Clinical risks and healthcare utilization of hematopoietic cell transplantation for sickle cell disease in the USA using merged databases.

Advances in allogeneic hematopoietic cell transplantation for sickle cell disease have improved outcomes, but there is limited analysis of healthcare utilization in this setting. We hypothesized that, compared to late transplantation, early transplantation (at age \u3c10 \u3eyears) improves outcomes and decreases healthcare utilization. We performed a retrospective study of children transplanted for sickle cell disease in the USA during 2000-2013 using two large databases. Univariate and Cox models were used to estimate associations of demographics, sickle cell disease severity, and transplant-related variables with mortality and chronic graft-versus-host disease, while Wilcoxon, Kruskal-Wallis, or linear trend tests were applied for the estimates of healthcare utilization. Among 161 patients with a 2-year overall survival rate of 90% (95% confidence interval [CI] 85-95%) mortality was significantly higher in those who underwent late transplantation versus early (hazard ratio (HR) 21, 95% CI 2.8-160.8, P=0.003) and unrelated compared to matched sibling donor transplantation (HR 5.9, 95% CI 1.7-20.2, P=0.005). Chronic graftversus host disease was significantly more frequent among those translanted late (HR 1.9, 95% CI 1.0-3.5, P=0.034) and those who received an unrelated graft (HR 2.5, 95% CI 1.2-5.4; P=0.017). Merged data for 176 patients showed that the median total adjusted transplant cost per patient was $467,747 (range:$344,029-$799,219). Healthcare utilization was lower among recipients of matched sibling donor grafts and those with low severity disease compared to those with other types of donor and disease severity types (

Using Fludarabine to Reduce Exposure to Alkylating Agents in Children with Sickle Cell Disease Receiving Busulfan, Cyclophosphamide, and Antithymocyte Globulin Transplant Conditioning: Results of a Dose De-Escalation Trial

AbstractHigh-dose busulfan, cyclophosphamide, and antithymocyte globulin (BU-CY-ATG) is the most commonly used conditioning regimen in HLA-matched related hematopoietic cell transplantation for children with sickle cell disease. Disease-free survival with this regimen is now approximately 95%; however, it produces significant morbidity. We hypothesized we could create a less toxic regimen by adding fludarabine (FLU) to BU-CY-ATG and reduce the dosages of busulfan and cyclophosphamide. We conducted a multicenter dose de-escalation trial with the objective of decreasing the doses of busulfan and cyclophosphamide by 50% and 55%, respectively. Using day +28 donor-predominant chimerism as a surrogate endpoint for sustained engraftment, we completed the first 2 of 4 planned levels, enrolling 6 patients at each and reducing the total dose of cyclophosphamide from 200 mg/kg to 90 mg/kg. On the third level, which involved a reduction of i.v. busulfan from 12.8 mg/kg to 9.6 mg/kg, the first 2 patients had host-predominant T cell chimerism, which triggered trial-stopping rules. All 14 patients survive disease-free. No patients suffered severe regimen-related toxicity. Our results suggest BU-FLU-CY-ATG using lower dose CY could be a less toxic yet effective regimen. Further evaluation of this regimen in a full-scale clinical trial is warranted

Using Fludarabine to Reduce Exposure to Alkylating Agents in Children with Sickle Cell Disease Receiving Busulfan, Cyclophosphamide, and Antithymocyte Globulin Transplant Conditioning: Results of a Dose De-Escalation Trial

AbstractHigh-dose busulfan, cyclophosphamide, and antithymocyte globulin (BU-CY-ATG) is the most commonly used conditioning regimen in HLA-matched related hematopoietic cell transplantation for children with sickle cell disease. Disease-free survival with this regimen is now approximately 95%; however, it produces significant morbidity. We hypothesized we could create a less toxic regimen by adding fludarabine (FLU) to BU-CY-ATG and reduce the dosages of busulfan and cyclophosphamide. We conducted a multicenter dose de-escalation trial with the objective of decreasing the doses of busulfan and cyclophosphamide by 50% and 55%, respectively. Using day +28 donor-predominant chimerism as a surrogate endpoint for sustained engraftment, we completed the first 2 of 4 planned levels, enrolling 6 patients at each and reducing the total dose of cyclophosphamide from 200 mg/kg to 90 mg/kg. On the third level, which involved a reduction of i.v. busulfan from 12.8 mg/kg to 9.6 mg/kg, the first 2 patients had host-predominant T cell chimerism, which triggered trial-stopping rules. All 14 patients survive disease-free. No patients suffered severe regimen-related toxicity. Our results suggest BU-FLU-CY-ATG using lower dose CY could be a less toxic yet effective regimen. Further evaluation of this regimen in a full-scale clinical trial is warranted

Across the Myeloablative Spectrum: Hematopoietic Cell Transplant Conditioning Regimens for Pediatric Patients with Sickle Cell Disease

