Preliminary Results of a Phase II Study of Flavopiridol (Alvocidib) in Relapsed Chronic Lymphocytic Leukemia (CLL): Confirmation of Clinical Activity in High-Risk Patients and Achievement of Complete Responses (CR).

Background: Relapsed CLL patients (pts) with del(17p13) and other high-risk genetic features respond poorly to most standard therapies. Flavopiridol (alvocidib) induces p53-independent apoptosis of CLL cells in vitro. We previously conducted a phase I study of flavopiridol using a pharmacokinetically (PK) derived dosing schedule of 30-min IV bolus (IVB) followed by 4-hr continuous IV infusion (CIVI). Clinical activity (response rate 45%) was seen in high-risk pts, but several pts required hemodialysis for severe tumor lysis syndrome (TLS) and hyperkalemia.

Study Design and Treatment: We report preliminary results of an ongoing phase II study of flavopiridol in relapsed CLL. Pts with symptomatic, relapsed CLL who have failed (or could not receive) fludarabine and have WBC < 200 × 10⁹/L are eligible. Pts receive flavopiridol by 30-min IVB followed by 4-hr CIVI weekly for 4 doses, every 6 weeks for up to 6 cycles. Pts receive 30 mg/m² IVB + 30 mg/m² CIVI for dose 1, and pts receive 30 mg/m² IVB + 50 mg/m² CIVI with the second and all subsequent doses if severe TLS is not observed.

Results: We report results of the first 31 pts (19 male). Median age was 65 years (range, 41–82), with 9 pts ≥ 70 years of age. Median number of prior therapies was 6 (range, 1–11), and 30 pts had failed fludarabine. Pts had bulky Rai stage I/II (n=5), III (n=5) or IV (n=21) disease, and 27 pts had bulky lymphadenopathy ≥ 5 cm. Therapy was well tolerated. No patients required hemodialysis, and toxicity was otherwise similar to the phase I study. Cytokine release syndrome related to interleukin (IL)-6 was observed in a majority of pts, and symptoms responded to dexamethasone. Pts received a median of 3 cycles (range, 0.25–6). Two pts completed all 6 cycles, and 2 pts continue to receive therapy. The most common reasons for early discontinuation of therapy were failure to respond (n=11) and patient choice (n=6). Fifteen of 31 pts responded (48%) by NCI Working Group criteria; 13 pts achieved a partial response (PR), and 2 pts attained CR. One CR pt achieved a flow negative bone marrow (BM), and the other CR pt had < 1% residual CLL in BM by flow cytometry. Five of 9 pts with del(17p13) responded (56%), 5 of 15 pts with del(11q22) responded (33%), and 7 of 18 pts with a complex karyotype responded (39%). Follow-up remains short, but progression-free survival will be updated.

Conclusions: This study confirms the significant clinical activity of flavopiridol in heavily pretreated, relapsed CLL pts with bulky adenopathy and poor-risk cytogenetic features. Furthermore, 2 pts achieved CR, including 1 pt with flow-negative BM. Limiting eligibility to WBC < 200 × 10⁹/L improved safety, and no pts required dialysis. However, cytokine release syndrome related to IL-6 was common and caused pts to elect to end therapy. Therefore, this study has been amended to give prophylactic dexamethasone, and the schedule has been shortened with the use of prophylactic pegfilgrastim, in order to improve tolerability. Accrual to the amended study is ongoing.