Symptomatic Sickle Cell Disease Research Articles

Comparison of Outcomes of Hematopoietic Cell Transplantation (HCT) for Asymptomatic Patients with Sickle Cell Disease (SCD) and That of Propensity Matched Symptomatic Patients Undergoing HCT

Introduction Hematopoietic cell transplantation (HCT), a potential curative option for sickle cell disease (SCD) has typically been offered to patients with severe disease manifestations. With improved outcomes, especially in young children receiving HCT from HLA identical donors, some clinicians are performing HCT for patients without severe manifestations. HCT is associated with risk of substantial short-term morbidity, death, and long-term sequelae. Performance of HCT in patients who have not yet suffered from complications of SCD, raises unique issues of cost-benefit tradeoff, ethics, and healthcare equity. Further, it is unknown whether patients who have not suffered complications of SCD would have better outcomes following HCT. The objective of this study was to compare the outcomes for asymptomatic patients in patients undergoing HCT for SCD and propensity matched symptomatic SCD patients undergoing HCT. Methods: We queried the HCT for SCD dataset of patients undergoing HCT between 1990-2022 and reported to the Center for International Bone Marrow Research (CIBMTR) registry. Transplant essential data had been submitted for all patients while a subset of patients was assigned to the comprehensive research form (CRF) track. On these patients HCT centers submitted detailed SCD specific baseline data, as well as outcomes relevant to SCD and organ specific complications. The main reason for HCT is one of the variables collected in the CRF. Thus, we selected patients in the CRF track for further study. We describe demographics, baseline characteristics, transplant essential outcomes including overall survival (OS) and event free survival (EFS), graft failure (GF), Acute graft versus host disease (aGVHD) and chronic GVHD (cGVHD), venocclusive disease of the liver (VOD), post-transplant pneumonia/acute chest syndrome or other pulmonary complications(ACS), nephropathy, stroke, avascular necrosis (AVN), vasocclusive crises (VOC). We created a propensity score model, adding baseline variables. For each categorical outcome variable, frequency tables and tests of difference in proportions were derived. Descriptive statistics and tests of difference in means were derived for the two numeric outcome variables. In addition, survival analysis (Cox regression modeling) was conducted to determine the time until an individual experienced graft failure or death and whether event rates were associated with group classification adjusting for age and donor type. Results: For the entire cohort of 1718 patients undergoing HCT from 1990 to 2022 patients were followed for a median 47.8 months (0.3-312.9), 73.4% of patients with age at HCT <18 years and 74.7% with Karnofsky-Lansky score ≥ 90. The 3-year OS was 91.2%, 3-year EFS 75.5%, and GF rate was 17.9%, aGVHD grades II-IV occurred in 18.3%, and cGVHD developed in 22.3%. A total of 763 patients were assigned to the CRF track. The main reason for HCT was reported for these patients, and 49 patients were reported to be asymptomatic at baseline. In the asymptomatic patients majority of the HCT were performed for patients under the age of 10 years (n = 33) in patients with Hemoglobin SS (n = 45) and most occurred between 2013-2018 (n = 24). Average follow up period was 48 months. The most common graft source and conditioning regimens utilized were bone marrow (n = 35) HLA identical sibling donor type (63.2%, n = 31), and reduced intensity conditioning (n = 25) respectively. Other donor types included HLA mismatched relative (n = 9), mismatched unrelated donor and cord blood (n = 5), and matched unrelated was used in 4 patients. There was one death, at 16.5 months with cGvHD. GF occurred in 14.3%, OS was 97.9%, EFS 83.67%, 20.4% developed aGvHD and 28.5% developed cGvHD and none developed secondary malignancies or post-transplant lymphoproliferative disorders. Propensity matched control group (Figure 1) was constructed based on age at HCT, donor type, graft type, HCT comorbidity index, SCD type. There was good variable balance with a small standardized mean difference for matched observations. There were no statistically significant differences in least mean squares for EFS, death, OS, GF, AGVHD, CGVHD, VOD, VOC, AVN, stroke or ACS between the propensity matched groups ( Figure 1). Discussion: Complications and outcomes of HCT in asymptomatic patients with SCD patients is similar to that in propensity matched symptomatic SCD patients undergoing HCT.

Outcomes after RIC and Abatacept-Based Acute and Chronic Gvhd Prophylaxis in Allogeneic Transplantation for Sickle Cell Disease - Can Calcineurin Inhibitor Use be Curtailed?

