Option For Sickle Cell Disease Research Articles

Clinical Practice Patterns in Sickle Cell Disease Treatment: Disease-Modifying and Potentially Curative Therapies.

Therapeutic options for sickle cell disease (SCD) have increased recently as well as the development of updated national guidelines. It is not known how these options are being offered or to what degree guidelines are incorporated into clinical practice. This study aimed to describe practice patterns for pediatric hematologists regarding the use of disease-modifying and potentially curative therapies for SCD. A 9-section, cross-sectional electronic survey was disseminated during a 3-month period via SurveyMonkey, to members of the American Society of Pediatric Hematology/Oncology Hemoglobinopathy Special Interest Group (ASPHO HSIG). A total of 88 physician members of the ASPHO HSIG were surveyed. Ninety percent of respondents (72/80) start hydroxyurea routinely in patients with HbSS and HbSβ0 thalassemia, regardless of disease severity. Laboratory monitoring was recommended every 3 months for stable dosing in 63.8% (51/80). New therapies were recommended for patients on hydroxyurea who were still experiencing SCD complications: L-glutamine 68.5% (37/54) or crizanlizumab 93.1% (54/58). Voxelotor was recommended for patients on hydroxyurea with low hemoglobin in 65.1% (43/66) of cases. Matched sibling transplant was considered for any disease severity by 55.1% (38/69). Gene therapy trials are offered on-site by 29% (20/69). Our study demonstrated the enhanced utilization of hydroxyurea while revealing the unexplored potential of other disease-modifying therapies in SCD. These findings underscore the importance of continued knowledge acquisition about the long-term efficacy of new medical therapies and addressing barriers to the use of proven therapies and guide the development of future studies of optimal SCD management.

Hematopoietic Stem Cell Transplantation: An Approach in the Treatment of Sickle Cell Disease

Hematopoietic Stem Cell Transplantation (HSCT) is a treatment indicated for various types of hematological neoplasms, such as leukemia, lymphoma, multiple myeloma, and other autoimmune hematological diseases and immunodeficiencies. Sickle cell disease (SCD) is an inherited blood disorder that shortens the survival of red blood cells, causing anemia. This research sought to address advances and new perspectives in HSCT in the treatment of sickle cell disease. Currently, HSCT is the only curative option for patients with sickle cell disease and aims to restore normal hematopoiesis and thus prevent damage from successive episodes of sickling. Allogeneic HSC transplantation has become an increasingly acceptable treatment option for sickle cell disease. Currently, even with advances in supportive therapy to prevent complications of SCD, access to care for this disease is unequal. However, worldwide, 120 million people are affected by the disease, and of these, 66% live in Africa. Therefore, in Africa and Asia, the number of patients tends to grow. Therefore, it is important to apply and expand neonatal screening programs, and the need for investment in health policies, especially in these countries where the disease is more severe.

Patients, Parents and Providers Perspectives Toward Treatment Options for Sickle Cell Disease

Introduction Sickle cell disease (SCD) is the most common hemoglobinopathies in the world. It is more prevalent in malaria endemic areas where most low-and-middle-income countries (LMIC) are found. Because of challenges in accessing care, persons with SCD (PWSCD) in these settings have a poor outcome and up to 50% die before the age of five years in some places. Those who survive early childhood develop complications at a young age causing their families significant emotional and socioeconomic distress. Effort in LMIC is being directed toward screening for SCD and early initiation of treatment which has improved overall survival and quality of life of PWSCD. However, there are concerns about adherence to treatment due to pill fatigue, persistent SCD symptoms, end organ damage despite available treatment, and side effects of medications. With improved care, SCD is evolving into a chronic illness even in LMIC and PWSCD are surviving into adulthood. These countries will soon face the challenge of handling lifestyle and health demands of an emerging adult and aging PWSCD. There have been significant advances in disease modifying (DM) and curative treatment for SCD in high-income-countries (HIC) and the two promising treatment modalities for cure are bone marrow transplant and gene therapy which can be life changing for PWSCD and their families despite treatment related adverse events. Curing SCD may help prevent long-term complications. It is therefore important to explore the perspectives of PWSCD, their parents and SCD providers toward traditional and novel therapies for SCD as the initial step in planning for improved access to SCD treatment in LMIC. Objective To explore the attitudes of PWSCD, Parents (caregivers) of PWSCD and SCD care providers toward traditional and novel therapies for SCD in a LMIC setting. Methodology This was a mixed methods study conducted at a referral facility for PWSCD in western Kenya. It included 5 focused group discussions (FGD) of 6 - 7 consented participants; 2 with patients, 2 with parents and 2 with SCD providers. FGDs were conducted by trained clinicians and lasted 2 hours. A discussion guide which included information on novel therapies was applied to direct the audio-recorded sessions conducted in local dialect. FGD and analysis were iterative with each thematic content analyzed independent of the others and key concepts arising from these sessions explored. Necessary adjustments were made to the discussion guide for subsequent sessions based on emerging themes. The recorded material was then transcribed in verbatim and translated for analysis using a qualitative analysis tool. Results and Discussion This study enrolled 13 PWSCD, 13 parents of PWSCD and 6 SCD providers (n=32). Participants had similar attitudes towards SCD barriers and novel treatments. 96.9% of participants reported using hydroxyurea and folic acid for themselves, their loved one, or their PWSCD. Over the past year, 83.1% of PWSCD reported painful crisis while 33.% had been hospitalized despite adherence to treatment (table 1). Most participants (65.4%) would consider using novel SCD treatments with hesitations being cost, treatment adverse effect, and distance to treatment location. After the educational intervention, participants were more likely to opt for gene therapy (65.4%) than stem cell transplant (19.2%) or remaining on their current regimen (15.6%) (Table 2). Only one SCD providers' FGD was conducted due to their limited availability from competing clinical duties. Some patients who reported being on recommended treatment continued to have health events and complications that made them, their parents or providers want an alternative treatment. Most participants preferred a curative treatment option for their disease despite the challenges mentioned, which highlighted their willingness to participate in clinical trials. While there are infrastructural challenges in LMIC, they have the highest number of PWSCD that would benefit from new DM and curative treatment for SCD despite being underrepresented in clinical trials. They are the most impacted by complications associated with SCD due to sub-optimal care thus need for action to reverse this. Conclusion This study highlights the importance of involving population in LMIC in efforts to find better treatment for PWSCD. There is a need to conduct a similar study involving a larger cohort in future to further explore more perspectives.

