Comparison of Allogeneic Matched Related Haematopoietic Stem Cell Transplantation After a Reduced Intensity Conditioning Regimen With Standard of Care in Adolescents and Adults With Severe Sickle Cell Disease
- Conditions
- Sickle Cell Disease
- Interventions
- Procedure: Allogeneic matched related haematopoietic stem cell transplantationOther: Standard arm
- Registration Number
- NCT04046705
- Lead Sponsor
- Assistance Publique - Hôpitaux de Paris
- Brief Summary
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.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- NOT_YET_RECRUITING
- Sex
- All
- Target Recruitment
- 78
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description HLA matched haematopoietic stem cell transplantation Allogeneic matched related haematopoietic stem cell transplantation Peripheral blood stem cell from matched HLA related donor. Control arm Standard arm Best standard care : Patients 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 TP, initiation of a new drug proved to improve SCD and having authorization to use in France.
- Primary Outcome Measures
Name Time Method 2 year event-free survival 2 years post-inclusion 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
- Secondary Outcome Measures
Name Time Method Percentage of transferrin saturation at 24 months LH count at 24 months Gonadic function will be measured using LH
Overall survival 2 years post-inclusion Number of days requiring hospitalization 2 years post-inclusion Number of days requiring hospitalization at 2 years post-inclusion with exclusion of the 5 first months post-inclusion
Number of vaso-occlusive crisis (VOC) requiring hospitalization 2 years post-inclusion Number of acute chest syndrome (ACS) requiring hospitalization 2 years post-inclusion Number of hospitalizations in intensive care unit 2 years post-inclusion Number of priapism 2 years post-inclusion Number of stroke episodes 2 years post-inclusion LDH count every 3 months (from inclusion to 24 months) and at Month 1, Month 2 and Month 3 in the transplant arm Changes in LDH
Percentage of patients with an aminotransferase value higher than five times the normal value every 3 months (from inclusion to 24 months) and at Month 1, Month 2 and Month 3 in the transplant arm Changes in aminotransferase
Percentage of patients with a gamma-GT value higher than five times the normal value every 3 months (from inclusion to 24 months) and at Month 1, Month 2 and Month 3 in the transplant arm Changes in gamma-GT
Percentage of patients with an Alkaline phosphatase value higher than five times the normal value every 3 months (from inclusion to 24 months) and at Month 1, Month 2 and Month 3 in the transplant arm Changes in alkaline phosphatase
Percentage of patients with a bilirubin value higher than three times the normal value every 3 months (from inclusion to 24 months) and at Month 1, Month 2 and Month 3 in the transplant arm Changes in bilirubin
Percentage of patients with a prothrombin value less than 70% every 3 months (from inclusion to 24 months) and at Month 1, Month 2 and Month 3 in the transplant arm Changes in TP
Activated partial thromboplastin time higher than 1.5 times the normal value every 3 months (from inclusion to 24 months) and at Month 1, Month 2 and Month 3 in the transplant arm Changes in TCK
Rate of hemoglobin every 3 months (from inclusion to 24 months) and at Month 1, Month 2 and Month 3 in the transplant arm Changes in hemoglobin level
Hematocrit every 3 months (from inclusion to 24 months) and at Month 1, Month 2 and Month 3 in the transplant arm Changes in hematocrit
Mean corpuscular volume every 3 months (from inclusion to 24 months) and at Month 1, Month 2 and Month 3 in the transplant arm Changes in mean corpuscular volume
Hemoglobin variants every 3 months (from inclusion to 24 months) and at Month 1, Month 2 and Month 3 in the transplant arm Changes of percentage of hemoglobin variants
Reticulocyte count every 3 months (from inclusion to 24 months) and at Month 1, Month 2 and Month 3 in the transplant arm Changes in percentage of reticulocyte
White blood cells count every 3 months (from inclusion to 24 months) and at Month 1, Month 2 and Month 3 in the transplant arm Changes in white blood cells
Platelets counts every 3 months (from inclusion to 24 months) and at Month 1, Month 2 and Month 3 in the transplant arm Changes in platelet counts
Microalbuminuria/creatininuria ratio at 24 months Ferritin level at 24 months Transferrin saturation level at 3 months FSH count at 24 months Gonadic function will be measured using FSH
Testosterone count at 24 months Gonadic function will be measured using testosterone level in men
