Sunday, October 1, 2023
| 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
| 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
| 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
| 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
Physicians - maximum of 1.00 AMA PRA Category 1 Credit(s)™
ABIM Diplomates - maximum of 1.00 ABIM MOC points
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.
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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.
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.
