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BioOncology Watch Timely Information for Practicing
Physicians |
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DECEMBER 2000 Non-Hodgkin’s Lymphoma (NHL) Astatine-211 (211At)-labeled rituximab (chimeric anti-CD20
monoclonal antibody). E. Aurlien
and coworkers performed preclinical studies to investigate the ability of 211At-rituximab,
a short-range [PC1]a-particle-emitting
radioimmunoconjugate, to selectively kill NHL cells in vitro with acceptable
bone marrow cell toxicity. Two
B-lymphoma cell lines (RAEL and K422) and normal human hematopoietic
progenitor cells were incubated with 211At-rituximab and plated in
clonogenic assays for survival analyses. Following a 1-hour incubation, the
survival of the normal progenitor cells was found to be significantly greater
than that of the NHL cells with a high tumor cell/normal bone marrow cell
kill ratio (4.1/1.0 log cell kill).
Biodistribution studies of 211At-rituximab in Balb/c mice
showed similar stability to that of 125I-rituximab. This study provides evidence that a-emitting
radioimmunoconjugates have selective anti-tumor activity and indicates that
testing of 211At-rituximab in patients with NHL is warranted. (Aurlien E, et al. Br J Cancer 2000;83:1375-1379) Iodine-131-tositumomab multimodal therapy. Oliver Press and colleagues conducted a phase
I/II trial to estimate the maximum tolerated dose (MTD) of iodine-131 (131
I)-tositumomab (anti-CD20 monoclonal antibody, Coulter Pharmaceuticals Inc.)
that can be combined with etoposide (60 mg/kg) and cyclophosphamide (100
mg/kg) followed by autologous stem-cell transplantation (ASCT) in patients
with relapsed B-cell NHL (n=52). The
delivery of 25 Gy by 131I-tositumomab to critical normal organs
(especially heart and lungs) was found to be the MTD in this conditioning
regimen. Thirty-one patients were
evaluable for response to the conditioning regimen: 24 (77%) had a CR, 3
(10%) had a PR, 2 (6%) had stable disease, and 1 (3%) had progressive
disease. The estimated 2-year overall
survival (OS) and progression-free survival (PFS) for all treated patients
was 83% and 68%, respectively. These
findings compared favorably with those of a non-randomized control group who
received the same doses of etoposide and cyclophosphamide, but employed
external-beam total-body irradiation, rather than targeted 131I-tositumomab
prior to ASCT (OS of 53%, PFS of 36% at 2 years). This study demonstrates the feasibility of administering high
doses of 131I-tositumomab as a component of a conditioning regimen
and suggests that further studies are warranted. (Press OW, et al. Blood 2000;96:2934-2942) Leukemia
Immune gene therapy for chronic lymphocytic leukemia (CLL). William Wierda et al have observed that
activated T cells induce CLL B cells to become effective antigen-presenting
cells and that this effect is mediated by the ligand for CD40 (CD154). In addition, they have found that CLL
cells can be made to express CD154 by transduction with a
replication-defective adenovirus vector (Ad-CD154). Thus, they conducted a phase I study to assess the effects of a
single bolus infusion of autologous Ad-CD154-transduced CLL cells in patients
with B-cell CLL (n=11). Within 1-4
weeks of treatment patients developed an increase (>240%) in absolute
blood T-cell counts as well as a corresponding increase in the number of
leukemia-specific T-cells (demonstrated by ELISPOT assay and mixed lymphocyte
reactions). An increase in the
expression of immune molecules on non-infected, bystander CLL cells was also
observed. These findings were
associated with decreases in leukemia cell counts and lymph node size. The therapy was tolerated well and no
dose-limiting toxicity was identified.
This novel approach utilizing immune gene therapy may result in an
effective treatment for patients with CLL.
(Wierda WG, et al. Blood 2000;96:2917-2924) Inhibition
of Bcr-Abl tyrosine kinase. Clinical trials with STI571 (Novartis Pharmaceuticals), a
specific inhibitor of the Bcr-Abl tyrosine kinase, have shown this agent to
have anti-leukemia activity in all phases of chronic myelogenous leukemia
(CML) and in Philadelphia chromosome-positive acute leukemias. However, resistance to STI571 has
developed in preclinical models and relapses in patients with acute leukemias
have been problematic. In recent
animal model studies, Carbo Gambacorti-Passerini and associates have shown
that a combination of STI571 with erythromycin had greater anti-leukemia
activity than single-agent STI571 due to the ability of erythromycin to
prevent STI571 from being inactivated by a1 acid glycoprotein in plasma. The likely development of resistance to single-agent STI571 has
also led J. Tyler Thiesing et al to study combinations of STI571 with other
anti-leukemic agents. The combination
of interferon-alpha, daunorubicin, or cytosine arabinoside with STI571
demonstrated additive or synergistic anti-leukemia effects in proliferation
assays utilizing Bcr-Abl-expressing cell lines. However, STI571 plus hydroxyurea showed antagonistic
effects. In colony-forming assays of
CML patient samples, all combinations showed increased antiproliferative
effects compared to STI571. These
results suggest that combinations of STI571 with other agents may be more
effective than STI571 alone in the treatment of Bcr-Abl positive leukemias. (Gambacorti-Passerini C, et al. J Natl
Cancer Inst 2000;92:1641 and Thiesing JT et al. Blood 2000;96:
3195-3199) |
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