REGULAR ARTICLE Real-world effectiveness of caplacizumab vs the standard of care in immune thrombotic thrombocytopenic purpura Cristina Pascual Izquierdo,1, * María Eva Mingot-Castellano,2, * Ana E. Kerguelen Fuentes,3 José García-Arroba Peinado,4 Joan Cid,5 Maria Moraima Jimenez,6 David Valcarcel,6 Inés Gómez-Seguí,7 Javier de la Rubia,7 Paz Martin,8 Rosa Goterris,9 Luis Hernández,10 Inmaculada Tallón,11 Sara Varea,12 Marta Fernández,13 Nadia García-Muñoz,14 Míriam Vara,15 Miguel Fernández Zarzoso,16 Faustino García-Candel,17 María Liz Paciello,18 Irene García-García,18 Saioa Zalba,19 Verónica Campuzano,20 José María Gala,21 Downloaded from http://ashpublications.org/bloodadvances/article-pdf/6/24/6219/2054414/blooda_adv-2022-008028-main.pdf by guest on 04 October 2023 Julia Vidán Estévez,22 Gemma Moreno Jiménez,23 José Luis López Lorenzo,24 Elena González Arias,25 Carmen Freiría,26 María Solé,27 Laura Francisca Ávila Idrovo,28 José Carlos Hernández Castellet,29 Naylen Cruz,30 Esperanza Lavilla,31 Albert Pérez-Montaña,32 Jon Ander Atucha,33 María Esperanza Moreno Beltrán,34 Juán Ramón Moreno Macías,35 Ramón Salinas,36 and Julio del Rio-Garma,37 on behalf of Spanish Apheresis Group (GEA) and the Spanish Thrombotic Thrombocytopenic Purpura Registry (REPTT) 1 Department of Hematology, Hospital General Universitario Gregorio Marañón (HGUGM) Madrid, Instituto de Investigación Gregorio Marañón, Madrid, Spain; 2 Hematology, Hospital Universitario Virgen del Rocío, Instituto de Biomedicina de Sevilla, Seville, Spain; 3 Department of Hematology and Hemotherapy, Hospital La Paz, Madrid, Spain; 4 Banc de Sang i Teixits, Hospital Universitario Joan XXIII, Tarragona, Spain; 5 Apheresis and Cellular Therapy Unit, Department of Hemotherapy & Hemostasis, ICMHO, IDIBAPS, Hospital Clínic de Barcelona, Barcelona, Spain; 6 Department of Hematology, University Hospital Vall d’Hebron, Experimental Hematology, Vall d’Hebron Institute of Oncology (VHIO), Vall d’Hebron Barcelona, Spain; 7 Department of Hematology, Hospital La Fe, Valencia, Spain; 8 Therapeutic Apheresis Unit, Hematology Department, Hospital Clínico San Carlos, Madrid, Spain; 9 Hematology Service, Hospital Clínico Universitario de Valencia, INCLIVA Health Research Institute, Valencia, Spain; 10 Hospital General Universitario de Alicante, Alicante, Spain; 11 Hospital Virgen Macarena, Seville, Spain; 12 Hospital San Chinarro, Madrid, Spain; 13 Hospital Universitario de A Coruña, A Coruña, Spain; 14 Hospital de Bellvitge, Barcelona, Spain; 15 Hematology Department, Hospital Universitario de Cruces, Baracaldo, Spain; 16 Hospital Universitario Dr. Peset, Valencia, Spain; 17 Hospital Clínico Universitario Virgen de la Arrixaca, Murcia, Spain; 18 Hospital Universitario 12 de Octubre, Madrid, Spain; 19 Hospital Universitario de Navarra, Pamplona, Spain; 20 Hospital Universitario Burgos, Burgos, Spain; 21 Hospital Universitario Central de Asturias, Asturias, Spain; 22 Apheresis & Transfusion Unit, Department of Hematology & Hemotherapy, CAULE, Complejo Asistencial Universitario de León, León, Spain; 23 Department of Hematology, Hospital Universitario Ramon y Cajal, Madrid, Spain; 24 Department of Hematology Hospital Universitario Fundación Jiménez Díaz, Hematologia. Madrid, Spain; 25 Hospital Universitario de Villalba, Madrid, Spain; 26 Hospital Universitario de Castellon, Castelló, Spain; 27 Hospital Universitario Juan Ramón Jiménez, Huelva, Spain; 28 Hospital Universitario de Canarias, Tenerife, Spain; 29 Hospital Puerta del Mar, Cádiz, Spain; 30 Hospital Universitario Dr. Negrín, Las Palmas, Spain; 31 Hospital Universitario Lucus Augusti, Lugo, Spain; 32 Hospital Universitario Son Espases, Palma de Mallorca, Spain; 33 Hospital de Basurto, Bilbao, Spain; 34 Hospital Costa del Sol, Marbella, Málaga, Spain; 35 Hospital Universitario de Albacete, Albacete, Spain; 36 Hospital del Sagrat Cor, Universitat Internacional de Catalunya; Banc de Sang i Teixits de Catalunya, Barcelona, Spain; and 37 Department of Hematology, University Hospital of Ourense, Ourense, Spain Immune thrombotic thrombocytopenic purpura (iTTP) is a thrombotic microangiopathy Key Points caused by anti-ADAMTS13 antibodies. Caplacizumab is approved for adults with an acute • Caplacizumab reduces episode of iTTP in conjunction with plasma exchange (PEX) and immunosuppression. The exacerbation and objective of this study was to analyze and compare the safety and efficacy of caplacizumab vs refractoriness in iTTP. the standard of care and assess the effect of the concomitant use of rituximab. A retrospective • As initial therapy, study from the Spanish TTP Registry of patients treated with caplacizumab vs those who did caplacizumab not receive it was conducted. A total of 155 patients with iTTP (77 caplacizumab, 78 no accelerates response caplacizumab) were included. Patients initially treated with caplacizumab had fewer and reduces the need exacerbations (4.5% vs 20.5%; P < .05) and less refractoriness (4.5% vs 14.1%; P < .05) than for PEX and hospital those who were not treated. Time to clinical response was shorter when caplacizumab was stay. used as initial treatment vs caplacizumab used after refractoriness or exacerbation. The multivariate analysis showed that its use in the first 3 days after PEX was associated with a lower number of PEX (odds ratio, 7.5; CI, 2.3-12.7; P < .05) and days of hospitalization (odds ratio, 11.2; CI, 5.6-16.9; P < .001) compared with standard therapy. There was no difference in Submitted 6 May 2022; accepted 15 July 2022; prepublished online on The full-text version of this article contains a data supplement. Blood Advances First Edition 5 August 2022; final version published online 22 © 2022 by The American Society of Hematology. Licensed under Creative Commons December 2022. https://doi.org/10.1182/bloodadvances.2022008028. Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), *C.P.I. and M.E.M.-C. contributed equally to this study. permitting only noncommercial, nonderivative use with attribution. All other rights Requests for original data may be submitted to the corresponding author, María Eva reserved. Mingot-Castellano (mariae.mingot.sspa@juntadeandalucia.es). 27 DECEMBER 2022 • VOLUME 6, NUMBER 24 6219 time to clinical remission in patients treated with caplacizumab compared with the use of rituximab. No severe adverse event was described in the caplacizumab group. In summary, caplacizumab reduced exacerbations and refractoriness compared with standard of care regimens. When administered within the first 3 days after PEX, it also provided a faster clinical response, reducing hospitalization time and the need for PEX. Introduction treat patients with iTTP through the Sanofi MAP (Medical Access Program). The MAP allowed for the extended use of caplacizumab for 30 days after PEX, although it could be used even longer if Immune thrombotic thrombocytopenic purpura (iTTP) is a rare ADAMTS13 was abnormal. Patients with iTTP who received capla- Downloaded from http://ashpublications.org/bloodadvances/article-pdf/6/24/6219/2054414/blooda_adv-2022-008028-main.pdf by guest on 04 October 2023 disease characterized by microangiopathic hemolytic anemia, cizumab between June 2018 and November 2020 were included. severe thrombocytopenia (<30 × 109/L), and a variable degree of The decision to treat with caplacizumab depended on timely access ischemic organ damage.1 Organ ischemia includes basically the to MAP, clinical criteria, and the physicians’ knowledge of drug cerebral, myocardial, renal, and gastrointestinal systems.2 iTTP is availability. This group was compared with all the REPTT patients characterized by severely deficient activity (<10% levels) of treated during the same period who did not receive caplacizumab. ADAMTS13, a cleaving protease of von Willebrand factor (vWF). In iTTP, ADAMTS13 deficiency is acquired via the production of Demographic, clinical, and analytical data were collected retro- autoantibodies against ADAMTS13, which inhibit ADAMTS13 spectively from medical records. The expression “initial treatment” proteolytic activity toward vWF or increase its clearance.3,4 The is henceforth used to indicate the intention to use a drug or therapy lack of ADAMTS13 activity leads to platelet/vWF multimer aggre- from the beginning of treatment, although due to the procedures gation, causing microthrombi within small arterioles. required to obtain the medication it could be delayed several days. The caplacizumab treatment initiation day was defined as the day In Spain, the estimated annual incidence of iTTP is 2.67 individuals per PEX began. We considered caplacizumab to be a second-line million,5 in line with data reported in other western countries.6 Given the treatment if it was used due to exacerbation or refractoriness. rarity of the disease, iTTP registries are essential if a deeper knowledge of the disease and its management is to be obtained. The definitions of clinical response, clinical remission, exacerbation, and relapse considered were as previously defined by the Interna- iTTP is associated with high morbidity and mortality. If it is left tional Working Group for Thrombotic Thrombocytopenic Pur- untreated, the mortality rate rises to 90% but falls to 5% to 20% when pura.17,18 Refractoriness was defined as platelet counts <50 × 109/ appropriately treated.7,8 Death usually occurs within the initial days of L and persistently increased lactate dehydrogenase (LDH) levels management. Therefore, early diagnosis and treatment are of para- (>1.5 upper limit of normal) despite five PEX. Time to normalization mount importance. Until recently, the standard first-line therapy for of platelet count was defined as the time from the first PEX to the iTTP has been empirical and includes plasma exchange (PEX) and first day with a count ≥150 × 109/L. Exacerbation was defined as an concomitant immunosuppressive therapy (corticosteroids with or unjustified decrease in platelet counts and elevation of LDH within without rituximab).2,9 PEX and immunosuppressant treatment may 30 days as of the suspension of treatment for clinical remission and take several days or weeks, however, to produce a response. requiring the re-initiation of PEX. The survival analysis was measured Consequently, some patients, mostly those with risk factors for death, in days or months and was defined as the period between the PEX die of the disease.8,10 and the occurrence of the event of interest. ADAMTS13 levels Caplacizumab, a novel humanized nanobody targeting vWF that during follow-up were measured almost only in patients treated with blocks platelet–vWF aggregation, was the first drug approved