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BioOncology Watch Timely Information for Practicing
Physicians |
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march 2002 Rituximab
Effects on B-cell chronic lymphocytic leukemia (CLL). Rituximab binding to CD20 activates
complement-mediated lysis and antibody-dependent cellular cytotoxicity
(ADCC). It has also been shown that
anti-CD20 antibodies induce apoptosis in B-cell lines cultured under conditions
that preclude the activation of complement or ADCC. To analyze the mechanism of apoptosis induction, Irene Pedersen
et al. cultured freshly isolated B-cells in the presence of rituximab and a
cross-linking F(ab)2 fragment.
Cross-linking of rituximab was found to induce phosphorylation of
three MAP kinases, including p38. It
was also observed that a p38 inhibitor, SB203580, reduced the degree of
rituximab-induced apoptosis. In a
second investigation, John Byrd and associates sampled peripheral blood
leukemia cells from 10 patients with CLL pre- and post-treatment with
rituximab. They observed that
rituximab induced the activation of caspase-9, caspase-3, and poly ADP-ribose
polymerase (PARP) in CLL cells of some patients. These patients had lower blood leukemia cell counts following rituximab
therapy compared to those patients without caspase activation. In addition, a significant down-modulation
of the anti-apoptotic proteins XIAP and Mcl-1 was also noted. These findings suggest that the antitumor
activity of rituximab is, at least in part, due to the induction of apoptosis
through CD20 mediated signaling pathways and caspase activation. (Pedersen IM, et al. Blood
2002;99:1314-1319 and Byrd JC, et al. Blood 2002;99:1038-1043) Treatment of pure red blood cell aplasia (PRCA) in 2 CLL patients. Hassan
Ghazal describes 2 patients with B-cell CLL complicated by PRCA who were
successfully treated with rituximab.
In one patient PRCA was detected at diagnosis and in the other patient
PRCA was noted during fludarabine treatments. In both cases rituximab produced a dramatic response associated
with a rise in reticulocyte counts. A
normalization of blood counts, including hemoglobin levels, developed in a
short period of time. Although PRCA, a known complication in some patients
with CLL, is reportedly caused by a T-cell dysfunction, these rituximab
results indicate that further investigation of a possible role for B-cell
dysfunction is warranted. (Ghazal H. Blood
2002;99:1092-1094) Minimal residual disease (MRD)
after CHOP and rituximab. Allessandro
Rambaldi and colleagues studied MRD following sequential therapy with CHOP
and rituximab in previously untreated patients with follicular lymphoma. At baseline, the presence of
Bcl-2/IgH-positive cells in blood and/or marrow was demonstrated in all
patients by PCR analysis (n = 128).
Patients who achieved a clinical response to CHOP but remained
PCR-positive were eligible to receive intravenous rituximab 375 mg/m2
weekly for 4 weeks (n=77). Serial
molecular studies showed that 74% of patients converted to PCR negativity
following rituximab therapy. Patients
achieving a PCR-negative status had a freedom from recurrence (FFR) rate of
57% (95% CI, 23 to 81%) compared to a FFR rate of 20% (95% CI, 4 to 46%) for
patients who did not become PCR-negative (p<0.001). The estimated 3-year survival rate was 95%
(95% CI, 86 to 98%). This study
confirms that CHOP followed by rituximab treatment can induce complete
molecular remissions in >70% of patients with follicular lymphoma.
(Rambaldi A, et al. Blood 2002;99:856-862) Trastuzumab
First-line therapy for metastatic breast cancer. Vogel et al. conducted a multicenter study
in which 114 previously untreated patients with metastatic breast cancer that
overexpressed HER2 at the 2+ or 3+ level were randomized to receive
single-agent standard-dose trastuzumab (4 mg/kg followed by 2 mg/kg weekly)
or higher-dose trastuzumab (8 mg/kg followed by 4 mg/kg weekly). The overall objective response rate was
26% (95% CI: 18.2 to 34.4%) with 7 complete responses (CR) and 23 partial
responses. No differences in response
rates were observed between the standard-dose and the higher-dose
groups. All responses occurred in
those patients with 3+ HER2 overexpression by immunohistochemistry analyses
and the response rates in evaluable patients with and without HER2 gene
amplification by FISH analysis were 34% (95% CI: 23.9 to 45.7%) and 7% (95%
CI: 0.8 to 22.8%), respectively.
Cardiac dysfunction occurred in 2 patients. Other reported adverse events were chills, asthenia, fever,
pain and nausea. This study shows
that trastuzumab is an active first-line treatment for patients with
metastatic breast cancer. (Vogel CL,
et al. J Clin Oncol 2002;20:719-726) In combination with ZD1839. ZD1839 (Iressa: Astra-Zeneca Pharmaceuticals) is an oral
compound developed to selectively inhibit the tyrosine kinase activity of the
epidermal growth factor receptor (EGFR).
Joan Albanell and colleagues studied skin biopsies with an
immunohistochemical assay that utilized an antibody directed against
phosphorylated EGFR to measure ZD1839 effects on EGFR activation (104
biopsies from 65 cancer patients treated with ZD1839). These investigators observed that ZD1839
profoundly suppressed EGFR phosphorylation in all cells expressing EGFR
(p<0.001), inhibited MAPK activation (p<0.001), and increased apoptosis
(p<0.001) at doses well below the maximum tolerated dose level. A second investigation by Normanno and
coworkers studied the antiproliferative effects of ZD1839 and trastuzumab in
human breast cancer cell lines that express both EGFR and ErbB-2. ZD1839 reduced phosphorylation of both
MAPK and AKT intracellular transducers of growth factor signaling and
trastuzumab produced a reduction of AKT phosphorylation. Combination ZD1839 and trastuzumab therapy
resulted in increased levels of fragmented DNA compared to either agent alone
and were able to synergistically inhibit cell growth. These data suggest that combination
therapy with agents that target EGFR and ErbB-2 may have enhanced antitumor activity
against those breast cancers that express both receptors. (Albanell J, et al. J Clin Oncol
2002; 20:110-124 and Normanno N, et al. Ann Oncol 2002;13:65-72) |
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