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Abstracts and Commentary

Abstracts and Commentary

Optimizing the Activity
of Rituximab
Abstract #1398
Rituximab Therapy for Patients
With Newly Diagnosed,
Asymptomatic Advanced-Stage
Follicular Grade I Non-Hodgkin's
Lymphoma: A Phase II Trial in the
North Central Cancer Treatment Group
T. E. Witzig, A. M. Vukov, T. M. Habermann, S. Geyer, W. R.
Friedenberg, W. L. White, M. Salim, P. J. Flynn, T. R. Fitch,
R. F. Morton

Hematology, Mayo Clinic, Rochester, Minnesota; OHACI,
Peoria, Illinois; Medical Oncology/Hematology, Guthrie
Clinic, Milan, Pennsylvania; Medical Oncology, Allan Blair
Cancer Center, Regina, Saskatchewan, Canada; Oncologic
Consultants, PA, Minneapolis, Minnesota; Hematology/Oncology,
Mayo Clinic, Scottsdale, Arizona; Medical Oncology
and Medical Association, Iowa Oncology Research Association
CCOP, Des Moines, Iowa

Patients with newly diagnosed advanced-stage
follicular grade I non-Hodgkin's lymphoma (NHL)
are often asymptomatic and can be observed without
immediate chemotherapy without compromising survival.
Rituximab (Rituxan) immunotherapy offers a
new nonchemotherapy approach to this group of
patients.

Our goal was to assess the rate of complete remission
(CR) and partial remission (PR) to rituximab and
to determine the time to progression (TTP) and time
to subsequent chemotherapy (TTSC). Eligible patients
had biopsy-proven follicular grade I NHL,
measurable disease, stage III or IV, no prior therapy,
CD20+, and performance status (PS) 0-2. Patients
received rituximab 375 mg/m2 IV weekly * 4 doses.
No maintenance therapy was provided. Patients were
followed with physical exam, laboratory tests, and
CT scans every 3 months for the first year and every
6 months thereafter.

A total of 37 patients were accrued to this study
between July 1999 and May 2001. Forty-three percent
of patients were male; 89% were PS 0 and 11%
were PS 1. The median age was 59 years (range: 29
to 83 years). All patients were white except for 1
patient, who was Asian. Sixteen percent of patients
had elevated lactate dehydrogenase levels pretreatment.
Thirty-eight percent of patients had a low
International Prognostic Index (IPI), 46% low intermediate
IPI, and 16% high intermediate IPI. No
patients had B symptoms. All patients completed
treatment as per protocol.

The overall response rate (ORR) was 61%, with
25% CR. To date, 20 patients remain in unmaintained
remission, 2 died without disease progression, 3 died
of disease progression, and 12 have progressed and
are still alive. The median TTP was 1.67 years (range:
0.014 to 3+ years); and the TTSC was 1.75 years
(range: 0.014 to 3+ years). In general, rituximab was
well tolerated in this patient population. Severe (grade
3+) toxicity was seen in 4 patients (11%), where 2
patients (5%) had severe hematologic toxicity and 3
patients (8%) had severe nonhematologic toxicity.
These severe toxicities included rash (2), neutropenia
(1), leukopenia (1), infection without neutropenia (1),
and urticaria (1).

CONCLUSION: Rituximab can be safely administered
to patients with previously untreated advancedstage
follicular grade I NHL with minimal toxicity.
This therapy produces an ORR of 61% and prolonged
remissions have been documented. Rituximab offers
an acceptable alternative to observation in this patient
population.

Abstract #604
Prolonged Treatment With Rituximab
Significantly Improves Event-Free
Survival and Duration of Response
in Patients With Follicular Lymphoma:
A Randomized SAKK Trial
M. Ghielmini, S.-F. H. Schmitz, S. Cogliatti, G. Pichert,
M. Fey, D. Betticher, G. Martinelli, F. Peccatori, U. Hess,
R. Stahel, E. Zucca, R. Stupp, T. Kovacsovics, C. Helg,
A. Lohri, M. Bargetzi, D. Vorobiof, T. Cerny

Lymphoma Working Group, Swiss Group for Clinical Cancer
Research (SAKK), Bern, Switzerland

Clinical and pharmacokinetic data suggest that the
effect of rituximab (Rituxan) could be improved by
prolonged exposure to the drug. To verify this hypothesis
we performed a randomized trial of rituximab given
at the standard schedule vs a prolonged rituximab
treatment with additional maintenance cycles.