Introduction: Sickle cell disease (SCD) progression can be curtailed by successful allogeneic transplantation from suitable donors. Allogenic transplantation with reduced intensity immune suppressive conditioning (RIC) from sibling or unrelated donors was considered acceptable with the availability of an Human Leucocyte Antigen (HLA)-matched (8/8 loci) or minimally mismatched (7/8) donor on NCT00920972 and in 2018 the study was modified to include abatacept for acute and chronic graft-versus-host disease (GVHD) prophylaxis based on the incidence of severe chronic GVHD noted (13-38%) and the benefits described with abatacept1-3. An interim review of trial results following the modification of GVHD prophylaxis is presented. Methods: Patients with symptomatic SCD who were <21 years of age were enrolled on appropriate study cohorts based on the level of donor match. Cohort 1 included HLA matched donors and cohort 3 included donors mismatched at 1 of 8 major HLA loci (-A, -B, -C, -DRB1) by high resolution typing. Conditioning included alemtuzumab (distal: day -22 to -19), fludarabine (days -8 to -4) and melphalan (day -3). Thiotepa (day -4) was included for mismatched donors. GVHD prophylaxis included tacrolimus (day -1 and tapered 6-9 months later), methotrexate (days +1, 3 and 6) and abatacept (days -1, +5, 14, 28, 60, 90, 180, 270 and 365)4. Though the half-life of the drug is ~30 days, the interval was adjusted after day 100 to every 90 days to curb allogeneic T cell proliferation following complete elimination of the drug. No previous data exists on this approach. Outcomes tracked were GVHD, mortality and graft rejection (GR) (<25% donor myeloid cells/disease recurrence) Results: Nine related donor transplants (4-18 years, median 9y) and 9 unrelated donor transplants (URD) (7-20 years, median 16y) (5 mismatched) were undertaken consecutively after the addition of abatacept to the standard GVHD regimen. The duration of follow-up ranged from 2-59 months (median 44m). GR was noted in 2 patients. One patient with primary GR subsequently rejected a second graft after myeloablative conditioning. Another patient with secondary GR received a CD34-selected boost post-ATG unsuccessfully but stabilized after a flu/cy/ATG regimen and another CD34-selected boost. The most recent engraftment analysis in 17/18 patients is 98% (range, 46 to 100) for myeloid and 94.5% (range, 56 to 100) for lymphoid lineage cells. No patient developed > grade 2 acute or any chronic GVHD in the MSD group. In the URD group 1 patient each developed >grade 2 aGVHD and extensive cGVHD. Of evaluable patients, one remains on systemic immune suppression therapy >18 months post-transplant. The only mortality noted was after 2 subsequent transplants in the patient with GR. Seventeen patients remain disease free post-transplant. Disease free survival (DFS) is 94%. GVHD-free-DFS is 89%. The incidence of viral reactivation was 65% and 17% before and after day +100 respectively. Immune reconstitution was noted to normalize beyond 6-9 months. Conclusion: Transplant is beneficial in SCD, and an expansion of donor sources can help to increase the number of patients rendered disease-free. GVHD risks preclude consideration of allogeneic transplantation. A GVHD-free cure rate of >88% despite risk factors such as age and HLA-mismatch following RIC and abatacept-based GVHD prophylaxis is encouraging for allogeneic transplantation options for children and adolescents with SCD. Long-term follow-up is in progress.

Abstract 14059: Correlation Between Demographics, Clinical Characteristics, Hemolytic Markers, and Pulmonary Hypertension Confirmed by Invasive Hemodynamics in Sickle Cell Disease

Introduction: Pulmonary hypertension (PH) is a common complication and cause of death in sickle cell disease (SCD). Prior study demonstrated poor correlation between the assessment of mean pulmonary artery pressures (mPAP) by echocardiogram (TTE) and right heart catheterization (RHC) in SCD. Yet, most PH studies in SCD have used TTE for the identification of PH. We sought to better characterize the clinical features of symptomatic SCD patients with/without PH confirmed on invasive testing. Methods: All symptomatic, defined as dyspnea or shortness of breath, SCD patients with RHC between 2008-2017 in a single large center in the Chicagoland area were recruited. PH was defined by mPAP > 20 mmHg. Based on World Health Organization PH classification, Group 2 PH was differentiated from Group 1 PH by a pulmonary capillary wedge pressure (PCWP) ≥16 mmHg. Diagnosis and etiology of Group 1 PH was confirmed by chart review. We analyzed categorical and continuous variables using Pearson’s χ2 test and the Student’s t test, respectively, with Bonferroni correction as appropriate. Results: 62 individuals with SCD and invasive hemodynamic testing were identified. All were African American, 37% were female, 90.3% were homozygous SS genotype, and 74.2% were on hydroxyurea ( Table 1 ). Only mean LDH concentration was significantly different in those with PH compared to without (361 vs 448 U/L; P =0.02). Compared to Group 1 PH, those with Group 2 PH were younger (34.5 yr vs. 49 yr.; P =0.01), had higher mPAP (38 mmHg vs. 28 mmHg; P =0.002), had a higher prevalence of hypertension ( P =0.03) and chronic kidney disease ( P =0.004), and were frequently on a diuretic, angiotensin pathway blocking medication, calcium channel blocker, β-blockers, and/or nitrates ( Table 1) . Conclusions: In symptomatic patients with SCD, PH diagnosed on invasive hemodynamics is associated with higher LDH. Those with Group 2 PH tend to be younger, have worse renovascular disease, and require more cardiovascular medications.

Sickle cell disease patients with COVID-19 in Guadeloupe: Surprisingly favorable outcomes.

