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Clinical Trials |
-2a1
Cancer Therapy Evaluation Program, National Cancer Institute, Rockville, Maryland 20852 [T. A. D.]; Fred Hutchinson Cancer Research Center, Seattle, Washington 98104 [D. G. M.]; IDEC Pharmaceuticals Corp., San Diego, California 92121 [A. J. G-L., C. A. W., S. D.], University of Virginia Health Sciences Center, Charlottesville, Virginia 22908 [M. E. W.], University of Iowa, Iowa City, Iowa 52242 [G. J. W.]; and Stanford University Medical Center, Stanford, California 94305 [R. L.]
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ABSTRACT |
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 Top ABSTRACT INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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-2a in 38 patients with
relapsed or refractory, low-grade or follicular, B-cell NHL. IFN--2a
[2.5 or 5 million units (MIU)] was administered s.c., three times
weekly for 12 weeks. Starting on the fifth week of treatment, rituximab
was administered by i.v. infusion (375 mg/m2) weekly for 4
doses. All 38 patients received four complete infusions of rituximab
and were evaluable for efficacy, although 11 patients (29%) did not
receive all 36 injections of IFN. The mean number of IFN--2a
injections was 31 doses; the mean total units received were 141 MIU
(maximum, 180 MIU). The study treatment was reasonably well tolerated
with no unexpected toxicities stemming from the combination therapy. No
grade 4 events were reported. Frequent adverse events during the
treatment period included asthenia (35 of 38 patients), chills (31 of
38), fever (30 of 38), headache (28 of 38), nausea (23 of 38), and
myalgia (22 of 38). The overall response rate was 45% (17 of 38
patients); 11% had a complete response, and 34% had a partial
response. The Kaplan-Meier estimates for the median response duration
and the median time to progression in responders are 22.3 and 25.2
months, respectively. Further follow-up is needed to determine whether
this treatment combination leads to a significantly longer time to
progression than single-agent treatment with rituximab. |
INTRODUCTION |
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TopABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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120,000 of the NHL cases, who have a median
survival of 6.2 years (1)
. Most low-grade NHLs are of
B-cell origin and are responsive to initial therapy, but virtually all
advanced stage patients experience a continuous pattern of relapse and
eventually succumb to the disease or its complications, with subsequent
courses of chemotherapy leading to shorter remissions and inevitable
relapse (2
, 3)
. Thus, the search for effective novel
therapies and combinations of existing therapies continues as an
ongoing effort. Rituximab has demonstrated significant clinical activity in the treatment of relapsed or refractory, low-grade or follicular NHL (4, 5, 6, 7, 8, 9) . In a large efficacy study (n = 166) in which rituximab was given as four consecutive weekly infusions of 375 mg/m2, the ORR was 48% for the intent-to-treat population and 50% for the evaluable population. In evaluable patients, the median TTP and duration of response were 13.1 and 11.2 months, respectively (7, 8, 9) .
Rituximab is a mouse/human chimeric antibody containing human constant
regions (IgG1 
isotype) and murine variable regions that
specifically target the CD20 antigen (10)
. The CD20
antigen is expressed exclusively on mature B cells, including those in
most B-cell lymphomas, but not on normal plasma cells, pre-pre-(or
pro-)B cells, stem cells, or dendritic cells (11)
.
Rituximab treatment rapidly depletes the CD20+ normal and tumor B cells
in the peripheral blood and bone marrow. After depletion of CD20+ B
cells, the B-cell population is reconstituted from the stem cells and
pro-B cells, reaching normal levels within 9–12 months
(9)
. Rituximab is a well-tolerated outpatient treatment
completed in 22 days. Treatment-associated adverse events were
primarily grade 1 or 2 and infusion related, including transient fever,
chills, nausea, and headache (7
, 8)
.
Combination therapy with rituximab has been investigated with various agents. The safety and efficacy of rituximab given in combination with CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) chemotherapy was investigated in a Phase II trial. The combination therapy was very effective (ORR of 100% in all treated patients) and demonstrated a toxicity profile consistent with each therapy given separately (12) . Interim results from a Phase I/II trial of rituximab and granulocyte-colony stimulating factor combination therapy suggest that the treatment is well tolerated and at least as efficacious as rituximab given alone (13 , 14) . Rituximab given in combination with an 90yttrium-labeled anti-CD20 murine monoclonal antibody (IDEC-Y2B8) to patients with relapsed or refractory NHL has demonstrated an ORR of 67% in all patients, with an ORR of 82% in low-grade patients (15, 16, 17) .