A total of 202 patients with newly diagnosed or
resistant/relapsed follicular lymphoma (FL) were
enrolled. After a standard induction treatment with
rituximab (375 mg/m2 weekly * 4), patients responding
or with stable disease at week 12 were randomized
to either observation or maintenance therapy with an
additional rituximab administration (375 mg/m2) every
8 weeks (at months 3, 5, 7, and 9).

In 185 evaluable patients, response to induction
therapy was 46% (59/128) in pretreated patients and
67% (38/57) in chemotherapy-naive cases (P < .01).
Adverse predictors of response were bulky disease
(P = .002) and male gender (P = .04). The characteristics
of the 151 patients randomized to observation
vs maintenance therapy were as follows: median age,
57; performance status 0/1, 97%; stage III/IV, 85%;
bone marrow involvement, 52%; elevated lactate
dehydrogenase, 30%; previous radiotherapy, 18%;
previous chemotherapy, 66% (mean 2.3 regimens);
all characteristics were equally balanced between
both arms.

At a median follow-up of 35 months, the median
event-free survival from the initiation of induction
treatment was 12 months for the observation arm vs
23 months for the maintenance arm (P = .02), with a
hazard ratio of 0.57, the difference being more pronounced
in the subgroup of chemotherapy-naive patients
(19 vs 36 months, P = .009). Among patients
responding at week 12, 56% were still in remission at
12 months in the observation arm vs 80% in the
maintenance arm (P = .01). The median response
duration was 17 vs 36 months (P = .0009), with a
hazard ratio of 0.45.

After induction treatment, 34 patients further improved
the quality of response, and complete remission
rate increased from 10% at randomization to
16% at month 7, 23% at month 12, and 29% (44/151)
at further follow-up (no difference between the two
arms). The number of circulating B lymphocytes
tended to return to pretreatment levels after 1 year of
observation, while they remained low in patients
receiving prolonged treatment (65% vs 33% of baseline
level, P = .04). However, in both arms the IgG,
IgA, and IgM plasma levels remained stable and the
incidence of infections and other side effects was low.

CONCLUSION: The study shows that in patients
with FL, stable or responding after standard rituximab
treatment, the administration of an additional
four single doses of rituximab at 2-month intervals
reduces the risk of progression or relapse by 43%
among all randomized patients and by 55% among
responders, as well as significantly improves the
chance of remaining in remission at 1 year, without
inducing additional toxicity. This effect is obtained
mainly by the capacity of maintenance treatment to
prevent relapse in responding patients. The antitumor
effect of rituximab continues long after the end of its
administration.

Abstract #1390
Rituximab Re-Treatment in B-Cell Lymphoma
Patients: Efficacy and Toxicity
in 59 Patients Treated in One Center
B. Coiffier, F. Bouaffia, C. Thieblemont, O. Hequet,
P. Arnaud, C. Dumontet, D. Espinouse, G. Salles

Department of Hematology, CH Lyon-Sud, Hospices
Civils de Lyon, Pierre-Bnite, France

During the past 4 years,
483 patients with B-cell lymphoma
were treated in our
department with rituximab
(Rituxan) alone (166 patients),
in combination with
chemotherapy (302 patients),
or as maintenance therapy
(15 patients) in different studies
or as registered treatment.
Out of these 483 patients,
429 (89%) responded to treatment (complete response
[CR] + partial response [PR]): 132/166 (80%)
to rituximab alone and 282/302 (93%) to a combination
with chemotherapy. Out of these 429 patients,
117 (27%) had presented a disease progression at
time of analysis (median follow-up of around 18
months), 54/132 (41%) after rituximab alone, and
59/282 (21%) after rituximab in combination with
chemotherapy. Out of these 117 patients, 59 (50%)
received a second treatment with rituximab alone or
in combination with chemotherapy.

