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Table 1.  

Clinical feature No relapse (n = 312, 70.4%) Relapse (n = 131, 29.6%) P
Duration of follow-up (IQR), y 8.4 (5.7–10.4) 8.7 (5.6–10.9) .39
Age at presentation, y 45.0 45.1 .49
Age <25 y at presentation, n (%) 27 (8.7) 11 (8.4) .93
Gender (male/female), n (%) 79 (25.3)/233 (74.7) 43 (32.8)/88 (67.2) .11
Blood counts at presentation
   Hemoglobin, g/L 82 95 <.001
   Platelets, ×109/L 20 34 <.001
   Absolute reticulocytes, ×109/L 158 159 .95
Ethnicity, n (%) .019
   Caucasian 197 (63.1) 69 (52.7)
   Black African 32 (10.2) 13 (9.9)
   Black Caribbean 22 (7.1) 22 (16.8)
   Asian 26 (8.3) 14 (10.7)
   Mixed 5 (1.6) 4 (3.1)
   Other 6 (1.9) 3 (2.3)
   Unknown 24 (7.7) 6 (4.6)
Associated conditions, n (%) <.001
   Idiopathic 202 (64.7) 87 (66.4)
   HIV 17 (5.4) 3 (2.3)
   Drug-induced 5 (1.6) 0 (0)
   Other autoimmune disease 51 (16.3) 27 (20.6)
   Pancreatitis 11 (3.5) 0 (0)
   Pregnancy 10 (3.2) 8 (6.1)
   Other 16 (5.1) 7 (5.3)
Treatment at acute presentation, n (%)
   Corticosteroid 267 (85.6) 116 (88.5) .97
   Rituximab 169 (54.2)
   Mycophenolate mofetil 2 (0.6) 0
   Caplacizumab 7 (2.2) 3 (2.3)

Table 1. Clinical features and treatment of patients according to relapse status after acute presentation

Table 2.  

Demographics Frequent relapses (n = 28) Infrequent relapses (n = 103) P
Duration of follow-up (IQR), y 7.8 (4.4–9.5) 9.1 (6.5–11.1) .02
Age at initial presentation, y (range) 48.9 (38.4–53.2) 44.0 (32.8–54.3) .36
Age <25 y at presentation, n (%) 2 (7.1) 9 (8.7) .27
Gender (male/female), n (%) 9 (32.1)/19 (67.9) 34 (33.0)/69 (67.0) .93
Ethnicity, n (%) <.001
   Caucasian 13 (46) 56 (54)
   Black African 5 (17) 7 (7)
   Black Caribbean 6 (21) 11 (11)
   Asian 2 (7) 12 (12)
   Mixed 1 (4) 3 (3)
   Other 1 (4) 2 (2)
   Unknown 0 (0) 6 (6)
Treatment at acute presentation, n (%)
   Corticosteroid 24 (86) 86 (83)
   Rituximab 16 (57) 60 (58)
   Mycophenolate mofetil 0 (0) 1 (1)
   Caplacizumab 0 (0) 3 (3)

Table 2. Clinical features of patients according to relapse frequency

Table 3.  

Blood parameter Before treatment (range) Remission (range) Δ Change (range) P
Hemoglobin (g/L) 133 (122–145) 136 (125–150) 2 (−2 to 8) .19
Reticulocytes (×109/L) 60.2 (46.1–82.3) 57.1 (45.0–79.8) −0.7 (−12.3 to 9.3) .41
Platelets (×109/L) 254 (203–297) 272 (230–308) 18 (0–43) <.001
Lactate dehydrogenase (IU/L) 209 (179–243) 191 (171–215) −19 (−43 to 7) .0008
ADAMTS13 activity (%) 9.2 (5.0–14.0) 86.6 (66.2–100.5) 76.0 (60.6–89.0) <.001
Absolute no. CD19+ lymphocytes (×109/L) 0.2 (0.1–0.3) 0 (0–0) −0.1 (−0.3 to −0.1) <.001
CD19+ lymphocyte proportion (%) 10.8 (6.5–16.4) 0.1 (0–0.2) −11 (−15.1 to 6.6) <.001

Table 3. Laboratory parameters in patients receiving anti-CD20 treatment for ADAMTS13 relapse of TTP

Table 4.  

