A Novel Antibody-Based Minimal Intensity Conditioning Regimen for Children with Severe Organ Toxicity or DNA Repair Disorders.

Children with severe organ toxicities, DNA repair disorders and infants <1 year tolerate existing conditioning regimens, including reduced intensity conditioning, poorly. To reduce TRM in such patients, we used a minimal intensity conditioning regimen utilising 2 rat anti-CD45 monoclonal antibodies (Mabs) YTH24.5/YTH 54.12 for myelosuppression and Alemtuzumab (anti-CD52) for immunosuppression. As CD45 is expressed selectively on haemopoietic cells, the Mabs provide immunosuppression and transient myeloablation without the systemic toxicity associated with chemotherapy. 16 children (7 SCID, 5 CID, 2 dyskeratosis congenita, 1 reticular dysgenesis, 1 HLH) were transplanted at a median age of 11 months (5 months-11 years). Inclusion criteria were primary immunodeficiency (PID) in children age <1 (n=9), severe organ toxicity (n=14) and DNA repair defects/radiation sensitivity (n=4). Donors were MSD (n=5), MUD (n=9) and MMUD (n=2). Severe organ toxicity was defined as

• O₂ requirement at BMT/prior ventilation,

• FEV₁ or FVC < 60% predicted,

• Bilirubin >50 μM or ALT> 4 × normal or

• TPN dependent enteropathy.

The conditioning regimen consisted of Alemtuzumab 0.2mg/kg × 3 (MUD) or 0.1mg/kg × 3 (MSD) on D-8 to -6, YTH 24.5/54.12 0.4mg/kg on D-5 to -2, with Fludarabine 150mg/m² and Cyclophosphamide 1200mg/m². GVHD prophylaxis was with CSA and MMF. Stem cell source was PBSC in 5/16 patients, BM in 10/16 and cord blood in 1/16. The Mabs were well tolerated with no grade 4 toxicity and only 1 grade 3 toxicity attributable to the conditioning regimen. 15/16 patients engrafted, 1 rejected with autologous reconstitution. In 14 of these patients the median time to neutrophil recovery > 0.5 × 10⁹/L was 9.5 days (range 1–15). One patient who received a MMUD cord blood graft engrafted after an extended period of neutropenia. Of 15 engrafted patients, 7 achieved 100% donor chimerism, 3 100% donor chimerism in T-lymphoid lineage only, 4 high level mixed chimerism (MC) in both myeloid and lymphoid lineages and 1 low level MC. The latter patient has successfully been retransplanted with full intensity conditioning. Six patients developed significant aGVHD (3 grade 2, 3 grade 3). Since BM has been used as the stem cell source, only 1/10 has had aGVHD ≥grade 3. 5/14 evaluable patients developed cGVHD (limited n=3; extensive n=2), which has resolved in all cases. Of 13 evaluable patients, 12 had normal age-adjusted T-cell counts at a median of 9 months and normal B-cell counts at a median of 12 months, similar to immune reconstitution with more intensive protocols. One patient with dyskeratosis congenita died of late sepsis despite full donor engraftment and 1 patient with congenital auto-immune vasculitis died of Aspergillosis and relapsed disease in association with high level MC. At a median follow up of 23 months (range 5–45), 14/16 patients in this high risk cohort are alive and 12 are cured of their primary disease, giving a disease-free survival of 75%. In summary, Mab-based conditioning is well tolerated and achieves engraftment even in patients with severe organ toxicity or DNA repair defects, with a short period of neutropenia. The protocol enables transplantation in patients who previously would not be candidates for such a procedure and may additionally reduce late effects.