Final Results of a Dose Escalation Study of Flavopiridol in Acute Leukemias Using a Novel Treatment Schedule.

Use of a novel, pharmacokinetically derived schedule of flavopiridol given as a 30 minute (min) intravenous bolus (IVB) followed by 4 hour (hr) infusion (CIVI) resulted in marked improvement in efficacy in refractory chronic lymphocytic leukemia (CLL) compared with earlier studies using other schedules (Byrd, Blood 2007). We modified and intensified the Byrd hybrid IVB/CIVI regimen for single-agent flavopiridol administration in adult acute leukemias to determine the maximum tolerable dose. Using this schedule, 23 patients (pts) have been enrolled in this phase I study of flavopiridol by IVB/CIVI on days 1, 2, and 3. Prophylactic antidiarrheals (loperamide, cholestyramine) were aggressively used. Tumor lysis syndrome (TLS) precautions were utilized in all cases. Dose escalation was as follows (IVB/CIVI dose in mg/m²): 20/30 (n=3), 30/35 (n=7), 30/50 (n=3), 40/60 (n=8), and 50/75 (n=2). Pts had relapsed/refractory AML (n=19) or ALL (n=4) and were 23–78 yrs old (median age 62 yrs). The dose limiting toxicity was secretory diarrhea (Grade 3), occurring in both pts treated at the 50/75 level. Clinically significant diarrhea (<Grade 3) was very common at higher dose levels and more frequent in older pts. Diarrhea was worse after the first dose than on days 2 and 3, typically beginning 6–8 hrs after initiation of treatment and resolving after 4–6 hrs. Life-threatening TLS requiring hemodialysis was observed in one pt treated at 30/50 who presented with high WBC (48,600/μL); the pt subsequent expired to due systemic fungal infection. Clinically significant TLS occurred in one other pt; chemical evidence of tumor lysis was frequent. Additional significant drug-related toxicities (1 case each) included acute renal failure (ARF, Grade 2) and transient rise in AST/ALT (Grade 3, though not clinically significant). Myelosuppression was universal though difficult to assess separately from disease-related cytopenias. Additional pts are accruing at the 40/60 level to get further safety experience in both AML and ALL and to examine pharmacodynamic (PD) endpoints. Overall, average plasma levels were 1.0–2.5 μM during the infusion and declined with terminal half-lives comparable to previously reported 72 hr and more recent 4.5 hr infusions. Preliminary PD studies show downregulation of Mcl-1 protein by standard immunoblotting at 4 and/or 24 hrs in blood and/or bone marrow cells. Modest anti-leukemic activity has been observed with most pts experiencing transient reductions in WBC/circulating blasts for 10–14 days. One AML pt with refractory AML had CRp but of short duration (1 month). One pt experienced a platelet response (transfusion dependent at entry to 97,000/μL peak response). In conclusion, previous studies with 24 hr or 1 hr infusions of flavopiridol have shown dose limiting secretory diarrhea; the same toxicity limits dosing with the hybrid IVB/CIVI schedule, though the hybrid regimen allowed administration of slightly higher doses. Though TLS was observed, it did not appear to be solely dose-related, in contrast to the Byrd CLL study with the hybrid regimen. Given the activity and toxicities observed in this study, combination of flavopiridol with other agents including cytotoxic chemotherapy or novel agents should be considered in pts eligible to receive this intensive therapy. [NCI U01 CA 76576–05, NIH/NCI K23CA120708, Leukemia and Lymphoma Society, and D. Warren Brown Foundation]