Caplacizumab-yhdp (Cablivi)

Number: 0949

Table Of Contents

Policy
Applicable CPT / HCPCS / ICD-10 Codes
Background
References

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Policy

Scope of Policy

This Clinical Policy Bulletin addresses caplacizumab-yhdp (Cablivi) for commercial medical plans. For Medicare criteria, see Medicare Part B Criteria.

Note: Requires Precertification:

Precertification of caplacizumab-yhdp (Cablivi) is required of all Aetna participating providers and members in applicable plan designs.  For precertification of caplacizumab-yhdp (Cablivi), call (866) 752-7021 or fax (888) 267-3277. For Statement of Medical Necessity (SMN) precertification forms, see Specialty Pharmacy Precertification.

1. Criteria for Initial Approval

   Acquired thrombotic thrombocytopenic purpura (aTTP)

   Aetna considers caplacizumab-yhdp (Cablivi) medically necessary for treatment of persons with acquired thrombotic thrombocytopenic purpura (aTTP), after the plasma exchange period in the inpatient setting, when all of the following criteria are met:

   1. The member received the requested medication with plasma exchange; and
   2. The requested medication will be given in combination with immunosuppressive therapy; and
   3. The member will not receive the requested medication beyond 30 days from the cessation of plasma exchange unless the member has documented persistent aTTP; and
   4. The member has not experienced more than 2 recurrences of aTTP while on the requested medication. (A recurrence is when the member needs to reinitiate plasma exchange. A 28-day extension of therapy does not count as a recurrence.)

   Aetna considers all other indications as experimental and investigational.

2. Continuation of Therapy

   Aetna considers continuation of caplacizumab-yhdp (Cablivi) therapy medically necessary for acquired thrombotic thrombocytopenic purpura (aTTP) when all of the following criteria are met:

   1. The request for continuation of therapy is for extension of therapy after the initial course of the requested medication (initial course: treatment with the requested medication during and 30 days after plasma exchange); and
   2. The member has either of the following documented signs of persistent underlying aTTP:
      
      
      1. ADAMTS13 activity level less than 10%; or
      2. All of the following:
         
         
         1. Microangiopathic hemolytic anemia (MAHA) documented by the presence of schistocytes on peripheral smear; and
         2. Thrombocytopenia (platelet count below normal per laboratory reference range); and
         3. Elevated lactate dehydrogenase (LDH) level (LDH level above normal per laboratory reference range); and
            
   3. The requested medication will be given in combination with immunosuppressive therapy; and
   4. The member has not received a prior 28-day extension of therapy after the initial course of the requested medication for this course of treatment; and
   5. The member has not experienced more than 2 recurrences of aTTP while on the requested medication. (A recurrence is when the member needs to reinitiate plasma exchange. A 28-day extension of therapy does not count as a recurrence.)

3. Related Policies

   • CPB 0285 - Plasmapheresis/Plasma Exchange/Therapeutic Apheresis
   • CPB 0780 - ADAMTS13 Assay for Thrombotic Thrombocytopenic Purpura (TTP)

Dosage and Administration

Caplacizumab-yhdp (Cablivi) is available as 11 mg as a lyophilized powder in a single-dose vial for injection for intravenous or subcutaneous use.

Caplacizumab-yhdp (Cablivi) should be administered upon the initiation of plasma exchange therapy. Discontinue caplacizumab if the patient experiences more than 2 recurrences of aTTP, while on caplacizumab.

Withhold caplacizumab for 7 days prior to elective surgery, dental procedures or other invasive interventions. If emergency surgery is needed, the use of von Willebrand factor concentrate may be considered to correct hemostasis. After the risk of surgical bleeding has resolved, and caplacizumab is resumed, monitor closely for signs of bleeding. 

Acquired Thrombotic Thrombocytopenic Purpura (aTTP)

The recommended dose of caplacizumab is as follows:

Treatment during plasma exchange:

• First day of treatment: 11 mg bolus intravenous injection administered by a healthcare provider at least 15 minutes prior to plasma exchange followed by an 11 mg subcutaneous injection in the abdomen after completion of plasma exchange on day 1. Avoid injections around the navel. Do not administer consecutive injections in the same abdominal quadrant.
• Subsequent treatment: 11 mg subcutaneous injection once daily following plasma exchange.
• Treatment after the plasma exchange period: 11 mg subcutaneous injection once daily for 30 days beyond the last plasma exchange.
• Refractory aTTP treatment: If after initial treatment course, sign(s) of persistent underlying disease remain present, treatment with 11 mg subcutaneous injection once daily may be extended for a maximum of 28 days.