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.

Hope on the Horizon: New and Future Therapies for Sickle Cell Disease.

This article provides an overview of conventional, new, and future treatment options for sickle cell disease (SCD), a genetic disorder affecting the production of hemoglobin. Current treatments include hydroxyurea, a conventional SCD treatment that increases the levels of fetal hemoglobin, and new treatments such as voxelotor, a recently approved SCD treatment that selectively binds hemoglobin, preventing formation of sickled red blood cells. In addition to discussing the mechanisms of action of current SCD treatments, potential side effects are also discussed, highlighting the need for new treatments that can address the limitations of current treatments and improve the quality of life for people with SCD. Future treatments, such as gene therapy, are also explored as promising treatment options for SCD patients.

The perception of pediatric sickle cell anemia patient's caregivers toward hematopoietic stem cell transplantation (single-center experience, Saudi Arabia).

Sickle cell disease (SCD) is a relatively common genetic disorder in Saudi Arabia characterized by the predominance of sickle hemoglobin (HbS). Although multiple supportive care options exist for patients with SCD, hematopoietic stem cell transplantation (HSCT) is the only cure available and has become highly successful, with an almost 91% overall survival rate. However, pursuing this procedure is still restrained as a curative treatment option. Therefore, this study aimed to evaluate the perception of parents' caregivers at the National Guard Hospital pediatric hematology clinic regarding using HSCT as a curative approach for their children with SCD. This is a cross-sectional study of the interviewer-administered survey distributed utilizing electronic devices to caregivers of pediatric patients with SCD. Subjects were recruited from Pediatric Hematology & Oncology clinics at National Guard Hospital Affairs in King Abdulaziz Medical City, Jeddah, Saudi Arabia. An estimated sample size of 100 was initially calculated out of 140 pediatric SCD patients; 72 responses were collected from participants. All study participants gave informed consent. All results were analyzed using SPSS; moreover, statistics were set at a CI of 95% and a p < 0.05. In addition, inferential and descriptive statistics were done. Of all respondents, 42 (67.8%) would accept HSCT if their hematologist recommended it. However, approximately 7 (11.3%) were not interested in the procedure, and the rest, 13 (21%), were uncertain. The most reported reasons for HSCT rejection among all respondents were attributed to side effects 31 (50.8%), lack of knowledge 8 (13.1%), and misconception toward the procedure 22 (36.1%). The results of this study were consistent with the fact that most caregivers would follow along with HSCT if it seemed to be fit and was recommended by their hematologists. However, to the best of our knowledge, our study being the first of its kind in the region, further research in the kingdom on the perception of HSCT is needed. Nonetheless, further patient education, an increase in caregivers' knowledge, and enlightenment of the medical team on HSCT as a curative option for sickle cell disease are vital.

Impact of adherence to hydroxyurea on health outcomes among patients with sickle cell disease.

Although new pharmaceutical therapy options have recently become available, hydroxyurea is still the most commonly used and affordable treatment option for sickle cell disease (SCD). This study aimed to update the evidence on hydroxyurea adherence and its association with clinical and economic outcomes among individuals with SCD. This retrospective study used Texas Medicaid claims data from 09/2011-08/2016. Individuals were included if they had ≥1 inpatient or ≥2 outpatient SCD diagnoses, had ≥1 hydroxyurea prescription, were 2-63 years of age, and were continuously enrolled in Texas Medicaid between 6 months before and 1 year after the first hydroxyurea prescription fill date (index date). Hydroxyurea adherence (Medication Possession Ratio; MPR), vaso-occlusive crisis (VOC)-related outcomes, healthcare utilization and expenditures (SCD-related and all-cause) during the 1 year following the index date were measured. Bivariate and multivariable analyses were used to address the study objectives. Among 1035 included individuals (age: 18.8 ± 12.5 years, female: 52.1%), 20.9% were adherent to hydroxyurea (defined as MPR≥0.8). After adjustment for demographic and clinical characteristics, compared to being non-adherent, adhering to hydroxyurea was significantly associated with: a lower risk (Odds Ratio [OR]=0.480, p= .0007) and hazard rate (Hazard Ratio [HR]=0.748, p= .0005) of a VOC event, fewer VOC events (Incidence Rate Ratio [IRR]=0.767, p= .0009), fewer VOC-related hospital days (IRR=0.593, p= .0003), fewer all-cause and SCD-related hospitalizations (IRR=0.712, p= .0008; IRR=0.707, p= .0008, respectively) and emergency department visits (IRR=0.768, p= .0037; IRR=0.746, p= .0041, respectively), and lower SCD-related total healthcare expenditures (IRR=0.796, p= .0266). Efforts to increase adherence to hydroxyurea could improve clinical and economic outcomes among individuals with SCD.