Several trials have investigated the efficacy of combining immune system modulators, such as IFN, with chemotherapy for treatment of NHL (18, 19, 20, 21) . Preclinical studies in mice revealed a synergistic antitumor effect between IFN and monoclonal anti-idiotype antibodies (22 , 23) . Mechanisms by which IFN may increase the effectiveness of antibodies include the potentiation of antigen expression (24) , increased targeting of antibodies into tumors (25, 26, 27, 28) , and enhanced cytotoxicity of immunotoxins (29, 30, 31) . A combination trial investigated the effect of IFN therapy on the clinical efficacy of anti-idiotype antibodies in patients with NHL. Patients treated with the combination therapy demonstrated an improved initial response rate (9 of 12 responded) compared with patients who received anti-idiotype antibody alone (8 of 16 responded; Refs. 32 and 33 ).
IFN, as a single agent or in combination therapies, has demonstrated significant clinical activity in the treatment of low-grade NHL (34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44) . A 10-year literature review and analysis of results generated from various single-agent studies revealed that the overall response rate in 237 patients with relapsed, low-grade, or follicular NHL was 36% (45) . Adverse events were primarily flu-like symptoms, such as fever and fatigue (35) .
Data from trials of combination therapy reveal that the addition of IFN to anthracycline-containing chemotherapy regimens has been associated with significantly prolonged progression-free survival (TTP); however, IFN did not consistently increase response (37 , 38 , 42 , 44 , 46) . Three large multicenter trials from the Eastern Cooperative Oncology Group, the Groupe d’Etude des Lymphomes de l’Adulte (GELA), and the European Organization for Research and Treatment of Cancer investigated the administration of IFN in conjunction with chemotherapy or as maintenance therapy after chemotherapy. After a median follow-up period of 3 years, an increase in disease-free survival (TTP) was reported in the IFN-treated arms for the Eastern Cooperative Oncology Group, Groupe d’Etude des Lymphomes de l’Adulte, and European Organization for Research and Treatment of Cancer studies of 47, 60, and 45 weeks, respectively (38 , 42 , 44) . IFN has been approved in the United States for use as initial treatment of clinically aggressive follicular NHL in conjunction with anthracyclinecontaining combination chemotherapy because of a significant increase in the TTP (37 , 38 , 42 , 44 , 46) .
Given the efficacy of rituximab and IFN as single agents and the
preclinical results indicating synergistic effects between IFN and
anti-idiotypic antibodies, the safety and efficacy of rituximab given
in combination with IFN--2a (Roferon-A) was investigated. In a
12-week treatment course, patients with relapsed low-grade or
follicular NHL received IFN--2a, 5 MIU s.c. three times weekly
(weeks 1–12), and 4 infusions of rituximab, 375
mg/m2 given weekly (weeks 5–8).
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PATIENTS AND METHODS |
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TopABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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-2a
(Roferon-A) in patients with relapsed or refractory, low-grade or
follicular, NHL. Rituximab was administered as an i.v. infusion for 4
doses (375 mg/m2 given once weekly on weeks 5–8)
to patients who were receiving concurrent treatment with IFN [5 MIU
administered s.c., three times weekly for 12 weeks (weeks 1–12)]. The
treatment schedule for the combination therapy is displayed in Fig. 1
. This design should allow for
establishment of the effects of IFN- prior to infusion of rituximab,
and continues combination therapy for 2 months (1 month during
rituximab treatment and for 1 month after, when rituximab should still
be circulating in the patient’s serum).
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Patient Characteristics.
The patients’ characteristics are shown in Table 1
. Of the 38 patients enrolled in the
study, 28 (74%) patients were male and 37 (97%) were Caucasian. The
median age was 53 years (range, 31–80 years). Patients were a median
of 3.7 years from diagnosis, and 28 had stage III/IV disease at
diagnosis. The majority of patients (92%) had low-grade NHL (IWF types
A, B, or C; Ref. 3
); 4 patients (11%) were IWF type A,
and 31 patients (81%) were IWF type B or C. Three patients (8%) had
follicular intermediate-grade NHL (IWF type D). All patients had been
treated with at least one prior lymphoma therapy regimen (median, 2;
range, 1–6) and had at least one relapse prior to enrollment. A total
of 11 patients had at least one prior course of radiation therapy for
lymphoma. Five patients had undergone autologous bone marrow
transplantation.
