Stroke without cerebral arteriopathy in sickle cell disease children: causes and treatment.

Cerebral arteriopathy (CA) in children with sickle cell disease (SCD) is classically described as chronic stenosis of arteries in the anterior brain circulation, leading to ischemic stroke. Some studies have, however, reported strokes in children with SCD but without CA. In order to better understand the etiology and risk factors of these strokes, we retrospectively analyzed ischemic strokes occurring in a large cohort of children over a 13-year period. Between 2007 and 2020, 25 of 1,500 children with SCD had an ischemic stroke in our center. Among them, 13 (52%) had CA, described as anatomical arterial stenosis, while 12 (48%) did not. Patients with stroke without CA were older than patients with stroke attributed to SCD-CA (9.0 years old vs. 3.6 years old; P=0.008), and more frequently had SC genotype (25% vs. 0%, respectively). Their strokes more frequently involved the posterior circulation, with cerebellar involvement in 42%. Retained stroke etiologies in patients without typical SCD-related CA were reversible cerebral vasoconstriction syndrome, cerebral fat embolism, arterial thrombosis or thromboembolism, hyperviscosity, vasculitis in a context of infectious meningo-encephalitis, and severe hemodynamic failure. No recurrence was observed in the 24 months following stroke, even though 67% of the patients in this group were no longer receiving exchange transfusions. In conclusion, in a cohort of pediatric SCD patients with an efficient stroke screening strategy, half of the ischemic strokes that occurred were related to causes other than CA. They affected a different population of SCD children and systematic long-term transfusion programs may not be necessary in these cases.

Determinants of CD19-positive vs CD19-negative relapse after tisagenlecleucel for B-cell acute lymphoblastic leukemia.

Tisagenlecleucel therapy has shown promising efficacy for relapsed/refractory (R/R) B-cell precursor acute lymphoblastic leukemia (BCP-ALL). However, relapses occur in 30-50% of patients. Determinants for CD19pos versus CD19neg relapses are poorly characterized. We report on 51 patients with R/R BCP-ALL (median age 17 years) infused with tisagenlecleucel after lymphodepletion. Complete remission rate at D28 was 96%. Prior blinatumomab increased the risk of early failure at D28. The 18-month cumulative incidence of relapse (CIR), event-free survival (EFS), and overall survival (OS) were 51%, 44%, and 74%, respectively, at a median follow-up of 15.5 months. Factors associated with a high tumor burden (occurrence of cytokine release syndrome) and prior blinatumomab were associated with an increased CIR, and a shorter EFS and OS. Pre-lymphodepletion high disease burden (MRD ≥ 10-2, SHR 10.4, p = 0.03) and detectable MRD at D28 (SHR 7.2, p = 0.006) correlated with an increased risk of CD19neg relapse. Low disease burden (SHR 5.3, p = 0.03) and loss of B-cell aplasia (BCA) (SHR 21.7, p = 0.004) predicted an increased risk of CD19pos relapses. These data highlight the impact of prior therapy on patient outcome. Finally, detectable MRD at D28 and loss of BCA both define patients at high risk of relapse for whom additional interventions are needed.

Quality risk management of the chimeric antigen receptor T cell pharmaceutical circuit in one of the first qualified European centers.

