Hematological Improvement in AML/RAEB Elderly Patients Treated with Valproic Acid and Low-Dose ARA-C

Abstract

Histone deacetilase inhibitors (HDCAi) have been shown to modulate gene expression with pro-differentiative effects. Valproic acid (VPA) has HDCAi activity and synergizes with Ara-C to differentiate AML blasts in vitro. VPA is orally applicable and has a low toxicity prophile. We tried to assess the therapeutic activity of VPA in combination with low-dose Ara-C in elderly/frail AML/RAEB patients. We enrolled in this study 31 patients with Myeloid Pathologies. Fifteen pts had diagnosis of oligoblastic AML (M0:2, M1: 7, M2: 1, M4:1, M5: 4); 13 patients had RAEB (RAEB 1: 2, RAEB 2: 11) with the following IPSS: int-1=2, int-2= 2, high= 6. Three other patients had progression from previous MPS (1 from ET, 2 from LMMC). Median age was 70 yrs (range: 53 to 84). Median time from Diagnosis to treatment was 15 months (range 1 to 79). Clinical status at start of protocol was: at Diagnosis = 13 pts, Resistant after induction =6 pts, Relapsed after CR =11 pts, Relapsed after allogeneic transplant =1 pt). All patients were excluded from conventional chemotherapy for age and multiple comorbidities. In 27 out of 31, these comorbidities required therapy or periodic controls (grade 3), other 2 pts had one of G4 grade (life-threatening). Thirteen patients were defined “frail” because they presented 3 of G3 comorbidities or at least a G4 one. Twenty-nine pts were evaluated for autosufficiency with ADL score, 5 of them didn't reach the score of 6, showing impairment in their autosufficiency. Assessing functional autonomy, IADL score showed deficiency in 17 of 29 patients. In our protocol, VPA was administered in continuum to reach serum concentration of 50–100μg/ml. Ara-C was given in cycles of 8 days, 40 mg/day. Ammonium and valproic acid serum level was routinely checked. Bone marrow examination was done at the enrollement in the study, after sixth cycle of Ara-C and/or if improvement of blood counts were observed. In two patients that were in CR at the end of sixth cycle, VPA was maintained; other six cycles of Ara-C were given monthly and thereafter every third month until relapse. Six patients received the treatment for at least 6 cycles, the other patients had a median of 2 cycles, (range 1 to 4). Ten patients are still in treatment, 17 dropped out for progression/death, one patient underwent reduced intensity allotransplant while in remission. From the start of protocol, median overall survival was 4 mths, range 1 to 33 mths. Fifteen pts are alive now. Overall, 11 of 31 patients (35%) had hematological improvement (according to IWG, 2008), including 7 CR (22%) with clearing of blasts in the marrow and normalization of blood counts. The median cycle of improvement was 2 (range 1 to 4) and the median duration of improvement was 2 months (range 1 to 23 months), including two pts that lasted in CR for 10 and 23 months; 3 pts are still in CR at 5,8 and 10 mths from the starting of response, one patient is in Hematological Improvenment at 2 mths. Hematological toxicity requiring platelet transfusion was seen in 17 patients, while 10 pts required red cell transfusion. Transient hyperammoniemia was seen in one patient; liver toxicity in another patient. Neutropenia-related infections were seen in 3 pts. Adding VPA to low-dose Ara-C, some complete responses and some improvements in peripheral cytopenias can be achieved without a significant increase in toxicity. Therefore this therapeutic protocol is feasible for elderly/frail oligoblastic AML/RAEB patients who cannot have aggressive therapy.