Keywords
plasma exchange - thrombotic thrombocytopenic purpura - thrombotic microangiopathy
- rituximab - caplacizumab - ADAMTS13
Introduction
Thrombotic thrombocytopenic purpura (TTP) is a life-threatening disease characterized
by a severe deficiency in A Distintegrin And Metalloprotease with ThromboSpondin type 1 repeats, 13th member (ADAMTS13), the von Willebrand factor (vWF)-cleaving protease. This deficiency
leads to the accumulation of ultra-large vWF multimers both on the endothelial cells
surface and into the circulation. By binding to platelets, these ultra-large vWF multimers
prompt the formation of platelet-rich occlusive microthrombi in the microcirculation
which subsequently cause ischemic organ dysfunction. The most affected organs are
the central nervous system, the heart, and the digestive tract, but virtually all
organs might be involved. A consumptive thrombocytopenia reflects microthrombi formation,
whereas microangiopathic hemolytic anemia is related to red blood cells fragmentation
on microthrombi, with increased shear stress in the microcirculation that maintains
and amplifies these features. Accordingly, fragmented red blood cells, or schistocytes,
are observed on patients' blood smear. Additionally, elevated serum lactate dehydrogenase
(LDH) levels reflect hemolysis but primarily multivisceral ischemia. The disease affects
mostly adults with a female predominance (sex ratio ≈3/1) and a maximum incidence
between 30 and 50 years. TTP is a rare disease, with a prevalence of approximately
13 cases per million people and an incidence of approximately 1 to 2 new cases per
million people.[1] However, a history of immune-mediated TTP (iTTP) exposes survivors to more comorbidities
during long-term follow-up, including autoimmune diseases, hypertension, and major
depression, which could at least in part account for the shortened life expectancy
reported in this population.[2]
[3]
[4] The first TTP episode usually occurs during adulthood (∼90% of all TTP cases) or
less frequently in childhood (∼10% of all TTP cases).[1]
[5]
[6] TTP is a severe, potentially fatal disease if left untreated. However, an early
recognition of the diagnosis and an adapted treatment now allow achieving remission
rates of 90%.[7] Following the acute phase, TTP is associated with relapses when ADAMTS13 activity
remains persistently undetectable.[8]
TTP management has long been centered on the replenishment of the deficient ADAMTS13,
either by the sole administration of donor's plasma in the congenital form of the
disease (cTTP), or by the combined extracorporeal removal of patient plasma and its
replacement by donor's plasma, now referred to as therapeutic plasma exchange (TPE)
in the iTTP. In the latter, corticosteroids were then empirically added to the standard
treatment. Yet, the recent development of therapies targeting the pathophysiological mechanisms of the disease, that is, autoantibodies production or interaction between
platelets and vWF multimers, might change the therapeutic landscape of TTP in the
next few years. The purpose of this narrative review is to expose these recent advances
in TTP management and to detail how such therapies are translating into standard of
care and transform the historical, TPE-centered therapy of TTP for the benefit of
patients.
The Milestones of TTP Pathophysiology
The Milestones of TTP Pathophysiology
The first TTP case was described by Moschcowitz in 1924 in a 16-year-old girl who
suddenly developed weakness, pain, pallor, fever, and petechiae. Few days later, she
developed neurological disorders (hemiparesis and paralysis), became comatose, and
died. The autopsy analyzed the heart, the kidney, the spleen, and the liver (but not
the brain) and reported the presence of disseminated hyaline thrombi in the microcirculation.[9] In 1982, Moake et al demonstrated that TTP patients exhibited ultra-large VWF multimers
hyperadhesive to platelets in plasma, suggesting the role of VWF in TTP pathophysiology
and a deficient factor in plasma.[10] In 1998, the deficient factor was described as a protease cleaving vWF and preventing
the accumulation of proaggregant ultra-large multimers, and the antibodies responsible
for the inhibition of this enzyme were identified as a cause for iTTP.[11]
[12] It took some more years for this protease to be isolated[13] and identified as ADAMTS13.[14] Lastly, a genetic deficiency resulting of biallelic mutations of ADAMTS13 gene accounted for cTTP.[14] The rationale of plasmatherapy was then fully understood: first and foremost, TPE
achieves ADAMTS13 supplementation without risking fluid overload and subsequent complications
as well as removal of ultra-large vWF multimers and autoantibodies, although these
last mechanisms might be of lesser importance in clinical efficacy.
