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Figure 1.
Flow of Patients Through the DREPAGREFFE Study
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
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.

Table 1.  
Patient Characteristics Measured at Enrollment
Patient Characteristics Measured at Enrollment
Table 2.  
Cerebral Arterial Velocities, Ischemic Lesions, Stenoses, Cognitive Performances, Quality of Life, and Ferritin Levels at 1 Year and 3 Years in Both Groupsa
Cerebral Arterial Velocities, Ischemic Lesions, Stenoses, Cognitive Performances, Quality of Life, and Ferritin Levels at 1 Year and 3 Years in Both Groupsa
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Bernaudin  F, Pondarré  C, Galambrun  C, Thuret  I.  Allogeneic/matched related transplantation for β-thalassemia and sickle cell anemia.  Adv Exp Med Biol. 2017;1013:89-122. doi:10.1007/978-1-4939-7299-9_4PubMedGoogle ScholarCrossref
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Original Investigation
January 22, 2019

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

Author Affiliations
  • 1Referral Center for Sickle Cell Disease, Department of Pediatrics, Intercommunal Créteil Hospital, University Paris-Est, Créteil, France
  • 2Referral Center for Sickle Cell Disease, Medical Imaging Department, Intercommunal Créteil Hospital, Créteil, France
  • 3Bone Marrow Transplant Unit, Department of Hematology, Saint-Louis Hospital, University Paris-Diderot, Paris, France
  • 4Department of Pediatric Hematology, Robert-Debré Hospital, University Paris-Diderot, Paris, France
  • 5Referral Center for Sickle Cell Disease, Department of Pediatrics, Necker Hospital, University Paris-Descartes, Paris, France
  • 6Referral Center for Sickle Cell Disease, Pointe à Pitre, Guadeloupe, France
  • 7Department of Pediatric Hematology, la Timone Hospital, Marseille University, Marseille, France
  • 8Department of Pediatric Hematology, Hautepierre Hospital, Strasbourg University, Strasbourg, France
  • 9Department of Pediatric Hematology, Necker Hospital, University Paris-Descartes, Paris, France
  • 10Department of Pediatric Hematology, HIOP Lyon, Lyon, France
  • 11Referral Center for Sickle Cell Disease, Department of Pediatrics, Kremlin-Bicêtre Hospital, University Paris-Sud, Paris, France
  • 12Referral Center for Sickle Cell Disease, Department of Pediatrics, Robert-Debré Hospital, University Paris-Diderot, Paris, France
  • 13Department of Pediatric Hematology, Bordeaux Hospital, Bordeaux, France
  • 14Referral Center for Sickle Cell Disease, Department of Pediatrics, Fort de France, Martinique, France
  • 15Department of Child and Adolescent Psychiatry, Avicenne Hospital, Paris-13 University, Paris, France
  • 16Department of Medical Imagery, Debré Hospital, University Paris-Diderot, Paris, France
  • 17Department of Statistics, Saint-Louis Hospital, ECSTRA Team, UMR1153, INSERM, University Paris-Diderot, Paris, France
JAMA. 2019;321(3):266-276. doi:10.1001/jama.2018.20059
Key Points

Question  What is the association of matched sibling donor hematopoietic stem cell transplantation (MSD-HSCT) with subsequent transcranial Doppler (TCD) velocity in children with sickle cell anemia (SCA) and elevated TCD velocity?

Findings  In this nonrandomized controlled intervention study that included 67 children with SCA, TCD velocity in the artery with the highest recorded value was statistically significantly lower at 1 year in the MSD-HSCT group (129.6 cm/s) compared with the chronic transfusion group (170.4 cm/s).

Meaning  Among children with SCA requiring chronic transfusion for abnormally elevated TCD velocities, MSD-HSCT, compared with standard care, was significantly associated with lower TCD velocities at 1 year; further research may be warranted to assess the effects of MSD-HSCT on clinical outcomes.

