Improvement in Hemolytic Parameters and Tricuspid Regurgitant Jet Velocity (TRV) Following Non-Myeloablative Allogeneic Stem Cell Transplantation (allo-SCT) in Adults with Severe Sickle Cell Disease (SCD).
Authors: Hsieh Matthew M. , Link Beth , Machado Roberto , Kato Gregory , Gladwin Mark , Tisdale John F. 
Published: October 2019

Abstract
Although SCD has a variable clinical course, many individuals develop end-organ complications that are associated with significant morbidity and early mortality. SCD-related pulmonary hypertension is a frequently recognized complication (up to 30%), is associated with significant mortality, and is resistant to hydroxyurea or chronic exchange transfusions. Currently myeloablative allo-SCT in children under age 16 is curative in the majority, preventing or ameliorating many of the complications of the disease. However, it is unclear whether reduced intensity allo-SCT in adults that allows mixed hematopoietic chimerism could offer the same benefit. Furthermore, reversal of pulmonary hypertension has not been previously demonstrated in either setting. Beginning in 2003, we initiated an IRB approved clinical trial testing a nonmyeloablative approach in adults with severe SCD. Protocol entry criteria include end-organ complications, (stroke, pulmonary hypertension TRV≥ 2.5 m/s, or frequent vaso-occlusive crises or acute chest syndrome not ameliorated by hydroxyurea. Conditioning was achieved with low dose radiation, alemtuzumab, and sirolimus (rapamycin). All patients receive unmanipulated G-CSF mobilized peripheral blood progenitors obtained from an HLA-matched sibling. Assessment of donor chimerism is measured by microsatellite PCR of CD3 and CD14/15 positive white cells. Hemolysis is monitored by serial measurements of total bilirubin, lactate dehydrogenase, hemoglobin and absolute reticulocyte counts. Transthoracic echocardiography is performed in all patients, and serially in those with TRV ≥ 2.5 m/s. Transmitral flow, Doppler determinations of valvular regurgitant velocity, and left ventricular stroke volume are assessed and graded. A total of 8 patients have accrued. 4 of 8 patients met criteria for pulmonary hypertension. Post transplant follow-up for these 4 patients ranged from 7 to 36 months and stable donor lymphoid (13–39%) and myeloid (53–100%) chimerism was observed in all 4. This pattern of mixed chimerism was sufficient for full donor erythroid engraftment as all demonstrated normal hemoglobin, allowing for therapeutic phlebotomy to correct transfusional iron overload. Improvement in TRV and hemolytic parameters were observed (see table) as early as 3 months post transplant. The average pre- and post allo-SCT values were: TRV 3.1 → 2.5 m/s (p=0.13, Wilcoxon rank sum), total bilirubin 4.0 → 0.6 (p=0.1), lactate dehydrogenase 487 →178 units/L (p=0.2), hemoglobin (hgb) 8.6 → 12.6 g/dL (p=0.002), and reticulocyte (retic) count 326 → 68 k/uL (p=0.01). Our results indicate that reduced intensity allo-SCT in adults patients with SCD allows for full donor erythroid engraftment, normalization of blood counts, reversal of hemolysis, and improvement in TRV.
TRV and hemolytic parameters Patient 1 Patient 2 Patient 3 Patient 4 Average TRV Pre 3.7 2.6 3.4 2.6 3.08 (m/s) BMT 2.6 2.4 2.5 2.3 2.45 T bili Pre 8.3 4.0 1.9 1.9 4.0 (0.1–1.1 mg/dL) BMT 0.8 0.5 0.5 0.4 0.6 LDH Pre 1065 330 338 215 487 113–226 units/L) BMT 234 178 209 90 178 Hgb Pre 8.1 8.5 8.8 8.9 8.6 (g/dL) BMT 12.9 13.9 11.9 11.6 12.6 Retic Pre 344 213 417 331 326 (31–105 k/uL) BMT 76 32 76 87 68