Haemopoietic stem-cell transplantation with antibody-based minimal-intensity conditioning: a phase 1/2 study

Area of Science:

• Immunology
• Hematology
• Oncology

Background:

• Stem-cell transplantation (SCT) is a curative option for primary immunodeficiencies (PIDs).
• Conventional chemotherapy-based conditioning is associated with significant toxicity in high-risk patients, including those with organ damage or DNA repair disorders.
• There is a need for less toxic conditioning regimens to expand SCT eligibility for PIDs.

Purpose of the Study:

• To evaluate a novel antibody-based minimal-intensity conditioning (MIC) regimen for SCT in patients with PIDs.
• To assess the safety and efficacy of this MIC regimen in achieving engraftment without non-hematopoietic toxicity.

Main Methods:

• Sixteen high-risk patients with PIDs received SCT using an MIC regimen.
• The regimen included anti-CD45 monoclonal antibodies (YTH 24.5 and YTH 54.12) for myelosuppression, and alemtuzumab (anti-CD52), fludarabine, and low-dose cyclophosphamide for immunosuppression.
• Donors included matched siblings and unrelated donors (matched and mismatched).

Main Results:

• The antibody-based conditioning was well tolerated, with only two cases of grade 3 toxicity and no grade 4 toxicity.
• Engraftment was achieved in 15 of 16 patients (94%), with 11 (69%) achieving full or high-level mixed chimerism.
• At a median follow-up of 40 months, 13 of 16 patients (81%) were alive and cured of their underlying disease, with acceptable rates of acute and chronic graft-versus-host disease.

Conclusions:

• Antibody-based MIC conditioning is safe and effective for achieving curative engraftment in PID patients, including those with severe organ toxicity or DNA repair defects.
• This approach shifts the paradigm from intensive chemotherapy/radiotherapy, potentially reducing toxicity and late effects.
• This novel regimen may enable SCT for a broader range of primary immunodeficiency patients with matched donors.