BACKGROUND AIMS: According to European Directive 2001/83/EC, chimeric antigen receptor T (CAR T) cells belong to a new class of medicines referred to as advanced therapy medicinal products (ATMPs). The specific features and complexity of these products require a total reorganization of the hospital circuit, from cell collection from the patient to administration of the final medicinal product. In France, at the cell stage, products are under the responsibility of a cell therapy unit (CTU) that controls, manipulates (if necessary) and ships cells to the manufacturing site. However, the final product is a medicinal product, and as with any other medicine, ATMPs have to be received, stored and further reconstituted for final distribution under the responsibility of the hospital pharmacy. The aim of our work was to perform a risk analysis of this circuit according to International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use Q9 guidelines on quality risk management. METHODS: We evaluated the activities carried out by the Saint-Louis Hospital CTU and pharmacy. Process mapping was established to trace all the steps of the circuit and to identify potential risks or failures. The risk analysis was performed according to failure mode, effects and criticality analysis. The criticality of each risk (minor [Mi], moderate [Mo], significant [S] or major [Ma]) was scored, and corrective actions or preventive actions (CAPAs) for Mo, S and Ma risks were proposed. RESULTS: We identified five Mo, six S and no Ma risks for the CTU part of the process. The most frequent risk was traceability failure. To reduce its frequency, we developed and validated software dedicated to ATMP activities. Another S risk was non-compliance of CAR T cell-specific steps due to the significant variability between companies. Our CAPA process was to implement procedures and design information sheets specific to each CAR T-cell program. In addition, critical steps were added to the ATMP software. Our CAPA process allowed us to reduce the criticality of identified risks to one Mi, seven Mo and three S. For the pharmacy part of the process, five Mo, two S and one Ma risk were identified. The most critical risk was compromised integrity of the CAR T-cell bag at the time of thawing. In case of unavailability of a backup bag, we designed and validated a degraded mode of operation allowing product recovery. In this exceptional circumstance, an agreement has to be signed between the physician, pharmacy, CTU and sponsor or marketing authorization holder. The implemented CAPA process allowed us to reduce the criticality of risks to three Mi and five Mo. CONCLUSIONS: Our risk analysis identified several Mo and S risks but only one Ma risk. The implementation of the CAPA process allowed for controlling some risks by decreasing their frequency and/or criticality or by increasing their detectability. The close collaboration between the CTU and pharmacy allows complete traceability of the CAR T-cell circuit, which is essential to guarantee safe use.

Evaluation of Outcomes and Quality of Care in Children with Sickle Cell Disease Diagnosed by Newborn Screening: A Real-World Nation-Wide Study in France.

This study's objective was to assess, on a national scale, residual risks of death, major disease-related events, and quality of care during the first five years in children diagnosed at birth with sickle cell disease (SCD). Data were retrospectively collected from medical files of all children with SCD born between 2006-2010 in France. Out of 1792 eligible subjects, 1620 patients (71.8% SS or S/beta°-thalassemia -SB°-) had available follow-up data, across 69 centers. Overall probability of survival by five years was 98.9%, with 12/18 deaths related to SCD. Probability of overt stroke by five years in SS/SB° patients was 1.1%, while transcranial Doppler (TCD) was performed in 81% before three years of age. A total of 26 patients had meningitis/septicemia (pneumococcal in eight cases). Prophylactic penicillin was started at a median age of 2.2 months and 87% of children had received appropriate conjugate pneumococcal vaccination at one year. By five years, the probability of survival without SCD-related events was 10.7% for SS/SB° patients. In contrast, hydroxyurea was prescribed in 13.7% and bone marrow transplant performed in nine patients only. In this study, residual risks of severe complications were low, probably resulting from a good national TCD, vaccination, and healthcare system coverage. Nonetheless, burden of disease remained high, stressing the need for disease-modifying or curative therapy.

CAR-T cells : indications actuelles en pédiatrie et perspectives de développement.

CAR T CELLS: CURRENT INDICATIONS IN CHILDREN AND PERSPECTIVES: Acute lymphoblastic leukemia (ALL) is the first cause of cancer in children. Five-year overall survival is greater than 90% but leukemia remains a major cause of death from cancer in children. A new class of immunotherapy based on a chimeric antigen receptor "CAR" targeting the CD19 on the B leukemic cells and that is transduced in an autologous or allogenic T lymphocyte will allow to transform the prognosis of refractory or relapsed B-ALL. Overall response rates range from 60 to 90% in phase I-II studies in patients with second relapse or more or with refractory disease. Persistent remissions and even cures have been observed. These very good results could lead to use this treatment in first line for patients with very high-risk disease. However, CAR-T cells production, costs and adverse events management represent major issues for the future of this therapeutic. The occurrence of CD19 negative relapses has led to develop bispecific CAR-T cells. Allogeneic CAR would permit to obtain a "CAR garage" off the shelf available from the diagnosis. Perspectives for CAR-T cells are immense but will involve technological progresses around the CAR conception and production, leading to further improve results in leukemias (ALL but also AML) and lymphomas and hopefully to the emergence of efficacy in childhood solid tumors. Cet article fait partie du numéro supplément Les cellules CAR-T : une révolution thérapeutique ? réalisé avec le soutien institutionnel des partenaires Gilead : Kite et Celgene.