We investigate risk factors for hospitalization and difference between sickle cell syndromes in a cohort of COVID‐19 sickle cell disease (SCD) adult patients managed in the Reference Center of Guadeloupe. We retrospectively collected data of symptomatic SCD adult patients infected with SARS‐CoV‐2 between March and December 2020. Thirty‐eight SCD adult patients with symptomatic COVID‐19 infection were included during the first wave, representing 9.6% of the active patient file at our center. The median age (IQR) was 39 years (24–47). Four patients were obese and two had moderate renal failure. The median duration of symptoms (IQR) was 10 days (5–15). Seventeen (44.7%) patients were hospitalized, including two in intensive care unit (ICU) for acute chest syndrome. An 85‐year‐old SC patient with prostate cancer died. No difference was detected between inpatient and outpatient groups in terms of age, gender, BMI, SCD clinical complications, and in history SCD treatment. There was no difference for severity, hospitalization, length of stay, ICU stay, or death between SS or Sβ°‐thal patients and SC or Sβ+‐thal patients. These overall favorable outcomes among symptomatic patients may be related to the low prevalence of comorbidity known to be linked to the more severe forms of COVID‐19, but also to the prompt coordinated management of SCD patients in the Reference Center.

Appendicular Mucocele: About a Case Observed in Bamako

It is a globally rare condition that can present in a variety of clinical syndromes or can occur as an incidental surgical finding. It poses the double problem of its possible malignancy and the risk of gelatinous disease of the peritoneum in the event of perforation. We report a case treated in the “A” Surgery Department of the Point-G University Hospital Center (CHU) in Mali in 2022. It was a 62-year-old woman, a housewife who presented to the department. “A” surgery at the Point G University Hospital Center for pain in the iliac fossa. As a medical history, she was hypertensive on atenolol and a known diabetic on diet and metformin-based treatment, as well as symptomatic sickle cell disease (AS) and an undocumented history of peptic ulcer disease. The biological assessments revealed hyperleukocyte with granulocyte predominance. C-reactive protein was positive at 32 mg/l. Ultrasound revealed a 27 mm cystic dilation of the appendicitis in favor of appendicular mucocele. We proceeded with the appendix. The surgical specimen containing gelatinous fluid was removed and histological examination was in favor of a mucinous adenocarcinoma of the appendix.

Hematopoietic cell transplantation for sickle cell disease: updates and future directions.

Excellent outcomes in hematopoietic cell transplantation (HCT) from HLA-identical siblings, improvements in conditioning regimens, novel graft-versus-host disease prophylaxis, and the availability of alternative donors have all contributed to the increased applicability and acceptability of HCT for sickle cell disease (SCD). In young children with symptomatic SCD with an available HLA-identical related donor, HCT should be carefully considered. HCT from alternative donors is typically undertaken only in patients with severe symptoms, causing or likely to cause organ damage, and in the context of clinical trials. Patients undergoing HCT for SCD require careful counseling and preparation. They require careful monitoring of unique organ toxicities and complications during HCT. Patients must be prospectively followed for a prolonged time to determine the long-term outcomes and late effects of HCT for SCD. Thus, there is a need for a universal, longitudinal clinical registry to follow patients after HCT for SCD in conjunction with individuals who do not receive HCT to compare outcomes. Antibody-based conditioning and ex-vivo umbilical cord blood expansion are likely to improve the availability and acceptability of HCT. In addition, new disease-modifying drugs and the emerging option of the autologous transplantation of gene-modified hematopoietic progenitor cells are likely to expand the available therapeutic options and make decision-making by patients, physicians, and caregivers even more complicated. Future efforts must also focus on determining the impact of socioeconomic status on access to and outcomes of HCT and the long-term impact of HCT on patients, families, and society.

Haematopoietic progenitor cell transplantation in adults with symptomatic sickle cell disease: the time has arrived.

Haematopoietic progenitor cell transplantation in adults with symptomatic sickle cell disease: the time has arrived.

Impact of bone marrow transplantation for symptomatic sickle cell disease: an interim report

AbstractFifty children who had symptomatic sickle cell disease received matched sibling marrow allografts between September 1991 and March 1999, with Kaplan-Meier probabilities of survival and event-free survival of 94% and 84%, respectively. Twenty-six patients (16 male, 10 female) had at least 2 years of follow-up after transplantation and were evaluated for late effects of transplantation and for its impact on sickle cell-related central nervous system (CNS) and pulmonary disease. Patients ranged between 3.3 and 14.0 (median, 9.4) years of age and had a median follow-up of 57.9 (range 38-95) months after transplantation. Among 22 of 26 patients who had stable donor engraftment, complications related to sickle cell disease resolved, and none experienced further episodes of pain, stroke, or acute chest syndrome. All 10 engrafted patients with a prior history of stroke had stable or improved cerebral magnetic resonance imaging results. Pulmonary function tests were stable in 22 of the 26 patients, worse in two, and not studied in two. Seven of eight patients transplanted for recurrent acute chest syndrome had stable pulmonary function. Linear growth measured by median height standard deviation score improved from −0.7 before transplantation to −0.2 after transplantation. An adverse effect of busulfan conditioning on ovarian function was demonstrated in five of seven evaluable females who are currently at least 13 years of age. None of the four males tested had elevated serum gonadotropin levels. These data confirm that allogenic bone marrow transplantation establishes normal erythropoiesis and is associated with improved growth and stable CNS imaging and pulmonary function in most patients.