Effect of ABO Mismatch and RBC Alloimmunization on the Outcomes of Patients with Sickle Cell Disease Undergoing Hematopoietic Stem Cell Transplantation

Background: Hematopoietic stem cell transplantation (HSCT) remains the only well-established curative option for sickle cell disease (SCD) patients. Non-myeloablative (NMA) conditioning has been used to improve the outcomes and reduce toxicities in adult SCD patients. However, Recipient/Donor (R/D) ABO incompatibility and alloimmunization could be significant impediments to successful outcomes when transplanting SCD patients due to risks of hemolysis, delayed engraftment, poor graft function and graft failure (GF). Herein, we report our experience with allogeneic HSCT for SCD and the effects of RBC groups mismatch and alloimmunization on the outcome of transplanted patients. Methods: We conducted a retrospective analysis of all adolescents and adult SCD patients (age >14 year) that underwent HSCT from January 2015 to February 2022 at our center. All patients received Intravenous alemtuzumab (1 mg/kg divided over 5 days on days -7 to -3) and 300 cGy TBI on day -2 or -1 for conditioning. Pre-transplant preparation consisted of hydroxyurea at maximum tolerated dose for 2-3 months and one session of exchange transfusion. Peripherally mobilized stem cells targeting 10x106 /kg of CD34 cells were used. For graft versus host disease (GVHD) prophylaxis sirolimus was started on day -1 and continued for one year with tapering if lymphoid chimerism was > 50%. For Patients with major ABO incompatibility, we administered 2 doses of rituximab (375 mg/m2) and 3 sessions of plasmapheresis before starting the conditioning regimen targeting an isoheamagglutinin titer < 1/32. The primary objective was to determine the impact of RBC groups mismatch and alloimmunization on the outcome of transplanted patients. The secondary objective was to assess the impact of GF on overall survival (OS). Logistic regression was done to evaluate predictors for GF. Kaplan-Meier method was used for survival analysis. Results: A total of 194 patients were included with a median age of 26 years and 55.6% being males. The median baseline Hgb and HbS were 93 g/L and 71.3%, respectively. Indications of stem cell transplantations were most commonly due to recurrent vaso-occlusive crisis in 52.57% of patients, CNS disease in 19.58%, and acute chest syndrome in 17.01%. Other indications included sickle nephropathy, sickle hepatopathy, priapism and AVN in 10.82% of patients collectively. Around 59% of donors were sickle cell disease carriers, and 41% were healthy donors. After a median follow up of 28.8 months (5-83), sixteen patients (8%) experienced graft failure (3 with primary GF and 13 with secondary GF). On univariate analysis (table 1a), ABO minor incompatibility (odds ratio (OR), 3.63; 95% confidence interval (CI), 1.13 -11.65, P=0.029, and RBC alloantibodies against donor non-ABO antigens (OR, 4.22; 95% CI, 1.17 -15.14, P=0.039) were predictive for GF. However, on multivariate analysis (table 2a), only RBC alloantibodies against donor non-ABO antigens (OR, 8.29; 95% CI, 2.01 to 34.05, P=0.0033) was predictive of GF. None of the 16 patients with major ABO incompatibility developed GF. Two-years OS for all patients was 95%. The median OS for patients with GF was 98% compared to 74% patients without GF, P<0.0001) (Figure 1). Conclusion: In our SCD transplanted patients, RBC alloantibodies against donor non-ABO antigens was an independent risk factor for GF. Patients with GF had an inferior survival and strategies for decreasing the risks are needed. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Improved T-Cell Chimerism and Successful Withdrawal of Immunosuppression after Non-Myeloablative Stem Cell Transplantation for Sickle Cell Disease with Azathioprine/Hydroxyurea Preconditioning Added to Alemtuzumab/TBI Conditioning

