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BioOncology Watch Timely Information for Practicing
Physicians |
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november 2001 Chronic Myeloid Leukemia (CML) Resistance to STI-571. Durable responses to STI-571 therapy are achieved in patients with
chronic-phase CML, however in patients with blast crisis remissions usually
persist for only 2-6 months. To
characterize the mechanism of resistance to STI-571, Mercedes Gorre and
colleagues assessed BCR-ABL kinase activity in leukemia cells obtained from 9
patients with CML resistant to STI-571 by measuring the phosphotyrosine
content of Crkl, an adaptor protein that is phosphorylated by the BCR-ABL
protein. In all 9 patients, drug
resistance was associated with reactivation of BCR-ABL kinase activity. In 6 patients the development of drug
resistance was associated with a single amino acid substitution (isoleucine
for threonine) in a domain of the Abl kinase that forms a critical hydrogen
bond with STI-571. In the other 3
patients, STI-571 resistance was associated with progressive BCR-ABL gene
amplification. This study shows that
the BCR-ABL kinase remains active in leukemic cells resistant to
STI-571. Six of 9 patients had an
identical mutation associated with drug resistance, which suggests a need to
identify an inhibitor of the mutant BCR-ABL allele. (Gorre ME, et al. Science 2001;293:876-880) Acute Graft-Versus-Host Disease (GVHD) Anti-CD147 therapy. GVHD is
triggered by donor T lymphocytes that recognize recipient tissue as
foreign. Preclinical in vitro
studies have demonstrated that activated T and B lymphocytes are depleted by
a murine monoclonal antibody directed against CD147 (ABX-CBL; Abgenic,
Inc.). These findings led H. Joachim
Deeg and associates to conduct a dose-finding study of ABX-CBL in patients
with steroid-refractory GVHD following allogeneic transplantation
procedures. Among 51 evaluable
patients, 26 (51%) responded (13 complete remissions [CRs] and 13 partial
remissions [PRs]) to treatment with ABX-CBL.
Response rates were higher for those patients who received doses of
ABX-CBL ³
0.1mg/kg (44%) compared to those who received a dose of 0.01 mg/kg
(25%). The 6-month survival rate for
all patients was 44% (26 patients).
The dose-limiting toxicity was identified as myalgias at doses ³ 0.2
mg/kg. Based on these encouraging
results, a prospective study in which patients with acute steroid-refractory
GVHD are randomized to receive ABX-CBL or antithymocyte globulin therapy has
been initiated. (Deeg JH, et al. Blood
2001; 98:2052-2058) Myeloma Therapy with attenuated measles virus. Kah-Whye Peng et al reported that the live
attenuated Edmonton-B vaccine strain of measles virus (MV-Edm) replicates
efficiently in both a panel of 6 myeloma cell lines and in primary myeloma
cells isolated from bone marrow.
MV-Edm infection induced cytopathic effects in myeloma cells while
infected peripheral blood lymphocytes showed minimal changes. MV-Edm was found to inhibit the in vivo
establishment of myeloma cells as xenografts in immunocompromised mice. Moreover, significant antineoplastic
activity against ARH-77 and RPMI 8226 myeloma xenografts was observed
following treatment by direct injection intratumorally or by intravenous
administration of MV-Edm. Further
studies of MV-Edm as anti-myeloma treatment are warranted. (Peng K-W, et al. Blood
2001;98:2002-2007) Myelodysplastic syndrome (MDS) Thalidomide therapy. Thalidomide, an immunomodulatory agent with anticytokine
activities as well as antiangiogenic effects, was administered to patients
with MDS in a trial performed by Azra Raza and colleagues. Thalidomide was initiated at a dose of 100
mg/day orally and was escalated to a dose of 400 mg/day as tolerated. Sixteen patients (19%) showed
hematological improvement and 10 previously red blood cell
transfusion-dependent patients became transfusion independent. Among responders, 9 had refractory anemia
(RA), 5 had refractory anemia with ringed sideroblasts (RARS), and 2 had
refractory anemia with excess blasts (RAEB).
These data should be interpreted cautiously since responses were
limited to a restricted patient population and weak study enrollment and
assessment criteria were utilized. (Raza A, et al. Blood 2001;
98:958-965) Non-hodgkin’s lymphoma Pivotal trial of Iodine I 131 tositumomab. Mark Kaminski et al
evaluated tositumomab and iodine I 131 (Bexxar; Corixa Corp and
GlaxoSmithKline) in patients with chemotherapy-refractory low-grade or
transformed low-grade non-Hodgkin’s lymphoma (NHL) to compare its efficacy to
patients’ last qualifying chemotherapy (LQC) regimens. Sixty patients were treated with a single
course of iodine I 131 tositumomab; previously, they had been treated with at
least two protocol-specified qualifying chemotherapy regimens and had not
responded or progressed within 6 months after their LQC. Patients received a
median of four prior chemotherapy regimens. A partial or complete response
(CR) was observed in 39 patients (65%) after iodine I 131 tositumomab,
compared with 17 patients (28%) after their LQC (P<0.001). The
median duration of response (MDR) was 6.5 months after iodine I 131
tositumomab, compared with 3.4 months after the LQC (P<0.001). Two
patients (3%) had a CR after their LQC, compared with 12 (20%) after iodine I
141 tositumomab (P<0.001). The MDR for CR was 6.1 months after the
LQC and had not been reached with follow-up of more than 47 months after
iodine I 131 tositumomab. One patient was hospitalized for neutropenic fever;
five patients (8%) developed human anti-murine antibodies, and one developed
and elevated TSH level after treatment.
Myelodysplasia was diagnosed in four patients in follow-up. A single
course of iodine I 131 tositumomab was significantly more effective than the
LQC received by pretreated patients and had an acceptable safety profile in
patients with low-grade or transformed low-grade NHL. (Kaminski M, et al. J
Clin Oncol 2001;19:3918-3928) |
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