Panobinostat-Augmented Cytarabine and Daunorubicin (7+3) Induction for Older Patients with AML or High-Risk MDS Is Well Tolerated and Results in Favorable Clinical Outcomes: The Panda Trial

Introduction

Patients aged >60 years (y) with acute myeloid leukemia (AML) have inferior outcomes compared to those <60y.  Even those who tolerate induction chemotherapy achieve lower response rates with standard approaches and experience significant toxicity with more intensive combinations. The histone deacetylase (HDAC) inhibitor panobinostat (pano) potentiates anthracycline and ara-C cytotoxicity, likely through enhancement of DNA double-strand breaks leading to increased apoptosis (Maiso et al. 2009; Xie et al. 2013). We hypothesized that addition of short-course HDAC inhibition with pano prior to and during 7+3 induction therapy would be well-tolerated and lead to favorable outcomes in this patient population.

Methods

We conducted a phase I study in patients >60y with newly diagnosed AML or high-risk MDS combining pano at doses ranging from 20 mg to 60 mg given orally on days 1, 3, 5, and 8 of induction with daunorubicin (dauno) 60 mg/m2 on days 3–5 and ara-C 100mg/m2 continuously on days 3–10 (p+7+3). Patients were allowed retreatment on p+5+2, with pano on days 1, 3, and 5 at the same doses, if the nadir BM biopsy had residual leukemia.  Upon attainment of CR/CRi, patients were offered a second p+7+3 or alternative consolidation including allogeneic stem cell transplantation (alloHCT).  Dose-limiting toxicity was defined based on unexpected toxicities from 7+3 induction and a standard 3+3 design was utilized for dose escalation.  Peripheral blood mononuclear cells were isolated on days 1–5 and HDAC expression and histone acetylation were evaluated by western blot and quantified by densitometry.

Results

Overall, 22 patients were treated on the PanDA protocol. Treatment was well-tolerated in all dose-cohorts and the MTD was not reached. We treated 6 patients each at the 60 mg and 50 mg dose in the dose expansion phase due to recurrent grade 1 bradycardia. The median age was 67y — 60-69y (13), 70-79y (5), and >80y (4). Eleven patients had de novo AML, 7 had AML with myelodysplasia related changes, 2 had 2^ary AML from MPD, 1 treatment-associated myeloid neoplasm, and 1 had RAEB-2. Two patients had progressed on hypomethylating agents. Thirteen (62%) had intermediate-risk cytogenetics (cyto). Amongst 8 euploid patients, 2 had FLT3-ITDmut, 1 had FLT3-TKDmut and 2 had NPM1mut as the sole abnormality. Seven (33%) patients had complex/monosomic cyto.  There were no patients with favorable cyto.

There were no protocol-defined DLTs. The most common grade 2-4 TEAEs were febrile neutropenia (77%), electrolyte abnormalities (64%), diarrhea (55%), rash (55%), LFT abnormalities (32%), nausea (27%) and anorexia (27%).  Of note, 36% experienced asymptomatic sinus bradycardia peaking on day 6 following pano, dauno, and 5HT3 inhibitor anti-emetics.  Additionally, 9% experienced new onset grade 2 atrial fibrillation.  There was no evidence of myocardial dysfunction on echocardiogram following induction.  SAEs reported on study were sepsis (9%), typhlitis (5%), DIC (5%), pneumonitis (5%), and bowel perforation due to mucorales (5%).  There were 2 deaths (9%) during induction, one related to typhlitis and the other to sepsis.

Of 20 evaluable patients, 8 (40%) achieved CR/CRi . One patient received study treatment as consolidation, 3 received intermediate/high-dose ara-C, 1 received a hypomethylating agent, 2 underwent alloHCT and 1 had no further therapy. Median overall survival was 10 mos (ITT) and 16 mos for those who achieved a CR/CRi (p=0.005). Median relapse-free survival was 10 mos, range 3–27 mos (Figure 1).

Baseline expression of HDAC class 1, 2, 3 and 6 was evaluated and was not found to be associated with response to p+7+3 arguing against a direct role in p+7+3-induced cytotoxicity. However, global histone acetylation change after pano exposure (days 1–3) was significantly associated with eventual chemo-ablation at nadir (Figure 2). Ongoing studies are evaluating markers of DNA damage response and apoptosis in patients treated with PanDA vs. concurrent 7+3 controls. 

Conclusions

The addition of pano to 7+3 induction for older patients with AML is well-tolerated and results in clinical outcomes that are favorable in our very high-risk population. The recommended dose of pano is 50 mg daily on days 1, 3, 5, and 8 when combined with 7+3 induction in future studies. Importantly, histone acetylation change following exposure to pano but not baseline HDAC expression predicts sensitivity to combined therapy.