Although the survival of children with sickle cell disease (SCD) has dramatically improved over the last decades in the US and Europe, mortality remains high in adults. Moreover, many children and most adults develop a chronic debilitating condition due to organ damage. Allogeneic hematopoietic stem cell transplantation (HSCT) is currently the unique curative approach; it allows the cure of more than 95% of children transplanted from a matched related donor (MRD) after a myeloablative conditioning regimen.To date, few studies have addressed the role of HSCT in SCD adults, due to the risk of graft versus host disease (GVHD) and to the toxicity expected in older patients with a higher risk of organ damage. The development of safe, non-myeloablative conditioning regimens that allow stable mixed chimerism and avoid GVHD appears as an attractive option for HSCT to cure adults with severe SCD. The investigators design a prospective multicenter trial targeting patients over 15 years with severe SCD, and compare non-myeloablative transplant (when a matched related donor (MRD) is identified) versus no HSCT (for patients lacking MRD). The main objective is to assess the benefit of HSCT on the 2-year event free survival compared to standard care. The primary endpoint is the 2-year event free survival.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
78
Allogeneic matched related haematopoietic stem cell transplantation after a reduced intensity conditioning regimen
In the standard arm, patients who will not be transplanted, will receive the best standard care according to their situation and their previous treatment: initiation of hydroxyurea, continuation or optimization of the dose of hydroxyurea, initiation or continuation of transfusion program, initiation of a new drug proved to improve SCD and having authorization to use in France
2 year event-free survival
An event will be defined as : * death from any cause * or acute grade II-IV GVHD according to the Magic consortium 2016 classification or a moderate or severe chronic GVHD according to the NIH classification * or 3 hospitalizations for VOC defined according to usual criteria * or one ACS defined by usual clinical criteria and a pulmonary infiltrate on chest film and/or thoracic computed-tomography (CT) scan * or a stroke defined as a clinical event confirmed by an MRI * or a cerebral or cervical stenosis \>25% in a new territory, or increase \>25% of previous stenosis evaluated MRI and MRI * or a increased of at least +10% of tricuspid regurgitation velocity, (confirmed by 2 echocardiography performed with a delay of at least 3 months) compared with pre-inclusion value for patients with TRV≥2.7 at inclusion
Time frame: 2 years post-inclusion
Overall survival
Time frame: 2 years post-inclusion
Number of days requiring hospitalization
Number of days requiring hospitalization at 1 year post-inclusion with exclusion of the 5 first months post-inclusion
Time frame: 1 year
Number of days requiring hospitalization
Number of days requiring hospitalization at 2 years post-inclusion with exclusion of the 5 first months post-inclusion
Time frame: 2 years post-inclusion
Number of vaso-occlusive crisis (VOC) requiring hospitalization
Time frame: 1 year post-inclusion
Number of vaso-occlusive crisis (VOC) requiring hospitalization
Time frame: 2 years post-inclusion
Number of acute chest syndrome (ACS) requiring hospitalization
Time frame: 1 year post-inclusion
Number of acute chest syndrome (ACS) requiring hospitalization
Time frame: 2 years post-inclusion
Number of hospitalizations in intensive care unit
Time frame: 1 year post-inclusion
Number of hospitalizations in intensive care unit
Time frame: 2 years post-inclusion
Number of priapism
Time frame: 1 year post-inclusion
Number of priapism
Time frame: 2 years post-inclusion
Number of stroke episodes
Time frame: 1 year post-inclusion
Number of stroke episodes
Time frame: 2 years post-inclusion
LDH count
Changes in LDH
Time frame: every 3 months (from inclusion to 24 months) and at Month 1, Month 2 and Month 3 in the transplant arm
Percentage of patients with an aminotransferase value higher than five times the normal value
Changes in aminotransferase
Time frame: every 3 months (from inclusion to 24 months) and at Month 1, Month 2 and Month 3 in the transplant arm
Percentage of patients with a gamma-GT value higher than five times the normal value
Changes in gamma-GT
Time frame: every 3 months (from inclusion to 24 months) and at Month 1, Month 2 and Month 3 in the transplant arm
Percentage of patients with an Alkaline phosphatase value higher than five times the normal value
Changes in alkaline phosphatase
Time frame: every 3 months (from inclusion to 24 months) and at Month 1, Month 2 and Month 3 in the transplant arm
Percentage of patients with a bilirubin value higher than three times the normal value