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

Introduction

In children with sickle cell anemia (SCA), abnormally high flow velocity in the cerebral arteries is associated with ischemic stroke risk,1-3 stenoses,4,5 and silent cerebral infarcts.4,6 Strokes are a devastating complication, responsible for motor and neurocognitive sequelae,7 whereas silent infarcts are associated with cognitive deficiency8 and risk of overt stroke.9

In the early 1990s, the ability to detect patients at risk for stroke using transcranial Doppler (TCD) ultrasonography was a major step forward in the care of these children,1-4 with a 40% stroke risk within 3 years in patients with time-averaged mean of maximum velocities (TAMV) of 200 cm/s or greater, a 7% stroke risk in those with intermediate TAMV (170-199 cm/s), and a 2% stroke risk in those with TAMV less than 170 cm/s2. The STOP-1 (Stroke Prevention Trial in Sickle Cell Anemia 1) trial in patients identified as at risk of stroke by TCD demonstrated the efficiency of chronic transfusions, reducing by 90% the risk of first stroke.3 The STOP-2 study showed that stopping transfusions in patients with normalized velocities and no stenosis resulted in a high risk of recurrence of abnormal TCD velocities and stroke occurrence, suggesting that lifelong chronic transfusions might be needed for primary stroke prevention.10 The issues of alloimmunization, iron overload, and high cumulative incidence of abnormal TCD velocities (30%) in a newborn cohort11 requiring long-term transfusions led to consideration of other preventive approaches, such as switching to hydroxyurea12,13 and myeloablative matched sibling donor hematopoietic stem cell transplantation (MSD-HSCT).14 MSD-HSCT offers a 95% chance of cure in children with SCA and is associated with lower cerebral velocities.14,15 However, no controlled prospective study comparing MSD-HSCT with transfusion has been reported.

This study was performed to test the hypothesis that transplantation was associated with better cerebral vasculopathy outcomes than chronic transfusions in children with SCA and a history of abnormal TCD velocities.

Methods
Study Design and Oversight

The DREPAGREFFE study, approved by an institutional review board affiliated with the French Ministry of Health, was a nonrandomized, controlled, open-label intervention study conducted at 9 sites in France. The risks and benefits of chronic transfusion, hydroxyurea, and MSD-HSCT were clearly explained, both orally and in writing, to the parents or guardians, the patients, and their siblings. Written consent was obtained from parents as well as patients and siblings older than 7 years. Familial HLA typing was performed after consent and patients were assigned to the transplantation group if a matched sibling donor was available and to standard care (transfusion for at least 1 year) if no matched sibling donor was available. The rationale and detailed protocol have been published16 and are available in Supplement 1.

Study Population

Between December 31, 2010, and June 30, 2013, all consecutive patients with SCA (homozygous SS, sickle-cell/β0-thalassemia), younger than 15 years of age, receiving chronic transfusions for a history of abnormal TCD velocities (TAMV ≥200 cm/s) in the middle cerebral, anterior cerebral, internal carotid, and/or extracranial internal carotid17 arteries, and with at least 1 sibling without SCA from the same 2 parents were screened. Following a protocol amendment in February 2013, the initial 1-year trial follow-up was extended for 2 more years, ending in January 2017.

Group Allocation and Exposures

For eligible children, MSD-HSCT was performed in 6 different HSCT centers. Myeloablative conditioning consisted of intravenous busulfan, cyclophosphamide (200 mg/kg), and rabbit anti-thymocyte-globulin (20 mg/kg). Cell source was either bone marrow or cord blood. Graft-vs-host disease (GVHD) prophylaxis with cyclosporin A was given for 9 months after transplant. A short course of methotrexate was added for bone marrow HSCT only.

For children with no matched sibling donor, chronic transfusions were continued for at least 1 year, maintaining sickle cell hemoglobin level below 30% and total hemoglobin level between 9 and 11 g/dL. After 1 year of transfusions, local investigators could propose a switch to hydroxyurea with an overlap with transfusion of at least 3 months to patients with normalized velocities and no stenosis.

Study Visit Evaluation

Study visits were completed at baseline, 1 year, and 3 years and consisted of a physical examination including a neurologic examination and medical history, a complete blood cell count, measurement of ferritin levels, hemoglobin analysis by high-performance liquid chromatography, and TCD. Donor chimerism was analyzed in patients in the transplantation group.

