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BioOncology Watch Timely Information for Practicing
Physicians |
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may 2001 Non-Hodgkin's Lymphoma
(NHL) Clearing of bcl-2-positive cells with rituximab therapy. The t(14;18) reciprocal translocation (bcl-2
gene rearrangement) is present in up to 80% to 85% of follicular NHLs. The persistence of cells bearing the bcl-2
rearrangement in post-treatment bone marrow (BM) DNA extracts (detected by
polymerase chain reaction [PCR] assays) have documented that standard
chemotherapy regimens are incapable of eradicating minimal residual
disease. M.S. Czuczman et al
retrospectively reviewed the results of 2 trials of rituximab (Rituxan; IDEC
Pharmaceuticals) alone or in combination with CHOP (cyclophosphamide, doxorubicin,
vincristine, prednisone) chemotherapy in patients with follicular or
low-grade NHL to investigate its ability to eliminate bcl-2-positive cells as
measured by PCR analysis. In the
single-agent trial, 12 of 22 patients with repeat BM samples were
bcl-2-negative 3 months post-treatment.
In addition, 36 of 70 patients whose peripheral blood (PB) was
bcl-2-positive at baseline became persistently bcl-2-negative. Patients who achieved a bcl-2-negative
status were found to have a higher clinical response rate than those patients
who remained bcl-2-positive (73% vs 31%; P=0.018). In the rituximab-CHOP trial, 6 of 7
patients PCR-positive for bcl-2 in BM (and all 7 patients bcl-2-positive in
PB) were negative at the end of therapy.
A clinical response rate of 100% was achieved in these patients. These results show that rituximab can
eradicate bcl-2-positive cells from the PB and BM of patients with follicular
or low-grade NHL. Further follow-up
is necessary to determine if clearing cells bearing the bcl-2 translocation
will affect overall survival.
(Czuczman MS, et al. Ann Oncol 2001;12:109-114) Renal Cell Carcinoma (RCC)
Pegylated interferon alfa-2a (PEG-IFN). Robert Motzer and colleagues at Memorial
Sloan-Kettering Cancer Center conducted a phase I study of PEG-IFN (PEGASYS;
Hoffman-La Roche, Inc.) in previously untreated patients with advanced RCC
(n=27). PEG-IFN was administered
weekly by subcutaneous injection.
Dose-limiting toxicities consisting of grade 3 serum ALT elevation and
grade 3 fatigue were experienced at the 540 mg/week dose level. Other adverse events were headache, fever,
myalgias, nausea, and decreased appetite.
The weekly dosing schedule maintained the serum concentration of PEG-IFN
at close to peak levels and steady state was achieved in approximately 5
weeks. Neopterin and 2'-5'
oligoadenylate synthetase, 2 immunologic surrogates, were measured at all
doses. A partial response was
achieved in 5 patients (19%). The
recommended phase II dose for PEG-IFN is 450 mg/week and studies comparing the
efficacy and safety of PEG-IFN to that of IFNa in the treatment of patients
with advanced RCC are warranted. (Motzer RJ, et al. J Clin Oncol 2001;19:1312-1319) B-Lymphoproliferative
Disorder (BLPD) Anti-interleukin-6 (IL-6) treatment. Previous investigations have shown that
IL-6 promotes the growth of EBV-infected B cells and that patients with BLPD
produce high levels of IL-6. Given
the potential role of IL-6 in the pathogenesis of BLPD, Elie Haddad and
coworkers assessed the effectiveness and safety of anti-IL-6 monoclonal
antibody (mAb) therapy (B-E8; Diaclone) in a phase I/II trial of 12
recipients of transplanted organs who had BPLD refractory to the reduction of
immunosuppression. Anti-IL-6 mAb was
administered as a 30-minute intravenous infusion daily for 15 days and was
well tolerated. Five patients
received 0.4 mg/kg/day and 7 patients received 0.8 mg/kg/day. Complete and
partial remissions (CR and PR) were achieved in 5 and 3 patients,
respectively. Only 1 of these 8 patients
has been observed to develop a relapse.
Three patients died while in CR (10, 13, and 36 months after
treatment) due to chronic rejection (2 patients) and BLPD sequelae (1
patient). These data are encouraging
and further studies of anti-IL-6 mAb therapy in patients with BLPD are
warranted. (Haddad E, et al. Blood 2001;97:1590-1597) Tyrosine Kinase InhibitionSTI571 early clinical trials. STI571 (Novartis Pharmaceuticals) is a small molecule that inhibits
the enzymatic activity of several tyrosine kinases, including ABL, BCR-ABL
(the product of the Philadelphia [Ph] chromosome), platelet-derived growth
factor receptor, and the product of the
c-kit gene. Two reports by Brian Druker and colleagues documented the
activity of this novel agent in Ph-positive leukemias. The first report was of a phase I,
dose-escalation study of oral STI571 treatment in patients with
interferon-alfa-resistant chronic myeloid leukemia (CML) in chronic phase
(n=83). Doses ranged from 25 to 1000
mg/day, however, a maximum tolerated dose was not identified as treatments
were well tolerated at all doses tested.
Complete hematologic responses occurred in 53 of 54 patients treated
with ³300 mg/day
of STI571. Cytogenetic responses developed in 29 (31%) of these patients.
Complete cytogenetic remissions were achieved in 7 patients and 17 patients
had major cytogenetic responses. A
second dose-escalating pilot study was conducted in 58 patients with CML in
myeloid blast crisis (n=38) or Ph-positive acute lymphoblastic leukemia
(ALL)/CML in lymphoid blast crisis (n=20).
Daily oral doses of STI571 ranged from 300 to 1000 mg. Hematologic responses occurred in 55% (21
of 38) of patients with myeloid blast crisis (4 CRs) and 70% (14 of 20) of
patients with ALL/lymphoid blast crisis (4 CRs). Seven patients with myeloid blast crisis remain in remission
from 101 to 349 days after starting treatment while all but 1 of the
ALL/lymphoid blast crisis patients have relapsed. In addition, Heikki Joensuu et al report a favorable and
durable response to STI571 therapy in a patient with gastrointestinal stromal
tumor, a chemoresistant tumor that expresses a growth factor receptor with
tyrosine kinase activity (c-kit). These extremely encouraging data
demonstrate that the inhibition of abnormal tyrosine kinase activity that is
critical to the pathogenesis of disease is an effective therapeutic
intervention. (Druker BJ, et al. N
Engl J Med 2001;344:1031-1037; Druker BJ, et al. N Engl J Med
2001;344:1038-1042; Joensuu H, et al. N Engl J Med 2001;344:1052-1056) Multiple Myeloma (MM) Idiotype (Id)-specific cytotoxic T lymphocytes (CTLs). The
monoclonal immunoglobulin secreted by myeloma plasma cells carries Id-specific
antigenic determinants. Yue-Jin Wen
and associates used dendritic cells as antigen-presenting cells and myeloma
cells obtained from patients with MM to generate autologous Id-specific CTL
lines containing both CD4+ and CD8+ T cells.
The CTLs were found to lyse autologous primary myeloma cells. The cytotoxicity was major
histocompatibility complex (MHC) I and II restricted which indicated that
myeloma cells can process and present Id peptides in the context of their
surface MHC molecules. Concanamycin A experiments showed that cytotoxicity
occurred through the perforin-mediated pathway. This investigation is the first study to demonstrate that
Id-specific CTLs are able to lyse autologous myeloma cells, indicating that
Id-based immunotherapy may have a role in the treatment of MM. (Wen Y-J,
Barlogie B, Yi Q. Blood 2001;97:1750-1755) |
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