Clinical Activity of Flavopiridol in Relapsed and Refractory Chronic Lymphocytic Leukemia (CLL) with High-Risk Cytogenetic Abnormalities: Updated Data on 89 Patients (Pts).

Background: New therapies for relapsed CLL pts with poor-risk cytogenetic features, such as del(11q22), del(17p13) or a complex karyotype, are needed. Alemtuzumab (Campath-1H) is effective in this pt population but has infectious toxicity and is ineffective as a single agent in bulky nodal disease. Flavopiridol induces p53-independent apoptosis in CLL cells in vitro. We previously demonstrated the activity of flavopiridol in genetically high-risk CLL in a phase I study using a novel, pharmacokinetically (PK) derived dosing schedule, and we are currently pursuing a larger phase II trial of this drug. We present updated results of flavopiridol’s activity in high-risk pts in both studies.

Study Design and Treatment: Pts (n=89) with symptomatic, relapsed CLL who failed (or could not receive) fludarabine received flavopiridol by 30-min IVB followed by 4-hr CIVI weekly for 4 doses, every 6 weeks for up to 6 cycles. Pts received 30 mg/m² IVB + 30 mg/m² CIVI (n=20), 40 mg/m² IVB + 40 mg/m² CIVI (n=3), 30 mg/m² IVB + 30 mg/m² CIVI for the first 4 doses and 30 mg/m² IVB + 50 mg/m² CIVI for all subsequent doses (n=14) or 30 mg/m² IVB + 30 mg/m² CIVI for the first dose and 30 mg/m² IVB + 50 mg/m² CIVI for all subsequent doses (n=44). Eight pts who experienced severe tumor lysis syndrome did not undergo dose escalation as planned. A complex karyotype was defined as ≥ 3 unrelated abnormalities, and FISH for TP53 [del(17p13)] and ATM [del(11q22)] determined loss of those genes (regions).

Response Assessment: Median age was 61 years (range, 38–84), with 21 pts ≥ 70 years of age. Median number of prior therapies was 5 (range, 1–14); 87 pts had failed fludarabine therapy. Pts had bulky Rai stage I/II (n=18), III (19) or IV (n=52) disease. Pts received a median of 3 cycles (range, 0.25–6), 11 pts completed all 6 cycles, and 2 continue to receive therapy. All 89 pts were evaluated for response, including 6 pts who received only one dose due to grade 4–5 tumor lysis or other complications. Forty-one pts responded (46%) by NCI Working Group response criteria; 39 pts achieved a partial response (PR, 44%), and 2 pts with trisomy 12 achieved a complete response (CR, 2%). Fourteen of 29 pts with del(17p13) responded (48%), 22 of 37 pts with del(11q22) responded (59%), and 20 of 47 pts with a complex karyotype responded (43%). Thirty-three of 70 pts with bulky adenopathy >5 cm responded (47%). Progression free survival data will be updated at ASH.

Conclusions: Flavopiridol demonstrates significant clinical activity as a single agent in heavily pretreated, relapsed CLL pts with bulky adenopathy and poor-risk cytogenetic features such as del(17p13), del(11q22) and complex karytoypes. Further studies of this drug in CLL and other hematologic malignancies are ongoing.