Race, rituximab, and relapse in TTP.

Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is characterized by recurring episodes of thrombotic microangiopathy, causing ischemic organ impairment. Black patients are overrepresented in iTTP cohorts in the United States, but racial disparities in iTTP outcome and response to therapy have not been studied. Using the United States Thrombotic Microangiopathies Consortium iTTP Registry, we evaluated the impact of race on mortality and relapse-free survival (RFS) in confirmed iTTP in the United States from 1995 to 2020. We separately examined the impact of rituximab therapy and presentation with newly diagnosed (de novo) or relapsed iTTP on RFS by race. A total of 645 participants with 1308 iTTP episodes were available for analysis. Acute iTTP mortality did not differ by race. When all episodes of iTTP were included, Black race was associated with shorter RFS (hazard ratio [HR], 1.60; 95% CI, 1.16-2.21); the addition of rituximab to corticosteroids improved RFS in White (HR, 0.37; 95% CI, 0.18-0.73) but not Black patients (HR, 0.96; 95% CI, 0.71-1.31). In de novo iTTP, rituximab delayed relapse, but Black patients had shorter RFS than White patients, regardless of treatment. In relapsed iTTP, rituximab significantly improved RFS in White but not Black patients. Race affects overall relapse risk and response to rituximab in iTTP. Black patients may require closer monitoring, earlier retreatment, and alternative immunosuppression after rituximab treatment. How race, racism, and social determinants of health contribute to the disparity in relapse risk in iTTP deserves further study.

Real-world safety and effectiveness of recombinant porcine sequence factor VIII in acquired haemophilia A: A non-interventional, post-authorization safety study.

INTRODUCTION: Recombinant porcine factor VIII (rpFVIII, susoctocog alfa) is indicated for the treatment of bleeding episodes in adults with acquired haemophilia A (AHA). AIM: To provide long-term real-world safety and effectiveness data for rpFVIII in the management of AHA bleeding episodes. METHODS: US PASS (NCT02610127) was a multicentre, uncontrolled, open-label, post-marketing safety surveillance study conducted in adults with AHA. Data were collected retrospectively or prospectively for 180 days after rpFVIII treatment. The primary outcome was the incidence of treatment-related serious adverse events (SAEs). Secondary outcomes included haemostatic effectiveness of rpFVIII and rpFVIII utilization. RESULTS: Fifty-three patients were enrolled from December 2015 to June 2019 (prospective, n = 30; retrospective, n = 23). Six patients experienced seven treatment-related SAEs (incidence 12.0%). The most common treatment-related SAE was FVIII inhibition (inhibiting antibodies to rpFVIII; incidence 8.0%, 95% CI: 2.2-19.2). Five patients reported seven thromboembolic events; one was an SAE and possibly related to rpFVIII. Of bleeding events treated with rpFVIII, 80.3% (57/71) of bleeds resolved with rpFVIII. The median (range) dose of rpFVIII per infusion was 50 (10-300) units/kg, with a median (range) of 6.0 (1-140) infusions and a median (range) time from bleed onset to bleed resolution of 14.0 (2.0-132.7) days. CONCLUSION: In this real-world study of rpFVIII for AHA, no new safety signals were identified compared with previous clinical trial findings. Eighty percent of bleeds resolved with rpFVIII treatment.

Caplacizumab Treatment for Acquired Thrombotic Thrombocytopenic Purpura.

BACKGROUND: 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. METHODS: In this double-blind, controlled trial, we randomly assigned 145 patients with TTP 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 normalization of the platelet count, with discontinuation of daily plasma exchange within 5 days thereafter. Key secondary outcomes included a composite of TTP-related death, recurrence of TTP, or a thromboembolic event during the trial treatment period; recurrence of TTP at any time during the trial; refractory TTP; and normalization of organ-damage markers. RESULTS: 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. CONCLUSIONS: 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. (Funded by Ablynx; HERCULES ClinicalTrials.gov number, NCT02553317 .).

Safety and tolerability of solvent/detergent-treated plasma for pediatric patients requiring therapeutic plasma exchange: An open-label, multicenter, postmarketing study.

