Howard Woolley is a philanthropist with sustained commitments to medicine, education, and the performing arts. He is a member board of trustees at John Hopkins Medicine, Baltimore. He also fund for research studies for sickle cell disease through Gail Campbell Woolley Fund for Project ECHO to support Hopkins' efforts to improve sickle cell patient care, carrying forward his late wife's goals who died of sickle cell complications. He is a former senior vice president for Verizon Communications, a Fortune 16 company. He also served as public policy advisor to founding CEO of Verizon Wireless and all successors. He is a member of the National Association of Corporate Directors (NACD) and the Executive Leadership Council (ELC). He led effective Washington government relations office for Verizon Wireless. He had achieved strategic goals on multibillion dollar matters. Woolley also worked closely with general counsel on all political risk management issues and holds expertise in governance matters. Online profile

Approximately 100,000 Americans have sickle cell disease (SCD), a group of recessively inherited red blood cell disorders characterized by abnormal hemoglobin, called hemoglobin S or sickle hemoglobin, in the red blood cells. Persons with hemoglobin SS or hemoglobin Sß0 thalassemia, also known as sickle cell anemia (SCA), have the most severe form of SCD. Hemoglobin SC disease and hemoglobin Sß+ thalassemia are other common forms of SCD. Red blood cells that contain sickle hemoglobin are inflexible and can stick to vessel walls, causing a blockage that slows or stops blood flow. When this happens, oxygen cannot reach nearby tissues, leading to attacks of sudden, severe pain, called pain crises, which are the clinical hallmark of SCD. The red cell sickling and poor oxygen delivery can also cause damage to the brain, spleen, eyes, lungs, liver, and multiple other organs and organ systems. These chronic complications can lead to increased morbidity, early mortality, or both. Tremendous strides in treating and preventing the complications of SCD have extended life expectancy. Now, nearly 95% of persons born with SCD in the United States reach age 18 years; however, adults with the most severe forms of SCD have a life span that is 20–30 years shorter than that of persons without SCD. Abstract source Full text

Survival to adulthood for children with sickle cell disease (SCD) in the United States is above 95%, however morbidity and mortality substantially increase following departure from pediatric care. Acute healthcare utilization (emergency department visits and hospitalization) is highest during pediatric to adult care transition (ages 18–30). Deficits in planning and care coordination as patients move from the pediatric to adult care setting lead to breaks in care continuity and contribute to poor healthcare outcomes. A critical step in ensuring adequate care continuity during healthcare transition is engagement with the new adult provider. Although different service models of healthcare transition have been tested in other chronic diseases, there is insufficient research in the SCD population. Recognizing the need for better integration between pediatric and adult care, we implemented a co-location model of transition to adult care. Our co-location model consists of systematic overlap between pediatric and adult care by creating two levels of intersection at both the nursing and physician levels and offers organized disease education (Supporting Information). We hypothesized that among youth with SCD who received co-located pediatric–adult transitional care, acute healthcare utilization rates would not increase after transfer. Demographics, exposure to hydroxyurea and chronic transfusion therapy, acute care visits, hospitalizations, 30-day readmissions, and health-maintenance visits occurring during pediatric (ages 16–17) and adult (ages 18–19) care were collected. We compared the rate of acute healthcare utilization before and after transfer from pediatric to adult care among youth with SCD who received co-located care, and evaluated the relation between patient knowledge of SCD-related pain with healthcare utilization. Abstract source Full text

