How should caplacizumab be used for treatment of immune thrombotic thrombocytopenic purpura?

In past 30 years, therapeutic plasma exchange (TPE) has been the cornerstone for managing acquired or immune thrombotic thrombocytopenic purpura (iTTP) (1). Such a therapeutic modality in conjunction with other adjunctive therapies has significantly reduced the mortality rate to less than 5–20% (2-4). However, approximately 50% of patients who recover from the acute episode may experience the disease recurrence (e.g., exacerbation and/or relapses) (2,5,6). The off-label use of rituximab, a monoclonal antibody against CD20 on B cells, during acute episode or preventatively, has significantly reduced the rate of disease relapse (7,8). However, there is still unmet need for how to address acute ongoing microvascular thrombosis, which results in organ damage while waiting for the disappearance of autoantibodies against ADAMTS13, a plasma metalloprotease that cleaves von Willebrand factor (VWF) (9) and the normalization of plasma ADAMTS13 activity.

Caplacizumab, a nanobody against VWF (10) that binds the A1 domain of VWF (11) and inhibits the adhesion of activated platelets to endothelium-derived ultra large VWF (12,13). Thus, caplacizumab can effectively block the downstream thrombus formation, resulting from exaggerated platelet-VWF interaction due to lack of VWF proteolysis by plasma ADAMTS13. In 2019, the US Food and Drug Administration (FDA) approved caplacizumab for the treatment of adult patients with acquired TTP (i.e., mostly iTTP) in combination with TPE and other immunosuppressive therapies based on the promising results of phase II and III clinical trials (12,13). One year later, the International Society on Thrombosis and Haemostasis (ISTH) guidelines conditionally recommended the use of caplacizumab for all iTTP patients experiencing the first acute episode or subsequent relapsing events on top of TPE and other immunosuppressive therapies (14,15) (Figure 1). This triple therapy has been proposed to be the standard of care for iTTP today (16,17). Such a combined therapy has accelerated the normalization of platelet counts, reduced TTP-related complications (such as death and thromboembolic events), shortened the intensive unit and hospital stay, and reduced the duration of TPE (13,16). Most importantly, it has significantly reduced the rates of disease exacerbation during acute episode and the mortality rate of iTTP (13,16-19).

Figure 1 Schematic diagram demonstrates the process for the diagnosis and management of iTTP. When a patient presents with severe thrombocytopenia with platelet count <30×10⁹/L, creatine <2.26 mg/dL in the presence of hemolysis and schistocytes, but no history of malignancy and/or hematopoietic progenitor cell transplantation or known drugs that causes TMA, the likelihood of iTTP is very high (based on French Score). This patient will be benefited from ordering an ADAMTS13 test, immediate TPE and corticosteroids, and early caplacizumab. Otherwise, if the clinical probability of iTTP is low to intermediate, ADAMTS13 test should be ordered prior to TPE and corticosteroid, but no caplacizumab. Use ADAMTS13 activity result to guide further therapies as shown in the bottom of the diagram. This figure is adapted from Zheng et al. (15). *, in most initial iTTP cases, plasma ADAMTS13 activity is less than 5 U/dL (or 5% of normal) or undetectable. Normal ADATMS13 activity is 50–150 U/dL. Those with a relapsed episode may have higher ADAMTS13 activity. TMA, thrombotic microangiopathy; iTTP, immune thrombotic thrombocytopenic purpura; TPE, therapeutic plasma exchange.

However, there is still a question whether caplacizumab should only be reserved for severe or critically ill patients or for those who fail the initial TPE. In another word, should caplacizumab be prescribed upfront to all patients with acute iTTP? The answer is “yes”. However, patients who are allergic, or experience intracranial hemorrhage are contraindicated for caplacizumab. The provider’s hesitancy for not using caplacizumab upfront is primarily resulted from the lack of access to the drug such as in the developing countries and the concern of potentially added costs, even in the wealthy country like USA (20). It was estimated that an additional quarter million dollars may be spent for prescribing caplacizumab for each course of treatment of iTTP (20,21). However, this extra cost may still be worthwhile considering a potential fatality being prevented.