Design of the DREPAGREFFE trial: A prospective controlled multicenter study evaluating the benefit of genoidentical hematopoietic stem cell transplantation over chronic transfusion in sickle cell anemia children detected to be at risk of stroke by transcranial Doppler (NCT 01340404).

BACKGROUND: Children with sickle cell anemia (SCA) have an 11% risk of stroke by the age of 18. Chronic transfusion applied in patients detected to be at risk by transcranial Doppler allows a significant reduction of stroke risk. However, chronic transfusion exposes to several adverse events, including alloimmunization and iron overload, and is not curative. Hematopoietic stem cell transplantation allows termination of the transfusion program, but its benefit has not been demonstrated. DESIGN: DREPAGREFFE (NCT01340404) is a multicenter, prospective trial enrolling SCA children younger than 15years receiving chronic transfusion due to a history of abnormal transcranial Doppler (velocities ≥200cm/s). Only those with at least one non-SCA sibling and parents accepting HLA-typing and transplantation with a genoidentical donor were eligible. Chronic transfusion was pursued in patients with no available donor, whereas others were transplanted. Comparison between the 2 arms (transfusion vs transplantation) was analyzed using both genetic randomization and propensity-score matching as a sensitivity analysis. The primary end-point was the velocity measure at 1year. Secondary endpoints were the incidence of stroke, silent cerebral infarcts and stenoses, cognitive performance in comparison with siblings, allo-immunization, iron-overload, phosphatidyl-serine, angiogenesis/hypoxia, brain injury-related factor expression, quality of life and cost. OBJECTIVES: To show that genoidentical transplantation decreases velocities significantly more than chronic transfusion in SCA children at risk of stroke. DISCUSSION: DREPAGREFFE is the first prospective study to evaluate transplantation in SCA children. It compares the outcome of cerebral vasculopathy following genoidentical transplantation versus chronic transfusion using genetic randomization and causal inference methods.

Continuous Manual Exchange Transfusion for Patients with Sickle Cell Disease: An Efficient Method to Avoid Iron Overload.

Children with sickle cell anemia (SCA) may be at risk of cerebral vasculopathy and strokes, which can be prevented by chronic transfusion programs. Repeated transfusions of packed red blood cells (PRBCs) is currently the simplest and most used technique for chronic transfusion programs. However, iron overload is one of the major side effects of this therapy. More developed methods exist, notably the apheresis of RBC (erythrapheresis), which is currently the safest and most efficient method. However, it is costly, complicated, and cannot be implemented everywhere, nor is it suitable for all patients. Manual exchange transfusions combine one or more manual phlebotomies with a PRBC transfusion. At the Reference Center of Sickle Cell Disease, we set up a continuous method of manual exchange transfusion that is feasible for all hospital settings, demands no specific equipment, and is widely applicable. In terms of HbS decrease, stroke prevention, and iron overload prevention, this method showed comparable efficiency to erythrapheresis. In cases where erythrapheresis is not available, this method can be a good alternative for patients and care centers.

Improvement of medical care in a cohort of newborns with sickle-cell disease in North Paris: impact of national guidelines.

We conducted a retrospective study on newborns with sickle-cell disease (SCD), born 1995-2009, followed in a multicentre hospital-based network. We assessed patient outcomes, medical care and compliance with the national guidelines published in December 2005. Data from 1033 patients (742 SS/Sß°-thalassaemia) with 6776 patient-years of follow-up were analysed (mean age 7·1 ± 3·9 years). SCD-related deaths (n = 13) occurred only in SS-genotype patients at a median age of 23·1 months, mainly due to acute anaemia (n = 5, including 2 acute splenic sequestrations) and infection (n = 3). Treatment non-compliance was associated with a 10-fold higher risk of SCD-related death (P = 0·01). Therapeutic intensification was provided for all stroke patients (n = 12), almost all patients with abnormal transcranial Doppler (TCD) (n = 76) or with >1 acute chest syndrome/lifetime (n = 64) and/or ≥3 severe vaso-occlusive crises/year (n = 100). Only 2/3 of patients with baseline haemoglobin <70 g/l received intensification, mainly for other severity criteria. Overall, hydroxycarbamide was under-prescribed, given to 2/3 of severe vaso-occlusive patients and 1/3 of severely anaemic patients. Nevertheless, introduction of the on-line guidelines was concomitant with an improvement in medical care in the 2006-2009 cohort with a trend towards increased survival at 5 years, from 98·3% to 99·2%, significantly increased TCD coverage (P = 0·004) and earlier initiation of intensification of therapy (P ≤ 0·01).

