activity of flavopiridol in relapsed, genetically high risk CLL

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Activity of the cyclin-dependent kinase (CDK) inhibitor flavopiridol in

relapsed, genetically high risk chronic lymphocytic leukemia (CLL).

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.