In fact, each patient with acute iTTP should be considered “critically ill” as the patient may suddenly demise, resulting from ongoing thrombosis and damage in the major organs (i.e., heart, brain, pancreas, and adrenal glands, etc.). Cardiac arrhythmia appears to be the primary cause of sudden death in iTTP (22,23). Thus, an intensive care unit (ICU) monitoring is necessary and early administration of caplacizumab to stop the ongoing thrombosis during the acute events may reduce not only the in-hospital mortality rate, but also potential long-term complications, such as cognitive decline, depression, and major cardiovascular events recovering from acute iTTP. When everything is considered such as the costs of ICU and hospital stay, TPE, plasma products, the iTTP-related death, and the potential long-term sequelae, the addition of caplacizumab to daily TPE and immunosuppressives (e.g., corticosteroids and rituximab) is found to be more cost-effective than a dual therapy (e.g., TPE and immunosuppressives), and allows the better utilization of the scanty healthcare resources (e.g., TPE, ICU and hospital stay, etc.) (13,16).

Another question is how to use and when to stop caplacizumab. Typically, a patient with high likelihood of iTTP based on clinical criteria or risk score assessment or a confirmed iTTP should receive an intravenous loading dose of caplacizumab (10 mg) prior to the first round of TPE therapy; a subsequent dose (10 mg) should be injected subcutaneously daily right following the completion of each TPE. Caplacizumab treatment should continue for 30 days after the last round of TPE and may be extended for another 28 days if a patient still has low plasma ADAMTS13 activity (<10 IU/dL or 10% of normal) (13). More recently, it has been demonstrated that caplacizumab therapy can be safely discontinued when platelet counts and serum lactate dehydrogenase (LDH) levels are normalized, or plasma ADAMTS13 activity ≥20 U/dL (or 20% of normal) (13,14), consistent with the new definition of clinical remission or partial ADAMTS13 remission for safe discontinuation of caplacizumab therapy (24).

Future studies should be considered to determine whether the use of caplacizumab, corticosteroids, and rituximab without TPE will be sufficient to manage acute iTTP. Very limited clinical experience has already shown the efficacy and safety of managing iTTP with caplacizumab and immunosuppressives but without TPE (25,26); additionally, how recombinant ADAMTS13, which may come to clinic soon, will fit into the overall treatment scheme of iTTP remains to be determined.

In conclusion, caplacizumab in conjunction with TPE and other immunosuppressive therapies (e.g., corticosteroids and rituximab or other drugs), the triple therapy, should be considered upfront for all adult patients with high probability of iTTP or confirmed diagnosis of iTTP to reduce the mortality and potential long-term sequalae resulting from acute iTTP.

Acknowledgments

Funding: This work was supported in part by the grant from NHLBI HL144552 (to XLZ).

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Annals of Blood. The article has undergone external peer review.

Peer Review File: Available at https://aob.amegroups.com/article/view/10.21037/aob-21-87/prf

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://aob.amegroups.com/article/view/10.21037/aob-21-87/coif). XLZ serves as an unpaid editorial board member of Annals of Blood from March 2022 to February 2024. XLZ served as a speaker for Alexion and Sanofi, which terminated last year. He is serving as a consultant for several companies including Alexion, Sanofi, Takeda, and Biomedica. He is also the co-founder of Clotsolution. He received honorarium from several universities and professional conferences as a keynote speaker. The other author has no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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References