Background: Allogeneic hematopoietic stem cell transplantation (HSCT) is currently the only established curative treatment option for sickle cell disease (SCD). In adult SCD patients, myeloablative conditioning is associated with significant toxicity, primarily because of cumulative organ damage. Recently, matched sibling donor (MSD) transplantation with non-myeloablative conditioning (alemtuzumab/3 Gy total body irradiation (TBI)) showed promising outcomes in adult SCD patients. This chemotherapy-free regimen, typically resulting in mixed chimerism, is associated with mild toxicity with no reports of graft-versus-host disease (GvHD). Despite mixed chimerism, the red blood cell (RBC) phenotype is completely donor-derived. However, in a large series, 13% of patients experienced graft failure. Another 8.2% of patients could not stop their immunosuppression (sirolimus) after one year, because of low donor T-cell chimerism (<50%). Reported mean donor T-cell chimerism at 12-months post-transplantation was 48% (Br J Haematol. 2021 Feb;192(4): 761-768). We hypothesized, that the addition of azathioprine and hydroxyurea as preconditioning to the alemtuzumab/TBI conditioning regimen will reduce the risk of graft failure and improve donor T-cell chimerism, enabling successful withdrawal of sirolimus in all patients. Aim: To investigate the effects of adding azathioprine/hydroxyurea preconditioning to alemtuzumab/TBI conditioning on donor chimerism levels and the occurrence of graft failure in adult SCD patients receiving non-myeloablative MSD-HSCT. Methods: Adult SCD patients with an available HLA-identical sibling donor were eligible for this treatment. All patients received three months of azathioprine 150mg qd and hydroxyurea 25mg/kg qd preconditioning. After exchange transfusion (target HbS <30%), conditioning with alemtuzumab 1mg/kg total dose and 3Gy TBI started on day -7, followed by unmanipulated peripheral hematopoietic stem cell infusion on day 0. Sirolimus as GvHD and rejection prophylaxis started on day -1. Results: Twenty SCD patients (median age 26 (range 19-49) years) were transplanted with a median follow-up of 24.5 months (range 1-52 months). Patient and transplant characteristics are shown in Table 1. Median donor myeloid and T-cell chimerism of engrafted patients was 100% (range 87-100%) and 68.5% (range 37-89%) at 12-months post-transplantation and 94% (range 86-100%) and 78.5% (range 68-88%) at 18-months post-transplantation, respectively (Figure 1). These donor T-cell chimerism percentages are higher than previously reported with alemtuzumab/TBI conditioning only. All engrafted patients had a corrected SCD phenotype with normalized hemoglobin levels. Importantly, all patients with a follow-up of ≥ 12 months (n=12) could successfully taper and stop sirolimus without decreases in donor chimerism. One year estimated disease-free survival and overall survival were 94.7%. and 93.3%, respectively. One patient (5%) experienced graft failure without autologous regeneration and subsequently died after a series of complications, including EBV reactivation, post-transplantation lymphoproliferative disease, and systemic aspergillosis. Acute gastrointestinal GvHD grade 2 occurred in one patient (5%) and resolved quickly after treatment with prednisolone. Summary/Conclusion: Azathioprine/hydroxyurea preconditioning prior to alemtuzumab/TBI resulted in improved donor T-cell chimerism, potentially reducing the risk of graft failure after non-myeloablatieve MSD transplantation in SCD patients. Importantly, all engrafted patients reached donor T-cell chimerism >50% and were able to stop immunosuppressives as scheduled. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

CRISPR/Cas9 Genome-Edited Autologous Hematopoietic Stem Cell Transplantation Therapies for Sickle Cell Disease

Hematopoietic stem cell transplantation is the only curative option for sickle cell disease (SCD), a life-threatening genetic disorder that impacts millions worldwide, yet the majority of patients do not have a suitable donor for an allogeneic transplantation. Increased levels of fetal hemoglobin (HbF) are protective against complications of SCD. BCL11A is a transcription factor that binds to the y-globin promoter and controls fetal-to-adult hemoglobin switching. Reducing BCL11A expression or inhibiting its activity can induce expression of HbF in adult red blood cells. We have developed 2 genome editing strategies targeting BCL11A for the induction of HbF levels and report the preclinical development of two potentially curative CRISPR/Cas9 ex-vivo genome-edited autologous hematopoietic stem cell therapies: HIX763 and OTQ923. HIX763 is an investigational cell therapy product harboring a genome modification in the erythroid-specific enhancer region of the BCL11A gene on chromosome 2 resulting in reduced BCL11A expression only in erythroid cells. OTQ923 is an investigational cell therapy product generated by targeted disruption of the γ-globin gene promoter on chromosome 11 to presumably delete BCL11A binding regions in the targeted region. Both HIX763 and OTQ923 are intended to durably increase HbF to therapeutically effective levels to ameliorate complications of SCD. Both products showed editing-dependent upregulation of γ-globin, HbF expression and number of F-cells upon erythroid differentiation of edited hematopoietic stem cells from healthy donors and SCD patients. No off-target editing was identified for both HIX763 and OTQ923 through a complementary suite of genome-wide biochemical and cell-based assays including in silico off-target prediction, SITE-Seq, PanHeme analysis of known oncogenes and tumor suppressors, karyotyping, UnIT evaluation of chromosomal rearrangements, and on-target long-range sequencing analysis. A six-month tumorigenicity study revealed no tumor formation or clonal outgrowth upon transplantation of full human doses of HIX763 and OTQ923 into immunocompromised NOD scid gamma mouse (NSG) mice. Finally, a comparability assessment of OTQ923 produced using the research process and the clinical manufacturing process showed comparability in the quality of cells, as measured by off-target editing, genomic rearrangement, cell viability, editing efficiency, HbF induction, and in vivo engraftment. Together these studies demonstrate that the preclinical data adequately reflects the behavior of the cells intended for clinical use and supports advancing these drug products into clinical trials for the treatment of sickle cell disease.

