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BioOncology Watch Timely Information for Practicing
Physicians |
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JANUARY 2004 HIGHLIGHTS
OF THE 45TH ANNUAL MEETING OF THE AMERICAN SOCIETY OF HEMATOLOGY RITUXIMAB WITH
CHEMOTHERAPY AND AS A SINGLE AGENT Rituximab-CHOP
(R-CHOP) in patients with diffuse large B-cell lymphoma (DLBCL). Thomas Habermann et al conducted a phase III study in which 632
patients with previously untreated DLBCL were prospectively randomized to
receive R-CHOP or CHOP induction chemotherapy for 2 cycles. Responding patients (n = 415) were then randomized
a second time to receive either maintenance R or observation. With a median follow-up of 2.7 years, 540
patients were evaluable for induction therapy analyses and 348 patients were
evaluable for maintenance therapy analyses. The overall response rates to
R-CHOP and CHOP induction treatments were similar. Disease progression during
induction was also similar between the 2 treatment groups. The analysis of interaction between
induction and maintenance led the authors to conclude that 1) induction with
R-CHOP (followed by MR or observation) did significantly prolong TTF and 2)
maintenance R also significantly prolonged TTF in responders induced with
CHOP alone. However, no difference in overall survival has been observed to
date. In contrast, the 2-year overall
survival rate was greater (77% vs. 53%) for R-CHOP- versus CHOP-treated
patients with newly diagnosed DLBCL in a population-based retrospective
analysis (N = 294) performed by Laurie Sehn et al in R-CHOP for
follicular lymphoma. Wolfgang Hiddemann and others randomized 606
patients with previously untreated follicular lymphoma to receive up to 6
cycles of either R-CHOP or CHOP alone.
R 375 mg/m2 was given i.v. on Day 1 of each cycle. Responders to induction therapy were then
treated with interferon-alfa maintenance therapy or consolidation therapy
with myeloablative chemotherapy supported by autologous stem cell
transplantation (ASCT). Among 394
evaluable patients, the overall and complete response rates were similar for
the 2 treatment groups. However, with
a median follow-up of nearly 3 years, the median TTF has not yet been reached
for R-CHOP-treated patients compared to 2.6 years for CHOP-treated patients
(p < 0.0007). Toxicity was
comparable between the treatment groups except for a slight increase in grade
3 or 4 neutropenia (42% vs. 37%) and allergy-like symptoms (4% vs. 0%) in
R-CHOP-treated patients. These results
indicated that R-CHOP chemotherapy is associated with an improved TTF
compared to CHOP alone. (Abstract 352) R-CVP in follicular
lymphoma. Robert Marcus et al performed a phase III,
multicenter study in which 322 untreated patients with stage III or IV
follicular NHL were randomized to receive CVP (cyclophosphamide, vincristine,
prednisone) alone or R-CVP. R 375 mg/m2 was infused on Day 1 of
each 21-day CVP cycle. The overall
response rates were 81% and 57% in the R-CVP and CVP alone treatment groups,
respectively (p < 0.0001).
Furthermore, 40% of the R-CVP-treated patients achieved a complete
response compared to 10% of CVP-treated patients. The median time to progression (TTP) had
not been reached in patients treated with R-CVP while it was 13 months in
those who received CVP alone (p < 0.0001).
Both treatment regimens were tolerated well. These data demonstrate that the addition of
R to CVP improves the response rate and TTP in previously untreated patients
with follicular lymphoma compared to treatment with CVP alone. (Abstract 87) Rituximab (R) plus
fludarabine combination therapy of untreated chronic lymphocytic leukemia
(CLL). The treatment of previously untreated CLL was
evaluated in CALGB studies 9011 and 9712.
