Numerous preclinical studies have demonstrated synergistic interactions between proteasome and histone deacetylase (HDAC) inhibitors, particularly in B-cell malignancies (e.g., myeloma and lymphoma). However, investigation of this strategy in acute leukemias has been limited. Very recent preclinical findings have shown marked synergism between the HDAC inhibitor belinostat and the proteasome inhibitor bortezomib administered at very low (sub-micromolar) concentrations, in various cultured and primary acute myelogenous leukemia and acute lymphocytic leukemia specimens (Dai Y et al. Br J Haematol. 2011). These interactions were associated with multiple perturbations in survival signaling proteins, including inactivation of NF-kappa B, down-regulation of Bcl-xL and XIAP, and up-regulation of the pro-apoptotic protein Bim. These findings prompted initiation of a phase I trial with the primary objective of determining the recommended phase II doses (RPTDs) for the combination of bortezomib and belinostat in patients with relapsed or refractory acute leukemia, myelodysplastic syndrome (MDS), or chronic myelogenous leukemia in blast crisis (CML-BC).
To date, 13 patients have been enrolled. Patients with the following disease types have been treated: acute leukemia (n=9), MDS (n=3), and CML-BC (n=1). Patient characteristics include male/female ratio n = 6 (46%)/7 (54%), with a median age of 59 years [range 27–75]. ECOG performance score 0–2. The median number of prior therapies was 2 [range 2–5]. The schedule of administration was belinostat 30 minutes intravenous (IV) infusion on days 1–5 and 8–12; and bortezomib IV bolus preceding belinostat on days 1, 4, 8, 11; on a 21 day cycle. Dose level enrollment was: Level 1 = bortezomib 1.0 mg/m2, belinostat 500 mg/m2 (n=6); Level 2 = bortezomib 1.3 mg/m2, belinostat 500 mg/m2 (n=6); and Level 3 = bortezomib 1.3 mg/m2, belinostat 650 mg/m2 (n=1). The study is currently enrolling to dose level 3.
No dose-limiting toxicities (DLTs) have been observed to date. Non-DLTs (CTCAE v4) include: leukopenia (grade 4, 23%), thrombocytopenia (grade 3, 15%), and peripheral sensory neuropathy (grade 2, 23%). No serious adverse events have occurred at unexpected frequency or severity. Two deaths have occurred due to disease progression.
Of the 13 patients treated, 12 have been evaluable for response. There has been 1 complete response in this heavily pretreated population. This response was achieved in a patient with biphenotypic acute leukemia, refractory to 7+3 and Flag-Ida. The patient proceeded to allogeneic hematopoietic stem cell transplantation. Four patients had stable disease, and 7 patients had progressive disease. Correlative studies examining leukemic blast expression of nuclear RelA, Bim, Bcl-xL, and XIAP pre- and post-treatment are ongoing.
Collectively, these findings indicate that a regimen combining belinostat and bortezomib is well tolerated in patients with relapsed or refractory acute leukemia, MDS, or CML-BC. The maximum tolerated dose (MTD) has not been reached. Pending identification of the RPTDs, phase II evaluation of this therapeutic strategy, if warranted, should define its activity more definitively.
No relevant conflicts of interest to declare.
Asterisk with author names denotes non-ASH members.