ADAMTS13 specifically cleaves highly adhesive high-molecular-weight vWF multimers
(>20,000 kDa) into lower, less adhesive, molecular-weight multimers. This process
occurs in the microcirculation, where high shear stress conditions expose VWF to a
conformational change, from a globular to an elongated conformation making the binding
sites for GpIbα and ADAMTS13 available. Hepatic stellate cells, podocytes and renal
tubular epithelial cells, platelets, and endothelial cells produce an active ADAMTS13
protein. The N-terminal region of ADAMTS13 comprises a metalloprotease domain, a disintegrin-like
domain, a first thrombospondin type 1 repeat (TSP1), and Cys-rich and spacer domains;
the C-terminal region of ADAMTS13 comprises seven additional TSP1 repeats and two
CUB domains.[5]
Autoantibodies directed to ADAMTS13 in iTTP are polyclonal. They have a neutralizing
action inhibiting the catalytic activity of ADAMTS13 or a non-neutralizing action,
thanks to a complexation of ADAMTS13 and an acceleration of its clearance. IgG1 and
IgG4 are the most frequent IgG subclasses. IgA and IgG1 are associated with an increased
mortality rate, and IgG4 with a higher risk of relapse.[15] More recently, it was shown that the interaction between the C-terminal (CUB) domain
of ADAMTS13 and the spacer domain induces a folded conformation of ADAMTS13. This
CUB–spacer domain interaction is relieved by interaction of ADAMTS13 with the C-terminal
domains of VWF or by the addition of anti-CUB antibodies in vitro, resulting in the
conformational activation of ADAMTS13. ADAMTS13 switches from a folded conformation
to an open conformation. The spacer–CUB interaction is abrogated when ADAMTS13 is
conformationally activated. The activation of ADAMTS13 reveals a cryptic epitope in
the spacer domain, when the protease adopts an unfolded conformation, representing
the autoantigenic core for anti-ADAMTS13 autoantibodies in iTTP. The exposure of cryptic
epitopes in the spacer domain of ADAMTS13 is thus important in the pathophysiology
of iTTP. Anti-spacer domain antibodies were developed in vitro and recognize a cryptic
epitope in ADAMTS13. Recently, Roose and collaborators developed an original ELISA
to distinguish the conformation of ADAMTS13 (folded vs. open).[16] They demonstrated that an open conformation of ADAMTS13 is a hallmark of acute iTTP
and that ADAMTS13 adopts a folded conformation during remission.[16] Interestingly, this group could show that anti-ADAMTS13 autoantibodies can induce
a change in the conformation of ADAMTS13 and thus the exposure of cryptic epitopes
in its spacer domain. ADAMTS13 conformation could therefore be a new tool for iTTP
diagnosis and monitoring during follow-up.[17]
[18]
iTTP is due to a loss of self-tolerance of the immune system toward ADAMTS13, mainly
related to the presence of anti-ADAMTS13 autoantibodies. Specific alleles in the human
major histocompatibility complex (MHC) type II system have been identified as risk
factors for iTTP. Studies conducted in adult and also in pediatric Caucasian patients
led to the identification of the predisposing HLA class II loci DRB1*11 and DQB1*03
and the protective allele DRB1*04.[19]
[20]
[21]
[22] HLA alleles significantly associated with iTTP in the Japanese population differ
from those observed in the Caucasians.[23] Nevertheless, the HLA DR proteins encoded by DRB1*11 and DRB1*08:03 (main predisposing
allele in the Japanese) are each able to bind to an ADAMTS13 peptide in the CUB2 domain,
the sequence of which differs only by the shift of one amino acid.[23]
The example of cTTP clearly illustrates that ADAMTS13 deficiency is necessary but
not sufficient to induce a perceptible disease.[14] Indeed, several conditions such as infection, inflammation, or pregnancy act as
triggering factors by activating endothelial cells and thus increasing vWF production
(infections, inflammation, tissue attrition, etc.).[24] The imbalance between high concentrations of ultra-large vWF multimers and the low
cleaving activity of ADAMTS13 either inherited or acquired then leads to the disease.
Clinical Presentation: Do Not Miss the Diagnosis
Clinical Presentation: Do Not Miss the Diagnosis
Data obtained from large series of patients allowed a better understanding of the
clinical spectrum of TTP. cTTP might be observed in children and pregnant women, whereas
iTTP is more common during adulthood. In this last situation, an underlying condition
such as a pregnancy, a history of HIV infection, connective tissue disease or cancer,
or the use of antiplatelet agents is identified in 50% of iTTP cases[1] and need to be identified for appropriate management.
Patients usually present with mild fever (30–50% of cases) and symptoms related to
organs dysfunction. Neurologic symptoms are observed in more than 50% of patients
and range from headache to coma through transient and/or migratory focal deficiency,
stupor, and seizure. Cardiac involvement includes infarction, congestive heart failure,
arrhythmias, cardiogenic shock, and sudden cardiac arrest. Importantly, an elevated
serum troponin level upon presentation is a common event (observed in up to 60% of
patients) and represents an independent predictor of death, treatment refractoriness,
and subsequent acute myocardial infarction.[25] Life-threatening hemorrhage related to severe thrombocytopenia might occur. Renal
involvement is mild with typically a serum creatinine level <200 µmol/L (2.27 mg/dL).
