Refractory and relapsed acute leukemias are defined by their resistance to chemotherapeutic agents. Resistance in leukemia cells is thought to be at least in part mediated by the upregulation of nuclear factor- κB (NF-κB). It has been speculated that inhibition of NF-κB activity would render chemotherapy-resistant leukemic cells more susceptible to standard salvage regimens.
Bortezomib, whose mechanism of action involves rescuing malignant cells’ pro-apoptotic pathway through proteasome inhibition, is thought to indirectly inhibit NF-κB. The combination of mitoxantrone and etoposide has an acceptable, albeit moderate, frequency of inducing complete responses in relapsed/refractory acute myeloid leukemia with 35–45% CR rate of 4–5 month median duration. In this phase II trial, our group utilized bortezomib in an effort to potentiate the cytotoxic effects of mitoxantrone and etoposide in patients with relapsed or refractory acute leukemias.
Patients with relapsed or refractory acute myeloid or lymphoid leukemia (AML or ALL) were enrolled on a phase I-II dose escalation study of bortezomib (0.7, 1.0, or 1.3 mg/m2) on days 1 and 4 in combination with mitoxantrone 10 mg/m2 days 1–5 and etoposide 100 mg/m2 days 1–5. The phase 1 portion of the study was completed in late 2007. The phase 2 dose of bortezomib was 1.3 mg/m2. The primary endpoint was frequency of CR at count recovery with secondary endpoints including safety and tolerability. A Simon two-staged design was utilized and a preplanned interim analysis allowed the trial to proceed.
Forty-four evaluable subjects were enrolled in the phase II portion of the trial. There were 18 men (41%) and 26 (59%) women. The median age was 51 (range 19-71). Seventeen patients (38%) had received 2 or more prior therapies and 5 patients (11%) had relapsed following allogeneic transplants prior to study initiation. The majority of subjects had AML (80%). The CR rate was 0.27 (90% CI: 0.24, 0.50). The regimen was generally well tolerated with grade 3/4 febrile neutropenia in 17 patients (38%). Non-hematologic serious adverse events included: congestive heart failure (n=3, 7%), grade 3 mucositis (n=2, 5%), tracheal stenosis (n=1, 2%), and interstitial pneumonitis (n=1, 2%). Despite concerns about bortezomib-induced neuropathy, only one patient (2%) developed this complaint. Median survival for those who responded (n = 12) was 14.4 months (95% CI: 5.1, 25.7) and for non-responders (n=32) was 6.2 months (95% CI: 4.2, 10.0). The likelihood of achieving a CR was similar for patients with AML or ALL; 0.26 (95% CI: 0.13, 0.43) for AML and 0.33 (95% CI: 0.08, 0.70) for ALL. Sixteen of 44 patients underwent allogeneic stem cell transplant (7 in CR, 9 with residual disease) with 3 still alive at the conclusion of the study.
The addition of bortezomib to mitoxantrone and etoposide does not appear to improve CR rates over the standard salvage regimen alone, and outside the context of clinical investigation, we cannot recommend its routine use in acute leukemias. The use of other novel agents to enhance the efficacy of combination chemotherapy regimens is being explored, including the use of mTOR inhibitors. Further analysis including pharmacodynamic study of NF-κB inhibition may prove informative.
Off Label Use: The use of bortezomib in acute leukemias is off label but is studied in the presented research as a way to potentiate the other therapeutic agents. Mookerjee:AstraZeneca: Equity Ownership; Incyte: Employment, Equity Ownership. Kasner:Roche: Research Funding.
Asterisk with author names denotes non-ASH members.