Increase in platelet count in older, poor‐risk patients with acute myeloid leukemia or myelodysplastic syndrome treated with valproic acid and all‐trans retinoic acid

Abstract

BACKGROUNDThe authors investigated the efficacy and safety of the histone deacetylase inhibitors valproic acid (VPA) and all‐trans retinoic acid (ATRA) as differentiation agents in a cohort of older, poor‐risk patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS).METHODSTwenty older patients with recurrent or refractory AML or MDS were treated in a Phase II protocol with sequential VPA and ATRA therapy. VPA was started at a dose of 10 mg/kg per day and then escalated to achieve the serum concentration of 45–100 μg/mL. ATRA was added at 45 mg/square meters (sm) per day when VPA reached the target serum concentration. Only patients treated continuously for ≥ 2 months were considered evaluable.RESULTSHematologic improvement, according to World Health Organization criteria, was observed in 6 of 20 patients enrolled in the protocol but in 6 of 11 considered evaluable. In five patients, a major platelet response was observed, achieving platelet transfusion independence. Three of these five patients also exhibited a minor erythroid response. A sixth patient showed both a minor erythroid response and a platelet response. The median duration of response was 189 days (range, 63–550 days). No significant reduction in the blast count was observed. Grade 3 neurocortical toxicity was observed in four patients. Severe bone pain was experienced by 4 patients (2 Grade 4 and 2 Grade 3) and was associated with an increase in the peripheral blast cell count. Treatment with ATRA did not modify the response observed with VPA alone.CONCLUSIONSDifferentiation therapy with VPA was of clinical benefit in approximately 30% of elderly patients with AML and MDS of the refractory anemia with excess of blast type with unfavorable prognostic features. A striking platelet transfusion independence lasting several months may be obtained in some patients, reducing the burden of palliative care and improving the quality of life. Cancer 2005;. © 2005 American Cancer Society.

Effect of histone deacetylase inhibitor valproic acid on progenitor cells of acute myeloid leukemia

“…The poor responses of AML patients reported in previous clinical studies using VPA is consistent with these data. 10,15,17,18,19 Furthermore, our findings have clinical implications for the use of HDAC inhibitors in the treatment of AML as they raise the possibility that these compounds may stimulate leukemic progression. …”

Histone deacetylase inhibitors and the promise of epigenetic (and more) treatments for cancer

“…Unfortunately, synergism in efficacy might be accompanied by adverse effects that are rarely or never seen with HDACi alone, and caution should be employed when considering clinical studies that address HDACi in combination with other therapies. Clinical studies combining RA treatment with HDACi are in progress in patients with leukaemia, expecially in the elderly 119 . Of particular interest is the combination of HDACi with other drugs acting on epigenetic mechanisms.…”

Is there a role for all-trans retinoic acid in combination with recombinant erythropoetin in myelodysplastic syndromes? A report on 59 cases

“…21 Furthermore, some patients experienced multilineage response, as previously described with ATRA alone. 16,22 To confirm those findings in a larger number of patients, the Groupe Francophone des Myelodysplasies (GFM) designed a prospective multicenter phase II clinical trial combining EPO-b and ATRA in patients with MDS with less than 10% bone marrow blasts.…”

“…9 All-trans retinoic acid (ATRA) is a vitamin A derivative involved in normal hematopoiesis, particularly in terminal granulocytic differentiation. 10 In MDS, retinoids given as single agent [11][12][13][14] or combined with various drugs, including valproic acid, 15,16 interferon-a, 17 vitamin E derivatives, 18 vitamin D derivatives or androgens, 19 yield modest improvements in cytopenias, especially anemia.…”