Abstract
Background: Treatment options for relapsed CLL patients (pts) with high-risk genetic features, such as del(17p13) or a complex karyotype, are limited. Flavopiridol induces p53-independent apoptosis in CLL cells in vitro, but increased drug binding to human plasma proteins resulted in lack of clinical activity using 24–72-hr continuous IV infusion (CIVI) schedules. Pharmacokinetic (PK) modeling indicated that administering flavopiridol by IV bolus (IVB) followed by 4-hr CIVI would achieve the necessary concentration to induce apoptosis of CLL cells.
Study Design and Treatment: We conducted a phase I study of this PK-derived dosing schedule in relapsed CLL. Pts received flavopiridol by 30-min IVB followed by 4-hr CIVI weekly for 4 doses, every 6 weeks for up to 6 cycles. Fifty-eight pts (43 male) with relapsed CLL (n=48) or small lympocytic lymphoma (n=10) were enrolled. Median age was 60 years (range, 38–84). Median number of prior therapies was 4 (range, 1–14); 57 pts had received prior fludarabine, with 48 pts refractory to or intolerant of fludarabine. Pts had bulky Rai stage I/II (n=13) or III/IV (n=45) disease. In the initial 2 cohorts, pts received 30 mg/m2 IVB + 30 mg/m2 CIVI (n=20) or 40 mg/m2 IVB + 40 mg/m2 CIVI (n=3). Dose limiting toxicity was acute tumor lysis syndrome (TLS) in 2 pts in cohort 2. Thirty-five pts were enrolled in cohorts 3 and 4, in which flavopiridol was dose escalated to 30 mg/m2 IVB + 50 mg/m2 CIVI beginning with cycle 2 (n=14) or dose 2 of cycle 1 (n=14) if severe TLS was not observed. Seven pts experienced severe TLS and did not undergo dose escalation.
Response Assessment: Fifty-two of 58 pts were evaluable for response. Six pts who received only one dose of study drug due to grade 4–5 acute TLS and other complications were not evaluable for response. Twenty-six pts achieved a partial response (PR; 50%) by NCI Working Group response criteria. Median progression free survival (PFS) of all responders is 11 months (range, 5–29), and 10 pts remain in remission. Twenty-one of 39 evaluable pts with bulky adenopathy > 5 cm attained PR (54%). Thirteen of 27 evaluable pts with a complex karyotype achieved PR (48%); median PFS is 10 months (range, 5–16), and 4 pts remain in remission. Nine of 19 evaluable pts with del(17p13), corresponding to loss of the p53 tumor suppressor gene, attained PR (47%); median PFS is 10 months (range, 8–16), and 5 pts remain in remission. Seventeen of 21 evaluable pts with del(11q22), resulting in loss of the ATM tumor suppressor gene, achieved PR (81%); median PFS is 11 months (range, 8–15 months), and 6 pts remain in remission.
Conclusions: Flavopiridol is highly active in heavily pretreated, relapsed CLL pts with bulky adenopathy and poor-risk cytogenetic features such as a complex karyotype or del(17p13). Flavopiridol appears to be particularly active in pts with del(11q22), corresponding to loss of the ATM tumor suppressor gene. The mechanism of action of flavopiridol is under active investigation.
Response by Cytogenetic Abnormality Outcome All patients (n=58) Complex karyotype (n=29) Deletion of 17p13 (n=20) Deletion of 11q22 (n=22) Partial response 26 13 9 17 No response 26 14 10 4 Not evaluable 6 2 1 1 Median PFS 11 months 10 months 10 months 11 months
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