Management of immune thrombotic thrombocytopenic purpura with caplacizumab: a Canadian, single-centre, real-world experience

Abstract When combined with therapeutic plasma exchange (TPE) and immunosuppression, upfront universal administration of caplacizumab was shown to be effective in the management of immune thrombotic thrombocytopenic purpura (iTTP). However, access to this drug remains challenging in many jurisdictions. We retrospectively review results of a single-institution experience with caplacizumab over a 3-year period. During the study period, we treated 48 patients with iTTP, of which 11 (23%) received caplacizumab. Eight of these 11 patients (73%) were female; the median age was 45 years (IQR 37.0–58.5). All received TPE within 24 h of admission (median 9 exchanges, IQR 7.0–12.5), and high-dose steroids. Caplacizumab was initiated for a median of 6 days after admission (IQR 2.5–8.0) and continued for a median of 26 days (IQR 14.0–33.0). Five patients (45%) had refractory disease at caplacizumab initiation. Ten patients (91%) survived, reaching clinical remission. Platelet normalization was reached with a median of 4 days following caplacizumab initiation (IQR 1.5–4.0). Complications included minor bleeding (n = 1) and local allergic reaction (n = 1). No patients experienced TTP exacerbation; relapse occurred in two patients (18%) over 1–5 years of follow-up. Caplacizumab appeared to be effective and safe, despite delayed initiation and in the setting of refractory disease. Plain Language Summary Immune thrombotic thrombocytopenic purpura (TTP) is a rare, life-threatening blood condition characterized by low platelets, anemia, and formation of blood clots in the small blood vessels. The condition results from a patient’s immune system attacking a blood protein called ADAMTS13. The standard treatment for iTTP is plasma exchange (which replaces ADAMTS13) and medications, which suppress the immune system. Recently, a new medication, caplacizumab, has been shown to improve outcomes in iTTP, if combined with a standard treatment. However, this drug is expensive, and not readily available in all parts of the world, including Canada. In this article, we present the first Canadian experience with caplacizumab. Due to its limited access, the drug is frequently used in patients who are refractory to standard treatment or presented with severe organ damage. This contrasts with previously published studies, where it has been used upfront and in all patients with TTP. We find that caplacizumab may be safe and effective in this setting, demonstrating a low mortality rate and rapid recovery in most patients. While upfront and universal use of caplacizumab in the treatment of iTTP is optimal, our approach could be used in settings, where access to this medication is restricted.


Introduction
Thrombotic thrombocytopenic purpura (TTP) is a rare, lifethreatening disorder that presents with thrombocytopenia, hemolytic anemia, and often multi-organ damage.The underlying cause of this disorder is a congenital (cTTP) or immune (autoantibody mediated, iTTP) severe deficiency in the activity of the ADAMTS13 protease, which is responsible for cleaving ultra-large Von Willebrand factor multimers (ULVWF) into smaller units.The resulting accumulation of ULVWF binds platelets and creates microvascular thrombi.About half of the patients presenting with iTTP have evidence of neurological, cardiac, or renal involvement [1].Without appropriate treatment, the disease has a greater than 90% mortality rate.
As per the recently published evidence-based ISTH guidelines [2], iTTP treatment should include therapeutic plasma exchange (TPE) to replace ADAMTS13-deficient plasma with normal plasma and immunosuppression with steroids to suppress the production of pathogenic antibodies.In addition, once diagnosis has been confirmed, rituximab and caplacizumab could be added.Caplacizumab is a humanized single-variable-domain immunoglobulin fragment that specifically targets the A1 domain of VWF, blocking its interaction with the platelet GP1b-IX-V receptor [3].When added to standard of care treatment, it decreases the time to platelet normalization and improves TTPrelated outcomes including death and thromboembolic events as compared to placebo (TITAN and HERCULES trials) [4][5][6].While promising, clinical trial data may not always be generalizable to the real world, as patients must meet strict inclusion criteria and follow the treatment plan dictated by the trial.There are a few studies describing caplacizumab use and outcomes in real-world TTP patients, primarily in the upfront setting [7][8][9].In the refractory setting, its use has been described in less than 25 patients, in case reports and two real-world retrospective studies [10][11][12][13].Successful use has also been demonstrated in some patients without concurrent plasma exchange [9,14].Caplacizumab leads to a significant reduction in health-care utilization; however, due to its high price was found to be not costeffective in a recent analysis [15].Moreover, this medication is not yet widely accessible.
In Canada, caplacizumab was approved by Health Canada, but was not recommended for funding by the Canadian Agency for Drugs and Technologies in Health (CADTH) in part due to lack of real-world data on clinically relevant long-term outcomes, survival, and healthcare use [16].Thus, caplacizumab in Canada is currently only available for use through private insurance plans or industry compassionate programs.As a single institution with a large proportion of Canadian caplacizumab use, we aim to describe the first Canadian experience using caplacizumab to treat real-world TTP patients.

