Hematopoietic Stem Cell Transplantation For Sickle Cell Disease Research Articles

Hematopoietic Stem Cell Transplantation in Sickle Cell Disease: A Multidimentional Review.

While exagamglogene autotemcel (Casgevy) and lovotibeglogene autotemcel (Lyfgenia) have been approved by the US Food and Drug Administration (FDA) as the first cell-based gene therapies for the treatment of patients 12 years of age and older with sickle cell disease (SCD), this treatment is not universally accessible. Allogeneic hematopoietic stem cell transplant (HSCT) has the potential to eradicate the symptoms of patients with SCD, but a significant obstacle in HSCT for SCD is the availability of suitable donors, particularly human leukocyte antigen (HLA)-matched related donors. Furthermore, individuals with SCD face an elevated risk of complications during stem cell transplantation due to SCD-related tissue damage, endothelial activation, and inflammation. Therefore, it is imperative to consider optimal conditioning regimens and investigate HSCT from alternative donors. This review encompasses information on the use of HSCT in patients with SCD, including the indications for HSCT, conditioning regimens, alternative donors, and posttransplant outcomes.

Parental perspective on the risk of infertility and fertility preservation options for children and adolescents with sickle cell disease considering hematopoietic stem cell transplantation.

Allogeneic hematopoietic stem cell transplantation (HCT) performed in children from human leukocyte antigen (HLA)-identical related donors is associated with very high survival rates and disease-free survival. Patients are exposed to gonadotoxic alkylating agents or irradiation in the HCT conditioning regimen. Consequently, infertility is a major long-term complication of HCT for sickle cell disease (SCD). We sought to understand how caregivers perceive the risk of infertility from HCT, how they perceive the options for fertility preservation, and how this risk perception impacted their decision-making to pursue HCT. We conducted qualitative interviews with primary caregivers after a consultation for HCT for SCD. Data were analyzed using descriptive qualitative analysis. We interviewed 19 primary caregivers who had attended a consultation with an HCT physician (female, age 25-59 [median 39] years). Eleven participants reported that their child had an available HLA-matched donor. Analysis revealed that (i) mothers were worried about death and graft-versus-host disease from HCT, more than about the risk of infertility; (ii) parents have a realistic understanding of the risk of infertility after HCT and take it into consideration in decision-making; (iii) parents report multiple barriers to fertility preservation. For parents actively considering HCT for their child with SCD, the risk of infertility while important was not a barrier to pursuing HCT. Inconvenience and invasiveness of fertility preservation procedures are some of the barriers to pursuing fertility preservation for their child. Future research must aim at addressing these barriers to fertility preservation.

Abstract TP178: Cerebral Infarction after Hematopoietic Stem Cell Transplantation (HSCT) in Adult Patients with Sickle Cell Disease

Introduction: Symptomatic and silent cerebral infarcts (SCIs) are common in children and adults with sickle cell disease (SCD). SCIs are associated with cognitive performance and risk of future symptomatic stroke. The incidence of overt stroke and SCI post HSCT is low in children, but there is limited information in adults. We sought to determine the impact of HSCT on the rate of new symptomatic and silent cerebral infarcts in adults with SCD. Methods: The study population included patients with SCD (HbSS, HbSC, and HbS/beta-thalassemia) that were enrolled in NIH studies (14-H-0077, 09-H-0225) and underwent HSCT from 2004-19 and received pre- and post-transplant MRI studies. MRI FLAIR, T1, and T2 images were reviewed by two independent readers and scored for presence of prior ischemic stroke and silent cerebral infarct (≥ 3mm on T2 or FLAIR images in 2 imaging planes). Changes in SCIs and ischemic strokes were compared before and after transplantation. Results: Eighty-four patients were included in the study, mean age 32.3 yrs. (range 10-65 yrs.) and 57% male. Median follow-up period was 3.3 yrs. (range: 6 months -17 yrs.) for a total of 412 patient-years. Overall, 60% had evidence of SCI and or prior ischemic stroke at transplant; 54% (45/84) with SCI and 23% with imaging evidence of a prior stroke. During the follow-up period, 13% (11/84) patients developed new ischemic injury, two patients developed a new stroke and nine patients developed new SCIs. The post-HSCT incidence rate of new stroke was 0.49 events/100 patient-years, and SCIs was 2.2 events/100 patient-years. Patients who progressed compared to those who did not were older at transplant (36.1 yrs. vs. 31.2 yrs.; p=0.09), had a prior history of stroke (27% vs. 22%, p=0.71), had a prior history of SCI (64% vs. 52%, p=0.47), and a prior history of stenotic vasculopathy (18% vs. 14%, p= 0.65). Conclusions: The incidence of new ischemic events after HSCT for SCD in adults is low. Our rates are comparable to incidence rates reported in children with SCD after HSCT. While rates of progression were higher in patients with prior stroke, SCI, and vasculopathy, we did not find a significant difference between groups.

