Long-Term Cardiac Effects of Successful Non-Myeloablative HLA-Matched Sibling Transplants in Sickle Cell Disease

Abstract

INTRODUCTION Cardiopulmonary complications lead to early mortality in adults with sickle cell disease (SCD). We previously showed in a small single-center study that cardiac morphology improves by one year after successful non-myeloablative hematopoietic stem cell transplantation (HSCT). Since cardiac outcomes following HSCT are not well-described, we sought to extend our results to a larger group of SCD patients from the National Institutes of Health (NIH) and University of Illinois Chicago (UIC). METHODS The majority of patients received alemtuzumab, 300cGy total body irradiation, and sirolimus; 21 also received pentostatin and cyclophosphamide preconditioning. An echocardiogram (echo) and routine laboratory testing were done at baseline before HSCT and at 1 and 2 year time points. Patients with an echo at least one year following HSCT were included. A generalized estimating equation regression model approach was used to evaluate echo and laboratory changes from baseline adjusting for age, gender, and site. A more stringent p-value threshold of 0.005 was used for significance given the large number of outcomes tested. The reported p values compare baseline vs 1 year and 1 year vs 2 year changes. RESULTS The study population consisted of 88 patients (69 NIH, 19 UIC) who had stable engraftment and were free of dialysis or chronic transfusion therapy. Mean + SD age of patients was 31.5 ± 10.5 years and 36 (41%) are female. Hemoglobin improved significantly in the first year (baseline 8.9 ± 1.5 g/dl, 1 year 12.9 ± 2.3, p < 0.0001), and continued to improve at 2 years (13.6 ± 2.0, p<0.0001). Laboratory results showed improvements in LDH, total bilirubin, and absolute reticulocyte count within the first year after HSCT (data not shown). Body surface area (BSA) was noted to increase significantly in the first year after HSCT (baseline 1.8 ± 0.2 m 2, 1 year 1.9 ± 0.2, p = 0.0002) and then stabilized in the second year (1.9 ± 0.3, p=0.9). Diastolic blood pressure was 66 ± 12 mmHg at baseline and closely followed the BSA, increasing in the first year (73 ± 11, p < 0.0001) and then remaining unchanged in the second year (74 ± 11, p=0.36). Systolic blood pressure (baseline 118 ± 15 mmHg) did not change significantly. The left ventricular size, as measured by the left ventricular end-diastolic volume index (LVEDVI) was elevated at baseline (82.6 ± 21.5 ml/m2), decreased dramatically at 1 year (69.0 ± 14.7, p < 0.0001), and continued to improve significantly at 2 years (63.1 ± 15.0, p < 0.0001, Figure). LV mass index, which is closely related to volume changes, did not change in the first year (baseline 84.9 ± 23.7 g/m 2, 1 year 85.1 ± 20.9, p= 0.72); however, it improved significantly by 2 years (79.2 ± 17.7, p=0.0003). The left atrial size, as measured by the left atrial volume index, also decreased in the first year (baseline 41.4 ± 12.8 ml/m2, 1 year 28.9 ± 8.7, p < 0.0001) with no change in the second year (27.9 ± 8.2, p=0.05). Diastolic filling parameters, which are independent risk markers of mortality, were seen to parallel the volume changes with baseline E/A ratio decreasing in the first year after HSCT (baseline 1.6 ± 0.6, 1 year 1.4 ± 0.4, p < 0.0001) and then remaining unchanged at 2 years (1.4 ± 0.5, p=0.09). Tricuspid regurgitation velocity (TRV), which is also a well-known early mortality risk marker in SCD, decreased significantly in the first year (baseline 2.5 ± 0.4 m/s, 1 year 2.4 ± 0.3, p = 0.002), and suggested a trend towards improvement at 2 years (2.3 ± 0.3, p=0.01). In 37 patients with a high-risk TRV ≥2.5 m/s, there was a significant decrease in the first year (baseline 2.9 ± 0.3, 1 year 2.5 ± 0.3, p < 0.0001) and then no change at 2 years (2.4 ± 0.3, p=0.05) CONCLUSION Our findings from two independent centers demonstrate significant improvements in cardiac size, mass, diastolic function, and TRV after non-myeloablative HSCT. Volume overload secondary to anemia is responsible for cardiac remodeling in SCD, and as the anemia resolves and high flow rates decrease following HSCT, many of the cardiac changes also reverse. LV volume decreased significantly in the first year, and these improvements, along with decreased LV mass index, continued in the second year. 55% of patients with a high-risk TRV normalized their TRV at 2 years. As diastolic dysfunction and TRV have both been associated with early mortality in adults with SCD, our results suggest that successful HSCT may impact survival. A larger multi-center study with longer follow-up is indicated. Figure 1 Figure 1. Disclosures Rondelli: Vertex: Membership on an entity's Board of Directors or advisory committees. Saraf: Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Effect of allogeneic hematopoietic stem cell transplantation on sickle cell disease‐related organ complications: A systematic review and meta‐analysis

“…35 Mean left ventricular ejection fraction in adults decreased from 65% and 61.5% to 60% and 59.8% in these two studies, 34,48 but cardiac size, mass and diastolic dysfunction improved. 48 Peak TRJV was assessed before and after HSCT in seven studies. 19,22,24,34,35,43,48 However, only the largest three studies reported mean TRJV for the whole cohort before and after HSCT, and could be included in the meta-analysis.…”

“…There was no statistical difference in shortening fraction (SMD 0.24, p = .53), but left ventricular ejection fraction decreased following HSCT (SMD 0.53, p = <.01; Figure 2, Figure S2). The decrease in left ventricular ejection fraction was more pronounced in the two studies comprising adult patients, 34,48 compared to children. 35 Mean left ventricular ejection fraction in adults decreased from 65% and 61.5% to 60% and 59.8% in these two studies, 34,48 but cardiac size, mass and diastolic dysfunction improved.…”

“…The decrease in left ventricular ejection fraction was more pronounced in the two studies comprising adult patients, 34,48 compared to children. 35 Mean left ventricular ejection fraction in adults decreased from 65% and 61.5% to 60% and 59.8% in these two studies, 34,48 but cardiac size, mass and diastolic dysfunction improved. 48 Peak TRJV was assessed before and after HSCT in seven studies.…”

“…Nine studies evaluated cardiac function with echocardiography before and after HSCT (Table S4). 19,[22][23][24]34,35,43,48,49 Of these studies, three were used for the meta-analysis on shortening fraction, and three for left ventricular ejection fraction. 6,23,34,35,48 Clinical heterogeneity, as assessed with the "Clinical Diversity in Meta-analyses" tool, was low for shortening fraction and for left ventricular ejection fraction (score 11).…”

“…48 Peak TRJV was assessed before and after HSCT in seven studies. 19,22,24,34,35,43,48 However, only the largest three studies reported mean TRJV for the whole cohort before and after HSCT, and could be included in the meta-analysis. 34,35,48 Clinical heterogeneity among these three studies was low (score 11) according to the "Clinical Diversity in Meta-analyses" tool.…”