Voxelotor versus other therapeutic options for sickle cell disease: Are we still lagging behind in treating the disease?

BackgroundSickle cell disease (SCD) is one of the most prevalent hemoglobinopathies that affects around 275,000 neonates annually. Until 2017, hydroxyurea was the only available drug for SCD treatment. Later on, L‐glutamine and crizanlizumab have shown promising results in SCD therapy.ObjectivesThere were limited pharmacological options for the disease when in November, 2019, voxelotor was approved for the treatment of SCD patients after showing promising results in the clinical HOPE trial. Despite its favorable results, some life‐threatening side effects were also observed. Uncertainty regarding the use of available pharmaceutical therapies for SCD is the major hurdle for the survival of patients.Discussion & ConclusionAn immediate attention needs to be drawn towards the drawbacks of limited pharmacological options for SCD. Article calls out to conduct more extensive trials in this advanced era of medicine where ambiguity regarding the use of SCD drugs still prevails.

S105: ADDING AZATHIOPRINE/HYDROXYUREA PRECONDITIONING TO ALEMTUZUMAB/TBI CONDITIONING IMPROVES DONOR CHIMERISM IN MATCHED SIBLING DONOR STEM CELL TRANSPLANTATION IN ADULT SICKLE CELL DISEASE PATIENTS

Background: Allogeneic hematopoietic stem cell transplantation (HSCT) is currently the only established curative treatment option for sickle cell disease (SCD). In adults, myeloablative conditioning is associated with significant toxicity, primarily due to cumulative organ damage. Matched sibling donor (MSD) transplantation with non-myeloablative conditioning (alemtuzumab/3 Gy total body irradiation (TBI)) has shown promising results in adult SCD patients.1,2 Patients treated with this regimen had their sickle cell phenotype corrected with only mild complications and no reports of graft-versus-host disease (GvHD). However, most of the described patients did not reach complete donor chimerism with graft failure rates of 13%. Furthermore, in almost 10% of patients, immunosuppressives could not be withdrawn because of too low T cell chimerism (<50%).2 We hypothesized that adding azathioprine and hydroxyurea as preconditioning to the alemtuzumab/TBI regimen might improve donor chimerism, reduce the risk of graft failure and improve successful withdrawal of immunosuppressives. Aims: In this study we prospectively investigate the effects of azathioprine/hydroxyurea preconditioning on donor chimerism and graft failure in patients receiving non-myeloablative MSD HSCT for SCD. Methods: Adult SCD patients who had an HLA-identical sibling donor were eligible for this treatment. After 3 months of azathioprine 150mg qd and hydroxyurea 25mg/kg qd, erythrocyte exchange transfusion was performed on day –10, aiming for HbS <30%. Conditioning with alemtuzumab/TBI was started on day –7. Graft versus host disease (GvHD) prophylaxis consisted of sirolimus. Results: As of October 2021, 13 SCD patients (median age 30.6 (range 19–49) years) were transplanted. Twelve patients (92.3%) engrafted successfully. After a median follow-up of 24 months, median donor myeloid and T cell chimerism of engrafted patients were 100% (IQR 84–100%) and 77% (IQR 70.5%-82.5%), respectively. These donor chimerism percentages are higher than previously reported with alemtuzumab/TBI only. All engrafted patients had a corrected SCD phenotype with normalized hemoglobin levels. Patients reaching 1-year post-transplantation were able to stop sirolimus without decreases in chimerism. Summary/Conclusion: Azathioprine/hydroxyurea preconditioning prior to alemtuzumab/TBI results in improved donor chimerism, potentially reducing the risk of graft failure after non-myeloablatieve MSD transplantation in SCD patients. Importantly, all engrafted patients reached donor T cell chimerism >50% at 1-year post-transplantation and were able to stop immunosuppressives as scheduled.

Decision making for hematopoietic stem cell transplantation in pediatric, adolescent, and young adult patients with a hemoglobinopathy-Shared or not?

Hematopoietic stem cell transplantation (HSCT) offers an established curative option for sickle cell disease (SCD) and thalassemia patients but is associated with significant risks. Decision making is a complex process and shared decision making (SDM) could be a fitting approach in case of such preference-sensitive decisions. This study investigated what level of SDM is used in conversations with hemoglobinopathy patients and/or their caregivers considering HSCT as a curative treatment option. Longitudinal, descriptive study using the Observing-Patient-Involvement-in-Decision-Making scale (OPTION5 ) scale to determine the level of SDM in conversations with 26 hemoglobinopathy patients and/or their caregivers. The total mean OPTION5 score was 43%, which is a moderate SDM approach. There was no difference between conversations with thalassemia patients and SCD patients. Conversations needing an interpreter scored worse than nontranslated conversations. The best scoring OPTION5 item was item 3: "informing about the various treatment options" (mean score 2.3 on scale 0-4). For OPTION5 item 4: "eliciting patients' preferences" a more skilled effort was measured for SCD patients compared to thalassemia patients. The mean OPTION5 score of "moderate" was achieved mainly by giving information on available options, which is primarily a one-way communication. The SDM process can be improved by actively inviting patients to deliberate about options and including their elicited preferences in decision making.

Curative options for sickle cell disease: haploidentical stem cell transplantation or gene therapy?