1. Rock GA, Shumak KH, Buskard NA, et al. Comparison of plasma exchange with plasma infusion in the treatment of thrombotic thrombocytopenic purpura. Canadian Apheresis Study Group. N Engl J Med 1991;325:393-7. [Crossref] [PubMed]
2. Staley EM, Cao W, Pham HP, et al. Clinical factors and biomarkers predict outcome in patients with immune-mediated thrombotic thrombocytopenic purpura. Haematologica 2019;104:166-75. [Crossref] [PubMed]
3. Goel R, King KE, Takemoto CM, et al. Prognostic risk-stratified score for predicting mortality in hospitalized patients with thrombotic thrombocytopenic purpura: nationally representative data from 2007 to 2012. Transfusion 2016;56:1451-8. [Crossref] [PubMed]
4. Balasubramaniyam N, Kolte D, Palaniswamy C, et al. Predictors of in-hospital mortality and acute myocardial infarction in thrombotic thrombocytopenic purpura. Am J Med 2013;126:1016.e1-7. [Crossref] [PubMed]
5. Sui J, Lu R, Halkidis K, et al. Plasma levels of S100A8/A9, histone/DNA complexes, and cell-free DNA predict adverse outcomes of immune thrombotic thrombocytopenic purpura. J Thromb Haemost 2021;19:370-9. [Crossref] [PubMed]
6. Sui J, Cao W, Halkidis K, et al. Longitudinal assessments of plasma ADAMTS13 biomarkers predict recurrence of immune thrombotic thrombocytopenic purpura. Blood Adv 2019;3:4177-86. [Crossref] [PubMed]
7. Westwood JP, Thomas M, Alwan F, et al. Rituximab prophylaxis to prevent thrombotic thrombocytopenic purpura relapse: outcome and evaluation of dosing regimens. Blood Adv 2017;1:1159-66. [Crossref] [PubMed]
8. Goyal J, Adamski J, Lima JL, et al. Relapses of thrombotic thrombocytopenic purpura after treatment with rituximab. J Clin Apher 2013;28:390-4. [Crossref] [PubMed]
9. Zheng X, Chung D, Takayama TK, et al. Structure of von Willebrand factor-cleaving protease (ADAMTS13), a metalloprotease involved in thrombotic thrombocytopenic purpura. J Biol Chem 2001;276:41059-63. [Crossref] [PubMed]
10. Duggan S. Caplacizumab: First Global Approval. Drugs 2018;78:1639-42. [Crossref] [PubMed]
11. Lee HT, Park UB, Jeong TJ, et al. High-resolution structure of the vWF A1 domain in complex with caplacizumab, the first nanobody-based medicine for treating acquired TTP. Biochem Biophys Res Commun 2021;567:49-55. [Crossref] [PubMed]
12. Peyvandi F, Scully M, Kremer Hovinga JA, et al. Caplacizumab for Acquired Thrombotic Thrombocytopenic Purpura. N Engl J Med 2016;374:511-22. [Crossref] [PubMed]
13. Scully M, Cataland SR, Peyvandi F, et al. Caplacizumab Treatment for Acquired Thrombotic Thrombocytopenic Purpura. N Engl J Med 2019;380:335-46. [Crossref] [PubMed]
14. Zheng XL, Vesely SK, Cataland SR, et al. ISTH guidelines for treatment of thrombotic thrombocytopenic purpura. J Thromb Haemost 2020;18:2496-502. [Crossref] [PubMed]
15. Zheng XL, Vesely SK, Cataland SR, et al. ISTH guidelines for the diagnosis of thrombotic thrombocytopenic purpura. J Thromb Haemost 2020;18:2486-95. [Crossref] [PubMed]
16. Coppo P, Bubenheim M, Azoulay E, et al. A regimen with caplacizumab, immunosuppression, and plasma exchange prevents unfavorable outcomes in immune-mediated TTP. Blood 2021;137:733-42. [Crossref] [PubMed]
17. Zheng XL. The standard of care for immune thrombotic thrombocytopenic purpura today. J Thromb Haemost 2021;19:1864-71. [Crossref] [PubMed]
18. Peyvandi F, Callewaert F. Caplacizumab for Acquired Thrombotic Thrombocytopenic Purpura. N Engl J Med 2016;374:2497-8. [Crossref] [PubMed]
19. Peyvandi F, Cataland S, Scully M, et al. Caplacizumab prevents refractoriness and mortality in acquired thrombotic thrombocytopenic purpura: integrated analysis. Blood Adv 2021;5:2137-41. [Crossref] [PubMed]
20. Goshua G, Sinha P, Hendrickson JE, et al. Cost effectiveness of caplacizumab in acquired thrombotic thrombocytopenic purpura. Blood 2021;137:969-76. [Crossref] [PubMed]
21. Chaturvedi S. Counting the cost of caplacizumab. Blood 2021;137:871-2. [Crossref] [PubMed]
22. Hawkins BM, Abu-Fadel M, Vesely SK, et al. Clinical cardiac involvement in thrombotic thrombocytopenic purpura: a systematic review. Transfusion 2008;48:382-92. [Crossref] [PubMed]
23. Benhamou Y, Boelle PY, Baudin B, et al. Cardiac troponin-I on diagnosis predicts early death and refractoriness in acquired thrombotic thrombocytopenic purpura. Experience of the French Thrombotic Microangiopathies Reference Center. J Thromb Haemost 2015;13:293-302. [Crossref] [PubMed]
24. Cuker A, Cataland SR, Coppo P, et al. Redefining outcomes in immune TTP: an international working group consensus report. Blood 2021;137:1855-61. [Crossref] [PubMed]
25. Chander DP, Loch MM, Cataland SR, et al. Caplacizumab Therapy without Plasma Exchange for Acquired Thrombotic Thrombocytopenic Purpura. N Engl J Med 2019;381:92-4. [Crossref] [PubMed]
26. Völker LA, Brinkkoetter PT, Knöbl PN, et al. Treatment of acquired thrombotic thrombocytopenic purpura without plasma exchange in selected patients under caplacizumab. J Thromb Haemost 2020;18:3061-6. [Crossref] [PubMed]