Clinical feature Complete response (n = 149) Partial response (n = 22) Minimal response (n = 6) P
Age at treatment, y 46.6 55.8 59.0 <.001
Gender (male/female), n 45/104 8/14 4/2 .16
Ethnicity, n .09
   Caucasian 50 8 2
   Black African 16 4 4
   Black Caribbean 36 3 0
   Asian 21 3 0
   Mixed 2 0 0
   Other 6 0 0
   Unknown 18 4 0
Median no. of rituximab doses 4 4 4
Median dose of rituximab per cycle (mg) 500 500 500
Median total dose of rituximab (mg) 2000 1500 2000
Absolute no. CD19+ lymphocytes (×109/L) 0.001 0.002 0 .05
CD19+ lymphocyte proportion (%) 0.05 0.07 0.02 .33

Table 4. Clinical demographics, anti-CD20 therapy dosing, and CD19+ lymphocytes according to treatment response by ADAMTS13 activity

CME / ABIM MOC

Long-Term Risk of Relapse in Immune-Mediated Thrombotic Thrombocytopenic Purpura and the Role of Anti-CD20 Therapy

  • Authors: Andrew James Doyle, MD; Matthew James Stubbs, MD, PhD; Tina Dutt, MD, PhD; William A. Lester, MD; Will Thomas, MD; Joost J. van Veen, MD; Joannes Hermans, MD; Tanya Cranfield, MD; Quentin A. Hill, MD; Amanda Clark, MD; Catherine Bagot, MD; Steven Kenneth Austin, MD; John-Paul Westwood, MD(Res); Mari Thomas, MD, PhD; Marie Scully, MD
  • CME / ABIM MOC Released: 1/24/2023
  • Valid for credit through: 1/24/2024
Start Activity

  • Credits Available

    Physicians - maximum of 1.00 AMA PRA Category 1 Credit(s)™

    ABIM Diplomates - maximum of 1.00 ABIM MOC points

    You Are Eligible For

    • Letter of Completion
    • ABIM MOC points

Target Audience and Goal Statement

This activity is intended for hematologists, internists, and other clinicians caring for patients with immune-mediated thrombotic thrombocytopenic purpura (iTTP).

The goal of this activity is for learners to be better able to describe patient characteristics linked to iTTP relapse, relapse rates and patterns, and response to anti-cluster of differentiation (CD)20 therapy in persons with ADAMTS13 relapses (ADAMTS13 activity < 20% without thrombocytopenia), according to a study of 443 patients with iTTP relapses having > 3 years' follow-up over a 10-year period in the United Kingdom.

Upon completion of this activity, participants will:

  • Describe patient characteristics linked to Immune-mediated thrombotic thrombocytopenic purpura (iTTP) relapse and the rates and patterns of relapse, according to a study of 443 patients with iTTP relapses having > 3 years' follow-up over a 10-year period in the United Kingdom
  • Determine clinical features during ADAMTS13 relapses and response to anti-cluster of differentiation (CD)20 therapy in persons with ADAMTS13 relapses, according to a study of 443 patients with iTTP relapses having > 3 years' follow-up over a 10-year period in the United Kingdom
  • Identify clinical implications of patient characteristics linked to iTTP relapse, relapse rates and patterns, and response to anti-CD20 therapy in persons with ADAMTS13 relapses, according to a study of 443 patients with iTTP having > 3 years' follow-up over a 10-year period in the United Kingdom


Disclosures

Medscape, LLC requires every individual in a position to control educational content to disclose all financial relationships with ineligible companies that have occurred within the past 24 months. Ineligible companies are organizations whose primary business is producing, marketing, selling, re-selling, or distributing healthcare products used by or on patients.

All relevant financial relationships for anyone with the ability to control the content of this educational activity are listed below and have been mitigated according to Medscape policies. Others involved in the planning of this activity have no relevant financial relationships.


