Phase II Study of Bortezomib, Mitoxantrone and Etoposide In Relapsed/ Refractory Acute Leukemias

Abstract 2192

Bortezomib is a proteasome inhibitor known to affect multiple signaling pathways., The inhibition of nuclear factor KB (NF-KB) activation and the induction of apoptosis in cells that over-express bcl-2 have been implicated as an important mechanism of action in hematologic malignancies. The combination of mitoxantrone and etoposide has been successful in relapsed/refractory acute myeloid leukemia with complete remission (CR) rates of 35–45%, with median duration of CR of 4–5 months. Based on the ability to inhibit NF-KB, the addition of bortezomib to this regimen should render malignant cells more susceptible to mitoxantrone and etoposide.

Patients with relapsed or refractory acute myeloid or lymphoid leukemia were offered enrollment 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. Dose escalation was allowed if no patient in the previous cohort had dose limiting toxicity defined as > grade 3 toxicity definitely related to study drug. The phase 1 portion of the study was completed in late 2007 and reported at ASCO 2008. The phase 2 portion enrolled using a bortezomib dose of 1.3 mg/m2. To date the phase 2 portion has reached a pre-planned stopping point and enrolled 25 patients of whom 22 received therapy and are evaluable (1 patient enrolled but was found to be ineligible prior to starting therapy, 2 signed consent and subsequently refused therapy). The median age of patients on the phase 2 portion is 53 (range 32–76; 9 of 22 were age 60 or greater). Five patients had a diagnosis of Acute Lymphoblastic Leukemia (ALL); 17 had Acute Myeloid Leukemia (AML). The median number of prior therapies is 2, although several patients had multiple cycles of prior therapies and 5 had had prior allogeneic stem cell transplants. There were 13 female and 9 male subjects. Toxicity has been tolerable; one patient with history of prior stem cell transplant developed congestive heart failure presumed secondary to therapy which subsequently improved with medical management. One patient with a history of prior intubation developed respiratory distress from tracheal stenosis (likely unrelated to therapy). One patient had a CNS bleed and three had admissions for febrile neutropenia. Other patients developed febrile neutropenia but were not scored as Serious Adverse Events as the febrile neutropenia occurred while hospitalized and therefore did not require admission.

Patients were required to have a marrow aspirate at the nadir of their blood counts (approximately day 14) marrow aspirate and a recovery marrow aspirate to evaluate response. Eight of 22 patients (36.4%) had a response to therapy. This includes 2 who achieved a morphologic leukemia free state but who did not achieve full count recovery prior to the next therapy and 6 who achieved morphologic complete remission. This included 2 of the 5 (40%) patients with ALL and 6 of the 17 (35.3%) with AML. Ten patients subsequently underwent allogeneic stem cell transplant (1 unrelated donor, 8 haploidentical donors, one matched sibling donor). This included 5 patients who did not have a complete response to therapy, but had either stable disease or a reduction in leukemic burden after the study therapy. 8 of 22 (36.4%) are alive at a median of 121 days (range 53–277 days) following initiation of therapy. Fourteen of 22 patients expired at a median of 127 days (range 31–842) following initiation of therapy. Causes of death include relapse or progression of primary disease (n=10), complications of therapy/ cytopenias (n=2) and complications of stem cell transplant (n=2).

The combination of bortezomib, mitoxantrone and etoposide was well tolerated in this study, and the ability of bortezomib to enhance the effects of other cytotoxic agents may result in increased efficacy as well. The Phase 2 portion has reached the pre-planned evaluation point and the regimen has demonstrated reasonable efficacy in a heavily pre-treated patient population. The primary endpoint was disease status on recovery from study therapy (approximately day 28), with a treatment goal of moving patients to allogeneic stem cell transplant rapidly. Based on the interim analysis the study will accrue to a targeted enrolment of 44 patients.