Methods
We conducted a retrospective chart review at St. Michael's Hospital in Toronto, Canada, where we maintain a registry of all patients treated for TTP and other thrombotic microangiopathies.Patients with immune TTP and treated with at least one dose of caplacizumab from 1 January 2018 until 31 December 2021 were included in the study.Those who received caplacizumab as part of a clinical trial were excluded.The patients were identified using the existing registry and corresponding paper apheresis charts.Data were collected using electronic medical records.
TTP diagnosis was confirmed based on accepted clinical and laboratory findings, including thrombocytopenia (platelet count <150 × 109/L), anemia (hemoglobin <130 g/L), evidence of red blood cell fragmentation on blood film, and evidence of hemolysis (any two of the following: elevated lactate dehydrogenase, indirect hyperbilirubinemia, elevated reticulocyte count, low/ undetectable haptoglobin, or hemoglobinuria).In addition, patients must have had ADAMTS13 activity <10% at any point in their presentation/admission, measured at our institution using a commercial ELISA Technoclone Technozym ADAMTS13 activity assay.
All the patients were treated with daily centrifugal TPE (1.0-1.5 plasma volume) with plasma and high-dose steroids (at least 1 mg/kg/d of prednisone or equivalent) as soon as diagnosis was suspected.Rituximab (375 mg/m2 intravenously once per week for 4 weeks) is neither approved nor funded for treatment of iTTP in Canada, and its use was limited to refractory or relapsed cases.Caplacizumab was obtained via compassionate supply from the manufacturer.Prior to Health Canada's approval, the drug was used once through a special access program; following licensure, the drug was intermittently available through different manufacturers' compassionate programs on a named patient basis.In a few cases, there was a delay of more than 24 h between a request and drug receipt at the hospital.The dosing regimen was as per the HERCULES trial: 11 mg caplacizumab intravenously followed by TPE and another 11 mg subcutaneously.Subcutaneous doses were continued daily after TPE, and further after the completion of TPE until ADAMTS13 activity >10% (monitored approximately every 7 days) or other reason for discontinuation.In some instances, the loading intravenous dose was omitted for logistical reasons (indicated in the results).Informed consent was obtained prior to treatment with caplacizumab.Patients who required outpatient treatment with caplacizumab were taught to selfadminister the drug.
Data collected from the chart review included demographic information, laboratory data, clinical details, treatments, outcomes, and complications.Data were analyzed using simple descriptive statistics where applicable.Patient consent was waived due to the retrospective nature of the study.Institutional Research Ethics Board approval was obtained.

Participant characteristics
We identified a total of 48 patients admitted to our institution with a confirmed TTP episode (ADAMTS13 activity <10%) during the study period, 11 (23%) of which were treated with at least one dose of caplacizumab.Their baseline demographics and general TTP characteristics are shown in Table I.Of the 11 patients, 8 (73%) were female.All patients had immune TTP, confirmed with a high ADAMTS13 inhibitor titer.The median age at the current presentation was 45 years (IQR 37.0-58.5 years).The majority of patients (64%) were admitted with a new diagnosis of TTP; those who presented with relapse had a median of 3 previous episodes (IQR 2.5-4.0).
Clinical and laboratory characteristics of the initial presentations are also shown in Table I.All patients presented with significant thrombocytopenia (median platelet count 11, IQR 9-15 × 10 9 /L) and evidence of hemolysis (median lactate dehydrogenase 1181, IQR 1015.5-1809.0U/L).All but one patient also presented with anemia; the median hemoglobin level at presentation was 85 g/L (IQR 71.0-101.5 g/L).All ADAMTS13 activities taken at the presentation were <10%, confirming the diagnosis of an acute TTP episode.In terms of target organ damage, five patients (45%) presented with neurological symptoms, which are described in detail in Table I.Four patients (36%) presented with serum creatinine levels above the upper limit of normal, according to institutional reference ranges (median 89, IQR 80.0-160.5 umol/L).The median peak creatinine during admission was 111 umol/L (IQR 83.0-199.5 umol/L).All but one patient (91%) presented with elevated troponin (median 97, IQR 27.5-635.0ng/L), and all eventually had elevated troponin over the course of admission (median peak troponin 233, IQR 88.5-816.5 ng/L).

