Second-Line Low-Dose Cytarabine after First-Line Treatment with 5-Azacitidine in Elderly Patients with AML or High-Risk MDS Ineligible for Intensive Chemotherapy. A Retrospective Single Center Analysis
Authors: Jakob Christian , Gunther Benjamin , Dittberner Katharina , Boger Leonard , Bleienheuft Philipp , Breywisch Frank , Rothmann Frank , Peinert Stefan , Maschmeyer Georg 
Published: October 2019

Abstract
Introduction: Although there have been progress in treatment and outcomes of acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) in younger patients, treatment of elderly patients, who are not eligible for intensive treatment is still challenging. The demethylating agents azacitidine (AZA) or decitabine recently became a standard of care for first line treatment of elderly or unfit patients with high-risk MDS or AML. Despite the improvement in overall survival with epigenetic therapies, almost all patients eventually develop disease progression, for which no standard therapeutic option is available. The aim of this retrospective analysis was to evaluate the outcome of low-dose cytarabine (LDARAC) treatment compared to best supportive care (BSC) as second-line palliative treatment options after failure of AZA.
Patients and Methods: From 2009 to 2014 we treated 75 consecutive patients with newly diagnosed high-risk MDS or de novo AML, with AZA (75mg/m2 sc. d1-7, qd29). Patients who responded to AZA after at least four courses and had a subsequent relapse, as defined by worsening of peripheral blood counts, increase of blasts or increase in transfusion frequency, received a second-line treatment with subcutaneous LDARAC (2x 10 mg/m2/d sc., d1-10, qd29) until progression or were followed by best supportive care, including symptomatic treatment, transfusions or treatment of clinical infections- but without chemotherapy.
Results: After first-line AZA 48/75 (64%) achieved a partial hematologic response (n=23), stable disease (n=14) or clinical benefit (n=7). The median overall survival (OS) of all 48 patients with response or clinical benefit to AZA was 27 months. Median duration of response was 13 (4-56) months. Cytogenetic risk at diagnosis was a significant prognostic factor for OS (P<0.001), but not age or ECOG-PS (P=0.17 and P=0.68, respectively). After a median follow-up of 24 months, 31 patients had a loss of hematologic response. Fifteen of 31 relapsed patients were treated with a second-line therapy with LDARAC until progression. Two of those 15 patients received an initial re-induction therapy with intermediate dose cytarabine plus daunorubicine ("5+2"). 16 patients were followed by BSC. Four of 15 patients who were treated with LDARAC achieved a partial hematologic response and 6/15 had stable disease with a median response duration of 4 months. In the BSC group no objective responses were observed. The median overall survival from the time of progression on AZA (OS-2) was 7.2 months in patients treated with LDARAC versus 2.9 months in patients who received BSC care only (P<0.01). In a multivariate analysis response to LDARAC was the only significant prognostic factor for OS-2 (P =0.02, HR: 3.16), while age, ECOG-PS or cytogenetic risk did not reach statistical significance.
Conclusions: Our analysis shows that second-line treatment with LDARAC may add a survival benefit of approximately 3 months compared to BSC alone. The second overall survival (OS-2) of 7.2 months is within the range achieved with LDARAC as primary treatment for this patient population. Our data indicate that LDARAC can be considered as a reasonable therapeutic option after failure of first-line treatment with demethylating agents like AZA. This clinical observation is supported by recent pre-clinical data, showing that epigenetic modifications in AML cells can have a sensitizing effect for the subsequent administration of cytarabine.

Disclosures
No relevant conflicts of interest to declare.