Outcomes
Primary Outcome

The primary outcome was the highest TAMV recorded without angle correction in the 8 cerebral arteries at 1 year, classified as normal (TAMV <170 cm/s), intermediate (TAMV 170-199 cm/s), or abnormal (TAMV ≥200 cm/s). Transcranial Doppler imaging via a temporal window was performed on a duplex color Doppler.4,18 Assessment of the extracranial internal carotid artery was via the submandibular window.17

Secondary Outcomes

A total of 29 secondary outcomes were prespecified (eTable 1 in Supplement 2); of these, 25 are reported in this article—the highest TAMV in a cerebral artery at 3 years and 12 other outcomes measured twice (at 1 and 3 years), including percentage of patients with normalized velocity (TAMV <170 cm/s) in absence of occlusion; incidence of ischemic stroke; survival without ischemic stroke; incidence of cerebral ischemic lesions (measuring at least 3 mm) or stenosis (narrowing ≥25%) in patients previously free of those lesions; magnetic resonance imaging (MRI) scores of ischemic lesions; magnetic resonance angiography (MRA) scores of stenoses; iron overload measured by ferritin levels; erythroid alloimmunization; cognitive functioning; quality of life using child self-report; and quality of life based on parent report. Four other secondary outcomes, ie, phosphatidylserine expression, angiogenic factor at 1 year, and costs at 1 and 3 years, have not been analyzed and will be reported in the future.

MRI/MRA imaging, performed on a 1.5T instrument with FLAIR (fluid-attenuated inversion recovery) T1 diffusion-weighted and T2 diffusion-weighted sequences and circle of Willis 3D time of flight angiography (with cervical MRA added in June 201117), was reviewed by 2 experts blinded to the treatment group. Ischemic lesions in patients without a history of cerebrovascular events were considered silent cerebral infarcts. The MRI scores, ranging from 0 (best outcome) to 10 (worst outcome), were obtained by adding up the ischemic lesion scores from the left and right sides, ie, 3 for territorial or 2 for border zone (cortical and subcortical), 1 for white matter and 1 for basal ganglia infarcts, and 0 if absent on each side. The MRA stenosis scores, ranging from 0 (best outcome) to 32 (worst outcome), were defined as the weighted sums over the 8 assessed cerebral arteries (0 if no stenosis, 1 if mild stenosis [25%-49%], 2 if moderate stenosis [50%-74%], 3 if severe stenosis [75%-99%], and 4 if occlusion). These scores were defined by a committee of trial neuroradiologists. Full Scale IQ was measured by the Wechsler Preschool and Primary Scale of Intelligence–Third Edition for children aged 3 to 6 years and the Wechsler Intelligence Scale for Children–Fourth Edition for children aged 7 to 16 years (40 = worst outcome, 160 = best outcome). Quality of life assessment was collected using the French version of the Pediatric Quality of Life Inventory Generic Core Scale (0 = worst outcome, 100 = best outcome) via self-report for children and proxy report for parents.19,20

Post hoc outcomes included the proportion of patients in each TCD category (normal, intermediate, abnormal, occlusion), the subscores of both cognitive and quality of life scales, as well as anthropometric and biological measures that were performed to determine whether growth, anemia, and hemolysis could be affected by the treatments.

Adverse events were recorded in accordance with the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.03.

Statistical Analysis

The initial power analysis determined that for a type I error rate of 5% and 80% statistical power, 21 children should be included in the transplantation group and 42 children in the chronic transfusion group to demonstrate a minimal clinically important difference (MCID) of 40 cm/s, allowing a decrease of the stroke risk from 40% when TAMV was 200 cm/s or greater to 2% if TAMV was less than 170 cm/s2. We had previously observed such an MCID value, with the mean TAMV decreasing from 140 cm/s to 100 cm/s (SD, 40 cm/s) and assuming a prevalence of 1 of 3 donor availability.14 The protocol was amended in February 2013 because of a higher than expected prevalence of having a matched sibling donor (47.8% vs 33%) (eMethods in Supplement 2). Sample size computation was revised, showing that at least 63 children (32 transfused and 31 transplanted) would need to be enrolled to have 90% power to detect the same outcome difference, with a 50% matched sibling donor prevalence and variance ratio up to 1.5.

Baseline characteristics were summarized using mean (SD) or percentages. Two analyses of the primary and secondary outcomes were prespecified. First, analyses were performed according to the intention-to-treat principle, with group allocation based only on matched sibling donor availability.21-23 Second, to control for confounding24,25 (eFigure 1 in Supplement 2), the propensity score for undergoing transplantation was estimated by a multivariable logistic regression model, with donor availability as the dependent variable and age, sex, and number of siblings without SCA as covariates. Matching was performed using a 1:1 matching protocol with replacement, with a caliper width equal to 0.15 of the SD of the logit of the propensity score. To check for misspecification of the model, the balance across the study groups was assessed by the C statistic.25 Comparisons of the outcomes were performed in the matched sample by paired t test for continuous variables and McNemar test for binary variables. Treatment effect was estimated by the mean difference in outcomes, with exact 95% CIs computed from paired data.