Source: Genzyme 2020

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Table:

CPT Codes / HCPCS Codes / ICD-10 Codes

Code	Code Description
Information in the [brackets] below has been added for clarification purposes.   Codes requiring a 7th character are represented by "+" :
Other CPT codes related to the CPB:
36514	Therapeutic apheresis; for plasma pheresis
96365 – 96368	Intravenous infusion administration
96372	Therapeutic, prophylactic, or diagnostic injection (specify substance or drug); subcutaneous or intramuscular
96401	Chemotherapy administration, subcutaneous or intramuscular; non-hormonal anti-neoplastic
96409 – 96411	Chemotherapy administration, intravenous push technique
96413 – 96417	Chemotherapy administration, intravenous infusion technique
HCPCS codes covered if selection criteria are met:
C9047	Injection, caplacizumab-yhdp, 1 mg
ICD-10 codes covered if selection criteria are met:
D69.3	Immune thrombocytopenic purpura [acquired thrombotic thrombocytopenic purpura (aTTP)]
M31.10 - M31.19	Thrombotic microangiopathy [acquired thrombotic thrombocytopenic purpura (aTTP)]

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Background

U.S. Food and Drug Administration (FDA)-Approved Indications

• Cablivi is indicated for the treatment of adult patients with acquired thrombotic thrombocytopenic purpura (aTTP), in combination with plasma exchange and immunosuppressive therapy.

Caplacizumab-yhdp is available as Cablivi (Genzyme Corporation) and is a von Willebrand factor (vWF)-directed antibody fragment consisting of two identical humanized building blocks, connected by a three-alanine linker. Caplacizumab-yhdp (Cablivi) targets the A1-domain of vWF, and inhibits the interaction between vWF and platelets with a resultant reduction in both vWF-mediated platelet adhesion and platelet consumption (Genzyme, 2020).

Per the prescribing information, caplacizumab-yhdp (Cablivi) carries warnings and precautions for an increased risk of bleeding. Bleeding events were noted in approximately 58% of patients receiving Cablivi versus 43% of patients receiving placebo. Severe bleeding adverse reactions of epistaxis, gingival bleeding, upper gastrointestinal hemorrhage, and metrorrhagia occurred in 1% of subjects in clinical studies.

The most common adverse reactions (occurrence > 15%) are epistaxis, headache, and gingival bleeding (Genzyme, 2020).

Thrombotic Thrombocytopenia Purpura (TTP)

Thrombotic thrombocytopenic purpura (TTP) is characterized by severely reduced activity of the von Willebrand factor-cleaving protease ADAMTS13 (A Disintegrin And Metalloproteinase with ThromboSpondin‐1 motifs; 13th member of the family). An ADAMTS13 deficiency results in an accumulation of ultra-large von Willebrand factor (vWF), which leads to extensive clot formation in small blood vessels throughout the body, and ultimately causing severe thrombocytopenia, microangiopathic hemolytic anemia, and ischemia. Acquired TTP occurs in approximately three in one million adults and 1 in 10 million children annually and the incidence is increased in females and blacks. The diagnosis of acquired TTP is confirmed by the finding of severe ADAMTS13 deficiency (e.g., activity less than 10 percent of normal) and the presence of an ADAMTS13 inhibitor (autoantibody) in the appropriate clinical setting (e.g., a patient with microangiopathic hemolytic anemia and thrombocytopenia that responds to plasma exchange). However, some individuals with acquired TTP may have higher levels of ADAMTS13 activity, and in some an inhibitor may not be detectable. Diagnosis should not be considered confirmed (or excluded) based on ADAMTS13 testing alone. Initial symptoms of microangiopathic hemolytic anemia and thrombocytopenia may include fatigue, dyspnea, petechiae, or other bleeding. Patients may have symptoms of anemia and thrombocytopenia. However, not all patients are critically ill; some may have only minor complaints of weakness, dizziness, or gastrointestinal symptoms. In some patients, the diagnosis of TTP may not be considered until the complete blood count (CBC) reveals severe thrombocytopenia and microangiopathic hemolytic anemia. Neurologic and renal abnormalities may be seen but are not always present; when these occur, they are often mild (George 2021).