Microangiopathic hemolytic anemia and peripheral thrombocytopenia are constant clinical
features of TTP. Thrombocytopenia is profound, with a platelet count usually <30 G/L.
The direct antiglobulin test is negative. However, in 10% of cases, schistocytes may
be rare, and the direct antiglobulin test slightly positive, which may lead to confound TTP with autoimmune cytopenias, thereby exposing patients to a delayed diagnosis.
Therefore, a low schistocyte count and a positive direct antiglobulin test should
not systematically rule out TTP, especially when associated with organ failure.[26]
With the increasing availability of effective treatments, rapid diagnosis of TTP by
sensitive criteria is mandatory, and this urgency led to a decrease in the stringency
of the diagnostic criteria in the clinical trial that documented the effectiveness
of TPE. Consequently, the association of microangiopathic hemolytic anemia with peripheral
thrombocytopenia should be enough to strongly suggest a diagnosis of TTP, before organ
failure occurs.[27]
Although the identification of severe (activity <10%) autoimmune-mediated ADAMTS13
deficiency is required to document the diagnosis of iTTP, results of ADAMTS13 activity
measurements are rarely available in emergency situations. Moreover, commercial kits
may provide discrepant results in 12% of cases.[28] Until assays are able to provide accurate ADAMTS13 activity within some hours, clinical
scores for rapid prediction of individuals with severe ADAMTS13 deficiency will continue
to have an important role in diagnosis.[6] Two scores (the French score and more recently the PLASMIC score),[29]
[30] derived from standard parameters easily available on presentation, offer a comparable
and reliable way to identify patients with severe ADAMTS13 deficiency. Both scores
use absence of an associated condition (e.g., cancer, transplant, and disseminated
intravascular coagulation), severe thrombocytopenia (< 30 G/L), and mild renal involvement
(serum creatinine level < 2.0 or 2.27 mg/dL) as criteria for identifying patients
with probable TTP ([Table 1]). It is likely that platelet count and serum creatinine level are the most useful
and reliable values to predict severe ADAMTS13 deficiency. These scores are not aimed
at redefining TTP diagnostic criteria, which are based on severe ADAMTS13 deficiency,
but they can help rapidly identify patients who are most likely to have iTTP and therefore
most likely to benefit from emergency treatment including TPE.
Table 1
Comparison of the two clinical scores (French score and PLASMIC score) predicting
severe ADAMTS13 deficiency
|
French score
|
PLASMIC score
|
|
Platelet count
|
< 30 G/L (+1)
|
< 30 G/L (+1)
|
|
Serum creatinine level
|
< 2.25 mg/dL (+1)
|
< 2.0 mg/dL (+1)
|
|
Hemolysis
Indirect bilirubin > 2 mg/dL
Or reticulocyte count > 2.5%
Or undetectable haptoglobin
|
[a]
|
+1
|
|
No active cancer in previous year
|
[a]
|
+1
|
|
No history of solid organ or SCT
|
[a]
|
+1
|
|
INR < 1.5
|
[a]
|
+1
|
|
MCV < 90 fl[b]
|
–
|
+1
|
|
Prediction of severe ADAMTS13 deficiency
(activity <10%)[c]
|
0: 2%
1: 85%
2: 94%
|
0–4: 0–4%
5: 5–24%
6–7: 62–82%
|
Abbreviations: INR, international normalized ratio; MCV, red blood cell means corpuscular
volume (a surrogate for red cell fragmentation); SCT, stem cell transplantation.
Note: Each item is associated with one point (+1).
Source: Adapted from Coppo et al.[46]
a The French score considered patients with a TMA syndrome (which includes hemolysis
with schistocytes in the definition) and assumes that there is no history of or clinical
evidence for associated cancer, transplantation, or DIC; so these items are intrinsic
to the score.
b MCV was not incorporated in the French score.