There were few missing data for TCD imaging, ie, 2 of 201 (1%), and no difference between children with or without missing data on prespecified outcomes (eTable 2 in Supplement 2); thus, data were assumed to be missing at random. A sensitivity analysis was performed using multiple imputation. Post hoc treatment by stroke history interaction on the primary outcome was assessed.26

All statistical tests were 2-sided, with P < .05 denoting statistical significance. No adjustment of P values was performed to account for multiple comparisons, so all secondary analyses should be considered exploratory. All statistical analyses were performed using SAS version 9.3 (SAS Inc) and R version 3.5.1 (R Project for Statistical Computing [https://www.R-project.org/]).

Results
Study Participants

Among 121 patients with a history of abnormal TCD velocities, 47 did not have a sibling without SCA and 7 families refused HLA typing. Thus, 67 children (median age, 7.6 years; 32 boys, 35 girls) were enrolled. Thirty-two patients were included in the transplantation group and 35 in the standard care group. All patients were alive at 3 years, and no patient was lost to follow-up (Figure 1).

Baseline characteristics are summarized in Table 1. The parents of 61 patients were first-generation African emigrants, while 6 families living in the French West Indies had been African emigrants several generations ago. Seven patients had a history of overt stroke. The 2 groups differed on age, sex, and number of siblings. Based on the propensity score, 25 of the 32 transplanted children could be matched. Imbalances between groups were decreased after matching, with a C statistic index of 0.730 before matching and 0.496 after matching.

Treatment Strategies

The 35 patients with no matched sibling donor were maintained on chronic transfusion for at least 1 year after enrollment. Between 1 and 3 years, 15 patients were switched to hydroxyurea.

The 32 patients with a matched sibling donor were transplanted either with bone marrow (n = 24), cord blood (n = 4), or both (n = 4).

Primary Outcome

At 1 year, the highest TAMV was on average significantly lower in the transplantation group than in the standard care group (129.4 cm/s vs 169.3 cm/s; difference, −39.9 cm/s [95% CI, −58.8 to −21.0]; P < .001) (Table 2). In the matched sample, the highest TAMV was 129.6 cm/s in the transplantation group vs 170.4 in the standard care group (difference, −40.8 cm/s [95% CI, −62.9 to −18.6]; P < .001). There was no statistically significant interaction with history of stroke (P = .53).

Prespecified Secondary Outcomes

Results of the secondary outcomes according to treatment group, both in the original and the matched samples, are reported in Table 2. After multiple imputation, results were similar (eTable 3 in Supplement 2).

Velocities

At 3 years, TCD imaging was not assessed in 1 child in the standard care group. The highest TAMV was lower on average in the transplantation group than in the standard care group both in the original sample (112.4 cm/s vs 153.6 cm/s; difference, −41.2 cm/s [95% CI, −61.9 to −20.6]; P < .001) and in the matched sample (112.4 cm/s in the transplantation group vs 156.7 cm/s in the standard care group; difference, −44.3 cm/s [95% CI, −71.9 to −21.1]; P = .001) (Figure 2A). At 1 year, the percentage of patients with normalized velocity was also higher after transplantation than with standard care in the original sample (84.0% with transplantation vs 49.0% with standard care; difference, 35.0% [95% CI, 14.3% to 57.3%]; P = .001) and the matched sample (80.0% with transplantation vs 48.0% with standard care; difference, 32.0% [95% CI, 0.2% to 58.6%]; P = .045). At 3 years, the difference was still significant in the original sample (87.5% with transplantation vs 54.3% with standard care; difference, 33.2% [95% CI, 12.4% to 54.3%]; P = .002) but was not significant after matching (84.0% with transplantation vs 64.0% with standard care; difference, 20.0% [95% CI, −9.2% to 44.0%]; P = .16).

Overt Ischemic Strokes

No patient in either group experienced an overt ischemic stroke, and all were alive without ischemic stroke since enrollment.

Ischemic Lesions

One child from the standard care group did not undergo MRI or MRA at 1 or 3 years because of technical reasons. During the 3-year follow-up, 3 new patients in the standard care group developed cerebral ischemic lesions, whereas no new patient developed any cerebral ischemic lesions in the transplantation group. Infarct scores were not significantly different between both groups at 1 and 3 years, either in the original or the matched samples.

