scholarly journals Caplacizumab prevents refractoriness and mortality in acquired thrombotic thrombocytopenic purpura: integrated analysis

2021 ◽  
Vol 5 (8) ◽  
pp. 2137-2141
Author(s):  
Flora Peyvandi ◽  
Spero Cataland ◽  
Marie Scully ◽  
Paul Coppo ◽  
Paul Knoebl ◽  
...  
Keyword(s):  
Thrombotic Thrombocytopenic Purpura ◽  
Treatment Period ◽  
Statistical Power ◽  
Median Number ◽  
Integrated Analysis ◽  
Tolerability Profile ◽  
Efficacy And Safety ◽  
Thrombocytopenic Purpura ◽  
Count Response ◽  
The Individual

Abstract The efficacy and safety of caplacizumab in individuals with acquired thrombotic thrombocytopenic purpura (aTTP) have been established in the phase 2 TITAN and phase 3 HERCULES trials. Integrated analysis of data from both trials was conducted to increase statistical power for assessing treatment differences in efficacy and safety outcomes. Caplacizumab was associated with a significant reduction in the number of deaths (0 vs 4; P < .05) and a significantly lower incidence of refractory TTP (0 vs 8; P < .05) vs placebo during the treatment period. Consistent with the individual trials, treatment with caplacizumab resulted in a faster time to platelet count response (hazard ratio, 1.65; P < .001), a 72.6% reduction in the proportion of patients with the composite end point of TTP-related death, TTP exacerbation, or occurrence of at least 1 treatment-emergent major thromboembolic event during the treatment period (13.0% vs 47.3%; P < .001), and a 33.3% reduction in the median number of therapeutic plasma exchange days (5.0 vs 7.5 days) vs placebo. No new safety signals were identified; mild mucocutaneous bleeding was the main safety finding. This integrated analysis provided new evidence that caplacizumab prevents mortality and refractory disease in acquired TTP and strengthened individual trial findings, with a confirmed favorable safety and tolerability profile. These trials were registered at www.clinicaltrials.gov as #NCT01151423 and #NCT02553317.

Preemptive Rituximab Infusions Efficiently Prevent Relapses In Acquired Thrombotic Thrombocytopenic Purpura. Experience Of The French Thrombotic Microangiopathies Reference Center

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 448-448
Author(s):  
Miguel HIE ◽  
Julie Gay ◽  
Lionel Galicier ◽  
Francois Provot ◽  
Sandrine Malot ◽  
...  
Keyword(s):  
Thrombotic Thrombocytopenic Purpura ◽  
Median Number ◽  
Continuous Variables ◽  
Adamts13 Activity ◽  
Thrombocytopenic Purpura ◽  
History Of ◽  
Adamts13 Deficiency ◽  
Group 2 ◽  
Group 1