TTP had been a fatal diagnosis until the use of therapeutic plasma exchange in the early 1990s. The use of plasma exchange in association with corticosteroids until durable remission had been the standard of care for TTP treatment. Glucocorticoids are thought to reduce production of the ADAMTS13 inhibitor, thereby reducing the number of required plasma exchanges. The discovery of a dysfunction in ADAMTS13, provided a rationale for the evaluation of B‐cell depleting therapies. Rituximab is a monoclonal chimeric antibody against the CD20 antigen on the surface of B-cells and causes a rapid and profound decrease in circulating B cells. The addition of rituximab to the standard regimen in the mid‐2000s is now increasingly used frontline (George 2019).

Two major challenges with aTTP are the risks of recurrence and relapsed aTTP. Recurrence has been defined as a new decrease in the platelet count that necessitated the re-initiation of plasma exchange after normalization of the platelet count had occurred. An exacerbation is defined as a recurrence that occurred within 30 days after the last plasma exchange. A relapse is defined as a recurrence of an acute episode, manifested by thrombocytopenia and microangiopathic hemolytic anemia, in a patient who had a disease remission (i.e., normal platelet count for 30 days after stopping plasma exchange) following an episode of TTP. The continued presence of severe ADAMTS13 deficiency is consistent with continued activity of TTP as the cause of persistent or recurrent thrombocytopenia; however results of ADAMTS13 activity testing are not available immediately, and clinical assessment based on symptoms and platelet count are the most relevant information for decision making. However, if the initial diagnosis of acquired TTP was supported by the presence of severe ADAMTS13 deficiency (ie, activity <10 percent) and the presence of an inhibitor, and facilities for prompt measurements are available, a repeat ADAMTS13 activity measurement may be helpful, especially in situations where the diagnosis is uncertain. Conversely, non-severely deficient ADAMTS13 activity (ie, activity >10 percent) in a patient who has not received very recent plasma exchange therapy is suggestive of an alternative process. Lastly, refractory aTTP can be defined as disease that does not respond to initial therapy or TTP that initially responds with a normal platelet count followed by an exacerbation (recurrent thrombocytopenia and/or neurologic symptoms within the first 30 days of stopping plasma exchange therapy).

On February 6, 2019, the FDA approved Cablivi (caplacizumab-yhdp) injection, the first therapy specifically indicated, in combination with plasma exchange and immunosuppressive therapy, for the treatment of adult patients with acquired thrombotic thrombocytopenic purpura. Caplacizumab-yhdp targets the A1-domain of vWF, and inhibits the interaction between vWF and platelets, thereby reducing both vWF-mediated platelet adhesion and platelet consumption. The efficacy of caplacizumab was studied in a clinical trial of 145 patients who were randomized to receive either caplacizumab or a placebo (Scully et al; HERCULES trial). Patients in both groups received the current standard of care of plasma exchange and immunosuppressive therapy. The results of the trial demonstrated that platelet counts improved faster among patients treated with caplacizumab, compared to placebo. Treatment with caplacizumab also resulted in a lower total number of patients with either aTTP-related death and recurrence of aTTP during the treatment period, or at least one treatment-emergent major thrombotic event (where blood clots form inside a blood vessel and may then break free to travel throughout the body).

Scully et al (2019; HERCULES trial; NCT02553317) stated in acquired thrombotic thrombocytopenic purpura (TTP), an immune-mediated deficiency of the von Willebrand factor-cleaving protease ADAMTS13 allows unrestrained adhesion of von Willebrand factor multimers to platelets and microthrombosis, which result in thrombocytopenia, hemolytic anemia, and tissue ischemia. Caplacizumab, an anti-von Willebrand factor humanized, bivalent variable-domain-only immunoglobulin fragment, inhibits interaction between von Willebrand factor multimers and platelets. In this double-blind, controlled trial, 145 patients with TTP were randomly assigned to receive caplacizumab (10-mg intravenous loading bolus, followed by 10 mg daily subcutaneously) or placebo during plasma exchange and for 30 days thereafter. The primary outcome was the time to a response, which was defined as the time from the first intravenous administration of caplacizumab or placebo to normalization of the platelet count (i.e., a platelet count of at least 150,000 per cubic millimeter), with discontinuation of daily plasma exchange within 5 days thereafter. The four key secondary outcomes, which were hierarchically ranked on the basis of clinical relevance, were: a composite of TTP-related death, recurrence of TTP, or a major thromboembolic event during the trial treatment period; recurrence of TTP at any time during the trial, including the follow-up period; refractory TTP (defined by the lack of a doubling of the platelet count after 4 days of treatment and a lactate dehydrogenase level that remained above the upper limit of the normal range); and the time to normalization (i.e., to a level below the defined upper limit of the normal range) of three organ-damage markers (lactate dehydrogenase, cardiac troponin I, and serum creatinine).