Haematopoietic stem cell transplantation (HSCT) is curative in sickle cell disease (SCD); however, the lack of available matched donors makes this therapy out of reach for the majority of patients with SCD. Alternative donor sources such as haploidentical HSCT expand the donor pool to nearly all patients with SCD, with recent data showing high overall survival, limited toxicities, and effective reduction in acute and chronic graft-versus-host disease (GVHD). Simultaneously, multiple gene therapy strategies are entering clinical trials with preliminary data showing their success, theoretically offering all patients yet another curative strategy without the morbidity and mortality of GVHD. As improvements are made for alternative donors in the allogeneic setting and as data emerge from gene therapy trials, the optimal curative strategy for any individual patient with SCD will be determined by many critical factors including efficacy, transplant morbidity and mortality, safety, patient disease status and preference, cost and applicability. Haploidentical may be the preferred choice now based mostly on availability of data; however, gene therapy is closing the gap and may ultimately prove to be the better option. Progress in both strategies, however, makes cure more attainable for the individual with SCD.

Comparative Effectiveness of a Web-Based Patient Decision Aid for Therapeutic Options for Sickle Cell Disease: Randomized Controlled Trial.

BackgroundHydroxyurea, chronic blood transfusions, and bone marrow transplantation are efficacious, disease-modifying therapies for sickle cell disease but involve complex risk-benefit trade-offs and decisional dilemma compounded by the lack of comparative studies. A patient decision aid can inform patients about their treatment options, the associated risks and benefits, help them clarify their values, and allow them to participate in medical decision making.ObjectiveThe objective of this study was to develop a literacy-sensitive Web-based patient decision aid based on the Ottawa decision support framework, and through a randomized clinical trial estimate the effectiveness of the patient decision aid in improving patient knowledge and their involvement in decision making.MethodsWe conducted population decisional needs assessments in a nationwide sample of patients, caregivers, community advocates, policy makers, and health care providers using qualitative interviews to identify decisional conflict, knowledge and expectations, values, support and resources, decision types, timing, stages and learning, and personal clinical characteristics. Interview transcripts were coded using QSR NVivo 10. Alpha testing of the patient decision aid prototype was done to establish usability and the accuracy of the information it conveyed, and then was followed by iterative cycles of beta testing. We conducted a randomized clinical trial of adults and of caregivers of pediatric patients to evaluate the efficacy of the patient decision aid.ResultsIn a decisional needs assessment, 223 stakeholders described their preferences, helping to guide the development of the patient decision aid, which then underwent alpha testing by 30 patients and 38 health care providers and iterative cycles of beta testing by 87 stakeholders. In a randomized clinical trial, 120 participants were assigned to either the patient decision aid or standard care (SC) arm. Qualitative interviews revealed high levels of usability, acceptability, and utility of the patient decision aid in education, values clarification, and preparation for decision making. On the acceptability survey, 72% (86/120) of participants rated the patient decision aid as good or excellent. Participants on the patient decision aid arm compared to the SC arm demonstrated a statistically significant improvement in decisional self-efficacy (P=.05) and a reduction in the informed sub-score of decisional conflict (P=.003) at 3 months, with an improvement in preparation for decision making (P<.001) at 6 months. However, there was no improvement in terms of the change in knowledge, the total or other domain scores of decisional conflicts, or decisional self-efficacies at 6 months. The large amount of missing data from survey completion limited our ability to draw conclusions about the effectiveness of the patient decision aid. The patient decision aid met 61 of 62 benchmarks of the international patient decision aid collaboration standards for content, development process, and efficacy.ConclusionsWe have developed a patient decision aid for sickle cell disease with extensive input from stakeholders and in a randomized clinical trial demonstrated its acceptability and utility in education and decision making. We were unable to demonstrate its effectiveness in improving patient knowledge and involvement in decision making.Trial RegistrationClinicalTrials.gov NCT03224429; https://clinicaltrials.gov/ct2/show/NCT03224429 and ClinicalTrials.gov NCT02326597; https://clinicaltrials.gov/ct2/show/NCT02326597

Characterization of Immune Cells Producing Regulatory Cytokines That Mediate Engraftment in Sickle Cell Disease Patients after Haploidentical Peripheral Blood Stem Cell Transplantation