In CALGB 9011 patients received fludarabine monotherapy and in CALGB
9712 patients were randomized to receive fludarabine plus R concurrently or
fludarabine and R sequentially. John
Byrd and associates analyzed the benefit of adding R to fludarabine therapy
by comparing the outcomes of patients enrolled into CALGB 9011 (N = 179) to
those of patients enrolled into CALGB 9712 (N = 104). The analysis revealed a superior overall
and complete response rate, respectively for combination R-fludarabine therapy
compared to treatment with fludarabine alone. Moreover, the 2-year overall
and progression-free survival rates were 93% and 67%, respectively, for
R-fludarabine-treated patients compared to 81% and 45%, respectively, for
single-agent fludarabine-treated patients.
This analysis suggests that the addition of R to fludarabine treatment
improves clinical outcomes for patients with previously untreated CLL.
Further evaluation of combination R plus fludarabine therapy is warranted.
(Abstract 245) Maintenance therapy
vs. retreatment with rituximab (R) for patients with indolent non-Hodgkin's
lymphoma (NHL). John Hainsworth and colleagues randomized 90
patients with relapsed indolent NHL who had responded to standard salvage
induction R treatment to receive either maintenance R therapy (375 mg/m2
weekly for 4 weeks every 6 months for 24 months) or retreatment with standard
4-week R therapy at the time of lymphoma progression. The primary endpoint was duration of R
efficacy. After a median follow-up of 41 months, the median duration of R
efficacy was similar for the maintenance and retreatment groups (31 vs. 27
months). These data indicated that the
remission rate achieved with R retreatment had offset the improvement in actuarial
median progression-free survival time following R induction treatment gained
by maintenance R therapy (31 vs. 8 months).
More patients in the maintenance group remained in continuous
remission (45% vs. 24%) and further follow-up is needed to determine if this
advantage will translate into a longer duration of R efficacy for patients
given maintenance therapy. (Abstract
231) RADIOIMMUNOTHERAPY
(RIT) 90Y-ibritumomab for
relapsed B-cell NHL following high-dose chemotherapy and ASCT. Julie Vose et al treated 16 patients who had relapsed B-cell NHL
(follicular lymphoma [7], DLBCL [7], splenic marginal zone lymphoma [1], and
mantle cell lymphoma [1]) after receiving high-dose chemotherapy and ASCT
with 90Y-ibritumomab (Zevalin; IDEC Corporation) in a dose-finding phase I
study using the following dosing cohorts: 0.10 (n = 3); 0.15 (n = 4); and
0.20 (n = 9) mCi/kg. The overall
response rate was 45% and 3 of 6 evaluable patients treated with the 0.20
mCi/kg dose achieved a response.
Toxicities included grade 3 thrombocytopenia (4), neutropenia (2), and
anemia (1). The majority of the cytopenias occurred in patients treated with
the 0.20 mCi/kg dose of 90Y-ibritumomab.
This study shows that 90Y-ibritumomab therapy of patients with B-cell
NHL relapsing after high-dose chemotherapy and ASCT is feasible. A phase II trial has been initiated. (Abstract 92) NEW BIOLOGICAL
APPROACHES Novel strategies. John Leonard and colleagues presented 3 studies
that outline novel approaches to the treatment of NHLs. In one study, 13 NHL patients were retreated
with a second 4-week course of epratuzumab at the time of disease progression
after an initial course of single-agent epratuzumab. They found 2 of 6 patients who had
responded to the first epratuzumab course gained a response. In a second
study, 25 (58%) follicular NHL and 3 (50%) CLL/SLL patients responded when epratuzumab
was combined with rituximab (R) for relapsed or refractory follicular
low-grade NHL. In the third study,
Genasense (GS) was tested in 45 patients with mantle cell
lymphoma. All patients started with GS monotherapy
for up to 6 cycles; relapsed/refractory patients were allowed to receive an
additional 6 cycles of GS and chemotherapy-naive patients without a complete