Pre-transplant myeloid and immune suppression, upfront plerixafor mobilization and post-transplant cyclophosphamide: novel strategy for haploidentical transplant in sickle cell disease.

Allogenic hematopoietic stem cell transplant is the only curative option for symptomatic sickle cell disease (SCD). HLA haploidentical related donor transplants are associated with high graft failure rates. We conceptualized a novel protocol (APOLLO protocol) using pre-transplant immune and myelosuppression (PTIS) using fludarabine, cyclophosphamide, and dexamethasone followed by augmented John Hopkins protocol by adding thiotepa to conditioning. Twenty-five consecutive patients suffering from symptomatic SCD were enrolled into the study. We added upfront plerixafor to granulocyte colony stimulating factor (GCSF) for mobilization of healthy donors. Graft versus host disease (GvHD) prophylaxis was done using post-transplant cyclophosphamide, sirolimus, and mycophenolate mofetil. Graft failure was not seen in any of our patients. Five patients developed acute grade II/IV GvHD (4 classical acute, 1 late onset), 3 had limited chronic GvHD. Out of 25 evaluable patients, 22 are alive and disease free, making an overall survival (OS) and disease-free survival (DFS) of 88% with a median follow up of 485 days (range 198-802). T-cell-replete haploidentical transplant with PTIS, augmented John Hopkins conditioning and plerixafor based mobilization is a safe and effective way of treating patients suffering from SCD with minimal or no risk of graft failure and acceptable GvHD rates.

Reduced Intensity Conditioning for Haploidentical Bone Marrow Transplantation in Patients with Symptomatic Sickle Cell Disease: BMT CTN Protocol 1507

Background: Hematopoietic cell transplantation (HCT) has curative potential in sickle cell disease (SCD). A reduced intensity haploidentical bone marrow transplant (haplo-BMT) platform piloted by investigators at Johns Hopkins, addressed key barriers in HCT for SCD, donor availability and toxicity, but had a graft rejection rate of 43%. (Blood. 2012;120(22):4285-4291). Subsequently, a Vanderbilt University Medical Center supported multi-institution learning collaborative with London, France and United States was developed in 2013 with the objective of reducing this graft rejection rate. Evolution of this haplo-BMT platform with the addition of only thiotepa, resulted in a reduction in the graft rejection rate to 7% (1 of 15), an event free survival (EFS) of 93% (14 of 15), > 95% stable donor engraftment at 6 months and 100% overall survival (Biol Blood Marrow Transplant. 2019 Jun;25(6):1197-1209). Based on the preliminary data from the learning collaborative, we initiated an NIH sponsored BMT CTN, dual-strata, phase II, multi-center prospective clinical trial, (clinicaltrials.gov # NCT03263559) to estimate event free survival (EFS) at 2 years in children with neurological morbidity and adults with severe SCD. Study Design and Methods: Eligibility: Patients are stratified into 2 groups: (1) children with SCD (Hb SS or Sβ+ Thalassemia) between 5.00 - 14.99 years of age with central nervous system (CNS) disease (stroke, elevated transcranial Doppler (TCD) with evidence of intracranial vasculopathy; silent cerebral infarction) and (2) adults with severe SCD (Hb SS, SC, Sβ° thalassemia, Sβ+ Thalassemia, SD, S-OArab), between 15.00 - 45.99 years of age who have had a stroke, recurrent ACS, recurrent vaso-occlusive pain episodes, chronic transfusions to prevent sickle complications and tricuspid valve regurgitant jet velocity (TRJV) ≥2.7 m/sec. Participants must have an HLA haploidentical first degree relative donor with 2, 3, or 4 (out of 8) HLA-mismatches who is willing and able to donate bone marrow. Those with an HLA-matched sibling are excluded. Primary objective is to estimate EFS at 2 years after haplo-BMT in patients with SCD enrolled in each stratum. Secondary objectives include determining the effect of haplo-BMT on clinical and laboratory manifestations of SCD by 2 years post-transplant and determining the incidence of other transplant-related outcomes. A key secondary analysis will be central adjudication of CNS progression in children and adults with evidence of previous CNS injury. Treatment Description: Preconditioning with hydroxyurea 30mg/kg daily (Day -70 to Day -10). The conditioning regimen includes: Thymoglobulin (rATG) (0.5mg/kg on Day -9, 2mg/kg on Day -8, Day -7), Thiotepa 10mg/kg on Day -7, Fludarabine (30mg/m2 on Day -6 to Day -2), Cyclophosphamide 14.5mg/kg on Day -6 and Day -5, and TBI 200cGy on Day -1. Day 0 is the day of infusion with non T-cell depleted bone marrow. Cyclophosphamide 50 mg/kg and Mesna 40mg/kg is given on Days +3 and +4, and GVHD prophylaxis (sirolimus and mycophenolate mofetil) begin on Day +5 (Figure). Study Accrual and Endpoints: The target sample size is 40 patients enrolled and treated in each stratum; if the stopping rule for graft failure is triggered within the first 12 evaluable participants in either stratum using the 200cGy dose of TBI and the DSMB and sponsor approve the pre-defined switch in conditioning regimen, then accrual for that strata will restart under the modified conditioning regimen with 400 cGy TBI. The estimated accrual period is 4 years. The rate of overall mortality by Day 180 after starting hydroxyurea therapy pre-transplant, acute grade III-IV GVHD at 100 days, and severe chronic GVHD at 18 months post-transplant will be monitored by a sequential probability ratio test (SPRT) for censored exponential data for each of these. Graft failure at 100 days post-transplant will be monitored by using a SPRT for binary data. Conclusion: This NIH sponsored BMTCTN phase II trial of HLA-haploidentical HCT is active at 30 BMT CTN sites. This study will determine if a modulated conditioning regimen has adequate donor engraftment, with acceptable risks of transplant-related morbidity and mortality to support a future comparative clinical trial in SCD. Figure Disclosures Walters: AllCells, Inc: Consultancy; TruCode: Consultancy; Editas Medicine: Consultancy. Brodsky:Achillion: Research Funding; Alexion: Membership on an entity's Board of Directors or advisory committees, Other: Grant funding.