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-2a (Roferon-A, recombinant human leukocyte IFN; kindly provided
by Roche, Nutley, NJ) was to be administered as a s.c. injection three
times weekly at a dose of 5 MIU for 12 weeks. Self-administration was
permitted. If significant adverse events known to be associated with
IFN were documented, IFN dose modification was required. A 50% dose
reduction to 2.5 MIU/injection was implemented if any of the following
adverse events were observed: ANC <1,000/mm3,
platelets <75,000/mm3, or AST or ALT >6–11
times normal. The patient was instructed to discontinue IFN treatment
for 1 week if ANC was <500/mm3, platelets were
<50,000/mm3, or if AST or ALT values were >11
times normal. After 1 week, IFN treatment could be resumed at 2.5
MIU/injection only if the ANC was >3,000/mm3,
platelets were >100,000/mm3, and AST or ALT
values were <3 times normal. IFN treatment was to be permanently
terminated if abnormal thyroid stimulating hormone or T4 values were
observed. A total of four infusions of 375 mg/m2 rituximab (Rituxan, Mabthera; kindly provided by IDEC Pharmaceuticals Corp., San Diego, CA) were to be administered once weekly four times (weeks 5–8 of the treatment period) on an outpatient basis. Rituximab, diluted to 1 mg/ml with normal saline, was to be administered as an i.v. infusion at an initial dose rate of 50 mg/h for the first h. If no signs of toxicity were observed, the dose rate was to be escalated gradually (50 mg/h increments at 30-min intervals) to a maximum of 400 mg/h (300 mg/h maximum for the first infusion only). No dose reductions were allowed. The production of rituximab has been described previously (10) .
Patient Monitoring.
Toxicity was evaluated using the National Cancer Institute’s Common
Toxicity Criteria (Recommendations of Representatives of the National
Cancer Institute’s Clinical Cooperative Groups and the Cancer
Treatment Evaluation Program, February 1988). Disease assessment
included the following evaluations: physical examination and assessment
of performance status and B-symptoms (baseline, weeks 8 and 12, and
every 3 months through 2 years, then every 6 months), chest X-ray
(baseline), bone marrow biopsy (baseline and to confirm a CR, if
positive at baseline), and computed tomography or magnetic resonance
imaging (baseline, week 12, and every 3 months through 2 years, then
every 6 months).
Laboratory analyses included the following: serum chemistry and serum immunoglobulin assays at baseline, weeks 8 and 12, and then every 3 months through the first year of follow-up; HACA [detected using one-site (sandwich) ELISA (7 , 8) ] assays at baseline, week 12, and the third month of follow-up; complete blood count at baseline, weeks 5–12, and every 3 months through 2 years, and then every 6 months; and urinalysis at baseline, weeks 8 and 12, and the third month of follow-up. In addition, peripheral blood was analyzed by flow cytometry at baseline, weeks 6 and 8, and every 3 months for the first year of follow-up, and then every 6 months. Thyroid function (T4 and thyroid stimulating hormone) was assessed at baseline and at the sixth month of follow-up. Serum samples for pharmacokinetic analyses of rituximab were obtained for all patients prior to and immediately after each infusion, at weeks 9–12, and at the third month of follow-up.
Response Criteria.
Patients were evaluable for efficacy if they completed the four
infusions of rituximab, satisfied all prestudy entry criteria, and met
criteria for evaluation of response. Response categories consisted of
CR, PR, SD, and progressive disease (9
, 47, 48, 49, 50)
. CR
required the following: all lymph nodes visible on computed tomography
scan 
1 cm x 1 cm in size, any node previously palpable on
physical examination (and considered to be involved by lymphoma) must
not be palpable or must be negative for lymphoma on biopsy or
fine-needle aspiration; bone marrow, if initially positive at baseline,
must be histologically negative for lymphoma; and the liver and spleen,
if abnormal at baseline, should be normal in size and radiographic
appearance. PR was defined as 50% or greater decrease from baseline in
the sum of the products of the greatest perpendicular diameters of all
of the measured lesions (SPD) with no simultaneous increase
in size of any other lesion or no new lesions. SD referred to patients
who did not exhibit at least a 50% decrease or increase in
SPD. Progressive disease was classified as the observation
of a 50% increase from nadir in SPD or the appearance of a
new lesion. Response classifications of PR and CR were confirmed by
reassessment 28 days after the initial determination of response. TTP
(responders) and response duration were measured from the first
injection of IFN and from the initial observation of response,
respectively, until progression of disease.
Statistical Methods.
The Kaplan-Meier (51)
product-limits method was used to
analyze the TTP and duration of response; curves were generated using
PROC LIFETEST (52
, 53)
. The Wilcoxon rank sum test
(51)
was used for the comparison of serum concentration
data by clinical response. Clinical adverse event data were assigned
preferred terms using COSTART (54
, 55)
and were analyzed
by calculating the number and percentage of patients and events.
Investigators classified adverse events by their relationship to study
treatment and severity of the event (grade). If an individual event had
more than one grade, the most severe grade was used to characterize
this unified event.