Sickle cell disease (SCD) is an inherited blood disorder in which red blood cells are sickle-shaped as a result of an amino acid alteration from glutamate to valine at the sixth position of the β-globin chain. Hematopoietic stem cell transplant (HSCT) is a curative option for SCD, with both HLA-matched and haploidentical transplant being viable approaches. Stable mixed chimerism and tolerance induction are sufficient to reverse the sickle phenotype. Graft rejection and graft versus host disease may occur following nonmyeloablative haploidentical peripheral blood stem cell transplantation (PBSCT). Various regulatory cytokines have been identified as biomarkers of engraftment in graft transplantation. Previously, we observed that TGF-β, interleukin (IL)-7, and IL-10 cytokines were elevated in engrafted SCD patients as compared to those who rejected their grafts following haploidentical PBSCT. Now, we aim to identify the immune cell populations responsible for producing the above cytokines in both engrafted and rejected patients. The plasma samples of 21 SCD patients who underwent nonmyeloablative haploidentical PBSCT at the National Institutes of Health between March 2010 and September 2015 were evaluated previously by multiplexed magnetic bead enzyme linked immune sorbent assay. Here, we analyzed various immune cells which produce the above regulatory cytokines through multi-color flow cytometry in 8 out of the 21 patients (four engrafted and four rejected). We evaluated the cytokine producing capabilities via intracellular cytokine detection among T regulatory (Treg, CD3+CD4+CD25+Foxp3+) cells, Type 1 regulatory (Tr1, CD3+CD4+Foxp3-CD45RA-CD49+LAG3+) T cells, T helper 1 (Th1, CD3+CD4+Foxp3-CD45RO+CXCR3+) cells, T helper 17 (Th17, CD3+CD4+Foxp3-CD45RO+CCR6+) cells, natural killer (NK, CD3-CD56+NKG2D+) cells, B regulatory (Breg, CD3-CD56-CD19+CD24hiCD38hi)cells, polymorphonuclear-myeloid derived suppressor cells (PMN-MDSCs, CD45+CD14-CD15+CD11b+), monocytic-MDSCs (CD45+CD14+CD15-HLADRlow), early-MDSCs (CD45+Lin-HLADR-CD11b+CD33+), myeloid dendritic cells (mDCs, CD45+CD3-CD56-HLADR+CD11c+CD123-), and plasmacytoid dendritic cells (pDCs, CD45+CD3-CD56-HLADR+CD11c-CD123+). Cytokine producing cell frequencies were measured at five timepoints: baseline (day 0) and days 30, 60, 100, and 180 post-transplant (PT). Percentages of intracellular cytokine and cell population frequencies were assessed through flow cytometry analysis and statistical significance was determined by Student's t-test. We noted IL-10-producing Tregs were significantly elevated in engrafted patients at PT day 100 (p&amp;lt; 0.01, see Figure 1). Further, IL-10-producing Th1 cells were significantly higher in engrafted patients on PT day 30 (p&amp;lt; 0.01) and day 100 (p&amp;lt; 0.01). However, rejected patients had significantly higher amounts of IL-10-producing PMN-MDSCs (p&amp;lt; 0.01), and myeloid DCs (p&amp;lt; 0.01, see Figure 2), but their levels were lower than IL10-producing Tregs and Th1 cells of engrafted patients. There were no significantly different alterations of IL-10-producing cell frequencies among other cell populations (Tr1, Th17, NK, Breg, early-MDSCs, monocytic-MDSCs, and pDCs). In addition, there were no significant variations in TGF-β- and IL-7-producing cell frequencies in any of the immune cell populations tested. Overall, the engrafted patients showed higher IL-10-producing Tregs and Th1 cells at PT day 30 and/or day 100, which suggest that the immunosuppressive cytokine IL-10 may play an important role in engraftment. Further analyses with a larger sample size are indicated to evaluate whether IL-10 producing immune regulatory cells may serve as a biomarker to predict transplant outcome. Taken together, continuous regulatory cytokine analysis at serial time points pre- and post-transplant may aid in establishing mechanisms of successful engraftment and tolerance induction. Disclosures No relevant conflicts of interest to declare.

Parent and Guardian Knowledge of Hematopoietic Cell Transplantation as a Treatment Option for Sickle Cell Disease.

Beginning early in childhood, patients with sickle cell disease (SCD) are at risk of life-threatening and debilitating health events. Despite the high morbidity and mortality of this disease, hematopoietic cell transplantation (HCT), a curative treatment for SCD, remains underutilized. In the literature there is a paucity of data concerning medical decision maker (MDM) awareness of HCT as a treatment option for SCD. The objective of this study was to estimate the proportion of parents/guardians of children with SCD who are aware of HCT as a treatment option, and to identify the demographic factors associated with knowledge of this therapy's curative potential. Between November 2015 and December 2016, 327 parents/guardians were surveyed across 4 clinical sites in 3 Midwestern US cities. Although 82% of parents/guardians had heard of HCT in the past and 78% were aware of the therapy's curative potential, nearly half indicated that they did not know whether HCT could specifically cure their child of the disease. Respondents who had discussed HCT with their child's physician had 5 times higher odds of being aware of HCT's curative potential than those who had not. These findings suggest that additional efforts to enhance MDM knowledge of HCT as well as shared decision making in the use of this therapy, is warranted.

Simple chronic transfusion therapy, a crucial therapeutic option for sickle cell disease, improves but does not normalize blood rheology: What should be our goals for transfusion therapy?

Sickle cell anemia is characterized by a mutation resulting in the formation of an abnormal beta-hemoglobin called hemoglobin S. Hemoglobin S polymerizes upon deoxygenation, causing impaired red blood cell deformability and increased blood viscosity at equivalent hematocrits. Thus, sickle cell disease is a hemorheologic disease that results in various pathologic processes involving multiple organ systems including the lungs, heart, kidneys and brain. Red blood cell mechanics and the perturbations on blood flow-endothelial interaction underlie much of the pathology found in sickle cell disease. Transfusion therapy is one of the few therapeutic options available to patients, acting as both primary and secondary prevention of stroke. Transfusion therapy, both simple and exchange, is also used for unremitting and frequent pain crises and pulmonary hypertension. Therefore, understanding basic rheologic changes following transfusion inform other therapeutic options that aim to mitigate this diffuse pathologic process. This review will aim to highlight transfusion effects on blood rheology.