BACKGROUND: This study investigated the real-world safety and tolerability of solvent/detergent-treated (S/D) plasma for pediatric patients requiring therapeutic plasma exchange (TPE). STUDY DESIGN AND METHODS: LAS-213 was a multicenter, open-label, interventional, phase 4 study. Patients (≥2 to ≤20 years) receiving TPE therapy were eligible. A total plasma volume of 40-60 ml/kg was recommended, with an infusion rate not exceeding 0.020-0.025 citrate/kg body weight/min (<1 ml/kg body weight/min). The primary endpoint was assessment of safety, monitoring the following: serious adverse events (SAEs), adverse drug reactions (ADRs), thrombotic events (TEs), thromboembolic events (TEEs), and specific laboratory tests. RESULTS: In total, 41 children (2 to <12 years [n = 15]; 12 to <17 years [n = 13]; ≥17 years [n = 13]) underwent 102 TPEs with a total of 135,137 ml of S/D plasma exchanged. Each patient group received between 1 and 6 TPEs (mean: 2.5 TPEs). Actual dose administered per TPE was 4-72 ml/kg (mean: 28.6 ml/kg), with a mean total volume of 1324.9 ml (range: 113-4000 ml). Overall safety was excellent for 96/102 (94.0%) TPEs. Six TPEs had a "moderate" safety profile for four patients experiencing eight ADRs. Of these, seven were mild in intensity and one (pyrexia) was moderate, all resolving by study end. Mild citrate toxicity (n = 2) was the most common ADR. One SAE was reported but was unrelated to the study drug. No TEs, TEEs, or changes in laboratory safety parameters were reported. CONCLUSION: S/D plasma was well tolerated and demonstrated favorable safety, supporting the use of S/D plasma for TPE in pediatrics.

Ex vivo assays to detect complement activation in complementopathies.

In complement-driven thrombotic microangiopathies, failure to regulate complement activation leads to end-organ damage. The modified Ham (mHam) test measures complement-mediated killing of a nucleated cell in vitro but lacks a confirmatory assay and reliable positive controls. We demonstrate that C5b-9 accumulation on the surface of TF1 PIGAnull cells correlates with cell killing in the mHam. We also show that Sialidase treatment of cells or addition of Shiga toxin 1 to human serum serve as a more reliable positive control for the mHam than cobra venom factor or lipopolysaccharide. Simultaneously performing the mHam and measuring C5b-9 accumulation either in GVB++ or GVB0 MgEGTA buffer with the addition of complement pathway specific inhibitors (anti-C5 antibody or a factor D inhibitor, ACH-145951) can be used to localize defects in complement regulation. As more targeted complement inhibitors become available, these assays may aid in the selection of personalized treatments for patients with complement-mediated diseases.

A rare CALR variant mutation and a review of CALR in essential thrombocythemia.

Essential thrombocythemia (ET) is an indolent myeloproliferative neoplasm characterized by megakaryocyte hyperplasia, thrombocytosis, thrombotic and hemorrhagic complications, and potential transformation into myelofibrosis and acute myeloid leukemia. The vast majority of cases are driven by a somatic mutation in JAK2, CALR, or MPL. CALR, a gene that codes for the calcium-binding chaperone calreticulin, is the predominant mutation in patients with non-mutated JAK2 essential thrombocythemia, accounting for 20-25% of the overall somatic mutation frequency in ET. In this brief review of ET, we introduce a rare CALR mutation through a case presentation of a 58-year-old man with diffuse pulmonary emboli in the setting of thrombocytosis. We subsequently characterize the main types of CALR mutations and their value in diagnosis and prognosis of disease course, and lastly discuss the current clinical approach to ET.

Indications for and outcomes of therapeutic plasma exchange after cardiac transplantation: A single center retrospective study.

INTRODUCTION: Limited data are available describing indications for and outcomes of therapeutic plasma exchange (TPE) in cardiac transplantation. METHODS: In a retrospective study of patients who underwent cardiac transplantation at Duke University Medical Center from 2010 to 2014, we reviewed 3 TPE treatment patterns: a Single TPE procedure within 24 h of transplant; Multiple TPE procedures initiated within 24 h of transplant; and 1 or more TPE procedures beginning >24 h post-transplant. Primary and secondary outcomes were overall survival (OS) and TPE survival (TS), respectively. RESULTS: Of 313 patients meeting study criteria, 109 (35%) underwent TPE. TPE was initiated in 82 patients within 24 h, 40 (37%) receiving a single procedure (Single TPE), and 42 (38%) multiple procedures (Multiple TPE). Twenty-seven (25%) began TPE >24 h after transplant (Delayed TPE). The most common TPE indication was elevated/positive panel reactive or human leukocyte antigen antibodies (32%). With a median follow-up of 49 months, the non-TPE treated and Single TPE cohorts had similar OS (HR 1.08 [CI, 0.54, 2.14], P = .84), while the Multiple and Delayed TPE cohorts had worse OS (HR 2.62 [CI, 1.53, 4.49] and HR 1.98 [CI, 1.02, 3.83], respectively). The Multiple and Delayed TPE cohorts also had worse TS (HR 2.59 [CI, 1.31, 5.14] and HR 3.18 [CI, 1.56, 6.50], respectively). Infection rates did not differ between groups but was independently associated with OS (HR 2.31 [CI, 1.50, 3.54]). CONCLUSIONS: TPE is an important therapeutic modality in cardiac transplant patients. Prospective studies are needed to better define TPE's different roles in this patient population.

