The Combination of Fludarabine + Citarabine + Idarubicin (Flai), Followed by Post-Remission Maintenance, is a Safe and Effective Treatment for Elderly Patients with a ml or High Risk Mds

Research Article

Ann Hematol Oncol. 2015; 2(8): 1056.

The Combination of Fludarabine + Citarabine + Idarubicin (Flai), Followed by Post-Remission Maintenance, is a Safe and Effective Treatment for Elderly Patients with a ml or High Risk Mds

Crisà E, Cerrano M, Gatti T, Giai V, Aguzzi C, Boccadoro M and Ferrero D*

Department of Molecular Biotechnologies and Health Sciences, Hematology Section, University of Turin, Italy

*Corresponding author: Dario Ferrero, Hematology Section, University of Turin, Via Genova 3, 10126, Torino, Italy

Received: July 21, 2015; Accepted: November 15, 2015; Published: November 17, 2015

Abstract

Acute myeloid leukemia (AML) in the elderly has a dismal outcome due to both patients and disease characteristics. Fludarabine, high dose ARA-C and idarubicin combination (FLAI) has been reported to be effective in poor prognosis AML. Here we present our experience with FLAI induction regimen in patients over 60 with AML or high risk myelodysplasia (MDS) followed by post-CR maintenance (low-dose chemotherapy plus retinoids and vitamin D as differentiating agents) in patients unfit for allogeneic transplantation. Median age at diagnosis was 66 (60-78). Half (47%) of the patients were at poor prognosis for secondary/therapy related AML (26%) or MDS (21%). Thirty-seven percent of patients had an adverse karyotype. Twenty-two patients received FLAI at reduced intensity for reduced performance status.

CR rate was 59%, with 5% failing because of induction death and 36% because of resistant disease. CR achievement was not affected by age or dose reduction, only by cytogenetics.

The death rate in CR was 6% and the relapse rate was 60%, leading to 5-year overall and disease-free survival of 23 and 27% (median 14 and 20 months), respectively. Survival was negatively affected by adverse cytogenetics and by MDS diagnosis as compared to AML.

After CR, 7 patients underwent allogeneic transplantation (median survival not reached) and 24 received a maintenance treatment (median survival 47 months).

A good CR quality induced by FLAI and a benefit of the maintenance treatment may explain these fair long-term results. Our encouraging results should be confirmed in a randomized trial.

Keywords: FLAI; AML; MDS; Maintenance treatment

Introduction

Median age at diagnosis of acute myeloid leukemia (AML) has now reached 70 years old. Older patients have a dismal prognosis due to unfavorable prognostic factors, both disease related (i.e. AML secondary to myelodysplastic syndrome (MDS), higher incidence of complex karyotype) and patient related (comorbidities and performance status) [1].

The treatment choice can go from intensive chemotherapy to supportive care and often stays in the middle. Novel drugs have been studied but long term survival with low intensity treatment is still quite short.

It has been shown how the survival depends on the remission achievement, therefore current strategy is to choose the treatment aiming to achieve a complete response whenever the performance status allow it and regardless the age.

The purine analog fludarabine in addition to cytosine-arabinoside (ARA-C) increases the accumulation of ARA-C-5’-triphosphate, which is responsible for the cytotoxic effect in leukemic blasts, resulting in improved cell kill [2].

A number of phase 2 studies have been published on the combination of fludarabine, ARA-C and idarubicin to treat relapsed or refractory AML, high-risk MDS and AML in the elderly [3–12]. Remission rates vary from 50% to 60% and the median duration of remission from 4 to 12 months.

Some randomized studies comparing FLAG or FLAG-IDA to standard 3+7 regimes in young AML patients showed at least comparable results in terms of complete remission (CR) rates [13– 15].

Incidence of treatment-related deaths ranged from 7 to 30%, higher in the oldest studies and decreasing in the last decade.

In this study we present the data on our experience with FLAI as induction regimen, for elderly patients with AML or high risk MDS. We also re-evaluated a previously described post-CR maintenance treatment [16] in patients achieving CR with FLAI regimen and unable to undergo allogeneic stem cell transplantation (allo-HSCT).

Patients and Methods

Since 2002 we treated with FLAI induction therapy 61 patients aged over 60 years old, diagnosed with high risk MDS or AML, excluding APL. Surviving patients were censored at 30st June 2015.

The treatment schedule was fludarabine 30 mg/mq plus cytarabine 2g/m² days 1 to 5 and idarubicin 10 mg/m² on days 1, 3, 5. Patients with serious comorbidities and/or reduced performance status received the same schedule with a reduction of 30% in the idarubicin and cytarabine doses and 20% in fludarabine dose. Following completion of the induction schedule, responding patients could proceed to consolidation with another course of FLAI, reduced to 4 days. Few patients received a further consolidation course.

Subsequently, fit patients with an available donor underwent allo- HSCT. The other patients were scheduled to receive a maintenance treatment based on the alternation of low-dose cytarabine plus 6-mercaptopurine and 6-thioguanine together with differentiating agents (retinoid acid and dihydroxylate vitamin D3) [16].

Patients who failed to achieve CR after the FLAI regimen received a different intensive chemotherapy course (clofarabine + ARA-C N =4, idarubicin + ARA-C+ etoposide N=1) or palliative treatments. One patient with a very good partial remission received a second induction treatment with FLAI regimen.

CR was defined by marrow blasts <5% with normal cellularity and morphology plus blood counts with haemoglobin >10 g/dl, neutrophils >1.5x109/l, platelets >100x109/l. This slight degree of peripheral blood cytopenia was still considered compatible with a CR in the presence of normal marrow cellularity and blast proportion, since patients in the maintenance group were in continuous treatment and did not stop cytotoxic drugs for more than 3 weeks.

Relapse was defined by the reappearance of a marrow blast percentage higher than 5% or, for MDS patients, of treatment unrelated cytopenia.

Statistical methods

Demographic and clinical covariates were compared using Pearson chi-square test. Overall survival (OS) was calculated from diagnosis until death or last follow up, and disease free survival (DFS) was assessed from remission until relapse, death for any cause or last follow up. Kaplan-Meier method was used to estimate the probabilities of OS and DFS. Log-rank test was used to compare subgroups of patients in terms of OS or DFS. Univariate and multivariate analyses were performed using the Cox model. All statistical analyses were conducted using SPSS.

Results

Median follow up for censored patients was 51 months (range 6 to 140 months). For main patients characteristics see Table 1.