Faculty

  • Andrew James Doyle, MD

    University College London Hospitals NHS Foundation Trust
    Guy’s & St Thomas NHS Foundation Trust
    London, United Kingdom

     

  • Matthew James Stubbs, MD, PhD

    University College London Hospitals NHS Foundation Trust
    London, United Kingdom

     

  • Tina Dutt, MD, PhD

    Liverpool University Hospitals NHS Foundation Trust
    Liverpool, United Kingdom

     

  • William A. Lester, MD

    University Hospitals Birmingham NHS Foundation Trust
    Birmingham, United Kingdom

     

  • Will Thomas, MD

    Cambridge University Hospitals NHS Foundation Trust
    Cambridge, United Kingdom

     

  • Joost J. van Veen, MD

    Sheffield Teaching Hospitals NHS Trust
    Sheffield, United Kingdom

     

  • Joannes Hermans, MD

    Nottingham University Hospitals NHS Trust
    Nottingham, United Kingdom

     

  • Tanya Cranfield, MD

    Portsmouth Hospitals University NHS Trust
    Portsmouth, United Kingdom

     

  • Quentin A. Hill, MD

    Leeds Teaching Hospitals NHS Trust
    Leeds, United Kingdom

     

  • Amanda Clark, MD

    University Hospitals Bristol NHS Foundation Trust
    Bristol, United Kingdom

     

  • Catherine Bagot, MD

    Glasgow and Greater Clyde NHS Trust
    Glasgow, United Kingdom

     

  • Steven Kenneth Austin, MD

    Guy’s & St Thomas NHS Foundation Trust
    St George’s University Hospital NHS Foundation Trust
    London, United Kingdom

     

  • John-Paul Westwood, MD(Res)

    University College London Hospitals NHS Foundation Trust, London
    Cardiometabolic Programme
    University College London Hospitals Biomedical Research Centre
    National Institute for Health Research
    London, United Kingdom

     

  • Mari Thomas, MD, PhD

    University College London Hospitals NHS Foundation Trust, London
    Cardiometabolic Programme
    University College London Hospitals Biomedical Research Centre
    National Institute for Health Research
    London, United Kingdom

  • Marie Scully, MD

    University College London Hospitals NHS Foundation Trust
    Cardiometabolic Programme
    University College London Hospitals Biomedical Research Centre
    National Institute for Health Research
    London, United Kingdom

     

CME Author

  • Laurie Barclay, MD

    Freelance writer and reviewer
    Medscape, LLC

    Disclosures

    Laurie Barclay, MD, has the following relevant financial relationships:
    Formerly owned stocks in: AbbVie Inc.

Editor

  • Thomas L. Ortel, MD, PhD

    Associate Editor, Blood

Compliance Reviewer

  • Leigh Schmidt, MSN, RN, CNE, CHCP

    Associate Director, Accreditation and Compliance, Medscape, LLC

    Disclosures

    Leigh Schmidt, MSN, RN, CNE, CHCP, has no relevant financial relationships.


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  • Medscape, LLC designates this Journal-based CME activity for a maximum of 1.0 AMA PRA Category 1 Credit(s)™ . Physicians should claim only the credit commensurate with the extent of their participation in the activity.

    Successful completion of this CME activity, which includes participation in the evaluation component, enables the participant to earn up to 1.0 MOC points in the American Board of Internal Medicine's (ABIM) Maintenance of Certification (MOC) program. Participants will earn MOC points equivalent to the amount of CME credits claimed for the activity. It is the CME activity provider's responsibility to submit participant completion information to ACCME for the purpose of granting ABIM MOC credit.

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From Blood
CME / ABIM MOC

Long-Term Risk of Relapse in Immune-Mediated Thrombotic Thrombocytopenic Purpura and the Role of Anti-CD20 Therapy

Authors: Andrew James Doyle, MD; Matthew James Stubbs, MD, PhD; Tina Dutt, MD, PhD; William A. Lester, MD; Will Thomas, MD; Joost J. van Veen, MD; Joannes Hermans, MD; Tanya Cranfield, MD; Quentin A. Hill, MD; Amanda Clark, MD; Catherine Bagot, MD; Steven Kenneth Austin, MD; John-Paul Westwood, MD(Res); Mari Thomas, MD, PhD; Marie Scully, MDFaculty and Disclosures

CME / ABIM MOC Released: 1/24/2023

Valid for credit through: 1/24/2024

processing....

