Safety Profile of Genasense in Advanced CLL

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Pooled safety analysis of oblimersen alone or with fludarabine and

cyclophosphamide in patients with advanced chronic lymphocytic

leukemia.

Meeting: 2006 ASCO Annual Meeting

Abstract No: 6611

Citation: Journal of Clinical Oncology, 2006 ASCO Annual Meeting

Proceedings Part I. Vol 24, No. 18S (June 20 Supplement), 2006: 6611

Author(s): B. Koziner, S. O'brien, T. Boyd, L. Larratt, J. , A.

Chanan-Khan

Abstract: Background: Bcl-2 is an antiapoptotic protein linked to

chemotherapy resistance and poor prognosis in chronic lymphocytic

leukemia (CLL) patients (pts). Oblimersen (Obl), an anti-Bcl-2

oligonucleotide, has been shown to enhance apoptosis induced by

fludarabine (Flu) + cyclophosphamide (Cy) in pts with relapsed CLL.

We combined safety results from 2 CLL clinical trials to determine

the relative effect of Obl on treatment-emergent adverse events

(TEAEs) in Obl+Flu+Cy therapy.

Methods: This analysis included 30 pts who received Obl 3mg/kg/d

alone by continuous IV on days 5-7 and 230 pts who received Flu

25mg/m2/d + Cy 250mg/m2/d on days 5-7, every 28th day, either with

(n=115) or without (n=115) Obl 3mg/kg/d on days 1-7. Mean number of

cycles initiated were 3.3, 3.6, and 4.0 for Obl, Obl+Flu+Cy, and

Flu+Cy, respectively.

Results: The most frequent (>2% patients) grade 4 TEAEs were mainly

hematologic: neutropenia (Obl alone, 0.0%; Flu+Cy, 11.3%; Obl+Flu+Cy

7.0%), thrombocytopenia (3.3%, 1.7%, 4.3%), anemia (0.0%, 5.2%,

3.5%), febrile neutropenia (0.0%, 0.9%, 2.6%), hypotension (0.0%,

0.0%, 2.6%), and leukopenia (0.0%, 2.6%, 0.0%). Thrombocytopenic

events with Obl-Flu-Cy were reversible and were not associated with

clinically significant bleeding events. The most frequent non-

hematologic grade 3-4 TEAEs (>5%) were nausea (0.0%, 1.7%, 7.8%),

vomiting (0.0%, 0.9%, 6.1%), fatigue (3.3%, 4.3%, 6.1%), and dyspnea

(3.3%, 1.7%, 5.2%). Serious TEAEs occurred at a rate of 23.3%, 32.2%,

and 57.4%, respectively. TEAEs resulting in death occurred in 2 pts

(Obl alone), 5 pts (Flu+Cy), and 9 pts (Obl+Flu+Cy). One Obl+Flu+Cy

death was due to cytokine release reaction and one to tumor lysis

syndrome. Discontinuation due to TEAEs occurred in 20.0% of pts who

received Obl alone, in 34.8% of Flu+Cy pts, and in 34.8% of

Obl+Flu+Cy pts.

Conclusions: The addition of Obl to Flu+Cy was well tolerated, with

similar low frequencies of grade 3+4 TEAEs, primarily the same type

observed with Flu+Cy alone. Despite an increased incidence of serious

TEAEs observed with Obl+Flu+Cy, the percentage of patients who

discontinued protocol therapy due to a TEAE was the same in each

group. First cycle reactions mandate close observation when

initiating combination therapy.