Preservation and Transfer of HBV Immunity After Allogeneic HSCT for SCD

NCT ID: NCT05200338

Last Updated: 2023-06-08

Basic Information

• Recruitment Status: UNKNOWN
• Clinical Phase: NA
• Total Enrollment: 30 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2021-06-08
• Study Completion Date: 2024-12-31

Brief Summary

Sickle cell disease (SCD) patients ending with mixed mononuclear chimerism after non-myeloablative HSCT with alemtuzumab/TBI conditioning will probably preserve their immune response to vaccinations administered prior to the transplantation and will therefore not need to be revaccinated. Furthermore, SCD patients after haploidentical HSCT might benefit from adoptive transfer of immunity from their donors.

To test the first hypothesis, patients undergoing alemtuzumab/TBI HSCT will be vaccinated with a hepatitis B virus (HBV) vaccine before the transplant. To test the second hypothesis, haploidentical and matched related donors will be vaccinated 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.

Detailed Description

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.

Objectives: Primarily, to investigate whether recipient immunity is preserved and how fast it reconstitutes after non-myeloablative MSD HSCT resulting in mixed chimerism in adult SCD patients. Secondly, to investigate whether donor immunity is transferred to SCD patients after non-myeloablative haploidentical and MSD HSCT.

Study design: Prospective interventional cohort study. Six SCD patients per cohort will be vaccinated with a recombinant HBV vaccine before allogeneic MSD HSCT (cohort 1a) and haploidentical HSCT (cohort 1b). Six SCD patients not undergoing allogeneic HSCT will be vaccinated as controls (cohort 2). Six haploidentical donors and six matched sibling donors of unvaccinated receivers will be vaccinated against HBV before stem cell donation (cohort 3a and 3b, respectively). All vaccinated patients and the receivers of stem cells of vaccinated donors will receive a booster vaccination at 12 months post-transplantation. Follow-up will be until 2 years post-transplantation.

Study population: Adult SCD patients undergoing a matched sibling donor or haploidentical non-myeloablative allogeneic HSCT. HBV naive SCD patients not undergoing HSCT will serve as controls.

Main study parameters/endpoints: Primary endpoint: proportion of SCD patients with a preserved anti-HBs response following non-myeloablative HSCT with an HBV naive MSD. Secondary endpoints: proportion of SCD patients with a preserved HBV specific cellular immune response following non-myeloablative HSCT with an HBV naive MSD. Proportion of SCD patients with a preserved anti-HBs and/or HBV-specific cellular immune response following non-myeloablative HSCT with an haploidentical donor. Proportion of SCD patients adopting their donors anti-HBs and/or HBV-specific cellular immune response following non-myeloablative HSCT. Immune reconstitution as expressed by serum total IgG levels and peripheral blood T-lymphocyte subset counts (CD3+, CD4+, CD8+), B-lymphocyte subset counts (CD19+) and Natural Killer (NK) cell counts at 3-, 6-, 12- and 24-months post-transplantation as compared to baseline (pre-transplantation) values.

Conditions

Sickle Cell Disease

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: OTHER
• Blinding Strategy: NONE

Study Groups

Cohort 1a

SCD patients that are vaccinated against hepatitis B virus before matched sibling donor allogeneic SCT.

Group Type: OTHER

Engerix-B

Intervention Type: DRUG

Subjects are vaccinated with an accelerated scheme at 0, +1, +2 months with a booster at +12 months.

Cohort 1b

SCD patients that are vaccinated against hepatitis B virus before haploidentical donor allogeneic SCT.

Group Type: OTHER

Engerix-B

Intervention Type: DRUG

Subjects are vaccinated with an accelerated scheme at 0, +1, +2 months with a booster at +12 months.

Cohort 2

SCD patients that are vaccinated against hepatitis B virus without undergoing allogeneic SCT (control group).

Group Type: OTHER

Engerix-B

Intervention Type: DRUG

Subjects are vaccinated with an accelerated scheme at 0, +1, +2 months with a booster at +12 months.

Cohort 3a

SCD patients undergoing matched sibling donor allogeneic SCT whose donor is vaccinated against hepatitis B virus before stem cell collection.

Group Type: OTHER

Engerix-B

Intervention Type: DRUG

Subjects are vaccinated with an accelerated scheme at 0, +1, +2 months with a booster at +12 months.

Cohort 3b

SCD patients undergoing haploidentical donor allogeneic SCT whose donor is vaccinated against hepatitis B virus before stem cell collection.

Group Type: OTHER

Engerix-B

Intervention Type: DRUG

Subjects are vaccinated with an accelerated scheme at 0, +1, +2 months with a booster at +12 months.

Interventions

Engerix-B

Subjects are vaccinated with an accelerated scheme at 0, +1, +2 months with a booster at +12 months.

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

• Age 18 or older
• High performance liquid chromatography (HPLC) confirmed diagnosis of SCD (not applicable to participating donors).
• An indication for and a planned matched sibling or haploidentical donor non-myeloablative HSCT at the Amsterdam UMC, location AMC (not applicable to patients in cohort 2 (control group) and participating donors)
• Written informed consent

Exclusion Criteria

• History of either cleared, chronic or active HBV infection (positive HBsAg, anti-HBs, anti-HBc and/or HBV DNA)
• History of auto-immune diseases and/or use of immunosuppressive drugs
• History of HIV infection
• Known hypersensitivity to yeast of any vaccine constituent
• Donor with a history of HBV infection

• Minimum Eligible Age: 16 Years
• Maximum Eligible Age: 60 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)

OTHER

Sponsor Role: lead

Responsible Party

Erfan Nur

MD, PhD, Principal Investigator

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Erfan Nur, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)

Locations

Amsterdam Medical Centre

Amsterdam, , Netherlands

Site Status: RECRUITING

Countries

Netherlands

Central Contacts

Erfan Nur, MD, PhD

Role: CONTACT

e.nur@amsterdamumc.nl

0031-20-4442604

Management hematology

Role: CONTACT

hematology@amsterdamumc.nl

0031-20-4442604

Facility Contacts

Erfan Nur, MD, PhD

Role: primary

e.nur@amsterdamumc.nl

0031-20-4442604

Other Identifiers

METC 2021_091

Identifier Type: -

Identifier Source: org_study_id