A single arm phase 2 study with addition of Bortezomib to standard induction chemotherapy in adult acute lymphoblastic leukemia

Acute lymphoblastic leukemia (ALL) is an aggressive blood cancer, and is fatal unless treated appropriately at first presentation. Over several decades chemotherapy regimens have evolved to markedly improve outcomes in pediatric ALL, with regimens involving high dose therapy with Methotrexate. In adult patients outcomes are poor, with 5 year survival of 30-40%, hampered by adverse cytogenetic features, poor tolerance to increasing doses of chemotherapy, with prolonged cytopenia and higher incidence of infection-related mortality.

Several novel agents have been used in another poor prognostic group - relapsed pediatric ALL – with encouraging results. Of these, Bortezomib, is a proteasome inhibitor which is frequently used in the treatment of multiple myeloma and relapsed lymphoma. It is well tolerated and has minimal side effects. We plan to add Bortezomib to the induction phase of chemotherapy for adult B-cell ALL, to establish the feasibility and safety, and follow this with a randomized Phase II trial using standard chemotherapy with and without the use of Bortezomib.

Background:

Acute lymphoblastic leukemia (ALL) in adults is an aggressive disease, with poor long-term survival rates of 30-50%. Bortezomib has been shown to be safe and effective in the treatment of ALL in the relapsed setting, and the purpose of this study is to establish the safety of Bortezomib in newly diagnosed ALL. Methods:

This is a single arm Phase II trial to test the safety of Bortezomib in addition to standard induction chemotherapy in adult B cell acute lymphoblastic leukemia.

Primary Outcome:

Incidence of peripheral neuropathy post-induction (defined according to NIH criteria)21 > Grade 2 (see below) by clinical assessment

Secondary Outcomes:

Incidence of morphological remission (assessment by bone marrow morphological examination as part of standard therapy)

Incidence of Minimal residual disease positivity (assessment by flow cytometry as part of standard therapy)

Incidence of subclinical peripheral neuropathy (detected by NCV)

Target sample size and rationale: As this is a Phase II pilot study, we plan to use this protocol on 10 patients and if safety is established, a multicenter randomized trial is planned to assess efficacy (by MRD post-induction).