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Clinical Outcome of FLAG-IDA Chemotherapy Sequential Bone Marrow Transplantation (2019) 54:458–464 https://doi.org/10.1038/s41409-018-0283-5 ARTICLE Clinical outcome of FLAG-IDA chemotherapy sequential with Flu–Bu3 conditioning regimen in patients with refractory AML: a parallel study from Shanghai Institute of Hematology and Institut Paoli-Calmettes 1 2 3 2 3 2 1 Ling Wang ● Raynier Devillier ● Ming Wan ● Justine Decroocq ● Liang Tian ● Sabine Fürst ● Li-Ning Wang ● 2 1 2 1 Norbert Vey ● Xing Fan ● Didier Blaise ● Jiong Hu Received: 23 January 2018 / Revised: 28 June 2018 / Accepted: 30 June 2018 / Published online: 6 August 2018 © The Author(s) 2018. This article is published with open access Abstract The purpose of the study was to evaluate the feasibility of conditioning regimen with sequential chemotherapy (FLAG-IDA), followed by Fludarabine (5 days) + Busulfan (3 days) by parallel analysis of patients with refractory acute myeloid leukemia (AML) from two transplantation centers in China and France. A total of 47 refractory AML with median bone marrow blast of 35% (1–90%) and median age at 42 years (16–62) were enrolled. Thirteen patients received peripheral stem cell 1234567890();,: 1234567890();,: transplantation (HSCT) from HLA-matched sibling donor, while 18 and 16 from unrelated or haplo-identical donors, respectively. With a median follow-up of 24.3 months (1–70), 13 patients relapsed at a median time of 5.1 months (2.2–18.0) and 24 patients died due to relapse (n = 12) or non-relapsed mortality (NRM, n = 12). The estimated 3-year RR and NRM were 33.5 ± 5.7% and 25.7 ± 4.2%, respectively. The estimated 3-year overall survival (OS) and event-free survival (EFS) were 43.8 ± 7.8% and 42.3 ± 7.8%. In multivariate analysis, age (<40) and low bone marrow blast were associated with better EFS, while no difference was observed between the two centers. The patients enrolled in study were unselected, representing typical patients' population of refractory AML, and primary data demonstrated the feasibility of sequential conditioning regimen. Introduction These authors contributed equally: Ling Wang, Raynier Devillier. These authors jointly supervised this work: Didier Blaise, Jiong Hu. The prognosis of patients with refractory acute myeloid leu- kemia (AML) is poor. Primary treatment failure or primary * Didier Blaise refractory AML is usually defined by failure to achieve 50% [email protected] reduction in blast numbers or achieve a complete hematologic * Jiong Hu remission (CR) after two courses of induction chemotherapy, [email protected] while refractory-relapsed patients were defined as failure to obtain CR after relapse [1–3]. For these patients, the overall 1 Shanghai Institute of Hematology, Department of Hematology, response to salvage the chemotherapy of high-dose cytosine Blood and Marrow Transplantation Center, Collaborative Innovation Center of Hematology, Rui Jin Hospital, Shanghai Jiao arabinoside (Ara-C)-based regimen, including combination of Tong University School of Medicine, 18F/OPD Bldg 197 Rui Jin anthracycline, fludarabine, or gemtuzumab–ozogamicin, Road II, 200025 Shanghai, China remained <30–50%, and most patients eventually relapsed 2 Department of Hematology, Program of transplantation and cell within 3–6 months, even though, clinical remission (CR) can therapy, Program of leukemia, Centre de recherche en be achieved [4, 5]. Allogeneic stem cell transplantation (allo- Cancérologie de Marseille (CRCM), Institut Paoli-Calmettes, Aix HSCT) is considered as the only curative therapy for patients Marseille University, 232 Boulevard Sainte Marguerite, 13273, Marseille CEDEX 9, France with refractory AML. Based on the conventional condition- ing, high relapse rate (RR) and/or non-relapse mortality 3 Shanghai Clinical Research Center (SCRC), (Feng Lin International Centre), 18F Bldg A, 380 Feng Lin Road, 200032 (NRM) lead to dismal overall survival (OS) as low as Shanghai, China 10–20% [6, 7]. Clinical outcome of FLAG-IDA chemotherapy sequential with Flu–Bu3 conditioning regimen. 459 To tackle the problem, sequential transplant approach two participating center’s institutional review board. was developed, which combines intensive salvage che- Informed consent from patients and donors was obtained. motherapy to decrease the leukemia cell burden with Patients aged between 16 and 60 years were eligible for the reduced intensive conditioning regimen (RIC). The first study if they had a refractory AML defined by either: report of sequential FLAMSA strategy (fludarabine, inter- (i) primary induction failure (PIF) with less than 50% mediate dose Ara-C, and amsacrine followed by 4 Gy total reduction in bone marrow blast, with >15% residual blasts body irradiation, cyclophosphamide, and anti-thymocyte after one cycle of induction