Flavopiridol (Alvocidib) Induces Durable Responses in Relapsed Chronic Lymphocytic Leukemia (CLL) Patients with High-Risk Cytogenetic Abnormalities
Authors: Lin Thomas S. , Heerema Nyla A. , Lozanski Gerard , Fischer Beth , Blum Kristie A. , Andritsos Leslie A. , Jones Jeffrey A. , Flynn Joseph M. , Moran Mollie E. , Mitchell Sarah , Johnson Amy J. , Phelps Mitch A. , Grever Michael R. , Byrd John C. 
Published: April 2020

Abstract
Background: Relapsed CLL patients (pts) with high-risk cytogenetic features have limited treatment options. Flavopiridol induces p53-independent apoptosis of CLL cells in vitro. We previously demonstrated that a pharmacokinetically (PK) derived dosing schedule administering flavopiridol by 30-min IV bolus (IVB) followed by 4-hr continuous IV infusion (CIVI) achieves the necessary serum concentration to induce apoptosis and is clinically active in pts with relapsed, genetically high-risk CLL.
Study Design and Treatment: We report response and median progression free survival (PFS) results for 117 pts with relapsed CLL (n=107) or small lymphocytic lymphoma (n=10) treated on successive phase 1–2 studies of this PK-derived schedule. Pts received flavopiridol by 30-min IVB followed by 4-hr CIVI weekly for 4 doses every 6 weeks (n=79), or weekly for 3 doses every 4 weeks with pegfilgrastim support (n=38), for up to 6 cycles. Twenty pts received 30 mg/m2 IVB + 30 mg/m2 CIVI, and 3 pts received 40 mg/ m2 IVB + 40 mg/m2 CIVI. The remaining pts received 30 mg/m2 IVB + 30 mg/m2 CIVI for the first 1 or 5 dose(s) followed by dose escalation to 30 mg/m2 IVB + 50 mg/m2 CIVI beginning with dose 2 or dose 6 if severe tumor lysis was not observed.
Pt Characteristics: Eighty pts were male (68%), median age was 60 years (range, 36–84), and 22 pts were age 70 or older (19%). Median number of prior therapies was 4 (range, 1–14); 116 pts had received prior purine analog therapy, and 85 pts (73%) were refractory to (n=82) or intolerant of purine analog (n=3). Ninety-three pts were Rai stage III/IV (79%), and 85 pts had bulky lymph nodes □ 5 cm (73%).
Response Assessment: All 117 pts were evaluated for response by NCI 1996 Working Group criteria. Overall response rate (ORR) was 48%, including 52 partial responses (PR), 3 nodular PR (nPR), and 1 complete response (CR). Seven responders were taken to reduced intensity allogeneic stem cell transplants (SCT) and were censored. Median PFS of the 49 other responders was 10 months. Ten pts remain in remission with a median PFS of 12 months (range, 7–22.5). Six responders relapsed and received repeat flavopiridol therapy; 5 pts responded (4 PR, 1 CR) with a median PFS of 12.5 months. Forty-one of 85 pts (48%) with bulky adenopathy; 23 of 53 pts (43%) with a complex karyotype; 20 of 40 pts (50%) with del(17p13), resulting in loss of p53; and 29 of 49 pts (59%) with del(11q22), resulting in loss of the ATM tumor suppressor gene; responded to therapy. Median PFS was 10–12 months in all cytogenetic groups.
Conclusions: Flavopiridol achieves durable responses in heavily treated, relapsed CLL pts with bulky adenopathy and poor-risk cytogenetic features. Flavopiridol allows pts who are not SCT candidates to achieve sufficient reduction of their disease to undergo reduced intensity allogeneic SCT. Pts who respond to flavopiridol and subsequently relapse may respond to repeat therapy. Based on these promising results, a phase 2 registration study is ongoing.
All Patients Complex del(17p13) del(11q22) N 117 53 40 49 Response rate 48% 43% 50% 59% Median PFS 10.0 months 10.0 months 12.0 months 10.7 months