Rituximab was administered alone at the dose of
375 mg/m2/wk for 4 weeks or in combination with
chemotherapy the same day at 375 mg/m2 for all
chemotherapy cycles. These 59 patients were analyzed
for the response to the second rituximab treatment.
For the first treatment, rituximab was given
alone in 30 patients and associated with chemotherapy
in 29 patients and for the second treatment, in 32
and 27 patients, respectively. All but 4 patients
responded to this second treatment (CR 42%, PR
51%). The median time to progression and time to
next treatment were 12 and 13 months after the first
rituximab treatment and 20 and 21 months after the
second rituximab treatment, respectively. Eight patients
had a shorter time to progression after the
second rituximab cycle and in 4 patients it was
identical.

Progression and time to progression after the second
treatment were not associated with the number of
treatments before rituximab, the association or not
with chemotherapy for the first or second rituximab
cycle, the response to the first or second rituximab
treatment, or the status at time of second rituximab
treatment (progressive disease or partial response to
previous cycle). Of the 20 patients who progressed
after the second rituximab treatment, 12 received a
third rituximab cycle-6 alone and 6 with chemotherapy;
all 12 responded to the treatment and only 3 had
progressed at time of analysis with a median time to
progression of 13 months. No special adverse events
were observed with the different cycles of rituximab
but 3 patients had herpes zoster infection during or
just after the second cycle.

CONCLUSION: In conclusion, re-treatment with
rituximab alone or in combination with chemotherapy
was associated with very good response rates and
a longer progression-free survival after the second
rituximab treatment than after the first one. Rituximab,
alone or in combination with chemotherapy, is
recommended for re-treatment of patients who progressed
after a first rituximab treatment.

Abstract #3073
Rituximab Plus Chlorambucil in Low-
Grade Non Hodgkin's Lymphomas:
Clinical Results of a Phase II Study
G. Martinelli, D. Laszlo, P. Mancuso, P. Santoro,
G. Pruneri, A. Vanazzi, E. Zucca

Hematoncology Division, European Institute of Oncology,
Milan, Italy; Medical Oncology Department, Oncology
Institute of Southern Switzerland, Bellinzona, Switzerland

The monoclonal anti-
CD20 antibody rituximab
(Rituxan) has a well-established
efficacy in the
treatment of low-grade non-
Hodgkin's lymphomas
(NHLs), principally the follicular
subtype (60%). More
recently, the combination of
chemotherapy plus rituximab
has been demonstrated in a
randomized study of aggressive NHL patients to produce
better clinical results than chemotherapy alone.

Chlorambucil (Leukeran) is considered the drug of
choice for the treatment of low-grade NHL, mainly
for follicular: chlorambucil alone induces a response
rate of 70% with 30% to 40% of complete remission.
No data are available about the combination of
chlorambucil plus rituximab. The aim of this study is
to define the feasibility, toxicity, and efficacy of
rituximab plus chlorambucil in low-grade NHL.

Twenty-nine NHL patients (20 follicular, 6 marginal
zone, 3 chronic lymphocytic leukemia), median
age 40 years, were enrolled in the study between
November 2001 and April 2002. Fourteen patients
had received previous therapy. The treatment plan
consisted of chlorambucil at 6 mg/m2 daily administered
for 6 consecutive weeks combined with the standard
4-weekly rituximab at 375 mg/m2 administration
schedule. Patients responding to this induction phase
received further therapy with chlorambucil (2 weeks
every month for four additional cycles) in combination
with four monthly administrations of rituximab.

All patients were monitored weekly with white
blood cell counts during induction phase and then
once monthly. Peripheral blood immunophenotype
evaluation was performed at baseline, after the induction
phase, and then at the end of the treatment.
Clinical evaluation was performed after the induction
phase, then at the end of the entire therapy program.
All patients are evaluable for toxicity and response.

The most important hematologic toxicity observed
was National Cancer Institute Common Toxicity
Criteria (NCI-CTC) grade 3/4 neutropenia, experienced
by 13% of patients. Only one patient developed
severe anemia and thrombocytopenia. All hematologic
toxicity recorded was observed among pretreated
patients. Twelve patients developed an absolute
lymphopenia (NCI grade 3), and significant CD4+
reduction; however, no patients had an imbalance in
CD4+/CD8+ ratio and no severe infections were
recorded. Among 27 patients evaluable for response,
24 (89%) achieved an objective response with approximately
53% complete remissions.

CONCLUSION: The combination of rituximab
plus chlorambucil is well tolerated and active. Clinical
results achieved seem to confirm the possible
synergistic or additive effect of the combination, also in
low-grade NHL patients. A randomized trial is now
ongoing to further evaluate this promising combination.

