Haploidentical Aß T Cell Depleted HSCT Represents an Alternative Treatment Option in Pediatric and Adult Patients with Sickle Cell Disease (SCD)

Background: Sickle cell disease (SCD) is the most prevalent inherited hemoglobinopathy worldwide, which is associated with considerable morbidity and early mortality. Although HSCT with a MD offers a curative treatment option with an excellent 2-y OS of 95%, availability of MDs is limited and therefore haploidentical HSCT is increasingly explored. Here we update our in vitro T-depleted haploidentical HSCT approach, which is currently explored in a multicenter international trial (NCT04201210).

Methods: 29 pts with SCD or SCD-ß Thal (median age: 18 years; range: 2-32) received either a CD3 ⁺/CD19 ⁺ (n=9) or aß/CD19 ⁺ (n=20) T-haplo-HSCT and were compared with 20 SCD-pts receiving a BM graft from a MSD (median age: 23 years; range: 9-39) at our center. Indication for T-haplo HSCT pts included severe or moderate SCD related complications such as recurrent pain crisis (>5/year), acute chest syndrome, neurological events, osteonecrosis or nephropathy, transfusion-refractory allo-immunization. After exchange transfusion, almost identical conditioning regimens consisting of treosulfan, thiotepa, fludarabine (FTT) and ATG-Grafalon were applied in almost all pts, with the only difference in the timing of ATG (upfront in T-haplo-HSCT, prior to day 0 in MSD-HSCT). Immunosuppression (IST) was maintained for a minimum of 180 days consisting of calcineurin inhibitors (mainly tacrolimus) and MMF.

Results: The OS and DFS for MSD and T-haplo-HSCT was 95% and 83%, respectively (Table 1). The median follow-up was 49 months for MSD (range 5-118) and 67 months for T-haplo-HSCT (range 0.5-135). Neutrophil engraftment was achieved after a median of 29 days for MSD pts and 17 days for T-haplo-HSCT with a median of 2.8 x 10 ⁸ TNC/kg (range: 0.65-4.11) and 12 x 10 ⁶ CD3 ⁺/CD19 ⁺ or ab/CD19 ⁺ depleted CD34 ⁺ cells/kg (range: 4.8-49.2), respectively. One pt received two T-haplo HSCT due to primary graft failure after HHV6 infection with effective engraftment after the second transplantation. One pt required a stem cell boost of the same donor with slow subsequent engraftment and one pt died of infectious complications after the fourth T-haplo HSCT. A mixed chimerism <80% was observed in 1/20 MSD-HSCT (median 94.9%; range 40.5-100%) and in 2/29 T-haplo-HSCT pts (median 97.8%; range: 35.7 -100%). No severe cases of >°III aGVD was observed in both populations. MSD pts reached T cell counts >200/µl on day +62 (median; range: 24-293) and T-haplo-HSCT pts on day +136 (median; range: 25-758). Viral reactivation occurred both in T-haplo HSCT (20/29) and in MSD-BMT (9/20). However, one pt in the T-haplo group developed kidney failure after prolonged BKV infection and four of the T-haplo pts died of complications associated with severe CMV or HHV6 infections that were accompanied by hyperinflammation, macrophage activation and acute respiratory distress despite antiviral and anti-inflammatory treatment. One pt of the MSD group died of late treatment related toxicity in combination with preexisting SCD comorbidity. The last fatality occurred in 2020 with now 16 additional pts being transplanted safely, not least also because of a consistent letermovir prophylaxis. Overall, the treosulfan-based conditioning regimen was well tolerated with only one VOD/SOS and one CNS infarction being observed in this high-risk population. 4/20 pts in the MSD group and none in the T-haplo group developed PRES early after conditioning.

Conclusions: The safety and efficacy data of this pilot series of T-haplo-HSCT in SCD reveal that T-haplo-HSCT in advanced stage pediatric and adult SCD patients lacking a MSD is feasible. However, diligent viral monitoring and early treatment of viral reactivation, in particular HHV6 is mandatory as otherwise fatal infections may develop.