The median time to normalization of the platelet count was shorter with caplacizumab than with placebo (2.69 days [95% confidence interval {CI}, 1.89 to 2.83] vs. 2.88 days [95% CI, 2.68 to 3.56], P=0.01), and patients who received caplacizumab were 1.55 times as likely to have a normalization of the platelet count as those who received placebo. The percentage of patients with a composite outcome event was 74% lower with caplacizumab than with placebo (12% vs. 49%, P<0.001). The percentage of patients who had a recurrence of TTP at any time during the trial was 67% lower with caplacizumab than with placebo (12% vs. 38%, P<0.001). Refractory disease developed in no patients in the caplacizumab group and in three patients in the placebo group. Patients who received caplacizumab needed less plasma exchange and had a shorter hospitalization than those who received placebo. The most common adverse event was mucocutaneous bleeding, which was reported in 65% of the patients in the caplacizumab group and in 48% in the placebo group. During the trial treatment period, three patients in the placebo group died. One patient in the caplacizumab group died from cerebral ischemia after the end of the treatment period. The authors concluded that among patients with TTP, treatment with caplacizumab was associated with faster normalization of the platelet count; a lower incidence of a composite of TTP-related death, recurrence of TTP, or a thromboembolic event during the treatment period; and a lower rate of recurrence of TTP during the trial than placebo.

Knoebl et al (2020) studied patients who experienced an exacerbation while on blinded study drug treatment during the HERUCLES trial and were switched to receive open-label caplacizumab plus re-initiation of daily therapeutic plasma exchange (TPE). Exacerbations were defined as recurrence of disease occurring within 30 days after cessation of daily TPE. Thirty-one patients (placebo, n = 28; caplacizumab, n = 3) had an exacerbation during double-blind treatment. Twenty-eight patients switched to open-label caplacizumab (placebo, n = 26; caplacizumab, n = 2); the three others discontinued upon exacerbation. Median time to platelet count response (≥150 × 10⁹ /L) was 3.49 days upon receiving caplacizumab. There were no deaths. During open-label treatment, further exacerbation or a major thromboembolic event (vena cava thrombosis) was experienced by one patient (3.6%) each. Consistent with the double-blind phase, the most frequent treatment-emergent adverse events were catheter site hemorrhage (28.6%), headache (21.4%), and epistaxis (17.9%). These results suggest that caplacizumab was efficacious and well tolerated in patients with aTTP who experienced a disease exacerbation during double-blind treatment in HERCULES.

Peyvandi et al (2016; TITAN trial) stated acquired thrombotic thrombocytopenic purpura (TTP) is caused by aggregation of platelets on ultralarge von Willebrand factor multimers. This microvascular thrombosis causes multiorgan ischemia with potentially life-threatening complications. Daily plasma exchange and immunosuppressive therapies induce remission, but mortality and morbidity due to microthrombosis remain high. Caplacizumab, an anti-von Willebrand factor humanized single-variable-domain immunoglobulin (Nanobody), inhibits the interaction between ultralarge von Willebrand factor multimers and platelets. In this phase 2, controlled study, patients with acquired TTP were randomly assigned to subcutaneous caplacizumab (10 mg daily) or placebo during plasma exchange and for 30 days afterward. The primary end point was the time to a response, defined as confirmed normalization of the platelet count. Major secondary end points included exacerbations and relapses. Seventy-five patients underwent randomization (36 were assigned to receive caplacizumab, and 39 to receive placebo). The time to a response was significantly reduced with caplacizumab as compared with placebo (39% reduction in median time, P=0.005). Three patients in the caplacizumab group had an exacerbation, as compared with 11 patients in the placebo group. Eight patients in the caplacizumab group had a relapse in the first month after stopping the study drug, of whom 7 had ADAMTS13 activity that remained below 10%, suggesting unresolved autoimmune activity. Bleeding-related adverse events, most of which were mild to moderate in severity, were more common with caplacizumab than with placebo (54% of patients vs. 38%). The frequencies of other adverse events were similar in the two groups. Two patients in the placebo group died, as compared with none in the caplacizumab group. The authors concluded that caplacizumab induced a faster resolution of the acute TTP episode than did placebo. The platelet-protective effect of caplacizumab was maintained during the treatment period. Caplacizumab was associated with an increased tendency toward bleeding, as compared with placebo.

