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JULY 2005
Hematologic Malignancies
Chronic
lymphocytic leukemia (CLL): eradication of minimal residual disease (MRD)
with alemtuzumab. Paul Moreton and colleagues report results from 91 patients
with relapsed or refractory CLL who received alemtuzumab in multicenter
clinical trials from July
1996 to May 2003. Dosage was 30 mg three times per week, until maximum
response. MRD in blood and bone marrow was assessed by 4-color flow
cytometry. Overall, 55% of patients achieved a response: 36% complete response
(CR) and 19% partial response (PR). CLL was not detectable in the blood and
bone marrow of 18 (20%) patients.
Median treatment-free survival was longer in these MRD-negative
patients (median not reached), as compared with patients with MRD-positive CR
(20 months), PR (13 months), and no response (6 months) (P<0.0001). Median overall survival was also longer in
MRD-negative CR patients (median not reached) than in patients with
MRD-positive CR (60 months), PR (70 months), and no response (15 months) (P=0.0007). This analysis demonstrated
that the achievement of MRD-negative CR in alemtuzumab-treated patients with
relapsed or refractory CLL leads to improved clinical outcomes and that MRD-negative remissions should be a goal for future
CLL therapies. (Moreton
P, et al. J Clin
Oncol. 2005;23:2971–2979)
Bortezomib
plus doxorubicin: Phase I combination study. Preclinical data indicating
that proteasome inhibitors enhance the antitumor activity of anthracyclines
led Robert Orlowski and coworkers to perform a phase I dose-finding study of
the proteasome inhibitor bortezomib and pegylated liposomal doxorubicin (PegLD) in 42 patients with advanced hematologic
malignancies. Dose-limiting toxicities included thrombocytopenia, febrile
neutropenia, neuropathy, diarrhea, and pneumonia. The resulting recommended doses were
bortezomib 1.3 mg/m2 on days 1, 4, 8, and 11 and PegLD 30 mg/m2 on day 4 every 3 weeks. Activity
against multiple myeloma, T-cell non-Hodgkin's lymphoma (NHL), B-cell NHL,
and acute myeloid leukemia was observed.
Further studies of this combination therapy are warranted. (Orlowski RZ, et al. Blood. 2005;105:3058–3065)
Bendamustine
plus rituximab. Mathias Rummel
and others evaluated the combination of bendamustine 90 mg/m2
intravenously on days 1 and 2 and rituximab 375 mg/m2 on day 1
every 4 weeks in 63 patients with
relapsed or refractory low-grade or mantle cell NHL. Patients received up to
4 cycles of study treatment. Overall, 57 patients (90%) achieved a response
(60% CR rate). The response rate in patients with mantle cell lymphoma was
75% (50% CR). The median progression-free survival was 24 months (range, 5–44+
months); the median overall survival has not been reached. Grade 3 or 4 leuko-cytopenia occurred in 16% of patients. These
results demonstrated that the combination of bendamustine and rituximab is
highly active in patients with relapsed or refractory low-grade and mantle
cell lymphomas. (Rummel MJ, et al. J Clin Oncol. 2005;23:3383–3389)
BREAST
CANCER
Neoadjuvant
trastuzumab. Syed Mohsin and colleagues conducted a study in which 35
patients with previously untreated HER-2–overexpressing breast cancer were
given weekly trastuzumab ´ 3
followed by trastuzumab plus docetaxel for 12 weeks prior
to surgery. No tumors progressed, and 8 patients (23%) achieved a PR within
the first 3 weeks of single-agent
trastuzumab. Core biopsy specimens of the primary tumor showed apoptosis induced
within 1 week of initiating
trastuzumab. Tumors with high baseline
Ki67 were less likely to respond. This study showed that neoadjuvant
trastuzumab induces apoptosis and provides an explanation of its antitumor
activity. (Mohsin
SK, et al. J Clin
Oncol. 2005;23:2460–2468)
Phase II
trial of ZD6474. Kathy
Miller and others performed a phase II study of ZD6474, an inhibitor of both
vascular endothelial growth factor receptor-2 (VEGFR-2) tyrosine kinase and
epidermal growth factor receptor (EGFR) tyrosine kinase, in 46 patients with
previously treated metastatic breast cancer. No objective responses were
observed. The most commonly reported adverse events were mild to moderate
diarrhea and rash. This study showed that ZD6474 monotherapy has limited
activity in patients with previously treated metastatic breast cancer. (Miller KD, et al. Clin Cancer Res. 2005;11:3369–3376)
Colorectal Cancer
Bevacizumab
in combination with fluorouracil and leucovorin (FU/LV). The combination of bevacizumab (Avastin®;
Genentech, Inc.) with FU/LV was evaluated as first-line
therapy for metastatic colorectal cancer. Fairooz Kabbinavar and colleagues found the addition of
bevacizumab to FU/LV to improve overall and progression-free survival (P=0.008 and
P≤0.0001, respectively), as
compared with FU/LV alone. In addition, Herbert Hurwitz and coworkers
concluded that bevacizumab plus FU/LV is tolerated with acceptable toxicity
and is as effective as irinotecan plus FU/LV. In a second analysis by Kabbinavar et al, data from a randomized phase II trial
investigating the treatment of patients with metastatic colorectal cancer who
were not candidates for irinotecan
therapy were evaluated. Response rates and median progression-free survival
were found to be significantly greater in patients receiving bevacizumab plus
FU/LV than in patients receiving FU/LV alone. These studies show that the
addition of bevacizumab to FU/LV improves clinical outcomes in patients with
previously untreated metastatic colorectal cancer. (Kabbinavar FF,
et al. J Clin
Oncol. 2005;23:3706–3712; Hurwitz HI, et al. J Clin Oncol. 2005;23:3502–3508;
Kabbinavar FF, et al. J Clin Oncol. 2005;23:3697–3705)
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