Sequential Treatment with FLAG-IDA Salvage Chemotherapy Followed By Allogeneic Hematopoietic Cell Transplantation in Patients with Relapsed/Refractory Acute Leukemia
Authors: Shargian-Alon Liat , Wolach Ofir , Pasvolsky Oren , Raanani Pia , Yeshurun Moshe 
Published: October 2019

Abstract
Introduction
Patients with relapsed/refractory acute myeloid leukemia (AML) have a dismal prognosis. Achieving a remission with high-dose chemotherapy followed by allogeneic hematopoietic cell transplantation (alloHCT) remains the only curative approach. However, providing intensive salvage chemotherapy in order to obtain complete remission (CR) before alloHCT may be associated with significant morbidity that may preclude alloHCT. Furthermore, the lag period between the end of salvage chemotherapy and hematologic recovery may allow concomitant leukemic blast cell recovery. In attempt to solve this dilemma, Schmid et al. introduced in 2005 for the first time the sequential conditioning concept consisting of short course of chemotherapy to reduce the leukemic burden, followed shortly by RIC regimen.
Aim
Assess the feasibility of a transplantation strategy consisting of sequential cytoreductive chemotherapy with fludarabine, cytarabine, and idarubicin (FLAG-IDA) followed sequentially by tailored conditioning regimen and alloHCT (FLAG-IDA HCT)
Methods
A retrospective analysis of patients treated with the sequential FLAG-IDA HCT strategy in a single center between 01/2014 and 12/2017.
Salvage chemotherapy consisted of fludarabine 30mg/m2 (days 1-5), cytarabine 2g/m2 (days 1-5) and idarubicin 12mg/m2 (days 3-5; FLAG-IDA). Dose reduction for cytarabine (1g/m2) and idarubicin (8-10mg/m2) were allowed for older patients and those with cardiac dysfunction, respectively. FLAG-IDA was followed within 3 days by conditioning regimen tailored according to the patient's clinical condition and co-morbidities. Graft versus host (GVHD) prophylaxis consisted of cyclosporine and short course of methotrexate (MTX). In patients with liver toxicity, renal failure, or grade 3-4 mucositis, MTX was replaced by mycophenolate mofetil. Antithymocyte globulin (ATG, Fresenius) was given to patients transplanted from unrelated and mismatched donors.
Results
27 patients [median age, 64 years (range, 23 to 73) (3 patients >70 years)] received the sequential FLAG-IDA HCT regimen. Most (n=24) patients had AML followed by acute lymphoblastic leukemia, mixed phenotype acute leukemia and myelodysplastic syndrome (1 patient each). 52% (n=14) had primary refractory disease, 37% (n=10) had relapsed disease and 11% (n=3) were treated upfront for adverse-risk AML. All patients had active disease upon treatment initiation and 22% had more than 50% blasts in bone marrow (Table 1). Dose reduction of cytarabine and idarubicin were applied in 48% (n=13) and 26% (n=7) of the patients, respectively. A myeloablative conditioning (MAC), busulfex-based (n=3) or treosulfan-based (n=22), was applied in 25 patients (92%), and 11 (41%) received in-vivo T-cell depletion. 24 patients were transplanted from a matched sibling (n=12) or unrelated (n=12) donor and 3 from a mismatched donor, all but one from peripheral blood stem cell grafts. Median time to neutrophil and platelet engraftment was 12 (range, 8 to 26) and 14 (range, 8 to 68) days, respectively.
Six patients (22%) died by day +30, all from infectious complications. Among 21 evaluable patients by day +30, 20 (95%) were in CR with full donor chimerism. With a median follow up of 19 (range, 6 to 52) months, 6 patients are still alive and in CR. Median 1-year OS was 206 days (Figure 1). In total, 21 (77%) patients died: 9 (33%) from relapse, 7 (26%) from infectious complications and 5 (19%) from other causes (acute GVHD, n=3, sarcoma, n=1, late idiopathic neurotoxicity, n=1). Infectious complications were frequent; 32 episodes of clinically documented infections were noted in 18 (67%) patients. These included 25 blood stream infections in 16 patients: bacteremia (n=17) and candidemia (n=3). Grade 2-4 acute GVHD and grade 3-4 acute GVHD by day +100 were documented in 48% and 30% of the patients, respectively.
CONCLUSIONS
FLAG-IDA HCT is a feasible strategy for relapsed/refractory acute leukemia patients that would have otherwise an extremely dismal prognosis. Yet, this regimen is associated with high early non-relapse mortality. Modifications of this regimen are warranted in order to reduce non-relapse mortality, without compromising the anti-leukemic effect.

Disclosures
No relevant conflicts of interest to declare.