Long-term health outcomes following curative therapies for sickle cell disease.

Treatment options for patients with sickle cell disease (SCD) continue to rapidly expand and evolve. The goal of therapies such as an allogeneic hematopoietic stem cell transplant (HSCT), gene therapy, and gene editing is to cure rather than control SCD. The benefits of these therapies must be accompanied by minimizing long-term adverse health outcomes from SCD and its treatment. SCD can have adverse effects on a variety of organ systems, including the heart, lung, kidney, and reproductive system, leading to high disease burden, morbidity, and premature mortality in both pediatric and adult patients. While curative therapies are being increasingly used, there remains a paucity of data on the long-term health outcomes associated with these treatments in children and adults with SCD. There are data available regarding the effects of HSCT performed largely for malignant diseases, from which data on SCD outcomes may be extrapolated. However, given the significant differences between these 2 populations of patients who undergo HSCT, such extrapolation is imprecise at best. Furthermore, there are currently no published data on long-term health outcomes following gene therapy for SCD due to current short follow-up times. We summarize the limited data reported on health outcomes following HSCT for SCD and emphasize the need for more research within this area.

Global perspectives on cellular therapy for children with sickle cell disease.

Low-income and middle-income countries (LMICs), primarily in sub-Saharan Africa (SSA), predominantly experience the burden of sickle cell disease (SCD). High frequency of acute and chronic complications leads to increased utilization of healthcare, which burdens fragile health systems. Mortality for children with limited healthcare access remains alarmingly high. Cellular based therapies such as allogeneic hematopoietic stem cell transplant (HSCT) are increasingly used in resource-rich settings as curative therapy for SCD. Broad access to curative therapies for SCD in SSA would dramatically alter the global impact of the disease. Currently, application of cellular based therapies in LMICs is limited by cost, personnel, and availability of HSCT-specific technologies and supportive care. Despite the challenges, HSCT for SCD is moving forward in LMICs. Highly anticipated gene modification therapies have recently proven well tolerated and feasible in clinical trials in resource-rich countries, but access remains extremely limited. Translation of curative cellular based therapies for SCD should be prioritized to LMICs where the disease burden and cost of noncurative treatments is high, and long-term quality of life is poor. Focus on thoughtful modifications of current and future therapies to meet the need in LMICs, especially in SSA, will be especially impactful.

Evidence-Based Minireview: In young children with severe sickle cell disease, do the benefits of HLA-identical sibling donor HCT outweigh the risks?

Abstract In case 1, a 14-month-old male child with sickle cell disease (SCD) was referred for evaluation for an allogeneic hematopoietic stem cell transplant (HCT). The patient had a history of dactylitis 3 times in his first year of life and febrile episodes twice at the consult. His 4-year-old sister was found to be human leukocyte antigen (HLA) identical. The patient was started on hydroxyurea (HU) at 2.5 years of age. His parents again sought consultation when he was 5 years old because of concerns about his medical condition. At the time, the patient had experienced 2 vaso-occlusive pain episodes (VOEs) requiring hospitalization during the previous 2 years. He had also experienced intermittent pain crises requiring rest at home for 2 to 3 days. The child has not attended school in person due to the COVID-19 pandemic. The family is considering HCT but is ambivalent about it because of potential toxicity. In case 2, an 8-year-old female child is 3 years out from HCT for SCD from her HLA-identical sibling. Before HCT, despite receiving HU, she had experienced >5 VOEs requiring hospitalization and 2 episodes of acute chest syndromes in the previous 3 years. She had also been missing almost 50 days of school days each year. After HCT, she is now attending school regularly and participating in all normal age-appropriate activities. The parents believe that HCT has been transformative in their child's life.

A Decision Support Tool for Allogeneic Hematopoietic Stem Cell Transplantation for Children With Sickle Cell Disease: Acceptability and Usability Study.