Neurocognitive functioning in symptomatic adults with sickle cell disease: A description and comparison with unaffected siblings

ABSTRACT Children and adults with sickle cell disease (SCD) are at risk for neuropsychological deficits; however, the neurocognitive functioning of adults with SCD and related comorbidities has not been widely reported in the literature. We examined specific cognitive domains in symptomatic adults with SCD and compared them with their unaffected siblings. We also examined relationships between cognitive scores, patient-reported outcomes (PROs), and medical/laboratory values. Thirty patient-sibling pairs (M patient age = 32.5 years, M sibling age = 32.1 years) completed evaluations as part of a medical clinical trial (NCT00061568). All patient and sibling neurocognitive test scores were within normal limits. Patients scored significantly lower (M = 91.0 ± 11.3) than their siblings (M = 100.6 ± 12.3; t = −3.5, p < .01) on the Wechsler Processing Speed Index. They also indicated more problems than siblings on an executive functioning questionnaire, although these differences were nonsignificant after accounting for depressive symptoms. Higher fetal hemoglobin and lower creatinine correlated with better scores on particular cognitive and PRO measures. In summary, our sample of adults with symptomatic SCD demonstrated worse processing speed and experience more executive challenges than their siblings, despite treatment with hydroxyurea. These relative weakness likely relate to disease processes but the specific physiological mechanism is unclear.

Outcomes of Hospitalization for Stem Cell Transplant in Sickle Cell Disease: Are We There Yet?

Abstract Background: Sickle cell disease (SCD) is a common hemoglobinopathy, characterized by vaso-occlusive crises and affects over 100,000 people in United States. It afflicts long-lasting organ damage with a spectrum of clinical severity. Median survival for SCD is shortened to the 6th decade of life despite advances in medical care (Elmariah et al Am J Hematol 2014). Allogeneic stem cell transplant (SCT) is a potentially curative option and is increasingly considered in patients with severe symptomatic SCD. The use of SCT is limited by donor availability and treatment related complications. Several advancements in conditioning regimen and use of alternate donor source have favorably impacted the feasibility of this approach. We identified SCT performed for sickle cell disease in the Healthcare Cost and Utilization Project National Inpatient Sample (HCUP-NIS) from 2002-2014 in an attempt to identify hospitalization outcomes, factors affecting length of stay and healthcare utilization. Methods: HCUP-NIS is a 20% stratified sample of all discharges from hospitals across 46 states in the United States and incorporates weighting algorithms to predict nationwide estimates. We used International Classification of Diseases, Ninth Revision (ICD-9) procedure codes to identify HCT hospitalizations {Bone marrow (BM):41.02, 41.03, Peripheral blood (PB): 41.05, 41.08 and Cord blood (CB): 41.06} for sickle cell disease (282.5,282.6X -282.6X). We excluded patients who underwent SCT for indications other than SCD. Surveyfreq was used to calculate proportions and surveymeans was used to calculate median length of stay and hospital charges. Kruskal-Wallis test was used for non-parametric data. Chi-square for categorical data frequency, P value of &lt; 0.05 was statistically significant. All analysis was performed using SAS 9.4. Results: Outcomes were analyzed from a total of 742 hospitalizations for SCT from 2002-2014 (table 1). Median age for stem cell transplant was 9 years. GVHD occurred in 14% of stem cell transplants. Overall, in-hospital mortality was low at 2.6% while mortality in patients who developed GVHD was 14%. Bacterial infections (including C.difficile) occurred more commonly than viral or fungal infections (table 2). Patients who developed graft vs host disease (GVHD) were also more likely to have bacterial, viral and fungal infections than those without. Pain crisis was noted in 9% of total admissions while stroke occurred in 6%. Median length of stay (LOS) was 35 days and median charges were $359,646. If GVHD developed, median LOS increased to 54 days while median charges increased to $712,324. Similarly, bacterial sepsis was associated with a longer median LOS of 63 days while median charges increased to $626,986 (table 3). Conclusions: The rate of inpatient mortality with SCT in sickle cell disease is lower than the overall inpatient mortality rate for allogeneic SCT (7%; Godara et al bbmt 2018), indicating a favorable outcome for these patients. Infections do occur commonly during the course of hospitalization, especially in association with GVHD. Length of stay is adversely impacted by occurrence of GVHD, bacterial sepsis, C.difficile infection and viral infections. While we are limited by duration of follow up in our study, these patterns suggest some essential modifiers for inpatient morbidity and mortality, therefore require validation in a large prospective study. Disclosures No relevant conflicts of interest to declare.