Context Acquired thrombotic thrombocytopenic purpura (TTP) results from a severe, antibody-mediated, deficiency in the von Willebrand factor-cleaving protease ADAMTS13. Rituximab is increasingly used in this indication in patients with a suboptimal response to plasma exchange. When severe acquired ADAMTS13 deficiency persists during remission, the estimated incidence rate is of 0.4/year. So far, it is still controversial whether preemptive rituximab efficiently prevents relapses in these patients. Patients and methods We defined two groups of patients with a history of acquired TTP who displayed a persistent severe ADAMTS13 deficiency during remission. Patients of group 1 were treated with preemptive infusions of rituximab. Patients of group 2 were managed in centers in which preemptive rituximab infusions were not the standard of care. The relapse incidence was evaluated and compared between both groups. Patients were treated according to National recommendations and enrolled from 12 French centers during a 12-year period. Patients were explored for ADAMTS13 activity and peripheral B-cell count every 3 months. Only patients with a > 12-month follow-up after rituximab administration are reported here. Median (25th - 75th percentile) was determined for all continuous variables. Wilcoxon’s test was used to compare continuous variables and the chi-square test or Fisher’s exact test to compare binary data. Relapse-free survival was compared between both groups using the Kaplan-Meier estimator with the corresponding 95% confidence interval. Results Forty-eight patients (20.6%) with a history of acquired TTP displayed a persistent severe ADAMTS13 deficiency on remission or experienced a subsequent severe ADAMTS13 deficiency (24 cases each) after a median follow-up of 17 months (12-29 months). Anti-ADAMTS13 antibodies concentration was 44 U/mL (24-59 U/mL). Thirty patients received preemptive infusions of rituximab (group 1), whereas 18 others had no therapeutical intervention (group 2). In group 1, 16 patients experienced a past history of TTP with a median number of 2 (1-3) episodes, corresponding to a relapse incidence of 0.22 (0-0.57)/year. Rituximab infusions were performed 14.5 months (6.5-27.4 months) after the last TTP episode. A median number of 4 (1-4) rituximab infusions were performed. The median follow-up between the first preemptive infusion of rituximab and the last ADAMTS13 evaluation is of 36 months (24-65 months). After preemptive rituximab administration, only 3 patients experienced a clinical relapse (0 [0] episode/year), corresponding to a significant reduction in the relapse incidence (P < .01). ADAMTS13 activity was 58.5% (30.5%-86.3%). Three months after the first rituximab infusion, ADAMTS13 activity was 46% (30-68); it further increased until the 12th month, and subsequently decreased. Accordingly, B-cell lymphocytes remained undetectable until the 6th month, and progressively increased at the 9th month to reach normal values at the 18th month. Nine patients (30%) required one (5 cases), two (2 cases), three (1 case) or ten (1 case) additional courses of rituximab for a further decrease or a persistent undetectable ADAMTS13 activity, which allowed to maintain a detectable ADAMTS13 activity in all but one patients. The time between two consecutive courses of rituximab was 26 months (5-59 months). At the end of follow-up, ADAMTS13 activity remained normal in 18 patients; 10 patients had a moderate ADAMTS13 deficiency, and 2 patients had a persistently undetectable ADAMTS13 activity. In four patients (13%), rituximab alone failed to increase durably ADAMTS13 activity, which required additional immunosuppressive drugs. In group 2, 14 patients relapsed after a 66-month follow-up (36-105 months), corresponding to a higher relapse incidence than in patients who received preemptive infusions of rituximab (0.23 [0.1-0.46] relapse/year, P<.01). Moreover, 2 patients died of TTP in group 2, whereas no fatal outcome was recorded in group 1. Relapse free survival over time was significantly longer in group 1 (Log-rank test: P = .049). Five patients experienced adverse effects including benign infections in 2 cases. Conclusion Rituximab efficiently prevents TTP relapses in most patients with a persistent acquired ADAMTS13 deficiency, with acceptable side effects. Disclosures: Off Label Use: Rituximab Rituximab may prevent relapses in acquired thrombotic thrombocytopenic purpura.

A 14-Year Experience in the Management of Patients with Acquired Immune Thrombotic Thrombocytopenic Purpura in Northern Israel

2015 ◽  
Vol 134 (3) ◽  
pp. 170-176 ◽  
Author(s):  
Nadav Rinott ◽  
Tatiana Mashiach ◽  
Netanel A. Horowitz ◽  
Liliana Schliamser ◽  
Galit Sarig ◽  
...  
Keyword(s):  
Thrombotic Thrombocytopenic Purpura ◽  
Median Number ◽  
Retrospective Evaluation ◽  
Thrombocytopenic Purpura ◽  
Major Benefit ◽  
Life Threatening ◽  
Complicated Course ◽  
Relapse Rates

Acquired idiopathic thrombotic thrombocytopenic purpura (I-TTP) is a life-threatening microangiopathic disorder usually treated with therapeutic plasma exchange (TPE). The current study assessed the role of rituximab in the treatment of complicated I-TTP. The sequence of TTP events was compared in a group of I-TTP patients treated with TPE and a cohort of refractory or relapsed patients who also received rituximab. This retrospective evaluation included 45 I-TTP patients, treated between January 2000 and October 2013, who underwent at least 3 TPE procedures and were followed up until December 2013 or death. Thirty-one patients with an uncomplicated course received TPE only. Fourteen patients had a complicated course due to either a primary refractory/exacerbated disease (n = 5) or relapse (n = 9) and received rituximab together with TPE. The median number of TPE procedures performed in the first TTP episode in the uncomplicated cohort and groups with primary refractory or relapsed TTP was 11, 27 and 45, respectively. The relapse rates per follow-up year in the uncomplicated I-TTP, primary refractory and relapsed I-TTP groups were 0.18, 0.2 and 0.6 episodes, respectively. After rituximab therapy this rate dropped to 0.2 per year in the relapsed subgroup. In conclusion, about a quarter of patients with I-TTP had a complicated course and experienced a major benefit from rituximab in terms of effectiveness and safety.

