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Targeted Therapies Timely
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ABSTRACT HIGHLIGHTS OF THE 47TH ANNUAL MEETING OF THE AMERICAN SOCIETY
OF HEMATOLOGY NON-HODGKIN'S LYMPHOMA (NHL) Number of rituximab (R)-CHOP-14 cycles for elderly patients.
Pfreundschuh and colleagues conducted a multicenter
study (RICOVER-60 study) in which 1,330 elderly patients (61–80 years of age)
with CD20+ diffuse large B-cell lymphoma (DLBCL; stage I–IV) were randomized
to receive 6 or 8 cycles of CHOP-14 (CHOP given every 2 weeks instead of
every 3 weeks) with or without rituximab (R) (given on study days 1, 15, 29,
43, 57, 71, 85, and 99). The current data reported were from a planned
interim analysis performed on 828 evaluable patients. The primary endpoint
was freedom from treatment failure (FFTF), with events defined as disease
progression or relapse, need for additional therapy, failure to achieve a
complete response, or death. The FFTF rate was highly significantly better
for R-CHOP-14 than for CHOP-14 alone, such that the preplanned
criterion (O'Brien-Fleming boundary) for stopping the study was met. In
addition, after a median follow-up of 26 months, no difference was observed
between 6 or 8 cycles of R-CHOP-14 in the FFTF rate. These results suggest
that 6 cycles of R-CHOP-14 should be a standard initial therapy for elderly
patients with DLBCL. (Abstract 13) Rituximab-containing induction and
maintenance therapies in follicular lymphoma (FL). Hochster
and colleagues randomized 304 patients with stage III–IV FL (n=237) or small
lymphocytic lymphoma who had responded to 6 to 8 cycles of CVP chemotherapy
to receive 2 years’ maintenance R or observation. After a median follow-up of
3 years, progression-free survival (PFS) was longer in the R arm than in the
observation arm. In the subgroup with FL, both PFS and overall survival (OS)
were significantly longer in the R-treated patients than in the observed
patients. ¨ Solal-Celigny and coworkers
updated a phase III study (42 months of follow-up) in which 321 patients with
previously untreated stage Enzastaurin, a protein kinase Cβ (PK-Cβ) inhibitor.
Gene expression profiling has identified PK-Cβ
to be a therapeutic target for DLBCL. These findings led Robertson and
coworkers to investigate the use of enzastaurin, an orally administered
potent inhibitor of PK-Cβ, in a phase II study
of patients with relapsed DLBCL (N=55). The patients were given enzastaurin
500 to 525 mg once daily. Enzastaurin was well tolerated. One patient
achieved a CR, and 8 patients had stable disease. These results suggest that
enzastaurin is active in relapsed DLBCL. Further studies are warranted. (Abstract 934) HGS-ETR1.
HGS-ETR1 (TRM-1, mapatumumab) is a human
monoclonal antibody that is agonistic to the death receptor TRAIL-R1 (D4) and
has demonstrated preclinical evidence of antitumor activity. Younes and colleagues report preliminary data on the use
of HGS-ETR1 in 40 patients with relapsed or refractory NHL. Patients received
3 mg/kg (n=8) or 10 mg/kg (n=32) every 21 days for up to 6 cycles. Three
patients achieved a response (1 CR and 2 PRs), and
12 patients (30%) had stable disease. No patient discontinued treatment
because of adverse events. These early data indicate that HGS-ETR1 is active
in relapsed/refractory NHL, warranting studies in combination with agents active
in lymphoma. (Abstract 489) Anti-CD40 immunotherapy.
