Experience with a Reduced Toxicity Busulfan, Fludarabine Regimen in Children Undergoing Allogeneic HCT for Non-CGD Primary Immune Deficiencies Requiring Myeloablation

Abstract

Introduction A reduced toxicity busulfan, fludarabine regimen with alemtuzumab or anti-thymocyte globulin (Gungor et al.) was efficacious in patients undergoing allogeneic HCT for CGD. We report our experience with a similar approach for patients with non-CGD primary immune deficiencies needing a reduced toxicity myeloablative approach. Methods We retrospectively reviewed records of consecutive patients who underwent allogeneic HCT for primary immune deficiencies with a preparative regimen containing busulfan, fludarabine and alemtuzumab or anti-thymocyte globulin(ATG) at two transplant centers between 2015-2018. Busulfan was given twice daily over 4 days with target AUC of 1800 to 2000 μMol/min (based on q12 hr. dosing) or once daily over 4 days with a target AUC of 3600-4400 μMol/min (based on q24 hr. dosing). Fludarabine 180 mg/m2 or 160 mg/m2 was given divided over 6 days or 4 days, respectively. Serotherapy included alemtuzumab 0.3 - 0.5 mg/kg or ATG 7.5 mg/kg given divided over 3 days. GVHD prophylaxis consisted of cyclosporine and mycophenolate mofetil. Results Thirty-five patients (WAS=11, HLH=10, CD40L deficiency=6, IPEX/VEOIBD=4, IFNGR1 def./ SCN/CID/LAD=1) received busulfan, fludarabine and alemtuzumab or ATG for allogeneic HCT (first HCT in 26 patients and second HCT in 9 of 10 patients with HLH). Median age was 2.0 years (range, 0.3 years – 19.8 years). Patients received a graft from an HLA-matched related (n=10), unrelated (n=23), or single allele mismatched related or unrelated donor (n=2). All except one patient engrafted at a median of 13 days (range,11-34 days). One patient developed veno-occlusive disease and two patients developed diffuse alveolar hemorrhage. Seven patients (20%) developed grade 2-3 acute GVHD and 2 patients (5.7%) developed chronic GVHD. One patient developed primary graft failure and two patients secondary graft failure. Eighteen patients (51%) maintained >95% donor chimerism following allogeneic HCT. Sixteen patients (46%) developed mixed chimerism, predominantly in the T-cell lineage, but T-cell donor chimerism progressively increased post-HCT. At 1-year post-transplant, 13 of 16 patients (81%) with mixed chimerism had donor myeloid chimerism >90% and T-cell chimerism >75%. Two patients underwent a second transplant for graft failure. Overall survival was 86%(30 of 35) and event free survival was 77%(27 of 35) at 1 year. Conclusion Our experience suggests that a reduced toxicity busulfan, fludarabine regimen with alemtuzumab or ATG as serotherapy offers a promising approach with low toxicity, durable myeloid engraftment, low incidence of grade 2-4 GVHD and excellent overall survival, and can be considered for a variety of primary immune deficiencies where myeloablative HCT is desired.