Seuqential Intensive Chemotherapy (FLAG-IDA) Followed by Reduce-toxicity Conditioning (FLU-BU) for Refractory Acute Myeloid Leukemia: An Interim Analysis of Phase II Trial
Authors: Wang Ling , Tang Wei , Dou han-Bo , Hu Jiong 
Published: October 2019

Abstract
Abstract 4509
Allogeneic stem cell transplantation (Allo-SCT) is the most effective treatment for a variety of hematological malignancies. For high-risk or refractory AML, the outcome of allo-SCT with standard conditioning regimen remains poor. There are successful reports of 40∼50% DFS with sequential conditioning regimen for patients with high risk AML consisting of cytoreductive chemotherapy (FLAMSA) followed by reduced intensity (RIC) conditioning and prophylactic transfusion of donor lymphocytes infusion (DLI). But for very refractory patients such as patients with more than 2 cycles of previous chemotherapy, the outcome remain unsatisfactory (∼15%). Beside the treatment mortality, the important issue is the early relapse (usually less than 6 months). In this phase II trial (NCT01496547), we designed a preparation regimen including an intensive chemotherapy (FLAG-IDA) followed by a sequential (with interval of 7 days) reduced-toxicity regimen including (Fludarabine 30mg/m2 for 5 days + intravenous busulfan 3.2mg/kg for 3 days) and allo-SCT. The aim of study is to evaluate the efficacy and safety of such intensive regimen in young adults with refractory AML which has a very dismal prognosis (survival <10% in our history control series after allo-SCT with Bu-Cy conditioning). The inclusion criteria were as follow: primary refractory patients (non-remission after 2 cycles of induction chemotherapy); refractory relapsed patients or patients relapse very early during the consolidation therapy. Here we reported the outcome of the first 8 patients (all female, age 16∼39). All 8 patients had refractory disease with 3∼10 cycles (median 4) previous chemotherapy and blasts in bone marrow remained at 18∼90%. After the transplantation, 7 patients achieved neutrophils engraftment at 12∼17 days, in which 5 patients achieved platelet engraftment at 17∼28 days. One patient (UPN 7) died of infection before engraftment documented. In the remaining 7 patients, bone marrow blasts were cleared in all cases. Among these 7 patients, 1 died in remission due to CNS bleeding after recovering from grade III aGVHD. One patient relapsed 7 months after transplantation and died of disease 4 months later. Up to the last follow-up at 1st Aug 2012, 5 patients remain alive in continuous remission for 4+, 10+, 13+, 15+, 19+ months respectively. Based on our pilot study, we suggested that the sequential intensive cytoreduction chemotherapy (FLAG-IDA) followed by Flu-Bu conditioning regimen can be effective in refractory AML patients and achieved continuous remission for more than 6 months, thus providing an important treatment platform for further improvement such as prophylaxis DLI to enhance the graft-versus leukemia effect. Further enrolled of patients and longer follow-up is warranted.
Table. Patients' characteristics and outcome UPN Time of Tx Diagnosis Donor Sex Age Disease-status* Blasts in BM No cycles chemo Conditioning Post-Tx BM GVHD Current Status Leukemia-free (months) after Tx 1 2010–12 AML MUD F 16 Ref-Rel 90% 4 FLAG-IDA/FLU-Bu CR / Alive in CR 19+ 2 2011–3 AML MUD F 38 E-Rel 29% 4 FLAG-IDA/FLU-Bu CR / Alive in CR 15+ 3 2011–7 AML MUD F 34 P-Ref 25% 4 FLAG-IDA/FLU-Bu CRp / Death ″C relapse 7 4 2011–5 AML MUD F 39 P-Ref 18% 5 FLAG-IDA/FLU-Bu CR / Alive in CR 13+ 5 2011–10 AML Sib F 19 Ref-Rel 85% 6 FLAG-IDA/FLU-Bu CR cGVHD liver/skin Alive in CR 10+ 6 2012–3 AML Haplo F 16 Ref-Rel 90% 10 FLAG-IDA/FLU-Bu CRp III aGVHD Death ″C TRM ** 1.8 7 2012–4 AML MUD F 25 P-Rel 80% 3 FLAG-IDA/FLU-Bu / / Death ″C TRM *** / 8 2012–4 AML MUD F 37 P-Rel 18% 4 FLAG-IDA/FLU-Bu CR II aGVHD/cGVHD skin Alive in CR 4+ * Ref-rel: refractory relapse; E-rel: early relapse during consolidation; P-Ref: Primary refractory. ** Recover from III aGVHD involving skin, liver and intestine and eventually died of CNS bleeding because of low platelet. *** Died of infection (sepsis).

Disclosures:
No relevant conflicts of interest to declare.