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BioOncology Watch Timely Information for Practicing
Physicians |
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october 2001 Anti-CD20
Therapy
Chronic idiopathic thrombocytopenic
purpura (ITP). Roberto Stasi and colleagues administered a
course of intravenous rituximab 375 mg/m2 once weekly for 4 weeks
to 25 previously treated patients with chronic ITP (8 patients had failed
splenectomy). The proposed mechanism
of action is that the Fab portion of rituximab binds to CD20 antigen on B
lymphocytes and the Fc domain recruits immune effector functions to mediate
the lysis of B-cell clones responsible for the production of opsonizing
anti-platelet autoantibodies.
Responses were achieved in 13 (52%) patients, 7 of which were sustained
(6 months or longer). Five were
complete responses (platelet count >100,000/ul), 5 were partial responses
(platelet count 50,000 to 100,000/ul), and 3 were minor responses (platelet
count <50,000/ul but without the need for continued treatment). In 2 patients a repeat course of rituximab
induced a second response. These
preliminary findings suggest that rituximab may be an effective alternative
therapy for patients with chronic ITP and further studies are warranted. (Stasi R, et al. Blood 2001;98:952-957)
Mechanism of action.
Previous studies have found no difference in CD20 levels on the tumors
of follicular lymphoma patients, regardless of response to rituximab
treatments. In vitro, rituximab
cytoxicity in follicular lymphoma cells
is observed to be mediated by complement. Thus, Wen-Kai Weng and Ronald Levy investigated the expression
of complement inhibitors CD46, CD55, and CD59 on tumor cells from 29 patients
with follicular lymphoma who had been treated with rituximab (8, 11, and 10
patients had a complete response, partial response, and a minimal or no
response, respectively, to rituximab therapy). However, neither the
expression of CD46, CD55, or CD59 or the susceptibility to in vitro complement-mediated killing
was found to predict clinical outcome after rituximab treatment. Other potential mechanisms, including
antibody-dependent cellular cytoxicity, apoptosis, and CD20-mediated signal
transduction, should be explored to determine their roles in the antitumor
effect of rituximab. These findings differ from an earlier study by Golay et
al that showed that CD55, and to a lesser extent CD59, are important
regulators of complement-mediated rituximab cytotoxicity in follicular
lymphoma. (Weng W-K , Levy R. Blood 2001;98:1352-1357 and Golay J, et
al. Blood 2000;95:3900-3908) Plasma Cell Dyscrasia Treatment with thalidomide. Meletios Dimopoulos and coworkers
administered an oral combination of thalidomide and dexamethasone therapy to
44 heavily pretreated patients with multiple myeloma. A pulse-dexamethasone schedule was
utilized and thalidomide was initiated at a dose of 200 mg daily at bedtime
with dose escalation to 400 mg after 14 days. Twenty-four patients (55%) achieved a partial response with a
median time to response of 1.3 months and the median survival was 12.6
months. The thalidomide/dexamethasone
combination was effective in patients with and without prior resistance to
dexamethasone-based therapy and in patients with and without prior high-dose
chemotherapy. Mild to moderate toxicity
was observed with combination therapy including constipation, somnolence,
tremors, xerostomia, and peripheral neuropathy. Dimopoulos et al also conducted a phase II study in which 5
(25%) of 20 patients with Waldenstrom's macroglobulinemia achieved partial
responses following treatment with single-agent thalidomide at doses up to
600 mg. Median time to progression
was 4 months. These studies demonstrate the potential activity of thalidomide
in patients with plasma cell dyscrasias.
(Dimopoulos MA, et al. Ann Oncol 2001;12:991-995 and Dimopoulos
MA, et al. J Clin Oncol 2001;19:3596-3601) T-Cell
Prolymphocytic Leukemia (T-PLL) High remission rate with CAMPATH-1H.
Claire Dearden et al conducted a trial in which 39 patients with T-PLL
were treated with CAMPATH-1H, an anti-CD52 monoclonal antibody. Thirty-seven patients had received prior
treatments with a variety of agents, but none had achieved a complete
remission. CAMPATH-1H at a dose of 30
mg was given intravenously 3 times weekly and a response rate of 76% with 60%
complete remissions was observed. The
median disease-free duration for complete responders was 7 months (range,
4-45 months). Seven patients
subsequently received high-dose chemotherapy with autologous stem cell
transplantation and 3 remained in complete remission 5, 7, and 15 months
after autograft. The stem cell
harvest was found to be free of contamination with T-PLL cells by dual-color
flow cytometry and polymerase chain reaction. In addition, 4 patients had subsequent allogeneic stem cell
transplants and 3 remained in complete remission up to 24 months after
allograft. These data demonstrate the
effectiveness of CAMPATH-1H against T-PLL and the preliminary results show
that the use of stem cell transplantation as consolidation therapy following
CAMPATH-1H treatment warrants further study.
(Dearden CE, et al. Blood 2001;98:721-1726) Chronic
Myelogenous Leukemia (CML) Polyethylene glycol (PEG)
interferon (IFN)-a. Moshe Talpaz
et al report their phase I experience with PEG IFN-a-2b
(Schering Plough) in 27 patients with CML in whom IFN-a had
failed. Doses of weekly subcutaneous injections of PEG-IFN-a-2b were
started at 0.75 mg/kg and
were escalated up to 9.0 mg/kg. Dose-limiting toxicities were severe
fatigue, neurotoxicity, liver function abnormalities, and
myelosuppression. All 6 patients who
had been intolerant to IFN-a were
able to tolerate PEG-IFN-a-2b and
4 improved their cytogenetic response.
Among 19 patients with active disease, 2 (11%) achieved a complete
cytogenetic response and 7 (37%) had a complete hematologic response. Among 8 patients in complete hematologic
remission, 7 had improved cytogenetic responses. This study demonstrates the ease of administration of PEG-IFN-a-2b and
suggests that it may be associated with improved clinical outcomes for
patients with CML compared to IFN-a. (Talpaz M, et al. Blood 2001; 98:1708-1713) |
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