Responsiveness of PROMIS® Pediatric Measures to Hospitalizations for Sickle Pain and Subsequent Recovery.

The Patient-Reported Outcomes Measurement Information System(®) (PROMIS(®) ) created pediatric self-report scales measuring a variety of health attributes (domains), but their responsiveness to changes in health status has not yet been determined in children with sickle cell disease (SCD). A convenience cohort of symptomatic SCD children, aged 8-17 years, was asked to complete PROMIS pediatric scales at an initial clinic visit, at the end of a subsequent hospitalization for sickle pain, at a subsequent clinic visit or at home 2-3 weeks after hospitalization, and at a clinic visit 1-2 years after their initial assessment. A total of 121 participants (mean age 12.5 ± 3.1 years, 56.2% female) participated in the study. Pain interference and fatigue domain scores were elevated at baseline, increased substantially during hospitalization, and largely returned to baseline by the recovery period, whereas the depressive symptoms, anger, and anxiety domain scores displayed a less pronounced elevation during hospitalizations and a slower return to baseline levels. The two physical functioning scales showed a substantial decline in response to hospitalization, but only modest improvements at the recovery assessment, likely representing incomplete recovery. Several PROMIS pediatric measures were responsive to changes in health status associated with occurrence and resolution of acute vaso-occlusive pain requiring hospitalization. The substantial differences in these domains during SCD-related pain exacerbations support their potential usefulness in clinical research or in clinical practice. Further studies to characterize variations in symptom patterns over time may provide insights into strategies for more effective management of sickle pain.

Successful matched sibling donor marrow transplantation following reduced intensity conditioning in children with hemoglobinopathies.

Fifty-two children with symptomatic sickle cell disease sickle cell disease (SCD) (N = 43) or transfusion-dependent thalassemia (N = 9) received matched sibling donor marrow (46), marrow and cord product (5), or cord blood (1) allografts following reduced intensity conditioning (RIC) with alemtuzumab, fludarabine, and melphalan between March 2003 and May 2014*. The Kaplan-Meier probabilities of overall and event-free survival at a median of 3.42 (range, 0.75-11.83) years were 94.2% and 92.3% for the group, 93% and 90.7% for SCD, and 100% and 100% for thalassemia, respectively. Treatment-related mortality (all related to graft versus host disease, GVHD) was noted in three (5.7%) recipients, all 17-18 years of age. Acute and chronic GVHD was noted in 23% and 13%, respectively, with 81% of recipients off immunosuppression by 1 year. Graft rejection was limited to the single umbilical cord blood recipient who had prompt autologous hematopoietic recovery. Fourteen (27%) had mixed chimerism at 1 year and beyond; all had discontinued immunosuppression between 4 and 12 months from transplant with no subsequent consequence on GVHD or rejection. Infectious complications included predominantly bacteremia (48% were staphylococcus) and CMV reactivation (43%) necessitating preemptive therapy. Lymphocyte recovery beyond 6 months was associated with subsidence of infectious complications. All patients who engrafted were transfusion independent; no strokes or pulmonary complications of SCD were noted, and pain symptoms subsided within 6 months posttransplant. These findings support using RIC for patients with hemoglobinopathy undergoing matched sibling marrow transplantation (*www.Clinical Trials.gov: NCT00920972, NCT01050855, NCT02435901).

Hematopoietic stem cell transplantation in sickle cell disease: patient selection and special considerations.

