Clinical case

Three months after delivery of her first child, an otherwise healthy 30-year-old female presented with headaches and generalized malaise. For 3 days, she had experienced vomiting, diarrhea, easy bruising, and truncal petechiae. Laboratory tests revealed a platelet count of 11 × 109/L, a hemoglobin of 5.9 g/dL, numerous schistocytes on the peripheral blood smear, elevated lactate dehydrogenase and bilirubin levels, an undetectable haptoglobin, and a normal creatinine and prothrombin time (PLASMIC score1  7/7 points). The diagnosis of immune-mediated thrombotic thrombocytopenic purpura (iTTP) was confirmed by ADAMTS13 activity < 5% of normal in the presence of a strong functional ADAMTS13 inhibitor (>>2 Bethesda units/mL). Therapeutic plasma exchange (TPE) with replacement of plasma, glucocorticoids, and folic acid were initiated on the day of admission. Clinical response and a stable platelet count > 150 × 109/L were achieved with 5 sessions of TPE. Because of the rapid clinical response, treatment did not include rituximab, which is part of first-line treatment in many centers. After discharge on day 7, steroids were tapered over 4 weeks and discontinued. Among patients who reached remission from a first episode of iTTP, what types of outpatient clinical follow-up and laboratory testing are recommended to minimize the risk of relapse?

Introduction

Overall survival of patients presenting with their first episode of iTTP has improved significantly with the introduction of TPE in the early 1990s, by supplementing TPE with immune suppression in the 2000s, and, recently, with caplacizumab, an anti–von Willebrand factor nanobody that effectively inhibits the interaction between von Willebrand factor multimers and platelets but does not address the autoimmune response to ADAMTS13. At least half of survivors of an initial iTTP episode experience subsequently relapse(s) that are again associated with morbidity and mortality. In this minireview, we aim to examine recent literature on predictors of relapse in survivors of an initial iTTP episode, formulate a recommendation for patient follow-up, and discuss the possibility of minimizing the risk of relapse by preemptive treatment with rituximab.

Demographic risk factors of iTTP relapse

There are several nonmodifiable demographic risk factors for iTTP relapse. A recent multicenter cohort study that incorporated 124 patients from 6 major academic centers in Boston and Seattle identified the following clinical predictors associated with iTTP relapse: age younger than 25 years (hazard ratio [HR], 2.94; 95% confidence interval [CI], 1.2-7.2), non-O blood group (HR, 2.15; 95% CI, 1.06-4.39), and a prior episode of iTTP (HR, 2.97; 95% CI, 1.4-6.4).2  In another study of 70 patients in Germany, male patients had a 1.5-fold increased risk for relapse compared with female survivors.3 

Longitudinal measurement of ADAMTS13 activity as a predictor of iTTP relapse

In a natural history study from the Oklahoma TTP Registry, the investigators assessed the association between remission ADAMTS13 activity measurement and subsequent relapse in 67 iTTP patients who had ADAMTS13 activity determination(s) during follow-up.4  In this study, ADAMTS13 activity < 10% at any point during remission was documented in 30% of patients. Eventual relapse occurred in 55% of patients within this group compared with only 4% of those who had persistent ADAMTS13 activity > 60% and 25% of those with fluctuating ADAMTS13 activity values > 10%. In patients with an ADAMTS13 activity < 10% during remission, the time to relapse ranged from 0.3 to 9.5 years. Thus, relapse was far from imminent for patients with low ADAMTS13 activity. In a subsequent retrospective cohort study from Italy, a similar association was reported between remission ADAMTS13 activity and relapse in 60 iTTP patients studied from 2002 to 2018.5  ADAMTS13 activity < 20% and anti-ADAMTS13 antibody > 15 AU/mL at the time of remission, after 3 months, and at 6 months significantly correlated with iTTP relapse. Similar to the previous study, there was considerable heterogeneity in remission ADAMTS13 activity, and many patients with normal levels during follow-up experienced a relapse. There is emerging evidence that low-normal or reduced ADAMTS13 activity during remission is associated with an increased risk for ischemic stroke outside of iTTP relapse.6  Based on the existing evidence, we believe that assessment of ADAMTS13 activity should be performed regularly for a minimum of 2 years after an acute iTTP episode; long-term or even lifelong assessment is preferable.

