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

• Published in: The Lancet (British edition) Vol. 374; no. 9693; pp. 912 - 920
• Main Authors: Straathof, Karin C, MRCPCH, Rao, Kanchan, MRCPCH, Eyrich, Matthias, MD, Hale, Geoff, PhD, Bird, Prudence, PhD, Berrie, Eleanor, PhD, Brown, Lucinda, Adams, Stuart, PhD, Schlegel, Paul G, FRCP, Goulden, Nicholas, FRCPCH, Gaspar, H Bobby, Prof, Gennery, Andrew R, MD, Landais, Paul, MD, Davies, EG, FRCPCH, Brenner, Malcolm K, Prof, Veys, Paul A, FRCPCH, Amrolia, Persis Jal, Dr
• Format: Journal Article
• Language: English
• Published: Kidlington Elsevier Ltd 12.09.2009; Elsevier; Elsevier Limited
• Subjects: Alemtuzumab; Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy; Animals; Antibodies, Monoclonal - therapeutic use; Antibodies, Monoclonal, Humanized; Antibodies, Neoplasm - therapeutic use; Biological and medical sciences; Bone marrow; Bone marrow, stem cells transplantation. Graft versus host reaction; Child, Preschool; Cyclophosphamide - therapeutic use; Disease-Free Survival; Female; Follow-Up Studies; General aspects; Graft vs Host Disease - epidemiology; Graft vs Host Disease - etiology; Graft vs Host Disease - prevention & control; Hematopoietic Stem Cell Transplantation - adverse effects; Hematopoietic Stem Cell Transplantation - methods; Humans; Immunologic Deficiency Syndromes - therapy; Immunologic Factors - therapeutic use; Immunosuppressive Agents - therapeutic use; Infant; Internal Medicine; Kaplan-Meier Estimate; Leukocyte Common Antigens - antagonists & inhibitors; Male; Medical research; Medical sciences; Metabolic disorders; Mortality; Rats; Stem cells; Transfusions. Complications. Transfusion reactions. Cell and gene therapy; Transplantation Chimera; Transplantation Conditioning - adverse effects; Transplantation Conditioning - methods; Transplantation Conditioning - mortality; Transplants & implants; Treatment Outcome; Vidarabine - analogs & derivatives; Vidarabine - therapeutic use; Medicine; Antibody; Stem cell; Intensity; Phase II trial; Hematopoietic cell; Phase I trial; Stem cell transplantation; Non myeloablative treatment
• ISSN: 0140-6736; 1474-547X
• DOI: 10.1016/S0140-6736(09)60945-4

Summary Background Stem-cell transplantation can cure primary immunodeficiencies. However, in patients with pre-existing organ toxicity, patients younger than 1 year, and those with DNA or telomere repair disorders, chemotherapy-based conditioning is poorly tolerated and results in major morbidity and mortality. We tested a novel antibody-based minimal-intensity conditioning (MIC) regimen to assess whether this approach allowed curative donor stem-cell engraftment without non-haemopoietic toxicity. Methods 16 high-risk patients underwent stem-cell transplantation for primary immunodeficiencies with an MIC regimen consisting of two rat anti-CD45 monoclonal antibodies YTH24.5 and YTH 54.12 for myelosuppression, and alemtuzumab (anti-CD52) and fludarabine, and low dose cyclophosphamide for immunosuppression. Donors were matched siblings (n=5), and matched (9) and mismatched (2) unrelated donors. Findings Antibody-based conditioning was well tolerated, with only two cases of grade 3 and no grade 4 toxicity. Rates of clinically significant acute (n=6, 36%) and chronic graft-versus-host disease (GVHD) (n=5, 31%) were acceptable. 15 of 16 patients (94%) engrafted, of whom 11 (69%) achieved full or high-level mixed chimerism in both lymphoid and myeloid lineages, and three achieved engraftment in the T-lymphoid lineage only. One patient needed retransplantation. At a median of 40 months post-transplant, 13 of 16 patients (81%) in this high-risk cohort were alive and cured from their underlying disease. Interpretation Monoclonal antibody-based conditioning seems well tolerated and can achieve curative engraftment even in patients with severe organ toxicity or DNA repair defects, or both. This novel approach represents a shift from the paradigm that intensive chemotherapy or radiotherapy, or both, is needed for donor stem-cell engraftment. This antibody-based conditioning regimen may reduce toxicity and late effects and enable SCT in virtually any primary immunodeficiency patient with a matched donor. Funding None.