Type: Oral
Session: 331. Thrombotic Microangiopathies/Thrombocytopenias: Clinical and Epidemiological: A Brave New World: Novel Tools, Targets and Treatments in TTP
Hematology Disease Topics & Pathways:
Research, Bleeding and Clotting, Autoimmune disorders, Adult, Epidemiology, Clinical Research, Health outcomes research, Diseases, Thrombocytopenias, Immune Disorders, Thrombotic disorders, Survivorship, Technology and Procedures, Study Population, Human, Imaging
METHODS: The NeST study prospectively enrolled adult (age ≥ 18 years) patients with iTTP based on ADAMTS13 activity <10% during an acute episode. Participants undergo annual study visits during clinical remission that include the NIH Stroke Scale (to screen for acute stoke) and brain MRI. SCI is defined as an infarct like lesion (punctate T2 and FLAIR hyperintensity) ≥3 mm in size without corresponding neurodeficits. For quantitative measurement of SCI, we used the modified Age-Related White Matter Changes (ARWMC) scale ranging from a score of 0 to 30 that accounts for both sides of the brain (right and left) and prespecified brain regions (frontal, parieto-occipital, temporal, infratentorial/cerebellum, and basal ganglia). White matter hyperintensities are assigned a score of 0 to 3 in each region on both sides of the brain and the final score is the sum of all regions. We evaluated progression of SCI at 1 year using the Wilcoxon signed rank test (paired), and risk of overt stroke in patients with and without white matter lesions on baseline evaluation.
RESULTS: As of the data cutoff date of March 1, 2024, 40 patients completed the first study visit and 26 completed the second visit including MRI. Of the remaining 14, 3 declined second MRI; 3 lost to follow-up due to relocation, 1 unable to complete due to debilitating stroke and 7 were not yet due for 1-year follow-up. Median age was 48 (35,55) years, 78% were female and 75% identified as Black. The median time from iTTP diagnosis was 66 (14, 109) months and median number of iTTP episodes was 2(1,4). Additionally, 39% had hypertension, 19% had diabetes, and 18% had had stroke with iTTP episodes. NIH stroke scale was 0 at all visits. Any SCI/white matter lesion was seen in 31(77%) and median modified ARWMC score was 4 (IQR 1, 7).
SCI are progressive during iTTP remission. The median time between first (baseline) and second MRI was 13 (12-14) months. There were no intercurrent acute iTTP clinical relapse or ADAMTS13 relapse episodes between the two visits. Of 26 participants with repeat imaging, new or progressive lesions were seen in 38.5% (10/26). The median ARWMC score also significantly increased from 2 (0.6) to 2.5 (1,8) (P=0.002) on the follow up MRI. On multivariable logistic regression, age at enrollment [OR 1.12 (95%CI 1.01-1.27)] was significantly associated with SCI progression in a model adjusted for hypertension, diabetes, prior stroke, average intercurrent remission ADAMTS13 activity, and SCI on baseline evaluation.
SCI progression is associated with incident stroke. Over a median follow up of 37(21,43) months from enrollment, incident stroke occurred in 15% (6/40) including 19.3% (6/31) of those with any SCI on baseline MRI and 0% (0/9) in those without baseline SCI. In particular, rate if stroke was significantly higher in those with progressive SCI than those without progressive SCI (30% vs. 0%, P=0.020). Multivariable analysis did not identify significant risk factors, but analysis is limited by only 6 events.
CONCLUSION: SCI are progressive during iTTP remission even in the absence of acute iTTP episodes or ADAMTS13 relapse suggests that remission specific risk factors (including but not limited to targeting ADAMTS13) could be targeted to prevent SCI progression and related cognitive impairment. SCI progression is associated with stroke risk. SCI may be a feasible and shorter-term endpoint to reduce the duration and cost of clinical trials focused on mitigating adverse neurovascular outcomes in iTTP.
Disclosures: Chaturvedi: Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Alexion, AstraZeneca Rare Disease: Consultancy, Membership on an entity's Board of Directors or advisory committees; SOBI: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees. Gerber: Apellis Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Merck: Honoraria; Alexion Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Other: spouse employment and received stock.
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