Allogenic peripheral stem cell transplantation from HLA-matched related donors for adult sickle cell disease: remarkable outcomes from a single-center trial

Abstract

Adult patients with sickle cell disease (SCD) are highly susceptible to stem cell transplant complications, including drug toxicity, graft versus host disease (GVHD), and graft rejection due to SCD-related tissue damage, endothelial activation, and inflammation. The scarcity of compatible stem cells for transplantation further limits treatment options, with only 43 cases of adult allogeneic peripheral blood stem cell transplantation (allo-PSCT) from human leukocyte antigen (HLA)-identical sibling donors reported in the international registry for the period 1986-2013. Herein we report remarkable outcomes in a cohort of adult SCD patients who underwent allo-PSCT using a fludarabine (Flu), busulfan (Bu), and anti-T-cell lymphocyte globulin (ATG)-based conditioning regimen in combination with very low dose total body irradiation (TBI), followed by post-transplant cyclophosphamide (Cy) and sirolimus as GVHD prophylaxis. We performed a single-center, retrospective study consisting of 20 consecutive patients (mean age 33.4 years) who underwent allo-PSCT from HLA-matched related donors with a conditioning regimen of Flu 150/Bu 3.2/Cy 29/ATG 30 (Fresenius)/TBI 200 between September 2013 and September 2017. Data were validated by an independent data audit group of the affiliated JACIE-accredited transplantation center. All patients experienced a sustained donor cell engraftment. Full donor chimerism (total cell) occurred within 180 days in all patients. Mean duration of follow-up was 13.8 months (range: 0.3-50 months), with 12 (60%) patients completing 12 months. No non-relapse mortality or graft rejection occurred. Successful treatment was achieved without the presence of graft loss, grade III-IV acute GVHD, extensive chronic GVHD, or other major complications. Allo-PSCT in combination with Flu 150/Bu 3.2/Cy 29/ATG 30(Fresenius)/TBI 200- Cy/Sirolimus therapy yielded encouraging outcomes with no mortality and low incidence of GVHD. Further controlled studies will be necessary to compare transplant protocols and long-term outcomes.

Allogeneic Hematopoietic Stem Cell Transplantation for Adults with Sickle Cell Disease

“…More recent studies using fludarabine and lower doses of busulfan in SCD adults have demonstrated improvements in event-free and overall survival and in lower rates of acute and chronic GVHD, comparable to what has been observed in some pediatric cohorts (Table 2). In a retrospective study of 20 SCD adults (mean age of 33 years) undergoing HSCT using HLA-matched related donors at the University of Baskent, all 20 had stable engraftment at the last follow-up and 11 of 12 patients who completed one year of follow-up were off all immunosuppression [50]. In the prospective, multicenter STRIDE study of 22 adolescents and young adults (median age: 23 years) undergoing HSCT using either HLA-matched related or unrelated donors, two patients had secondary graft failures and two deaths were observed [35].…”

“…The Hematopoietic Cell Transplant Comorbidity Index (HCT-CI) incorporates 17 comorbidities into a weight score that is used to predict relapse and overall mortality after HSCT [69] An intermediate or high score has been observed in 77% of SCD adults undergoing HSCT using a nonmyeloablative conditioning regimen [58] and in 30% using a reduced-intensity conditioning regimen [50]. Although this tool is useful in several malignant and nonmalignant hematologic conditions, an increasing HCT-CI score was not associated with lower survival when it was applied to patients with hemoglobinopathies [70].…”

“…Several of the recent HSCT regimens in adults have demonstrated improvements in rates of VOC. In the reduced-intensity conditioning regimen developed by Ozdogu et al, the proportion of patients with ≥2 VOC/year improved from 90% pre-HSCT to no patients experiencing VOC after HSCT [50]. In the NIH cohort, pain-related admissions improved from a median of three/year pre-HSCT to zero/year at one year post-HSCT in those with stable long-term engraftment using the alemtuzumab/TBI regimen [73].…”

Stable renal function in children and adolescents with sickle cell disease after nonmyeloablative hematopoietic stem cell transplantation

“…They have fewer treatmentrelated toxicities and the potential to achieve stable donor myeloid cell engraftment. 2,[20][21][23][24][25][26][36][37][38] As little as 20%-25% donor myeloid engraftment can reverse the SCD phenotype. [39][40] However, the experience with NMA-HSCT to cure SCD is still limited, and there exists a critical need for objective assessment of longterm outcomes and toxicities from a renal perspective.…”

Development of Gene Editing Strategies for Human β-Globin (HBB) Gene Mutations

“…Allogeneic stem cell transplantation, a promising treatment for SCD and similar blood diseases, is based on the availability of suitable donors, harvesting of healthy HSCs and their transplantation to the patients (Kahraman et al, 2014;Ozdogu et al, 2018b;Shenoy, 2011;Yesilipek, 2007;Yesilipek et al, 2018). Even though there are successful results of this method, it is not a universal treatment because of insufficiency of available donors, the immune issues like graft versus host disease (GVHD) and other toxicities (Ozdogu et al, 2018a;Ozdogu et al, 2018b). Autologous transplantation of ex vivo corrected HSCs have been proposed as a promising method to eliminate the drawbacks of allogeneic transplantation (Simsek et al, 2010;Yucel and Kocabas, 2018).…”