Treatment
Treatment details for each patient are described in Table II.All patients received TPE within 24 h of admission.The median number of exchanges was 9 (IQR 7.0-12.5).With regard to replacement fluid, five patients received only cryosupernatant plasma (CSP), two patients received only solvent detergent plasma (SDP), and four patients received both CSP and SDP during treatment.All patients received high-dose of steroids of 1 mg/kg/day (or higher) daily until clinical remission, followed by a taper of 10 mg per week.Eight patients (73%) received at least one dose of rituximab or biosimilar during admission, which was mostly started in the setting of refractory disease (started median of 7.5 days into admission, IQR 6.8-12.5 days).Rituximab was administered in the same dose and frequency (375 mg/m2 weekly for 4 weeks) unless otherwise noted.
As caplacizumab is not publicly funded in Canada, it was obtained through compassionate supply.The reason for initiation   1, relative to caplacizumab initiation.In terms of complications of caplacizumab, one patient experienced a minor bleeding complication (menorrhagia) and one patient experienced a local cutaneous allergic reaction.Minor bleeding was defined using the WHO bleeding scale as Grade 2 or lower.There was no clinically significant bleeding, and no discontinuation due to bleeding.Of the 11 patients, 9 eventually reached an ADAMTS13 activity >10%, at which point caplacizumab was discontinued.This was reached in a median of 26 days (IQR 15-30 days).One patient had persistently low ADAMTS13 activity in remission.
ADAMTS13 trends per patient over the course of admission and caplacizumab treatment are shown in Figure 2.With regard to long-term outcomes, no patients experienced disease exacerbation while on caplacizumab (defined as reduction in platelet count/ increased LDH and need to restart TPE within 30 days of last TPE [17]).Two patients (18%) experienced TTP relapse (defined as reduction in platelet count/increased LDH and need to restart TPE after 30 days of the last TPE [17]) during the study period, after discontinuation of caplacizumab.These relapses occurred 1 and 3 years after treatment, with neither relapse involving reexposure to caplacizumab.

