Abstract
Background: New therapies for relapsed CLL pts with poor-risk cytogenetic features, such as del(11q22), del(17p13) or a complex karyotype, are needed. Alemtuzumab (Campath-1H) is effective in this pt population but has infectious toxicity and is ineffective as a single agent in bulky nodal disease. Flavopiridol induces p53-independent apoptosis in CLL cells in vitro. We previously demonstrated the activity of flavopiridol in genetically high-risk CLL in a phase I study using a novel, pharmacokinetically (PK) derived dosing schedule, and we are currently pursuing a larger phase II trial of this drug. We present updated results of flavopiridol’s activity in high-risk pts in both studies.
Study Design and Treatment: Pts (n=89) with symptomatic, relapsed CLL who failed (or could not receive) fludarabine received flavopiridol by 30-min IVB followed by 4-hr CIVI weekly for 4 doses, every 6 weeks for up to 6 cycles. Pts received 30 mg/m2 IVB + 30 mg/m2 CIVI (n=20), 40 mg/m2 IVB + 40 mg/m2 CIVI (n=3), 30 mg/m2 IVB + 30 mg/m2 CIVI for the first 4 doses and 30 mg/m2 IVB + 50 mg/m2 CIVI for all subsequent doses (n=14) or 30 mg/m2 IVB + 30 mg/m2 CIVI for the first dose and 30 mg/m2 IVB + 50 mg/m2 CIVI for all subsequent doses (n=44). Eight pts who experienced severe tumor lysis syndrome did not undergo dose escalation as planned. A complex karyotype was defined as ≥ 3 unrelated abnormalities, and FISH for TP53 [del(17p13)] and ATM [del(11q22)] determined loss of those genes (regions).
Response Assessment: Median age was 61 years (range, 38–84), with 21 pts ≥ 70 years of age. Median number of prior therapies was 5 (range, 1–14); 87 pts had failed fludarabine therapy. Pts had bulky Rai stage I/II (n=18), III (19) or IV (n=52) disease. Pts received a median of 3 cycles (range, 0.25–6), 11 pts completed all 6 cycles, and 2 continue to receive therapy. All 89 pts were evaluated for response, including 6 pts who received only one dose due to grade 4–5 tumor lysis or other complications. Forty-one pts responded (46%) by NCI Working Group response criteria; 39 pts achieved a partial response (PR, 44%), and 2 pts with trisomy 12 achieved a complete response (CR, 2%). Fourteen of 29 pts with del(17p13) responded (48%), 22 of 37 pts with del(11q22) responded (59%), and 20 of 47 pts with a complex karyotype responded (43%). Thirty-three of 70 pts with bulky adenopathy >5 cm responded (47%). Progression free survival data will be updated at ASH.
Conclusions: Flavopiridol demonstrates significant clinical activity as a single agent in heavily pretreated, relapsed CLL pts with bulky adenopathy and poor-risk cytogenetic features such as del(17p13), del(11q22) and complex karytoypes. Further studies of this drug in CLL and other hematologic malignancies are ongoing.
. | All Patients . | Loss TP53 . | Loss ATM . | Complex Karyotype . | Bulky nodes > 5 cm . |
---|---|---|---|---|---|
Patients | 89 | 29 | 37 | 47 | 70 |
Partial Response | 39 | 14 | 22 | 20 | 32 |
Complete response | 2 | 0 | 0 | 0 | 1 |
No response | 48 | 15 | 15 | 27 | 37 |
. | All Patients . | Loss TP53 . | Loss ATM . | Complex Karyotype . | Bulky nodes > 5 cm . |
---|---|---|---|---|---|
Patients | 89 | 29 | 37 | 47 | 70 |
Partial Response | 39 | 14 | 22 | 20 | 32 |
Complete response | 2 | 0 | 0 | 0 | 1 |
No response | 48 | 15 | 15 | 27 | 37 |
Author notes
Disclosure:Research Funding: Flavopiridol was provided by the Cancer Therapy Evaluation Program (CTEP) of the National Cancer Institute/National Institutes of Health (NCI/NIH). Funding for this research was provided by the NCI/NIH (5 U01 CA76576-07 to Dr. Grever; 1 R21 CA112947-01 to Dr. Lin), the Leukemia and Lymphoma Society (SCOR grant to Dr. Byrd), and the D. Warren Brown Foundation (to Dr. Byrd). Support was also provided by the CLL Research Consortium (NIH 5 PO1 CA081534 to Dr. Thomas J. Kipps, UCSD). Honoraria Information: Dr. Lin received honoria from sanofi-aventis for presentations at EHA 2006 and EHA 2007.
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