Normalisation of ADAMTS 13 Activity and Disappearance of ADAMTS 13 Antibody Following Rituximab in Acute Refractory Thrombotic Thrombocytopenic Purpura.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1230-1230
Author(s):  
Marie Scully ◽  
Jamie Cavenagh ◽  
Diane Hagger ◽  
Sylvia Benjamin ◽  
Ian Mackie ◽  
...  
Keyword(s):  
Thrombotic Thrombocytopenic Purpura ◽  
Intensive Therapy ◽  
Immunosuppressive Agents ◽  
Median Number ◽  
Primary Treatment ◽  
Infectious Complications ◽  
Igg Antibodies ◽  
Thrombocytopenic Purpura ◽  
Laboratory Parameters ◽  
Primary Treatment Modality

Abstract Thrombotic thrombocytopenic purpura (TTP) is a life threatening disorder characterised by thrombocytopenia and microangiopathic haemolytic anaemia associated with a deficiency in ADAMTS 13. Plasma exchange (PEX) remains the primary treatment modality in acute TTP, with various immunosuppressive agents (e.g. methylprednisolone, vincristine, ciclosporin (CSA)) and other disease modifying agents(e.g. defibrotide), added in refractory cases. However, mortality remains at 15–20%. Rituximab is a monoclonal CD 20 antibody, which acts specifically to clear peripheral B lymphocytes involved with antibody production. We have treated 15 patients with acute refractory TTP; 12 female and 3 male, with 2–8 weekly Rituximab infusions, 375mg/m2. Fourteen had neurological features and 3 had cardiac TTP at presentation. Patients received Rituximab because of progressive clinical disease or deterioration of laboratory parameters despite intensive therapy. On admission, median haemoglobin was 8.2 (range 5.1–12) g/dl, platelet count 14 (range 3–70) X 109/L, lactate dehydrogenase (LDH) 1620 (range 411–>2832) IU/L. All patients attained normal laboratory parameters and clinical remission within 22 days of starting Rituximab therapy. Three patients proceeded to further Rituximab based on ADAMTS 13 activity following 4 treatments. Twelve patients had initial ADAMTS 13 activities <5% (normal range (NR) 66–126% by collagen binding assay) and thirteen patients had normal ADAMTS 13 activity (median 78%) following Rituximab. IgG antibodies to ADAMTS 13 pre Rituximab were detected in thirteen patients but were undetectable post Rituximab. The median number of PEX pre Rituximab was 14 (1–35) and following the first Rituximab treatment, 6 (1–22), including weaning with an alternate day regime following clinical and laboratory remission. This difference was significant (p=0.042, Wilcoxon signed ranks test). To date (follow-up 1–27 months) there have been no TTP relapses. No significant decrease in CD 19 levels, immunoglobulin levels or infectious complications have been documented. These data suggest that patients with acute refractory TTP respond promptly to Rituximab, associated with a significant reduction in the requirement for PEX. Clinical and haematological remission was demonstrated and maintained within 3 weeks of Rituximab treatment in all patients. Only one patient failed to increment ADAMTS 13 activity. In all patients with IgG antibodies to ADAMTS 13, these disappeared within 28 days of Rituximab treatment. Rituximab therefore appears to be a safe, effective, targeted therapy for acute refractory TTP.

Clinical and Laboratory Features of Patients with Acquired Thrombotic Thrombocytopenic Purpura: Fourteen Years of the Milan TTP Registry

2019 ◽  
Vol 119 (05) ◽  
pp. 695-704 ◽  
Author(s):  
Ilaria Mancini ◽  
Silvia Pontiggia ◽  
Roberta Palla ◽  
Andrea Artoni ◽  
Carla Valsecchi ◽  
...  
Keyword(s):  
Plasma Exchange ◽  
Thrombotic Thrombocytopenic Purpura ◽  
Severe Disease ◽  
Age At Onset ◽  
Signs And Symptoms ◽  
Median Number ◽  
Cross Sectional Study ◽  
Interquartile Range ◽  
Cross Sectional ◽  
Thrombocytopenic Purpura

