Azacitidine (AZA) Combined with Idarubicin in Untreated Patients with High Risk MDS – Results of a Phase I/II Study of the Groupe Francophone Des Myelodysplasies

Abstract 1720 Background: hypomethylating agents, especially AZA, have become the reference treatment of higher risk MDS, but the median survival of about 2 years obtained with AZA remains modest, and must be further improved. In addition, if it is able to increase overall survival in MDS, AZA yields only about 30% of marrow response (including CR+PR+ mCR), Idarubicin given at conventional dose (12 mg/m2/d during 3 days) is the anthracycline of choice in the intensive chemotherapy given with cytarabine in patients with high risk MDS and, given as a single agent, induces up to 30% of complete remission (CR) in elderly AML patients. Thus, we designed a phase I/II study evaluating the safety and efficacy of 2 doses of Idarubicin combined with Azacitidine in high risk MDS patients (clinical trial NCT01305135). Methods: For this trial Azacitidine was combined with increasing doses of Idarubicin. Main Inclusion criteria were: (1) IPSS int 2 or high MDS, or CMML with WBC 10% or AML with 20–30% marrow blasts (corresponding to EU label for AZA) (2) Age 3 18 years (3) Performance Status (PS) St 2012. Results: The 20 study patients (from 8 centers) were enrolled b etween Dec 2010 and Feb 2012, including 7 women and 13 men with a median age of 75 years. At inclusion, WHO classification was RCMD in 1 pt, CMML in 1 pt, RAEB-1 in 6 pts, RAEB-2 in 7 pts, AML in 3 pts and unclassified in 2 pt. Median marrow blasts were 6.5% (0–26) Karyotype (IPSS) was favorable in 7 pts, int in 3 pts and unfav in 8 pts (2 pts had cytogenetic failure). IPSS was high in all patients. PS was 0 in 28% pts, 1 in 50% and 2 in 22%. A total of 92 cycles of treatment had been administrated with a median number of 5 cycles/patient and 10 pts had received 6 or more cycles. 14 patients had terminated the study due to side effects (severe febrile pancytopenia, n=2), disease progression (n=5, after 2–10 cycles), death (disease progression, severe septic shock after Cycle 2, and unrelated coma), stable disease after 6 cycles (n=3), and patient decision (n=1). Overall 7 pt had died. 18 SAEs were reported observed in 9 patients, including 10 episodes of febrile neutropenia, 3 episodes of bleeding and 5 unrelated SAE. Of the 20 patients enrolled in the study, 19 were evaluable for response after 3 cycles, including 10/10 in the First cohort and 9/10 in the second cohort. One patient achieved CR, 2 PR, 1 mCR and 2 additional patients achieved stable disease with HI, leading to an Overall response rate of 6/19 (32%). Two patients were still on study but did not reached cycle 6. Thus, after 6 cycles, 17 patients, only could be evaluated. Among them 9/17 (53%) patients were still on study, 2 pts had died, 3 progressed, 2 had experienced sides effects and had terminated the study and 1 pt had withdrawn consent. Two patients achieved CR (including 1 already in CR at cycle 3), 2 PR and 2 additional patients achieved stable disease with HI leading to an Overall response rate of 6/17 (35%). At the time of the present analysis, none of the responder had relapsed. Conclusion: The phase I/II results presented here show that Idarubicin can be combined to Azacitidine with acceptable toxicity. Whether the azacitidine- Idarubicin combination can improve the outcome of higher risk MDS patients will be evaluated in a phase II randomized trial comparing this combination (and other combinations of azacitidine with other drugs) to azacitdine alone alone. Data of the present phase I/II trial will be updated at the meeting. Disclosures: No relevant conflicts of interest to declare.