BackgroundIndividuals living with sickle cell disease (SCD) may benefit from a variety of disease-modifying therapies, including hydroxyurea, voxelotor, crizanlizumab, L-glutamine, and chronic blood transfusions. However, allogeneic hematopoietic stem cell transplantation (HCT) remains the only nonexperimental treatment with curative intent. As HCT outcomes can be influenced by the complex interaction of several risk factors, HCT can be a difficult decision for health care providers to make for their patients with SCD.ObjectiveThe aim of this study is to determine the acceptability and usability of a prototype decision support tool for health care providers in decision-making about HCT for SCD, together with patients and their families.MethodsOn the basis of published transplant registry data, we developed the Sickle Options Decision Support Tool for Children, which provides health care providers with personalized transplant survival and risk estimates for their patients to help them make informed decisions regarding their patients’ management of SCD. To evaluate the tool for its acceptability and usability, we conducted beta tests of the tool and surveys with physicians using the Ottawa Decision Support Framework and mobile health app usability questionnaire, respectively.ResultsAccording to the mobile health app usability questionnaire survey findings, the overall usability of the tool was high (mean 6.15, SD 0.79; range 4.2-7). According to the Ottawa Decision Support Framework survey findings, acceptability of the presentation of information on the decision support tool was also high (mean 2.94, SD 0.63; range 2-4), but the acceptability regarding the amount of information was mixed (mean 2.59, SD 0.5; range 2-3). Most participants expressed that they would use the tool in their own patient consults (13/15, 87%) and suggested that the tool would ease the decision-making process regarding HCT (8/9, 89%). The 4 major emergent themes from the qualitative analysis of participant beta tests include user interface, data content, usefulness during a patient consult, and potential for a patient-focused decision aid. Most participants supported the idea of a patient-focused decision aid but recommended that it should include more background on HCT and a simplification of medical terminology.ConclusionsWe report the development, acceptability, and usability of a prototype decision support tool app to provide individualized risk and survival estimates to patients interested in HCT in a patient consultation setting. We propose to finalize the tool by validating predictive analytics using a large data set of patients with SCD who have undergone HCT. Such a tool may be useful in promoting physician-patient collaboration in making shared decisions regarding HCT for SCD. Further incorporation of patient-specific measures, including the HCT comorbidity index and the quality of life after transplant, may improve the applicability of the decision support tool in a health care setting.

The Role of Hematopoietic Stem Cell Transplantation in the treatment of Sickle Cell Disease

Abstract
 
 Sickle cell disease (SCD) affects millions of people around the world and is associated with significant morbidity and premature mortality. It is a chronic, life-long illness that affects virtually every tissue in the body, worsens over time, with varying degrees of morbidity in everyone with the disease. 
 Before hematopoietic stem cell transplant (HCST), the mainstay of the management of SCD included early identification of the disease through newborn screening, infection prophylaxis with vaccinations and antibiotics, management of pain crises, blood transfusions, and hydroxyurea. These treatments although beneficial, do not cure SCD, stop the progressive end-organ damage associated with this disease, and are lifelong. Hematopoietic stem cell transplant is one of two treatment options that offer a cure for SCD and stops the progressive end-organ damage.
 The purpose of this article is to examine traditional treatments (best medical practice) and HCST for SCD and their associated complications. The role of HCST in the treatment of sickle cell disease, as well as recent research on HSCT as a cure for SCD, risk factors, patient selection, limitations, and future use of this treatment option, are also reviewed. Major issues surrounding the use of HCST for treating SCD include the optimal age for transplantation, disease severity, donor source, and the conditioning regimen before transplantation. The future of HCST including gene therapy is also discussed.

