A regimen with caplacizumab, immunosuppression, and plasma exchange prevents unfavorable outcomes in immune-mediated TTP

Abstract

The anti-von Willebrand factor nanobody caplacizumab was licensed for adults with immune-mediated thrombotic thrombocytopenic purpura (iTTP) based on prospective controlled trials. However, few data are available on post-marketing surveillance. We treated 90 iTTP patients with a compassionate frontline "triplet regimen" associating therapeutic plasma exchange (TPE), immunosuppression with corticosteroids and rituximab, and caplacizumab. Outcomes were compared to 180 historical patients treated with the standard frontline treatment (TPE and corticosteroids, with rituximab as salvage therapy). The primary outcome was a composite of refractoriness and death within 30 days since diagnosis. Key secondary outcomes were exacerbations, time to platelet count recovery, the number of TPE and the volume of plasma required to achieve durable remission. The percentage of patients in the triplet regimen with the composite primary outcome was 2.2% vs. 12.2% in historical patients (p=0.01). One elderly patient in the triplet regimen died of pulmonary embolism. Patients from this cohort experienced less exacerbations (3.4% vs. 44%, p<0.01); they recovered durable platelet count 1.8 times faster than historical patients (95% confidence interval, 1.41-2.36, p<0.01), with fewer TPE sessions and lower plasma volumes (p<0.01 both). The number of days in hospital was 41% lower in the triplet regimen than in the historical cohort (13 days vs. 22 days, p <0.01). Caplacizumab-related adverse events occurred in 46 patients (51%), including 13 major or clinically relevant non-major hemorrhagic events. Associating caplacizumab to TPE and immunosuppression, by addressing the three processes of iTTP pathophysiology, prevents unfavorable outcomes and alleviates the burden of care.

Thrombotic Thrombocytopenic Purpura: When Basic Science Meets Clinical Research

“…65 In the French cohort, patients in the caplacizumab-containing regimen received 50% fewer TPE sessions and 45% lower plasma volumes, while accordingly the number of days in hospital was 41% lower (p < 0.01 all). 67 In accordance with its mechanism of action, side effects associated with the use of caplacizumab in both studies were mainly represented by a greater occurrence of mucocutaneous bleeding such as epistaxis and gingival bleeding (►Table 4). However, these events were mild and rarely clinically significant, with no death attributable to treatment.…”

Should all patients with immune‐mediated thrombotic thrombocytopenic purpura receive caplacizumab?

“…Similarly, in the German cohort, about one‐third of patients who stopped caplacizumab while ADAMTS13 activity was still < 10% experienced a relapse, after a median time of 6.9 days 26 . Conversely, continuation of treatment until ADAMTS13 activity recovers allows overcoming relapse risk upon discontinuation 26 (Coppo et al) 20 . From these studies, ADAMTS13 activity emerges as a crucial biomarker to guide treatment duration.…”

“…20 Moreover, exacerbations in the triplet cohort were only observed in 3.4% of patients vs 44% in the historical cohort (P < .01), with 50% fewer TPE sessions and 45% lower plasma volumes, while accordingly the number of days in hospital was 41% lower (P < .01 all) (Coppo et al). 20 This study provided two different modalities of use of rituximab (ie, frontline in the triplet regimen but as a salvage therapy in the historical cohort). However, this work was not only aimed at demonstrating the superiority of the addition of caplacizumab to the standard treatment; instead, it shows that a strategy addressing the three aspects of iTTP pathophysiology simultaneously from diagnosis is superior to more sequential/escalating strategies, whereas the risk/benefit effect remains acceptable.…”

“…This strategy resulted in a significantly lower incidence of a composite outcome of iTTP refractoriness or death within 30 days since diagnosis in the 90 patients treated with this “triplet regimen” as compared with historical controls treated with TPE and corticosteroids, with rituximab as salvage therapy (2.2% vs 12%, P = .01) (Coppo et al) 20 . Moreover, exacerbations in the triplet cohort were only observed in 3.4% of patients vs 44% in the historical cohort ( P < .01), with 50% fewer TPE sessions and 45% lower plasma volumes, while accordingly the number of days in hospital was 41% lower ( P < .01 all) (Coppo et al) 20 . This study provided two different modalities of use of rituximab (ie, frontline in the triplet regimen but as a salvage therapy in the historical cohort).…”

“…This approach allows obtaining an ADAMTS13 activity ≥ 20% after a median time of 28 (14-42) days post-TPE as compared with 48 (24-43) days in historical controls for which the use of rituximab was less common (68%) and/or delayed. (Coppo et al) 20.…”