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BioOncology Watch Timely Information for Practicing
Physicians |
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July 2002 Radioimmunotherapy 90Y ibritumomab tiuxetan vs. rituximab. 90Y ibritumomab tiuxetan (Zevalin®,
IDEC Pharmaceuticals) is made up of ibritumomab, the parent anti-CD20
antibody of rituximab, and tiuxetan, a high-affinity chelation site for the
pure beta emitter 90Y. Thomas Witzig and colleagues conducted a
phase III study in which patients with relapsed or refractory low-grade,
follicular, or transformed CD20+ NHL were randomized to receive either
radioimmunotherapy with 90Y ibritumomab tiuxetan as a
single dose (0.4 mCi/kg) or rituximab 375 mg/m2 IV weekly for 4
doses. Patients in the radioimmunotherapy group were also pretreated with 2
doses of rituximab (250 mg/m2) to improve biodistribution and one
dose of indium-111 ibritumomab tiuxetan for imaging and dosimetry. The
overall response rate for the radioimmunotherapy patients was 80% compared to
56% for the rituximab patients (p=0.002). Also, the complete remission (CR)
rates were 30% and 16% for the radioimmunotherapy and rituximab groups, respectively
(p=0.04). Median durations of response and median times to progression were
similar for the 2 treatment groups. Reversible myelosuppression was the most
common adverse event associated with 90Y ibritumomab tiuxetan treatments.
This trial demonstrated that 90Y ibritumomab tiuxetan is
well tolerated and produces higher remission rates than rituximab alone in
patients with relapsed or refractory low-grade CD20+ NHL. (Witzig TE, et al. J
Clin Oncol 2002; 20:2453-2463) 131I tositumomab treatment of mantle cell lymphoma (MCL). MCL is an aggressive lymphoma associated with short remission durations
following either conventional-dose chemotherapy or high-dose therapy (HDT)
supported by autologous stem cell transplantation (ASCT). Ajay Gopal et al.
treated 16 consecutive patients with relapsed or refractory MCL with an
infusion of 131I tositumomab, a radiolabeled anti-CD20 monoclonal
antibody, followed by HDT (etoposide
and cyclophosphamide) and ASCT. The antibody dose was 1.7 mg/kg and the
amount of 131I was calibrated to deliver 20 to 25 Gy to normal
organs. Among 11 evaluable patients, the complete and overall response rates
were 91% and 100%, respectively. Twelve patients have not developed disease
progression 6 to 57 months after ASCT and the 3-year survival rate is
estimated to be 93%. There were no treatment-related deaths reported. The
addition of 131I tositumomab to HDT may provide durable remissions
for patients with relapsed or refractory MCL. (Gopal AK, et al. Blood
2002;99:3158-3162) Waldenstrom’s Macroglobulinemia
(WM) Rituximab treatment. In a phase II
study, Meletios Dimopoulos and associates investigated the use of rituximab
in the treatment of WM, a hematologic malignancy characterized by CD20+
lymphoplasmacytic cells. Twenty-seven patients were treated with rituximab
375 mg/m2 IV weekly for 4 weeks. Patients who had not developed
disease progression within 3 months after the completion of rituximab therapy
received a second 4-week cycle of study treatment. Partial responses were
achieved in 6 (40%) of 15 previously untreated patients and in 6 (50%) of 12
previously treated patients. With a median follow-up of 15.7 months, the
median time to progression was 16 months and 9 of 12 responding patients
remained progression-free. Approximately 25% of patients experienced mild
infusion-related toxicities. These results show that rituximab therapy is
well tolerated by WM patients and that rituximab is active against WM.
(Dimopoulos MA, et al. J Clin Oncol 2002;20:2327-2333) Chronic Lymphocytic Leukemia (CLL) Campath-1H after fludarabine failure. B-cell CLL is the most common adult leukemia in Western nations.
Although a patient with CLL may have a long clinical course, the median
survival is only 8 months after fludarabine treatment has failed. Michael Keating
and colleagues conducted a multicenter phase II study in which 93 previously
treated (exposed to alkylating agents and failed fludarabine) patients with
B-cell CLL received Campath-1H (alemtuzumab), an anti-CD52 monoclonal
antibody. Thirty-three percent of patients achieved a response (2% CR) and
the median time to progression for responders was 9.5 months. The median
survival time was 16 months (95% CI: 11.8-21.9) overall and 32 months for
responders. Thirty percent of patients became neutropenic and grade 3 or 4
infections were reported in 25 (26.9%) patients. However, only 3 (9.7%)
responders developed grade 3 or 4 infection. This phase II study demonstrated
that Campath-1H has activity in a high-risk group of patients with B-cell CLL
with acceptable toxicity. (Keating MJ, et al. Blood 2002;99:3554-3561) Multiple Myeloma Nuclear factor (NF)-kB blockade. The transcription factor NF-kB has
been found to be important for the survival of activated B cells. In
addition, it is constitutively active in several malignancies. Thus, Nicholas
Mitsiades and colleagues investigated the role of NF-kB activity in multiple myeloma. A specific inhibitor of NF-kB, SN50, was utilized in their experiments. SN50 induced apoptosis in
multiple myeloma cells (cell lines as well as patient myeloma cells) and it
activated caspase-9 and caspase-3. Moreover, the expression of inhibitors of
apoptosis (XIAP, cIAP-1, cIAP-2, and survivin) was down regulated. SN50
pretreatment also sensitized myeloma cells to TNF-a-induced apoptosis and inhibited the expression of intracellular
adhesion molecule-1. These studies indicate that NF-kB activity may be important for the proliferation of malignant myeloma
cells and therefore is a target for novel therapies against multiple myeloma.
(Mitsiades N, et al. Blood 2002;99:4079-4086) Phase I Studies of New Therapies Oncolytic virus. PV701 is an
attenuated strain of Newcastle disease virus, an avian paramyxovirus. This
virus strain has been found to directly lyse human cancer cells in vitro,
to activate T-cell specific antitumor immunity, and to activate tumoricidal
macrophages. In a phase I study of 79 patients with advanced solid tumors, a
100-fold dose intensification was achieved and the maximum-tolerated dose was
identified. Objective responses were also observed and progression-free
survival ranged from 4 to 31 months. Further investigation is warranted.
(Pecora AL, et al. Blood 2002;99:2251-2266) Farnesyl transferase inhibitor. A phase I study (n=28) of R115777, a farnesyl transferase inhibitor,
has recently been completed. Myelosuppression was found to be the
dose-limiting toxicity. However, continuous dosing of R115777 was well
tolerated at a dose of 300 mg bid. Antitumor activity (1 partial response, 1
minimal response, 3 with stable disease) was detected in this refractory
patient population. Further clinical testing is warranted. (Crul M, et al. J
Clin Oncol 2002;20:2726-2735) Cancer vaccine. Keith Knutson
and colleagues administered 6 monthly vaccinations with HER-2/neu-derived
HLA-A2 peptide (p369-377) (500 ug) admixed with GM-CSF (100 ug) to 6 HLA-A2
patients with HER-2/neu-overexpressing malignancies (breast and ovarian
cancers). They found that the vaccination induced HER-2/neu peptide specific
IFN-g-producing CD8+ T cells. However, the responses were short-lived and
were of a small magnitude. CD4+ T-cell activity may be required for lasting
immunity to this epitope. (Knutson KL, et al. Clin Cancer Res
2002;8:1014-1018) |
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