AlloSCT from HLA-matched MSD has been successful for high-risk SCD, and is the only known curative therapy (Talano/Cairo et al EJH, 2014). We have recently demonstrated 100% EFS and absence of sickle cell symptoms following reduced toxicity conditioning in HLA matched sibling donor (MSD) or cord blood AlloSCT (Bhatia/Cairo et al BMT, 2014). However, 5 out of 6 children lack an HLA MSD without SCD. Only 19% of recipients of African descent will identify a well-matched unrelated donor (MUD) and results after unrelated UCBT are poor (Radhakrishnan/Cairo et al BBMT, 2013). Recent results utilizing matched unrelated donors in a multi-center trial showed unacceptable rates of cGVHD at 62% (95% CI 41-77) (Shenoy et al Blood, 2016). We demonstrated CD34+ selection followed by T-cell addback from MUD in pediatric recipients led to 100% engraftment with minimal aGVHD (Geyer/Cairo et al BJH, 2011). Limitations in the past of various T-cell depletion methods have included a higher incidence of graft failure, delayed immune reconstitution, opportunistic fungal infection and higher incidence of cGVHD. FHI TCD AlloSCT utilizing the approach of CD34+ enrichment and T-cell addback could expand the donor pool and improve outcomes for patients with high risk SCD and have similar outcomes to AlloSCT from HLA MSD. Abstract source

Health is not just defined as the absence of disease, but also as the state of physical, emotional, and social well-being. Sickle cell anemia (SCA)-children have poor health-related quality of life (HRQL), principally because of poor physical functioning and severe pain. Improving HRQL has become an important goal of medical care. We present here the results of HRQL at 1 year in the DREPAGREFFE trial. DREPAGREFFE, a French prospective, Mendelian randomized trial with 2 arms (transfusions/transplantation) defined by random-availability of a HLA-matched sibling, enrolled SCA-children younger than 15, regularly transfused for history of abnormal velocities by TCD, with at least one non-SCA sibling, and parents agreeing to HLA-typing and transplantation. Conditioning consisted of intravenous busulfan, cyclophosphamide and rabbit anti-thymocyte globulin. HbS was maintained below 30% when transfused. Between 12/2010 and 6/2013, 67 SCA-children (7 with stroke history) were enrolled. Thirty-two had a genoidentical donor and were transplanted, while 35 (no donor) were included in the transfusion arm. No stroke was observed during the 12-months follow-up. All transplanted patients successfully engrafted; three acute-GvHD (grade≥II) were observed, but none chronic-GvHD. All patients were alive at 1-year. Transplanted patients had the same hemoglobin electrophoresis as their donor and significantly lower median [IQR] cerebral velocity, and more had normalized velocities compared to the transfusion arm. However, no significant difference in cognitive performance was observed between the 2 arms at 1-year. HRQL at 1-year, was one of the trial secondary outcome. Data were collected using the PedsQL 4.0 Generic Core Scale, a generic HRQL questionnaire with a child self-report for aged 5 through 18 and a parent proxy-report for children aged 2 through 18. The scale contains 23 items assessing physical (8), emotional (5), social (5), and school functioning (5). Four composite scores (physical, emotional, social, and school functioning) were calculated. Scores ranged from 0 to 100, with the higher scores indicating higher HRQL. At 1 year, the child self-report showed significantly better scores in transplanted than transfused children for physical health (p=0.048) and school functioning (p=0.031) (Table). Significant differences were observed for items describing “hurt” (p=0.006) and “low energy” (p=0.021), and those about missing school due to “not feeling well” (p=0.029) or “going to the hospital” (p=0.001). The parent proxy-report showed highly significant better scores in transplanted children for all scales: physical (p<0.001), emotional (p<0.001), social (p=0.005) and school functioning (p<0.001). We show here that SCA-children have better physical health and school functioning after transplantation than on chronic transfusion, and that the differences observed concern the hurt, energy and school missings, while parents report strong differences for all items. Improvement of HRQL has been previously reported after transfusions