SGN-40 (Seattle Genetics, Inc.) is a humanized anti-CD40 antibody that
is currently undergoing phase I testing (Advani et al.)
in patients with NHL. The rationale for evaluating SGN-40 in NHL is that CD40
can regulate apoptosis in transformed cells and is expressed by most B-cell
malignancies. This novel agent is administered intravenously once per week
for 4 weeks. The maximum tolerated dose (MTD) had not been reached, but
preliminary evidence of antitumor activity was noted at the 2 mg/kg dose
level. Several patients have experienced an increase in plasma TNF-alpha and
IL-6 levels following the first infusion (but not after subsequent
infusions). No grade 4 toxicities were reported, although 1 patient developed
grade 3 unilateral conjunctivitis and loss of vision that resolved within 6
weeks. This trial is ongoing.
(Abstract 1504) Phase II study of
thrombospondin-mimetic peptide (ABT-510). ABT-510
(Abbott) is a nonapeptide that mimics the anti-angiogenic activity of
thrombospondin-1. Levine and coworkers are conducting a study in which 67
patients with relapsed or refractory lymphoma have been randomized to receive
ABT-510 at a dose of 10 mg bid or 100 mg bid by subcutaneous injection. Preliminary data were available for 56
patients. In the 100 mg bid group, 3 PRs have been
achieved. No responses have been achieved in the 10 mg bid group; in fact, 15
of 15 patients in this group developed disease progression within 12 months.
Thus, the 10 mg bid arm was discontinued. The most frequent adverse events
have been asthenia (39%), injection site reaction (39%), diarrhea (24%), and
anorexia (20%). Further study of this novel agent is warranted. (Abstract 1493) LEUKEMIA New agents for imatinib-resistant BCR-ABL–expressing leukemias.
Multiple studies of experimental agents aimed at the treatment of
imatinib-resistant BCR-ABL–expressing leukemias were reported. One of these
agents, dasatinib (Bristol-Myers Squibb) is an oral inhibitor of BCR-ABL and
SRC kinases. Current studies of dasatinib include 4 separate trials (the
START studies) investigating its use in patients who have
imatinib-resistant/intolerant chronic-phase chronic myeloid leukemia (CML),
accelerated-phase CML, CML in blast crisis, and CML in lymphoid blast crisis
or Philadelphia chromosome-positive (Ph+) acute
lymphoblastic leukemia (ALL). Preliminary data obtained from the first 28 to
35 patients entered into each of these studies show that major hematologic
responses and cytogenetic responses have been achieved in a substantial
proportion of patients in each study. The most important dasatinib-associated
toxicity has been grade 4 neutropenia and/or thrombocytopenia. Promising data
were also presented on a second new oral agent, AMN107. This aminopyrimidine
ATP-competitive inhibitor of BCR-ABL is 50- to 60-fold more potent than
imatinib against BCR-ABL–expressing cell lines. A phase I study of 119 patients with Ph+ leukemias demonstrated that AMN107 was active in
patients both with and without BCR-ABL mutations. The dose selected for
further study was 400 mg bid; neutropenia and hyperbilirubinemia were
identified as dose-limiting toxicities.
(Abstracts 37, 39, 40, 41, 42) Lenalidomide treatment of relapsed or refractory chronic lymphocytic
leukemia (CLL). Chanan-Khan and
coworkers reported preliminary results from a phase II study evaluating
single-agent lenalidomide (an oral immunomodulatory agent derived from thalidomide)
as therapy for patients with relapsed or refractory CLL. Among 17 evaluable
patients, 11 patients (64.6%) achieved a response (2 CRs
and 9 PRs). Another 5 patients had stable disease.
A total of 29 patients were evaluable for safety. A flare reaction,
manifested by tender swelling of lymph nodes and/or rash, was observed in
almost all patients. Grade 3 or 4 hematologic toxicity occurred in 7
patients, and febrile neutropenia developed in 3 patients. Tumor lysis
syndrome was observed in 2 patients. These findings indicate that
lenalidomide is an active agent for CLL treatment, and further studies are
warranted. (Abstract 447) Phase I/II study of HuMax-CD20 in CLL.