Preservation of Organ Function after Transplantation for Sickle Cell Disease

Background Recipients of successful allogeneic hematopoietic stem cell transplant (HSCT) for sickle cell disease (SCD) have hemoglobin S levels that reflect those of the donor. SCD related organ damage targets vital organs and is variable based on age and disease severity, and can be further compromised by transplant related complications. Organ function parameters are generally not primary end-points for clinical trials but need longitudinal follow up. This study aims to describe organ function in transplant recipients followed for one or more years after HSCT for SCD. Methods Following Institutional Review Board approval, a retrospective chart review was undertaken of SCD patients >1-year from HSCT with donor engraftment. Demographic data and organ functions (lung, brain and eyes) pre, at one-year, and at most recent assessment were compared for each patient. Organ functions reviewed included, creatinine, brain imaging, intelligence quotient (IQ), pulmonary function, retinal examination, and ferritin levels. Results Twenty-two patients were included in this review. There were 10 matched sibling donor, 8 matched or mismatched unrelated donor, 1 haploidentical, and 3 cord blood transplant recipients. Four patients received repeat donor cell infusion for waning donor chimerism followed by stabilization. Median age at first HSCT was 10 years (range 4-21 years). Eleven patients had MRI changes pre-HSCT. At 1-year, 4 of 17 transplant recipients had new MRI changes (2 patients with PRES and 2 with worsening infarction). At last follow up 3 of 18 patients demonstrated new MRI changes: bilateral temporal mesial sclerosis (1) and silent infarcts (2). IQ testing was available both at baseline and anytime beyond 1 year in 7 patients. IQ improved or remained stable in 5 patients and was lower in 2 patients, but remained in the average range. Pulmonary function tests were available for 21 patients of which 4 patients had restrictive lung disease. Ferritin levels decreased in 13 of 18 patients beyond the first year post-HSCT. Ophthalmologic exams at baseline and after transplant were performed in 12 patients. While SCD retinopathy was detected at baseline in two patients, no retinopathy was noted after HSCT. Follow up is in progress for additional organs such as the heart and kidneys. Discussion Long-term follow up of SCD related parameters post-HSCT demonstrates the effect of the intervention on disease manifestations. Our data demonstrates stability or improvement in organ function in the majority of patients after HSCT. This retrospective analysis is limited by the lack of uniform assessment of SCD related parameters and by obstacles such as provider changes and insurance denials. Though our data indicates improvement in SCD parameters post-HSCT, it also underscores the importance of systematic follow up prospectively through clinical trials and registries following curative therapy for SCD.

Curative Allogeneic Stem Cell Transplantation Is Safe and Feasible in Adult Patients with Sickle Cell Disease Despite Lack of Matched Sibling Donor and Presence of Sickle Cell-Related Co-Morbidities

Introduction:Sickle cell disease (SCD) affects 300,000 annual births globally, and about 100,000 individuals in the United States. Allogeneic hematopoietic stem cell transplant (HSCT) remains the only cure. HSCT risks necessitate a risk-benefit analysis in each case. Excellent long-term overall survival (OS) of 91-95% has been described with matched-sibling (SIB) HSCT, but fewer than 15% of SCD patients have a SIB donor. Matched unrelated donor (MUD) availability is limited for ethnic groups afflicted with SCD. Alternative donor HSCT from mismatched unrelated donors (MMUD) or haploidentical donors improves donor availability but increases toxicity and risk of graft failure. SCD-induced organ damage is another limitation to HSCT. In this study, we review our experience with HSCT for SCD and demonstrate that most patients can receive a curative HSCT despite lack of SIB donor and presence of significant co-morbidities.Methods:All adult SCD patients who received HSCT at our center since 2014 were included. Patients had at least 2 hospitalizations per year for pain crises despite hydroxyurea compliance and evidence of end-organ damage. Patients with a SIB donor (n=6) received conditioning with alemtuzumab and 3Gy TBI (per Hsieh et al, 2009). Patients with MUD/MMUD (n=4) or haploidentical (n=1) donors received conditioning with alemtuzumab, fludarabine, melphalan, and a CD34+ selected graft with CD3+ cell add back on an ongoing clinical trial for non-malignant hematologic diseases. One patient s/p kidney transplant and liver failure requiring TIPS procedure was conditioned with alemtuzumab and 4Gy TBI, received a 10/10 MUD graft, and given post-HSCT cyclophosphamide (50 mg/kg d+3) along with sirolimus continuation as GVHD prophylaxis. GVHD prophylaxis otherwise consisted of sirolimus (n=10) and tacrolimus (n=1). All patients received a G-CSF mobilized peripheral blood stem cell (PBSC) graft and underwent RBC exchange to achieve Hgb S <30%.Results:Twelve patients are included in this analysis. Median age was 28.7 (18.5 - 44.2) years with 6 males and 6 females. Median follow up was 13.6 months (range 1.4 - 51.3). Two patients had stage V renal disease with one patient on active dialysis. Two patient were s/p kidney transplant with one patient awaiting a 2nd kidney transplant. Median CD34 cell dose in SIB and MUD/MMUD HSCT was 14.8 and 8.5 x 10e6 CD34/kg respectively. Median T cell add back in CD34-selected M/MMUD recipients was 2.5 x 10e5 CD3/kg. No G-CSF was used. All patient engrafted with no cases of graft failure or treatment related mortality (TRM). Median time to neutrophil engraftment for SIB and M/MMUD recipients was 24.5 and 19 days respectively. Median time to platelet engraftment was 19 days for M/MMUD recipients and 2 of 6 SIB recipients required only 1 platelet transfusion each. The patient s/p kidney allograft and TIPS for liver failure engrafted neutrophils and platelets on day +22 and +26 respectively. All patients are alive and free of SCD. Available chimerism analysis at 6 months (n=8) shows median myeloid chimerism to be the same in SIB and M/MMUD recipients (99.7%) where median T Cell chimerism was 35% and 65% for SIB and M/MMUD recipients respectively. Chimerism at 1 year shows stable myeloid engraftment and median T cell chimerism of 61.5% for SIB recipients.Two cases of PRES were noted after HSCT, one in a patient on tacrolimus after which the CD34-selected protocol was modified to include sirolimus as GVHD prophylaxis. Another case of PRES was noted on sirolimus which was switched to prednisone and mycophenolate mofetil. Two patients discontinued sirolimus due to myalgias and were switched to tacrolimus on days +44 and +58 with resolution of symptoms.Acute/Late acute GVHD occurred in 4 patients. Three cases were noted in patients treated on the CD34-selected protocol; two MMUD (Grade III and Grade I) and one haploidentical (Grade III) graft recipients. One case of late acute liver GVHD, evident in elevation of liver enzymes and alkaline phosphatase with evidence of hepatitis on biopsy, occurred in a SIB recipient (Grade I). All cases responded to corticosteroid therapy.Conclusion:SCD patients with or without a SIB donor can be offered a curative HSCT that is safe without TRM. SCD patients with severe SCD-related organ damage can also be offered HSCT however further research is warranted to identify optimal conditioning and GVHD prophylaxis regimens for these patients. DisclosuresReshef:Kite Pharma: Consultancy; Atara Biotherapeutics: Consultancy; Bristol-Myers Squibb: Consultancy; Takeda Pharmaceuticals: Consultancy; Pfizer: Consultancy; Incyte: Consultancy.