Stenoses on MRA

In the standard care group, 2 new patients developed stenosis during the 3 years, and 1 patient in whom stenosis had disappeared at 1 year with chronic transfusion developed stenosis again when taking hydroxyurea, whereas no new patient developed stenosis after transplantation. Stenosis scores were not significantly different between groups at 1 and 3 years (Figure 2B).

Cognitive Performance

Sixty children were assessed for cognitive performance at 1 year and 45 at 3 years. No significant difference was found between groups at 1 year (74.6 in the transplantation group vs 83.9 in the standard care group; difference, −9.3 [95% CI, −18.7 to 10.3]; P = .13) and 3 years (76.4 in the transplantation group vs 79.4 in the standard care group; difference, −3.0 [95% CI, −13.7 to 7.7]; P = .77).

Quality of Life

Quality of life was assessed in 58 patients at 1 and 3 years. In the original sample, transplanted children reported better quality of life than those receiving standard care only at 3 years (84.8 in the transplantation group vs 73.2 in the standard care group; difference, 11.6 [95% CI, 5.0 to 18.1]; P = .001), while their parents reported improved quality of life at 1 year (88.3 in the transplantation group vs 69.7 in the standard care group; difference, 18.6 [95% CI, 12.1 to 25.0]; P < .001) and 3 years (84.0 in the transplantation group vs 73.1 in the standard care group; difference, 11.0 [95% CI, 2.6 to 19.3]; P = .01). No differences were found in the matched sample.

Ferritin

Ferritin level was significantly lower in the transplantation group than in the standard care group in the original and matched samples 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). (To convert ferritin values to pmol/L, multiply by 2.247.)

Erythroid Alloimmunization

No incidence of erythroid alloimmunization was observed in either group at both 1 and 3 years.

Post Hoc Outcomes

At 3 years, occlusions were present in the transplantation group in 4 patients, while all others had normalized velocities. In the standard care group, 6 patients had occlusion, 2 still had velocities of 200 cm/s or greater, and 6 had intermediate velocities (170-199 cm/s) (eTable 4 in Supplement 2). Detailing of the cognitive scores (eTable 5 in Supplement 2) showed a significantly higher progression of the processing speed index in the transplantation group from 1 to 3 years than in the standard care group. Children in the transplantation group (eTable 6 in Supplement 2) reported higher physical and school functioning at 1 and 3 years than those in the standard care group. Parents reported higher health-related quality of life in all functioning domains (eTable 7 in Supplement 2) in the transplantation group than in the standard care group at 1 year after transplantation and higher physical and emotional functioning at 3 years. Height and weight were not different between groups. At 1 and 3 years, leukocyte, neutrophil, platelet, and reticulocyte counts, bilirubin level, and lactate dehydrogenase level were significantly lower and hemoglobin level significantly higher in the transplantation group than in the standard care group (eTable 8 in Supplement 2).

Adverse Events

In the standard care group, a reversible hyperammonemic coma without cerebral infarct on MRI occurred in a patient treated with deferasirox. One case of papillary necrosis, 1 case of pneumonia, and 1 cytomegalovirus primary infection with hepatic cytolysis were observed during the first year. Thereafter, among the 15 patients switched to hydroxyurea, recurrence of abnormal TCD velocities was observed 6 months after transfusion cessation in 1 patient who again received chronic transfusion.

In the transplantation group, acute GVHD with only cutaneous manifestations was observed in 5 patients: grade I (n = 2), grade II (n = 2), and grade III (n = 1). Cumulative incidence of acute GVHD grade II or higher was 9.4% (95% CI, 0% to 19.8%). At 3 years, no patient had SCA symptoms or chronic GVHD. No veno-occlusive disease was observed. The other adverse events were posterior reversible encephalopathy syndrome with seizures (n = 2); asymptomatic reactivation of cytomegalovirus (n = 11) or Epstein-Barr virus (n = 6; of these, 5 required treatment); hemorrhagic cystitis (n = 4); aspergillosis (n = 1); hematemesis with pneumonia (n = 1); transitory hemolytic anemia (n = 1); prolonged reversible thrombopenia (n = 1); and reversible peripheral facial paralysis (n = 1) during the first year. No adverse event occurred between year 1 and year 3.

Discussion

In this multicenter study comparing outcomes after transplantation vs standard care in children with SCA and a history of abnormal TCD velocities, based on a propensity score–matched analysis, MSD-HSCT was associated with a significant reduction in cerebral velocities of 40 cm/s at 1 year. This large difference favoring the transplantation group met the study definition of the MCID, which was chosen based on an association with a reduction in the risk of stroke2 and confirms findings from a previous retrospective cohort study.14 The result is likely attributable in part to the correction of anemia but also to the exclusive presence of normal red blood cells after transplantation, in contrast to the simultaneous presence of normal and sickled red blood cells in the circulation after transfusion.