at 3-years in a randomized trial (Silent Infarct Transfusion) (DeBaun 2014), and after transplantation in non-randomized study (Bhatia 2015), but this is the first randomized trial comparing transfusion to transplantation in SCA. It has been shown that parents usually report worse HRQL for their child than the child self-reports (Panepinto 2010). This disagreement between parents and children has been reported to be related to parents’ distress or disease severity. In contrast, in the present trial, parents of transplanted children reported a better HRQL than their child, suggesting better parental well-being, which is probably related to the better HRQL observed in their child and to anticipation of a better future. Abstract source

The widespread application of allogeneic hematopoietic stem cell transplantation (HSCT) to cure patients with clinically aggressive sickle cell disease (SCD) has been limited by a lack of HLA-matched sibling donors. HSCT from a haploidentical donor represents a feasible option to increase transplant availability to a majority of the patients. However, current published studies using haploidentical donors in adults with SCD have resulted in long-term event-free survival rates of only 50-57%. Here we describe 10 consecutive haploidentical HSCT (haplo-HSCT) performed in adult patients with clinically aggressive SCD lacking an HLA-matched sibling donor. The median age of recipients was 27 years (range, 20-52 years) and all 10 patients met at least two standard SCD eligibility criteria for HSCT (Table 1). Based on our successful experience in matched related peripheral blood stem cell (PBSC) HSCT using a nonmyeloablative conditioning regimen with alemtuzumab 1mg/kg and 3 Gy total body irradiation (TBI), we initially performed two haplo-HSCT using the same conditioning regimen followed by high dose post-transplant cyclophosphamide (PT-Cy) at 50mg/kg on day+3 and +4. Both SCD patients failed to engraft donor cells and recovered autologous neutrophils on day +39 and day +34, respectively. In the following 8 patients, transplanted between September 2015 and March 2017, we utilized a modified version of the Hopkins protocol with: fludarabine 30mg/m2, Cy 14.5mg/kg, 3 Gy TBI (increased from the original 2 Gy dose), antithymocyte globulin 0.5mg/kg, PT-Cy 50mg/kg, and infusing mobilized PBSC instead of marrow cells (Table 1). G-CSF at 5µg/kg was administered starting on day +12 post-HSCT in neutropenic patients with HbS <30% and the median time to neutrophil engraftment was 22 days (range, 18-23 days). All 8 patients initially engrafted donor cells and only 1 (12%) subsequently developed secondary graft failure. The remaining 7 (88%) currently maintain a stable donor cell engraftment. Transplant related toxicities included: neutropenic fever resolving after antibiotic therapy (n=8/8), >= grade II mucositis (n=3/8), CMV reactivation (n=2/8), and small intracranial hemorrhages (n=2/8) on (i) day +10 in a patient refractory to platelet transfusions that resolved after cross-matched platelets became available, and, (ii) on day +12 in a patient with prior stroke history that resolved after increasing the platelet threshold from 50 to 100 x103/µL. Acute GVHD >= grade 2 was seen in 2/8 patients (one non-compliant with immunosuppressive treatment), with complete resolution after steroid therapy in one case, and transformation into chronic GVHD (skin, eye and liver) in the other. No other cases of chronic GVHD have been observed to date. With a median follow up of 9 months (range, 5-22 months), all 8 patients are alive and 7 (88%) maintain >90% donor cell chimerism with an improved median hemoglobin concentration from 8.8g/dL (range, 6.4-12.8g/dL) to 13.3g/dL (range, 9.9-15.3g/dL). Our study demonstrates that modifying the Hopkins conditioning regimen by increasing the TBI dose from 2Gy to 3Gy and using PBSC instead of bone marrow grafts allows 88% of SCD patients to achieve stable donor engraftment without severe toxicity. We also demonstrate that G-CSF can be safely administered to adult patients with SCD after HSCT. Haploidentical HSCT is the only curative option for many adult patients with clinically advanced SCD and our study suggests a basis for larger, multicenter clinical studies. Abstract source