Improved Splenic Function After Hematopoietic Stem Cell Transplant for Sickle Cell Disease.

Splenic dysfunction is a significant complication of sickle cell disease (SCD). Hematopoietic stem cell transplant (HSCT) is a proven cure for SCD; however, its long-term effect on splenic function is not well characterized. We conducted a retrospective cohort study of pediatric patients who had HSCT for SCD at two transplant centers. (99m) Tc liver-spleen (LS) scans were blindly reviewed and classified as demonstrating absent, decreased, or normal splenic uptake. Considering all engrafted nonsplenectomized Hb SS and Sβ(0) -thalassemia patients with LS scans available, at a median of 2.0 years post-HSCT (range 1.0-9.3 years) eight of 53 (15%) had normal, 40 of 53 (75%) decreased, and five of 53 (9%) absent splenic uptake. More patients had splenic uptake after HSCT: pre-HSCT 14/38 (37%) versus post-HSCT 34/38 (89%), P < 0.0001. Older age at HSCT was associated with worse splenic function post-HSCT (median age at HSCT for absent uptake 16.6 years vs. present uptake 8.0 years, P = 0.030). Extensive chronic GVHD was also more common in patients with absent splenic uptake compared to patients with present uptake (absent 40% vs. present 6%, P = 0.064). HSCT significantly improves splenic function for most pediatric patients with SCD, but older patient age at time of HSCT and extensive chronic GVHD appear to be risk factors for poor post-HSCT splenic function.

Hematopoietic Stem Cell Transplantation from HLA Identical Sibling Forsickle Cell Disease an International Survey on Behalf of Eurocord-Monacord, EBMT Paediatric Disease Working Party and CIBMTR