The study was not powered to detect differences in secondary outcomes; thus, whether reducing velocities by approximately 40 cm/s via MSD-HSCT will be further associated with reduced incidence of stenosis and silent infarct, and with improvement of cognitive functioning, remains to be determined. Nevertheless, no infarct or stenosis occurred after MSD-HSCT, whereas these did occur in 9% and 6% of patients, respectively, in the standard care group.

Chronic transfusions in patients with abnormal TCD velocities have been reported to reduce the risk of first stroke by 90% at 30 months,3 from 11%7 to only 1.9%11 by age 18 years in a newborn cohort screened with TCD, and from 0.88 per 100 person-years in 1991-1998 to 0.17 per 100 person-years in 2000 in California,27 but the STOP-2 trial suggested that lifelong chronic transfusions might be needed for primary prevention of stroke.10 Hydroxyurea was not inferior to chronic transfusion, after at least 1 year of chronic transfusion, in maintaining velocities at 24 months in patients without history of stroke and with a history of abnormal velocities, but among the 83 patients who completed the study treatment, 19 (22.9%) still had intermediate or abnormal velocities.13 Moreover, recurrence of abnormal TCD velocities was observed in about one-third of the patients from another cohort as late as 4 years after hydroxyurea initiation, whereas no such recurrence was observed after transplantation.28 Normalization of velocities appears to be a surrogate for prevention of stroke and, in the present trial, the percentage of children with normalized velocities was 30% higher after transplantation at 1 year. These data suggest that MSD-HSCT might allow cessation of transfusions and hydroxyurea in patients with a history of abnormal TCD velocities.

The risk-benefit balance between MSD-HSCT and other treatments needs to be considered. Chronic transfusion exposes patients to a high risk of alloimmunization and iron overload and requires good venous access. Concerns have been raised about long-term hydroxyurea treatment, such as infertility risk in men29 and adherence, while MSD-HSCT may be responsible for early death, GVHD, and sterility risk. However, since the first MSD-HSCT results reported by Belgian,30,31 French,14,32 and US33,34 teams, significant progress has been made. In France, transplant-related mortality has been reduced to 1.3% since 2005,35 favorably comparing with the 2.5% risk of SCA-related death observed by age 18 years.11 The risk of chronic GVHD has been limited by administering high doses of antithymoglobulin and was not observed in this young cohort. The risk of infertility is significant with myeloablative HSCT but may be minimized by performing ovarian36 or testis37 pretransplant cryopreservation or by using nonmyeloablative conditioning.38 Another concern about MSD-HSCT is that matched sibling donors are not always available; the observed proportion of patients with a matched sibling donor was higher than previously reported in the US literature38 but consistent with the high number of siblings without SCA in this cohort.

Limitations

This study has several limitations. First, a short-term end point (cerebral velocities at 1 year) was used rather than stroke rate, based on the low risk of stroke in children with SCA and a history of abnormal velocities because of chronic transfusion and hydroxyurea use. Choosing stroke rate as the outcome would have made the trial unfeasible; moreover, normalization of velocity can be a surrogate end point for stroke. Second, treatment allocation was based on availability of a sibling donor and not true randomization. Nevertheless, all children received the allocated treatment. Moreover, imbalances in potential confounding factors such as the number of siblings without SCA were handled using propensity score matching, which allows generation of exchangeable groups with respect to the observed confounders24,25 but does not remove the potential for unmeasured confounding. Third, no adjustment for multiple comparisons was performed; thus, analyses of secondary outcomes should be considered exploratory. Fourth, practical application of these results may not be possible in regions of the world without access to comprehensive medical care.

Conclusions

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.

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Article Information

Corresponding Author: Françoise Bernaudin, MD, Pédiatrie, Centre de Référence des Syndromes Drépanocytaires Majeurs, Centre Hospitalier Intercommunal de Créteil, 40 avenue de Verdun, 94010 Créteil, France (francoise.bernaudin@chicreteil.fr).

Accepted for Publication: November 26, 2018.

Author Contributions: Drs Bernaudin and Chevret had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Bernaudin, Verlhac, Dalle, Taïeb, Chevret.

