Activity of the cyclin-dependent kinase (CDK) inhibitor flavopiridol in relapsed, genetically high risk chronic lymphocytic leukemia (CLL)

Abstract

7007 Background: The targeted CDK inhibitor flavopiridol induces p53-independent apoptosis in CLL cells. We demonstrated the activity of flavopiridol in relapsed, high risk CLL in a phase I study of a pharmacokinetically derived dosing schedule (Lin et al, Blood 108: 93a, 2006; Byrd et al, Blood 109: 399, 2007). We report a phase II trial to confirm these findings. Methods: Patients (pts) with relapsed CLL with WBC < 200 x 109/L received flavopiridol by 30-min IV bolus (IVB) followed by 4-hr continuous IV infusion (CIVI). Pts received 30 mg/m2 IVB + 30 mg/m2 CIVI for dose 1, with escalation to 30 mg/m2 IVB + 50 mg/m2 CIVI beginning at dose 2. Therapy was given weekly for 4 doses every 6 weeks for up to 6 cycles. The study was amended to change the schedule to 3 doses every 4 weeks to improve tolerance. Results: Sixty-two pts were enrolled. Median age was 61 years (range, 31–82), 40 were male (65%), and 11 were > 70 years. Median number of prior therapies was 4 (range, 1–11). All pts had failed purine analog therapy. Rai stage was I/II (n=14) or III/IV (n=48). Three pts did not undergo dose escalation due to grade 4–5 tumor lysis with dose 1, and 2 pts required dialysis. Cytokine release syndrome (CRS) was common and was associated with IL-6 release, but was averted by use of pre-treatment dexamethasone. Pts received a median of 4 cycles (range, 0.25–6), 15 pts completed all 6 cycles, and 6 continue therapy. Thirty pts responded (48%) by NCI 96 criteria, with 26 partial responses (42%) and 4 complete responses (6.5%) including 1 pt with del(17p13) and a complex karyotype. Responses were seen in 9 of 18 pts (50%) with del(17p13), 11 of 28 pts (39%) with del(11q22), and 10 of 25 pts (40%) with a complex karyotype. Overall, 19 of 44 pts with high-risk cytogenetics (43%) and 21 of 44 pts with lymph nodes > 5 cm responded (48%). Of 26 pre-amendment pts, 2 completed therapy and 10 responded (38%). In contrast, 13 of 36 post-amendment pts completed 6 cycles and 20 responded (56%). Conclusions: The targeted CDK inhibitor flavopiridol has pronounced clinical activity in relapsed CLL pts including pts with bulky adenopathy and poor-risk cytogenetics such as del(17p13). Prophylactic steroids eliminated IL-6 release and CRS, allowed more pts to complete therapy, and resulted in a higher response rate. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration sanofi-aventis sanofi-aventis sanofi-aventis