Abstract
BackgroundA large proportion of patients with acute myeloid leukemia (AML) are not fit for intensive and potentially curative therapy due to advanced age or comorbidity. Previous studies have demonstrated that a subset of these patients can benefit from disease-stabilizing therapy based on all-trans retinoic acid (ATRA) and valproic acid. Even though complete hematological remission is only achieved for exceptional patients, a relatively large subset of patients respond to this treatment with stabilization of normal peripheral blood cell counts.MethodsIn this clinical study we investigated the efficiency and safety of combining (i) continuous administration of valproic acid with (ii) intermittent oral ATRA treatment (21.5 mg/m2 twice daily) for 14 days and low-dose cytarabine (10 mg/m2 daily) for 10 days administered subcutaneously. If cytarabine could not control hyperleukocytosis it was replaced by hydroxyurea or 6-mercaptopurin to keep the peripheral blood blast count below 50 × 109/L.ResultsThe study included 36 AML patients (median age 77 years, range 48 to 90 years) unfit for conventional intensive chemotherapy; 11 patients responded to the treatment according to the myelodysplastic syndrome (MDS) response criteria and two of these responders achieved complete hematological remission. The most common response to treatment was increased and stabilized platelet counts. The responder patients had a median survival of 171 days (range 102 to > 574 days) and they could spend most of this time outside hospital, whereas the nonresponders had a median survival of 33 days (range 8 to 149 days). The valproic acid serum levels did not differ between responder and nonresponder patients and the treatment was associated with a decrease in the level of circulating regulatory T cells.ConclusionTreatment with continuous valproic acid and intermittent ATRA plus low-dose cytarabine has a low frequency of side effects and complete hematological remission is seen for a small minority of patients. However, disease stabilization is seen for a subset of AML patients unfit for conventional intensive chemotherapy.
Highlights
A large proportion of patients with acute myeloid leukemia (AML) are not fit for intensive and potentially curative therapy due to advanced age or comorbidity
Valproic acid is the histone deacetylase (HDAC) inhibitor used in most of these studies, but butyric acid and depsipeptide seem to have similar effects [7]. These previous studies demonstrate that HDAC inhibitors, usually administered in combination with alltrans retinoic acid (ATRA), induce disease stabilization with improvement of normal peripheral blood cell counts for a subset of AML patients
Five additional AML patients unfit for intensive chemotherapy were admitted to our hospital but were not included in the study; these patients were (i) one patient with relapsed AML who did not accept inclusion; Table 1 The frequencies of relapsed and secondary acute myeloid leukemia (AML), signs of differentiation (FAB subclasses, CD34 expression) and genetic abnormalities among unselected AML patients unfit for intensive therapy
Summary
A large proportion of patients with acute myeloid leukemia (AML) are not fit for intensive and potentially curative therapy due to advanced age or comorbidity. Valproic acid is the HDAC inhibitor used in most of these studies, but butyric acid and depsipeptide seem to have similar effects [7] Taken together, these previous studies demonstrate that HDAC inhibitors, usually administered in combination with alltrans retinoic acid (ATRA), induce disease stabilization with improvement of normal peripheral blood cell counts for a subset of AML patients. Based on the overall results from several studies including more than 200 patients, complete hematological remissions seem very uncommon [8,9,10,11,12,13,14,15] The duration of these responses varies, but they may last for more than a year. Our results demonstrate that the treatment was well-tolerated and disease stabilization with improvement of normal peripheral blood cell counts was observed for a subset of patients
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