AbstractAcquired thrombotic thrombocytopenic purpura (TTP) is a rare thrombotic microangiopathy caused by the immune-mediated severe deficiency of ADAMTS13. We hereby report the demographic and disease-related data of acquired TTP patients recorded in the Milan TTP Registry (www.ttpdatabase.org). We performed a cross-sectional study of 302 individuals enrolled in our registry for an acute episode of acquired TTP occurred between 2002 and 2015 (female 77%; median age at onset 40 years, interquartile range: 30–50). Twenty per cent of patients had concomitant autoimmune disorders. Among potential triggers of acute episodes, infections were the most prevalent (27%), followed by estroprogestinics use and pregnancy (5 and 4% of women, respectively). At presentation, systemic (72%), bleeding (68%) and neurological (43%) symptoms were the most frequent, whereas a lower prevalence of renal (18%) and cardiovascular (10%) signs and symptoms was observed. Almost all acute events were treated by plasma exchange and steroids, and 15% by rituximab. Exacerbation of acute TTP occurred in 15% of events. The TTP-related mortality was 5%. In survivors, the median number of plasma exchange procedures to remission was 9 (interquartile range: 6–14), longer for first events than relapses (median difference 3, 95% confidence interval: 2–4). Of 251 survivors of the first TTP episode with at least a 6-month follow-up, 55% had a relapse. In conclusion, acquired TTP is a severe disease with highly variable clinical presentation, usually requiring a long hospitalization. The Milan TTP Registry represents a powerful tool to improve our knowledge and management of acquired TTP.

P0202FIRST REAL-LIFE DATA OF PATIENTS TREATED FOR THROMBOTIC THROMBOCYTOPENIC PURPURA FROM THE FRENCH THROMBOTIC MICROANGIOPATHIES NETWORK

2020 ◽  
Vol 35 (Supplement_3) ◽  
Author(s):  
Mehdi Maanaoui ◽  
Eric Maury ◽  
AUGUSTO Jean François ◽  
Jean Michel Halimi ◽  
Christelle Barbet ◽  
...  
Keyword(s):  
Platelet Count ◽  
Serum Creatinine ◽  
Plasma Exchange ◽  
Thrombotic Thrombocytopenic Purpura ◽  
Clinical Practices ◽  
Thrombotic Microangiopathies ◽  
Thrombocytopenic Purpura ◽  
Multicentric Study ◽  
Count Response ◽  
Reported Data

Abstract Background and Aims Caplacizumab, a bivalent Nanobody, targets the A1 domain of von Willebrand Factor, inhibiting the interaction between ultra-large vWF and platelets in the treament of Acquired Thrombotic Thrombocytopenic Purpura (aTTP). Results of the Phase 3 HERCULES study confirm that treatment with caplacizumab reduces the time to platelet count response, resulting in faster resolution of aTTP. Treatment with caplacizumab also resulted in a highly clinically meaningful reduction in aTTP-related death, recurrence of aTTP, or a major thromboembolic event during study drug treatment. Data from clinical practice confirming the clinical trial data is still scarce. We report here the first real world evidence collected in the French thrombotic microangiopathies network. Method Patients with an acute episode of aTTP were included in an observational prospective multicentric study. The diagnosis of aTTP was done according to the French score (platelet count &lt; 30 g/l and serum creatinine&lt; 200µmol/l) or ADAMTS13 activity if available. Adult patients were proposed to be treated with daily plasma exchange (PE) in addition to corticosteroid and frontline rituximab plus early initiation of caplacizumab. PE was stopped after 2 days of platelet count normalization. Results Fifty patients (36 females, median age of 46 years old) were treated for aTTP. 30 patients (60%) had cerebral involvement and 13 (26%) had cardiac involvement. Cardiac troponin I was above upper normal value for 61% of patients. Before treatment, median platelet count was 16 g/l and median serum creatinine was 86 µmol/l. Three initial clinical suspicions of aTTP were finally diagnosed as HUS (2 patients) or vitamin deficiency (1 patient) resulting in the stop of treatment. A median number of 6 plasma exchanges was administered (min:3 - max:16). 375mg/m rituximab injections (3 to 4 for 35/43 patients with reported data) were mostly initiated within 3 days after the first plasma exchange. Caplacizumab treatment was initiated early (37/42 patients with reported data within 2 days after 1st plasma exchange) with a total median duration of treatment of 33 days (min:18 - max:35). The median platelet count normalization was 5 days (min:4 - max:6). 6/41 (14,6%) experienced exacerbations. No deaths and no patients refractory to therapy were reported. Eight adverse events related to caplacizumab therapy were reported, all with good outcomes. Conclusion Concomitant start of additional treatments allow to target severe ADAMTS13 deficiency and platelet aggregation which causes early mortality. The clinical French score seems useful in clinical practices.

Sign in / Sign up

Export Citation Format

Share Document