Abstract #2246
Phase II Study With Fludarabine and
Cyclophosphamide Plus Rituximab in
Relapsed Follicular Lymphoma Patients
S. Sacchi, A. Tucci, F. Merli, L. Orsucci, G. Cervetti,
U. Occhini, M. Liberati, G. Tarantini, V. Callea,
M. Brugiatelli, V. M. Lauta, L. Baldini, S. Luminari,
M. Federico

Dipartimento di Oncologia ed Ematologia, Universit di
Modena e Reggio Emilia, Modena, Italy; Servizio di Ematologia,
Spedali Civili, Brescia, Italy; Servizio di Ematologia,
Az. Osp. Santa Maria Nuova, Reggio Emilia, Italy; Divisione
di Ematologia, Az. Osp. Santo Giovanni Battista, Torino, Italy;
Divisione di Ematologia, Az. Osp. Pisana Ospedale Santa
Chiara, Pisa, Italy; Servizio di Ematologia, Az. Osp. Arezzo,
Arezzo, Italy; Istituto di Scienze Oncologiche, Policlinico
Monteluce, Perugia, Italy; Divisione di Ematologia, Osp.
Civ. Santa Nicola Pellegrino, Trani, Italy; Divisione di Ematologia,
P. Osp. Riuniti "Bianchi, Melacrino, Morelli," Reggio
Calabria, Italy; Divisione di Ematologia, Az. Osp. "Papardo,"
Messina, Italy; Sezione di Medicina Interna ed Oncologia
Clinica, Az. Osp. Policlinico, Bari, Italy; Divisione di Ematologia,
Ospedale Maggiore, IRCCS, Milano, Italy

Both cyclophosphamide (Cytoxan, Neosar) and
fludarabine (Fludara) have individual antilymphoma
activity, and the combination of rituximab (Rituxan)
plus fludarabine has been shown to have synergistic
activity against resistant lymphoma cell lines in vitro.
In March 2000, we started a phase II multicenter
clinical trial to test the safety
and efficacy of the fludarabine/
cyclophosphamide plus
rituximab combination in patients
with relapsed follicular
lymphoma. We have
recently completed the enrollment
of 48 patients in the
trial. Patients received four
doses of rituximab (375 mg/
m2/d) in combination with 4
cycles of fludarabine (30 mg/m2/d for 3 days) and
cyclophosphamide (300 mg/m2/d for 3 days) every 21
days.

Patient characteristics: 45% males, 55% females;
median age: 62 years (range: 44-71); stage IV, 47%
patients; systemic symptoms, 8.5% of patients; elevated
lactate hydrogenase, 15% of patients. Rearrangement
of the bcl-2 gene was evaluated with
polymerase chain reaction in 38 patients (79%) on
bone marrow or peripheral blood mononucleated
cells; 22 patients showed bcl-2 rearrangement (58%).
Median number of previous chemotherapy regimens
was 1.7 (range: 1-4); median duration of last remission
before registration into the trial was 12 months
(range: 1-68 months).

Thirty-nine patients were available for evaluation
at the time of current analysis. One patient did not
complete therapy due to severe cytopenia. The response
rate in the intent-to-treat analysis was 97%,
with 74% complete responses and 23% partial responses.
Out of 18 patients with molecular monitoring
of disease before and after chemotherapy, 15
patients (83%) obtained molecular remission in the
bone marrow.

After a median follow-up of 12 months (range: 1-
25 months), median duration of remission was 13
months; 20% of patients were only recently registered
into the trial and had a short follow-up (less than
4 months). Overall, 8 patients relapsed (21%). One
patient died due to severe neutropenia that occurred
during chemoterapy; two patients died due to lymphoma
progression. Complete responses are ongoing
in 28 patients.

As far as toxicity is concerned, World Health
Organization (WHO) grade III/IV leukopenia was
observed in 10 patients, with 4 patients presenting a
WHO grade IV granulocytopenia. WHO grade IV
infections were observed in only one patient, who had
a pulmonary infection after the third cycle. Nonhema-
tologic toxicity was minimal. During follow-up, one
patient had a renal cell tumor and one patient had
myelodysplasia, 3 and 6 months after the end of
treatment, respectively.

