Comparable Outcome of CD3+-/CD19+ Depleted Haploidentical with Matched Sibling Donor Hematopoietic Stem Cell Transplantation for Advanced Stage Sickle Cell Disease: Result of a Pilot Study

Introduction

Sickle cell disease (SCD) is an inherited disorder with an estimate of 300.000 affected newborns per year worldwide. Despite significant improvements in preventive measures, supportive care and conventional therapy, substantial morbidity and mortality with a reduced life expectancy persists. Allogeneic hematopoietic stem cell transplantation (HSCT) with a matched sibling donor (MSD) is currently the curative standard of care for SCD patients (pts). But MSD and unrelated matched donor availability is <20% and graft- versus-host disease (GvHD) remains to be associated with significant morbidity and mortality with T cell repleted grafts and standard GvHD prophylaxis, which is unacceptable, particularly in pts with non-malignant diseases. A T cell depleted haploidentical HSCT (T-haplo-SCT) expands donor availability while exhibiting low GvHD rates. In our single center pilot study, we compared T-haplo-SCT with a MSD HSCT in pts with advanced stage SCD, using almost identical transplant conditions except donor source and GvHD prophylaxis.

Methods

17 pts were transplanted for advanced stage SCD-related complications. Five SCD pts received bone marrow (BM) from a MSD and 12 peripheral blood stem cells (PBSC) from a haploidentical donor. The conditioning regimen for both groups consisted of thiotepa (2x5mg/kg), fludarabine (4x40mg/m²), treosulfan (3x14g/m²) and anti-thymocyte globulin (ATG, Neovii, 3x15mg/kg), given on day -9 to -7 for T-haplo-SCT and on days -3 to -1 for MSD. In addition, Cyclosporine A (CSA) or Tacrolimus and MMF was applied for GvHD prophylaxis. All pts underwent exchange transfusions prior to conditioning and means of fertility preservation. The MSD pts included four females and one male, median age 22 years (range 9 to 25 years). Three suffered from homozygous SCD, two from HbS/ß-thalassemia. The BM graft consisted of a median of 2,2 x 10⁶ CD34+ cells/kg bodyweight, with a A/S in three and a A/A genotype in two donors. In T-haplo-SCT, five were females and seven were males. Median age was 18 yrs (range 3 to 28 yrs). Nine had homozygous SCD, three HbS/ß-thalassemia. The PB grafts consisted of a median of 12,2 x 10⁶ CD34+ cells, 11,2 x 10³ CD3+ and 23,3 x 10³ CD19+ cells/kg. Haploidentical donors were fully haplotype mismatched relatives (1 mother, 8 fathers, 1 cousin, 1 sister and one step sister). Donor genotype was Hb A/A in one and Hb A/S in all others.

Results

The median follow-up was 21 months in the MSD group and 26 months in T-haplo-SCT group. The median hospitalization was 38 days for both. The median time to engraftment was faster in T-haplo-SCT versus MSD: 16 versus 23 days for leukocytes, 18 versus 23 days for granulocytes and 11 versus 21 days for thrombocytes. The median T (>500/µl) and B cell recovery (>100/µl) in T-haplo-SCT versus MSD was 115 versus 103 days and 85 versus 140 days, respectively.

Two pts in the T-haplo-SCT group developed a stable mixed PB chimerism with no SCD-related complications off immunosuppression. Lineage specific chimerism analyses of red cell precursors (CD235a, glycophorine A) in the BM of these pts showed a complete red cell chimerism. The median HbS level off immunosuppression was comparable in both groups (37-38%). In all 17 pts, the conditioning regimen was well tolerated. Mild veno-occlusive disease (VOD/SOS) was diagnosed in 1 MSD patient and a transient thromboembolic event in one T-haplo-SCT patient. One patient developed a life threatening capillary leak syndrome during ATG treatment and subsequent PRES and was rescued by a switch to everolimus MMF prophylaxis. One patient from the T-haplo-SCT succumbed to a CMV pneumonitis combined with rotavirus gastroenteritis. None of our pts developed a grade III-IV acute GvHD. Five T-haplo-SCT and one MSD patient developed steroid responsive grade I-II acute GvHD. One of five MSD and three of twelve T-haplo-SCT pts developed mild to moderate steroid responsive chronic GvHD, which resolved in the meantime. CMV and EBV reactivations were observed but could be treated with standard of care except one patient mentioned above. One patient after T-haplo-SCT developed BK virus nephritis. All pts are stably engrafted off immunosuppression and free of SCD-related complications.

Conclusions

In our experience T-haplo-SCT with CD3+/CD19+ depleted PBSC is safe and efficient with a very low incidence of GvHD and is at least comparable to MSD HSCT, even for advanced stage SCD pts.