Stem Cell Transplantation in Advanced Stage Sickle Cell Disease with Haploidentical T-Cell Depleted PBSC Yields Comparable Outcomes to Matched Sibling Donor Bone Marrow: Results of a Pilot Study

Background: Sickle cell disease (SCD) is an inherited disorder with an estimate of 300,000 affected newborns per year worldwide. Despite improvements in preventive measures and conventional therapy, substantial morbidity and mortality, resulting in a reduced life expectancy persist. Allogeneic hematopoietic stem cell transplantation (HSCT) with a matched sibling donor (MSD) is currently the curative standard of care. However, matched donor availability is <20% and unrelated donor (MUD) HSCT is associated with unacceptably high rates of severe graft-versus-host disease (GvHD). A T-cell depleted HSCT from a haploidentical relative (T-haplo-HSCT) expands donor availability while exhibiting low GvHD rates and thus could offer cure to the remaining 80% of SCD patients (pts).

Methods: We report the results of 29 pts with advanced stage SCD transplanted with either a T-cell depleted haploidentical regimen (20 pts, median age 13 years, range 3-31 years) or with bone marrow from a matched family donor (MSD, 9 pts, median age 14, range 9-25 years). Indication for HSCT was advanced stage SCD related complications. Pts with a MSD received a bone marrow (BM) graft. Pts requiring an alternative donor were transplanted with an αß/CD19 (n=5) or CD3/CD19 (n=15) depleted graft from a haploidentical family donor. The conditioning regimen for both groups was identical except that antithymoglobulin (ATG-Neovii^®) was given upfront on day -10 to -8 in T-haplo-HSCT and on day -3 to -1 in MSD. Chemotherapy consisted of thiotepa 2 x 5 mg/kg, fludarabine 4 x 40 mg/m² and treosulfan 3 x 14 g/m², given between days -10 and -2. Post-HSCT immunosuppression consisted of mofetil mycophenolate and tacrolimus or cyclosporine A for a duration >6 months in T-haplo-HSCT and <6 months in MSD, depending on chimerism. The MSD group received a graft containing a median of 2.4 x 10⁸ cells/kg body weight (BW). The T-haplo-SCT group received a peripheral stem cell allograft with a median of 13.1 x 10⁶ CD34+ cells/kg BW.

Results: The conditioning regimen was well tolerated in all pts with no high-grade transplant related toxicity. The overall (OS) and disease-free survival (DFS) with a median follow-up of 17 months in 20 advanced stage mostly adolescent and adult T-haplo-HSCT pts and 22 months in 9 MSD HSCT pts was 90% vs. 100%, respectively. Engraftment was achieved in most pts with stable chimerism over 90%, except for 4 pts with a stable MC in the T-haplo SCT group and 1 patient in the MSD group off immunosuppression. All pts presented a complete BM engraftment of red cell precursors. Only one patient in the T-haplo-HSCT group with a mixed chimerism is still under immunosuppression.

The post-HSCT bacterial infectious complications were comparable in both groups and the most common observed viral infections were systemic cytomegaly virus (CMV), adenovirus (ADV), polyomavirus (BKV) and Epstein Barr virus (EBV) reactivations which were successfully treated with intravenous antiviral drugs or virus specific T-cells.

Two patients in the T-haplo-HSCT group achieved a DFS off immunosuppression but succumbed to post-HSCT complications. One developed a rotavirus gastroenteritis and an uncontrolled CMV pneumonitis. The other a late graft failure and succumbed to a macrophage activation syndrome.

None of our pts developed a Glucksberg Grade III-IV acute GvHD and in the T-haplo SCT group 4 pts (20%) and in the MSD group 2 pts (22%) developed a steroid sensitive mild to moderate cGvHD (fasciitis/oral as well as mild cutaneous GvHD). No extensive cGvHD was observed.

To our knowledge this is the largest group of advanced stage SCD pts transplanted with either a T-haplo-HSCT or a MSD approach, according to donor availability, with an almost identical regimen in a direct comparative design. These preliminary results demonstrate increasing evidence for the feasibility, safety and efficacy of a T-haplo-HSCT using CD3/CD19 or αβ/CD19 depleted grafts, in order to offer a curative option to the majority of pts with SCD. A prospective, stratified non-inferiority trial is in preparation (EudraCT number 2018-002652-33) in order to confirm these preliminary results in a large prospective cohort.