Efficacy of Fludarabine and Cytarabine Combination for Salvage Treatment of Refractory/Relapsed Myelodysplastic Syndrome (MDS) and Acute Myeloid Leukemia (AML): Promising Results from a Single Center Experience.
Authors: Tassara M. , Ciceri F. , Crotta A. , Peccatori J. , Servida P. , Bregni M. , Bernardi M. 
Published: October 2019

Abstract
Background: response of refractory or relapsed MDS/AML to current standard chemotherapy (CHT) is unsatisfactory; high dose CHT without hematopoietic stem cell support is often unsuccessful because of its high toxicity. As the only curative chance for these patients (pts) is to receive an allogeneic stem cell transplantation (AlloSCT) in a complete remission (CR) or in a minimal residual disease status, a salvage treatment with the highest efficacy and lowest toxicity is warranted; if no donor is available, consolidation with intensified-dose CHT and autologous stem cell transplantation (ASCT) is the preferable alternative. Fludarabine+cytarabine (FLA) containing regimens have shown promising results in CR induction of poor prognosis MDS/AML at diagnosis. Fludarabine has no direct activity on myeloid malignancies but improves cytotoxicity of cytarabine by increasing intracellular concentration of its toxic metabolite, ara-CTP, in leukemic blasts; priming of myeloid precursors with G-CSF increases the sensibility of leukemic blasts to cytarabine by committing them to phase S of the cell-cycle.
Aim: we retrospectively evaluated the efficacy and toxicity of FLA regimens in pts with refractory or relapsed MDS/AML, treated at our Center.
Patients and Methods: 25 pts in the period 6/1999–6/2005; median age 55 (18–72), 11 pts > 60 years. Diagnosis (FAB): AML 20, sAML 4, AREB 1 (IPSS: INT-2), no therapy-related AML/MDS. Cytogenetics: normal 15, poor 3, good 1, intermediate 6. Eight pts (32%) had refractory disease to standard induction CHT and 17 pts (68%) had relapsed disease after a median of 3 CHT cycles (range 1–4); 11 of them relapsed after ASCT. Median CR duration (17 pts): 10 months (range 1–59). Salvage treatment: 20 FLAG-Ida regimen, 4 FLAG, 1 FLAG+liposomal dauno.
Results: overall response rate (RR) was 68%: 15 CR (60%), 2 PR (8%), 7 NR (28%); 1 pt not evaluable for prolonged marrow hypoplasia. RR for refractory and relapsed disease was 37.5% (CR 25%) and 88.2% (CR 82.3%) respectively. RR for <60 and ≥60 years-old pts was 67.4% (CR 57.1%) and 63.6% (CR 63.6%), respectively. RR for AML and sAML was 76% (CR 65%) and 80% (CR 80%), respectively. Toxicities: no treatment related deaths; FUO/sepsis 96% (24 pts); invasive fungal infections 8% (2 pts). No further major toxicities. Nine patients received further CHT after salvage with FLA, 8 for CR consolidation, 1 for reinduction: 5 FLAG, 3 high dose cytarabine, 1 gentuzumab-ozogamicine. Fourteen patients (56%) received a SCT: 2 ASCT, 12 AlloSCT. At transplant 10 pts (71%) were in CR, 3 (21%) had overt disease, 1 had an hypoplastic marrow. Relapses in pts who obtained a CR were 5 (33%), 2 before transplant and 3 after transplant (1 ASCT, 2 AlloSCT). After a median follow-up of 7 months (range 2–72) from the beginning of rescue treatment, 16 pts have died (64%), 12 with progressive/refractory disease, 4 in CR (1 sepsis after CHT, 2 transplant related toxicity, 1 Guillain-Barrè syndrome); 9 patients (36%) are alive, all in CR; six of them after SCT (1 ASCT, 5 AlloSCT). Median OS is 209 days (44–1993) 7 months (range 2–72), median DFS is 163 days (13–922) 5 months (range 1–30).
Conclusions: FLA regimens induced a significant rate of responses in relapsed pts, with tolerable toxicity, also in the elderly subgroup. Consolidation with high dose CHT and ASCT or with AlloSCT could induce prolonged OS and DFS. Response and outcome of refractory diseases seem to have a worse trend.