One out of every five hundred African American children in the United States has sickle cell disease (SCD). While multiple disease-modifying therapies are available, hematopoietic cell transplantation (HCT) remains the only curative option for children with SCD. HLA-matched sibling HCT has demonstrated excellent efficacy, but its availability remains limited; alternative donor strategies are increasingly explored. While Busulfan-Cyclophosphamide has become the most widespread conditioning regimen employed in HCT for pediatric SCD, many other regimens have been examined. This review explores different conditioning regimens across the intensity spectrum: from myeloablative to non-myeloablative. We describe survival and organ function outcomes in pediatric SCD patients who have received HCT and discuss the strengths and weaknesses of the various conditioning intensities. Finally, we posit novel directions in allogeneic HCT for SCD

The Significance of Red Blood Cell Antigen Matching on Bone Marrow Transplant Outcomes in Patients with Sickle Cell Disease

Background: Hematopoietic stem cell transplant (HSCT) is the only potential curative therapy for sickle cell disease (SCD) currently. While significant research has been performed on the clinical impact of ABO-incompatible HSCT in patients with SCD, only preliminary studies have analyzed the outcomes of HSCT with non-ABO red blood cell (RBC) antigen discordance. Objectives: To investigate the frequency and clinical significance of minor RBC antigen discordance on HSCT outcomes in patients with SCD. Design/Methods: This study is a retrospective analysis of a cohort of patients with SCD who received a HSCT from 1995 to 2015, at a single institution. Results: Of the 48 patients with SCD who received HSCT, 17 (35.4%) had available data on minor RBC antigens for both donor and recipient. All 17 patients received transplants from HLA and ABO-matched related donors. There were 52.9% males, 88.2% African Americans, and mean age at time of transplant was 8.4 years old. Several different conditioning regimens were used, including reduced intensity regimens. The primary indications for transplant were history of stroke (47%), vasoocclusive crisis (29.4%), and acute chest syndrome (17.6%). Prior to transplant, alloantibodies were present in 35.3% of the subjects, the majority being anti-Rhesus-C. The majority of patients (94.1%) had at least 1 minor RBC antigen discordant with their donor. Fourteen patients (82.4%) had 1-3 discordances. The most common discordant blood group systems were the Rhesus (47%), MNS (35.3%), and Dombrock (29.4%) systems. None of the subjects developed novel antibodies following HSCT, despite discordances. Overall, there was little correlation between the number of minor RBC antigen discordances and HSCT outcomes (overall survival, graft failure, transfusion requirements, time to engraftment, time to transfusion independence, and complications). However, patients with two or more minor RBC discordances appeared to have more chronic GvHD, while patients with one discordance were more likely to develop acute GvHD. Conclusions: There appeared to be a trend towards increasing cGVHD in patients who had greater numbers of discordant minor RBC antigens, but no other association with clinical HSCT outcomes; however, given the limited size of this cohort, further studies are required

Gene therapy for sickle cell disease: moving from the bench to the bedside.

Gene therapy as a potential cure for sickle cell disease (SCD) has long been pursued, given that this hemoglobin (Hb) disorder results from a single point mutation. Advances in genomic sequencing have increased the understanding of Hb regulation, and discoveries of molecular tools for genome modification of hematopoietic stem cells have made gene therapy for SCD possible. Gene-addition strategies using gene transfer vectors have been optimized over the past few decades to increase expression of normal or antisickling globins as strategies to ameliorate SCD. Many hurdles had to be addressed before clinical translation, including collecting sufficient stem cells for gene modification, increasing expression of transferred genes to a therapeutic level, and conditioning patients in a safe manner that enabled adequate engraftment of gene-modified cells. The discovery of genome editors that make precise modifications has further advanced the safety and efficacy of gene therapy, and a rapid movement to clinical trial has undoubtedly been supported by lessons learned from optimizing gene-addition strategies. Current gene therapies being tested in clinical trial require significant infrastructure and expertise, given that cells must be harvested from and chemotherapy administered to patients who often have significant organ dysfunction and that gene-modification takes place ex vivo in specialized facilities. For these therapies to realize their full potential, they would have to be portable, safe, and efficient, to make an in vivo–based approach attractive. In addition, adequate resources for SCD screening and access to standardized care are critically important for gene therapy to be a viable treatment option for SCD

Cellular Therapy for Sickle Cell Disease.

Sickle cell disease (SCD) is a monogenic red cell disorder affecting over 300,000 annual births worldwide and leading to significant organ toxicity and premature mortality. While chronic therapies such as hydroxyurea have improved outcomes, more durable therapeutic and curative options are still being investigated. Newer understanding of the disease has implicated invariant NKT (iNKT) cells as a critical immune profile that potentiates SCD. Hence, targeting this cell population may offer a new approach to disease management. Hematopoietic stem cell transplant (HSCT) is a curative option for patients with SCD, but the under-representation of minorities on the unrelated donor registry means that this is not a feasible option for >75% of patients. Work in this area has therefore focused on increasing the donor pool and decreasing transplant-related toxicities to make this a treatment option for the majority of patients with SCD. This review focuses on the currently available cell and gene therapies for patients with SCD, and acknowledges that newer gene editing approaches to improve gene therapy efficiency and safety are the next wave of potentially curative approaches