Preemptive rituximab strategy to prevent iTTP relapse

Over the past decade, preemptive rituximab therapy in iTTP patients with reappearing ADAMTS13 antibodies and severe ADAMTS13 deficiency in remission has shown promise (Table 1). In a retrospective study from France, preemptive rituximab use in 30 patients with ADAMTS13 < 10% led to an increase in ADAMTS13 activity (median, 46%) 3 months later, and the frequency of relapse decreased from 0.57 episodes per year (interquartile range [IQR], 0.46-0.7) to 0 episodes per year (IQR, 0-0.81; P < .01).7  In a subsequent prospective study of the same group that was carried out between 2012 and 2017, 92 patients were treated with preemptive rituximab at doses of 375 to 500 mg/m2 (1-4 infusions at the discretion of the treating physician) when ADAMTS13 remained at or dropped to <10% during remission. The median cumulative relapse incidence before and after treatment was 0.33 episodes per year (IQR, 0.23-0.66) and 0 episodes per year (IQR, 0-1.32; P < .01).8  The optimal dose and schedule of preemptive rituximab have not been determined. In a retrospective study from the United Kingdom, the investigators compared different weekly doses, administered for 4 weeks, of preemptive rituximab in 45 patients: 24 episodes were treated with 375 mg/m2, 17 episodes were treated with a fixed dose of 500 mg, and 19 episodes were treated with a fixed dose of 200 mg.9  There was no difference in the proportion of patients who had ADAMTS13 recovery, or subsequent relapse, however, the proportion of patients requiring retreatment was lower following standard-dose compared with reduced-dose regimens (Table 1).

Table 1.

Key studies for preemptive rituximab strategy in iTTP management

StudyPopulationWithout preemptive rituximabPreemptive rituximab treatment
Hie et al7  233 French iTTP patients with >1 y of follow-up (2000-2012). 48 had ADAMTS13 < 10% during follow-up; of these, 30 received preemptive rituximab, 375 mg/m2 (1, 2, or 4 infusions). TTP recurrence: 0.57 episodes per year (IQR, 0.46-0.70) At 3 mo posttreatment: ADAMTS13 recovery‡ in 87%. No TTP recurrence episode per year (IQR, 0-0.81). Subsequent retreatment with preemptive rituximab necessary in 30%. 
Retrospective* 
Jestin et al8  92 French iTTP patients with >1 y of follow-up (2012-2017). 92 with ADAMTS13 < 10% during follow-up. 92 received preemptive rituximab 375-500 mg/m2 (1-4 infusions). TTP recurrence: 0.33 episodes per year (IQR, 0.23-0.66) At 3 mo posttreatment: ADAMTS13 recovery‡ in 86%. No TTP recurrence episodes per year (IQR 0-1.32). Recurrence of ADAMTS13 < 10% in 45/79 (57%) patients. Subsequent retreatment with preemptive rituximab in 48% of patients. 
Prospective* 
Westwood et al9  45 British iTTP patients with 76 episodes of ADAMTS13 <= 15% (2005-2016) received preemptive rituximab: 375 mg/m2 (n = 24; 4 infusions) or 500-mg fixed dose (n = 17; 4 infusions), 200-mg fixed dose (n = 19; 4 infusions), or various dose regimens (n = 16) TTP recurrence incidence not reported At 1 mo posttreatment, ADAMTS13 recovery‡ in 92%. 20/45 (44.4%) patients received ≥ 2 preemptive treatments with rituximab. 
Retrospective† 
StudyPopulationWithout preemptive rituximabPreemptive rituximab treatment
Hie et al7  233 French iTTP patients with >1 y of follow-up (2000-2012). 48 had ADAMTS13 < 10% during follow-up; of these, 30 received preemptive rituximab, 375 mg/m2 (1, 2, or 4 infusions). TTP recurrence: 0.57 episodes per year (IQR, 0.46-0.70) At 3 mo posttreatment: ADAMTS13 recovery‡ in 87%. No TTP recurrence episode per year (IQR, 0-0.81). Subsequent retreatment with preemptive rituximab necessary in 30%. 
Retrospective* 
Jestin et al8  92 French iTTP patients with >1 y of follow-up (2012-2017). 92 with ADAMTS13 < 10% during follow-up. 92 received preemptive rituximab 375-500 mg/m2 (1-4 infusions). TTP recurrence: 0.33 episodes per year (IQR, 0.23-0.66) At 3 mo posttreatment: ADAMTS13 recovery‡ in 86%. No TTP recurrence episodes per year (IQR 0-1.32). Recurrence of ADAMTS13 < 10% in 45/79 (57%) patients. Subsequent retreatment with preemptive rituximab in 48% of patients. 
Prospective* 
Westwood et al9  45 British iTTP patients with 76 episodes of ADAMTS13 <= 15% (2005-2016) received preemptive rituximab: 375 mg/m2 (n = 24; 4 infusions) or 500-mg fixed dose (n = 17; 4 infusions), 200-mg fixed dose (n = 19; 4 infusions), or various dose regimens (n = 16) TTP recurrence incidence not reported At 1 mo posttreatment, ADAMTS13 recovery‡ in 92%. 20/45 (44.4%) patients received ≥ 2 preemptive treatments with rituximab. 
Retrospective† 

TTP, thrombotic thrombocytopenic purpura.