c Results correspond to those of the derivation cohort and those of the validation
by (French score) the bootstrap resampling technique (internal validation),([29]
[30]) or (PLASMIC score) different samples of patients from the same institution (internal
validation) or from a different institution (external validation).[29]
[30]
Historical Treatment
TPE still remains the centerpiece of iTTP treatment (Category I, Grade 1A).[31]
[32] Its effectiveness was suggested by the mention of transfusion exchange techniques
as early as the description of the disease by Moschcowitz in 1924.[9] Several variants of transfusion exchange have subsequently been used and, remarkably,
only the techniques including plasma infusion proved efficacy.[33]
[34]
[35]
[36] This important clinical observation had two important consequences: first, it led
to the conclusion that a deficient factor was provided by plasma (which paved the
way for the identification of ADAMTS13); second, it defined TPE as the reference treatment
of iTTP for decades. The superior efficacy of TPE compared with the sole infusion
of plasma in early studies probably relies on the difference in volume (three times
higher for TPE) and therefore on the quantity of ADAMTS13 infused.[32]
In the specific context of iTTP, the clinical benefit of TPE could result from three
actions: the removal of autoantibodies directed against ADAMTS13; the removal of ultra-large
vWF multimers; and most importantly, the supplementation in ADAMTS13 without risking
fluid overload. TPE needs to be started as soon as possible because any delay worsens
the prognosis.[37]
[38] TPE can be performed either using centrifugation or filtration depending on team's
experience and/or availability of the corresponding device. Centrifugation plasmapheresis
is the historical modality and consists in the centrifugation of whole blood to separate
plasma from platelets, white blood cells, and erythrocytes. This technique requires
one (discontinuous flow) or two (continuous flow) peripheral venous accesses depending
on the device used and allows only low blood flow rates (50–80 mL/min). Anticoagulation
is most often performed by using citrate-dextrose solution, which is almost completely
eliminated along with plasma. It is common to start the treatment by exchanging 1.5
times the estimated plasma volume and then reducing the exchanged volume to 1.0 times.
The replacement fluid should be plasma only since other fluids do not bring ADAMTS13.
Various preparations of plasma have been tested based on the rationale of varying
content in vWF multimers, while ADAMTS13 activity remains constant.[39] To date, there is no clearly demonstrated superiority between quarantine fresh frozen
plasma, amotosalen-inactivated plasma, and solvent-detergent inactivated plasma. Of
note, methylene blue photo-inactivated plasma was associated with more TPE sessions
versus fresh frozen plasma to achieve durable remission[40]
[41]
[42]; moreover, its use has been discontinued in several countries as side effects were
more prevalent. In patients who do not improve with standard treatment, twice-daily
TPE has been reported as an available salvage strategy.[43]
[44] TPE should be continued until remission, as defined by platelet recovery (platelet
count > 150 G/L for more than 48 hours), LDH decrease, and clinical improvement.[45] Historically, TPE used to be tapered over several weeks to prevent (and/or to control
more rapidly) an exacerbation of the disease after cessation. However, the increasing
use of concomitant immunosuppressive strategies as well as the use of caplacizumab
should allow interrupting TPE abruptly without any detrimental consequence. The accurate
monitoring of ADAMTS13 activity provides confidence in this attitude when a recovery
of ADAMTS13 activity is observed (at least >20% activity). Conversely, a persistently
suppressed (i.e., < 10%) ADAMTS13 activity, although it does not necessarily preclude
TPE cessation—especially under the coverage of anti-vWF therapy, should plead for
an optimization of immunosuppression.[46]
In addition to disease-driven complications, patients are exposed to complications,
directly resulting from TPE and related to vascular access and to the volume of the
extracorporeal circuit and/or the replacement fluid ([Table 2]). It is noteworthy that the frequency of TPE-related complications decreases over
time as a result of both experience of teams and the progressive decrease in the number
of TPE sessions.[47]
Table 2
Complications of TPE for iTTP
|
Catheter-related complications
Catheter-related bleeding
- Hemothorax
- Retroperitoneal hemorrhage
- Insertion-site hemorrhage
Catheter-related thrombosis
Catheter-related local or systemic infection
Catheter dysfunction
TPE procedure-related complications
Hypotension
Arrhythmia
Hypocalcemia
Hypokalemia
Filter clotting (filtration)
Reactions to plasma
- Anaphylaxis
- Serum sickness
- Transfusion-related acute lung injury
|
Abbreviations: iTTP, immune-mediated thrombotic thrombocytopenic purpura; TPE, therapeutic
plasma exchange.