Hematopoietic stem cell transplantation remains the only curative treatment currently in use for patients with sickle cell disease (SCD). The first successful hematopoietic stem cell transplantation was performed in 1984. To date, approximately 1,200 transplants have been reported. Given the high prevalence of this disorder in Africa, and its emergence in the developed world through immigration, this number is relatively small. There are many reasons for this; primary among them are the availability of a donor, the risks associated with this complex procedure, and the cost and availability of resources in the developing world. Of these, it is fair to say that the risks associated with the procedure have steadily decreased to the point where, if currently performed in a center with experience using a matched sibling donor, overall survival is close to 100% and event-free survival is over 90%. While there is little controversy around offering hematopoietic stem cell transplantation to symptomatic SCD patients with a matched sibling donor, there is much debate surrounding the use of this modality in “less severe” patients. An overview of the current state of our understanding of the pathology and treatment of SCD is important to show that our current strategy is not having the desired impact on survival of homozygous SCD patients, and should be changed to significantly impact the small proportion of these patients who have matched siblings and could be cured, especially those without overt clinical manifestations. Both patient families and providers must be made to understand the progressive nature of SCD, and should be encouraged to screen full siblings of patients with homozygous SCD for their potential to be donors. Matched siblings should be referred to an experienced transplant center for evaluation and counseling. In this review, we will discuss the rationale for these opinions and make recommendations for patient selection.

Reduced toxicity, myeloablative conditioning with BU, fludarabine, alemtuzumab and SCT from sibling donors in children with sickle cell disease

BU and CY (BU/CY; 200 mg/kg) before HLA-matched sibling allo-SCT in children with sickle cell disease (SCD) is associated with ~85% EFS but is limited by the acute and late effects of BU/CY myeloablative conditioning. Alternatives include reduced toxicity but more immunosuppressive conditioning. We investigated in a prospective single institutional study, the safety and efficacy of a reduced-toxicity conditioning (RTC) regimen of BU 12.8-16 mg/kg, fludarabine 180 mg/m(2), alemtuzumab 54 mg/m(2) (BFA) before HLA-matched sibling donor transplantation in pediatric recipients with symptomatic SCD. Eighteen patients, median age 8.9 years (2.3-20.2), M/F 15/3, 15 sibling BM and 3 sibling cord blood (CB) were transplanted. Mean whole blood and erythroid donor chimerism was 91% and 88%, at days +100 and +365, respectively. Probability of grade II-IV acute GVHD was 17%. Two-year EFS and OS were both 100%. Neurological, pulmonary and cardiovascular function were stable or improved at 2 years. BFA RTC and HLA-matched sibling BM and CB allo-SCT in pediatric recipients result in excellent EFS, long-term donor chimerism, low incidence of GVHD and stable/improved organ function.

Stem cell transplantation after reduced‐intensity conditioning for sickle cell disease

Sickle cell disease (SCD) is still associated with substantial morbidity and reduced life expectancy. Disease-related mortality rises to 14% in adolescents and young adults. Overall and disease-free survival following haematopoietic stem cell transplantation (HSCT) is 90% and 95%, respectively. To reduce transplant-associated late effects, the feasibility of a highly immunosuppressive reduced-intensity conditioning (RIC) regimen was explored in children with SCD and a matched sibling donor. Eight patients (median age, 9yr) and symptomatic SCD were included. The conditioning regimen consisted of fludarabine, melphalan and either thiotepa or total lymphoid irradiation plus antithymocyte globuline or alemtuzumab. The graft was bone marrow in seven and cord blood in one case. The conditioning regimen was well tolerated and no severe infectious complications occurred. All patients displayed mixed chimaerism on day +28. After a median follow-up of 4yr, 3/8 patients have mixed leucocyte chimaerism and 8/8 patients have 100% donor erythropoiesis. HSCT from matched sibling donors following a RIC regimen was well tolerated and resulted in cure in all patients studied. If confirmed in larger patient cohorts, these observations will have important implications for the indications of HSCT in children with SCD.

Myocardial Infarction in Sickle Cell Disease: Use of Translational Imaging to Diagnose an Under-Recognized Problem

Sickle cell disease (SCD) is an inherited disorder in which microvascular occlusion causes complications across multiple organ systems. The precise incidence of myocardial ischemia and infarction (MI), potentially under-recognized microvascular disease-related complications, remains unknown. The absence of typical atherosclerotic lesions seen in other patients with MI suggests a microvascular mechanism of myocardial injury. Cardiac magnetic resonance (CMR) can demonstrate microvascular disease, making it an appealing modality to assess symptomatic SCD patients. We demonstrate in several dramatic instances how CMR is uniquely able to depict cardiac microvascular obstruction in patients with SCD and chest pain, without which the possibility of myocardial injury would almost certainly be otherwise neglected. Much remains unknown regarding ischemic heart disease in patients with SCD including prevalence, detection, and management. Further work to define evaluation and management algorithms for chest pain in SCD and to develop risk assessment tools may reduce sudden cardiac death in this population.