Acquisition, analysis, or interpretation of data: Bernaudin, Verlhac, Peffault de Latour, Dalle, Brousse, Petras, Thuret, Paillard, Neven, Galambrun, Divialle-Doumdo, Pondarré, Guitton, Missud, Runel, Jubert, Elana, Ducros-Miralles, Drain, Arnaud, Kamdem, Malric, Elmaleh-Bergès, Vasile, Leveillé, Socié, Chevret.

Drafting of the manuscript: Bernaudin, Verlhac, Dalle, Taïeb, Chevret.

Critical revision of the manuscript for important intellectual content: Bernaudin, Verlhac, Peffault de Latour, Dalle, Brousse, Petras, Thuret, Paillard, Neven, Galambrun, Divialle-Doumdo, Pondarré, Guitton, Missud, Runel, Jubert, Elana, Ducros-Miralles, Drain, Arnaud, Kamdem, Malric, Elmaleh-Bergès, Vasile, Leveillé, Socié.

Statistical analysis: Bernaudin, Arnaud, Chevret.

Obtained funding: Bernaudin, Chevret.

Administrative, technical, or material support: Verlhac, Peffault de Latour, Missud, Jubert, Malric, Elmaleh-Bergès, Socié, Chevret.

Supervision: Bernaudin, Verlhac, Paillard, Galambrun, Socié.

Conflict of Interest Disclosures: Dr Bernaudin reported receiving travel fees and an honoraria from Addmedica and consulting fees from BlueBirdBio. Dr Verlhac reported receiving lecture honoraria from Addmedica and consulting fees from Novartis. Dr Peffault de Latour reported receiving grants from Alexion, Amgen, and Novartis and receiving personal fees from Alexion and Novartis. Dr Dalle reported receiving a grant from the French government (Direction de l’Hospitalisation et de l’Organisation des Soins); receiving honoraria from Jazz Pharmaceuticals, Mallinkrodt, Sanofi Genzyme, Gilead, Chimerix, Astellas, Incyte, and ElsaLys; and receiving nonfinancial support from Novartis. Dr Petras reported receiving a ticket for travel from Addmedica. Dr Divialle-Doumdo reported receiving a ticket for travel from Addmedica. No other authors reported disclosures.

