Phase II Study of Bortezomib as a Single Agent in Patients with Previously Untreated or Relapsed/Refractory Acute Myeloid Leukemia Ineligible for Intensive Therapy
We explored the safety and efficacy of bortezomib given as single agent in patients with untreated or relapsed/refractory acute myeloid leukemia (AML), unfit for conventional chemotherapy. Fourteen patients were treated with bortezomib 1.5？mg/m2 administered twice weekly for two weeks, every 3 weeks. Median age was 70 years (range 60–81) and the median number of cycles delivered was 2 (range 1–4). Of 13 evaluable patients, in 8 (61%), the administration of bortezomib resulted in an antileukemic effect as demonstrated by peripheral blood and/or bone marrow blast reduction. In 4 (50%) of these 8, a decrease by 37% of transfusion requirement was also observed . Overall median survival was 4 months (range 0.25–10). Neurotoxicity was the most frequent adverse event with 7 of 13 (54%) patients experiencing grades 3-4 peripheral neuropathy. Neurotoxicity led to treatment discontinuation in 4 (57%) of 7. In conclusion, the observed anti-leukemic activity of bortezomib indicates that there is room for designing additional studies in which combination with other chemotherapeutic agents should be considered. Clinical registration no.: EUDRACT 2006-006923-38. 1. Introduction In spite of significant therapeutic improvements, a large proportion of patients affected with acute myeloid leukemia (AML) relapse or are primary refractory to treatment [1]. In this population, comorbidities and poor performance status (PS) often preclude administration of additional intensive treatments. For the same reasons, more than 50% of elderly with previously untreated AML are considered not eligible for intensive therapy [2]. Overall, these categories of patients have a very unfavorable prognosis and demand for alternative strategies is insistent. Among novel agents, bortezomib is a dipeptidyl boronic acid with a potent and selective proteasome inhibitory activity. Bortezomib has demonstrated significant activity against a wide spectrum of human cancer cells [3] as well as a number of plasma cell lines and primary cells from patients with multiple myeloma, non-Hodgkin lymphoma, and chronic lymphocytic leukemia, and it has nowadays become a pivotal drug in the treatment of multiple myeloma [4]. The previous hypothesis was that bortezomib, by proteasome inhibition, inhibits IkBα degradation that in turn switches off NF-κB pathway. NF-κB is a key transcription factor constitutively activated in neoplastic cells from solid tumors and hematological malignancies. More recent evidences demonstrate that bortezomib shows an important role in disrupting a network that operates on the basis of
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