Treatment of High-Risk Sickle Cell Disease (SCD) with Familial Haploidentical (FHI) T-Cell Depleted (TCD) Stem Cell Transplantation with T-Cell Addback (IND 14359)

Background: Patients with sickle cell disease (SCD) have an average life expectancy of 39 years. The only known curative therapy is allogeneic stem cell transplantation (AlloSCT) from an HLA-matched donor (Talano/Cairo EJH, 2014). We have demonstrated 100% EFS and absence of sickle cell symptoms following reduced intensity conditioning and matched sibling bone marrow or cord blood AlloSCT (Bhatia/Cairo et al, BMT, 2014). However, matched sibling donors (MSD) and matched unrelated donors (MUD) are limited and unrelated cord blood transplant results are poor (Radhakrishnan K/Cairo et al., BBMT 2013, Kamani et al., BBMT, 2012). FHI TCD stem cell transplantation has been used with high engraftment and low aGVHD rates in high risk thalassemia patients and similar results were reported with both malignant and nonmalignant diseases (Sodani et al., Blood, 2010). Using a similar approach, we reported the success of CD34 selection with T-cell addback following MUD transplant in children (Geyer/Cairo BJH, 2012). FHI TCD AlloSCT could expand the donor pool and improve outcomes for patients with high risk SCD.

Objective: To determine the safety and feasibility of FHI TCD AlloSCT with T-cell addback in patients with high-risk SCD.

 

Methods: A multicenter consortium was developed to investigate this approach (Fig. 1). Patients (2-<21 yrs) without an 8/8 HLA MSD or MUD and who have ≥1 high-risk SCD features are eligible. Patients receive hydroxyurea (60mg/kg/d) and azathioprine (3mg/kg/d) day -59 – day -11, fludarabine (30mg/m²/d x5d), busulfan (3.2mg/kg/d x4d), thiotepa (10mg/kg x1d), cyclophosphamide (50mg/kg x4d), R-ATG (2mg/kg/d x4d), and TLI (500cGy) followed by FHI TCD AlloSCT.  We utilize the CliniMACS® System (IND 14359) to enrich for peripheral blood hematopoietic progenitor cells with a target dose of 10 x 10⁶ CD34+ cells/kg and 2 x 10⁵ CD3+ T cells/kg added back as a final CD3/kg concentration.

Results: Seven patients have received AlloSCTs from maternal donors. Neutrophil engraftment has been rapid (median 9d; range, 9-13d) and none has developed GVHD. All patients have achieved ≥94% whole blood chimerism and CD71 (erythroid) chimerism (Fig. 2). Six evaluable patients achieved full donor (≥95%) peripheral blood chimerism by day 60, and 3 of 6 achieved full donor CD3 chimerism in that time (Fig. 2). Absolute CD4 counts of ≥200/mm³ have been achieved in all patients ≥270 days post-transplant.  There have been no serious bacterial infections and only 1 viral infection. Six of 7 patients are alive and free of disease (day +24 to +710) with 1 death of VOD at day +59.

Early results indicate FHI TCD AlloSCT is feasible and well tolerated in high-risk SCD patients.  A larger cohort is needed to assess long-term safety and outcomes. (Supported by grants from the FDA [5R01FD004090] and Otsuka and CliniMACS^® supplies from Miltenyi Biotec) (IND#14359; NCT01461837; http://www.sicklecelltransplantconsortium.org)