Elsevier

Leukemia Research

Volume 35, Issue 8, August 2011, Pages 991-997
Leukemia Research

Hematologic improvement and response in elderly AML/RAEB patients treated with valproic acid and low-dose Ara-C

https://doi.org/10.1016/j.leukres.2011.02.021Get rights and content

Abstract

The histone deacetylase inhibitor (HDACi) valproic acid (VPA) has been shown to be active on acute myeloid leukemia (AML) and refractory anemia with excess of blasts (RAEB). Thirty-one elderly AML/RAEB patients (AML n = 25; RAEB n = 6) with a high rate of comorbidity were entered in a phase II study with low-dose cytarabine (Ara-C) and VPA. Fitness was evaluated by means of the Comprehensive Geriatric Assessment (CGA), including the Cumulative Illness Rating Scale (CIRS) score, the self-sufficiency scores of Activity of Daily Living (ADL) and Instrumental Activity of Daily Living (IADL). Eight patients obtained a lasting complete remission and 3 other patients obtained hematologic improvement for a total response rate of 35%. Five of 11 responding patients were relapsed or resistant after a previous treatment with Ara-C. Seven of 11 responding patients were assessed as frail at enrolment and/or had IADL impairment. Grades 3 and 4 toxicities were mainly hematological. Low-dose Ara-C and VPA is a relatively non-toxic combination with good therapeutic activity in elderly patients with AML/RAEB. This therapeutic approach represents an alternative treatment for patients who cannot undergo standard induction therapy.

Introduction

Therapy for AML patients who cannot undergo standard induction protocols because of age, comorbidity or clinical condition has for years been limited to support and cytoreduction [1]. For these patients, a new strategy includes molecules with differentiating or proapoptotic activity [2], [3], [4]. These molecules could achieve therapeutic effect without inducing aplasia. Histone deacetylase inhibitors (HDCAi) have been shown to modulate gene expression with pro-differentiative effects [5], [6]. In this category, valproic acid (VPA) is a short-chain fatty acid with HDCAi activity. This drug has been shown to overcome the differentiation block in AML blasts [7]. VPA can be used orally and has a low toxicity profile. We aimed to assess the therapeutic activity and feasibility of use of VPA in combination with low-dose Ara-C in elderly and frail AML/RAEB patients.

Section snippets

Study group eligibility

Written informed consent was obtained before therapy. Diagnosis of AML and RAEB was defined according to the French–American–British (FAB) classification and WHO recommendation [8], [9]. IPSS scores were calculated for each RAEB patient [10]. Specific criteria for enrolment in the study were absence of indications for standard chemotherapy due to: (1) AML patients being considered unfit for aggressive chemotherapy for documented comorbidity and/or age over 65 years; (2) primary refractory or

Patients

Between November 2005 and May 2008, 31 patients with advanced AML/RAEB were enrolled. Patient's characteristics are listed in Table 1. Median age was 72 years (range of 55–84 years). Twenty-five patients had AML; in this group 14 patients had diagnosis of de novo AML, 6 patients had AML with dysplasia, 3 patients had AML progression from MDS, 2 patients had AML transformation from essential thrombocythemia and chronic myelomonocytic leukemia. Six patients had RAEB-2. In 2 of these, the disease

Discussion

The treatment outcome for elderly patients with AML/RAEB is unsatisfactory and has not substantially improved over recent years [1], [16], [17]. These patients are excluded from clinical trials because they are considered not fit enough, although there is no general consensus on determining which patients over the age of 65 are good candidates for intensive therapy. These patients may benefit from treatments with new drugs with differentiating activity more than conventional cytotoxic therapies

Conflict of interest statement

None declared.

Acknowledgements

This work was partially supported by fund from AIL (Associazione Italiana Ricerca sul Cancro).

Author's contributions: MTC, FS, AB, LDP, SG, DP, MP, VP, FZ, AT, MGA, GC served as investigators on this trial, enrolling patients and contributed to data interpretation, reviewed and provided their comments on this manuscript. AL did the initial conception and design of the study. MTC drafted the final manuscript. SP served as the trial statistician.

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