Introduction:Hematopoietic stem cell transplantation (HSCT) is, to date, the only curative therapy for sickle cell disease (SCD). However, HSCT is offered to relatively few patients with SCD for a number of reasons including lack of a suitable HLA-matched donor, lack of consensus on indications for HSCT, the potential for trading one chronic condition (i.e., SCD) for another, such as chronic graft-versus-host disease (GVHD), and the mortality associated with the procedure. To-date, most HSCTs for SCD have utilized matched siblings as donors and are performed in children and adolescents. We report outcomes after HLA-matched sibling HSCT of patients reported to the Eurocord-Monacord/European Group for Blood and Marrow Transplantation (EBMT) and Center for International Blood and Marrow Transplant Research (CIBMTR).Material and methods:One thousandpatients with SCD received HLA identical sibling HSCT between 1991 and 2013; n=439 from CIBMTR and n=561 from EBMT centers. HSCTs were performed in 90 centers in 23 countries.Results:Median age at HSCT was 9 years (range 1-54y); 85% of patients were aged <16 years. Approximately half of patients were female and 53% of HSCTs were performed after 2007. Most patients (94%) were homozygotes for hemoglobin S (HBS). The most common indication for HSCT was stroke. Other indications included: central nervous system event lasting longer than 24 hours, elevated cerebral arterial velocity, acute chest syndrome or vaso-occlusive crisis requiring hospitalization. Red blood cell transfusions were given before HSCT to 93% and hydroxyurea to 56% of the evaluable patients (N=510). Most HSCTs (n=872; 87%) used myeloablative-conditioning regimens, mainly based on the combination of busulfan with cyclophosphamide (n=719; 82%) or fludarabine (n=82; 9%). One hundred and twenty six patients (13%) received reduced intensity conditioning regimens; fludarabine with cyclophosphamide was the predominant regimen (n=48; 38%). Most regimens included in vivo T-cell depletion (71%) with anti-thymocyte globulin (n=630) or alemtuzumab (n=76). The predominant GVHD prophylaxis regimens were cyclosporine alone (19%), or combined with methotrexate (56%). The predominant stem cell source was bone marrow (84%); peripheral blood and cord blood were employed in 7% and 9% of patients, respectively. The median follow-up was 45 (1.1-324.6) months.The cumulative incidence (CI) of neutrophil engraftment at day+60 was 98% (96.6% for CB, 98.3% for BM and 95.2% for PB) with a median time to recovery of 19 days, while that for platelet engraftment was 98 % (96±2% for CB, 99±1% for BM and 98±9% for PBSC) with a median time to recovery of 25 days. Twenty-six patients experienced primary and 47 patients secondary graft failure; 67 patients died mainly due to GVH or infection. The 3-year probabilities of overall (OS) and event-free survival (EFS, alive with engraftment) were 94% (95% CI 92-95) and 90% (95% CI 68-82), respectively. According to stem cell source, 3-year OS was 99% after CB, 94% after BM and 80% after PBS (p<0.0001). In multivariate analysis, every year in age increment (HR 1.1, 95% CI 1.07-1.14, p<0.001) and use of peripheral blood (HR 3.43, 95% CI 1.49-7.88, p=0.004) were associated with higher mortality. In univariate analysis, EFS was better in patients receiving myeloablative compared to reduced intensity conditioning (91±1% vs 82 ±1%, respectively; p<0.001). In multivariate analysis, EFS was lower with every year in age increment (HR 1.05, 95% CI 1.02-1.07, p<0.001), peripheral blood grafts (HR 1.83, 95% CI 1.07-3.15, p=0.03) and HSCTs prior to 2000 (HR 0.77, 95% CI 0.64-0.92, p=0.005). CI of acute GVHD grade 2-4 was 14.4% (12.2-16.7) of chronic GVH 13.3 (11-15.8). Risks of acute GVHD were higher with increasing age (HR1.04 95% CI 1.01-1.07, p=0.008). None of the variables tested were associated with chronic GVHD.Conclusion:This large registry based international study shows that HLA identical sibling transplant is successful more than 90% of the patients with severe SCD with limited transplant related complications (rejection, GVHD). Strategies aimed at lowering graft failure and GVHD are desirable to further optimize the observed 3-year event-free survival. Importantly, these data should increase awareness to early referral to HSCT of patients with severe SCD. DisclosuresWalters:ViaCord and AllCells, Inc: Other: Medical director. Bertrand:ERYTECH Pharma: Consultancy. Peters:Medac: Research Funding; Fresenius: Research Funding; Amgen: Research Funding; Jazz: Research Funding; Novartis: Research Funding; Pfizer: Research Funding; Sanovi: Research Funding; Pierre-Fabre: Research Funding.

Cerebral Vascular Abnormalities in Pediatric Patients With Sickle Cell Disease After Hematopoietic Cell Transplant