Acute splenic sequestration crisis in sickle cell disease: cohort study of 190 paediatric patients.

Acute splenic sequestration crisis (ASSC) is an unpredictable life-threatening complication of sickle cell disease (SCD) in infants. Here, our objective was to update available clinical information on ASSC. We retrospectively studied the 190 patients who were diagnosed at birth with SS or Sbeta(0) in the Paris conurbation between 2000 and 2009 and who experienced ASSC. They had 437 ASSC episodes (0.06/patient-year). Median age at the first episode was 1.4 years (0.1-7) and 67% of patients had more than one episode. Age was the only factor predicting recurrence: the risk was lower when the first episode occurred after 2 years versus before 1 year of age (hazard ratio, 0.60; 95% confidence interval, 0.41-0.88; P=0.025). A concomitant clinical event was found in 57% of episodes. The mortality rate was 0.53%. The treatment consisted in watchful waiting without prophylactic blood transfusions or splenectomy in 103 (54%) patients and in a blood transfusion programme in 55 (29%) patients. Overall, splenectomy was performed in 71 (37%) patients, at a median age of 4.5 years (range, 1.9-9.4). In conclusion, aggressive treatment may be warranted in patients experiencing ASSC before 2 years of age. Randomized controlled trials are needed to define the best treatment modalities.

Impact of early transcranial Doppler screening and intensive therapy on cerebral vasculopathy outcome in a newborn sickle cell anemia cohort.

Transcranial Doppler (TCD) is used to detect children with sickle cell anemia (SCA) who are at risk for stroke, and transfusion programs significantly reduce stroke risk in patients with abnormal TCD. We describe the predictive factors and outcomes of cerebral vasculopathy in the Créteil newborn SCA cohort (n = 217 SS/Sß(0)), who were early and yearly screened with TCD since 1992. Magnetic resonance imaging/magnetic resonance angiography was performed every 2 years after age 5 (or earlier in case of abnormal TCD). A transfusion program was recommended to patients with abnormal TCD and/or stenoses, hydroxyurea to symptomatic patients in absence of macrovasculopathy, and stem cell transplantation to those with human leukocyte antigen-genoidentical donor. Mean follow-up was 7.7 years (1609 patient-years). The cumulative risks by age 18 years were 1.9% (95% confidence interval [95% CI] 0.6%-5.9%) for overt stroke, 29.6% (95% CI 22.8%-38%) for abnormal TCD, which reached a plateau at age 9, whereas they were 22.6% (95% CI 15.0%-33.2%) for stenosis and 37.1% (95% CI 26.3%-50.7%) for silent stroke by age 14. Cumulating all events (stroke, abnormal TCD, stenoses, silent strokes), the cerebral risk by age 14 was 49.9% (95% CI 40.5%-59.3%); the independent predictive factors for cerebral risk were baseline reticulocytes count (hazard ratio 1.003/L × 10(9)/L increase, 95% CI 1.000-1.006; P = .04) and lactate dehydrogenase level (hazard ratio 2.78/1 IU/mL increase, 95% CI1.33-5.81; P = .007). Thus, early TCD screening and intensification therapy allowed the reduction of stroke-risk by age 18 from the previously reported 11% to 1.9%. In contrast, the 50% cumulative cerebral risk suggests the need for more preventive intervention.

Sickle cell children traveling abroad: primary risk is infection.

