopenia with a normal clotting screen
• Elevated Lactate Dehydrogenase (>1.5 ULN)
• Patients without neurological dysfunction able to give informed consent
• Patients of reproductive age (must avoid pregnancy for 12 months and/or normalized B cell function after receiving Rituximab. Estrogen containing oral contraceptive pills and the morning after pills should be avoided in female TTP patients)
• Patients with an acute deterioration in neurological function which may include encephalopathy, such as altered personality, problems with short term memory and coma can be included when consent has been given by next of kin or from the appropriate legal representative.

Exclusion Criteria:

• Pregnant or breast-feeding women
• HIV-positive patients
• Patients with childhood TTP (age <18yrs)
• Patients with Hemolytic Uremic Syndrome
• Patients with diarrhea positively or negatively associated with renal failure
• Transplant associated thrombotic microangiopathy
• Active malignancy except for appropriately treated localized epithelial cancers or cancers in remission

Baseline Characteristics:

• 86 patients screened:
  • 40 patients included
  • Causes of screen failure included: 7 deaths within 24 hours, 14 secondary TTP, 10 other TMAs, 2 declined entry, 13 did not meet entry criteria.
• 34 de novo cases, 6 relapsed cases. 40 historical controls from Southeast England registry.
• Patients matched on age, sex, index vs relapse presentation, symptoms (e.g. neurologic, fever, renal, abdominal, cardiac), hemoglobin, platelet count, LDH, bilirubin, creatinine, ADAMTS13 activity and anti-ADAMTS13 IgG.
• Trial patients:
  • Median Hgb 8.6 g/dL, platelet count 13,000/L, LDH 2088 IU
  • 77% of patients had neurologic symptoms, 47% had fever, 47% had abdominal symptoms, 47% had increased troponin.
  • 22/40 (55%) were white
• Control patients:
  • Median Hgb 8.5 g/dL, platelet count 14,000/L, LDH 1724 IU
  • 26/40 (65%) were white

Interventions

• All patients received corticosteroids per local guidelines and plasma exchange with fresh frozen plasma (FFP) on consecutive days until platelet count remained above 150,000/L for two consecutive days.
• All trial patients received 4 doses of once weekly rituximab 375 mg/m2.
• 6 patients received up to four additional treatments based on persistently abnormal ADAMTS13 activity or persistent anti-ADAMTS13 IgG.
• 4 patients also received vincristine during their acute episode.
• Historical controls:
  • Other treatments included cyclosporine, defibrotide, cyclophosphamide, vincristine, splenectomy.
  • 2 patients received rituximab during remission.

Outcomes

Primary outcome:

• Median number of plasma exchange treatments in the trial group was 16.5 (range 4-34) vs in the historical control group was 18 (range, 6-92), p = 0.5.

Secondary outcomes:

• Efficacy outcomes:
  • Median length of stay: trial 16.5 days (5-49) vs control 20 (5-62), p = nonsignificant)
  • Presenting CD19+ lymphocyte count was 23% (range 2.6% to 39.9%) which decreased to 0.5% (0% to 2.78%) prior to the 4th dose of rituximab. B cell recovery occurred in 75% of patients by 12 months.
• Deaths/relapse:
  • There were 3 deaths in the trial group occurring at 11, 15, and 25 days after admission due to neurologic and or cardiac manifestations.
  • There were 3 deaths in the historical controls, 2 during the initial presentation and 1 in relapse.
  • In the trial group 4 of 37 surviving patients experienced a relapse with a median time to relapse of 27 months (17-31). In the historical control group, there were 21 of 38 patients experiencing relapse with a median time to relapse of 18 months (3-60). This reduction in relapse risk from 57% to 10% was significant, p = 0.0011.

Safety:

• There were no documented increase in infections, with the majority of infections 1-year post-rituximab being viral infections.

Commentary:

In this study by Scully et al of adding rituximab to standard of care in patients with acute immune TTP, patients treated with rituximab patients did not achieve remission faster however there was a significant reduction in risk of relapse from 57% to 10%. In addition, rituximab-treated patients in this study had a longer median time to relapse compared to historical controls (27 months vs 18 months). Mechanistically, reductions in B cell numbers and anti-ADAMTS13 IgG occur within the first to second week from the initial dose of rituximab, and correspondingly patients achieve sustained improvement of ADAMTS13 activity. Importantly, there were no significant increases in infections in rituximab treated groups and B cell recovery occurs around 9-12 months after the initial dose of rituximab.

There are some notable limitations to this study. First, this was a non-randomized study with comparisons to historical controls. Confirmation of an undetectable ADAMTS13 was not required for enrollment, so some patients without true immune TTP may have been included as evidenced by the upper range of ADAMTS13 activity of 32%; however, this is matched somewhat in the control group where the upper range of ADAMTS13 activity was 40%. In addition, 15 of the 40 control patients received some additional immunosuppressive therapy, which would have biased the results against rituximab, however the authors note an approximately 50% relapse rate in the historical control group regardless of if the received additional immunosuppression.

In summary, rituximab added to steroids and plasma exchange is effective to reduce the risk of relapse in patients with TTP and is largely considered standard of care therapy during acute presentations. Furthermore, subsequent studies have also suggested the benefit of early rituximab administration in patients with decreased ADAMTS13 activity without clinical TTP while in remission.³

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