Stroke is a common sequela of sickle cell disease (SCD). Patients with SCD who undergo hematopoietic stem cell transplantation (HSCT) with successful engraftment will not experience sickling. This ameliorates one aspect of stroke risk; however, the significance of preexisting cerebrovascular abnormalities remains unclear. We performed a literature search for neurological outcomes following HSCT for SCD. We searched for relevant neuroimaging and neurosurgical protocols. We identified 4 unique studies encompassing 196 patients. Of these, 81 had a history of a stroke, transient ischemic attack (TIA), cognitive dysfunction or cerebrovascular abnormalities identified by pretransplant neuroimaging, achieved stable engraftment, and had long-term follow-up. Of the 81 patients, 1 had peritransplant (10 days prior transplant to 50 days posttransplant) TIA. One had posttransplant TIA within 36 to 72 months. None had strokes. Forty-five underwent cerebral imaging at nonuniform intervals. Among this group, 32 (71%) had stable cerebrovascular abnormalities on imaging, 6 (13%) had improvement, and 7 (16%) showed worsening. Cerebrovascular abnormalities identified on neuroimaging may stabilize, improve, or worsen in patients after successful HSCT. Some patients may have neurological events such as TIA. Neurological outcomes in children with SCD post-HSCT have been inadequately studied.

An educational symposium for patients with sickle cell disease and their families: Results from surveys of knowledge and factors influencing decisions about hematopoietic stem cell transplant

The only available cure for sickle cell disease (SCD) is hematopoietic stem cell transplant (HSCT). One important barrier to HSCT in SCD is lack of patient and family knowledge. To improve awareness of HSCT as a curative option for SCD, we hosted half-day educational symposia in 2011 and 2012. Symposia included didactic lectures by HSCT experts, small group sessions, and question and answer sessions with SCD patients and their families who had undergone HSCT. In 2011, we distributed anonymous pre- and post-symposium knowledge tests to determine how much attendees had learned about transplant. In 2012, we asked attendees to rate the importance of various medical and psychosocial factors in the decision to pursue HSCT. Results from 2011 showed that knowledge about HSCT increased significantly after the symposium. Concern about the risk of transplant decreased slightly, but not significantly, following the symposium, and the majority of attendees expressed a desire to speak with physicians further about HSCT. In 2012, families reported that risk of death, prevention of SCD complications, and risk of serious complications were the most important considerations for their decisions about HSCT. A half-day symposium for SCD patients and their families can increase knowledge about HSCT. Education about risks and benefits of HSCT is key, as families consider these medical factors to be most important to their decision to pursue transplant. Our symposia can be replicated across the country to increase knowledge about HSCT for SCD and impact the number of patients who pursue HSCT.

Stem Cell Transplantation for Children with Sickle Cell Anemia: Factors Associated with Parent and Patient Interest

Abstract 1079▪▪This icon denotes a clinically relevant abstract BACKGROUND:Sickle cell disease (SCD) is the most common inherited blood disorder in the United States affecting more than 70,000 children and adults. SCD is associated with significant morbidity and mortality with a mean life expectancy of approximately 45 years in patients with more severe Hb SS. Allogeneic hematopoietic stem cell transplant (HSCT) is the only curative treatment for sickle cell disease. Currently hematologists consider HSCT only for patients with a history of multiple pain crises, stroke, renal disease and/or multiple episodes of acute chest syndrome. However, factors that influence patients' and parents' interest in HSCT for SCD are not known. METHODS:We designed and administered a 40 question survey to assess the interest in HSCT as a cure for SCD in parents and adolescents with HbSS or HbSBetaThalassemia0. The survey tool assessed factors that may influence interest in HSCT including demographic data, disease severity, views on prognosis and Health Related Quality of Life (PedsQL4.0). All participants were given a handout on the risks and benefits of a HSCT prior to completing the survey. Participants' who responded they definitely or probably would undergo HSCT if recommended by their hematologist were categorized as “likely would undergo HSCT” while participants who responded they would maybe, probably not, or definitely would not undergo HSCT were categorized as “less likely would undergo HSCT”. RESULTS:Ninety parents and 42 adolescents completed the survey, with only 1 parent refusing to participate. Forty six percent (39/85) of parents would likely have their child undergo HSCT and 34% (14/41) of adolescents would likely undergo HSCT if it was recommended by their hematologist. Adolescents with better social function and better overall emotional function were more likely to undergo transplant (50% (10/20) vs. 19% (4/21), p=0.04) (53% (9/17) vs. 21% (5/24), p=0.03), respectively. Parents of children age>7 who believe their child’s life span will be shortened secondary to SCD were more likely to undergo transplant (100% (3/3) vs. 35% (15/43), p=0.03). In addition, parents of children who have received an exchange transfusion were more likely to undergo transplant (62% (18/29) vs. 38% (20/53), p=0.04). Disease severity represented by the number of pain crises, episodes of acute chest, or presence of a stroke were not associated with increased parent or adolescent interest in HSCT. In addition, 50% (11/22) of parents of children who would not qualify for HSCT based on current disease severity criteria would likely undergo HSCT. In this cohort, parents who believed their child’s disease would not get better were more likely to go forward with transplant (100% (5/5) vs. 31% (5/16), p=0.007). The majority of parents believe their child’s sickle cell disease will get better (63% (55/87)), will not likely prevent their child from achieving life goals (83% (71/86)), and will not shorten their child’s lifespan (88% (74/84)). Forty six percent (19/41) of adolescents believe their sickle cell disease will get better, 74% (31/42) believe it will not prevent them from achieving life goals, and 64% (27/42) believe sickle cell disease will not shorten their lifespan. CONCLUSIONS:There is a strong interest in HSCT in our patient cohort that was not pre-selected based on disease severity. Parents had an interest in HSCT based on both disease severity and perception of prognosis, while adolescents' interest in HSCT was directly related to higher psychosocial functioning. The current standard inclusion criteria for HSCT for children with SCD exclude a number of children whose parents are interested in HSCT. The finding of perception of a normal life span in the majority of patients and parents is troubling and suggests a need for more thorough education regarding the long term sequelae of SCD and the role for HSCT as a cure. Disclosures:No relevant conflicts of interest to declare.

