Preliminary Results from a Phase 2 Trial of AG-858, an Autologous Heat Shock Protein-Peptide Vaccine, in Combination with Imatinib in Patients with Chronic Phase Chronic Myeloid Leukemia (CML) Resistant to Prior Imatinib Monotherapy.

AG-858 is an autologous polyvalent heat shock protein-peptide complex vaccine produced from the individual patient’s leukocytes collected via leukapheresis. This ongoing trial investigates AG-858 plus imatinib in patients with Philadelphia-chromosome (Ph + ) CML in first chronic phase, who are cytogenetically positive following prior treatment with imatinib monotherapy. Eligible patients had an ECOG score of 0 or 1, no evolution of the Ph + clone, and previously received ≥400 mg/day of imatinib either as monotherapy or together with other treatments. Dosing of imatinib must have been unchanged and other therapies must have been discontinued for at least six months prior to study entry. Imatinib resistance was defined as: less than a complete cytogenetic response (CCyR) after ≥1year of imatinib OR stable cytogenetic status (without response or progression) at three consecutive timepoints over ≥6months OR cytogenetic progression at two consecutive timepoints ≥1month apart. AG-858 was to be administered in 50μg doses via intradermal injection once per week for up to eight weeks. Imatinib dose could not be changed other than reduced for toxicity. Endpoints are cytogenetic response (CyR) measured by bone marrow cytogenetics and molecular response (≥2-log reduction of BCR-ABL/ABL ratio (%) detected by RQ-PCR) in peripheral blood in patients who achieve CCyR post vaccination. Patients were followed for response at 3-month intervals. As of 6 May 2005, 27 patients with a median age of 61 years (34 to 75) and a male:female ratio of 11:16 were treated. Median imatinib dose at study entry and median treatment duration were 600mg and 2.7 years, respectively. Twenty-six patients completed AG-858 treatment of which 22 received eight doses. Cytogenetic data were available for 22 treated patients at baseline and 3-month follow-up, and for 18 patients at 6-months. The median proportion of Ph + marrow metaphases at study entry was 80%; nine patients had ≤30%. One patient with 92% Ph + metaphases at study entry had a partial CyR (reduction to 20%) at 3 months. Two of the nine patients with ≤30% Ph + metaphases at study entry (13% and 2%) had a CCyR at 3 months. These two patients achieved a 1 to 2-log reduction of BCR-ABL/ABL ratio (%) at 3-months along with their CCyR, but were cytogenetically positive at 6 months (6% for both), four months after completion of vaccination. No other patients responded to date. Adverse events considered related to AG-858, which occurred in more than one patient, were dizziness (15%), nausea (11%) and bruising (7%). No serious adverse events considered related to AG-858 were reported. These preliminary data suggest AG-858 vaccination is associated with low toxicity and may induce CCyR in patients with imatinib-resistant CML and low cytogenetic disease burden. CCyR may not be durable after vaccination is discontinued. Further study is needed to understand the role of AG-858 in patients with less advanced CML such as minimal residual disease and the potential influence of booster vaccinations on duration of response.