Preservation and Transfer of Hepatitis B Virus Immunity After Non-Myeloablative Allogeneic Hematopoietic Stem Cell Transplantation in Adult Sickle Cell Disease Patients (Protect Study)

Rationale: Sickle cell disease (SCD) is an inherited hemoglobinopathy, characterized by chronic hemolytic anemia and microvascular occlusions leading to pain attacks and progressive deterioration of organ function. As a result, SCD patients have a significantly reduced life expectancy. Allogeneic hematopoietic stem cell transplantation (HSCT) is currently the only available curative treatment for SCD. Recently, a mild non-myeloablative conditioning regimen for HSCT with alemtuzumab (1mg/kg) and low dose (3Gy) total body irradiation (TBI) has been developed for adult SCD patients with a matched sibling donor (MSD) and been implemented in the Netherlands since 2018. The post-transplant setting of SCD patients treated with the alemtuzumab/TBI regimen differs greatly from that in other transplantation regimens usually used as treatment for malignant hematological diseases. Because of its mild character, the conditioning regimen typically results in mixed chimerism. In most patients, stable T-cell donor chimerism of around 50% is achieved. Thus, approximately half of the adaptive immunity is still patient-derived. However, whether these patients preserve their immune response after the transplantation, is not known.

Another promising development is the improvement of HSCT conditioning regimens for adult SCD patients with an haploidentical related donor. At the Amsterdam UMC, haploidentical HSCT has been implemented in 2020 using antithymocyte globulin, fludarabine, cyclophosphamide, thiotepa and low-dose (2Gy) TBI as conditioning regimen and post-transplantation cyclophosphamide (PTCy) as in vivo T-cell depletion. Besides improved engraftment rates, this conditioning regimen is also associated with a reasonably swift immune reconstitution. Unlike the conditioning with alemtuzumab/TBI in MSD HSCT, the above-mentioned conditioning for haploidentical HSCT results in full donor chimerism. Patients losing their immune response due to HSCT might benefit from the transfer of protective immunity from the stem cell donor. Two previous studies have demonstrated the adoption of immunity against hepatitis B virus (HBV) by transplant recipients. However, transplant recipients are also at high risk of gradual disappearance of protective antibodies. In contrast to our study patient population, these studies were conducted in mostly heavily pretreated patients with malignant hematological diseases undergoing myeloablative conditioning regimens.

Currently, it is common practice to revaccinate all patients post-transplant according to the revaccination schedules used for other allogeneic HSCT recipients. However, revaccinating might not be necessary in SCD patients undergoing non-myeloablative HSCT, as they might either preserve their immunity (mixed chimerism after alemtuzumab/TBI conditioning) or benefit from transfer of immunity (haploidentical HSCT)).

The investigators hypothesize, that patients ending with mixed mononuclear chimerism after HSCT will preserve their immune response to vaccinations administered prior to the transplantation and will therefore not need to be revaccinated. Furthermore, the investigators hypothesize, that SCD patients after haploidentical HSCT can benefit from adoptive transfer of immunity from their donors.

To test the first hypothesis, the investigators will vaccinate patients undergoing the alemtuzumab/TBI HSCT with a hepatitis B virus (HBV) vaccine before the transplant. To test the second hypothesis, the investigators will vaccinate haploidentical and matched related donors prior to stem cell donation against HBV. Neither the patient nor the donor may previously have been immunized against HBV in all cohorts. Post-transplantation, the investigators will be able to evaluate whether SCD patients preserve their pre-transplant immune response in the post-transplantation period. Furthermore, the investigators will determine whether donors transfer their immunity to HSCT recipients with SCD disease.