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Targeted Therapies Formerly BioOncology Watch www.tgt-therapies.com |
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NOVEMBER
2004 CHRONIC MYELOID
LEUKEMIA (CML) Major molecular
responses. Tim
Hughes and colleagues of the International Randomized Study of Interferon
versus STI571 (IRIS) Study Group utilized real-time quantitative PCR to
measure the level of BCR-ABL transcripts in the blood of patients when they
first attained a complete cytogenetic remission and
at subsequent times to assess patterns of response and determine the
prognostic value of a molecular response.
In the IRIS trial, 1106 patients with CML in chronic phase were
randomized to receive imatinib or interferon alfa plus cytarabine. The study design and treatment plan have
been reported previously (N Engl J Med 2003;348:994-1004). After 12 months of treatment, 68% of
patients in the imatinib group and 7% of patients
in the interferon plus cytarabine group had
achieved complete cytogenetic remission. Among these patients with complete cytogenetic remissions, levels of BCR-ABL transcripts had
decreased by ³ 3 logs in 57% of imatinib-treated
patients compared to 24% of interferon plus cytarabine-treated
patients (p <0.003). The
probability of remaining progression-free at 24 months was 100%, 95%, and 85%
(p<0.001) for patients who at 12 months had the following responses to
therapy: 1) complete cytogenetic remission and a
reduction of BCR-ABL transcript levels of ³ 3 logs; 2)
complete cytogenetic remission and a reduction of
BCR-ABL transcript levels of <3 logs; and 3) less than a complete cytogenetic remission, respectively. An estimated 39% of patients treated with imatinib compared to only 2% of patients treated with
interferon plus cytarabine had a reduction in
BCR-ABL transcript levels of ³ 3 logs (p
<0.001). The results of this study
show that patients who had a reduction in the level of blood BCR-ABL
transcripts of ³ 3 logs had a negligible risk of
disease progression over the following 12 months. The authors propose that a reduction of ³
3 logs in BCR-ABL transcript blood levels be used to define a major molecular
response in CML. (Hughes TP, et al. N Engl J Med
2003;349:1423-1432) NON-HODGKIN'S
LYMPHOMA
Rituximab
treatment of MALT lymphomas. Mucosa-associated
lymphoid tissue (MALT) lymphomas are associated with an indolent clinical
course, but have short progression-free survival times. Although eradication of Helicobacter
pylori with antibiotics has been shown to effectively treat localized
gastric MALT lymphoma, the therapeutic options for MALT-lymphoma patients who
have no evidence of Helicobacter pylori infection or who have
non-gastric or disseminated disease continue to include chemotherapy,
radiotherapy, and surgery. CD20
antigen is expressed on the surface of malignant cells in virtually all MALT
lymphomas; thus, Annarita Conconi
and the International Extranodal Lymphoma Study
Group conducted a phase II study to evaluate the activity of rituximab (375 mg/m2 weekly for 4 weeks) in 35
patients with previously untreated (n = 11) and treated (n = 24) MALT
lymphomas. Rituximab
treatment resulted in a 73% response rate (15 complete and 10 partial
responses) and rituximab was well tolerated. Previously untreated patients had an 87%
response rate compared to a 45% response rate for previously treated patients
(p = 0.03). The median duration of response
was 10.5 months. The median time to treatment
failure was longer in previously untreated patients (22 vs. 12 months). These results demonstrate that rituximab has activity against CD20+ MALT lymphomas. (Conconi A, et
al. Blood 2003;102:2741-2745) High-dose radioimmunotherapy (HD-RIT) vs. conventional high-dose
therapy (C-HDT). Ajay
Gopal et al. analyzed data obtained from 125
consecutive patients with relapsed follicular lymphoma who had been treated
at the Fred Hutchinson Cancer Research Center with either myeloablative
anti-CD20 HD-RIT (131I- tositumomab)
(n = 27 patients treated in a phase I or a phase II study) or C-HDT supported
by autologous stem cell transplantation (n = 98
patients treated between 1990 and 1998).
Patients treated with HD-RIT had improved progression-free and overall
survival times compared to patients treated with C-HDT. The estimated 5-year overall and
progression-free survival rates for HD-RIT-treated patients were 67% and 48%,
respectively, and 53% and 29% for C-HDT-treated patients, respectively. The 100-day treatment-related mortality
rates were 3.7% and 11% for the HD-RIT and C-HDT groups, respectively and the
estimated probabilities for the development of secondary MDS/AML were similar
between the 2 treatment groups. These
data indicate that HD-RIT is an attractive alternative to C-HDT for the
treatment of patients with relapsed follicular lymphoma. (Gopal AK, et al.
Blood 2003;102:2351-2357) VACCINE THERAPY Strategies to
increase T-cell reactivity. Three
recent studies report vaccine strategies to improve anti-tumor T-cell function. Isabelle Bedrosian
et al randomized 27 patients with stage IV melanoma to receive peptide-pulsed
dendritic cell vaccinations by either intravenous, intranodal, or intradermal
routes of administration. They found
the intranodal route to result in superior T-cell
sensitization. Tanja
Maier et al administered autologous tumor-lysate-pulsed dendritic cell
vaccinations by intranodal injections (median of
9.5 weekly vaccinations) to 10 patients with cutaneous
T-cell lymphoma. Five patients
achieved responses (1 complete response).
The median duration of partial response was 10.5 months and the
complete response was ongoing at 19 months.
Selected patients had massive infiltration of CD8+ and TIA+ cytotoxic T cells at the site of regressing lesions. Igor Astsaturov
and others injected 7 melanoma patients with high-dose interferon-alpha (20
MU/m2 x 20 doses) after the completion of a recombinant viral
vaccination (expressing gp100) protocol.
They found that the interferon treatment recalled gp100-reactive T
cells in patients who had previously responded to vaccination and tumor
regression was observed in 2 patients.
These studies show that cancers can be susceptible to vaccine
strategies that enhance the activity of tumor-reactive T cells. (Bedrosian I, et al. J
Clin Oncol
2003;21:3826-3835; Maier T, et al. Blood
2003;102:2338-2344; and Astsaturov I, et al. Clin Cancer Res
2003;9:4347-4355) |
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