Caplacizumab Model-Based Dosing Recommendations in Pediatric Patients

Bergstrand et al (2022) noted that aTTP is a rare and life-threatening autoimmune thrombotic microangiopathy.  Caplacizumab, evaluated in phase-II and phase-III clinical trials in adults, shortened the time to platelet count response and reduced aTTP exacerbations, has a favorable safety profile, and can potentially reduce refractoriness and mortality associated with aTTP.  Since no children with aTTP were enrolled in these clinical trials, caplacizumab has been initially approved for use only in adult patients with aTTP (10 mg).  Pediatric dosing recommendations were developed using model-based simulations.  A semi-mechanistic pharmacokinetic/pharmacodynamic population model has been developed describing the interaction between caplacizumab and von Willebrand factor antigen (vWF:Ag) following intravenous (IV) and subcutaneous (SC) administration of caplacizumab in different adult populations, at various dose levels, using non-linear mixed-effects modeling.  Based on the allometrically scaled pharmacokinetic/pharmacodynamic model, different dosing regimens were simulated in 8,000 children (aged 2 to 18 years).  Simulated caplacizumab exposures and vWF:Ag levels across different age categories were compared to an adult reference group.  A simulated daily dose of 5 mg in children weighing less than 40 kg and of 10 mg in children weighing 40 kg or more resulted in similar exposures and vWF:Ag suppression across age and weight groups.  The authors concluded that despite the lack of pediatric clinical data, the findings of this modeling and simulation analysis constituted the basis for the European extension of indication for caplacizumab (10 mg) to adolescents aged 12 years or older and with a body weight 40 kg (88 lbs) or more.  This represented a rare case in which regulatory authorities have deemed a modeling and simulation study robust enough to approve a variation of indication.

Immune-Mediated Thrombotic Thrombocytopenic Purpura

Izquierdo et al (2022) stated that immune TTP (iTTP) is a thrombotic microangiopathy caused by anti-ADAMTS13 antibodies.  These researchers compared the safety and effectiveness of caplacizumab versus the standard of care (SOC) and examined the effect of the concomitant use of rituximab.  They carried out a retrospective study from the Spanish TTP Registry of patients treated with caplacizumab versus those who did not receive it.  A total of 155 patients with iTTP (77 caplacizumab, 78 no caplacizumab) were included.  Patients initially treated with caplacizumab had fewer exacerbations (4.5 % versus 20.5 %; p < 0.05) and less refractoriness (4.5 % versus 14.1 %; p < 0.05) than those who were not treated.  Time to clinical response was shorter when caplacizumab was used as initial treatment versus caplacizumab used after refractoriness or exacerbation.  The multi-variate analysis showed that its use in the first 3 days following PE was associated with a lower number of PE (odds ratio [OR], 7.5; CI: 2.3 to 12.7; p < 0.05) and days of hospitalization (OR, 11.2; CI: 5.6 to 16.9; p < 0.001) compared with standard therapy.  There was no difference in time to clinical remission in patients treated with caplacizumab compared with the use of rituximab.  No severe adverse event (AE) was described in the caplacizumab group.  The authors concluded that caplacizumab reduced exacerbations and refractoriness compared with SOC regimens.  When administered within the first 3 days following PE, it also provided a faster clinical response, reducing hospitalization time and the need for PE.  Moreover, these researchers stated that although caplacizumab has shown safety and effectiveness in the treatment of iTTP and the International Society on Thrombosis and Hemostasis recommends it for the treatment of TTP, the health authorities in Spain are still reluctant to expedite its use as initial treatment.  This is probably because the current treatment of iTTP has been shown to be effective and that caplacizumab has a high cost, which is perceived as a barrier to its widespread use.  Although there are already cost analysis studies in the U.S. (which indicated it as not cost-effective), there is a lack of analysis studies in Spain and in other European countries.  However, it has been suggested that modifying the current SOC could reduce prices.  This change of management also implies a paradigm shift in iTTP treatment.  In fact, some studies supported the use of caplacizumab without PE in selected patients, and treatment without PE would be simpler and safer.  However, these investigators stated that controlled trials are needed to enact progress in this regard. 

