The combination of vorinostat, a panhistone deacetylase inhibitor with activity in relapsed AML (Blood 2008;111:1060), with idarubicin and ara-C has synergistic antileukemia activity in a sequence dependent fashion were optimal effect is observed when vorinostat precedes ara-C (Blood 2006;108:1174 and CCR 2009;15:1698). In a phase I trial, we documented the maximal tolerated dose of vorinostat to be 500 mg orally three times a day for 3 days with standard dose idarubicin (BJH 2010; 150:72). Based on this we performed a phase II trial of vorinostat with idarubicin and ara-C in front line AML and higher risk MDS. Patients ages 15 to 65 years with appropriate organ function and no core binding factor abnormality were candidates. Induction therapy was vorinostat 500 mg orally three times a day (days 1 to 3), idarubin 12 mg/m2 IV daily × 3 (days 4 to 6), cytarabine 1.5 gm/m2 IV as a continuous infusion daily for 3 or 4 days (days 4 to 7). Patients in remission could be treated with 5 cycles of consolidation therapy with lower doses of the combination and up to 12 months of maintenance with single agent vorinostat. The study was designed to stop early if excess toxicity or low probability of event free survival (EFS) >28 weeks were likely. After a 3 patient run-in phase, 75 patients were treated. Median age was 52 (19–65) years, 29 (39%) were diploid and 11 (15%) were Flt-3 ITD. Therapy was well tolerated: no excess vorinostat related toxicity was observed. Induction mortality was 4%. Common toxicities included: diarrhea (72%), nausea and vomiting (65%), and skin toxicity (38%). No cardiac toxicity was observed. CR was documented in 57 (76%) patients and CRp in additional 7 (9%) for an overall response rate (ORR) of 85% (95% CI 0.75–0.91). No differences in response were observed in patients younger or older than 60 years. Seven (9%) patients received 2 cycles of induction therapy and 4 (44%) responded including 2 CR and 2 CRps. When analyzed based on molecular or cytogenetic features, 10 of the 11 patients with Flt-3 ITD achieved a CR and 1 a CRp (ORR 100%). All 6 NPM1 mut/Flt-3 wild type (WT) patients achieved CR. Presence of Ras mutations had no impact on response. Of the diploid patients, 25 (86%) achieved a CR and 2 a CRp (7%) (ORR 93%). Patients with other cytogenetic alteration excluding −5/–7 had an ORR of 93% including 23 (79%) CR and 4 CRp (14%). Only 9 (53%) patients with −5/−7 achieved a CR and 1 (6%) a CRp for an ORR of 64% (p=0.018). Responses were significantly higher than with standard IA therapy. With a median follow up of 82 weeks (5 to 132 weeks), the median OS for the whole group was 82 (range 3–134) and EFS 47 (3–134) weeks. Median OS and EFS for patients with Flt-3 ITD were 91 (range 6 to 134) and 66 (6–134) weeks. There was a trend towards better survival in the Flt-3 ITD patients versus the unmutated group (p=0.067). Patients with diploid cytogenetics had a median OS and EFS of 105 (5–134) and 68 weeks (5–134). There was a trend towards better survival in the diploid patients versus non-diploid patients (p=0.09). Survival was poorer in patients with −5/−7: OS was 34 weeks (range 3–92) and EFS 14 (3–92). Non-diploid non −5/−7 patients had a median OS of 92 weeks (5–119) and EFS was not reached (NR) (5–119). Nineteen patients (25%) were transplanted in CR#1. All patients had achieved CR/CRp before SCT. Eleven (57%) received an unrelated donor including 2 umbilical cords and two 1 antigen mismatch. Fifteen patients (79%) received ablative preparative regimens. Median OS and EFS had not been reached in the 19 patients transplanted. Robust induction of histone H3 acetylation was documented in 2 patients (2%). No induction of beclin was observed in any of the patients. Baseline levels of NRF2 were elevated in 6 of 34 patients (17%), CYBB 21 of 34 (61%), FOXO3 5 of 34 (14%), SOD1 11 of 34 (32%), SOD2 5 of 34 (14%), GST-PI 2 of 34% (6%), IL6 3 of 49 (6%), TIMP1 7 of 49 (14%), MMP9 4 of 49 (8%) and p38MAPK in 3 of 49 (6%). mRNA upregulation occurred in all genes starting as early as day 3 of therapy. Baseline levels of NRF2 and CYBB were associated with longer survival. No association between age or cytogenetics were found with NRF2 or CYBB. In summary, the combination of vorinostat with IA is associated with high induction response rates. Toxicity and EFS rules were not met and the study beat expectations. Further studies comparing it to standard IA or “7+3” programs and in patients with Flt-3 ITD should be proposed.
No relevant conflicts of interest to declare.
Asterisk with author names denotes non-ASH members.