Final Report of a Phase II Trial of Vorinostat, Idarubicin and Cytarabine In Previously Untreated Acute Myelogenous Leukemia (AML) or High Risk Myelodysplastic Syndrome (MDS)

Vorinostat (Vor) is an oral HDAC inhibitor with activity in AML. In vitro, the combination of Vor with idarubicin (Ida) and ara-C (A) is synergistic. We have performed a phase I trial of Vor and Ida and demonstrated that doses of vorinostat up to 500 mg po TID daily × 3 are safe in combination with Ida. Based on this, we developed a phase II trial to study the safety and activity of the triple combination in patients (pts) with AML or higher-risk MDS.

Pts ages 15 to 65 years with ECOG performance of ≤ 2 with a AML by WHO criteria or INT-2 or high risk MDS by IPSS were eligible. The study had 2 phases: an initial run-in phase followed by an actual phase II. For the run-in phase pts with relapsed or refractory disease were eligible. For the phase II, pts should not have received any prior therapy for AML or higher risk MDS. Other inclusion criteria were adequate renal, hepatic, cardiac functions. Pts with APL or CBF were excluded. In the run in phase, Vor was used at the highest possible dose (500 mg po TID × 3 days on days 1 to 3) in combination with Ida-A. Once the dose of Vor was defined in the run-in phase, the phase II was to start with a primary endpoint of event free survival (EFS). The trial was monitored every 6 months and was to be stopped early if it was unlikely that the median EFS rate will be at least (more than 2%) 7 months. The study was also monitored for Vor-related excess toxicity. Pts could receive up to 2 induction cycles, 5 cycles of consolidation and 12 of maintenance. Induction therapy: Vor 500 mg po TID × 3 days, Ida 12 mg/m² IV over 1 hour qd × 3 (days 4 to 6) and A 1.5 g/m² IV as a continous infusion (CI) over 24 h qd (days 4 to 7). Pts who achieve a CR or CRp (CR with incomplete platelet recovery) could receive consolidation therapy as follows: Vor 500 mg po TID × 3 days on days 1 to 3, Ida 8 mg/m2 IV over 1 hour daily × 2 days (days 4 and 5) and A 0.75 g/m2 IV CI over 24 h qd × 3 days (days 4 to 6). During maintenance phase, Vor was 200 mg po TID QD x14 every 28 days for 12 cycles. PD analysis included histone acetylation, analysis of autophagy and ROS activation.

3 pts were treated in the run in phase with no toxicity. All 3 responded to therapy and the study continued to the phase II. The phase II has completed accrual at 75 pts. This was the max. number anticipated if the study was to be successful. No stopping rules for EFS or toxicity were met. Pt characteristics are as follows: median age 52 years (range 19–65), WBC 5 ku/L (range 0.7 to 111), peripheral blood blasts 14% (0-92), BM blasts 40% (11-95), cytogenetics (diploid 29 (38%), -5/-7 (22%), the rest complex), Flt3 mutation in 11 (14%). Response rate is as follows: CR 57 (76%), CRp 7 (10%) for an overall response (ORR) of 86%. Diploid pts had a CR of 86% and CRp of 7% for an ORR of 93%. Pts with other CG alterations had a CR of 76%, CRp 9%, ORR 85% (p=0.03). Pts with Flt-3 ITD had a CR of 91% and CRp of 9% for an ORR of 100%. This was in contrast to an ORR of 85% for the wt Flt-3 group (p=0.2). Four pts (6%) required 2 cycles of induction for response. Induction mortality was in 3 pts (4%). No excess toxicity was observed compared to standard Ida and Ara-C therapy. With a median follow of 6.7 (0.9 to 19.4) months: OS was 15.7 months (range 0.7 to 19.4) (64% at 1 year), remission duration (RD) 9.5 months (0-18.2) and EFS 10.2 (0.7-19.4). For diploid pts, OS was 17.7 (0.9 to 19.4), RD NR (0.7 to 14.1) and EFS NR (0.9-19.4). In pts with other CG alterations was OS was 11.7 (0.7-18.9) (p=0.3); RD 8.3 (0.7-14.1), p=0.05, and EFS 8.5 (0.7 to 15), p=0.05. Probability of survival at 1 year was 73% for diploid and 58% for others. For Flt-3+ OS was 18.2 (1.4 to 18.2) vs. 15.7 (0.9-19) in wt Flt-3 (p=0.4), RD NR (0.2 to 16.6) vs 9(0-14.5) months in wt and EFS NR vs 10.2 (0.9-15-7) in wt (p=NS). OS at 1 year was 91% for Flt-3+ vs. 60% for wt Flt-3. Induction of histone H3 acetylation on day 3 was documented in only 2 of 15 (13%) pts. Beclin, a marker of autophagy, was expressed at baseline in all 15 cases analyzed. Sequential gene expression of Nrf2, CYBB, FoxO3, SOD1,2 and GST-pi was measured sequentially by Q-PCR. No activation of any of these genes was observed with therapy. Biomarkers of DNA repair (H2AX) are ongoing.

The combination of Ida-A Vor is safe in pts with AML/MDS. ORRs are very high with this combination, particularly in diploid and Flt-3 ITD pts. Longer follow up is needed to assess effect on survival. Studies specific for Flt3 mutated pts and in combination with standard “7+3” therapy are ongoing.

No relevant conflicts of interest to declare.