A new perspective in the management of ATTP: the nephrologist approach – Organised by SANOFI GENZYME

Symposium Summary

Written by Jasna Trbojevic-Stankovic
All the companies reviewed and approved the contents

Would you like to know more?

Welcome and introduction

Paul Brinkkötter, Germany

Acquired thrombotic thrombocytopenic purpura (aTTP) is a rare blood disorder with an incidence of 2-13 cases per million/year. It presents with features of thrombotic microangiopathy (TMA), including widespread platelet consumption into microthrombi, microangiopathic haemolytic anaemia , and ultimately ischemia and end-organ complications. At a virtual satellite symposium held during the fully virtual ERA-EDTA 2021 congress, Dr Ralph Wendt, Professor François Provôt and Professor Paul Brinkkötter discussed the challenges of diagnosing aTTP, the acute treatment of this life-threatening disorder, and how experience through learning is improving patient care and reducing mortality.

Diagnosing aTTP and its challenges

Ralph Wendt, Germany

TTP is caused by innate or acquired deficiency of ADAMTS13 (A Disintegrin-like And Metalloproteinase with ThromboSpondin type 1 motif, member 13), a protease that cleaves von Willebrand factor (VWF) multimers. aTTP, also known as immune-mediated TTP (iTTP), results from autoantibodies against ADAMTS13. Signs and symptoms of an acute aTTP flare include petechiae and purpura, headache and/or confusion or stroke-like symptoms, fatigue, dyspnoea due to anaemia, cardiac and gastrointestinal symptoms.

Dr Wendt advised that any clinical suspicion of TMA should prompt urgent testing of ADAMTS13 activity. If ADAMTS13 activity is <10%, the patient has TTP. A positive test for the antibody to ADAMTS13 means that the diagnosis is aTTP, while a persistent negative antibody result suggests congenital TTP (cTTP) associated with ADAMTS13 gene mutation. He added that severe ADAMTS13 deficiency alone without signs of TMA and especially organ involvement does not represent an acute TTP flare, relapse or exacerbation, and is no reason to start treatment. It could, however, eventually lead to a TTP flare, which may be unpredictable and be the result of minor triggers or even no identifiable triggers.

Since aTTP is a dangerous disorder that is associated with high mortality when untreated, rapid diagnosis and initiation of treatment are critical. The two standard methods of diagnosing severe ADAMTS13 deficiency are fluorescence resonance energy transfer (FRET) and classic chromogenic enzyme linked immunosorbent assay (ELISA). Both are time consuming, require considerable technical skill, and may not be immediately available. Rapid testing for ADAMTS13 activity is now available, but compared with gold-standard ELISA, it is associated with 20% overdiagnosis of severe ADAMTS13 deficiency, as well as the more concerning false exclusion of patients with TTP.

In clinical practice, rapid identification of TMA patients who most likely have aTTP, and who will benefit most from emergency treatment, often depends on clinical judgement and can be ascertained by clinical scores, such as the PLASMIC and French scores. A PLASMIC score of ≥6 or a French score of ≥2 indicates a high probability for TTP. Dr Wendt concluded that, in clinical practice, it is possible to combine rapid testing with a clinical scoring system, but clinicians should be aware of possible misdiagnosis. Waiting for results of ADAMTS13 activity should not, however, delay treatment; if clinical scoring indicates a high probability of TTP, treatment should be initiated immediately to reduce the high mortality seen in untreated patients.

Acute aTTP treatment: where do we stand in 2021?

François Provôt, France

Despite treatment with therapeutic plasma exchange (TPE) and immunosuppression with steroids and rituximab, aTTP has acute mortality rate of up to 20%. In addition, refractory disease occurs in up to 42% of patients and may lead to poor outcomes. There is therefore a need for targeted, rapid-acting treatment to reduce early mortality and morbidity.

Caplacizumab is a nanobody (a single variable domain immunoglobulin) that specifically targets microthrombi formation by inhibiting the interaction between the A1 domain of VWF and the platelet GP1b receptor. In 2018, caplacizumab was approved in Europe for the treatment of aTTP based on data from two clinical trials: the phase 2 TITAN trial and the phase 3 HERCULES trial. The two studies included a total of 220 adults with acute aTTP diagnosed by clinical presentation, who were randomized to either caplacizumab or placebo plus TPE and immunosuppression during TPE treatment, and after TPE cessation for 30 days in TITAN and 30-58 days in HERCULES.

Professor Provôt reported that in an integrated analysis of TITAN and HERCULES, compared with placebo, caplacizumab significantly reduced the number of deaths (0 vs 4; p<0.05) and the incidence of refractory TTP (0 vs 8; p<0.05) during the treatment period. Treatment with caplacizumab also resulted in a faster time to platelet count response (HR 1.65; p<0.001); a 72.6% reduction in the proportion of patients with the composite endpoint of TTP-related death, TTP exacerbation or occurrence of at least one treatment-emergent major thromboembolic event during treatment (13.0% vs 47.3%; p<0.001); and a 33.3% reduction in the median number of TPE days (5.0 vs 7.5 days). No new safety concerns were highlighted, with mild mucocutaneous bleeding being the main adverse effect.

According to Professor Provôt, this integrated analysis is the first publication in which no aTTP-related deaths have been reported in randomized trials. He added that, because of its rapid onset of action, caplacizumab might act as ‘bridge’ until rituximab efficacy is achieved. The faster time to platelet recovery also raises the possibility of reducing the number of TPE days and time in hospital, especially in critical care.

