Abstract
Abstract 3595
The overexpression of proteasomes and constitutive activation of NF-KB in acute myeloid leukemia (AML) cells suggest that proteasome inhibitors (PI) such as Bortezomib (Bz) may be an effective therapy. PI or a decoy NF-KB oligonucleotide increases chemosensitivity to both anthracyclines and cytarabine. Thus, PI may improve the effectiveness of MEC (mitoxantrone, etoposide, cytarabine), a standard regimen for relapsed/refractory (R/R) AML. The primary objectives of this study were to determine the dose-limiting toxicity (DLT), maximum tolerated dose (MTD), and recommended Phase 2 dose of Bz in combination with MEC in patients (pts) with R/R AML. Secondary objectives included evaluating the preliminary activity of this combination and correlating CD74 antigen expression with response. CD74 may identify a subset of leukemias in which NF-KB is operative, with increased sensitivity to PI (Attar et al. CCR 2008; 14: 1446–54).
Methods:
All pts were treated at the Cleveland Clinic from August 2010-July 2012. This protocol was reviewed and approved by the institution's review board. Eligibility included: age 18–70 yrs, R/R AML, cardiac ejection fraction ≥ 45%. CD74 was assessed by flow cytometry using CD45 PE (BD Biosciences San Jose, CA) and CD74-Alexa 488 (AbD Serotec Raleigh, NC). All pts received MEC: mitoxantrone (6 mg/m2/d), etoposide (80 mg/m2), and cytarabine (1000 mg/m2) Days 1–6. Bz was administered IV on Days 1, 4, 8, and 11 and was dose escalated using a standard 3 × 3 design. Dose levels (DL) were: −1 (0.40 mg/m2), 1 (0.70 mg/m2), 2 (1.00 mg/m2), 3 (1.30 mg/m2). One cycle of treatment was administered. Response was assessed by bone marrow aspirate/biopsy by Day 45, and CR was defined by IWG criteria (Cheson, 2006). Toxicities secondary to neutropenia or sepsis were not considered DLTs. DLT included: (1) ≥ Grade 4 non-hematologic toxicity (NHT) with the exception of nausea, vomiting, alopecia, and drug-related fevers; (2) any ≥ Grade 3 neurologic toxicity; (3) grade 4 platelet or neutrophil count 50 days beyond the start of chemotherapy (not related to leukemia); (4) Any grade 3 NHT > grade 2 by 45 days beyond the start of chemotherapy. The following were redefined as not being DLT: (1) anorexia requiring TPN; (2) fatigue requiring bed rest; (3) grade 2, 3, and 4 hyperbilirubinemia were redefined as 1.5-<10x ULN, 10.0–20.0 × ULN, and > 20 × ULN respectively.
Results:
Seventeen pts have enrolled; and 15 are evaluable for response. The median age was 54 years (range 33–69), 7 (47%) were male, and median baseline WBC 3.58 K/μL (range 0.96–76.53). The median time from initial diagnosis to enrollment was 7.1 months (range 1.4–84.9) and 2 pts had a history of an antecedent hematologic disorder. Nine pts (60%) were in first relapse, 2 (13%) in second relapse, and 4 (27%) refractory. One pt had received a prior allogeneic hematopoietic stem cell transplant; and 4 out of 15 pts (27%) had adverse cytogenetics at the time of relapse based on CALGB 8461 criteria. At DL 1, 1 DLT occurred (Grade 4 thrombocytopenia). No DLTs occurred at DL 2. Three pts were enrolled on DL 3, with one DLT occurring thus far (Grade 4 transaminases: likely related to leukemia). Only one pt had their Day 11 Bz held secondary to Grade 2 ileus (DL 1). Overall, 3 pts (all on DL 1) have died from blood stream infections. In addition to Grade 4 hematologic toxicity, the most commonly reported adverse events (AEs) have been gastrointestinal (GI). GI toxicities were the mostly commonly reported AEs attributable to Bz. Nine pts reported constipation and/or abdominal pain (7: Grade 1 or 2; 2: Grade 3). Six of the 15 evaluable pts (40%) have achieved a complete remission (CR) or CRp (complete remission without platelet recovery). Eight of the fifteen pts had CD74 expression testing, but only 6 of 8 were evaluable for response. The median CD74 expression was higher in refractory pts (35.9%) (range 14–87) than in responders (3.2%) (range 0.9–16).
Conclusions:
The MTD of MEC in combination with Bz will be reported at the meeting; but currently we are in the last DL (3) and the MTD has not been reached. The toxicities of the combination are similar to that of MEC, except potentially an increase in GI toxicities. We await the results of preliminary response in the expanded cohort of pts, once the MTD is achieved. Higher CD74 expression appears to correlate with refractory disease rather than response in this R/R AML cohort, but larger pt numbers are needed to confirm this.
Disclosures:
Advani: Millenium: Research Funding. Hsi:Millenium: Research Funding.
Survival Following Relapse in Children with Acute Myeloid Leukemia: A Report from AML-BFM and COG
