In:
Blood, American Society of Hematology, Vol. 110, No. 11 ( 2007-11-16), p. 3107-3107
Kurzfassung:
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
Materialart:
Online-Ressource
ISSN:
0006-4971
,
1528-0020
DOI:
10.1182/blood.V110.11.3107.3107
Sprache:
Englisch
Verlag:
American Society of Hematology
Publikationsdatum:
2007
ZDB Id:
1468538-3
ZDB Id:
80069-7