Scullly et al (2022) noted that management of iTTP usually relies on PE and immunosuppression; however, a 10 % to 20 % mortality rate is still observed.  Caplacizumab binds to VWF and directly inhibits platelet aggregation; addition of caplacizumab to historical treatment induced faster resolution of platelet count in clinical trials.  In 2019, a modified-Delphi study was carried out with U.K. experts, to develop consensus statements on management of acute TTP and the potential role of caplacizumab.  An unmet need was acknowledged, and areas requiring improvement included: time to diagnosis and treatment initiation; time to platelet normalization (TTPN) during which patients remain at risk of persistent microvascular thrombosis and organ damage; and incidence of subsequent exacerbations and relapses.  Caplacizumab addition to historical treatment within 24 hours (after confirmatory assay) would significantly reduce TTPN, which directly influences acute outcomes, with manageable bleeding risk and reduced burden on healthcare systems.  Expert panelists agreed that poor outcomes in iTTP largely result from failure to rapidly control microvascular thrombosis.  They stated that use of caplacizumab during a confirmed iTTP episode could offer better control and may plausibly improve long-term outcomes.  Moreover, these investigators stated that this consensus must be validated with further clinical trials and robust real-world evidence.   These researchers stated that in the opinion of the panel, there is potential for caplacizumab, in combination with PE and immunosuppression, to improve the lives of patients and reduce the burden on the healthcare system, by reducing the risk of detrimental health outcomes compared to PE and immunosuppression alone.  Early data from national cohorts published in 2020 and 2021 indicated a positive effect of the more widespread use of caplacizumab in the management of acute iTTP; however, robust follow‐ups are needed to better understand the long‐term impact of caplacizumab. 

Tse et al (2023) stated that when combined with TPE and immunosuppression, upfront universal administration of caplacizumab was shown to be effective in the management iTTP; however, access to this drug remains challenging in many jurisdictions.  In a retrospective study, these investigators examined results of a single-center experience with caplacizumab over a 3-year period.  During the study period, these researchers treated 48 patients with iTTP, of which 11 (23 %) received caplacizumab; and 8 of these 11 patients (73 %) were women; the median age was 45 years (inter-quartile range [IQR] 37.0 to 58.5 years).  All received TPE within 24 hours of admission (median of 9 exchanges, IQR 7.0 to 12.5), and high-dose steroids.  Caplacizumab was initiated for a median of 6 days after admission (IQR 2.5 to 8.0 days) and continued for a median of 26 days (IQR 14.0 to 33.0 days). Five patients (45 %) had refractory disease at caplacizumab initiation; 10 patients (91 %) survived, reaching clinical remission.  Platelet normalization was reached with a median of 4 days following caplacizumab initiation (IQR 1.5 to 4.0 days).  Complications included minor bleeding (n = 1) and local allergic reaction (n = 1).  No patients experienced TTP exacerbation; relapse occurred in 2 patients (18 %) over 1 to 5 years of follow-up.  The authors concluded that caplacizumab appeared to be safe and effective, despite delayed initiation and in the setting of refractory disease.  Moreover, these researchers stated that further investigations are needed to examine the long-term outcomes and cost-effectiveness of caplacizumab, which will inform future decisions on public funding. 

The authors stated that the drawbacks of this trial included its retrospective design, small sample size (n = 48), and the lack of a control group.  Furthermore, these investigators did not collect economic data to evaluate cost-effectiveness. 

Furthermore, UpToDate reviews on “Immune TTP: Initial treatment” (George and Cuker, 2023a), and “Immune TTP: Treatment of clinical relapse” (George and Cuker, 2023b) do not mention caplacizumab as a management / therapeutic option.