response after the first 6 cycles of GS were then treated with GS plus R-CHOP
for up to 6 cycles. Among 18 evaluable
relapsed/refractory patients, one achieved a complete response and 7 had
stable disease. In chemotherapy-naive patients, there were 5 stable diseases
and 8 progressive diseases. In 8 evaluable patients who received GS plus
R-CHOP, there were 2 complete and 4 partial responses and 2 stable
diseases. These novel approaches
warrant further study. (Abstracts 233,
490, and 2375) New monoclonal
antibody therapies. Several new monoclonal antibodies are undergoing
evaluation. John Byrd et al reported
interim results from a phase I study of an anti-CD23 monoclonal antibody
(lumiliximab; IDEC Pharmaceuticals) in patients with relapsed or refractory
CLL. Lumiliximab was tolerated well
and clinical activity was noted. Rhona
Stein and others reviewed the preclinical evaluation of an anti-CD74
monoclonal antibody (LL1; Immunomedics, Inc.) as a potential therapy against
B-cell malignancies. LL1 is taken up
by lysosomes and may be an effective means to deliver antitumor agents. A fully human anti-CD30 monoclonal antibody
(MDX-060; Medarex, Inc.) has been evaluated in a phase I/II study of patients
with relapsed or refractory Hodgkin's Disease or anaplastic large cell
lymphoma by Stephen Ansell and colleagues.
Minimal toxicity was encountered and activity was observed in one
patient. Myron Czuczman et al. tested
an anti-CD80 monoclonal antibody (galiximab; IDEC Pharmaceuticals) in a
multicenter phase I/II trial in patients with relapsed or refractory
follicular lymphoma. No dose-limiting
toxicities were experienced and responses were observed in all treatment
groups. (Abstracts 248, 630, 632, and 2393) VACCINE THERAPY Use in patients
with mantle-cell lymphoma (MCL). John Leonard and co-workers
evaluated a personalized Id vaccine consisting of a recombinant Id protein
conjugated to Keyhole Limpet Hemocyanin (KLH) administered with GM-CSF in 27 patients
with MCL following CHOP chemotherapy.
Anti-idiotype immune responses were observed and among 11 MCL
patients, median time to progression had not been reached with a median
follow-up of 522 days after the completion of CHOP. In a second study, Wyndham Wilson and
colleagues evaluated an Id-vaccine given to 25 MCL patients following
completion of rituximab (R)-containing chemotherapy (EPOCH-R). Patients received Id-KLH/GM-CSF x 5 over 6
months and at 24 months median follow-up, the event-free and overall survival
rates were 50% and 100%, respectively.
These studies show that an Id-vaccination therapeutic approach may
potentially improve time to disease progression following chemotherapy for
aggressive lymphoma. (Abstracts 357
and 358) MYELODYSPLASTIC
SYNDROMES (MDS) CC-5013 treatment
of MDS-associated anemia. Alan List and colleagues investigated the use of
CC-5013 (Celgene, Inc.), a novel oral immunomodulatory drug (IMiD) in a
single-center study of MDS patients with red blood cell (RBC)
transfusion-dependent (≥ 4 units/8 weeks) or symptomatic anemia (hemoglobin [Hgb] <9 g/dL). Among 33 evaluable patients, 26 patients had
failed prior erythropoietin therapy and 17 patients had failed prior
thalidomide treatment. Twenty-one
patients experienced an erythroid response during CC-5013 therapy and 19
patients had a major erythroid response (RBC transfusion independence or a
> 2 g/dL Hgb increase). The
responses have been durable as the median time to treatment failure had not
been reached. Responses were
associated with an increased bone marrow apoptotic index and near complete
suppression of bone marrow plasma VEGF.
Grade 3 or 4 marrow suppression was dose-dependent and was the most
common adverse event. Grade 1 or 2
toxicities included scalp pruritus (10), diarrhea (9), urticaria (3), and
hypothyroidism (2). These data
indicate that CC-5013 has erythropoietic and cytogenetic remitting activity
in patients with MDS and warrant further study. (Abstract 641) |
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