Association of Matched Sibling Donor Hematopoietic Stem Cell Transplantation With Transcranial Doppler Velocities in Children With Sickle Cell Anemia

Abstract

Importance: In children with sickle cell anemia (SCA), high transcranial Doppler (TCD) velocities are associated with stroke risk, which is reduced by chronic transfusion. Whether matched sibling donor hematopoietic stem cell transplantation (MSD-HSCT) can reduce velocities in patients with SCA is unknown.

Objective: To determine the association of MSD-HSCT with TCD velocities as a surrogate for the occurrence of ischemic stroke in children with SCA.

Design, setting, and participants: Nonrandomized controlled intervention study conducted at 9 French centers. Patients with SCA were enrolled between December 2010 and June 2013, with 3-year follow-up ending in January 2017. Children with SCA were eligible if younger than 15 years, required chronic transfusions for persistently elevated TCD velocities, and had at least 1 sibling without SCA from the same 2 parents. Families agreed to HLA antigen typing and transplantation if a matched sibling donor was identified or to standard care in the absence of a matched sibling donor.

Exposures: MSD-HSCT (n = 32), compared with standard care (n = 35) (transfusions for ≥1 year with potential switch to hydroxyurea thereafter), using propensity score matching.

Main outcomes and measures: The primary outcome was the highest time-averaged mean of maximum velocities in 8 cerebral arteries, measured by TCD (TCD velocity) at 1 year. Twenty-five of 29 secondary outcomes were analyzed, including the highest TCD velocity at 3 years and normalization of velocities (<170 cm/s) and ferritin levels at 1 and 3 years.

Results: Sixty-seven children with SCA (median age, 7.6 years; 35 girls [52%]) were enrolled (7 with stroke history). In the matched sample, highest TCD velocities at 1 year were significantly lower on average in the transplantation group (129.6 cm/s) vs the standard care group (170.4 cm/s; difference, -40.8 cm/s [95% CI, -62.9 to -18.6]; P < .001). Of the 25 analyzed secondary end points, 4 showed significant differences, including the highest TCD velocity at 3 years (112.4 cm/s in the transplantation group vs 156.7 cm/s in the standard care group; difference, -44.3 [95% CI, -71.9 to -21.1]; P = .001); normalization rate at 1 year (80.0% in the transplantation group vs 48.0% in the standard care group; difference, 32.0% [95% CI, 0.2% to 58.6%]; P = .045); and ferritin levels at 1 year (905 ng/mL in the transplantation group vs 2529 ng/mL in the standard care group; difference, -1624 [95% CI, -2370 to -879]; P < .001) and 3 years (382 ng/mL in the transplantation group vs 2170 ng/mL in the standard care group; difference, -1788 [95% CI, -2570 to -1006]; P < .001).

Conclusions and relevance: Among children with SCA requiring chronic transfusion because of persistently elevated TCD velocities, MSD-HSCT was significantly associated with lower TCD velocities at 1 year compared with standard care. Further research is warranted to assess the effects of MSD-HSCT on clinical outcomes and over longer follow-up.

Trial registration: ClinicalTrials.gov Identifier: NCT01340404.

Figure 1.. Flow of Patients Through the DREPAGREFFE Study

Only 18 of 35 patients in the standard care group had cognitive testing at 3 years despite several offers of appointment. This was probably attributable to the high number of other appointments in these patients (trimestral consultation, hospitalizations for vaso-occlusive crises), whereas the transplanted patients were only seen once a year after the first year. MRA indicates magnetic resonance angiography; MRI, magnetic resonance imaging; MSD-HSCT, matched sibling donor hematopoietic stem cell transplantation; SCA, sickle cell anemia; TCD, transcranial Doppler. ^aOne child was not assessed at enrollment with TCD imaging and MRI/MRA because of assessment 3 months before enrollment. ^bOne child did not undergo MRI/MRA because of technical reasons. ^cOne child was not assessed with TCD imaging because of missed appointment and 1 did not undergo MRI/MRA because of technical reasons.

Figure 2.. Time Course of Velocity and MRA Score Outcomes During the 3-Year Follow-up in Both Groups After Matching on Propensity Score Including Siblings Without SCA, Age, and Sex

Spaghetti plots represent individual patient data. In each boxplot, the central rectangle spans the first quartile to the third quartile (ie, the interquartile range [IQR]); the segment inside the rectangle indicates the median; the whiskers above and below the box indicate the locations of the suspected outlier thresholds, ie, set at 1.5× IQR above the third quartile or below the first quartile; and circles indicate the values above the suspected outlier threshold, ie, 1.5× IQR above the third quartile. A, Time-averaged mean of maximum velocities (TAMV) in the artery with the highest value. Only 1 patient with a stroke history still had abnormal high velocities with occlusion in another artery at 3 years after transplantation. B, Magnetic resonance angiography (MRA) score. Colored lines in the spaghetti plots indicate instances for which multiple patients had the same trajectory; Ns for those trajectories are indicated in matching colors. In the patients with stroke from the transplantation group, the stenosis score increased mainly during the first year after transplantation but only in the arteries responsible for the original stroke. However, no stroke recurrence was observed. In patients without stroke, the stenosis score did not increase. In the standard care group, the stenosis score increased in 3 patients among the patients without stroke, despite chronic transfusion. Range of possible scores, 0 to 32; see “Methods” for details of scoring. SCA indicates sickle cell anemia.