Sickle cell disease increases risk for transplant-associated thrombotic microangiopathy
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SALT LAKE CITY — Sickle cell disease increased risk for transplant-associated thrombotic microangiopathy among children who underwent hematopoietic stem cell transplantation, according to study results.
This association — reported at Tandem Meetings | Transplantation & Cellular Therapy Meetings of ASTCT and CIBMTR — persisted even though study participants with sickle cell disease were more likely than those without sickle cell disease to have 10/10 haploidentical matched sibling donors.
Data derived from Schoettler ML, et al. Abstract 21. Presented at: Tandem Meetings | Transplantation & Cellular Therapy Meetings of ASTCT and CIBMTR; April 23-26, 2022; Salt Lake City.
“It is very important to monitor patients with sickle cell disease and to collect data [on transplant-associated thrombotic microangiopathy (TA-TMA)] really carefully,” Michelle Long Schoettler, MD, pediatric hematologist at Children’s Healthcare of Atlanta and assistant professor of pediatrics in Emory University School of Medicine, told Healio. “There are a number of new clinical trials coming out with alternative donors and TA-TMA data are not standardly in all clinical trials. I think our findings highlight the importance of looking for that.”
Background and methodology
TA-TMA — a severe complication that arises in approximately 20% to 30% of pediatric allogeneic HSCTs — has been linked to endothelial dysfunction and activated complement.
“Renal biopsy is the gold standard for diagnosis, though it is rarely obtained,” Schoettler said during a presentation. “About half of patients have a self-remitting course, and the remainder develop multiorgan dysfunction and/or die.”
Aside from case reports, the risk for TA-TMA among patients with sickle cell disease is unknown.
Schoettler and colleagues hypothesized that TA-TMA rates after HSCT would be higher among individuals with sickle cell disease than without. They also expected to observe higher rates of pre-HSCT markers of endothelial dysfunction and complement among individuals with sickle cell disease.
Researchers conducted a single-institution, retrospective study of 115 children who underwent haploidentical or 8/8 matched sibling donor first HSCT between January 2015 and June 2020.
Investigators used single and multiplex assays in pre-HSCT blood samples available in a banked institutional biorepository to measure markers of complement and endothelial activation, including C3a, C5a, sC5b-9, Bb, endothelin-1, syndecan-1, sVCAM-1 and sICAM-1.
Fifty-two children (45.2%; mean age, 9.6 years; 94% Black, 0% white) had sickle cell disease and 63 (54.8%; mean age, 9.1 years; 19% Black, 38% white) underwent HSCT for non-sickle cell disease indications.
A higher percentage of study participants with sickle cell disease received matched sibling donor HSCT (88% vs. 71%; P = .02) and bone marrow cell grafts (100% vs. 73%).
Study results
A higher percentage of participants with sickle cell disease developed TA-TMA (15% vs. 2%).
Three (50%) of six participants with sickle cell disease who underwent haploidentical transplant developed TA-TMA, as did four (8.6%) of the 46 who underwent matched sibling donor transplant.
Median time from HSCT to TA-TMA diagnosis in the sickle cell disease cohort was 71 days (range, 30-546).
Seven (88%) of the eight patients with sickle cell disease who developed TA-TMA had associated multiorgan dysfunction. Three received eculizumab (Soliris, Alexion) therapy and remained alive at data cut-off. One case self-resolved, and the others required changes to immune suppression medications.
All patients with sickle cell disease who developed TA-TMA survived.
The one patient without sickle cell disease who developed TA-TMA was diagnosed on day 34 after HSCT. The patient received complement inhibition with two agents but did not respond to treatment and died.
Analysis by donor type showed patients with sickle cell disease exhibited considerably higher risks for TA-TMA than those who underwent HSCT for non-sickle cell disease indications (all HLA matches, OR = 9.64; 95% CI, 1.15-81.17; matched sibling donors only, OR = 4.19; 95% CI, 0.45-39.03; haploidentical donors only, OR = 37; 95% CI, 1.5-885.8).
Researchers reported no statistically significant difference in acute GVHD rates between study participants with or without sickle cell disease (grade 0 to grade 2, 92% vs. 95%; grade 3 to grade 4, 8% vs. 5%).
Samples obtained prior to HSCT showed no differences in levels of sC5b-9, C5a, C3a or complement Bb among study participants with sickle cell disease (n = 22) vs. those without (n = 17).
However, those with sickle cell disease exhibited significantly higher baseline sVCAM-1 and p-selectin levels, both of which are markers of endothelial dysfunction.
Researchers observed no difference in pre-HSCT complement markers or markers of endothelial activation at baseline among patients who later developed TA-TMA and those who did not.
All study participants with sickle cell disease remained alive at 1 year, compared with 78% of study participants who underwent transplant for non-sickle cell disease conditions (P = .0007).
Schoettler acknowledged study limitations.
“Universal TA-TMA screening was not in place and, thus, we may have underestimated incidence,” she said.
Further analyses in larger cohorts are necessary to determine if race is an independent risk factor for TA-TMA, Schoettler said.
Larger studies are needed to confirm whether there are measurable differences in markers of endothelial activation prior to HSCT among patients with sickle cell disease vs. those without and — if so — whether those differences have clinical meaning.
Also, researchers did not have available samples at the time of TA-TMA diagnosis. Investigating markers of endothelial and complement activation over time may prove more enlightening, Schoettler said.
“The reason we performed this research was to see if we could identify patients who are at highest risk for TA-TMA, and the biomarkers we looked at [before transplant] did not do that,” Schoettler told Healio. “In the future, I think checking serial markers at later time points — maybe day 14 or day 30 — might help identify those at highest risk.”
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Schoettler ML, et al. Abstract 21. Presented at: Tandem Meetings | Transplantation & Cellular Therapy Meetings of ASTCT and CIBMTR; April 23-26, 2022; Salt Lake City.
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