Abstract and Introduction

Abstract

Disease relapse is recognized as a risk in immune-mediated thrombotic thrombocytopenic purpura (iTTP) after treatment of the acute presenting episode. Identification of patients at risk of relapse and its patterns are yet to be clearly established. We reviewed patients with iTTP having had >3 years of follow-up over 10 years in the United Kingdom to identify patient characteristics for relapse, assess relapse rates and patterns, and response to anti-CD20 therapy in those with a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13) relapses (ADAMTS13 activity of <20% without thrombocytopenia). We identified 443 patients demonstrating relapse rates of 40% at 5-year follow-up. At 10-year follow-up, no difference in relapse was observed irrespective of whether rituximab was used at acute presentation (P = .39). Black Caribbean ethnicity increased the risk of disease relapse in the British population. There was a distinct population of patients (6%) that relapsed early with subsequent frequent relapses occurring on average within 2 years (average time to relapse in subgroup, 1.7 years). Overall, nearly 60% of relapses described were ADAMTS13 relapses, with subsequent treatment reducing the risk of progression to clinical relapses. We demonstrate that iTTP diagnosed in the latter part of the study period had lower rates of clinical relapses (22.6% vs 11.1%, P = .0004) with the advent of regular monitoring and preemptive rituximab. In ADAMTS13 relapses, 96% responded to anti-CD20 therapy, achieving ADAMTS13 activity of >20%. Anti-CD20 therapy was demonstrated to be an effective long-term treatment regardless of relapse pattern and there was no loss of this treatment response after subsequent treatment episodes.

Introduction

Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is a rare, life-threatening condition associated with significant morbidity and mortality if not treated promptly. Immunoglobulin G (IgG) autoantibodies cause an acquired deficiency of the von Willebrand factor cleaving protein, a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13) by mediating either an increased clearance of the protein or inhibition of its enzymatic function.[1] A key component of treatment in the acute phase of the condition is the early eradication of B lymphocytes producing anti-ADAMTS13 antibodies.[2] The use of rituximab, a chimeric anti-CD20 monoclonal antibody, has become established in iTTP over the last decade.[2–4]

Relapse in iTTP can present as either a "clinical relapse" with an associated thrombocytopenia (platelets <150 × 109/L) or an "ADAMTS13 relapse" with ADAMTS13 activity levels of <20%, without thrombocytopenia or microangiopathic hemolytic anemia.[5] ADAMTS13 relapse usually progresses to clinical relapse if treatment is not initiated, with an increased risk of morbidity and mortality associated with the latter.[5,6] Relapses of iTTP occur in 15% to 30% of patients by 2 years with rates increasing with the duration of follow-up.[5–8] The use of rituximab has been shown to prolong the time to the first episode of disease relapse in the short term, compared with those who did not have rituximab during their acute presentation.[2,5,9–11] As such, patients with iTTP require long-term monitoring of ADAMTS13 levels to allow for early recognition of relapsing disease.

At present, the mechanism for disease relapse of iTTP has not yet been clearly elucidated, but the presence of CD19+ B lymphocytes is seen at the time of relapse.[5,12] Although B-cell recovery is recognized as a preceding event to relapse, not all patients that have B-cell recovery after immunosuppression develop relapses of iTTP. There are limited clinical parameters that can be used to identify or prognosticate patients for risk of relapse, and therefore, guide intensity of ADAMTS13 surveillance. Potential risk factors for relapse in 1 case series were age of <25 years, non-O blood group, having previous episodes of TTP relapse, and not receiving rituximab at initial presentation.[6] Patients having 1 relapse episode are at an increased risk of having subsequent relapses: 25% of patients at 1 year and 49% at 3 years.[5,9,10]

Preemptive rituximab has been shown by various groups as being a treatment option for ADAMTS13 relapse, with 94% of patients achieving normalization of ADAMTS13 levels.[5,10,13] After anti-CD20 treatment, B lymphocytes are initially significantly depleted but become detectable after 6 to 9 months with normalized levels after 18 months.[2,10,12] Relapse-free survival is prolonged in the short term by rituximab but after 5 years, these rates show no difference.[9]

At present, national registry data has been limited by small cohort sizes or short duration of follow-up in order to detect meaningful data on relapse in iTTP. We aimed to review the long-term follow-up of patients with iTTP from a large national, multicenter registry over a 10-year period with a minimum of 3 years of follow-up per patient. We evaluated the features of iTTP relapse in all identified patients and reviewed the responses to anti-CD20 antibody treatment in patients that had ADAMTS13 relapses.