A Pilot Study of Reduced Toxicity Conditioning (RTC) with Busulfan (Bu), Fludarabine (Flu), and Alemtuzumab Followed by Allogeneic Stem Cell Transplantation (AlloSCT) to Induce Sustained Mixed Donor Chimerism In Patients with Symptomatic Sickle Cell Disease (SCD)

AbstractAbstract 3504The only known curative therapy for patients with SCD is a matched family donor AlloSCT (Walters et al, NEJM, 1996). Complications after myeloablative AlloSCT are numerous and include death, graft versus host disease (GVHD), and infections, making reduced toxicity conditioning regimens more appealing. A major obstacle allowing most SCD patients to undergo SCT is the lack of an unaffected, HLA-matched identical sibling (Bhatia et al, BMT, 2008). Umbilical cord blood (UCB) has been proven to be an excellent alternate donor source that can safely reconstitute hematopoiesis after AlloSCT in pediatric recipients with non-malignant conditions (Cairo et al, BBMT, 2008). In this study, we report the results of a RTC regimen followed by an AlloSCT from matched family and unrelated UCB donors in selected patients with symptomatic SCD. Between August 27, 2004 and March 2, 2010, 18 patients (14M:2F) with symptomatic SCD (HbSS=10, HbSC=4, HbSßThal=4) underwent an AlloSCT. Indications for SCT included: ACS (n=8), CVA (n=2), multiple VOC (n=9), splenic sequestration (n=6) and retinopathy (n=1). Conditioning was Bu (4mg/kg × 4d < 4 yrs and 12.8mg/kg × 4d > 4 yrs), Flu (30mg/m2 × 6d), and Alemtuzumab (2mg/m2 × 1d, 6mg/m2 × 2d, and 20mg/m2 × 2d). Median age was 6.29 yrs(1.3–19.2). Median follow-up was 26 months. Donor sources: 8-6/6 HLA-matched sibling bone marrow (BM), 2–6/6 sibling UCB, 1–6/6, 4–5/6 and 3–4/6 unrelated UCB. Donors were HbAA (n=13), HbAC (n=1), HbAS(n=3), or ßThal trait (n=1). Sibling BM recipients received a median total nucleated cell (TNC) dose/kg of 7.16 × 108 (range 2.27–11.31) and a median CD34 cell dose/kg of 5.38 × 106 (range 1.50–6.83). Recipients of related or unrelated UCB received a median TNC dose/kg of 4.35 × 107 (range 3.40–9.10) and a median CD34 cell dose/kg of 2.21 × 105 (range 0.60–7.94). All received tacrolimus and mycophenolate mofetil as GVHD prophylaxis (Bhatia/Cairo et al, BBMT, 2009) and phenytoin or keppra as seizure prophylaxis for 180 days post SCT. Patients receiving sibling donor AlloSCT had a median time to neutrophil engraftment of 16 days (range 13–41). Among evaluable unrelated UCBT recipients, median time to neutrophil engraftment was 34 days (range 27–47). Four patients (all unrelated UCBT) experienced primary graft failure at day +60 post-SCT secondary to CMV (n=2), adenovirus, and low Bu Css levels with early withdrawal of MMF. Patients with sibling donors had a median time to platelet engraftment of 26 days (range 17–75). Of evaluable unrelated UCB recipients, median time to platelet engraftment was 54 days (range 43–70). Patients achieved mean whole blood donor chimerism of 71.0, 79.6, 85.7, 92.9, 90.7% and 93.2% at days 30, 60, 100, 180, 365 and 730 post-transplant, respectively. Mean erythroid (CD71) donor chimerism at these time points was 78.1, 81.1, 86.6, 90.5, 87.9% and 94.0%, respectively. Patients with non-sickle cell trait donors had median HbS levels of 0% at 1 yr (n=8) and 2 yrs (n=3) post-SCT; those with sickle cell trait donors had median HbS levels of 38.3% at 1 yr (n=3) and 39% at 2yrs (n=3) post-SCT. Among evaluable patients, the Kaplan-Meier probability of grade II-IV acute GVHD is 33.3% and of chronic GVHD is 8.3%. Among the ten donor-recipient pairs in which at least one member of the pair had CMV positivity, four experienced CMV reactivation on days +13, +26, +30 and +32 (BM: n=2, unrelated UCB: n=2). Of the four patients with primary graft failure (all unrelated UCBT recipients), one resumed chronic transfusions, two died of complications from disseminated CMV and adenoviral infections, and one received a second myeloablative SCT 1 yr after initial SCT and died of fungal sepsis. Among all patients, the Kaplan-Meier probability of OS is 81.8% (100% with sibling donors, 62.5% with UCB donors) and of EFS is 77.8% (100% with sibling donors, 50% with UCB donors) with none of these patients showing any evidence of SCD symptomatology post-SCT. The longest follow-up is 2134 days. In summary, we report the largest experience of RTC and matched family AlloSCT in selected children with symptomatic SCD with persistent long-term donor chimerism and absence of SCD symptoms or progression of disease. However, with the high incidence of viral infections and toxic deaths following unrelated UCBT, it is too premature to extend this treatment option to those SCD patients lacking a sibling donor. Disclosures:No relevant conflicts of interest to declare.

S17 A pilot study of the prevalence of sleep disordered breathing (SDB) and nocturnal hypoxia in symptomatic adults with Sickle Cell Disease (SCD) and its relationship with disease severity

IntroductionThere are few effective therapies available for the long-term management of the cardiac and renal sequelae of SCD. Identifying reversible factors, which exacerbate disease severity, would facilitate development of new...