Prasugrel hydrochloride for the treatment of sickle cell disease

ABSTRACTIntroduction: Therapeutic options for sickle cell disease (SCD) are limited and, currently, only one drug (hydroxyurea) has FDA approval for the treatment of adult SCD. While this genetic disease is caused by hemoglobin polymerization, subsequent downstream events trigger platelet activation, vaso-occlusion and the disease’s complex pathophysiology.Areas covered: The oral thienopyridine, prasugrel hydrochloride, irreversibly inhibits the P2Y12 receptors, inhibiting ADP-dependent platelet activation. We discuss recent clinical trials evaluating the pharmokinetics of prasugrel and its potential for use in SCD.Expert opinion: Prasugrel administration in SCD appears to be well tolerated and safe. However, although this drug modestly inhibits platelet activity in these patients, administration of prasugrel to a large group of children and adolescents for up to 24 months failed to convincingly reduce vaso-occlusive complications. Speculatively, prasugrel may be of occasional use for off-license purposes in patients unable or unwilling to take hydroxyurea (particularly in 12–17-year olds). Although there is currently no prospect of prasugrel being licensed for use in SCD, the success of on-going trials of other antiplatelet agents in SCD might lead to further trials of prasugrel in SCD.

Parent and Guardian Knowledge of Hematopoietic Cell Transplantation As a Treatment Option for Sickle Cell Disease

Introduction: Beginning early in childhood, patients with sickle cell disease (SCD) are at risk of life-threatening and debilitating health events. Despite the high morbidity and mortality of this disease, hematopoietic cell transplantation (HCT), the only curative therapy for SCD, remains underutilized. Between 2008 and 2012, an average of 76 HCTs per year were performed on patients with SCD in the United States (US), a remarkably low rate considering that nearly 100,000 people in the US are living with this disease and approximately 1,000 infants are born with SCD in the US each year. Multiple factors may contribute to the low rates of HCT in this population. However, there is a paucity of data concerning the level of awareness of HCT among parents and guardians of children with SCD, an important factor to consider in the assessment of HCT utilization rates.Objectives: To identify the proportion of parents and guardians of children with SCD who are aware of HCT as a treatment option, and to evaluate the relationship between patient demographics and parental/guardian awareness of this treatment option.Methods: A 25-item paper-based survey was developed to assess parent/guardian awareness of HCT, based upon feedback from leaders in SCD community health organizations and pediatric hematologists. The survey was administered to parents/guardians of pediatric patients with SCD during routine outpatient appointments with their child’s hematologist and at SCD community events sponsored by participating clinical sites. The survey was anonymous, and a $5.00 gift card was provided to all participants who completed the survey. Participants were recruited from four clinical centers across three cities in the Midwestern United States. All parents/legal guardians of children (<18 years of age) with SCD, who have not undergone HCT, were eligible to participate. Multivariable logistic regressions were performed to assess the relationship between the following variables and parent/guardian awareness of HCT as a treatment option for SCD: accrual site, patient age, number of full siblings, parent/guardian education level, parent/guardian relationship to patient, duration of custody, and SCD genotype.Results: 229 respondents (95% biological parent, 1% adoptive parent, 4% legal guardian) have participated in the study to date. 95% of all eligible parents/guardians agreed to participate. 82% of study respondents indicated that they have heard of HCT as a treatment option for SCD (N=187). 53% indicated that their child's physician has talked to them about HCT at some point in the past (N=120). On average, patients were 2.84 years old when the parent/guardian first heard about HCT (N=178, 95% CI: 2.31-3.37); patients were 3.08 years old on average when the child's physician first mentioned HCT (N=113, 95% CI: 2.42-3.75). 76% of respondents indicated that they are aware that HCT can potentially cure SCD (N=172). Higher parent/guardian education level and SS genotype were associated with having heard about HCT as a treatment option. SS genotype was associated with having been informed about HCT by their child's physician. Having been informed about HCT by their child's physician was associated with parent/guardian awareness that HCT is a potentially curative treatment.Conclusions: The majority of parents/guardians of children with SCD enrolled in this study have heard of HCT and are aware that HCT is a potentially curative treatment. In this population, non-physician sources of information and parent/guardian education level play an important role in awareness of this treatment modality. Physician-family discussion about HCT plays an important role specifically in parent/guardian awareness of the curative potential of this treatment. These data underscore the importance of physicians discussing HCT with families, particularly those who have limited resources to research treatment options on their own. DisclosuresQuinn:Amgen: Research Funding; Eli Lilly: Research Funding; Silver Lake Research Corporation: Consultancy. Hsu:Centers for Medicare and Medicaid Innovation: Research Funding; Mast Therapeutics: Research Funding; Pfizer: Consultancy, Research Funding; Purdue Pharma: Research Funding; Sancilio: Research Funding; Gerson Lehman Group: Consultancy; Eli Lilly: Research Funding; EMMI Solutions: Consultancy; Astra Zeneca: Consultancy, Research Funding; Hilton Publishing: Consultancy, Research Funding. Piccone:Novartis: Other: Speaker.