Abstract
Myelodysplastic syndrome (MDS) defines a group of heterogeneous hematologic malignancies that often progresses to acute myeloid leukemia (AML). The leading treatment for high-risk MDS patients is azacitidine (Aza, Vidaza®), but a significant proportion of patients are refractory and all patients eventually relapse after an undefined time period. Therefore, new therapies for MDS are urgently needed. We present here evidence that acadesine (Aca, Acadra®), a nucleoside analog exerts potent anti-leukemic effects in both Aza-sensitive (OCI-M2S) and resistant (OCI-M2R) MDS/AML cell lines in vitro. Aca also exerts potent anti-leukemic effect on bone marrow cells from MDS/AML patients ex-vivo. The effect of Aca on MDS/AML cell line proliferation does not rely on apoptosis induction. It is also noteworthy that Aca is efficient to kill MDS cells in a co-culture model with human medullary stromal cell lines, that mimics better the interaction occurring in the bone marrow. These initial findings led us to initiate a phase I/II clinical trial using Acadra® in 12 Aza refractory MDS/AML patients. Despite a very good response in one out 4 patients, we stopped this trial because the highest Aca dose (210 mg/kg) caused serious renal side effects in several patients. In conclusion, the side effects of high Aca doses preclude its use in patients with strong comorbidities.
Highlights
Myelodysplastic syndromes (MDS) represent a group of myeloid neoplasms characterized by blood cytopenia and an increased risk of leukemic transformation
The increase in caspase 3 induced by Aza matched with the induction of apoptotic cell death already reported in other MDS/acute myeloid leukemia (AML) sensitive cell lines [6,23]
The effect of different concentrations of Aca on OCI-M2S and OCI-M2R cell proliferation was unaffected by qVD a pan-caspase inhibitor, indicating that it does not rely on apoptosis induction (Figure 2A), whereas the effect of Aza was impaired by qVD in OCI-M2S cells (Figure 2B) in agreement with the known proapoptotic effect of this drug
Summary
Myelodysplastic syndromes (MDS) represent a group of myeloid neoplasms characterized by blood cytopenia and an increased risk of leukemic transformation. Due to the progressive aging of the population in western countries, the number of MDS patients will significantly increase in the decades. In this context, MDS will be one of the most challenging issues for hematologists and health care providers in the near future. Azacitidine (Aza, Vidaza®), a pyrimidine nucleoside analog is routinely used as the leading treatment for myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) patients ineligible for intensive chemotherapy [1,2]. In MDS patients treated with Aza the overall survival is significantly prolonged by 10 months versus conventional care. Overall survival (OS) of these patients is very poor [3]
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