Flamsa Sequential Chemotherapy Followed By Reduced Intensity Conditioning and Allogeneic Hematopoietic Transplantation for High Risk Acute Myeloid Leukemia Patients
Authors: Michallet Mauricette , Sobh Mohamad , Detrait Marie Y. , Labussiere-Wallet Helene , Hayette Sandrine , Tigaud Isabelle , Elhamri Mohamed , Gilis Lila , Lebras Laure L , Barraco Fiorenza , Ducastelle Sophie , Bozzoli Valentina , Nicolini Franck E. , Thomas Xavier 
Published: October 2019

Abstract

Advances in chemotherapy have improved the prognosis of patients with acute myeloid leukemia (AML), however, high-risk patients still have a poor outcome. In this category of patients, the only therapeutic strategy with curative potential remains allogeneic hematopoietic stem cell transplantation (allo-HSCT). With the aim to improve the effect of allo-HSCT by sequential use of chemotherapy followed by reduced intensity conditioning (RIC), we conducted a prospective study in high-risk AML patient. The high-risk population included intermediate II [t(9;11)(p22;q23); MLLT3-MLL, cytogenetic abnormalities not classified as favorable or adverse] and unfavourable patients [inv(3)(q21q26.2) or t(3;3)(q21;q26.2); t(6;9)(p23;q34); t(v;11)(v;q23); MLL rearranged, -5 or del(5q); -7; abnl(17p); complex karyotype] (Dohner et al. Blood 2010), secondary AML, and patients requiring 2 induction courses to obtain CR. The chemotherapy sequential regimen consisted in fludarabine 30 mg/m², high-dose cytarabine 2 g/m², and amsacrine 100 mg/m² from days -12 to -9 (FLAMSA). After 3 days of rest, RIC consisted of 4 Gy total-body irradiation (TBI) on day -5, cyclophosphamide (40 mg/kg with HLA-identical sibling, 60 mg/kg for unrelated or mismatched donors) on days -4 and -3, and rabbit antithymocyte globulin (ATG, Genzyme) (5 mg/kg total dose) from day -3 to day -1. In a group of patients, TBI was replaced by iv. busulfan (BU) (Busilvex, Pierre Fabre) 3.2 mg/kg/d during either 4 or 2 days according to patient age (>55 years) (from day -7 to -4 or from day -5 to -4). Peripheral-blood stem cells (PBSC) were preferred; bone marrow (BM) and cord blood (CB) were also accepted. Graft-versus-host disease (GvHD) prophylaxis consisted in cyclosporine from day -1, and mycophenolate mofetil (15 mg/kg bid), starting from day 0. In the absence of GvHD, MMF was discontinued by day+50 and cyclosporine was tapered from day +60 to +90. Except for CB transplantation, patients received 3 prophylactic increased doses of donor lymphocyte infusions (DLI) if they were in CR and GvHD-free at day +120 or 30 days after discontinuation of immunosuppressive agents starting at 1x106 CD3+ cells/kg. Between January 2007 and December 2013, 66 consecutive AML patients were included; 33 males and 33 females with a median age at allo-HSCT of 52 years (range: 19-66), 59 (89%) were de novo AML and 7 (11%) secondary AML. At transplantation, 22 (33%) patients were in CR (20 CR1 and 2 CR2) and 44 (67%) were in less than CR. Stem cell source was PBSC for 52 (79%) patients, CB for 6 (9%) and BM for 2 patients. Donors were 10/10 HLA matched siblings in 24 (36%) patients, 10/10 HLA matched unrelated in 18 (27%) patients and HLA mismatched for the rest of patients [unrelated 9/10 (n=18), CB 4/6 (n=6)]. For ABO compatibility, 32 (48%) were compatible, 13 (20%) had minor incompatibility and 21 (32%) had major incompatibility. For conditioning, 49 (74%) patients received TBI, 17 (26%) received BU. After transplantation, 59 (89%) patients engrafted, 7 patients did not engraft and died early (2 from relapse and 5 from infection). At day 90 post-allo-HSCT, among evaluated patients (N=52), 37 (71%) showed total donor chimerism, 15 (29%) had mixed chimerism. There were 24 patients with acute GvHD [10 gr I, 3 gr II and 7 gr III and 4 gr IV] with a cumulative incidence of 27% for grade ≥II; and 17 chronic GvHD [10 limited and 7 extensive], among them 5 after DLI, with a cumulative incidence of 48% at 2 years. After a median follow-up of 7 months (range: 0.1-76), the 2-years probability of overall survival (OS) and progression-free survival for the whole population were 30% (confidence interval: 24-36) and 40% (confidence interval: 37-52) respectively with a cumulative incidence of transplant-related mortality of 30% at 2 years. When stratifying on disease status at transplantation, patients in CR had significantly better OS and PFS at 2 years compared to patients in less than CR with 45% versus 18% (p=0.013) and 73% versus 22% (p=0.001) respectively. No statistical difference was found in outcomes of TBI compared to BU conditioning.
Patients in CR showed very promising results and could benefit the most from this strategy. A high rate of deadly infections was observed, thus an efficient prophylactic anti-infectious strategy is recommended. Patients not in CR remain having poor outcome and maybe new transplantation strategy using haploidentical donors could be interesting to evaluate in this population.
Figure 1 Figure 1.

Disclosures
No relevant conflicts of interest to declare.