in caplacizumab according to MAP requirements. Adverse events were the European Union for iTTP (2018). It has shown a fast effect also recorded and graded according to the Common Toxicity within hours, preventing thrombi formation. Early caplacizumab has Criteria for Adverse Events. Refractoriness was defined as platelet been shown to reduce the time to clinical response, refractoriness, counts <50 × 109/L and a persistently raised LDH level (>1.5 upper mortality rate, and recurrence rate, and is efficacious both in the limit of normal) despite five PEX. First PEX to exacerbation was initial episode and in exacerbation or relapse.11-13 defined as an unjustified decrease in platelet counts and raise of LDH before 30 days from treatment suspension due to clinical Several European registries have already reported their experience remission and that requires re-start PEX. PEX ADAMTS13 levels outside clinical trial populations.14-16 To provide real-world evi- during follow-up were measured almost only in patients treated with dence in our country, the objective of this study was to retro- caplacizumab according to MAP requirements. spectively analyze the efficacy and safety of caplacizumab in patients with iTTP included in the Spanish TTP Registry (Registro The primary end point was the time to clinical response since the Español de PTT [REPTT]) and to compare these data vs a cohort first PEX. The secondary end points were the total number of PEX of patients not treated with this drug. Finally, we sought to describe procedures, hospital stay, and percentage of clinical remission. the role of rituximab associated with caplacizumab. Statistical analysis A descriptive analysis of the demographic and clinical data was Methods performed. For continuous variables, the mean and standard In this retrospective study, subjects were identified from the REPTT. deviation or median with interquartile range (IQR) were calculated. During the study period, caplacizumab was only available in Spain to Categorical variables are presented as number (n) and frequencies 6220 IZQUIERDO et al 27 DECEMBER 2022 • VOLUME 6, NUMBER 24 (percentages). The Shapiro-Wilks normality test was used to not treated with caplacizumab. Four (5.2%) of 77 patients treated decide whether t test/analysis of variance or Mann-Whitney/ with caplacizumab presented exacerbations, and 5 (6.5%) of Kruskal-Wallis tests should be used and whether the normality 77 had refractoriness, compared with 16 (20.5%) of 78 and 11 assumption was fulfilled to compare groups for quantitative out- (14%) of 78 in the nontreated group, respectively. When the comes. Pearson’s χ2 test and Fisher’s exact test were used for patients treated with caplacizumab as initial treatment were bivariate comparisons with nominal variables. Kaplan-Meier survival analyzed, only 4.5% of them experienced exacerbations, compared estimates were used to describe “time to” variables. Cox regres- with 20.5% of those not treated with caplacizumab (P < .05). In sion was used to evaluate factors related to “time to” variables. addition, fewer patients treated initially with caplacizumab were Multivariate regression analysis was used to evaluate factors refractory compared with those not treated with caplacizumab related to length of hospitalization, intensive care unit stay, and (4.5% vs 14.1%; P < .05) (Table 3). Overall, caplacizumab as initial number of PEX procedures. treatment rescued 95% of refractory patients (18 of 19) and 93% of patients with exacerbations (13 of 14). Downloaded from http://ashpublications.org/bloodadvances/article-pdf/6/24/6219/2054414/blooda_adv-2022-008028-main.pdf by guest on 04 October 2023 No formal sample size calculation was performed. All tests were two-sided, and P < .05 was considered statistically significant. The Fewer of the patients treated with caplacizumab (3 of 77 [3.8%]) statistical analysis was conducted by using SPSS version 25.0 died than those who were not treated with it (6 of 78 [7.7%]), albeit (IBM SPSS Statistics, IBM Corporation, Armonk, NY). All patients without statistically significant differences. Two of 3 patients in the gave their informed consent for their data to be recorded in the caplacizumab group died during an acute episode (supplemental REPTT to be used for research purposes. The Ethics Committee of Table 1). The third patient was a 48-year-old patient who died the Hospital Clínic de Barcelona evaluated and approved the study 4 months after achieving clinical remission and normalization of protocol. The study was conducted according to the Declaration of ADAMTS13 in the context of cytomegalovirus and Aspergillus Helsinki. infection. This patient was treated with steroids (156 days from start to suspension), 21 daily PEX, rituximab 375 mg/m2 per week Results for 44 total doses, and N-acetyl cysteine. Caplacizumab was started because of exacerbation. The patient achieved clinical Patient characteristics response after 13 PEX after diagnosis, but she experienced In this retrospective study, 155 patients with iTTP from 35 centers an exacerbation 9 days later, whereupon PEX and caplacizumab were included: 77 received caplacizumab and 78 did not (control were reinitiated, and a clinical response was obtained in 8 days. group). All the patients were also treated with PEX and prednisone A