Organ dysfunction rare among children who underwent HSCT for sickle cell disease
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SALT LAKE CITY — Prevalence of organ dysfunction appeared low among pediatric patients who underwent hematopoietic stem cell transplantation for sickle cell disease, according to retrospective study results.
“In this pediatric cohort of [patients with sickle cell disease] who received transplant with heterogenous conditioning intensity and donor matching, we don’t see a signal that they have much cardiac, pulmonary or neurologic dysfunction,” researcher Elizabeth O. Stenger, MD, assistant professor in the department of pediatrics in the division of hematology, oncology and bone marrow transplantation at Emory University School of Medicine, told Healio.
“We also found predictors for dysfunction in those three organs in line with what we expected,” added Stenger, who presented the findings at Tandem Meetings | Transplantation & Cellular Therapy Meetings of ASTCT and CIBMTR.
Background
Despite treatment advances, individuals with sickle cell disease experience significant morbidity and early mortality.
HSCT is the only curative option supported by long-term data. However, limited sickle cell disease-specific data exist about long-term organ dysfunction after transplant, according to study background.
Stenger and colleagues aimed to assess prevalence of and risk factors for post-transplant organ dysfunction among patients with sickle cell disease.
Researchers hypothesized that most patients would have stable to improved organ function after transplant, and that four factors — age at transplant, conditioning intensity, donor matching and history of graft-versus-host disease — would predict organ dysfunction.
Methodology
Stenger and colleagues used the Sickle Cell Transplant Advocacy & Research Alliance registry to retrospectively collect data on 247 patients (median age, 9.4 years; interquartile range, 5.5-14.1; 45.8% female) at least 1 year beyond successful HSCT.
Approximately two-thirds of the cohort had a severe clinical disease phenotype (65.4%). Among those with severe disease, primary indications for transplant included recurrent vaso-occlusive episodes (52.%), recurrent acute chest syndrome (44%) and neurological events.
Slightly more than one-third (36.9%) of patients were on hydroxyurea treatment prior to transplant and about half (52.3%) had received chronic blood transfusions.
Researchers evaluated prevalence of cardiac, pulmonary and neurologic dysfunction in this cohort. They also performed multivariable Cox regression analysis to assess risk factors for organ dysfunction.
Investigators defined cardiac dysfunction as ejection fraction less than 55% or shortening fraction less than 28%. They defined pulmonary dysfunction as restrictive lung disease with forced vital capacity less than 80% or obstructive lung disease with forced expiratory volume in one second (FEV1)/forced vital capacity (FVC) less than 70%. They defined neurologic dysfunction as new or progressive vasculopathy or infarct.
Most patients (76.9%) had matched related donors, whereas 11.7% had matched unrelated donors, 10.5% had mismatched unrelated donors and 0.8% had mismatched related donors. The majority of patients received bone marrow stem cells (83.3%) and myeloablative conditioning (57.1%).
Results
After median follow-up of 3 years (interquartile range, 2-6), 59 patients (24%) developed acute GVHD and 21 (9%) developed severe acute GVHD (grade 1/grade 2, 64.4%; grade 3/grade 4, 35.6%).
Sixty-one patients (24.8%) developed chronic GVHD (mild, 33.3%; moderate, 15%; severe, 28.3%).
Fourteen patients (5.9%) remained on systemic immunosuppression at last follow-up.
Thirteen patients (5%) died after transplant — seven due to GVHD, four due to infection and one due to sepsis.
Researchers obtained post-HSCT organ assessments at a median 2 years (range, 1-14).
Results showed cardiac dysfunction increased significantly from before HSCT to after. Absolute values of ejection fraction decreased from 67.1% to 64.4% (P < .001), shortening function decreased from 37.1% to 36.1% (P = .04).
The percentage of patients with low ejection fraction increased from 0.6% before HSCT to 6% after (P = .007), and the percentage of those with low shortening function increased from 0% before HSCT to 4.6% after (P = .003).
The percentage of patients with pulmonary dysfunction remained stable, with no significant changes observed in FEV1, FVC or diffusing capacity of the lung for carbon monoxide.
“Looking at the proportion of patients with either restrictive or obstructive lung disease or normal pulmonary function tests, we saw no difference when we made a pre- to post-transplant comparison,” Stenger said.
Eight patients experienced stroke after HSCT (ischemic, n = 7; hemorrhagic, n = 1). These occurred at a median 47 days (range, 0-243) after transplant.
Researchers performed pre- and post-HSCT brain MRI for 159 patients, with the following post-HSCT findings: normal, 28.3%; stable, 50.3%; new infarct, 4.4%; progressive vasculopathy, 3.8%; new vasculopathy, 3.8%; and progressive infarct, 3.8%.
Risk factors
Multivariable analysis identified several pre- and post-HSCT factors significantly associated with risk for cardiac dysfunction (grade 3/grade 4 acute GVHD, OR = 2.71; 95% CI, 1.04-5.62; myeloablative conditioning, OR = 2.41; 95% CI, 1.09-6.77), as well as new or progressive central nervous system disease (CNS indication for transplant, OR = 2.48; 95% CI, 1.65-3.74).
Researchers identified no factors significantly associated with pulmonary dysfunction.
Stenger and colleagues established a composite organ dysfunction score — ranging from 0 to 6 — based on changes in cardiac function, pulmonary function and brain MRI results.
After adjusting for CNS indication, year of transplant and history of acute GVHD, those who had a severe clinical phenotype had significantly higher odds for developing a higher composite organ dysfunction score (OR = 1.64; 95% CI, 1.02-2.63).
Patients who underwent transplant at age 16 years or older had a significantly higher risk for developing dysfunction in at least one organ after transplant (OR vs. patients aged younger than 6 years = 2.26; 95% CI, 1.35-3.47).
“The results support consideration of transplanting patients at a younger age and using less intense conditioning,” Stenger told Healio. “Doing so at a younger age, before there is organ damage, is safer and, thus, you’re going to have a higher chance of better outcomes and long-term benefit.”
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Stenger EO et al. Abstract 58. Presented at: Tandem Meetings | Transplantation & Cellular Therapy Meetings of ASTCT and CIBMTR; April 23-26, 2022; Salt Lake City.
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