HuMax-CD20 is a human monoclonal antibody that targets a novel epitope
of CD20 on B cells. In a SCID mouse model, HuMax-CD20 has been shown to
inhibit the proliferation of engrafted B-cell tumors more efficiently than
rituximab. Coiffier and colleagues studied 4 weekly
intravenous infusions of HuMax-CD20 in relapsed or refractory CLL patients.
Doses up to 2000 mg have been evaluated, and the MTD has not been reached.
The following 5 HuMax-CD20–related serious adverse events have been reported:
hepatic cytolysis, herpes zoster, neutropenia (2), and death due to
pneumonia. Marked reductions in
CD19+CD5+ cell counts and improvements in lymphadenopathy have been observed.
These data suggest that HuMax-CD20 is a potentially active agent against
relapsed or refractory CLL. (Abstract
448) MULTIPLE MYELOMA Combination lenalidomide plus dexamethasone.
Dimopoulos and colleagues conducted a
double-blind trial in 351 relapsed or refractory multiple myeloma patients
randomized to oral lenalidomide (25 mg QD for 3 weeks every 4 weeks) plus
high-dose dexamethasone or placebo plus high-dose dexamethasone. Response
rates were higher in the combination arm than in the placebo/dexamethasone
arm (58% vs. 22%). With study duration of 18 months, median TTP was 13.3
months in the combination group and 5.1 months in the placebo/dexamethasone
group. TTP differences surpassed the prespecified
O'Brien-Fleming boundary for superiority. Thromboembolic events occurred in
8.5% of lenalidomide/dexamethasone patients vs. 4.5% of control
patients. Grade 3 or 4 neutropenia
occurred in 16.5% of the combination therapy arm and 1.2% of the control arm.
Otherwise, the safety profiles of the 2 treatment groups were similar.
Combination lenalidomide and dexamethasone is effective for
relapsed/refractory multiple myeloma; however, prophylactic antithrombotic
therapy should be considered.
(Abstract 6) BREAST CANCER (reported from the 28th Annual Trastuzumab-based regimens. A total of 3,222
patients with HER2-amplified breast cancer with lymph node involvement or
high-risk lymph node–negative disease were enrolled into the BCIRG 006 study
(Slamon et al) and randomized to receive (1) 3
months of doxorubicin (A) and cyclophosphamide (C) followed by 3 months of
docetaxel (T) (AC-T); (2) 3 months of AC followed by 3 months of T with 1
year of trastuzumab (H) (AC-TH); or (3) 18 weeks of T plus carboplatin with 1
year of H (TCH). The report presented results from the first preplanned interim analysis conducted after 322 events
(relapse, second primary breast cancer, or death) had occurred (median
follow-up, 23 months). Disease-free survival (DFS) was significantly longer
in both of the H-containing regimens than in the AC-T regimen. There was no
difference in DFS between the 2 H-containing regimens. Symptomatic cardiac
events occurred in 1.2%, 2.3%, and 1.2% of patients in the AC-T, AC-TH, and
TCH treatment groups, respectively. LVEF declines of >15% occurred in
0.6%, 2.4%, and 0.4% of patients in the respective treatment groups. These
results confirm the benefit of adding H to effective breast cancer
chemotherapy. The data also demonstrate that fewer cardiac events occur when
H is given without prior A therapy.
Further follow-up is needed to compare the efficacy of TCH with AC-TH.
(Abstract 1) Oral ibandronate reduces markers of bone turnover.
Ibandronate is a bisphosphonate that is available in both intravenous
and oral formulations. Lichinitser et al conducted
a study in 256 breast cancer patients with ≥1 osteolytic lesions who
were randomized to receive 12 weeks of oral ibandronate 50 mg daily or
intravenous zoledronic acid 4 mg every 4 weeks. Comparable reductions in
markers of bone turnover occurred in the 2 treatment groups. Studies that
assess skeletal-related events are needed to determine whether the clinical
benefit of oral ibandronate therapy is comparable to that of intravenous
zoledronic acid therapy. (Abstract 6033) |
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