total of 9 PEX and a further 30 doses of caplacizumab 1 mg/kg per day or the equivalent dose of corticosteroids (stan- were used. The patient had no other infectious risk factors or dard therapy). Eighty-four percent (65 of 77) of the patients treated immunodeficiency other than immunosuppressive treatment for with caplacizumab also received rituximab, and almost 68% (53 of an acute iTTP episode. Supplemental Table 1 summarizes the 78) of the patients treated with standard therapy alone also clinical characteristics and evolving features of the 8 patients received rituximab. The reasons for starting treatment with capla- (2 with and 6 without caplacizumab) who died during an acute cizumab and rituximab are described in Figure 1. episode. The starting day of caplacizumab was variable (median time from PEX was 5 days; IQR, 2-11 days), with a median duration of 35 Time to platelet count normalization, PEX, and days (IQR, 31-40 days). Overall, 44 (57%) patients received length of hospital stay caplacizumab as initial treatment, and the other 33 patients The median time to clinical response was shorter in patients received caplacizumab as second line: 19 (24.7%) at refractori- treated with caplacizumab as initial treatment compared with ness and 14 (18.2%) after exacerbation. The median time to start patients not treated with caplacizumab: 8.5 (IQR, 6-12.5) days vs caplacizumab treatment in each of these subgroups is shown in 14 (IQR, 7-21) days (P = .009). To assess the real impact of Table 1. The median follow-up of the caplacizumab group was 216 caplacizumab treatment on the course of the disease and to avoid days (IQR: 141-417 days) vs 214 days (IQR: 138-467 days) in the potential biases, we compared the subgroup of patients treated non-caplacizumab group. with caplacizumab as initial treatment (n = 44) vs patients treated The demographic and initial disease characteristics of the patients with caplacizumab only after an exacerbation or refractoriness. The included in the study are described in Table 2. No differences were median time to clinical response was shorter when caplacizumab observed between treatment groups regarding gender or age. In was used initially than when it was used after refractoriness or an the caplacizumab cohort, 65% of the episodes were disease onset exacerbation (median, 5 days vs 15 days; P < .01; hazard ratio, compared with 92% in the nontreated group (P < .001). Before 2.30; 95% CI, 1.41-3.76) (Figure 2). treatment, signs of bleeding diathesis were more frequent in the Moreover, among patients who received caplacizumab as initial caplacizumab group (58.4% vs 29.5%; P < .001). The patients treatment, the time to clinical response was significantly shorter in enrolled had a median platelet count of 12 × 109/L, and more than patients treated within the first 3 days compared with those who one-half of them presented neurologic involvement. There were no started later. When caplacizumab was started within the first 3 differences in the laboratory parameters at diagnosis between days, the median time to platelet count normalization was 4 days groups. (IQR, 3-5 days), compared with 5 days (IQR, 5-9 days) if it was started between 4 and 6 days, and 14.5 days (IQR, 10-26.5 days) Description of caplacizumab use and disease course if it was delayed for ≥7 days (P = .003) (supplemental Table 2). In Global clinical remission was high and similar between groups: other words, the earlier the caplacizumab treatment was started, 95.7% of patients treated with caplacizumab and 94.8% in patients the faster a clinical response was achieved. 27 DECEMBER 2022 • VOLUME 6, NUMBER 24 CAPLACIZUMAB IN iTTP 6221 Total number of patients with iTTP N=155 Treated with caplacizumab N=77 Not treated with Initial treatment N=44 (57.1%) caplacizumab Refractoriness N=19 (24.7%) N=78 Exacerbation N=14 (18.2%) Downloaded from http://ashpublications.org/bloodadvances/article-pdf/6/24/6219/2054414/blooda_adv-2022-008028-main.pdf by guest on 04 October 2023 Treated with Not treated with Treated with Not treated with rituximab rituximab rituximab rituximab N=53 (68%) N=25 (32%) N=65 (84%) N=12 (16%) Rituximab as initial Rituximab after: Rituximab as initial Rituximab after: treatment Refractoriness: N=3 (5.7%) treatment Refractoriness: N=19 (29.2%) N=40 (75%) Exacerbation: N=10 (18.9%) N=35 (54%) Exacerbation: N=11 (16.9%) Figure 1. Patient distribution. Efficacy outcomes linked to health care resource utilization were the caplacizumab group (n = 65), rituximab was used as initial compared between patients treated initially with caplacizumab and treatment only in 35 (53.8%) patients, compared with 40 (75%) in patients not treated with caplacizumab. Caplacizumab reduced the the non-caplacizumab group (n = 53). Of all patients treated with number of PEX (P < .05) and length of hospitalization (P < .001). rituximab (n = 111), those treated with caplacizumab achieved No difference in the length of intensive care unit stay between clinical response 1.96 times faster than those without caplacizu- treatments was observed (P = .796) (Table 4). Subsequently, a mab: 14 days vs 24 days (hazard ratio, 1.96; 95% CI: 1.29-2.99; multivariate analysis was performed to identify factors linked to P < .001) (Figure 3). length of hospitalization and number of PEX, and it transpired that