Optimal Conditioning Regimen for Haplo-Identical Stem Cell Transplantation in Adult Patients with Acquired Severe Aplastic Anemia: Prospective De-Escalation Study of TBI and ATG Dose

Background Recent advances in controlling graft failure and graft-versus-host disease (GVHD) due to barrier of HLA incompatibilities in haplo-identical stem cell transplantation from related mismatched donor (Haplo-SCT) extended its application to severe aplastic anemia (SAA). Therefore, studies for searching optimal conditioning regimen and strategy of graft manipulations for SAA patients who receive Haplo-SCT are needed. This prospective study was aimed to explore the optimal conditioning regimen to ensure engraftment with minimal toxicity in adult patients with SAA who received Haplo-SCT.

Methods We have explored a safe and sufficient dose of ATG in combination with 800 cGy TBI and fludarabine (Flu, 30 mg/m²/day) for 5 days using step by step dose de-escalation based on the transplant-related mortality (TRM) and toxicity. The dose of ATG was de-escalated from 10 mg/kg (group 1), 7.5 mg/kg (group 2), to 5 mg/kg (group 3) and from October 2014, the TBI dose also reduced to 600 cGy with fixed dose of Flu and ATG (5mg/kg) (group 4). If any patient developed TRM with engraftment in each group, we moved to next group. For GVHD prophylaxis, a combination of tacrolimus and short-course methotrexate was used. G-CSF mobilized PBSCs were used as stem cell source without manipulation. Considering the importance of both survival and GVHD rate when testing conditioning regimen, GVHD-free survival, defined as grade 3-4 acute GVHD, chronic GVHD requiring systemic treatment, or death was addressed.

Results Twenty-nine patients including 18 men and 11 women were enrolled. The median age was 31 (17-52) years. Median CD34⁺ cells transplanted were 5.84x10⁶/kg (1.45-16.2). All patients achieved primary engraftment. Thirteen patients (7 of 10 in the group 1-3, 6 of 19 in the group 4) had CMV DNAemia requiring pre-emptive therapy including 3 patients with CMV disease (2 pneumonia, 1 colitis). Three patients (2 in the group 1, 1 in the group 2) developed EBV-associated PTLD, of whom two patients with monomorphic type received rituximab and chemotherapy. The incidence of acute GVHD (grade ≥2) and chronic GVHD (≥ moderate) were 24% and 17%, respectively. With a median follow-up of 41.4 (31.9-48.9) months in the group 1-3 and 10.1 (1.3-20.6) months in the group 4, probability of overall survival (94.1% in the group 4 vs. 70% in the group 1-3, P = 0.292) and GVHD-free survival (73.3% in the group 4 vs. 50% in the group 1-3, P = 0.161) were improved in the group 4.

Conclusions This study explored the optimal conditioning with step by step de-escalation dose of ATG and TBI to reduce TRM with sustained graft function. TBI-600 cGy/Flu/low-dose ATG resulted in feasible outcomes of Haplo-SCT for adult patients with SAA.