Changes in bilirubin
Time frame: every 3 months (from inclusion to 24 months) and at Month 1, Month 2 and Month 3 in the transplant arm
Percentage of patients with a prothrombin value less than 70%
Changes in TP
Time frame: every 3 months (from inclusion to 24 months) and at Month 1, Month 2 and Month 3 in the transplant arm
Activated partial thromboplastin time higher than 1.5 times the normal value
Changes in TCK
Time frame: every 3 months (from inclusion to 24 months) and at Month 1, Month 2 and Month 3 in the transplant arm
Rate of hemoglobin
Changes in hemoglobin level
Time frame: every 3 months (from inclusion to 24 months) and at Month 1, Month 2 and Month 3 in the transplant arm
Hematocrit
Changes in hematocrit
Time frame: every 3 months (from inclusion to 24 months) and at Month 1, Month 2 and Month 3 in the transplant arm
Mean corpuscular volume
Changes in mean corpuscular volume
Time frame: every 3 months (from inclusion to 24 months) and at Month 1, Month 2 and Month 3 in the transplant arm
Hemoglobin variants
Changes of percentage of hemoglobin variants
Time frame: every 3 months (from inclusion to 24 months) and at Month 1, Month 2 and Month 3 in the transplant arm
Reticulocyte count
Changes in percentage of reticulocyte
Time frame: every 3 months (from inclusion to 24 months) and at Month 1, Month 2 and Month 3 in the transplant arm
White blood cells count
Changes in white blood cells
Time frame: every 3 months (from inclusion to 24 months) and at Month 1, Month 2 and Month 3 in the transplant arm
Platelets counts
Changes in platelet counts
Time frame: every 3 months (from inclusion to 24 months) and at Month 1, Month 2 and Month 3 in the transplant arm
Microalbuminuria/creatininuria ratio
Time frame: at 3 months
Microalbuminuria/creatininuria ratio
Time frame: at 6 months
Microalbuminuria/creatininuria ratio
Time frame: at 12 months
Microalbuminuria/creatininuria ratio
Time frame: at 24 months
Ferritin level
Time frame: at 3 months
Ferritin level
Time frame: at 6 months
Ferritin level
Time frame: at 12 months
Ferritin level
Time frame: at 24 months
Transferrin saturation level
Time frame: at 3 months
Percentage of transferrin saturation
Time frame: at 6 months
Percentage of transferrin saturation
Time frame: at 12 months
Percentage of transferrin saturation
Time frame: at 24 months
LH count
Gonadic function will be measured using LH
Time frame: at 24 months
FSH count
Gonadic function will be measured using FSH
Time frame: at 24 months
Testosterone count
Gonadic function will be measured using testosterone level in men
Time frame: at 24 months
Spermogram
Gonadic function will be measured using spermogram in men
Time frame: at 24 months
Oestrogen count
Gonadic function will be measured using oestrogen level in women
Time frame: at 24 months
AMH count
Gonadic function will be measured using AMH level in women
Time frame: at 24 months
Incidence of amenorrhea
Gonadic function will be measured using incidence of amenorrhea in women
Time frame: at 24 months
Number of parity
Time frame: at 24 months
Percentage of patients with a proliferative retinopathy
Changes in retinopathy status (appearance, disappearance, improvement, aggravation)
Time frame: at 12 months
Percentage of patients with a proliferative retinopathy
Changes in retinopathy status (appearance, disappearance, improvement, aggravation)
Time frame: at 24 months
Percentage of patients with a hemorrhagic retinopathy
Changes in retinopathy status (appearance, disappearance, improvement, aggravation)
Time frame: at 12 months
Percentage of patients with a hemorrhagic retinopathy
Changes in retinopathy status (appearance, disappearance, improvement, aggravation)
Time frame: at 24 months
Percentage of patients with retinal detachment
Changes in retinopathy status (appearance, disappearance, improvement, aggravation)
Time frame: at 12 months
Percentage of patients with retinal detachment
Changes in retinopathy status (appearance, disappearance, improvement, aggravation)
Time frame: at 24 months
Proportion of patients with keratitis
Changes in retinopathy status (appearance, disappearance, improvement, aggravation)
Time frame: at 12 months
Proportion of patients with keratitis
Changes in retinopathy status (appearance, disappearance, improvement, aggravation)
Time frame: at 24 months
Proportion of patients with uveitis
Changes in retinopathy status (appearance, disappearance, improvement, aggravation)
Time frame: at 12 months
Proportion of patients with uveitis
Changes in retinopathy status (appearance, disappearance, improvement, aggravation)
Time frame: at 24 months
Tricuspid regurgitant jet velocity
Heart function will be assessed by a transthoracic echocardiography and using tricuspid régurgitant jet velocity
Time frame: at 12 months
Tricuspid regurgitant jet velocity