Spermogram at 24 months Gonadic function will be measured using spermogram in men
Oestrogen count at 24 months Gonadic function will be measured using oestrogen level in women
AMH count at 24 months Gonadic function will be measured using AMH level in women
Incidence of amenorrhea at 24 months Gonadic function will be measured using incidence of amenorrhea in women
Number of parity at 24 months Percentage of patients with a proliferative retinopathy at 24 months Changes in retinopathy status (appearance, disappearance, improvement, aggravation)
Percentage of patients with a hemorrhagic retinopathy at 24 months Changes in retinopathy status (appearance, disappearance, improvement, aggravation)
Percentage of patients with retinal detachment at 24 months Changes in retinopathy status (appearance, disappearance, improvement, aggravation)
Proportion of patients with keratitis at 24 months Changes in retinopathy status (appearance, disappearance, improvement, aggravation)
Proportion of patients with uveitis at 24 months Changes in retinopathy status (appearance, disappearance, improvement, aggravation)
Tricuspid regurgitant jet velocity at 24 months Heart function will be assessed by a transthoracic echocardiography and using tricuspid régurgitant jet velocity
Left atrial dimension at 24 months Heart function will be assessed by a transthoracic echocardiography using left atrial dimension indexed to body surface
Left ventricular dimension at 24 months Heart function will be assessed by a transthoracic echocardiography using left ventricular dimension indexed to body surface
Ventricular mass index value at 24 months Heart function will be assessed by a transthoracic echocardiography using ventricular mass index
Left ventricular ejection fraction at 24 months Heart function will be assessed by a transthoracic echocardiography using left ventricular ejection fraction
Forced Expiratory Volume in one second (FEV) at 24 months Lung function will be evaluated Forced Expiratory Volume in one second (FEV) , %
DLCO at 24 months Lung function will be evaluated using DLCO the diffusion capacity of carbon monoxide
Forced vital capacity at 24 months Lung function will be evaluated using forced vital capacity (FVC)
6 minutes walk test at 24 months Lung function will be evaluated using 6 minutes walk test
Number of new episodes of avascular osteonecrosis at 24 months Number of patients for each location of new episodes of avascular osteonecrosis at 24 months Location of new episodes of avascular osteonecrosis will be assessed using radiography and magnetic resonance imaging
Fractures at 24 months Number of new episodes of fractures
Central nervous system function at 24 months Central nervous system function will be assessed using magnetic resonance Imaging with ARM/MRI
Iron overload at 24 months Iron overload will be assessed using liver and heart magnetic resonance Imaging in patients with ferritin \> 1000 microg/L
Red blood cell packed transfused at 24 months 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)
Number of delayed hemolytic transfusion reaction (DHTR) at 24 months 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
Proportion of patients with new RBC alloantibodies at 24 months New RBC alloantibodies will be assessed using blood test
Percentage of patients with an oral opioid consumption at 24 months Quality of life evaluated using MOS SF36 questionnaire at 24 months 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
Depression and Anxiety status at 12 months 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).Weight at 24 months Evolution of weight
RBC and WBC adherence at 24 months Study of RBC and WBC adherence on lymphocytes subpopulation (including NK-T cells). Modulation of WBC and RBC surface markers by allograft.
Expression of RBC and WBC surface markers at 24 months Expression of RBC and WBC surface markers on lymphocytes subpopulation
Number of severe infections at 24 months A severe infection will be defined as a CTAE score of grade 3 or 4
GvHD incidence at 24 months Grading of GvHD at 12 months Grading of GvHD will be assessed using magic consortium 2016 and NIH classification
Mast cell mediator release at 24 months Master cell mediator release will be assessed using plasma sample. Modulation of mast cell mediators release by allograft (tryptase, substance P and histamine)
Chimerism in HSCT at 24 months 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
Number of days of hospitalization Number of days of hospitalization from inclusion at M24 Number of days of hospitalization from inclusion
Inflammatory cytokines at 24 months Inflammatory cytokines will be measured using serum sample. Modulation of inflammatory cytokine (TNF-alpha, IL-1, IL-6...) by allograft