Source: Adapted from Nguyen et al.[47]
Historically, and despite the lack of strong clinical evidence, corticosteroids have
been empirically administered to achieve this goal.[31] Corticosteroids are usually used at doses of 1 to 1.5 mg/kg/day of prednisone or
equivalent, although higher doses might be of interest. In a multicentric randomized
open-label trial, 60 patients were randomized to receive either methylprednisolone
1 or 10 mg/kg/day for 3 days, followed by 2.5 mg/kg/day in addition to TPE. After
23 days of treatment, a significant reduction in the proportion of patients refractory
to therapy was noted in the high-dose group (23.4 vs. 53.4, respectively, p = 0.03).[48]
Recent Therapeutic Advances in TTP Management
Recent Therapeutic Advances in TTP Management
Immunomodulation with Rituximab at the Acute Phase
The success of rituximab in the treatment of various autoimmune conditions such as
idiopathic thrombocytopenic purpura and autoimmune hemolytic anemia prompted its evaluation
in iTTP, first for patients with a suboptimal response to treatment (i.e., patients
experiencing an exacerbation or a refractory disease). In these reports, rituximab
used as a salvage therapy resulted in higher remission rates (82–100%) with faster
responses to treatment and consequently fewer slow responders.[49]
[50] Interestingly, despite an often more severe initial presentation, patients who received
rituximab experienced fewer 2-year relapses that occurred later in accordance with
a prolonged immunosuppression. Given these encouraging results, a randomized trial
was initiated by the Transfusion Medicine/Hemostasis Clinical Trials Network to evaluate
the efficacy of systematic administration of rituximab as part of the frontline management
of iTTP.[51] Unfortunately, because of a very low rate of inclusion, this study was prematurely
terminated and the only evidence available comes from an open-label trial from the
South East England TTP study group.[52] In this study, the early (≤3 days from admission) administration of rituximab in
addition to a standard therapeutic regimen including TPE and corticosteroids resulted
in a high response rate with fewer relapses. Additionally, there was a trend toward
a shorter duration of TPE therapy for rituximab-treated patients when compared with
historical controls. Interestingly, a subsequent study from the same group compared
the outcome of patients who received rituximab early (≤ 3 days, most of these patients
having been included in the aforementioned trial) versus late (> 3 days) and confirmed
the benefit of an early administration with regard to the time to remission (median,
12 vs. 20 days, respectively, p < 0.001), the number of TPE procedures (median, 16 vs. 24, respectively, p = 0.03), and the length of hospital stay (median, 16 vs. 23 days, respectively, p = 0.01).[53]
Following this line of thought, frontline adjuvant rituximab should now be administered
to all patients to achieve rapid, efficient, and durable immunosuppression and prevent
short-term relapses ([Fig. 1]).[46] Furthermore, it appears that rituximab is well tolerated, with no increase in the
overall infections rate.[49]
[50]
[52] Moreover, this strategy could be cost-effective by saving a full cumbersome management
in case of relapse.[54] However, the optimal dose and timing of rituximab infusions remain to be determined.
Indeed, most studies used a 4-week regimen of once-weekly 375 mg/m2 infusion. A more intensive regimen has been evaluated considering the fact that a
substantial amount of rituximab was eliminated during TPE; however, kinetics of B-cell
depletion in this work proved to be similar to previous studies.[49] Conversely, lower doses of rituximab (100 mg/week for 4 weeks or 375 mg/m2 × 2 to 3 infusions) showed a similar efficacy.[55]
[56]
Fig. 1 Current management of immune-mediated thrombotic thrombocytopenic purpura (adapted from Coppo et al[46]). Treatment with TPE and corticosteroids should be initiated as soon as the diagnosis
is made or even suggested. Of utmost importance, to avoid a delay in the optimal management,
TTP diagnosis should be suspected on the basis of clinical scores aimed at predicting
a severe ADAMTS13 deficiency.[29]
[30] If the clinical probability of iTTP is high, the anti-vWF agent caplacizumab as
well as frontline rituximab should also be associated with TPE and corticosteroids.
Response to therapy should be assessed at least daily by repeated platelet count,
LDH, and clinical assessment. Patients experiencing refractoriness after 4 days or
an exacerbation of the disease should be intensified. There is no consensual recommendation;
we propose the use of twice-daily TPE. *For the more severe patients, pulses of cyclophosphamide,
vincristine, cyclosporine, splenectomy, or bortezomib should be considered. §Details in [Table 1]. £If the likelihood for ADAMTS13 activity <10% is intermediate (e.g., PLASMIC score = 5;
[Table 1]), we recommend empiric treatment for iTTP because of the potential harms of withholding
or delaying treatment, particularly TPE. This salvage treatment should be subsequently
completed with immunosuppressive strategies and caplacizumab only when/if severe ADAMTS13
deficiency is confirmed. $In our practice, if the clinical probability of iTTP diagnosis is intermediate (French
score = 1), rituximab is started after severe ADAMTS13 deficiency is ascertained (whereas
daily TPE, corticosteroids, and caplacizumab are started frontline). iTTP, immune-mediated
thrombotic thrombocytopenic purpura; TPE, therapeutic plasma exchange.
Prevention of Relapses with Rituximab
Each relapse exposes the patient to risk of death and to complications related to
TPE or to intensive care unit hospitalization. Therefore, the prevention of relapse
in TTP represents a major goal. As detailed earlier, the use of rituximab in the acute
phase of the disease dramatically decreases the relapse rate at 1 year. However, beyond
this period, anti-ADAMTS13 autoantibodies may recur along with peripheral B-cell reconstitution,
exposing patients to risk of clinical relapse. These observations provided a rationale
to evaluate the efficacy of rituximab in iTTP as preemptive therapy for patients in
clinical remission, but with persistent or recurrent severe ADAMTS13 deficiency. In
this context, rituximab remarkably reduces the incidence of TTP relapse by diminishing
the production of anti-ADAMTS13 antibodies and rapidly restoring ADAMTS13 activity,
which parallels peripheral B-cell depletion.[17]
[57]
[58] In our practice, we assess ADAMTS13 regularly during follow-up (typically every
3 months). After serial ADAMTS13 assessments have remained normal (>50%) durably (typically
3 years), measurements are spaced out to twice a year for 2 years and then yearly.