Heart function will be assessed by a transthoracic echocardiography and using tricuspid régurgitant jet velocity
Time frame: at 24 months
Left atrial dimension
Heart function will be assessed by a transthoracic echocardiography using left atrial dimension indexed to body surface
Time frame: at 12 months
Left atrial dimension
Heart function will be assessed by a transthoracic echocardiography using left atrial dimension indexed to body surface
Time frame: at 24 months
Left ventricular dimension
Heart function will be assessed by a transthoracic echocardiography using left ventricular dimension indexed to body surface
Time frame: at 12 months
Left ventricular dimension
Heart function will be assessed by a transthoracic echocardiography using left ventricular dimension indexed to body surface
Time frame: at 24 months
Ventricular mass index value
Heart function will be assessed by a transthoracic echocardiography using ventricular mass index
Time frame: at 12 months
Ventricular mass index value
Heart function will be assessed by a transthoracic echocardiography using ventricular mass index
Time frame: at 24 months
Left ventricular ejection fraction
Heart function will be assessed by a transthoracic echocardiography using left ventricular ejection fraction
Time frame: at 12 months
Left ventricular ejection fraction
Heart function will be assessed by a transthoracic echocardiography using left ventricular ejection fraction
Time frame: at 24 months
Forced Expiratory Volume in one second (FEV)
Lung function will be evaluated Forced Expiratory Volume in one second (FEV) , %
Time frame: at 12 months
Forced Expiratory Volume in one second (FEV)
Lung function will be evaluated Forced Expiratory Volume in one second (FEV) , %
Time frame: at 24 months
DLCO
Lung function will be evaluated using DLCO the diffusion capacity of carbon monoxide
Time frame: at 12 months
DLCO
Lung function will be evaluated using DLCO the diffusion capacity of carbon monoxide
Time frame: at 24 months
Forced vital capacity
Lung function will be evaluated using forced vital capacity (FVC)
Time frame: at 12 months
Forced vital capacity
Lung function will be evaluated using forced vital capacity (FVC)
Time frame: at 24 months
6 minutes walk test
Lung function will be evaluated using 6 minutes walk test
Time frame: at 12 months
6 minutes walk test
Lung function will be evaluated using 6 minutes walk test
Time frame: at 24 months
Number of new episodes of avascular osteonecrosis
Time frame: at 24 months
Number of patients for each location of new episodes of avascular osteonecrosis
Location of new episodes of avascular osteonecrosis will be assessed using radiography and magnetic resonance imaging
Time frame: at 24 months
Fractures
Number of new episodes of fractures
Time frame: at 24 months
Central nervous system function
Central nervous system function will be assessed using magnetic resonance Imaging with ARM/MRI
Time frame: at 12 months
Central nervous system function
Central nervous system function will be assessed using magnetic resonance Imaging with ARM/MRI
Time frame: at 24 months
Iron overload
Iron overload will be assessed using liver and heart magnetic resonance Imaging in patients with ferritin \> 1000 microg/L
Time frame: at inclusion
Iron overload
Iron overload will be assessed using liver and heart magnetic resonance Imaging in patients with ferritin \> 1000 microg/L
Time frame: at 12 months
Iron overload
Iron overload will be assessed using liver and heart magnetic resonance Imaging in patients with ferritin \> 1000 microg/L
Time frame: at 24 months
Red blood cell packed transfused
Number of red blood cell packed transfused from 6 months post-inclusion (pre and early post-transplant transfusion are a standard of care and may not be counted)
Time frame: at 24 months
Number of delayed hemolytic transfusion reaction (DHTR)
DHTR will be defined as associated with hemoglobinuria/dark urine in the month following transfusion +/- bone pain with increased hemolytic markers and drop in HbA or new RBC allo-Ab
Time frame: at 3 months
Number of delayed hemolytic transfusion reaction (DHTR)
DHTR will be defined as associated with hemoglobinuria/dark urine in the month following transfusion +/- bone pain with increased hemolytic markers and drop in HbA or new RBC allo-Ab
Time frame: at 6 months
Number of delayed hemolytic transfusion reaction (DHTR)
DHTR will be defined as associated with hemoglobinuria/dark urine in the month following transfusion +/- bone pain with increased hemolytic markers and drop in HbA or new RBC allo-Ab
Time frame: at 12 months
Number of delayed hemolytic transfusion reaction (DHTR)
DHTR will be defined as associated with hemoglobinuria/dark urine in the month following transfusion +/- bone pain with increased hemolytic markers and drop in HbA or new RBC allo-Ab