DREPAGREFFE Trial Investigators: Françoise Bernaudin, MD, Referral Center for Sickle Cell Disease, Department of Pediatrics, Intercommunal Créteil Hospital, University Paris-Est, Créteil; Suzanne Verlhac, MD, Referral Center for Sickle Cell Disease, Medical Imaging Department, Intercommunal Créteil Hospital, Créteil; Régis Peffault de Latour, MD, PHD, 3Bone Marrow Transplant Unit, Department of Hematology, Saint-Louis Hospital, University Paris-Diderot, Paris; Jean-Hugues Dalle, MD, PHD, Department of Pediatric Hematology, Robert-Debré Hospital, University Paris-Diderot, Paris; Valentine Brousse, MD, Referral Center for Sickle Cell Disease, Department of Pediatrics, Necker Hospital, University Paris-Descartes, Paris; Eléonore Petras, MD, Referral Center for Sickle Cell Disease, Pointe à Pitre, Guadeloupe; Isabelle Thuret, MD, Department of Pediatric Hematology, la Timone Hospital, Marseille University, Marseille; Catherine Paillard, MD, PHD, Department of Pediatric Hematology, Hautepierre Hospital, Strasbourg University, Strasbourg; Bénédicte Neven, MD, PHD, Department of Pediatric Hematology, Necker Hospital, University Paris-Descartes, Paris; Claire Galambrun, MD, Department of Pediatric Hematology, la Timone Hospital, Marseille University, Marseille; Lydia Divialle-Doumdo, MD, Referral Center for Sickle Cell Disease, Pointe à Pitre, Guadeloupe; Corinne Pondarré, MD, PHD, Referral Center for Sickle Cell Disease, Department of Pediatrics, Intercommunal Créteil Hospital, University Paris-Est, Créteil; Corinne Guitton, MD, Referral Center for Sickle Cell Disease, Department of Pediatrics, Kremlin-Bicêtre Hospital, University Paris-Sud, Paris; Florence Missud, MD, Department of Pediatric Hematology, Robert-Debré Hospital, University Paris-Diderot, Paris; Camille Runel, MD, Department of Pediatric Hematology, Bordeaux Hospital, Bordeaux; Charlotte Jubert, MD, Department of Pediatric Hematology, Bordeaux Hospital, Bordeaux; Gisèle Elana, MD, Referral Center for Sickle Cell Disease, Department of Pediatrics, Fort de France, Martinique; Elisabeth Ducros-Miralles, PhD, Referral Center for Sickle Cell Disease, Department of Pediatrics, Intercommunal Créteil Hospital, University Paris-Est, Créteil; Elise Drain, MD, Department of Child and Adolescent Psychiatry, Avicenne Hospital, Paris-13 University, Paris; Olivier Taïeb, MD, PHD, Department of Child and Adolescent Psychiatry, Avicenne Hospital, Paris-13 University, Paris; Cécile Arnaud, MD, Referral Center for Sickle Cell Disease, Department of Pediatrics, Intercommunal Créteil Hospital, University Paris-Est, Créteil; Annie Kamdem, MD, Referral Center for Sickle Cell Disease, Department of Pediatrics, Intercommunal Créteil Hospital, University Paris-Est, Créteil; Aurore Malric, MD, Referral Center for Sickle Cell Disease, Department of Pediatrics, Intercommunal Créteil Hospital, University Paris-Est, Créteil; Monique Elmaleh-Bergès, MD, Department of Medical Imagery, Debré Hospital, University Paris-Diderot, Paris; Manuela Vasile, MD, Referral Center for Sickle Cell Disease, Medical Imaging Department, Intercommunal Créteil Hospital, Créteil; Emmanuella Leveillé, RN, Referral Center for Sickle Cell Disease, Department of Pediatrics, Intercommunal Créteil Hospital, University Paris-Est, Créteil; Gérard Socié, MD, PHD, Bone Marrow Transplant Unit, Department of Hematology, Saint-Louis Hospital, University Paris-Diderot, Paris; Sylvie Chevret, MD, PHD, Department of Statistics, Saint-Louis Hospital, ECSTRA Team, UMR1153, INSERM, University Paris-Diderot, Paris; Emmanuelle Lesprit, MD, Hôpital Trousseau, Paris; Mariane de Montalembert, MD, PhD, Hôpital Necker-Enfants Malades, Paris; Malika Benkerrou, MD, Hôpital Robert-Debré, Paris; Maryse Etienne-Julian, MD, PhD, Hôpital Pointe à Pitre, Guadeloupe; Claire Berger, MD, Hôpital de St-Etienne; Françoise Fréard, neuropsychologist, Yacine Khelif, and Myriam Bernaudin, PhD, Normandie University, Le Centre national de la recherche scientifique, CERVOxy Group, Caen; Philippe Chadebech, PhD, France Pirenne MD, PhD, EFS Ile de France, INSERM U955, équipe 2 Créteil; Alain Fischer, MD, PhD, Hôpital Necker-Enfants Malades, Paris; Yves Bertrand, MD, PhD, HIOP Lyon; Gérard Michel, Hôpital de la Timone, Marseille; Patrick Lutz, MD, PhD, Laurence Lutz, MD, Hôpital Hautepierre, Strasbourg; Jean-Pierre Vannier, MD, PhD, Hôpital Charles Nicoll, Rouen; Marguerite Michau, MD, Yves Perel, MD, PhD, Hôpital de Bordeaux.

Funding/Support: This work sponsored by the Assistance Publique-Hôpitaux de Paris was supported by an institutional grant “Programme Hospitalier de Recherche Clinique” from the French Ministry of Health. Grants from the “Cordons de Vie” association allowed cognitive testing at the 3-year follow-up. Pierre Fabre Medicament provided a grant for language revision of the manuscript.

Role of the Funder/Sponsor: The funders/sponsors had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; or the decision to submit the manuscript for publication.

Additional Contributions: We are deeply grateful to the patients, their siblings, and parents who participated in this trial, all the nurses and physicians from Centers for Sickle Cell Disease and from the Francophone Society of Hematology and Cell Therapy who all contributed to the management of patient care, and Martine Torres, PhD, freelance editor, who received compensation for her critical reading of the manuscript and editorial assistance. We also thank physicians who referred patients to centers involved in the trial: Fabienne Toutain, MD, Hôpital de Rennes; Jean-François Brasme, MD, Hôpital d’Angers; François Gouraud, MD, Hôpital de Meaux; Christine Orzechowski, MD, Hôpital de Bry sur Marne; Nadia Firah, MD, Hôpital de Pau.

Data Sharing Statement: See Supplement 3.

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