Infancy is a critical time during which the first complications of sickle cell anemia (SCA) emerge. Very early prognostic factors of severity are needed to select high-risk children to offer precisely tailored therapy. Our hypothesis was that clinical, biological or genetic parameters measurable soon after birth (3 to 6 months of age) could predict severe outcomes in the first two years of life in SCA infants. Methods: Infants with SCA were offered to participate in a prospective study (ClinicalTrials.gov: NCT01207037) that included clinical and laboratory assessment at enrollment (3-6 months) and at 12, 18 and 24 months of age. The prognostic performance of conventional and SCA-specific biomarkers (notably erythroid adhesion markers, dense cells, ektacytometry indices) on disease severity was assessed using Cox’s proportional hazard regression models. The disease severity was defined as time to first occurrence of either acute splenic sequestration (ASS), vaso occlusive (VOC) event requiring hospitalization, transfusion, conditional or abnormal Trans Cranial Doppler, acute chest syndrome and death. Hazard ratios (HRs) were calculated with 95% Cis. Results: Fifty-seven infants (55 SS; 2 Sβ°; 54.4% males), diagnosed through neonatal screening, were included in the study at a mean age of 4.4 ± 1 months and longitudinally assessed with a median follow-up of 19.4 months (range 3.1-23.2). Only 1 of 57 infants had experienced a SCA-related event prior to enrolment (dactilytis). At inclusion, clinical examinations were unremarkable except for pallor found in 15 (26,3%) and none of the infants had an enlarged or palpable spleen. Growth parameters were normal. Main biological characteristics were a mild hemolytic anemia (Hb 9.3 ±1.3 g/dL; reticulocytes count: 151.2 ±76 x 109/L), increased HbF level (3.8 ±1.3 g/dL. or 41.4 ±11.7%) and presence of dense red cells (23.1 % ±10.8). Genetic analysis showed one alpha globin deletion in 18 (32.1%) and a balanced distribution of beta globin haplotypes: 16 (30.8%), 18 (34.6%) and 18 (34.6%) in the favorable (SEN/SEN, BEN/SEN, CAM/SEN or SEN/ATYP), unfavorable (CAR/CAR, CAM/CAR, CAR/ATYP or BEN/CAR) and intermediate category (other) respectively. During the 2 years duration of the study, 44 of 57 (77%) infants required 157 hospital admissions, median (range): 2 (1-12) per patient. Infection was a leading cause of hospitalization although no serious adverse event related to pneumococcal infection was noted. Eight (14%) children experienced an episode of ASS at a median (range) age of 13.4 months (7.8- 15.9) while 13 infants (22.8%) experienced at least one VOC event at a median age of 12.7 months (7-22.5), with 6 experiencing ≥ 2 episodes. Nineteen infants (33.3%) required at least one transfusion with 10 (17.6%) requiring more than 2. Altogether, 22 (38.6%) infants of this cohort experienced a SCA-related severe clinical event by 24 months of age. The Kaplan Meier estimate of the 24-month event-free rate was 54.4% (95% CI, 39.7 to 74.5%). Abstract source

Hematopoietic cell transplantation (HCT) is currently the only cure for sickle cell disease (SCD), with excellent survival using a matched related donor (MRD). Disease specific HCT registries have significantly advanced understanding of outcomes, via more comprehensive data collection in a larger number of patients. Such data may provide long-term outcomes after HCT, resulting in identification of advantages and disadvantages over conservative therapy, helping to focus future efforts on avoiding or improving the latter. Methods: A multicenter retrospective registry of transplanted SCD patients was created through the Sickle Transplant Alliance for Research (STAR). Baseline, transplant, and long-term (most recent if >2 yrs from HCT, otherwise 1 yr) outcome data was collected from 10 centers. Disease recurrence was defined as acute SCD symptoms with hemoglobin S >50%. Graft rejection was defined as whole blood or myeloid donor chimerism <5%. Pulmonary function testing values were converted to functional categories per previous reports. Pre- and post-HCT values were compared using McNemar’s test and extensions. P-values <0.05 were considered statistically significant. Results: Overall, 174 of 196 patients survived ≥1-yr post-HCT, with last assessment at 1186 d (Interquartile