Gemtuzumab Ozogamicin in Combination with Vorinostat and Azacitidine As Induction and Post-Remission Therapy in Older Patients with Relapsed or Refractory Acute Myeloid Leukemia (AML): A Phase 1 Study

The anti-CD33 immunoconjugate, gemtuzumab ozogamicin (GO), is efficacious in only a minority of AML patients when used alone. Emerging data suggest that epigenetic modifiers may chemosensitize to GO. For example, histone deacetylase (HDAC) inhibitors such as vorinostat increase CD33 expression and lower the apoptotic threshold to GO in vitro, while DNA methyltransferase I inhibitors such as azacitidine enhance GO efficacy in vitro and show promise when combined with GO in early clinical studies. These studies, together with the improved clinical activity when HDAC inhibitors are used with DNA methyltransferase I inhibitors, prompted a phase 1 study (NCT00895934) of GO with vorinostat and azacitidine for primary refractory AML or AML in first relapse (remission duration ≤12 months) requiring 1^st salvage therapy.

Patients aged ≥50 years were eligible if they had an ECOG performance status of 0–3 and had adequate organ function. Patients with prior hematopoietic stem cell transplantation were eligible if relapse occurred 6–12 months post-transplant. Excluded were patients with a second active malignancy, prior treatment with any of the study drugs, or central nervous system disease. Hydroxyurea was given to reduce the total white blood cell count to <25,000/μL before treatment. Patients were assigned to therapy according to a “3+3” study design. If there was persistent leukemia (>20% blasts in non-hypoplastic bone marrow) on day 15, the first cycle was repeated, and patients came off study if, after repetition, there was disease progression. In all other patients, a second cycle was begun if peripheral blood counts had recovered (blood count recovery was not required for patients with persistent leukemia) and all toxicities had resolved to ≤grade 2. Patients came off study if a partial remission (PR; >50% decrease of bone marrow blast percentage) was not achieved by the end of cycle #3, or if a complete remission (CR) or CR with incomplete peripheral blood count recovery (CRi) was not achieved by the end of cycle #6. Dose-limiting toxicity (DLT) was defined as: 1) any grade 3 non-hematologic toxicity lasting >48 hours that results in >7 day delay of the subsequent treatment cycle, with the exception of febrile neutropenia or infection; 2) any grade ≥4 non-hematologic toxicity, with the exception of febrile neutropenia/infection or constitutional symptoms if recovery to grade ≤2 within 14 days; and 3) prolonged myelosuppression (platelet count <20,000/μL and/or absolute neutrophil count <500/μL at day 42 after treatment in patients without evidence of persistent leukemia).

15 patients (8 male, 7 female), median age 65.7 (range, 50.2–69.8) years, with either primary refractory disease (n=6) or first relapse (n=9; median duration of first CR: 6 months) were enrolled on this study and received a median of 2 (range, 1–3) cycles of therapy (see Table):

One DLT of death due to sepsis and respiratory failure occurred at dose level 4 after cycle 1, defining this level as maximum tolerated dose (MTD). Death within 8 weeks of therapy initiation occurred in 5 patients (33.3%). Besides grade 3–4 cytopenias, the most common grade³3 adverse events were: neutropenic fever (n=8) or documented infection (n=5), hypoalbuminemia (n=3), and acute renal failure (n=2). As detailed in the table, 2 patients (13.3%) each achieved either a CR or a CRi for a total CR/CRi rate of 4/15 (26.7%); 2 additional patients (13.3%) met morphological criteria for CRi but had MRD (<5% abnormal blasts) by flow cytometry. Nine patients (60.0%) either had RD (n=8; 53.3%) or experienced DA (n=1; 6.7%). An exact 95% confidence interval about the CR rate is 0–32% compared to an expected CR rate of 15% in 1^st salvage patients with CR durations of 0–12 months. Thus, the study is continuing (at dose level 4).

The combination of GO, vorinostat, and azacitidine appears feasible and shows anti-AML activity in this cohort of difficult-to-treat patients.

Off Label Use: The presentation discusses a phase 1 study using azacitidine, vorinostat, and gemtuzumab ozogamicin for treatment of adults with relapsed/refractory AML; none of these 3 drugs is currently approved for this use in the U.S. Medeiros:Celgene: Honoraria, Research Funding.