No differences were observed in the median time to relapse patients treated with caplacizumab within 3 days from the first PEX between patients treated with caplacizumab plus rituximab vs had shorter hospitalizations (11.2 days fewer on average). More- patients treated with caplacizumab alone (Figure 4) or in patients over, a hemoglobin level <8 g/dL was related to longer hospitali- treated with caplacizumab and rituximab as initial treatment vs zations (7.5 more days on average) (supplemental Table 3). patients treated after an exacerbation or refractoriness (not Furthermore, treatment with caplacizumab within the first 3 days shown). After the treatment response analysis, we estimated from the first PEX was related to less need for PEX. In contrast, the median time to ADAMTS13 >10%, and no differences were older patients and treatment with rituximab were associated with a found between patients treated with caplacizumab plus rituximab higher number of PEX. Neurologic manifestations were associated vs patients treated with caplacizumab alone (28 vs 29 days; with both shorter hospitalizations and fewer PEX. We were unable hazard ratio, 0.93; 95% CI, 0.39-2.23; P > .05) (supplemental to identify any variable associated with the use of rituximab or the Figure 1). presence of neurologic alterations that might have skewed these findings. Safety data Influence of the use of rituximab on patient response Overall, 36% of the patients treated with caplacizumab reported Up to 84% (65 of 77) of the patients treated with caplacizumab adverse events. Bleeding events were reported in 16 (20%) of 77 also received rituximab, a higher percentage than the patients after receiving caplacizumab, although only 2 were clas- non-caplacizumab group (68% [53 of 78]) (P = .018) (Figure 1). In sified as grade ≥2. Gingivorrhagia was the most common bleeding event, followed by metrorrhagia (19% and 10%, respectively). Fifty- five percent of all bleeding events resolved spontaneously; in the Table 1. Time to start caplacizumab treatment as initial treatment rest of the cases, suspending caplacizumab for <48 hours sufficed, or after refractoriness or exacerbation in days with no need for hemostatic treatment. Thrombocytosis occurred in N Median IQR P 20% of patients treated with caplacizumab (supplemental Table 4). Initial treatment 44 2 1-4 <.0001 One patient died only 1 day after starting caplacizumab due to mul- Exacerbation 19 14 10-16 tiorgan failure with intracranial hemorrhage, confirmed in the necropsy Refractoriness 14 10 8-13 (supplemental Table 1). Reviewing the clinical course, her doctors did not describe the adverse event as related to caplacizumab but rather 6222 IZQUIERDO et al 27 DECEMBER 2022 • VOLUME 6, NUMBER 24 Table 2. Baseline patient characteristics Baseline characteristic Caplacizumab cohort (n = 77) Non-caplacizumab cohort (n = 78) P Female, N (%) 58/77 (75%) 61/78 (78%) .6711 Age, mean ± SD, y 47.1 ± 14 46.5 ± 14 .833 First episode iTTP, N (%) 50/77 (65%) 72/78 (92%) <.001 Symptoms/signs, N (%) Anemic syndrome* 41/77 (53.2%) 36/78 (46.2%) .3772 Neurologic involvement 43/77 (55.8%) 47/78 (60.3%) .4510 Neurologic focal signs† 22/43 (51.2%) 16/47 (34.0%) Headache 11/43 (25.6%) 15/47 (31.9%) Downloaded from http://ashpublications.org/bloodadvances/article-pdf/6/24/6219/2054414/blooda_adv-2022-008028-main.pdf by guest on 04 October 2023 Others 11/43 (25.6%) 10/47 (21.3%) Elevated troponin 22/44 (50%) NA Hemorrhagic diathesis‡ 45/77 (58.4%) 23/78 (29.5%) <.001 Mucocutaneous hemorrhage 39/45 (86.7%) 18/23(78.3%) .010 Menorrhagia 5/46 (10.9%) 0/23 (0%) Others 1/45 (2.2%) 5/23 (21.7%) Renal insufficiency/failure§ 19/77 (24.7%) 19/76 (25.0%) .9629 Laboratory parameters at diagnosis, median (IQR) [range] Hemoglobin, g/dL 8.7 (7.2-11.1) [5.7-16.6] 8.7 (6.85-10.3) [5.7-14.6] .219 Platelets, ×109/L 12 (8-20) [3-94] 12 (8-17.5) [3-57] .802 WBC, ×109/L 8.19 (6.7-11.4) [3.2-23] 9.1 (7.13-12.09) [3.2-23.3] .226 Indirect bilirubin, mg/dL 1.61 (0.995-2.35) [ 0.2-8] NA LDH, U/L 1040 (607-1546) [169-7334] 1086 (715.5-1550) [291-7334] .497 Creatinine, mg/dL 0.95 (0.73-1.2) [0.45-2.78] 0.92 (0.72-1.3) [0.54-5.49] .803 ADAMTS13, % 0 (0-0.5) [0-13] 0 (0-0.5) [0-19] .954 ADAMTS13 inhibitor, BU 3.3 (7-20.93) [0-112.2] NA BU, Bethesda unit; LDH, lactate dehydrogenase; NA, not available; SD, standard deviation; WBC, white blood cells. Boldface means statistical significant. *Includes fatigue, weakness, and dizziness symptoms. †Includes stroke, cardiovascular events, and transient ischemic attacks. ‡Required only 1 red blood cell transfusion and stopping caplacizumab treatment for 48 hours in 1 patient with rectal bleeding due to gut polyposis. The event remitted and did not require vWF or other treatments. §Defined as creatinine level >1.5 mg/dL. to thrombocytopenia, endothelial impairment due to hypoxia, and solve TTP. The patient had also received steroids for 156 days, cardiorespiratory arrest prior to multiorgan failure. although the dose is unknown. No other rituximab-related adverse events were described. As described earlier, one of the patients treated with rituximab developed severe infections that led to death outside the acute episode 4 months later. Infections occurred as an adverse Discussion event when the patient was treated with immunosuppressants to This study