Novel therapeutic approaches for thrombotic thrombocytopenic purpura.

PURPOSE OF REVIEW: Acquired thrombotic thrombocytopenic purpura is an immune-mediated thrombotic microangiopathy caused by antibodies to ADAMTS13 (A Disintegrin And Metalloproteinase with a ThromboSpondin type 1 motif, member 13). Standard treatment with therapeutic plasma exchange and immunosuppression with steroids results in high remission and low mortality rates. However, a number of patients remain refractory to frontline therapy and/or experience multiple relapses. This study reviews emerging therapies for thrombotic thrombocytopenic purpura. RECENT FINDINGS: Studies indicate that reducing anti-ADAMTS13 antibody levels through B-cell depletion or proteasome inhibition is effective for the management of refractory disease. Preliminary reports examining anti-CD20 therapy for the treatment of initial disease or as maintenance therapy for seropositive patients suggest the addition of immunosuppression in other disease phases may delay relapse. Exciting developments in targeted therapies to von Willebrand Factor and recombinant ADAMTS13 hold promise for transforming disease management. SUMMARY: Approximately half of patients diagnosed with acquired thrombotic thrombocytopenic purpura experience refractory and/or relapsing disease. For these patients, a hematologic remission may be an insufficient therapeutic goal. With recent developments, it is now possible to envision a multifaceted approach targeting disease mechanisms that may dramatically improve outcomes for this otherwise debilitating disease.

rVWF: treatment finally reaches the modern age.

In this issue of Blood, Gill et al describe the results of the first phase 3 clinical trial evaluating recombinant von Willebrand factor (rVWF) for the treatment of hemorrhagic events in all patients with von Willebrand disease (VWD).

The thrombotic microangiopathy Registry of North America: A United States multi-institutional TMA network.

The thrombotic microangiopathy (TMA) Registry Network of North America (TRNA) is a collaborative network organized for the purpose of developing a multi-institutional registry and network to conduct clinical studies in a rare patient population. The TRNA was founded in 2013 by four academic medical centers (Columbia University Medical Center, Duke University Medical Center, University of Alabama at Birmingham, and University of Pennsylvania) to develop a national and demographically diverse dataset of patients with TMA. A clinical database was developed by network members using REDCap (Research Electronic Data Capture), a web-based database developed for clinical research. To facilitate rapid Institutional Review Board (IRB) approval at multiple sites, the TRNA utilized IRBshare, a streamlined IRB process to allow patient recruitment and enrollment into the TMA registry. This article reviews the process used to establish the TRNA network and discusses the significance of the first multi-institutional clinical apheresis network developed in the United States. J. Clin. Apheresis 31:448-453, 2016. © 2015 Wiley Periodicals, Inc.

A machine learning approach to predict mortality due to immune-mediated thrombotic thrombocytopenic purpura.

Background: Mortality due to immune-mediated thrombotic thrombocytopenic purpura (iTTP) remains significant. Predicting mortality risk may potentially help individualize treatment. The French Thrombotic Microangiopathy (TMA) Reference Score has not been externally validated in the United States. Recent advances in machine learning technology can help analyze large numbers of variables with complex interactions for the development of prediction models. Objectives: To validate the French TMA Reference Score in the United States Thrombotic Microangiopathy (USTMA) iTTP database and subsequently develop a novel mortality prediction tool, the USTMA TTP Mortality Index. Methods: We analyzed variables available at the time of initial presentation, including demographics, symptoms, and laboratory findings. We developed our model using gradient boosting machine, a machine learning ensemble method based on classification trees, implemented in the R package gbm. Results: In our cohort (n = 419), the French score predicted mortality with an area under the receiver operating characteristic curve of 0.63 (95% CI: 0.50-0.77), sensitivity of 0.35, and specificity of 0.84. Our gradient boosting machine model selected 8 variables to predict acute mortality with a cross-validated area under the receiver operating characteristic curve of 0.77 (95% CI: 0.71-0.82). The 2 cutoffs corresponded to sensitivities of 0.64 and 0.50 and specificities of 0.76 and 0.87, respectively. Conclusion: The USTMA Mortality Index was acceptable for predicting mortality due to acute iTTP in the USTMA registry, but not sensitive enough to rule out death. Identifying patients at high risk of iTTP-related mortality may help individualize care and ultimately improve iTTP survival outcomes. Further studies are needed to provide external validation. Our model is one of many recent examples where machine learning models may show promise in clinical prediction tools in healthcare.

Validation of the high-dose heparin confirmatory step for the diagnosis of heparin-induced thrombocytopenia.