Time frame: at 24 months
Proportion of patients with new RBC alloantibodies
New RBC alloantibodies will be assessed using blood test
Time frame: at 3 months
Proportion of patients with new RBC alloantibodies
New RBC alloantibodies will be assessed using blood test
Time frame: at 6 months
Proportion of patients with new RBC alloantibodies
New RBC alloantibodies will be assessed using blood test
Time frame: at 12 months
Proportion of patients with new RBC alloantibodies
New RBC alloantibodies will be assessed using blood test
Time frame: at 24 months
Percentage of patients with an oral opioid consumption
Time frame: at 3 months
Percentage of patients with an oral opioid consumption
Time frame: at 6 months
Percentage of patients with an oral opioid consumption
Time frame: at 12 months
Percentage of patients with an oral opioid consumption
Time frame: at 24 months
Quality of life evaluated using MOS SF36 questionnaire
Quality of life evaluated using MOS SF36 questionnaire (Medical Outcomes Study - 36-Item Short Form Health Survey). SF-36 is a set of generic, coherent, and easily administered quality-of-life measures. These measures rely upon patient self-reporting. Items are grouped into three categories: functional status, well-being, overall health assessment. In two dimensions, the answer is binary (yes / no) and in the other 6 in ordinal quality (3 to 6 possible answers). For each dimension, the scores for the different items are coded and then summed and transformed linearly on a scale ranging from 0 to 100. A physical composite score and a mental composite score can be calculated according to an established algorithm
Time frame: at 3 months
Quality of life evaluated using MOS SF36 questionnaire
Quality of life evaluated using MOS SF36 questionnaire (Medical Outcomes Study - 36-Item Short Form Health Survey). SF-36 is a set of generic, coherent, and easily administered quality-of-life measures. These measures rely upon patient self-reporting. Items are grouped into three categories: functional status, well-being, overall health assessment. In two dimensions, the answer is binary (yes / no) and in the other 6 in ordinal quality (3 to 6 possible answers). For each dimension, the scores for the different items are coded and then summed and transformed linearly on a scale ranging from 0 to 100. A physical composite score and a mental composite score can be calculated according to an established algorithm
Time frame: at 6 months
Quality of life evaluated using MOS SF36 questionnaire
Quality of life evaluated using MOS SF36 questionnaire (Medical Outcomes Study - 36-Item Short Form Health Survey). SF-36 is a set of generic, coherent, and easily administered quality-of-life measures. These measures rely upon patient self-reporting. Items are grouped into three categories: functional status, well-being, overall health assessment. In two dimensions, the answer is binary (yes / no) and in the other 6 in ordinal quality (3 to 6 possible answers). For each dimension, the scores for the different items are coded and then summed and transformed linearly on a scale ranging from 0 to 100. A physical composite score and a mental composite score can be calculated according to an established algorithm
Time frame: at 12 months
Quality of life evaluated using MOS SF36 questionnaire
Quality of life evaluated using MOS SF36 questionnaire (Medical Outcomes Study - 36-Item Short Form Health Survey). SF-36 is a set of generic, coherent, and easily administered quality-of-life measures. These measures rely upon patient self-reporting. Items are grouped into three categories: functional status, well-being, overall health assessment. In two dimensions, the answer is binary (yes / no) and in the other 6 in ordinal quality (3 to 6 possible answers). For each dimension, the scores for the different items are coded and then summed and transformed linearly on a scale ranging from 0 to 100. A physical composite score and a mental composite score can be calculated according to an established algorithm
Time frame: at 24 months
Depression and Anxiety status
Depression and anxiety will be assessed using Hospital Anxiety and Depression Scale (HADS) questionnaire. The HAD scale is a self-assessment scale for detecting states of depression and anxiety in the setting of an hospital medical outpatient clinic. HADS is a self-administered scale of 14 items which assessed levels of depression and anxiety, divided into 2 subscales of 7 items (Anxiety or HADS-A, Depression or HADS-D). Each item is scored on a scale of 0 to 3. A score is generated for each of the two sub-scales (sum of the 7 items, ranging from 0 to 21). Limit scores, for each of the scores, distinguish: non-cases or asymptomatic ones (score ≤ 7); probable or borderline cases (score 8-10); clearly or clinically symptomatic cases (score ≥ 11).
