Abstract
5-azacytidine (AZA) has become standard treatment for patients with higher-risk myelodysplastic syndrome (MDS). Response rate is about 50% and response duration is limited. Histone deactylase (HDAC) inhibitors are attractive partners for epigenetic combination therapy. We treated 24 patients with AZA (100 mg/m2, 5 days) plus valproate (VPA; continuous dosing, trough serum level 80–110 μg/ml). According to WHO classification, 5 patients had MDS, 2 had MDS/MPD, and 17 had acute myeloid leukemia (AML). Seven patients (29%) had previously received intensive chemotherapy, and five had previous HDAC inhibitor treatment. The overall response rate was 37% in the entire cohort but significantly higher (57%) in previously untreated patients, especially those with MDS (64%). Seven (29%) patients achieved CR (29%) and two PR (8%), respectively. Hematological CR was accompanied by complete cytogenetic remission according to conventional cytogenetics in all evaluable cases. Some patients also showed complete remission according to FISH on bone marrow mononuclear cells and CD34+ peripheral blood cells, as well as by follow-up of somatic mitochondrial DNA mutations. Four additional patients achieved at least marrow remissions. Factors influencing response were AML (vs. MDS), marrow blast count, pretreatment, transfusion dependency, concomitant medication with hydroxyurea, and valproic acid (VPA) serum level. This trial is the first to assess the combination of AZA plus VPA without additional ATRA. A comparatively good CR rate, relatively short time to response, and the influence of VPA serum levels on response suggest that VPA provided substantial additional benefit. However, the importance of HDAC inhibitors in epigenetic combination therapy can only be proven by randomized trials.
Highlights
In recent years, epigenetic therapy has become a treatment option for patients with higher-risk myelodysplastic syndrome (MDS) who are not considered candidates for intensive induction chemotherapy or allogeneic stem cell transplantation (SCT)
The demethylating agent 5-azacytidine (AZA) can achieve substantial survival benefit for patients with higher-risk MDS and patients with acute myeloid leukemia (AML) who have a bone marrow blast count of 20–30% (RAEB-T according to the FAB classification) (Fenaux et al 2009)
In 2001, two independent groups showed that the antiepileptic drug valproic acid (VPA) has Histone deactylase (HDAC) inhibitory activity and induces differentiation of malignant myeloid cells, an ability that is enhanced by all-trans retinoic acid (ATRA) (Göttlicher et al 2001; Phiel et al 2001). Stimulated by these findings, we studied the clinical effect of VPA at serum concentrations of 50–100 μg/ml in 23 patients with AML or MDS as monotherapy or in combination with (ATRA) (Kuendgen et al 2004)
Summary
Epigenetic therapy has become a treatment option for patients with higher-risk myelodysplastic syndrome (MDS) who are not considered candidates for intensive induction chemotherapy or allogeneic stem cell transplantation (SCT). The demethylating agent 5-azacytidine (AZA) can achieve substantial survival benefit for patients with higher-risk MDS and patients with acute myeloid leukemia (AML) who have a bone marrow blast count of 20–30% (RAEB-T according to the FAB classification) (Fenaux et al 2009). Complete response (CR) rates are not higher than 10–20% (Fenaux et al 2009; Silverman et al 1994; Silverman et al 2002, and Silverman et al 2006), almost half of the patients with intermediate-II or high-risk disease according to IPSS (Greenberg et al 1997) show hematological improvement. To further improve remission rates, time to response and response duration, combinations of AZA with other agents are being evaluated
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