The diagnosis of heparin-induced thrombocytopenia (HIT) requires detection of antibodies to the heparin/platelet factor 4 (PF4) complexes via enzyme-linked immunosorbent assay. Addition of excess heparin to the sample decreases the optical density by 50% or more and confirms the presence of these antibodies. One hundred fifteen patients with anti-heparin/PF4 antibodies detected by enzyme-linked immunosorbent assay were classified as clinically HIT-positive or HIT-negative, followed by confirmation with excess heparin. A multivariate logistic regression model was fitted to estimate relationships between patient characteristics, laboratory findings, and clinical HIT status. This model was validated on an independent sample of 97 patients with anti-heparin/PF4 antibodies. No relationship between age, race, or sex and clinical HIT status was found. Maximal optical density and confirmatory positive status independently predicted HIT in multivariate analysis. Predictive accuracy on the training set (c-index 0.78, Brier score 0.17) was maintained when the algorithm was applied to the independent validation population (c-index 0.80, Brier score 0.20). This study quantifies the clinical utility of the confirmatory test to diagnose HIT. On the basis of data from the heparin/PF4 enzyme-linked immunosorbent assay and confirmatory assays, a predictive computer algorithm could distinguish patients likely to have HIT from those who do not.

Long-term follow-up of patients treated with caplacizumab and safety and efficacy of repeat caplacizumab use: Post-HERCULES study.

INTRODUCTION: Caplacizumab demonstrated efficacy and safety in patients with immune-mediated thrombotic thrombocytopenic purpura (iTTP) in the phase 3 HERCULES trial. However, data on long-term outcomes following caplacizumab treatment are limited. OBJECTIVES: The post-HERCULES trial (NCT02878603) evaluated long-term outcomes of patients with iTTP treated with caplacizumab in HERCULES and safety and efficacy of repeated caplacizumab use. PATIENTS/METHODS: Over 3 years of follow-up, patients could receive open-label caplacizumab with therapeutic plasma exchange (TPE) and immunosuppressive therapy (IST) in case of recurrence. Adverse events (AEs) were assessed during the overall study period (intention-to-observe [ITO] population) and during recurrences (recurrence population). TTP-related events (TTP-related death, recurrence, major thromboembolic events) were assessed in the efficacy ITO population (patients without recurrence during HERCULES or before post-HERCULES). RESULTS: Among 104 enrolled patients, incidences of AEs and serious AEs were similar between patients who had received caplacizumab + TPE + IST during HERCULES (n = 75) and those treated with placebo + TPE + IST (placebo; n = 29). TTP-related events occurred in 8% of patients (4/49) randomized to caplacizumab during HERCULES versus 38% (11/29) randomized to placebo. Nineteen patients had ≥1 recurrence; 13 of these were treated with caplacizumab. The first recurrence episode was resolved or resolving for all patients treated with caplacizumab, including nine patients with repeat caplacizumab use. All second recurrences (6/6) were resolved. Safety profile of caplacizumab for treatment of recurrence was consistent with HERCULES; most bleeding events were nonserious. No major cases of organ dysfunction were observed. CONCLUSIONS: Long-term follow-up supports the safety and efficacy of caplacizumab for iTTP and its repeated use for recurrences.

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

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.

Caplacizumab in adult patients with acquired thrombotic thrombocytopenic purpura.

Thrombotic thrombocytopenic purpura (TTP) is usually a fatal disease caused by a deficiency of the metalloproteinase, ADAMTS13, often due to autoimmunity. This leads to the development of pathogenic multimers of von Willebrand factor (vWF), causing an inappropriate interaction of platelets and vWF. This results in a thrombotic microangiopathy, which is treated with therapeutic plasma exchange and immune suppression. Although this treatment has reduced the mortality of TTP to only about 20%, there have been no recent significant advances in the treatment of TTP. Recently, a novel agent has been approved for use in TTP. Caplacizumab, which binds to the A1 domain of vWF, prevents the adhesion of platelets to vWF. It is a first in-class 'nanobody', that in clinical trials has shown marked efficacy in treating TTP and its complications. This review will discuss the development and implications of caplacizumab in the treatment of TTP.

Efficacy and safety of open-label caplacizumab in patients with exacerbations of acquired thrombotic thrombocytopenic purpura in the HERCULES study.

BACKGROUND: Acquired thrombotic thrombocytopenic purpura (aTTP) is a rare, life-threatening autoimmune thrombotic microangiopathy. Caplacizumab, an anti-von Willebrand Factor Nanobody® , is effective for treating aTTP episodes and is well tolerated. OBJECTIVES AND METHODS: In the phase 3 HERCULES trial (NCT02553317), patients with aTTP received double-blind caplacizumab or placebo during daily therapeutic plasma exchange (TPE) and for ≥30 days thereafter. Patients who experienced an exacerbation while on blinded study drug treatment switched to receive open-label caplacizumab plus re-initiation of daily TPE. Exacerbations were defined as recurrence of disease occurring within 30 days after cessation of daily TPE. RESULTS: 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%). CONCLUSIONS: 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.