Acquired thrombotic thrombocytopenic purpura (aTTP) is an immune-mediated life-threatening thrombotic microangiopathy (TMA). Daily therapeutic plasma exchange (TPE) and the optimized use of rituximab have dramatically improved the overall prognosis, however the rate of disease recurrence remains high. Acute-phase treatment and specific predictors of relapse can be relevant for an optimal patient management.
In a large multicenter cohort of aTTP patients, we aimed to analyze the effect of acute-phase treatment on disease recurrence and to identify predictive variables of relapse.
From 2002 to 2018, 325 TMA were referred to our Centers. A complete ADAMTS13 activity deficiency (<10%) was diagnostic for TTP in 163 patients. An anti-ADAMTS13 Ab titer >15U/L was considered positive and identified aTTP cases. Seventy-four aTTP patients with complete medical records were enrolled into the study and prospectively monitored. Complete response (CR) to treatment was defined as platelets >150x109/L for >2 days and LDH normalization, lasting for 30 days; a suboptimal response included exacerbation (EX) = recurrent disease within 30 days after reaching CR; and refractoriness (REF) = no treatment response by day 30.
aTTP patient characteristics at diagnosis are shown in the Table. Sixty-three patients were evaluated for treatment response. Two (3%) early deaths were due to myocardial infarction and diffuse rectal ischemia after 7 and 10 days from diagnosis, respectively. Forty patients (64%) obtained a CR after a median time to response (mTTR) of 10 days and a median number of TPE (mTPE) of 7; 21 (33%) obtained a suboptimal response: 13 EX (mTTR 31 days, mTPE 13), and 8 REF (mTTR 42.5, mTPE 19). Thirteen patients with a suboptimal response to TPE were treated with rituximab, all obtaining CR. TTR to 1st line treatment <13 days significantly correlated with a sustained CR (p = 0.004). At remission, 57% of patients showed normal levels (>50%) of ADAMTS13 activity, while 20% a moderate (21–50%), 10% a severe (10–20%), and 11% a complete (<10%) deficiency. A complete or partial recovery of ADAMTS13 activity was associated to negative Ab levels in 90% of cases. Twenty-one patients (34%) relapsed, 14 of them had multiple relapses. Median follow-up was 7 years. Patients were evaluated for predictive parameters of disease recurrence. By multivariate analysis, the association of ADAMTS13 activity ≤20% with a high anti-ADAMTS-13 titer during remission, and a TTR to 1st line treatment ≥13 days, were independent prognostic factors of relapse (p = 0.003 and p = 0.004, respectively). Furthermore, the use of rituximab in patients with a suboptimal TPE response significantly reduced relapse rate (p = 0.002). By Cox regression analysis, patients with ADAMTS13 activity ≤20% plus anti-ADAMTS13 Ab titer >15U/L at remission had an increased risk of relapse (HR 1.98, CI 95% 1.087–3.614; p < 0.02).
In conclusion, our study shows that the association of a low ADAMTS13 activity with high anti-ADAMTS13 antibodies is highly predictive of disease relapse. Moreover, a shorter time to 1st line CR achievement and the salvage use of rituximab in suboptimal responders to TPE significantly reduces relapse. These observations support the use of new therapeutic strategies able to provide faster responses to 1st line TPE treatment in these patients.