Outcomes in clinical trials are reflected in real-world experience with caplacizumab. The French experience began in September 2018 and includes 90 patients with acute aTTP, who all received the same regimen as in HERCULES. The percentage of patients with the composite primary outcome of refractoriness and death within 30 days of diagnosis was 2.2% vs 12.2% in historical controls (p=0.01). Compared with controls, patients receiving caplacizumab also had fewer exacerbations (3.4% vs 44%, p<0.01), recovered durable platelet count 1.8 times faster (95% CI 1.41-2.36; p <0.01) with fewer TPE sessions and lower plasma volumes (p<0.01 both). As in the randomized trials, there were no unexpected adverse events.

Professor Provôt concluded that standard of care for acute aTTP is now TPE, immunosuppression with corticosteroids and rituximab, and caplacizumab. However, despite improved treatment, it is likely that many patients die before TTP is diagnosed and it remains essential to raise awareness of the diagnosis among clinicians.

Experience through learning: clinical pearls

Paul Brinkkötter, Germany

A 46-year-old white male presented to the emergency department in late summer 2018 with generalized weakness, low platelets, petechial hemorrhages of the skin, high LDH, schistocytes and anemia. He had acute kidney injury with a creatinine of 5.31 mg/dl. His PLASMIC score was 5, reflecting a moderate risk of ADAMTS13 activity <10%-a diagnosis confirmed by laboratory testing showing ADAMTS13 activity of ≤0.3%, below the limit of detection.

The patient responded well after receiving high-dose glucocorticoids and TPE within a few hours of admission. Platelet count normalized within two days but fell after the two-day weekend break in treatment. Despite restarting TPE and initiating rituximab, disease activity could not be controlled. Following a compassionate use agreement on 1st September 2018, caplacizumab was started. The patient responded rapidly, and disease activity remains under control. However, very low ADAMTS13 levels continued, and caplacizumab treatment was extended for a total of 58 days according to the HERCULES study protocol.

Professor Brinkkötter reported that during treatment, the patient showed a highly dynamic platelet response, most likely reflecting the bone marrow response, and considered that this phenomenon can easily be misinterpreted as an exacerbation or early relapse, especially when caplacizumab is discontinued. It is therefore critical to monitor clinical symptoms and LDH levels and other markers for hemolysis. This patient’s LDH levels remained within the normal range, and experience was similar in the first 60 German patients treated with caplacizumab in 2018-19.

Median time to ADAMTS13 >10% in the German cohort was 21 days after the last TPE. 11 patients, whose ADAMTS13 activity was <10% when stopping caplacizumab, experienced disease exacerbation or relapse.

Professor Brinkkötter commented that these data indicate that ADAMTS13 activity can serve as a biomarker to guide therapy and assess relapse risk. If activity remains suppressed, there is a 50% risk of relapse, especially within the first month. Reflecting other published data, all relapses in the German cohort occurred within two weeks of stopping caplacizumab at a mean of 6.9 (3.9-9.9) days.

There is an ongoing debate whether early use of rituximab can shorten time to ADAMTS13 normalization. There was no clear effect on ADAMTS13 normalization in 48 of 60 patients in the German cohort, who were receiving rituximab front line. However, Professor Brinkkötter regarded these data as inconclusive since physicians tended to withhold rituximab in milder cases or give it primarily in refractory disease or exacerbations. He also considered the pathophysiology concept supporting use of rituximab in acute aTTP to be convincing.

Caplacizumab is now recommended as first-line therapy in current guidelines, and Professor Brinkkötter concluded that German and French data confirm its real-world effectiveness in acute episodes of aTTP. Treatment of aTTP has become success story and the disorder has lost much of the fear it held since it was first described in 1924.

Further reading

Diagnosing aTTP and its challenges
Brocklebank V, et al. Thrombotic microangiopathy and the kidney. Clin J Am Soc Nephrol 2018;13(2):300-317

Mackie I et al. International Council for Standardization in Haematology (ICSH) recommendations for laboratory measurement of ADAMTS13. Int J Lab Hematol 2020;42(6):685-696

Coppo P, et al. Thrombotic thrombocytopenic purpura: Toward targeted therapy and precision medicine. Res Pract Thromb Hemost 2019;3(1):26–37

Sukamer S, et al. Thrombotic thrombocytopenic purpura: pathophysiology, diagnosis, and management. J Clin Med 2021;10(3):536

Acute aTTP treatment in 2021
Joly BS, et al. Understanding therapeutic targets in thrombotic thrombocytopenic purpura. Intensive Care Med 2017;43(9):1398-1400

Peyvandi F, et al. Caplacizumab prevents refractoriness and mortality in acquired thrombotic thrombocytopenic purpura: integrated analysis. Blood Adv 2021

Coppo P, et al. A regimen with caplacizumab, immunosuppression, and plasma exchange prevents unfavorable outcomes in immune-mediated TTP. Blood 2021;137(6):733-742

A new perspective in the management of aTTP
Volker LA, et al. ADAMTS13 and VWF activities guide individualized caplacizumab treatment in patients with aTTP. Blood Adv 2020;4(13):3092-3101

Zheng XL, et al. ISTH guidelines for treatment of thrombotic thrombocytopenic purpura. J Thromb Haemost 2020;18(10):2496-2502