Real-world insights on the management of immune-mediated thrombotic thrombocytopenic purpura with caplacizumab

TO THE EDITOR:

Immune-mediated thrombotic thrombocytopenic purpura (iTTP), also known as acquired TTP, is a life-threatening rare blood disorder caused by autoantibody-mediated severe deficiency of a disintegrin and metalloproteinase with thrombospondin type 1 motif, member 13 (ADAMTS13).¹ ADAMTS13 cleaves ultralarge von Willebrand factor (VWF) multimers into smaller multimers, preventing spontaneous platelet binding. ADAMTS13 deficiency leads to the accumulation of ultralarge VWF multimers and subsequent microthrombus formation, resulting in thrombotic microangiopathy (TMA).¹ 

Therapeutic plasma exchange (TPE) and immunosuppressive therapy are the mainstay treatments for adult patients with iTTP, with International Society on Thrombosis and Haemostasis guidelines recommending the addition of caplacizumab.² Caplacizumab is a VWF-directed antibody fragment that prevents the binding of platelets to ultralarge VWF multimers.^2,3 Clinical trials and European real-world studies support the efficacy and safety of caplacizumab for patients with iTTP, showing that caplacizumab treatment is well tolerated and associated with rapid platelet recovery.^4-10 Caplacizumab was approved for use in the European Union in 2018¹¹ and has been commercialized and reimbursed in Belgium since September 2019.¹² A recent Belgian real-world evidence (RWE) study compared the outcomes of secondary TMA vs other TMAs (including TTP), but it was conducted before the availability of caplacizumab and reported high mortality rates (28%) in TTP.¹³ Our objective was to report real-world data on iTTP management, caplacizumab use, health care resource utilization, and the overall outcomes and safety of caplacizumab treatment.

We conducted a retrospective analysis of hospital chart data from adult patients (aged ≥18 years) with iTTP who were hospitalized and treated with caplacizumab in 13 Belgian hospitals. Hospitals were selected based on having ≥2 patients treated during the first 2 years of caplacizumab reimbursement (ie, by September 2021) and were equally distributed across the country. Retrospective medical data were collected (1 September 2019 to 15 January 2022). Patients were included if they received caplacizumab treatment that was initiated and ended within the study period. No exclusion criteria were applied. Patient demographics, treatment characteristics, health care resource utilization, efficacy, and safety outcomes are presented. Continuous variables were described as mean (standard deviation [SD]), and categorical variables were analyzed as unadjusted rates. Analyses were performed in 2 subgroups to identify differences in disease characteristics and management for first diagnosed episodes and relapse episodes.

Thirty-nine iTTP episodes (25 first diagnoses and 14 relapse episodes) were identified in 33 patients who were hospitalized and treated with caplacizumab. Most patients (81.8%) experienced 1 episode, and none experienced >2 episodes (Table 1). Most patients were admitted to hospital from home (first diagnoses, n = 13 [52.0%]; relapse episodes, n = 14 [100.0%]). Of the remaining 12 patients with first diagnoses, 10 (40.0%) were referred from hospitals without iTTP expertise, 1 (4%) was referred from hospital consultation, and 1 (4%) was referred from a rehabilitation center. An intensive care unit stay was required for 60% of first diagnosed episodes and 28.6% of relapse episodes (duration data are shown in Table 1).

Caplacizumab was initiated quickly after hospital admission for both subgroups (Figure 1A). The mean interval between diagnosis confirmation (ADAMTS13 activity testing) and caplacizumab initiation was 0.4 (SD, 5.0) days and –0.7 (SD, 1.6) days for first diagnosed and relapse episodes, respectively. Treatment started the same day as TPE in 74.4% of all episodes. Mean number of caplacizumab doses per episode was 39.2 (14.7) for first diagnosed episodes and 31.9 (8.4) for relapse episodes (Figure 1B). Five patients needed >60 doses, including 2 patients who developed an exacerbation. The mean caplacizumab treatment duration was 39.6 (SD, 15.3) days and 32.7 (SD, 10.1) days in first diagnosed and relapse episodes, respectively (Table 1). All patients were treated with caplacizumab, TPE, and immunosuppressive therapy. The mean time to TPE initiation after hospital admission was 2.3 (SD, 4.6) days in patients with first diagnosed episodes and 0.4 (SD, 0.5) days in patients with relapse episodes. The mean TPE duration was similar for both subgroups. The most common corticosteroid therapy was methylprednisolone, which was often dosed at 1 mg/kg per day tapered over 4 weeks. Rituximab therapy was used for 24 first diagnoses (96%) vs 9 relapse episodes (64.3%); the most frequently used (24/33 [72.7%]) dosing scheme was 375 mg/m² on days 1, 8, 15, and 22.