When ADAMTS13 activity becomes undetectable (activity <10% or even <20%), a single
infusion of rituximab 375 mg/m2 is administered. In more than 80% of patients, ADAMTS13 activity post-rituximab is
detectable or even normalizes (20% to >50%) as early as 4 to 6 weeks after infusion.
However, in up to 50% of patients, ADAMTS13 recovery is transient and drops again
with peripheral B-cell reconstitution, typically 12 months later. Consequently, further
rituximab infusions may be required to maintain a detectable ADAMTS13 activity and
prevent clinical relapse.[17]
[58] Patients with persistent severe (activity < 10–20%) ADAMTS13 deficiency are exposed
to a high risk of relapse, with a 7-year cumulative incidence of relapse of 74%.[17] Moreover, 10 to 15% of patients are primarily unresponsive to rituximab or experience
refractoriness after an initial response. In these cases, a more intensive regimen
inspired from those used in lymphoid malignancies and consisting of 4 to 6 weekly
infusions and/or maintenance treatment (4 infusions/year for 2 years) may overcome
rituximab refractoriness.[59]
[60] Recently, subcutaneous preemptive rituximab was shown to have similar efficacy than
IV perfusion as a preemptive treatment for iTTP and could ease the management of these
patients, notably when repeated administrations are needed, by decreasing the burden
of care and improving patients' satisfaction. Therefore, subcutaneous rituximab could
represent a new standard of care in the prevention of iTTP relapses.[61]
Inhibiting the vWF/Platelets Axis with Caplacizumab
More recently, therapies targeting the interaction between platelets and vWF multimers
have been developed with the aim to prevent the formation of microthrombi and subsequent
microcirculation occlusion and ischemic organ damage. Caplacizumab (Cablivi, Ablynx,
a Sanofi Company), formerly known as ALX-0081 (intravenous administration) and ALX-0681
(subcutaneous administration), is a bivalent nanobody, that is, a humanized single-variable
domain antibody derived from the homodimeric heavy-chain antibodies naturally occurring
in camelids. This small format of 28 kDa offers several theoretical advantages compared
with classically manufactured antibodies: rapid distribution and rapid clearance to
allow both a rapid onset of action and a limitation of potential toxicity; specific,
high affinity, and irreversible binding to the target and direct action without Fc-mediated
recruitment of cellular effectors or complement activation, preventing potential adverse
effects. Caplacizumab targets the A1 domain of ultra-large vWF multimers and thus
blocks its interaction and binding to the platelet glycoprotein Ib–IX–V receptor,
which is the critical first step of platelet aggregation. The drug was first developed
as an antithrombotic agent in the context of myocardial infarction, but greater interest
has soon been paid to its therapeutic potential in TTP, and development for the first
indication has since been discontinued. Indeed, in the absence of interaction between
platelets and vWF, the formation of occlusive microthrombi can be prevented. In a
preclinical baboon model of iTTP obtained by the administration of a neutralizing
anti-ADAMTS13 antibody, the daily administration of caplacizumab allowed a rapid (<1
day) and profound inhibition of vWF activity as measured by ristocetin cofactor activity
which recovered 7 days after treatment cessation (for a review, see the article by
Poullin et al[62]). This inhibition of vWF activity translated into clinical efficacy with a rapid
recovery of platelet count and a decrease in LDH level along with a trend toward the
resolution of the microangiopathic hemolytic anemia in treated animals compared with
untreated controls. However, at postmortem analysis, the proportion of occluded vessels
did not differ between groups, suggesting that caplacizumab was not able to clear
previously formed microthrombi.[63]
Preliminary data showed that effective, steady-state concentration was reached in
humans following once-daily subcutaneous administration of caplacizumab 10 mg and
this therapeutic schedule was then adopted for clinical trials with the addition of
one intravenous dose prior to the first TPE, to achieve an immediate onset of action.
So far, caplacizumab has been evaluated in two randomized controlled trials ([Table 3]). In the phase II TITAN trial, the addition of caplacizumab to standard treatment
and for 30 days after the last TPE resulted in a significant reduction in the time
to response, defined as the time to confirmed normalization of the platelet count
(median: 2.97 days, vs. 4.79 days in placebo).[64] Two deaths occurred in the placebo group versus none in patients treated with caplacizumab.