provides real-world data on the efficacy and safety of caplacizumab in patients with iTTP managed in Spain, confirming Table 3. Outcomes of patients treated with caplacizumab as the therapeutic benefits of caplacizumab used as initial treatment. initial treatment vs patients not treated with caplacizumab Our results emphasize the beneficial outcomes of caplacizumab patients with iTTP treated patients with iTTP not use, especially in the first 3 days, since it is associated with a faster with caplacizumab as treated with caplacizumab clinical response, less refractoriness and subsequently fewer initial treatment (n = 44) (n = 78) P exacerbations, and shorter length of hospitalization. Clinical remission 42/44 (95.5%) 73/78 (93.6%) .6501 The patients included in our study were similar to those described Exacerbation 2/44 (4.5%) 16/78 (20.5%) .023 in other iTTP registries. Our sample is fully representative of the Refractoriness* 2/44 (4.5%) 11/78 (14.1%) .042 iTTP population, although no sample size was calculated. Both Death 2/44 (4.5%) 6/78 (7.7%) .567 groups of patients (treated and not treated with caplacizumab) *The 2 patients who were refractory to treatment were those who died, although they were treated in the same period and had practically the same were different from the other 2 who had an exacerbation. number of patients. As expected, most patients were female (women are 2-3 times likelier to develop iTTP), in their fourth to fifth 27 DECEMBER 2022 • VOLUME 6, NUMBER 24 CAPLACIZUMAB IN iTTP 6223 Time to platelets !150u109/L 1.00 0.75 p=.01 0.50 0.25 Downloaded from http://ashpublications.org/bloodadvances/article-pdf/6/24/6219/2054414/blooda_adv-2022-008028-main.pdf by guest on 04 October 2023 Caplacizumab others Caplacizumab 1st line 0.00 0 10 20 30 40 50 60 70 80 90 100 Follow up (days) Number at risk Caplacizumab others 32 21 12 7 7 4 3 2 2 1 1 Caplacizumab 1st line 43 8 3 3 2 2 2 0 0 0 0 Figure 2. Survival analysis. Time to clinical response in patients treated with caplacizumab as initial treatment (n = 43*) vs caplacizumab used in refractoriness or exacerbation (n = 32*). (It should be noted that all patients also received PEX and corticosteroids). *Missing values. decade of life, presenting neurologic symptoms at baseline, as count normalization and clinical remission was much shorter previously reported.7 Most of the patients received caplacizumab among patients who received caplacizumab within 3 days of the as initial treatment (57%), and the rest started only after an exac- first PEX; this subsequently prevented unfavorable clinical out- erbation or refractoriness. It should be pointed out that all patients comes. Patients treated with caplacizumab as initial treatment also received caplacizumab within a MAP setting, which is therefore a had significantly fewer exacerbations and less refractoriness than different scenario from routine clinical practice in Spain. As patients receiving steroids and PEX. These data reinforce the explained in the Methods, treatment with caplacizumab or not current role of caplacizumab as initial treatment and the importance depended on timely access to the MAP, clinical judgment and of its rapid availability in the hospital setting to avoid delays in physicians’ knowledge of drug availability. obtaining a response. Our data show that early treatment with caplacizumab permits a The early prevention of microcirculation occlusion and ischemic faster clinical response, confirming previous findings from both organ damage with caplacizumab may avoid long-term complica- clinical studies and real-world data.11,12,14-16 The time to platelet tions and eventually death.19 Therefore, these data support the need for treatment with caplacizumab during the period in which a patient Table 4. Response of patients treated with caplacizumab as initial is at risk to avoid exacerbations. Because more than one-half of the treatment vs patients not treated with caplacizumab in terms of patients already presented signs or symptoms of organ ischemia at number of PEX, days of hospitalization, and days in the intensive baseline, prompt treatment response is of paramount importance. In care unit fact, caplacizumab acts rapidly by preventing the formation of patients with iTTP treated patients with iTTP with caplacizumab as not treated with thrombi in the microcirculation and has been shown to be effective in initial treatment caplacizumab P overcoming factors associated with mortality,11,12,14-16 yielding a No. of PEX favorable outcome vs standard treatment. N 44 76 .017 In the current study, the patients treated with caplacizumab pre- Mean ± SD 12.39 ± 11.8 18.51 ± 19.05 sented less mortality (3 patients [3.9%]) than those not treated Median (IQR) 8.5 (6-12.5) 14 (7-21.5) with caplacizumab (6 patients [7.7%]). This difference was not Days of hospitalization significant, in line with data from clinical trials, in which mortality was considered a composite variable.11,12 Fortunately, deaths for N 44 51 .001 iTTP are rare, and only 1 death may cause mortality percentages to Mean ± SD 14.68 ± 12.36 21.94 ± 14.42 vary significantly due to the small sample size of the series. It should Median (IQR) 12 (9-15) 19 (12-27) be noted that one of the patients treated with caplacizumab died Days in ICU months after the acute episode and that one