Discussion
In this single-institution case series, we describe the real-world use of caplacizumab in Canadian patients with TTP.Caplacizumab appeared to be effective in reaching platelet normalization (median 4 days) and clinical remission.It was well tolerated, with no discontinuation due to adverse events.ADAMTS13 recovery (>10%) was eventually reached in 9 of 11 patients, with most patients discontinuing caplacizumab successfully without exacerbation or relapse (2 relapses within the study time frame).Our mortality rate was low (1/11) despite caplacizumab often being given in the setting of refractory disease and not as upfront therapy; initiation of treatment occurred after median 6 days of TPE.
Our efficacy data are comparable to results from clinical trials and existing real-world cohort studies.Integrated analysis from the TITAN and HERCULES trials showed a median time to platelet normalization of 2.75 days with upfront caplacizumab use, significantly decreased compared to placebo [6].In terms of real-world studies, Volker et al. reported a median time to platelet normalization of 3 days in a cohort of 60 patients treated with caplacizumab, with a median of 3 days following TPE initiation in Germany [9].Dutt et al. reported a similar median time to platelet normalization of 3 days in a cohort of 85 patients treated in the UK, with a median of 2 days following TPE [7].Coppo et al. compared a cohort of 90 patients treated in France with upfront triple therapy to historical controls and reported a median of 5 days to platelet normalization (faster than control) [8].Finally, Pascual Izquierdo et al. used data from the Spanish TTP registry to compare 77 patients treated with caplacizumab to 78 treated without; the time to clinical response was 5 days in the subgroup of 44 patients treated upfront with caplacizumab (started median 2 days after TPE) [18].Both clinical trials and real-world studies have also demonstrated a reduced duration of TPE with caplacizumab treatment [4][5][6]8].In our study, the median time to platelet count normalization from caplacizumab initiation was 4 days (IQR 1.5-4.0).While we had no comparator group, caplacizumab use resulted in a quick discontinuation of TPE (median 4 days after initiation, IQR 3-6).Caplacizumab treatment was initiated median 6 days after TPE in our study, which is later than trials and most other real-world studies as described above.One real-world study in the United States described a similar median time to caplacizumab initiation of 5 days following TPE, although reasons for delayed use were not specified and noted to be at physicians' discretion [13].While upfront therapy is optimal based on clinical trial data, our approach to initiation in a select group of patients (refractory disease, prior refractoriness, significant end-organ damage) was used due to limited access to the drug.Indeed, when separating upfront and refractory patients, treatment began earlier in those without refractory disease (median 2.5 days vs. 8.0 days), in line with time to initiation from other real-world studies [7,9].In these patients treated upfront, platelet normalization was reached faster (median 2.5 days vs. 4.0 days), although numbers were smaller.Data from the Spanish TTP registry similarly found that although caplacizumab was successful in rescuing patients with refractoriness and exacerbations (95% and 93% respectively), time to clinical response was faster in patients treated with caplacizumab upfront [18].Logothetis et al. present data on 10 patients treated with caplacizumab, 6 of which were refractory [13].While their median time to initiation was similar to our study (5 days), they did not analyze refractory patients separately, preventing a comparison of outcomes.Our results along with these studies suggest that caplacizumab can still be effective when initiated later in the course of treatment for refractory cases, however it may be more effective when initiated earlier.A prospective powered study would be needed to confirm these results.
None of our patients experienced TTP exacerbation during or after caplacizumab treatment; this is in line with results from integrated trial analysis and real-world data, which describe reduced rates of Caplacizumab to treat real-world immune TTP 5 exacerbation compared to placebo/controls [4][5][6]8,18].Data from the TITAN and HERCULES trials revealed a relatively high risk of exacerbation after caplacizumab discontinuation, especially if ADAMTS13 activity remains <10% [4,5].Similarly, recurrence or exacerbation after caplacizumab treatment described in real-world studies most often occurred when ADAMTS13 activity <10%; discontinuation in these studies was based on a combination of clinical remission and ADAMTS13 recovery [7,8].Based on these data, while the drug summary of product characteristics advises continuing caplacizumab for 30 days post discontinuation of TPE (and extension as required thereafter), we similarly discontinued based on clinical remission and routine ADAMTS13 monitoring.In our study, almost all but one patient reached ADAMTS13 >10%, at which point caplacizumab was discontinued; median length of caplacizumab treatment was 26 days, slightly lower than other real-world studies where duration was >30 days [7][8][9].Relapses occurred over a year later in two patients during the study period, both of whom did not have persistently low ADAMTS13 activity in remission.
The effect of caplacizumab on the risk of venous thromboembolic events (VTE) is unclear.In TITAN, 2.9% of the patients on caplacizumab vs. 8.1% in placebo arms developed VTE [19].However, in real-world studies, the risk of VTE was similar between caplacizumab and control groups, suggesting that caplacizumab was not effective in preventing VTE.For example, Coppo et al. reported that VTE in 12% of the patients who received caplacizumab vs. 11.1% in those who did not; none were on pharmacologic thromboprophylaxis [8].Dutt et al. reported VTE in 5% of the patients on caplacizumab vs. 5% in control group, where similarly thromboprophylaxis was withheld while on caplacizumab [7].In our study, one patient experienced a VTE during admission, following discontinuation of caplacizumab and before thromboprophylaxis was initiated.While some studies report high VTE rates in TTP populations [20][21][22][23][24], the risk of VTE while on caplacizumab and use of pharmacologic thromboprophylaxis in this setting should be further explored.
Regarding safety, caplacizumab in our case series was well tolerated; we reported very few complications of treatment, including one minor bleeding event and one local allergic reaction.Both clinical trial and real-world data identify minor bleeding as the most common adverse effect of caplacizumab [4,5,7,8].Despite being often initiated in refractory settings, our study also demonstrated a low mortality rate.One refractory patient died of cardiac arrest less than one day after initiation of caplacizumab.While other real-world studies report similarly low mortality rates, many of the reported deaths also involved late initiation of caplacizumab [7,9] suggesting that if initiation is delayed, it may not be able to eliminate TTP-related mortality.
Despite positive clinical trial and real-world data, the role of caplacizumab in the treatment of TTP has been debated, mainly due to its inability to treat the underlying ADAMTS13 deficiency and high cost [25].While there are limited data on its costeffectiveness, a few studies have suggested that it is not costeffective compared to standard of care alone if used as per label [15,26].This small case series along with existing real-world evidence suggest that TTP-related mortality with caplacizumab treatment is low, even in the context of refractory disease that may occur in up to 42% of TTP patients [6].Refractoriness is associated with adverse outcomes, including mortality; for example, refractoriness was 4 times more common in non-survivors vs. survivors of TTP [27].We describe caplacizumab use in a Canadian context, in which it was successful as a salvage therapy in many patients who were refractory to standard treatment.The limitations of our study include its small sample size, retrospective nature, and lack of a control group.We also did not collect economic data to evaluate cost-effectiveness.
We report the first single-center cohort of real-world Canadian TTP patients treated with caplacizumab.While it was used in cases of refractory disease (45% of the patients) or significant end-organ damage, caplacizumab was associated with a low mortality rate and no exacerbations.Its efficacy was comparable to existing clinical trial and real-world data, with rapid platelet normalization and discontinuation of TPE; despite small sample size and lack of control, our data suggest better efficacy when caplacizumab was initiated earlier.We also demonstrate the discontinuation of caplacizumab based on routine ADAMTS13 monitoring until >10%.Our approach should be validated in larger studies but could be considered in resource-constrained settings.Further studies are needed to evaluate the long-term outcomes and cost-effectiveness of caplacizumab, which will inform future decisions on public funding.

