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Targeted Therapies Formerly BioOncology Watch www.tgt-therapies.com |
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JANUARY
2005 HIGHLIGHTS OF THE 46TH ANNUAL MEETING OF THE AMERICAN
SOCIETY OF HEMATOLOGY ( CHRONIC MYELOID
LEUKEMIA (CML) BMS-354825: phase I
study in imatinib-resistant disease.
Charles Sawyer and colleagues reported preliminary results from a
phase I study of BMS-354825, a novel dual SRC/ABL kinase
inhibitor, in MANTLE-CELL LYMPHOMA
(MCL) Rituximab plus HCVAD (R-HCVAD) alternating
with rituximab plus high-dose methotrexate-cytarabine
(R-M/A). Jorge Romaguera and others administered R-HCVAD alternating
every 21 days with R-M/A to patients with previously untreated MCL in a phase
II study. The CR/CRu rate after 6 cycles of
treatment in 97 evaluable patients was 87%. With a
median follow-up of 40 months, the 3-year survival rate was 81%. Grade 4 hematologic toxicity was significant, and 8 deaths were
reported (sepsis [3], transformation to MDS/acute leukemia [3], pulmonary
hemorrhage [1], and unknown [1]).
These findings indicate that this intensive regimen is effective treatment
for patients with previously untreated MCL. Further studies are
warranted. (Abstract 128) CCI-779 for relapsed
MCL. Thomas Witzig et
al. reported a high response rate in patients with relapsed cyclin D1–positive MCL treated with single-agent CCI-779,
a novel inhibitor of the PI3K pathway at the level of mTOR,
in a phase II study. Thirty-five patients received 250 mg of intravenous
CCI-779 weekly. The overall response
rate was 38% among 34 evaluable patients (1 CR and
12 PR). The median time to response
was 1 month (range, 1–8 months), and the median duration of response was 5.7
months (95% CI: 5.2–13.2 months). Grade 3 or 4 toxicities occurred in 32
patients; thrombocytopenia was the most commonly reported grade 3/4 adverse
event. Platelet counts typically recovered within 1 week. Only 4 patients were able to tolerate
sustained weekly doses of 250 mg per week of CCI without dose reduction. The
substantial antitumor activity demonstrated by
CCI-779 in this trial warrants further study.
Lower doses of CCI-779 are currently being evaluated in an NCCTG
trial. (Abstract 129) Phase II study of bortezomib. Andrew Belch and
others performed a phase II trial in which patients with advanced MCL who
received 0–2 prior chemotherapy regimens were treated with the proteasome inhibitor bortezomib
1.3 mg/m2 IV bolus on days 1, 4, 8, and 11 every 3 weeks. An
overall response rate of 33% was observed in 24 evaluable
patients. Among the first 14 patients enrolled, 5 serious adverse events
occurred in patients with pre-existing edema, dyspnea,
or effusions. The eligibility criteria were then amended to exclude such
patients. Bortezomib-related ≥grade 2 adverse
events included sensory neuropathy (12%), neuropathic
pain (12%), myalgia (12%), fatigue (60%), diarrhea
(20%), and nausea (14%). Thus, while bortezomib
exhibits activity against MCL, higher doses appear unfeasible in the MCL
patient population. (Abstract 608) DIFFUSE B-CELL LYMPHOMA Rituximab plus CHOP (R-CHOP). Thomas Miller et al. added 4 infusions of rituximab (375 mg/m2 on days –7, 1, 22, and
43) to 3 cycles of standard CHOP followed by involved-field radiotherapy (RT)
in aggressive diffuse B-cell lymphoma patients with limited disease (stage I
with at least one adverse prognostic factor: age >60 years, elevated serum
LDH, or performance status 2). In 62 evaluable
patients, the 2-year progression-free and overall survival rates were 94% and
95%, respectively. These results
compared favorably with a historical experience in a similar group of
patients evaluated in SWOG study 8736 who were treated with 3 cycles of CHOP
alone followed by involved-field RT. In this historical group, the progression-free
and overall survival rates measured at 2 years were 85% and 93%,
respectively. Short-term toxicity was similar for patients receiving R-CHOP
or CHOP alone. These encouraging results merit further study of the addition
of rituximab to standard CHOP treatments. (Abstract 158) FOLLICULAR LYMPHOMA Natural history
changed by new therapies. Until recently, the natural
history of follicular lymphoma had not changed over 30 years. Richard Fisher
and associates analyzed data from recent studies investigating new treatment
options. Their analysis showed that a treatment approach utilizing CHOP
followed by monoclonal antibody therapy (specifically, rituximab
or I131-tositumomab), as compared with ProMACE and
CHOP alone chemotherapeutic regimens, has resulted in increases in 4-year
progression-free (61% vs. 48% and 46%, respectively) and overall survival (91%
vs. 79% and 69%) rates. These data indicate that novel sequential therapies
have had a significant impact on the natural history of follicular lymphoma. (Abstract 583) Fc gamma receptor polymorphisms.