of the patients without N 42 71 .796 caplacizumab did not receive any PEX procedure. Nevertheless, Mean ± SD 2.31 ± 2.62 2.79 ± 3.51 the mortality rate was higher than reported by other real-world studies (1.1% to 1.7%)14,16 and in clinical trials.11,12 However, Median (IQR) 2 (0-4) 2 (0-4) this study included patients by intention to treat, thus accounting ICU, intensive care unit; SD, standard deviation. for deaths without initiating treatment. Furthermore, the current study had a follow-up of ~215 days, much longer than clinical trials 6224 IZQUIERDO et al 27 DECEMBER 2022 • VOLUME 6, NUMBER 24 Time to clinical response 1.00 p=.001 0.75 0.50 0.25 PEX + rituximab Downloaded from http://ashpublications.org/bloodadvances/article-pdf/6/24/6219/2054414/blooda_adv-2022-008028-main.pdf by guest on 04 October 2023 PEX + capla + rituximab 0.00 0 10 20 30 40 50 60 70 80 90 100 Follow up (days) Number at risk PEX + rituximab 51 44 29 22 17 12 12 12 12 11 10 PEX + capla + rituximab 60 40 19 12 9 8 7 6 6 5 4 Figure 3. Survival analysis. Time to clinical response in patients treated with rituximab + PEX, with or without the addition of caplacizumab (n = 111*). (It should be noted that all patients also received corticosteroids.) *Seven patients were lost to follow-up: 2 patients receiving rituximab and 5 patients receiving rituximab and caplacizumab. Capla, caplacizumab. (28-30 days), which increases the chance of recording more death (mean, 14.68 vs 9.9 days of hospitalization).12 However, the data events. In contrast, another study reported a higher mortality rate are not comparable because clinical trials operate under stricter with caplacizumab (5.2%) than the rate reported in this study.15 timings, and, in our study, 43% of the patients received caplaci- Such differences could probably be explained by patients’ base- zumab only after experiencing refractoriness or an exacerbation, line characteristics affecting iTTP disease severity and outcomes. thus contributing to longer hospital stays Importantly, treatment with caplacizumab also diminishes health Rituximab9 reportedly reduces relapses, and our study found care disease burden. The length of hospitalization was reduced by analogous results. Moreover, patients treated with caplacizumab 37% and the need for PEX was reduced by 39% vs those who plus rituximab presented relapses similar to patients receiving received other drugs, in line with previously published real-world caplacizumab alone and no differences in time to relapse. Never- data.14 Hospitalization data from our series were similar to other theless, conclusions cannot be drawn on account of the short real-world data studies14,15 and even lower than a German real- follow-up and limited sample size. In the acute episode setting, our world study (21.6 days of hospitalization).16 In contrast, days of series found that the addition of rituximab to caplacizumab did not hospitalization were almost twice those reported in clinical trials accelerate response. In fact, clinical remission was achieved earlier Time to relapse 1.00 0.75 0.50 p=.779 0.25 PEX + rituximab PEX + capla + rituximab 0.00 0 3 6 9 12 15 18 21 24 Follow up months Number at risk PEX + rituximab 12 12 10 9 7 6 5 4 3 PEX + capla + rituximab 63 52 34 21 16 11 7 5 2 Figure 4. Time to relapse in patients treated with caplacizumab + rituximab vs patients treated with caplacizumab alone (n = 75*). (It should be noted that all patients also received PEX and corticosteroids.) *Two patients were lost to follow-up in the caplacizumab + rituximab group. Capla, caplacizumab. 27 DECEMBER 2022 • VOLUME 6, NUMBER 24 CAPLACIZUMAB IN iTTP 6225 when caplacizumab was given as a single agent (12 patients) than the results obtained are valid for the purpose of drawing appro- when it was combined with rituximab (60 patients). Nevertheless, priate conclusions. Caplacizumab reduces exacerbations and the results should be approached with caution due to the small refractoriness and disease burden. Its greatest efficacy is observed sample size of the caplacizumab-only group. when it is used early (within 3 days) because it clearly reduces the number of days to clinical response and clinical remission, Because these drugs have different mechanisms of action, capla- hospitalization time, and the number of PEX. Caplacizumab is cizumab and rituximab are complementary agents for disease well tolerated, with mild bleeding events (mostly grade ≤2) that do management, with add-on benefits at different moments of the not require any intervention in the majority of cases. Therefore, acute episode. Thus, caplacizumab acts very quickly and should be caplacizumab is a good drug for serious clinical situations administered, if possible, within the first days after PEX. not previously covered in the treatment of iTTP and should be Conversely, rituximab reaches its greatest potential 2 weeks after it used early, as an initial treatment, together with PEX and is started, and hence it plays a greater role in the consolidation of immunosuppression. Downloaded from http://ashpublications.org/bloodadvances/article-pdf/6/24/6219/2054414/blooda_adv-2022-008028-main.pdf by guest on 04 October 2023 response and in preventing early exacerbations or relapses through its immunosuppressive effect. It is well known that caplacizumab does not address ADAMTS13 Acknowledgments deficiency and that concomitant immunosuppression is required. The authors thank Maite Artés from Adelphi Targis S.L. and Alba We found no difference in time to ADAMTS13 recovery between Gómez for their support in the medical writing process. patients treated with caplacizumab alone or caplacizumab plus rituximab. Unfortunately, we were unable to analyze the evolution of ADAMTS13 at follow-up after the acute episode in patients treated Authorship without caplacizumab because ADAMTS13 levels were not avail- Contribution: C.P.I., M.E.M.