Time frame: at 3 months
Depression and Anxiety status
HADS is a self-administered scale of 14 items which assessed levels of depression and anxiety, divided into 2 subscales of 7 items (Anxiety or HADS-A, Depression or HADS-D). Each item is scored on a scale of 0 to 3. A score is generated for each of the two sub-scales (sum of the 7 items, ranging from 0 to 21). Limit scores, for each of the scores, distinguish: non-cases or asymptomatic ones (score ≤ 7); probable or borderline cases (score 8-10); clearly or clinically symptomatic cases (score ≥ 11).
Time frame: at 6 months
Depression and Anxiety status
Depression and anxiety will be assessed using Hospital Anxiety and Depression Scale (HADS) questionnaire. The HAD scale is a self-assessment scale for detecting states of depression and anxiety in the setting of an hospital medical outpatient clinic. HADS is a self-administered scale of 14 items which assessed levels of depression and anxiety, divided into 2 subscales of 7 items (Anxiety or HADS-A, Depression or HADS-D). Each item is scored on a scale of 0 to 3. A score is generated for each of the two sub-scales (sum of the 7 items, ranging from 0 to 21). Limit scores, for each of the scores, distinguish: non-cases or asymptomatic ones (score ≤ 7); probable or borderline cases (score 8-10); clearly or clinically symptomatic cases (score ≥ 11).
Time frame: at 12 months
Weight
Evolution of weight
Time frame: at 3 months
Weight
Evolution of weight
Time frame: at 6 months
Weight
Evolution of weight
Time frame: at 12 months
Weight
Evolution of weight
Time frame: at 24 months
Number of severe infections
A severe infection will be defined as a CTAE score of grade 3 or 4
Time frame: at 24 months
GvHD incidence
Time frame: at 12 months
GvHD incidence
Time frame: at 24 months
Grading of GvHD
Grading of GvHD will be assessed using magic consortium 2016 and NIH classification
Time frame: at 12 months
Chimerism in HSCT
Chimerism in HSCT will be assessed on total blood population and on T subset. In patients transplanted in Paris area, a more extensive centralized chimerism will be performed if donor T lymphocyte chimerism will be under 70% at 3 months post-transplant. Chimerism analysis by PCR microsatellite or by quantitative real-time PCR of insertion/deletion
Time frame: at 1 month
Chimerism in HSCT
Chimerism in HSCT will be assessed on total blood population and on T subset. In patients transplanted in Paris area, a more extensive centralized chimerism will be performed if donor T lymphocyte chimerism will be under 70% at 3 months post-transplant. Chimerism analysis by PCR microsatellite or by quantitative real-time PCR of insertion/deletion
Time frame: at 2 months
Chimerism in HSCT
Chimerism in HSCT will be assessed on total blood population and on T subset. In patients transplanted in Paris area, a more extensive centralized chimerism will be performed if donor T lymphocyte chimerism will be under 70% at 3 months post-transplant. Chimerism analysis by PCR microsatellite or by quantitative real-time PCR of insertion/deletion
Time frame: at 3 months
Chimerism in HSCT
Chimerism in HSCT will be assessed on total blood population and on T subset. In patients transplanted in Paris area, a more extensive centralized chimerism will be performed if donor T lymphocyte chimerism will be under 70% at 3 months post-transplant. Chimerism analysis by PCR microsatellite or by quantitative real-time PCR of insertion/deletionchimerism will be performed if donor T lymphocyte chimerism will be under 70% at 3 months post-transplant.