BACKGROUND: Pediatricians taking care of sickle cell children in France are concerned about giving travel advice. Very few articles are published and no study has been done about it. A lot of pediatricians are using their own experience to decide if sickle cell children can travel abroad. Studying the consequences of such travel for sickle cell children is important to discuss common recommendations. METHODS: We conducted a prospective study from June 2006 to December 2007 on desires to travel expressed during our consultations with sickle cell children. We studied notable events that occurred during travel and at least 2 months after return. RESULTS: Of 52 desires to travel, 10 were cancelled. All of the 42 trips were to Africa. Median duration of travel was 1.29 months (0.5-3). Median age at travel was 7.6 years (0.2-17.7). Events during travel were two hospitalizations (4.8%), a transfusion (2.4%), and four paramedical or medical examinations (9.6%). After return, four events occurred: two SS children had Plasmodium falciparum malaria (4.8%) and two had digestive bacteremia (4.8%) in SC and Sbeta+ children. No event occurred during plane travel. None of our patients died. CONCLUSIONS: The primary risk for sickle cell children traveling to Africa is infection: malaria first and digestive septicemia second. These risks are increased by long travel and poor sanitary conditions. Each travel should be prepared a long time before departure, and each pediatrician should insist on malaria prophylaxis and sanitary conditions, especially for young children. Trips should be shorter than 1 month when possible. A longer prospective study will be done to confirm these results.

Immunogenicity and safety of a pneumococcal conjugate 7-valent vaccine in infants with sickle cell disease.

OBJECTIVES: To evaluate safety and immunogenicity of the pneumococcal 7-valent conjugate vaccine (PCV7) when administered to infants with sickle cell disease (SCD) at 2, 3, and 4 months of age with a booster dose of a 23-valent pneumococcal polysaccharide vaccine (PS-23) at 15 to 18 months of age. METHODS: This open-label multicenter study in France enrolled 2-month-old infants with SCD. Blood samples for the determination of antibody concentrations to vaccine serotypes were obtained immediately before and 1 month after the primary immunization, and before and 1 month after the PS-23 booster. Local and systemic reactions were recorded on diary cards. RESULTS: Of the 51 infants enrolled, 49 received primary immunization and 46 received the booster dose. After primary immunization > or =95% of the subjects had antibody titers > or =0.35 microg/mL for the 7 serotypes. After boosting, geometric mean concentrations were high for all serotypes, ranging from 6.32 microg/mL (serotype 18C) to 29.49 microg/mL (serotype 4). Except for 1 case after administration of the booster dose, all fevers reported were less than 39 degrees C. No vaccine-related serious adverse events were reported. CONCLUSIONS: PCV7 administered at 2, 3, and 4 months of age in infants with SCD was well-tolerated, highly immunogenic, and primed for immune memory as indicated by the dramatic response to the PS-23 dose administered at 15-18 months in this study. However, the current recommended schedule is to boost with the PCV7 at 12-15 months of age and for these high-risk children, to enlarge the protection with a subsequent PS-23 dose at 2 years of age.

Long-term follow-up of pediatric sickle cell disease patients with abnormal high velocities on transcranial Doppler.

Cerebral arteriopathy can be detected in children with sickle cell disease (SCD) by transcranial Doppler (TCD). Abnormally high velocities are predictive of high stroke risk, which can be reduced by transfusion therapy. We report the results of the screening of 291 SCD children followed in our center, including the clinical and imaging follow-up of 35 children with abnormal TCDs who were placed on transfusion therapy. We postulated that patients with normal MRA findings and abnormal TCD velocities that normalized on a transfusion program could be safely treated with hydroxyurea (HU). We report their outcome (median follow-up of 4.4 years). Of 13 patients with normalized velocities on transfusion, 10 had normal MRAs, and transfusion therapy was stopped and HU begun. Four of these ten patients redeveloped high velocities off transfusion, so currently only six remain transfusion-free. Six other transplanted patients remain transfusion-free. Abnormal TCD velocities detect a high-risk group, justifying the research for suitable transplant donors. Multicenter studies comparing HU therapy to long-term transfusion might help identify which patients can avoid transfusion and its complications while avoiding vasculopathy.

[Infection in sickle cell disease]. / Infections bactériennes dans la drépanocytose.

Bacterial infection is frequent in patients with sickle cell disease. Pneumococcal bacteremia is particularly severe in young children. The risk persists in adults, especially for nosocomial infections. Prevention is directed against pneumococcal disease and includes both vaccination and prophylactic antibiotics.