However, relapses were more frequent in the caplacizumab group with seven patients
relapsing within 10 days after caplacizumab had been stopped. In these seven patients,
ADAMTS13 activity was persistently less than 10%. These results were then confirmed
in a phase III randomized clinical trial.[65] Again, the addition of caplacizumab to standard treatment resulted in a significant
reduction in the time to platelet count response (platelet count normalization rate:
1.55, 95% CI: 1.10—2.20, p < 0.01). Additionally, there was a significant reduction in a composite secondary
endpoint of iTTP-related death, recurrence of iTTP, or one or more major thromboembolic
event during the study treatment period compared with placebo (12.5 vs. 49.3%, respectively,
p < 0.0001). Unlike for the phase II trial, investigators were encouraged to extend
the blinded treatment for a maximum of 4 weeks along with optimization of the immunosuppression
regimen if there was evidence of an ongoing disease, that is, a persistently suppressed
ADAMTS13 activity. This strategy translated into a reduced rate of iTTP recurrence
(including exacerbation and relapse) in the caplacizumab group (12.5 vs. 38.4%, respectively,
p < 0.001). Lastly, when patients in the placebo group experiencing an exacerbation
of the disease were crossed-over to received caplacizumab, a rapid and sustained response
was systematically observed, further supporting the efficacy of caplacizumab.[66]
Table 3
First-line treatment with caplacizumab versus placebo in iTTP: data from TITAN and
HERCULES randomized controlled trials
|
Reference
|
Number of patients: caplacizumab vs. placebo
|
Mean age (y) (range)
|
Female, N (%)
|
CR (%)
|
Recurrence[a] (%)
|
Exacerbation (%)
|
Relapse (%)
|
Mortality in the acute phase (%)
|
Mean TPE duration (d)
|
|
TITAN[8]
|
75 (36 vs. 39)
|
42 (19–72)
|
44 (59)
|
81 vs. 46
|
38.9 vs. 38.4
|
8.3 vs. 28.2
|
30.6 vs. 7.7[b]
|
0 vs. 5.1
|
5.9 vs. 7.9
|
|
HERCULES[9]
|
145 (72 vs. 73)
|
46 (18–79)
|
100 (69)
|
NA
|
12.5 vs. 38.3
|
4.2 vs. 38.3
|
8.3 vs. 0[c]
|
0 vs. 4.1
|
5.8 vs. 9.4
|
Abbreviations: CR, complete remission; iTTP, immune-mediated thrombotic thrombocytopenic
purpura; TPE, therapeutic plasma exchange.
a Recurrence was defined as exacerbation and/or relapse.
b 12 months of follow-up.
c 2 months of follow-up.
Two groups have recently reported their experience with the use of caplacizumab outside
the context of a randomized controlled trial. These experiences differ in the strategy
used. In the French cohort, caplacizumab was part of a frontline therapeutic strategy
in association with TPE and immunosuppression with corticosteroids and frontline rituximab.
This strategy resulted in a significantly lower incidence of a composite outcome of
iTTP refractoriness or death within 30 day 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 = 0.01). Moreover, exacerbations in the triplet cohort were observed only in 3.4%
of patients versus 44% in the historical cohort (p < 0.01).[67] Conversely, in a German cohort where caplacizumab was administered frontline in
only 58% of patients and as a salvage therapy in the others, 31.7% experienced a refractory
disease, including one death.[68] Taken together, these real-life data confirm the efficacy of caplacizumab and suggest
that the agent should be part of the frontline therapy, in accordance with the strategy
evaluated in RCTs to prevent more systematically unfavorable outcomes.
Impressively, treatment with caplacizumab resulted in a substantial reduction in the
burden of care, with a 38% relative reduction in the number of days of TPE compared
with placebo (mean: 5.8 vs. 9.4 days, respectively) and a 41% relative reduction in
the volume of plasma used. Moreover, the duration of hospitalization stay was shortened
with a 65% relative reduction in the length of stay in the intensive care unit (ICU)
(3.4 vs. 9.7 days, respectively) and a 31% relative reduction in the total number
of days in hospital (9.9 vs. 14.4 days, respectively).[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. Long-term efficacy and safety of caplacizumab is now being
evaluated in all patients who completed the HERCULES trial in a phase IIIb prospective
follow-up study (Post-HERCULES trial, NCT02878603). These positive results encouraged
investigators to treat patients suffering from iTTP who cannot receive plasma or TPE,
with the association of caplacizumab and immunosuppression, with successful results.[69]
[70] A perspective from such observations is to foresee TPE-free regimens.[71]
Table 4
Adverse events in patients treated with caplacizumab versus placebo
|
Adverse event
|
TITAN
Caplacizumab vs. placebo
|
HERCULES
Caplacizumab vs. placebo
|
|
Bleeding
|
54.2 vs. 37.8
|
64.8 vs. 47.9
|
|
Gingival bleeding
|
14.3 vs. 5.4
|
18.3 vs. 1.4
|
|
Epistaxis
|
31.4 vs. 10.8
|
32.4 vs. 2.7
|
|
Hematuria
|
0 vs. 2.7
|
7.0 vs. 2.7
|
|
Catheter-site hemorrhage
|
NA
|
7.0 vs. 6.8
|
|
Subarachnoid hemorrhage
|
2.9 vs. 0
|
1.4 vs. 0
|
|
Headache
|
34.3 vs. 27
|
22.5 vs. 8.2
|
|
Pyrexia
|
17.1 vs. 16.2
|
14.1 vs. 8.2
|
|
Myalgia
|
20.0 vs. 2.7
|
NA
|
|
Urticaria
|
NA
|
16.9 vs. 6.8
|
Abbreviation: NA, not available.
