Journal Club – TTP

Kühne L, Knöbl P, Eller K, et al. Management of immune thrombotic thrombocytopenic purpura without therapeutic plasma exchange. Blood. 2024 Oct 3;144(14):1486-1495.

Clinical Question

Can patients with immune thrombotic thrombocytopenic purpura (iTTP) be managed safely and effectively with caplacizumab and immunosuppression without the addition of therapeutic plasma exchange (TPE)?

Background

Immune TTP is a condition defined by loss of the functional protease ADAMTS13 due to inhibitory autoantibodies, leading to ultralarge vWF multimers that accumulate on the endothelial surface and bind platelets, resulting in severe thrombocytopenia, microvascular occlusion, tissue ischemia and dysfunction. When untreated, iTTP results in >90% mortality. Patient survival in iTTP has improved dramatically over the past three decades with the use of TPE and immunosuppression in acute management. Caplacizumab is a bivalent antibody fragment that binds the A1-domain of VWF and blocks its interaction with platelet surface glycoprotein GPIb, reducing VWF-mediated platelet adhesion and consumption. Its use in acute iTTP leads to faster platelet count normalization and fewer days of TPE needed.¹ Caplacizumab was approved by the FDA for the initial management of iTTP in 2019 together with TPE and immunosuppression. This retrospective cohort study was designed to evaluate the efficacy and safety of the use of caplacizumab and immunosuppression together without the use of TPE in patients with acute iTTP.

Guidelines

The International Society on Thrombosis and Haemostasis (ISTH) recommends the use of TPE with addition of corticosteroids in patients with acute iTTP (strong recommendation) and suggests the further addition of rituximab (conditional recommendation) as well as caplacizumab (conditional recommendation).² Similarly, the British Society for Haematology (BSH) recommends initial management of iTTP with TPE (grade 1A recommendation) with the addition of corticosteroids and rituximab (grade 1B recommendations) and caplacizumab (grade 1A).³

Study Design:

• Retrospective cohort study
• Setting:  Austria and Germany:
  • Austrian Thrombotic Microangiopathy Registry
  • German REACT-2020 TTP registry
• N=100:
  • 41 treated with caplacizumab and immunosuppression (TPE-free cohort)
  • 59 treated with caplacizumab, immunosuppression, and TPE (TPE cohort)
• Primary outcome:  Time to platelet count normalization
• Key secondary outcomes:
  • Efficacy outcomes:
    • Proportion achieving clinical response
    • Proportion achieving clinical exacerbation
    • Proportion developing refractory iTTP (defined as persistent thrombocytopenia, lack of a sustained platelet count increment or platelet count of <50 × 10⁹/L, and a persistently elevated lactate dehydrogenase (LDH) level (>1.5 × upper limit of normal) despite 5 days of TPE)
    • Number of iTTP-related deaths
    • Time to platelet count doubling
  • Safety outcomes:
    • Major bleeding

Population:

Inclusion Criteria:

• Patients included in the ATMAR or German REACT-2020 Registries
• Acute iTTP and treated with at least a single dose of caplacizumab
• TPE-free cohort:
  • Increase in platelet count, stable condition, and stable organ function after first dose of caplacizumab

Exclusion Criteria:

• TPE cohort:
  • Delayed start of caplacizumab >1 day after start of TPE

Baseline Characteristics:

• Sex:  71 women, 27 men
• Age:  Overall median of 46 y (range 20-83)
• Overall 62% with first iTTP episode, 35% with relapsed iTTP
• TPE-free cohort
  • Median platelet count 16, median LDH 703, median creatinine 0.95
  • 38% with initial troponin elevation
  • 9.5% with Glasgow Coma Score <15
• TPE cohort
  • Median plt count 12, median LDH 1052, median creatinine 1.07
  • 45.8% with initial troponin elevation
  • 18.6% with Glasgow Coma Score <15

Interventions

• All patients received caplacizumab at standard dosing.
• All patients received glucocorticoids.
• Patients in the TPE cohort received daily TPE for a median of 5 days.
• Most patients (90.5% of TPE-free cohort and 81.4% of TPE cohort) received rituximab.
• Additional immunosuppressants were used in 1 patient in the TPE-free cohort and 6 patients in the TPE cohort.

Outcomes

Primary outcome:

• Median time to platelet count normalization in the TPE-free cohort was 3 days (range 1-12) and in the TPE cohort was 4 days (range 2-27), p=0.31.

Secondary outcomes:

• Efficacy outcomes:
  • Percent of patients achieving a clinical response:  97.6% in TPE-free cohort vs 96.6% in TPE cohort
  • Percent of patients with exacerbation:  4.8% in TPE-free cohort vs 15.3% in TPE cohort; p=0.12
  • Percent of patients with refractory iTTP:  0% in TPE-free cohort vs 1.7% in TPE cohort
  • iTTP-related deaths:  0 in TPE-free cohort vs 1 in TPE-cohort
  • Median time to platelet count doubling:  1 day in TPE-free cohort (range 1-7) vs 1 day in TPE cohort (range 1-4)
• Safety outcomes
  • Percent of patients experiencing any bleeding events:  11.9% in TPE-free cohort vs 3.4% in TPE cohort, p=0.12
  • Percent of patients experiencing major bleeding:  4.8% in TPE-free cohort vs 0% in TPE cohort, p=0.17

Commentary:

In this retrospective cohort study by Kühne et al, patients with acute iTTP managed with a TPE-free strategy of caplacizumab and immunosuppression showed equivalent median time to platelet count recovery compared to patients receiving standard of care with caplacizumab, immunosuppression, and TPE. Analysis of key secondary efficacy and safety endpoints did not show any significant difference between a TPE-free strategy and standard of care. These results begin to suggest a potential paradigm shift in the management of acute iTTP, questioning the necessity of TPE that has been a cornerstone of iTTP management for over 30 years, as established by Rock and colleagues in their landmark 1991 trial.⁴

There are some notable limitations to this study that must be considered. First, this was a retrospective cohort study and is subject to potential selection bias due to lack of randomization. Patients in the TPE-free cohort had baseline lower median serum LDH concentrations, and fewer patients had an abnormal Glasgow Coma Score at the time of treatment initiation, suggesting there may have been a bias toward recruiting patients with milder cases of iTTP to a TPE-free strategy. Another limitation is the selection of the primary endpoint of median time to platelet count recovery. The addition of caplacizumab to standard of care has been shown previously to significantly shorten time to platelet count recovery over standard of care in larger prospective randomized trials, and this has correlated with a significant decrease in the number of iTTP recurrences but not with a decrease in the number of iTTP-related deaths.¹ Therefore, the utility of time to platelet count recovery as a surrogate for other more clinically meaningful endpoints is not entirely clear. Finally, this study was not powered to detect significant differences in secondary safety endpoints, and safety events are limited to those included in the registries. Patients in the TPE-free cohort experienced an absolute risk increase of 8.5% for any bleeding event (3.5-fold relative risk increase) and 4.8% absolute risk increase for major bleeding compared to patients in the TPE cohort. Future studies of TPE-free management strategies will have to pay careful attention to possible increased risks in bleeding.

Despite the limitations of this cohort study, it is worth noting that there were 0 iTTP-related deaths in the TPE-free cohort. This strongly supports that caplacizumab and immunosuppression together without TPE can be an effective life-saving strategy, especially in patients for whom TPE is not an option (e.g. patients who decline plasma or blood products, or patients with a life-threatening allergy to plasma). These promising results also pave the way for future studies to investigate the role of a TPE-free management approach in a prospective fashion.

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