Differentiation Therapy for Poor Risk Myeloid Malignancies: Results of a Dose Finding Study of Bryostatin-1 (BRYO) + GM-CSF.

Clinically effective differentiating therapy has been limited to the use of all-trans-retinoic acid in patients (pts) with acute promyelocytic leukemia. We recently demonstrated that the in vitro activity of many pharmacologic differentiating agents, including the protein kinase C agonist bryo, was dependent on their ability to block cell cycle and maximized by the addition of growth factors. We studied the safety and efficacy of continuous infusion bryo in combination with GM-CSF (125 ug/m²/day SC) in patients (pts) with refractory and poor risk myeloid malignancies. Bryo was dose escalated using the Continual Reassessment Method from 6ug/m²/day to 20ug/m²/day for 14 days monthly and followed by 16ug/m²/day to 20ug/m²/day over 21 days each month. The treatment plan called for 2 cycles of combination therapy prior to response evaluation. A total of 32 patients with refractory or poor risk myeloid malignancies (9 relapsed or refractory AML, 1 therapy-related AML, 2 poor risk AML age >70, 19 poor risk MDS, 1 progressive PNH) were treated. The median age of subjects was 65 (range 23–75) yrs and a total of 73 (58 full + 15 partial) cycles were administered. The dose-limiting toxicity of the combination mirrored results from previous trials of bryo; grade 3–4 myalgias and arthralgias were observed in 12 of 14 pts at the highest dose levels (18 and 20ug/m²/day x 14 days, 16ug/m²/day x 21 days). Three pts discontinued therapy within a week of cycle 1 and were not considered evaluable for response. Eighteen (62%) pts responded (2 CRs and 16 PRs), 6 (21%) had stable disease, and 5 (17%) progressed. The PRs included 15 lineage responses and 1 bone marrow response (<5% blasts) with persistent cytopenias. The 2 CRs included a 59 yr old with poor risk MDS treated @ 20ug/m²/day x 14 days followed by a 2^nd cycle @ 18ug/m²/day x 14 days (dose-reduced due to toxicity) who achieved a CR and continues to show improving cytogenetics at 11 mos and a 74 year old with newly diagnosed primitive leukemia (>50% marrow blasts) who received a single cycle @ 16ug/m²/day x 21 days and remains in CR at 5 mos. Both pts refused further courses due to myalgias and arthralgias, and interestingly, the CRs were not achieved until 4–6 weeks after completion of therapy. Our newly developed assay (sensitivity 50 pg/ml) detected measurable bryo only at the highest doses which supported the correlative in vitro assays that detected in vivo differentiation at the same doses. Bryo + GM-CSF has remarkable clinical activity in refractory myeloid malignancies, but is intolerable at biologically active doses. These results do suggest that strategies utilizing differentiating agents in conjunction with growth factors warrant further investigation.