Polymorphisms of the Fc gamma receptor (at
position 158 [CD16] and position 131 [CD32]) have been associated with higher
affinity binding of human IgG1, greater in vitro ADCC, and improved outcomes
in follicular lymphoma patients following single-agent rituximab
therapy. In the present investigation, David Maloney and coworkers evaluated
DNA samples from patients with advanced follicular lymphoma (n = 87) treated
in a phase II study (SWOG 9800) with sequential CHOP followed by rituximab therapy. They did not find a correlation
between Fc gamma receptor phenotype and the 2-year
progression-free survival rate. This study demonstrated that the antitumor activity of CHOP followed by rituximab therapy is not dependent on the presence of
high-affinity Fc gamma receptor polymorphisms. (Abstract 589) Minimal residual
disease (MRD) analysis. Jesper
Jurlander et al., from the Nordic Lymphoma Group,
identified 23 patients with follicular lymphoma who had achieved a clinical
CR in a randomized phase II study (Study M39035) with rituximab-based
therapy and who also had tumor markers (t[14;18]
fusion transcript or clonal rearrangement of Ig heavy chain) detectable by standard DNA-based PCR in
the diagnostic bone marrow/blood sample. Blood and marrow samples from these
patients were tested for MRD at 10–16 weeks, 38–40 weeks, and 52 weeks
following treatment. No evidence of MRD was found at any of the 3 time points
in 14 patients. The median duration of clinical CR in these 14 patients was
62 months, compared with 21 months in the 9 patients with detectable MRD at
one or more time points (P <
0.005). Nine of 14 patients remained in complete molecular remission at a
median follow-up of 62 months. These data showed that long-term molecular
remissions are possible in follicular lymphoma patients treated with rituximab-based therapy and that MRD status during the
first year was predictive of clinical outcome. (Abstract 1393) B-CELL LYMPHOMA Preclinical studies
of an anti-CD40 antagonistic antibody. Wen-Kai Weng et al. utilized a
novel anti-CD40 antagonistic monoclonal antibody (CHIR-12.12) to disrupt the
CD40/CD40L interaction. In vitro studies showed that CHIR-12.12 inhibited
proliferation of follicular lymphoma and CLL/SLL cells in a dose-dependent
manner; it was also found to induce effective ADCC of follicular lymphoma
cells in a study using purified NK cells from a healthy donor. Thus,
CHIR-12.12 blocks CD40/CD40L–induced tumor proliferation and mediates
ADCC. Clinical development of this
promising monoclonal antibody is warranted.
(Abstract 3279) Radioimmunotherapy (RIT).
F. Morschhauser et al. treated relapsed or
refractory diffuse large B-cell lymphoma in elderly patients with a single
dose of 90Y-ibritumomab tiuxetan (Zevalin®) in a phase II study. In 103 evaluable patients, the overall response rate was 44%, but
the response rate was 52% in patients previously treated with chemotherapy
alone and 19% in patients who had previously received rituximab
therapy. No unexpected toxicities were encountered. John Leonard et al. retrospectively
analyzed 230 patients from 5 studies to determine the relationship between tositumomab/131I-tositumomab
(Bexxar® regimen) antitumor
activity and the number of prior chemotherapy regimens. At each successive
treatment course, the Bexxar response rate and the duration
of response were consistently greater than after chemotherapy. Although the
response rate decreased with the number of prior therapies, duration of
response remained consistently durable across the range of prior therapies. Andrew
Belch evaluated lymphorad-131 (LR131) in 10 patients with relapsed or
refractory follicular lymphoma. LR131
is made up of B Lymphocyte Stimulator (BLyS)
protein labeled with iodine 131. BLyS protein is a B-cell
maturation factor that binds to immunoglobulin-positive B cells. LR131
targeted sites of disease seen on CT and PET in 10 of 10 patients. Among 8 evaluable patients, 2 CRs, 2 PRs, and 1 SD were achieved. Treatments were tolerated with
mild-to-moderate, reversible toxicity.
(Abstracts 130, 132, and 750) T-CELL LYMPHOMA Novel agents. Bexarotene (a synthetic retinoic acid X
receptor agonist) was administered orally to 37 patients with T-cell lymphoma
for a median of 13 months. Twenty-four patients responded (64.8%), and the
peripheral CD8+ T-cell count returned to within normal range in 26 patients
after a median of 6.5 weeks of treatment. Denileukin
difitox (Ontak®),
a fusion protein comprising IL-2 and the enzymatically
active domain of diphtheria toxin, was given by IV infusion (18 ug/kg once daily for 5 days every 3 weeks) to patients
with relapsed or refractory T-cell lymphoma (patients with cutaneous T-cell lymphoma were excluded). In 7 patients
with CD25+ disease, there were 2 CRs, 3 PRs, and 1 SD. Of 7 patients with CD25– disease, there
were 2 PRs and 4 SDs. Overall response rate was 50%, and
treatment was well tolerated. Additional
patients are being studied. (Abstracts 744 and 2641) BREAST CANCER
(REPORTED FROM THE Combined blockade of erbB receptor network. C.L. Arteaga et al. conducted a phase II study in which
patients with metastatic breast cancer were treated
with trastuzumab 2 mg/kg/week and gefitinib 250–500 mg/day. Eligibility criteria included
0–2 previous chemotherapy regimens for metastatic
breast cancer, LVEF ≥50%, no prior exposure to trastuzumab,
and breast cancers with HER2 overexpression by immunohistochemistry and/or HER2 gene amplification by
FISH. Patients were treated until disease progression. The primary objective
was to demonstrate an increase in progression-free survival. Progression-free
survival increased from 50% to 65% at 6 months for chemotherapy-naive
patients and from 50% to 70% at 3 months for patients previously treated with
chemotherapy. Interim analysis of 36 patients showed that median time to
progression was only 2.9 months and 2.2 months in the chemotherapy-naive
group and the previously treated group, respectively. No ≥grade 3
cardiac toxicities were reported. Time
to progression was shorter than previously reported in patients treated with
single-agent trastuzumab, suggesting an
antagonistic interaction between trastuzumab and gefitinib. The authors concluded that these findings do
not support the further use of trastuzumab-gefitinib
combination therapy, and the study was discontinued. (Abstract 25) |
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