Sequential Conditioning Regimen with Thiotepa, Clofarabine and Busulfan (TEC/CloB2A2) and Post-Transplant Cyclophosphamide in Adults with Refractory AML: A Retrospective Monocentric Study

Background : Since almost 20 years, sequential allogeneic stem cell transplantation is proposed to fit and relatively young patients with refractory hematologic malignancies (mainly acute myeloid leukemia (AML)) and who will otherwise die from the disease. This procedure is characterized by the use of a renforced conditioning regimen combining a debulking chemotherapy followed after 3 days of rest by the conditioning regimen itself. However, the results overall remain dismal as only a small proportion of patients are finally cured. Recently, a combination of thiotepa, etoposide, cyclophosphamide (TEC) followed by fludarabine/busulfan/ATG (FB2A2) using any type of donor for refractory hematologic malignancies have shown some promising results (Dulery, 2018). As clofarabine may have better antileukemic effect than fludarabine, we have investigated in our patients with refractory AML a new sequential approach combining TEC+clofarabine/busulfan/ATG (TEC/CloB2A2). Methods : We have investigated in our Hematology Department a new sequential conditioning regimen replacing fludarabine by clofarabine as part of a TEC/FB2A2 regimen with the hope to obtain less relapse and better survival in a cohort of patients with refractory AML. The TEC/CloB2A2 regimen consisted of Thiotepa 5 mg/kg at day(d)-13, Cyclophosphamide 400 mg/m²/d from d-12 to d-9 and Etoposide phosphate 100 mg/m²/d from d-12 to d-9, followed after 3 days of rest, by Clofarabine 30 mg/m²/d from d-5 to d-1, Busulfan 3,2 mg/kg/d d-5 and d-4 and Thymoglobuline 2,5 mg/kg/d d-3 and d-2. GVHD prophylaxis consisted of high-dose of post-transplant Cyclophosphamide (PTCY) 50 mg/kg/d at d+3 and d+5 in combination with mycophenolate mofetyl and cyclosporine starting at d+6. Any type of donor have been considered. Results : Between February 2020 and August 2022, 12 patients have been treated. Patient characterisitcs are given in the Table. Median age was 58 years (y) old. The majority of patients had primary refractory AML (n=9). This was the first transplant for all patients. One patient needed desensibilization before conditioning due to high level of anti-HLA antibodies directed against the donor. All but 2 donors were haploidentical. One patient with a matched donor did not receive PTCY after transplant. Two patients died during the aplasia phase, one at d+6 of sepsis and multiple organ failure (MOF) and one at d+30 of disseminated fungal infection. The median time of neutrophils (> 1 Giga/L) and platelets (> 5