The mean time from caplacizumab initiation to sustained platelet count was 4.6 (SD, 3.3) days for first diagnosed episodes and 6.0 (SD, 5.9) days for relapse episodes. Exacerbations (2/39 [5.1%] episodes) occurred after caplacizumab was interrupted due to the absence of ongoing disease symptoms. One patient did not have ADAMTS13 testing at the time of interruption, and the other had ADAMTS13 activity level <10%, suggesting the underlying cause of disease was still present. Of the 6 patients who developed a relapse (6/39 [15.4%] episodes), 3 patients experienced relapse ∼1 week after caplacizumab termination. The reason for caplacizumab termination in these 3 patients was platelet count normalization for ≥30 days after TPE termination and symptom resolution. ADAMTS13 activity was <10% for all, suggesting that the underlying cause of disease was unresolved. No patients were refractory to treatment or passed away (Table 1).

Adverse events occurred in 6 patients (24.0%) with first diagnosed episodes and 3 patients (21.4%) with relapse episodes. Bleeding events were reported in 3 of 25 first diagnosis (12.0%) and 2 of 14 relapse episodes (14.3%), respectively (Table 1). Two bleeding events, one jugular catheterization and one small intestine bleeding (both caplacizumab-related), were reported as serious adverse events; these were addressed by pausing the treatment for 1 day and by discontinuing treatment, respectively. Thromboembolic events occurred in 7 patients (28.0%) with first diagnoses and 1 patient (7.1%) with relapse episodes. Of these, 5 of 7 events (71.4%) in the first diagnosis subgroup and 1 of 1 event (100%) in the relapse subgroup were considered complications of iTTP. None of the thromboembolic events were regarded as a complication of caplacizumab.

Our study showed that caplacizumab was initiated soon after hospital admission and diagnosis, alongside TPE and immunosuppressive therapy as per international recommendation,² resulting in rapid recovery of platelet count and a brief (<1 week) TPE duration, in line with results reported in the HERCULES trial.¹⁰ Although the practice of ADAMTS13 testing at diagnosis is well established, this study shows that additional ADAMTS13 testing should be used to optimize treatment because it can guide timing of treatment discontinuation.² Suppressed ADAMTS13 activity (<10%) in patients who experienced relapses was also reported in TITAN and HERCULES trials.^9,10 The authors feel that the observed exacerbations and relapses might have been avoided if treatment was prolonged until ADAMTS13 activity normalization. Although the new outcome definitions list partial remission as ADAMTS13 ≥20% but less than the lower limit of normal,¹⁴ the exact/best threshold to distinguish risk of relapse is uncertain. The proportion of patients with a bleeding event was lower than that observed in clinical trials (65% and 21% in HERCULES and post-HERCULES, respectively)^10,16 but was in line with or lower than other RWE studies; these included 13 of 90 patients (14.4%) with major bleeding/clinically relevant nonmajor bleeding⁵ and 16 of 77 patients (20%) with bleeding events.⁷ Limitations are linked to the rarity of iTTP, resulting in the small number of patients with available data, together with decentralized care for patients with iTTP across different hospitals. Additionally, due to the retrospective nature of this study, underrecording may have occurred in hospital charts, and data may not have been reported immediately (patients with iTTP are often hospitalized as emergency cases).

In conclusion, these findings on caplacizumab treatment in Belgian hospitals are in line with other published RWE^4-8 and support results from clinical trials.^9,10 

The hospital chart review was approved by all ethics committees of local hospitals before the start of the study.

Acknowledgments: Medical writing support was provided by Sarah Meadows and Hanna Mourad-Agha of Fishawack Communications Ltd, part of Avalere Health, and was funded by Sanofi. Saskia Cant of Wissa BV provided editorial assistance. The authors extend their deepest gratitude to Bernard De Prijck, who has been a key contributor since the inception of this project. Far surpassing a typical review, he was instrumental in meticulously crafting the abstract and ensuring the poster's impactful presentation at the European Hematology Association 2023 (#P1608).

The study was funded by Sanofi.

Sanofi reviewed and provided feedback for the manuscript.

Contribution: All authors participated in data interpretation and manuscript writing/reviewing for this work and approved the submitted version of the manuscript.

Conflict-of-interest disclosure: S.L. and C.M. are employees of Sanofi and may hold shares and/or stock options in the company. I.M. has received a travel grant from Sanofi for EHA 2022. D.B. has received travel and congress fees from Sanofi. A.D.V. has previously received fees from AbbVie. D.D. reports consultancy for Sanofi and honoraria from Sanofi. A.S. has received travel and congress fees from Sanofi. The remaining authors declare no competing financial interests.

Correspondence: Daan Dierickx, Department of Hematology, University Hospitals Leuven, Herestraat 49, B-3000 Leuven, Belgium; email: daan.dierickx@uzleuven.be.