chemotherapy, or persistence of globulin (ATG)) achieved an improved OS and leukemia- >5% leukemic blasts in the bone marrow after two induc- free survival (LFS), particularly for patients with only 1–2 tion chemotherapy, or persisting hypoplasia defined by a cycles of chemotherapy before transplantation. However, hypocellular bone marrow and incomplete reconstitution of for patients who received three or more cycles of che- cell counts in the peripheral blood (absolute neutrophil motherapy, the overall outcome remained unsatisfactory in count < 0.5 × 109/L or platelet count < 50 × 109/L) at day terms of high RR and NRM [8]. We developed a new 100 after starting chemotherapy; (ii) early relapse, with the transplantation protocol with a salvage chemotherapy duration of first remission <6 months; (iii) relapse disease composed of granulocyte colony-stimulating factor (G- refractory to at least one cycle of salvage chemotherapy CSF), fludarabine, Ara-C, and idarubicin (FLAG-IDA) containing high-dose Ara-C; or (iv) patients with multiple given before transplantation. With a 7-day interval, relapses. Induction and re-induction chemotherapy were reduced-intensity conditioning with fludarabine and 3-day given according to the two institutions’ preference. All busulfan (Flu–Bu3) were given usually at the hematological donor/recipient pairs were typed at the allelic level (HLA-A, nadir of previous FLAG-IDA chemotherapy. In our pre- HLA-B, HLA-Cw, HLA-DRB1, and HLA-DQB1). Trans- vious phase II clinical study, we tested the feasibility and plantation was performed in case of either fully outcome of this regimen in patients with refractory AML matched sibling donor (MSD) or 9–10 out of 10 matched and demonstrated a significantly reduced relapse and unrelated stem cell donors (match, MUD) or haplo- improved OS compared with allo-HSCT with conventional identical-related donors (Haplo). Exclusion criteria were conditioning regimen [9]. patients with active leukemic infiltration of the central Based on this intense transplantation protocol, the fea- nervous system, AML with M3 subtype, serum creatinine sibility of the strategy remains to be determined. We are above 1.0 mg/dL, creatinine clearance less than 60 mL/min, particularly interested to compare the real practice of bilirubin above 1.5 mg/dL, aminotransferases or alkaline refractory AML treatment in two centers in terms of phosphatase above 2.5 times the upper normal limit, acute patients’ characteristics (median age and GVHD prophy- or chronic heart failure, and pregnancy. laxis strategy) and to confirm the feasibility of this trans- plantation strategy. Thus the study was designed to compare Treatment the overall outcome between the two centers and then to confirm the feasibility of this sequential transplantation Patients included in the study proceeded directly to the approach in refractory AMLs. These parallel studies were sequential cytoreductive chemotherapy followed by allo- developed at Rui Jin hospital (RJH, Shanghai, China) and HSCT. The chemotherapy regimen consisted of 30 mg/m2/ Institut Paoli-Calmettes (IPC, Marseille, France) for patients day fludarabine and 1 g/m2/day Ara-C for 5 consecutive with refractory AML to evaluate the overall transplantation days (day-21 to day-17) and idarubicin 12 mg/m2/day (RJH) outcome and confirm the feasibility of the sequential regi- or 10 mg/ m2/day (IPC) for 3 days (day-17 to day-15). No men, combining FLAG-IDA, before allo-HSCT, with other chemotherapy was given within 3 weeks of FLAG- Flu–Bu3 regimen in a heavily treated, but relatively young IDA chemotherapy, except for hydroxyurea in case of patients population from RJH and also in a more elderly, hyperleukocytosis. Seven days after chemotherapy, pre- although less heavily treated patients’ series (IPC) with PT- parative regimen was given with 30 mg/m2/day fludarabine CY as GVHD prophylaxis. for 5 consecutive days (days −7to−3) and 3.2 mg/kg/day i.v. busulfan for 3 consecutive days (days −5 and −3) [9]. Day 0 was designated as the day of graft infusion with Patients and methods G-CSF-mobilized peripheral blood stem cell for all patients. There were two different prophylaxis strategy for acute graft Study design and inclusion criteria versus host disease (aGVHD). In RJH, the regimen included standard cyclosporine with short-course methotrexate This retrospective study included a total of 47 patients (MTX) and mycophenolate mofetil (MMF) for MSD, while diagnosed with refractory AML who underwent allo-HSCT additional ATG for 4 consecutive days (days −4to−1) was between 2011 and 2016. The study was approved by the given in case of MUD (1.5 mg/kg/day) or Haplo (2.5 mg/ 460 L. Wang et al. Table 1 Patient’s characteristics Total RJH IPC P No. of patients 47 27 20 0.22 Sex: Male/female 17/30 11/16 6/14 0.18
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