Expression of Proliferation Related Genes in Myelodysplastic Syndromes (MDS) and Secondary Acute Myeloid Leukemia (AML) Patients with Resistance to Low Dose Vidaza and Thalidomide.

Vidaza and Thalidomide were administered to 29 patients with MDS or AML. Vidaza was given at a dose of 75mg/kg subq X 5 days q28 days and Thalidomide starting at 50mg/day and increasing to 100mg. Therapy was well tolerated. Median age was 70 years, and there were 16 males. Two patients had RA, 2 RARS, 9 RAEB, 4 CMMoL, 10 AML and 2 Unknowns. According to IPSS, 1 had low, 7 had Int-1, 5 had Int-2 and 4 had high risk disease, and 2 unclassified and 10 had AML. Eleven patients had normal, 14 abnormal and 4 unknown cytogenetics. Hematologic improvement (HI) was seen in 14 and stable disease in 6 while 5 had disease progression. cDNA from pre-therapy BM mononuclear cells of 28/29 patients was hybridized to Affymetrix HG-U133AA microarrays and data was analyzed using the GenePattern software package. Marker genes were selected using ClassNeighbors algorithm with the signal-to-noise metric. When comparing resistant disease (RD) patients with HI (6) and others (2), of the 40 top marker genes over-expressed in the RD group, 21 are directly associated with cellular proliferation and can be divided into 3 groups. Group I (cell cycle) consisted of 9 genes; BUB1B, CCNA2, TMPO, CDC2, CCNB1, UBE2C, TTK, CDC20 and MCM5. Group II (replication repair) had 5 genes; TOP2A, RRM2, RFC3, FEN1, RNAH2A. Group III (spindle/chromosome structure) had 7; KIF2C, NUSAP1, CENPF, MK167, SPAG5, CENPA and STK6. Over-expression of these genes would indicate rapid cellular proliferation which may be an underlying cause of drug resistance. These results are especially striking since the treatment regimen consisted of a combination of two drugs, Vidaza and thalidomide, which purportedly act through different mechanisms. We conclude that the RD patients share a molecular signature which is also consistent with a demonstrated mechanism of cell cycle resistance, and underscores the future clinical usefulness of this methodology.