Disclosure statement
KP has participated in clinical trials with Sanofi, Takeda, and Roche.She has participated in advisory board, consulting, and industry-sponsored educational events with Sanofi and Takeda.BT and MB have no conflicts to disclose.

Funding
The author(s) reported that there is no funding associated with the work featured in this article.

Figure 2 .
Figure 2. Individual patient ADAMTS13 activities are plotted longitudinally.Days shown relative to initiation of caplacizumab (day 0).All ADAMTS13 activities taken while on caplacizumab treatment were recorded.Institutional reference range for ADAMTS13 activity is <10 U/mL.
: https://doi.org/10.1080/09537104.2022.2157807Caplacizumab to treat real-world immune TTP 3 depended on the individual patient context; these included refractory disease (5/11) and upfront therapy, which included previous refractoriness (1/11), significant end organ damage at presentation (for example, focal neurological deficit; 4/11), and other (1/ 11).Caplacizumab was initiated for a median of 6 days after admission (IQR 2.5-8.0 days) and continued for a median of 26 days (IQR 14-33 days).Most patients (8/11, 73%) received an intravenous loading dose.TPE was discontinued for a median of 4 days (IQR 3-6 days) after initiation of caplacizumab.Clinical outcomes and treatment complications for the study population are displayed in TableIII.These outcomes are also displayed separately for patients treated upfront with caplacizumab versus those treated for refractory disease.The median length of hospital stay was 14 days (IQR 10.5-17.0), and median length of ICU stay was 2 days (IQR 2.0-2.8).Ten of 11 patients reached clinical remission in median of 11 days from admission DOI(IQR 5.0-12.8)and median of 4 days after starting caplacizumab (IQR 1.5-4.0).One refractory patient died of cardiac complications from TTP after only receiving one dose of caplacizumab.Other than this patient, no patient had exacerbation of organ damage once caplacizumab was started.Of the surviving patients, platelet normalization was reached in a median of 4 days following caplacizumab initiation (IQR 1.5-4.0).Clinical remission and platelet normalization were reached in a median of 2.5 days (IQR 1-4 days) in the 6 patients without refractory disease, compared to 4 days (IQR 3.8-4.2) in the 5 patients treated for refractory disease.Individual platelet and lactate dehydrogenase trends are displayed in Figure

Table III .
Clinical outcomes and complications of caplacizumab treatment for total study cohort, upfront, and refractory patients.