CONCLUSION: The combination of fludarabine/
cyclophosphamide plus rituximab is associated with
acceptable toxicity and an excellent response rate in
this group of heavily pretreated patients with relapsed
follicular lymphoma. Further follow-up is required to
evaluate response duration and survival in the whole
group of patients.

Abstract #1401
Combined Fludarabine, Mitoxantrone,
and Rituximab Achieves a High
Response as Initial Treatment for
Advanced Low-Grade Non-Hodgkin's
Lymphoma
S. A. Gregory, P. Venugopal, S. Adler, S. Enschede,
F. Yunus, T. M. O'Brien, K. F. O'Donnell, E. L. Robin
Section of Hematology, Rush-Presbyterian-St. Luke's Medical

Center, Chicago, Illinois; Boston Baskin Cancer Group,
Memphis, Tennessee; The Community Hospital of Munster,
Munster, Indiana

This phase II study was
undertaken to evaluate the
safety and efficacy of fludarabine
(Fludara) plus mitoxantrone
(Novantrone)
followed by consolidation
with the anti-CD20 monoclonal
antibody rituximab in
treating low-grade non-
Hodgkin's lymphoma. This
regimen uses the synergistic
effect of fludarabine and mitoxantrone observed in
vitro, and combines it with a third agent with a
complementary mode of action and proven activity in
low-grade lymphoma.

For eligibility, patients must have previously untreated
CD20-positive low-grade non-Hodgkin's lymphoma,
with a Karnofsky performance status of 70.
Treatment consists of 4 to 6 cycles of chemotherapy,
which includes fludarabine at 25 mg/m2 on days 1-3
plus mitoxantrone at 12 mg/m2 on day 1 of each 28-
day cycle. If patient attains a complete remission
(CR) after 4 cycles of chemotherapy, rituximab is
administered at 375 mg/m2 weekly for 4 weeks, 4-6 weeks after the last dose of chemotherapy. If CR is
not attained after 4 cycles, the patient receives 2 more
cycles of chemotherapy and then proceeds to rituximab
therapy after a 4-6 week delay. The total
number of patients registered is 41; 33/41(80%) were
stage IV, 3 (8%) stage III, and 5 (12%) stage II.

The histologic classification of the 41 patients is as
follows: 11(27%) small lymphocytic lymphoma, 18
(44%) follicular small cleaved, 6 (15%) follicular
mixed, 2 (5%) mantle cell lymphoma, 3 (7%) maltoma,
and 1 (2%) marginal zone. Ten patients were
inevaluable for the following reasons: 1 has not
completed therapy, 2 ineligible, 3 patient removal, 1
autoimmune hemolytic anemia, 1 death not related to
treatment, and 2 patients were removed due to prolonged
cytopenia.

Of 31 patients evaluated for response, 30 responded.
The overall response rate is 97%(n = 30) (CR
45%, n = 14, and PR 52%, n = 16); 50% (n = 7) of
patients in CR have remained in remission longer
than 24 months (24+, 24+, 30+, 24+, 34+, 24+, 24+
months). 31% (n = 5) of patients in PR have remained
in remission for longer than 12 months (12+, 15+,
15+, 18+, 28+ months). 30% (n = 9) of patients have
progressed after achieving a remission (3+, 3+, 5+,
7+, 7+, 11+, 13+, 13+, and 25+ months).

Serious adverse events included grade 3 and 4
neutropenia (n = 64 episodes in 163 cycles of chemotherapy),
neutropenic fever (n = 7), shortness of
breath (n = 2), one epsiode of retinal detachment, and
one episode of thrombus formation. Three patients
had 25% dose adjustments for prolonged neutropenia.
Two patients were discontinued due to neutropenia.
Grade 1/2 neutropenias, anemias, and
thrombocytopenias usually resolved during or before
rituximab infusion. Documented infections were rare
with one episode of pneumonia. Antimicrobial anaphylaxis
was not used.

CONCLUSION: A regimen of fludarabine plus
mitoxantrone followed by rituximab is highly effective
and well tolerated when used as primary therapy
in advanced-stage low-grade non-Hodgkin's lymphoma.
Moderate to severe neutropenia occurred
during therapy, but documented infection occurred in
only one patient and neutropenic fevers in seven
patients. This treatment results in a high rate of
overall response and durable remissions.

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