Note: Data are provided as percent.
Source: Adapted from Peyvandi et al and Scully et al.[64]
[65]
Several salvage therapies have been addressed in refractory patients, including mainly
cyclophosphamide, vincristine, cyclosporine, or splenectomy and more recently anti-plasma
cell agents.[46] However, given the impressive efficacy of caplacizumab translating in a very few
number of unfavorable outcomes, their role in the modern treatment strategy including
TPE, corticosteroids, and rituximab and caplacizumab, needs to be revisited.
The Next Step in TTP Management: The Recombinant Human ADAMTS13?
Another major therapeutic achievement in the field of TTP is the development of a
recombinant human ADAMTS13 (rhADAMTS13) (BAX930, Baxalta, part of Shire). In a phase
I study conducted in patients suffering from cTTP, the administration of rhADAMTS13
led to a dose-dependent detection of vWF-cleavage products as well as a trend toward
LDH decrease and platelet count improvement. Additionally, administration of the recombinant
enzyme was well tolerated, and importantly, no patient developed detectable neutralizing
anti-ADAMTS13 antibodies.[72] The half-life of the recombinant form of ADAMTS13 was comparable to this of the
wild-type protein, that is, ∼3 days. Of note, this half-life represents the lowest
known clearance rates of proteases in circulating human plasma.[73] rhADAMTS13 is now being evaluated in cTTP in a phase 3 trial (NCT03393975). Additionally,
it has been shown that rhADAMTS13 was able to restore vWF-cleaving activity when added
to the plasma of iTTP patients with inhibitory autoantibodies, with a linear correlation
between autoantibodies titer and required rhADAMTS13.[74] Furthermore, amino acid substitution in the spacer domain of ADAMTS13 results in
several gain of function variants, some of which are being resistant to inhibition
by autoantibodies from patients with iTTP and therefore could be of interest in the
specific context of iTTP.[72] There is no doubt that the evaluation of a rhADAMTS13 will be the next major step
in the search for the optimal iTTP therapeutic strategy. The success of such an approach
would allow a fully targeted, plasma-free therapeutic strategy, devoid of TPE-related
complications and associated costs.
Perspectives: Future Directions
Perspectives: Future Directions
The therapeutic landscape of TTP is shifting toward more precision medicine and targeted
therapies. A triplet regimen systematically associating ADAMTS13 supply through TPE,
immunosuppression with corticosteroids and rituximab, and caplacizumab, by addressing
the three components of iTTP pathophysiology ([Fig. 2]), should further improve survival and long-term outcome in these patients.
Fig. 2 The three axes of iTTP management in the acute phase. LDH, lactate dehydrogenase; TPE, therapeutic plasma exchange; vWF, von Willebrand
factor.
Now that the therapeutic armamentarium allows remission in almost all cases of the
once-fatal TTP, research should gradually shift to other horizons and three issues
emerge particularly. First, the availability of agents able to alleviate the burden
of care (caplacizumab, and soon rhADAMTS13) could lead to the suppression of the cumbersome
management with TPE and outpatient or home treatment. This goal, however, should be
addressed through formal clinical trials, with the need to assess the cost-effectiveness
of such new strategy. Second, there is a need to further optimize the follow-up of
patients once remission is achieved. In iTTP, it has already been shown that regular,
lifetime monitoring of ADAMTS13 activity with preemptive administration of rituximab
can prevent the occurrence of a relapse. It is now necessary to define the ideal monitoring
strategy as well as the schedule of rituximab administration and the best strategy
to manage patients for whom the administration of rituximab would not be sufficient
to restore detectable ADAMTS13 activity. Finally, future work should focus on whether
newest therapeutic regimens can reduce the incidence of several comorbidities occurring
during long-term follow-up, and prevent premature death. No doubt that the history
of TTP treatment will require additional chapters to be written in the forthcoming
years.