*

Treatment trigger: ADAMTS13 < 10%.

†Treatment trigger: ADAMTS13 ≤ 15%. In 2 instances, treatment was initiated when ADAMTS13 activity was 16% and 17%.

‡ADAMTS13 recovery was reported differently in the 3 studies: In Hie et al,7  median ADAMTS13 activity at 3 months was 46% (IQR, 30-68). Jestin et al8  documented ADAMTS13 activity in 76 of 79 patients; it was normal in 56% (42/76) of patients and moderately decreased in 30% (23/76) of patients. In Westwood et al,9  ADAMTS13 ≥ 30% in 70/76 (92%) episodes; complete remission as ADAMTS13 activity ≥ 60% in 60/76 (79%) episodes, and partial remission as ADAMTS13 activity in 30% to 59% in 10/76 (13%) episodes.

Summary

Based on recent key publications, we have reviewed the clinical predictors and biomarkers of iTTP relapse after remission, as well as the utility of preemptive rituximab therapy when ADAMTS13 deficiency reappears (Table 2). To minimize the risk of overt clinical relapse and the associated risk for morbidity and mortality, we recommend regular measurement of ADAMTS13 activity, and preemptive rituximab treatment should be discussed with the patient as soon as remission ADAMTS13 activity drops to 10% to 20% (grade 1B). Although a standard-dose regimen of rituximab was used in most studies, a single dose (375 mg/m2), with ADAMTS13 activity measured 4 weeks later, can be considered (grade 2C). After preemptive rituximab, resumption of follow-up with regular ADAMTS13 determination is advised. Routine medical care, cardiovascular risk reduction, and depression screening are beyond the scope of this minireview.

Table 2.

Recommendations for postremission laboratory surveillance and preemptive treatment of patients with iTTP

Timing of follow-upADAMTS13 activity and CBCPreemptive rituximab
First 3 mo after stopping TPE ADAMTS13 monthly; CBC every 1-2 wk until steroids have been discontinued and then monthly Consider treatment when ADAMTS13 activity drops to 10-20% during follow-up in remission 
3 to 24 mo Every 3 mo Optimal dose and schedule have not been determined; most studies have used the standard regimen for B-cell neoplasia (375 mg/m2 per wk for 4 wk). 
24 to 60 mo Continue every 3 mo or extend interval to every 6-12 mo* Associated favorable risk-benefit ratio. 
61+ mo No evidence, but recommend ongoing (yearly) surveillance*  
Timing of follow-upADAMTS13 activity and CBCPreemptive rituximab
First 3 mo after stopping TPE ADAMTS13 monthly; CBC every 1-2 wk until steroids have been discontinued and then monthly Consider treatment when ADAMTS13 activity drops to 10-20% during follow-up in remission 
3 to 24 mo Every 3 mo Optimal dose and schedule have not been determined; most studies have used the standard regimen for B-cell neoplasia (375 mg/m2 per wk for 4 wk). 
24 to 60 mo Continue every 3 mo or extend interval to every 6-12 mo* Associated favorable risk-benefit ratio. 
61+ mo No evidence, but recommend ongoing (yearly) surveillance*  

CBC, complete blood count.

*

The patient’s preference has to be taken into account; consider demographic risk factors of relapsing courses2,3  in decision making.

†Other doses and <4 weekly infusions of rituximab may be effective in normalizing ADAMTS13 activity. Administration of 1 rituximab infusion (fixed or body weight–adapted dose), followed by re-measurement of ADAMTS13 activity after 1 month, is an alternative approach. However, according to Jestin et al,8  the median time to first retreatment in patients receiving 4 rituximab infusions was 40 months (IQR, 18.1-57) compared with 18.9 months (IQR, 14.3-26) and 18.1 mo (IQR, 11.3-22) in those receiving 2 or 1 infusion(s), respectively (P = 0.01). Similarly, Westwood et al9  documented a lower incidence rate for retreatment following preemptive rituximab in standard-dose regimens (0.17 per year) compared with reduced-dose regimens (0.38 per year) (P = 0.039).

Correspondence

Johanna A Kremer Hovinga, Department of Hematology and Central Hematology Laboratory, Inselspital, CH-3010 Bern, Switzerland; email: johanna.kremer@insel.ch.

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Competing Interests

Conflict-of-interest disclosure: J.A.K.H. has received research funding from Baxalta US Inc. (now part of Takeda) and is a member of advisory boards for Shire (now part of Takeda) and Ablynx (now part of Sanofi). A.L. has received research funding support from the Cancer Prevention and Research Institute of Texas (RR190104), the Hemostasis and Thrombosis Research Society (Mentored Research Award) supported by an independent medical educational grant from Shire, and National Hemophilia Foundation Shire Clinical Fellowship Award.

Author notes

Off-label drug use: None disclosed.