Myelodysplastic Syndrome Patients Obtaining a Cytogenetic Response to Outpatient Decitabine Experience Improved Hematological Responses and Longer Survival: Additional Analyses From the ADOPT Trial.

The multi-center ADOPT trial (J Clin Oncol 2009; 27:3942) demonstrated that decitabine (Dacogen), a cytidine analog with hypomethylating and direct cytotoxic properties, when administered to MDS patients with IPSS '0.5 on an outpatient schedule of 20 mg/m2 IV infusion 5 days per month resulted in an overall improvement rate of 51%, including 32% complete responses (CR+mCR), using the International Working Group 2006 criteria. The impact of obtaining a cytogenetic response to decitabine therapy on subsequent hematological parameters or survival is the focus of this analysis.

99 patients with de novo or secondary MDS were enrolled on the ADOPT trial. 49 patients had abnormal cytogenetics at baseline. 33 patients underwent at least one successful post-treatment karyotypic analysis and were therefore evaluable for cytogenetic response. Data analysis utilized student t-tests and comparisons of proportions.

17/33 evaluable patients (52%) achieved a cytogenetic response, with 11 complete responses and 6 partial responses (i.e., >50% reduction in abnormal metaphases). Responses were noted among patients in all IPSS cytogenetic risk categories: low risk cytogenetics 3/3 (100%), intermediate risk cytogenetic 5/8 (62%), and high risk cytogenetic (43%). Cytogenetic responses by abnormality included: -Y (3/3), del 5q (1/7) 1, del 20q (1/2), complex (6/14), chromosome 7 abnormalities (6/14), +8 (5/6), and others (3/7). Baseline characteristics were similar among cytogenetic responders and non-responders: mean age 72.2 vs 68.6 years (p=0.30), males 94 vs 63% (p=0.07), secondary MDS 24 vs 13% (p=0.72), high risk IPSS 35 vs 63% (p=0.21), int-2+high risk IPSS 59 vs 85% (p=0.20), blasts <10% 59 vs 31% (p=0.21), red cell transfusion dependent 41 vs 69% (p=0.21) and platelet transfusion dependent 6 vs 19% (p=0.54). The median time to cytogenetic response was 2.3 months, coinciding with the first post-treatment marrow sampling timing. Of the 17 cytogenetic responders, 13 (76%) had a clinical hematological responses (10 CR and 3 mCR) which was significantly higher (p=0.003) than the 3 of 16 evaluable patients (18%) not experiencing a cytogenetic response. Among cytogenetic responders the duration of the hematological response (451 days, 95% CI 143, NE) also was greater than the duration of hematological response among cytogenetic non-responders (219 days, 95% CI 184, NE). 71% (12/17) of cytogenetic responders were red cell transfusion independent on study by IWG criteria compared to 44% (7/16) non-cytogenetic responders (p=0.22). Significantly more cytogenetic responders achieved prolonged red cell transfusion independence lasting at least 24 weeks (10/17; 59%) compared to cytogenetic non-responders (3/16; 19%) (p=0.04). 88% (15/17) of cytogenetic responders were platelet transfusion independent during the study compared to 75% (12/16) non-cytogenetic responders (p=0.61). Higher rates of prolonged platelet transfusion independence lasting at least 24 weeks were achieved among 82% (14/17) cytogenetic responders versus only 38% (6/16) cytogenetic non-responders (p=0.03). Achieving a cytogenetic response correlated with improved survival. Cytogenetic responders had a median survival of 627 days (95% CI 420,760) versus 318 days (95% CI 265, 447) for cytogenetic non-responders.

Outpatient administration of decitabine (20mg/m2 IV 5 days per month) resulted in cytogenetic responses in 52% of patients with MDS with baseline cytogenetic abnormalities, with a median time to response of 2.3 months. Patients achieving a cytogenetic response had higher rates of hematological responses, longer durations of transfusion independence, and a doubling of projected survival. This analysis suggests that a deeper early response documented by cytogenetics with decitabine correlates with improved long term outcomes, and supports early cytogenetic testing to predict hematological response.

Goldberg:Eisai, Inc.: Research Funding.