range, IQR: 760, 2351). Of these, 70.4% underwent HCT for clinically severe SCD from 1993-2016 (median, 2011), at 9.8±5.2 yrs (range, 1.6-25.6). Seventy-five percent (n=131) of patients received stem cells (87.0% marrow) from a MRD, and 58.1% received myeloablative conditioning, 93.7% with in vivo T cell depletion. Fourteen patients (8.1%) had rejection/disease recurrence 0.8-3.4 mo post-HCT; of these, 7 underwent a 2nd HCT. Overall, 45 patients (25.9%) developed chronic GVHD, at a median of 226 d (IQR: 140, 336), which was severe in 11 (24.4%) and extensive in 5 (11.1%). Ten patients required systemic immunosuppression 15-39 mo post-HCT, while 157 patients discontinued such at a median of 237 d (IQR: 173, 408). Donor chimerism was maintained long-term at a median of 100% in unsorted (n=101) and sorted (T: n=85, myeloid: n=69) samples, as reflected in median post-HCT hemoglobin levels of 13.0 g/dL (n=169; IQR: 11.8, 13.9). Posterior reversible encephalopathy syndrome (PRES) was reported in 18 patients (10.3%); 12 developed seizures with PRES and 9 without (12.1% with seizures). Of the 105 patients with available pre- and post-HCT brain MRIs, 2 developed new infarcts, 6 had new vasculopathy, and 10 had progression of previous infarct or vasculopathy; all but 2 of these patients had CNS disease pre-HCT . While there was no difference between pre- and post-HCT pulmonary functions (P=0.79; n=91), 10 patients normalized and 11 had deterioration. In the 13 patients with either a restrictive or obstructive pattern post-HCT, 47% had acute chest syndrome as an indication for HCT. One patient with poor cardiac function transitioned to normal function post-HCT, while 5 had a lower EF (p=0.103) and 4 a lower SF (p=0.05) post-HCT. All patients who developed an abnormal EF or SF received myeloablative conditioning (88.9%) or underwent HCT for clinically severe SCD (66.7%). Mean TR jet velocity was normal in the 64 patients that underwent this evaluation post-HCT. Immune reconstitution was robust, with median ALC 2587 (n=151; IQR: 2000, 3357) and present/normal splenic uptake on nuclear medicine scan in 90.9% (n=44). Bone age was delayed in 44.9% (n=69). Bone mineral density showed a mean spine and body Z score of -0.56 and -0.50, respectively (n=92). In post-pubertal females, 22 had normal menstruation (48.9%) and 23 menstrual irregularity (51.1%), with 13 on hormone replacement therapy; data was not obtained in 15. Abstract source

Background: We undertook a large multisite observational study (the ESCAPED Trial), collecting prospective data on experiences of care for adult patients with sickle cell disease (SCD) who were being treated in the acute setting for a painful vaso-occlusive crisis (VOC). Our aim is to compare patient centered outcomes following management of acute VOC events in the emergency department or in the infusion center. Acute care in the emergency department (ED) has historically been marked by long delays, lack of efficacy, and conflict. SCD patients report not having enough involvement in decisions about their own care and also that providers do not demonstrate respect, trust, and compassion. Little is known about patient’s perception of safety in the acute setting and this issue was raised by our PCORI patient advisory council prior to the start of our study. Here, we examine patient’s perception of safety in the acute care setting. Methods: The ESCAPED Trial is an ongoing, prospective cohort study that is recruiting across four sites (Baltimore, Cleveland, Milwaukee, and Baton Rouge). 483 adults with SCD who live in proximity to one of the study sites have been recruited and are being followed for 18 months. Data from visits for all acute, uncomplicated VOCs are collected and participants are asked to complete a survey within 72 hours of their acute visits. Included in the survey are questions about perceptions of safety. We tested for associations between subject characteristics and perceptions of safety using a generalized linear mixed model including a random intercept to control potential clustering within subjects. The questions about safety included in the study were: Overall level of medical safety (defined as ''freedom from any medical error or mistake'') you felt during your acute stay with a 5 point Likert response