Pregnancy-Related Acquired Thrombotic Thrombocytopenic Purpura

Odetola et al (2023) stated that TTP is not uncommonly observed in pregnancy, either with the 1st episode or with the exacerbation of known disease.  The management of TTP in pregnancy can be challenging if there is refractoriness to the use of TPE and high-dose corticosteroids.  Caplacizumab is approved for the treatment of acquired TTP but there is sparse data on its use in pregnant patients.  Ante-natal and peripartum hemorrhage is a theoretical concern with the use of the medication in the obstetric population.  However, as options for treatment of TTP in the patients who have refractory disease are significantly limited, off-label use of caplacizumab to achieve disease control and prevent materno-fetal morbidity and mortality is a reasonable consideration.  These investigators described the successful use of caplacizumab in a pregnant patient with acquired TTP and the associated favorable outcome.  The patient suffered an exacerbation following initial TPE and became refractory to both PE and high-dose corticosteroids.  Off-label use of caplacizumab resulted in hematologic recovery and successful delivery of a healthy neonate.  The authors concluded that the findings of this case represented a contribution to the sparse literature on the use of this effective medication in an often-challenging clinical situation. 

Coppo and Joy (2023) noted that therapeutic options in immune-mediated TTP (iTTP) during pregnancy are limited besides TPE and corticosteroids.  The study by Odetola et al (2023) suggested that caplacizumab represents a reasonable option in iTTP during pregnancy, especially when the disease is not rapidly controlled with the standard TPE-corticosteroid association.  These investigators stated that so far, only 1 additional case of pregnancy-associated iTTP treated with caplacizumab has been published (Kuhne et al, 2022).  Subject was an 36-year-old pregnant women who was treated with TPE and multiple immunosuppressive agents for iTTP at 17-week of pregnancy that was complicated by an unresponsive exacerbation, caplacizumab was added, allowing platelet count recovery after 3 days.  However, the fetus experienced severe fetal growth retardation with the development of oligohydramnios, placental hydrops and suspected pre-eclampsia leading to pregnancy termination.  The authors have also documented chronic placental insufficiency and fetal thrombosis as major causes for severe early-onset intra-uterine growth retardation.  Although the transplacental transfer of maternal anti-ADAMTS13 antibodies has been described, no cases of fetal iTTP were reported so far, suggesting that intra-uterine fetal death was due to an impaired placental perfusion resulting from ongoing iTTP in this case.  More importantly, no apparent bleeding complication was noted, specifically no signs of retroplacental hematoma.  Interestingly, a transplacental transfer of caplacizumab from mother to fetus was documented.  Caplacizumab was qualitatively identified in amniotic fluid and fetal blood above the assay's limit of detection and its estimated concentration at 50 ng/ml, corresponding to 5-fold to 10-fold lower the estimated concentration in maternal blood.  Although it could be argued that the dose of caplacizumab used may not be sufficient to prevent fetal thrombosis, the most plausible scenario was the formation of placental microthrombi before the use of caplacizumab.  From these statements, the conclusion of the authors was that caplacizumab rapidly improved the mother's condition; but may have been used too late to save fetal life. 

The authors stated that several lessons can be drawn from these 2 single observations for the management of iTTP during pregnancy.  The 1st was that apparently, pregnancy does not modify the effectiveness of caplacizumab as in both cases this agent could control a refractory disease upon its introduction.  Second, one observation was reminiscent of the poor fetal outcome with uncontrolled maternal iTTP, likely due to massive placental ischemia.  Lastly, and despite a transplacental transfer of caplacizumab, it is worth noting that no AEs were recorded in either the mothers or the surviving neonate.  Altogether, and taking into account the usual caution required when considering single case reports, the experience reported by Odetola et al (2023) in conjunction with that of Kuhne et al (2022) suggested that caplacizumab represents a reasonable option in iTTP during pregnancy, especially when the disease is not rapidly controlled with the standard TPE-corticosteroid association.  This therapeutic option needs to be discussed within a multi-disciplinary team, and to fully involve the patient.  In this context, delaying the introduction of caplacizumab may expose both the mother and the fetus to a fatal outcome.  These observations also encourage for further formal assessments in the use of caplacizumab for the treatment of iTTP during pregnancy. 

Furthermore, an UpToDate review on “Thrombocytopenia in pregnancy” (George and McIntosh, 2023) does not mention caplacizumab as a management / therapeutic option.

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References