Time frame: at 6 months
Chimerism in HSCT
Chimerism in HSCT will be assessed on total blood population and on T subset. In patients transplanted in Paris area, a more extensive centralized chimerism will be performed if donor T lymphocyte chimerism will be under 70% at 3 months post-transplant. Chimerism analysis by PCR microsatellite or by quantitative real-time PCR of insertion/deletion
Time frame: at 9 months
Chimerism in HSCT
Chimerism in HSCT will be assessed on total blood population and on T subset. In patients transplanted in Paris area, a more extensive centralized chimerism will be performed if donor T lymphocyte chimerism will be under 70% at 3 months post-transplant. Chimerism analysis by PCR microsatellite or by quantitative real-time PCR of insertion/deletion
Time frame: at 12 months
Chimerism in HSCT
Chimerism in HSCT will be assessed on total blood population and on T subset. In patients transplanted in Paris area, a more extensive centralized chimerism will be performed if donor T lymphocyte chimerism will be under 70% at 3 months post-transplant. Chimerism analysis by PCR microsatellite or by quantitative real-time PCR of insertion/deletion
Time frame: at 18 months
Chimerism in HSCT
Chimerism in HSCT will be assessed on total blood population and on T subset. In patients transplanted in Paris area, a more extensive centralized chimerism will be performed if donor T lymphocyte chimerism will be under 70% at 3 months post-transplant. Chimerism analysis by PCR microsatellite or by quantitative real-time PCR of insertion/deletion
Time frame: at 24 months
Number of days of hospitalization
Number of days of hospitalization from inclusion
Time frame: Number of days of hospitalization from inclusion at M24
RBC and WBC adherence
Study of RBC and WBC adherence on lymphocytes subpopulation (including NK-T cells). Modulation of WBC and RBC surface markers by allograft.
Time frame: at inclusion
RBC and WBC adherence
Study of RBC and WBC adherence on lymphocytes subpopulation (including NK-T cells). Modulation of WBC and RBC surface markers by allograft.
Time frame: at 12 months
RBC and WBC adherence
Study of RBC and WBC adherence on lymphocytes subpopulation (including NK-T cells). Modulation of WBC and RBC surface markers by allograft.
Time frame: at 24 months
Expression of RBC and WBC surface markers
Expression of RBC and WBC surface markers on lymphocytes subpopulation
Time frame: at inclusion
Expression of RBC and WBC surface markers
Expression of RBC and WBC surface markers on lymphocytes subpopulation
Time frame: at 12 months
Expression of RBC and WBC surface markers
Expression of RBC and WBC surface markers on lymphocytes subpopulation
Time frame: at 24 months
Mast cell mediator release
Master cell mediator release will be assessed using plasma sample. Modulation of mast cell mediators release by allograft (tryptase, substance P and histamine)
Time frame: at inclusion
Mast cell mediator release
Master cell mediator release will be assessed using plasma sample. Modulation of mast cell mediators release by allograft (tryptase, substance P and histamine)
Time frame: at 12 months
Mast cell mediator release
Master cell mediator release will be assessed using plasma sample. Modulation of mast cell mediators release by allograft (tryptase, substance P and histamine)
Time frame: at 24 months
Inflammatory cytokines
Inflammatory cytokines will be measured using serum sample. Modulation of inflammatory cytokine (TNF-alpha, IL-1, IL-6...) by allograft
Time frame: at inclusion
Inflammatory cytokines
Inflammatory cytokines will be measured using serum sample. Modulation of inflammatory cytokine (TNF-alpha, IL-1, IL-6...) by allograft
Time frame: at 12 months
Inflammatory cytokines
Inflammatory cytokines will be measured using serum sample. Modulation of inflammatory cytokine (TNF-alpha, IL-1, IL-6...) by allograft
Time frame: at 24 months
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