varying from excellent to poor and During your acute visit, were you ever concerned that any of the following would occur?: ‘Falling and being injured’, ‘A mistake or error with medications’, ‘Problems with medical equipment’, ‘A mistake by nurses’, ‘A mistake by physicians’, ‘Being mistaken for another patient’, ‘Wrong test/procedure’ or ‘Would be misdiagnosed’ with yes/no responses. Results: The average length of follow-up to date is 16.2 months with a range of (6-18) months. This analysis includes 324 subjects (324/483, 67%) who have had acute visits during the study period. These 324 subjects have had 2250 acute visits and this analysis includes 1366 survey responses from those visits. 60.5% of the sample are female, the average age of subjects is 33.8 years. The mean number of visits is 10.7 (sd 13.7) with a range of (1- 81). Participant responses can be found in the Table. In multivariate analysis, controlling for place of visit, male subjects were 63% (95%CI: 32% to 80%) more likely than women to report that the level of medical safety during their acute visit was only fair or poor. Male subjects were 3.64 (95%CI: 1.24, 10.63) times more likely to be concerned about problems with medical equipment, 2.87 (95% CI: 1.32 to 6.24) times more likely to be concerned that a physician would err, and 3.46 (95% CI: 1.41 to 8.50) times more likely to think that they would be misdiagnosed compared to female respondents. There were no sex differences in concerns over falls, being mistaken for the wrong patient, that nurses would err, that there would be a medication error or having the wrong test/procedure performed. Abstract source

Introduction: Vaso-Occlusive Crisis (VOC), the most common manifestation of sickle cell disease (SCD), is the first cause of death, particularly when complicated by an acute chest syndrome (ACS). In the PRESEV1 study, we developed a predictive score of secondary ACS in SCD patient admitted in the hospital for VOC (AUC = 0.840 [95% CI: 0.780 – 0.900]), with a negative predictive value of 98.8% for the low level risk and a positive predictive value of 39.5%. The aim of the PRESEV-2 study is to validate the predictive score of ACS on adults and children with SCD in Europe and Africa. Herein we present preliminary data on 235 adults with a severe VOC included in 11 referral centers from 4 countries. Patients and Methods: We conduct an international multicenter prospective observational study. The primary outcome measure is the occurrence of an ACS. The ACS is defined as a new auscultatory abnormality (crepitation or bronchial breathing) OR the association of a new radiologic infiltrate AND chest pain or decreased breath sounds. Secondary outcome measures are length of hospitalization, transfusion, morphine consumption, mortality and hospitalization in intensive care unit. Inclusion criteria are: SS or S-b0 thalassemia patients, VOC admitted at the emergency unit (VOC is defined as pain or tenderness affecting at least one part of the body not attributable to other causes) that required hospitalization and opioids (level 3). Exclusion criteria are: no inaugural ACS, homeless patients, pregnancy, deprived of their liberty or under guardianship, unable to understand the purpose and conditions of carrying out the study, unable to give consent. Results: From march 2016 to june 2017, 112 adult patients were included in Africa and 122 adults in Europe. Patients in Africa were younger than in Europe with a mean age, respectively, of 26 ± 7 yrs and 29 ± 8 yrs (p=0.008). Sex ratio (M/F) in Africa was 0.84 and 0.95 in Europe. Use of hydroxyurea was significantly higher in Europe (65%) than in Africa (6%) (p<0.0001). The ACS incidence was significantly higher in Africa than in Europe, respectively 22% and 11% (OR=2.24; p=0.03), in both areas the time for ACS appearance was the second day. Transfusion was performed in 27% in Africa and 6% in Europe (p<0.001), ACS was the main cause of transfusion (53.3% in Africa and 62.5% in Europe). Patients with ACS were more transfused in Africa than in Europe, respectively 64% and 35.7% but the difference was not significant. Mortality was 3.6% in Africa and was not observed in Europe; circumstances of death were stroke (1), profound anemia (1), kidney failure (1) and VOC (1). Abstract source