Safety and efficacy of targeted busulfan therapy in children undergoing myeloablative matched sibling donor BMT for sickle cell disease

Busulfan influences engraftment and toxicities during hematopoietic stem cell transplantation (HSCT). We report our single-institution experience of targeted busulfan therapy for myeloablative, matched sibling donor (MSD) HSCT for sickle cell disease (SCD) and assess the relationships of busulfan levels to engraftment and toxicities. Twenty-seven patients with SCD underwent MSD HSCT from 1993 to 2007, 25 with busulfan measurements. The conditioning regimen was busulfan (initial dose 0.875 mg/kg for 16 doses), CY and antithymocyte globulin. Busulfan area under curve (AUC) was determined with the first dose, and dose adjustments were made to target the desired AUC range. Median AUC was 963 μmol min/L (range 780-1305 μmol min/L). Engraftment occurred in all cases: 21 (84%) full donor chimerism (> 95% donor cells), 4 (16%) partial donor chimerism. Hepatic veno-occlusive disease (VOD) occurred in 8 (32%) patients. Lower AUC was seen with partial donor chimerism (862 ± 73 μmol min/L) versus full donor chimerism (AUC 1018 ± 122 μmol min/L) (P = 0.022). VOD was not associated with busulfan AUC (P = 0.153). Of 25 patients, 24 survived with median follow-up of 4.9 years. Our experience shows that targeting busulfan AUC above the range used in previous multicenter trials appears safe and may contribute to sustained engraftment in SCD.

Berkeley Sickle Mice Demonstrate CD8- and NK1.1-Dependent Increased Rejection of Allogeneic Hematopoietic Stem Cell Transplants.

While hematopoietic stem cell transplantation (HSCT) represents the only curative therapy for sickle cell disease, sickle patients undergoing HSCT face many complications, including an increased risk of graft rejection compared to non-sickle patients.We have used the Berkeley sickle mouse model to study the potential mechanisms underlying this increased risk of rejection. Using a CD28/CD40 costimulation-blockade-based non-myeloablative HSCT regimen, we transplanted Berkeley sickle mice with fully allogeneic SJL bone marrow. While the vast majority (>85%, n=25) of control C57BL/6 animals became stably chimeric and immunologically donor-tolerant with this transplant regimen, sickle mice were much more prone to reject the transplant (~20% graft acceptance, n=25). Both CD8+ cells and NK1.1+ cells were found to contribute to this rejection, as depletion of either of these cell populations led to a marked increase in the percent of engrafted mice (>85% graft acceptance, n=15–25), while depletion of CD4+ cells led to the opposite effect, with 0% (n=25) animals engrafted in this depletion cohort.The increased propensity of HSCT rejection in the Berkeley sickle mice may, in part, be explained by the presence of increased numbers of donor-reactive T cells (5–10-fold compared to C57BL/6 controls) in naïve sickle mice, despite their lack of exposure to donor antigens, and their housing in a Specific-Pathogen-Free environment. We speculate that these increased numbers of anti-donor T cells may occur as a result of heightened inflammation in the context of active sickle cell disease, which could lead to increased expansion and persistence of a T cell repertoire containing anti-donor heterologous T cell immunity. This heterologous immunity may have a profound effect on the success of HSCT for sickle cell disease, especially when non-myeloablative regimens are employed.