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BioOncology Watch Timely Information for Practicing
Physicians |
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january 2002 Highlights of the 43rd
annual meeting of the American Society of hematology December 7-11, 2001 Follicular
Non-Hodgkin's Lymphoma (NHL) CHOP followed by anti-CD20
monoclonal antibody therapy. Two multicenter phase II Southwest Oncology Group (SWOG)
studies have been conducted in which newly diagnosed patients with follicular
NHL, who had achieved at least a partial response to 6 cycles of standard-dose
CHOP chemotherapy (cyclophosphamide, doxorubicin, vincristine, and
prednisone), were administered additional treatments with anti-CD20
monoclonal antibodies. David Maloney
et al followed CHOP treatments with 4 weekly doses (375 mg/m2/week)
of rituximab (a monoclonal antibody directed against CD20). Of 73 patients evaluable for toxicity, 1
patient had grade 4 neutropenia and 12 patients developed grade 3
toxicities. Sixteen (19%) of 84
evaluable patients had an improvement in tumor response following treatment
with rituximab. The overall response
rate was 72% (including 54% confirmed or unconfirmed CRs). Oliver Press et al
gave 35 mg of tositumomab (Bexxar®) labeled with 48 to 115 mCi of
I131 (based on the clearance rate of a dosimetric dose infusion) as
anti-CD20 therapy. In 60 patients
evaluable for safety there were no treatment-related deaths and 8 patients
had 10 grade 4 toxicities (neutropenia [4], leukopenia [2], thrombocytopenia
[2], anaphylactoid reaction [1], chest/back pain [1]). Of 71 patients evaluable for efficacy, 17
(24%) experienced an improvement in tumor response with the addition of I131
tositumomab. Overall, 51 patients
(80%) achieved a remission, including 37 patients (52%) with a confirmed or
unconfirmed complete remission (CR).
These preliminary data demonstrate that monoclonal antibody treatments
following CHOP chemotherapy are feasible in previously untreated patients
with follicular NHL. This treatment approach is currently the subject of a
large-scale randomized phase III SWOG study in newly diagnosed follicular NHL
patients (CHOP plus I131 tositumomab vs CHOP plus rituximab vs
CHOP alone). (Abstracts 3504 and
3502) Pharmacogenomic study of
rituximab-treated follicular NHL patients. Rituximab is an IgG1 anti-CD20 antibody
and in vitro studies have suggested that effector cells (NK cells and
macrophages) that express the IgG Fc receptor (FcgRIIIa+)
play an important role in activating the antitumor effects of rituximab. The FcgRIIIa receptor is encoded by the FCGR3A gene, which
has a functional dimorphism with either phenylalanine (F) or valine (V) at
the amino acid 158 position. In
addition, V confers a higher affinity for IgG1 and an increased ADCC. Guillaume Cartron and colleagues
determined the FCGR3A genotype (by nested PCR followed by
allele-specific restriction enzyme digestion) in 49 newly diagnosed patients
with follicular NHL who were treated with rituximab. Twenty percent of patients were homozygous
for FCGR3A-158V, 35% were homozygous for FCGR3A-158F, and
45% were heterozygous for FCGR3A-158F. The objective response rates at 2 months
and 1 year following rituximab treatment were 100% and 90% in
FCGR3A-158V homozygous patients compared to 67% and 51% for
FCGR3A-158F carriers (P=0.03).
In addition, molecular responses at 1 year were attained in 5 of 6
patients homozygous for FCGR3A-158V compared to 5 of 16
FCGR3A-158F carriers (P=0.04).
These data indicate that FCGR3A genotype is predictive
for the achievement of clinical and molecular responses to rituximab in
follicular NHL patients. (Abstract
2523) Tolerability of salvage
treatments after radioimmunotherapy. Mark Kaminski and coworkers reviewed the salvage therapies for
28 patients with follicular NHL who had received I131 tositumomab
as front-line treatment. The salvage
therapies were as follows: 17 patients received ³1
chemotherapy regimen (including 4 patients who underwent stem cell
transplants); 12 patients received rituximab (with or without chemotherapy);
8 patients were given localized irradiation; and 1 patient was retreated with
tositumomab. The median number of
salvage regimens was 2.5 (range, 1 to 7).
No patient had salvage therapy discontinued for cytopenias due to a
hypocellular marrow. Stem cell
mobilization and marrow engraftment were accomplished without
difficulty. No cases of
myelodysplasia or acute myeloid leukemia have been observed. Furthermore, Stephen Ansell and associates
also report that salvage therapy after Y90 ibritumomab tiuxetan
(Zevalin) administration to previously treated patients with follicular NHL
was tolerated with acceptable toxicity.
They retrospectively reviewed 34 patients who received a median of 3
regimens post-Zevalin treatment. Only
1 patient required a dose reduction at the start of salvage chemotherapy due
to cytopenia and 1 patient died of infectious complications after the
administration of a third post-Zevalin chemotherapy regimen. Thirteen patients were given growth factor
support and 10 patients were hospitalized for cytopenias. These results show that
post-radioimmunotherapy salvage chemotherapy is feasible. (Abstracts 2526 and 2533) Mantle
Cell Lymphoma (MCL) Rituximab-hyperCVAD therapy. In a single-center phase II (single-arm)
trial, Jorge Romaguera and colleagues treated newly diagnosed MCL patients
with a modified hyperCVAD regimen (CVAD plus methotrexate and cytosine
arabinoside) in which rituximab 375 mg/m2 was given on day 1 of
each cycle. Stem cell transplantation
was also eliminated for patients who achieved a CR within 6 cycles of
treatment. With a median follow-up of
14 months, the authors reported a CR rate of 89% (50 of 75 patients) and
2-year failure-free and overall survival rates of 72% and 90%, respectively. Patients over the age of 65 years
responded well to this therapy with a CR rate of 90%, a 2-year failure-free
survival rate of 60%, and a 2-year overall survival rate of 96%. Sixty percent of patients had grade 4
hematologic toxicities and grade 3 infections occurred in 14% of patients.