-C., J.C., and J.d.R.-G. contributed to able in the majority of these patients. the design of the study, data collection, statistical analysis, and writing of the final manuscript; A.E.K.F. and J.G.-A.P. contributed to The safety outcomes of the current study are consistent with those the data collection; C.P.I. and M.E.M. coordinated the team; and all previously reported. Because caplacizumab interferes with vWF, it authors contributed to the data collection, participated in the clin- is associated with mucocutaneous bleeding, similar to patients with ical management of these patients, contributed to the literature von Willebrand disease.20 In our series, the most common bleeding review on the topic, and critically reviewed the manuscript. event was gingivorrhagia, in line with data from pivotal trials11,12 and real-world data.14-16 Although the bleeding rate was higher Conflict-of-interest disclosure: M.E.M.-C. has received honoraria in patients with caplacizumab, most events were mild in severity for consulting and as a speaker from Sobi, Amgen, Takeda, Sanofi, (grade ≤2). Novo Nordisk, Grifols, Novartis, CSL Behring, Werfen; and grant founding from Novo Nordisk, Amgen, Takeda, Alexion. C.P.I. has Although caplacizumab has shown safety and efficacy in the served as a consultant and provided expert testimony for Sanofi treatment of iTTP and the International Society on Thrombosis and and Takeda. A.E.K.F. has received honoraria for consulting and as a Haemostasis recommends it for the treatment of TTP,9 the health speaker for Sanofi and Novartis. J.G.-A.P. has received honoraria authorities in Spain are still reluctant to expedite as its use as initial for consulting and as a speaker for Sanofi. J.C. has received treatment. This is probably because the current treatment of iTTP research funding from Cerus, Kawasumi Laboratories, and Sanofi; has been shown to be effective and that caplacizumab has a high and has received speaker or advisory fees from Cerus, Fresenius cost, which is perceived as a barrier to its widespread use. Kabi, Grifols, MacoPharma, Sanofi, and TerumoBCT. R.G. has Although there are already cost analysis studies in the United received honoraria from Sanofi for consulting activities. J.d.l.R. has States21 (which indicate it as non–cost-effective), there is a lack of served as a consultant and has provided expert testimony for analysis studies in Spain and in other European countries. How- Sanofi. J.d.R.-G. has received honoraria for consulting from Takeda ever, it has been suggested that modifying the current standard of and Sanofi. D.V. has received honoraria from Sanofi as speaker and care could reduce prices.15,22-24 This change of management also for consulting activities. I.G.-S. has received honoraria for consul- implies a paradigm shift in iTTP treatment. In fact, some articles ting and as a speaker from Terumo BCT, Takeda and Sanofi. support the use of caplacizumab without PEX in selected J.R.R.M. has received honoraria for consultancy on advisory boards patients,16,25,26 and treatment without PEX would be simpler and and as a speaker from Janssen, AbbVie, AstraZeneca, CSL- safer. Controlled trials are called for to enact progress in this Behring, Takeda, and GSK. The remaining authors declare no regard. competing financial interests. As in all retrospective studies, this work has inherent limitations ORCID profiles: C.P.I., 0000-0001-5442-4886; M.E.M.-C., associated with the nature of its design. The data used were not 0000-0001-9083-855X; J.C., 0000-0001-5445-4508; J.d.l.R., specifically collected for the study; in this regard, certain variables 0000-0002-8354-768X; F.G.-C., 0000-0002-6369-6004; I.G.-G., with the potential to affect outcome may have been overlooked. In 0000-0002-2228-6754; V.C., 0000-0001-7862-7055; J.M.G., addition, only some patients were treated with caplacizumab as 0000-0001-5992-1961; E.L., 0000-0003-1490-0678. initial treatment due to some clinicians’ lack of familiarity with the drug and the paperwork required to access the MAP. However, the Correspondence: María Eva Mingot-Castellano, Hematology, study focused on a by no means negligible number of patients Hospital Universitario Virgen del Rocío, Instituto de Biomedicina de treated early and homogeneously with caplacizumab. Therefore, Sevilla, Seville, Spain; email: mariae.mingot.sspa@juntadeandalucia.es. 6226 IZQUIERDO et al 27 DECEMBER 2022 • VOLUME 6, NUMBER 24 References 1. George JN, Nester CM. Syndromes of thrombotic microangiopathy. N Engl J Med. 2014;371(7):654-666. 2. Sukumar S, Lämmle B, Cataland SR. Thrombotic thrombocytopenic purpura: pathophysiology, diagnosis, and management. J Clin Med. 2021;10(3): 1-24. 3. Sadler JE. 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