Review of the management of patients with immune thrombotic thrombocytopenic purpura with persistently low adamts-13 activity - a challenge beyond rarity. Free

INTRODUCTION: Immune thrombotic thrombocytopenic purpura (iTTP) is characterized by the presence of autoantibodies or an inhibitor against ADAMTS13 enzymatic activity. The current standard of care includes immunosuppressive therapy (corticosteroids and anti-CD20 agents) aimed at eradicating the autoantibody and restoring normal ADAMTS13 activity. However, a subset of patients fails to achieve this therapeutic target, exhibiting persistently low enzymatic activity.

Although it is well established that persistently low ADAMTS13 activity is associated with an increased risk of thrombotic events and disease relapse, the underlying mechanisms of treatment failure and the optimal management strategy remain unclear. This study examines such cases within the Spanish TTP Registry to define their clinical and laboratory characteristics and evaluate their response to various therapeutic interventions.

MATERIALS AND METHODS: Patients diagnosed with iTTP included in the registry were reviewed. The analysis focused on those who, despite having received immunosuppressive treatment with corticosteroids and anti-CD20 agents, maintained ADAMTS13 activity levels <10% at ≥90 days after initiation of such treatment.

RESULTS: A total of 11 patients meeting the specified criteria were identified, 7 women and 4 men.

At diagnosis, the mean age was 43 years (range: 24–71). Laboratory parameters at presentation were: mean hemoglobin 9 g/dL (range: 6.5–12.7), mean platelet count 13.3 × 10³/mm³ (range: 5–22), and mean LDH 1,561 U/L (range: 405–4574). The most common clinical presentations were mucocutaneous symptoms in 4 patients, neurological symptoms in 4, renal in 2, and other manifestations in 1.

ADAMTS13 activity levels at diagnosis were below 0.5% in all patients. After 3 months of immunosuppressive treatment, activity remained below 6% in all cases, except for 2 patients for whom this data was unavailable, although both subsequently showed levels below 10%. ADAMTS13 autoantibodies were still detectable during clinical remission in 9 patients; the 2 patients without detectable antibodies had negative mutational studies.

All patients received therapeutic plasma exchange during the acute episodes. Additionally, all were treated with immunosuppressive therapy including corticosteroids and anti-CD20 agents at some point during their disease course. 7 patients were treated with caplacizumab and 1 with recombinant ADAMTS13. Eight patients have been followed for more than 2 years (range: 11 months to 2 years); among them, 6 experienced relapses and/or exacerbations. These patients received additional treatments including mycophenolate (4), cyclosporine (2), bortezomib (2), and splenectomy (1). Three patients with less than two years of follow-up have not presented relapses or exacerbations. Two of them were treated with mycophenolate and one with daratumumab.

Different immunosuppressive treatment combinations per patient:

2 patients: Corticosteroids+AntiCD20

1 patient: Corticosteroids+AntiCD20+Splenectomy

4 patients: Corticosteroids+AntiCD20+Mycophenolate

1 patient:Corticosteroids+AntiCD20+Mycophenolate+Daratumumab

1 patient: Corticosteroids+AntiCD20+Cyclosporine+Bortezomid

1 patient: Corticosteroids+AntiCD20+Cyclosporine+Bortezomib+Splenectomy

1 patient: Corticosteroids+Anti-CD20+Cyclosporine+Bortezomib+Mycophenolate.

CONCLUSIONS - A small proportion of patients with iTTP don´t respond to first-line therapy and these individuals are at high risk of relapse.

- There is no established consensus on second- or subsequent-line therapies for patients with persistently low ADAMTS13 activity, nor on the use of prophylactic strategies, this is reflected in the heterogeneity of immunosuppressive regimens used in our cohort.

- We aim to continue and expand this study in order to improve the management of these rare and challenging cases.