These results compare favorably with those previously achieved with CHOP-like
regimens and hyperCVAD supported with stem cell transplantation, especially
in patients over 65 years of age.
(Abstract 3030) Diffuse Large B-Cell Lymphoma (DLCL) Rituximab plus CHOP. Bertrand Coiffier and colleagues provided
an update of the GELA study (GELA LNH 98-5 Study) in which 399 elderly
patients with DLCL were randomized to receive either 8 cycles of standard
CHOP every 3 weeks or 8 cycles of rituximab (375 mg/m2 on day 1 of
each 3-week cycle) plus CHOP (R-CHOP).
The median time of follow-up was 18 months. The benefit of the addition of rituximab to CHOP was
illustrated by findings that patients in the R-CHOP group, compared to those
treated with CHOP alone, had a greater CR rate (77% vs 64%; P=0.007),
a longer 18-month disease-free survival rate (76% vs 64%; P=0.0195),
and a longer 18-month overall survival rate (73% vs 61%; P=0.0065). These data demonstrate that the addition
of rituximab enhances the effectiveness of CHOP therapy for elderly DLCL
patients. Additional data were presented during the meeting and previously
observed 18-month treatment differences persisted with a median follow-up of
2 years. The authors also assessed
the cost-effectiveness of R-CHOP versus CHOP from a French health system
perspective. In a 10-year model, the
estimated cost per year of life gained was 22,150 [euros] while the total
added cost per patient was 15,190 [euros] (a ratio that is generally considered
to be favorable by health authorities).
Thus, this study indicated that the cost-effectiveness of R-CHOP is
favorable. (Abstracts 3025 and 3586) CHEMOTHERAPY PLUS
RITUXIMAB
Non-Hodgkin’s lymphoma. Several phase II studies of rituximab combined
with other chemotherapy regimens as treatment for patients with NHL have been
conducted. Wyndham Wilson and
associates reported preliminary results that indicate that the addition of
rituximab to dose-adjusted (DA)-EPOCH may overcome bcl-2 associated
chemotherapy resistance. For 23
patients with previously untreated DLCL given rituximab plus DA-EPOCH, no
patients had progressed after achieving a CR with a median follow-up of 9
months, and bcl-2-positive tumors were not associated with a shorter progression-free
survival. Patient enrollment and
follow-up are ongoing. Myron Czuczman
and coworkers combined rituximab with fludarabine to treat patients with
low-grade lymphoma (n=40). A 90%
response rate (36 of 40 patients) was achieved and the median duration of
response had not been reached at 15+ months (range, 4+ to 36+ months). Rituximab plus the MINE regimen
(mitoxantrone, ifosfamide, etoposide) was administered to 30 NHL patients by
C. Emmanoullides et al as salvage therapy and to mobilize stem cells. Adequate numbers of stem cells were
collected and molecular analyses for major bcl-2 translocation or clonal
immunoglobulin gene rearrangement was negative in 10 patients and positive in
only 5 patients. No unusual
transplant complications occurred and of 20 patients who received autologous
stem cell transplants, only 4 patients had developed disease progression with
a median follow-up of 15 months.
Finally, a regimen of Taxol, topotecan, and rituximab was utilized by
Anas Younes and coworkers to treat relapsed aggressive B-cell NHL
(n=45). The response rate achieved
with this combination therapy (55% in primary refractory patients and 80% in
non-primary refractory patients) compares favorably with previous studies of
Taxol and topotecan. These studies
suggest that the addition of rituximab to standard chemotherapy regimens
improves response rates for NHL patients and is generally well
tolerated. Further follow-up is
needed and additional studies are warranted.
(Abstracts 1447, 2518, 3077, and 1456) Cutaneous
T-Cell Lymphoma (CTCL) Treatment with Campath-1H. Campath-1H is a humanized anti-CD52
monoclonal antibody that binds to malignant B- and T-cells. H. Hagberg and associates performed a
phase II study that evaluated Campath-1H (alemtuzumab) as therapy for CTCL
including mycosis fungoides and Sézary syndrome. They reported the results for 17 evaluable patients. The median number of previous antitumor
regimens for these patients was 3 (range, 1 to 5). The response rate to Campath-1H was 71% (41% CR rate) and the
median time to treatment failure had not been reached (range, 3+ to 18+
months). Pruritic symptoms were
alleviated in all but 1 responding patient.
Grade 4 neutropenia occurred in 4 (24%) patients, cytomegalovirus
reactivation developed in another 4 (24%) patients, and 1 patient had a
generalized herpes simplex infection.
In a second report, Theodora Foukaneli et al provided data concerning
3 previously treated patients with Sézary syndrome who were treated with
Campath-1H. A response was achieved
in all 3 patients (2 CRs) and treatment was tolerated well without
significant toxicity. These reports
suggest that Campath-1H is active against CTCL and further studies are
warranted. (Abstracts 3352 and 556) |
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