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RESULTS |
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TopABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Adverse Events.
Adverse events were classified as having occurred during the treatment
period (the time interval between the first IFN injection and 30 days
after last treatment) or during the long-term follow-up period (the
time interval between 31 days after last treatment and 1 year after the
first IFN injection). Adverse events were classified further by their
relationship to study drug. Events were classified as being possibly or
probably related to rituximab, IFN, or to both drugs. If the event was
not considered to be related to treatment, it was classified as having
an unknown relationship or as related to neither drug (such as related
to a concurrent illness or study disease). The most frequent adverse
events are summarized in Table 2
. No
grade 4 events were reported.
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During the treatment period, 28 grade 3 adverse events were reported in 12 patients. The majority of the grade 3 events (23 of 28; 82%) were reported as IFN related. The most common grade 3 events were malaise, asthenia, and myalgia. Five patients either had reductions in their IFN dosing units to 2.5 MIU/dose for at least one cycle (three injections) or did not complete all 36 injections because of these adverse events. Two patients experienced serious adverse events that required hospitalization: concurrent grade 1 dyspnea and grade 2 pneumonia; and a grade 3 neutropenic fever. Both patients recovered after receiving medication and were discharged from the hospital within 4 days. No deaths were attributed to the study treatment or occurred during the treatment period. Deaths were reported in seven off-study patients, all of whom had progressive disease and had received additional therapy after completing this study.
Infections.
Patients were monitored for infections for a year after their first
injection of IFN. Patients treated with antibacterial agents in whom no
organism was isolated were presumed to have a bacterial infection.
Fifteen grade 1 or grade 2 infections were reported in 10 patients; of
these 15 infections, 87% were bacterial and included bronchitis,
pneumonia, sinusitis, upper respiratory infection, and a staph skin
infection. One of the 10 patients was hospitalized with grade 2
pneumonia, received antibiotics, and was discharged after 3 days.
Analysis of Peripheral Blood B Cells and Immunoglobulin Levels.
The peripheral blood B-cell normal range is considered to be 32–341
cells/µl as determined by fluorescence-activated cell sorter
analysis. Rituximab treatment resulted in a rapid depletion of
peripheral blood B cells, as measured by CD19-positive cells; the CD19
(pan-B) antigen rather than the CD20 antigen was used as a B-cell
marker because rituximab inhibits the binding of CD20-detecting
antibodies. The median B-cell count had declined to near zero prior to
the second rituximab dose. Recovery began between 6 and 9 months after
completion of rituximab treatment. Median absolute T-cell counts and
the median absolute NK cell counts in peripheral blood remained
relatively stable throughout the study.
Serum immunoglobulin levels (IgG, IgA, and IgM) were measured at baseline and at specified intervals for 1 year. Mean serum IgG and IgA levels did not fall outside of the normal range throughout the study. The mean IgM level remained within the normal range, except when it fell below normal at one time point at month 4.
Hematological and Chemistry Laboratory Effects.
Most hematological effects from treatment were mild and transient.
Anemias in eight patients were classified as grade 1 or 2, and
hemoglobin levels for all patients recovered to at least 9.9 g/dl by
the end of the study. One patient received a RBC transfusion for grade
2 IFN-related anemia on day 48. Two grade 3 neutropenic events occurred
in two patients. One patient who experienced a grade 3 neutropenic
fever on day 176 attributed to rituximab treatment and study disease
was hospitalized on day 179 and received antibiotics. The fever
resolved, and the patient was discharged after 4 days. Another patient
experienced grade 3 neutropenia on the day of the fourth rituximab
infusion that was attributed to the combination therapy. The patient
recovered within 16 days without receiving medication. Twenty-four
thrombocytopenic events were reported; 20 of the events were considered
to be related to treatment (10 IFN related, 6 rituximab related, and 4
attributed to combination therapy), 3 events were attributed to
lymphoma, and 1 was of an unknown relationship. All events were grade 1
or 2 and transient. Platelet values for all patients recovered to a
grade 1 level by the end of the treatment period.
There were no clinically significant abnormalities of grade 2 or greater in laboratory values throughout the study. No patients developed a detectable HACA titer during the treatment or follow-up periods.
Clinical Response.
All 38 patients were evaluable; 4 of the 38 patients (11%) had a CR,
and 13 patients (34%) had a PR, for an overall response rate of 45%.
A summary of clinical response is found in Table 3
. A univariate analysis of baseline
prognostic factors such as age, sex, B symptoms, performance
status, stage of disease, extranodal disease, splenomegaly, bone marrow
infiltration, elevated lactate dehydrogenase, and response to prior
therapy demonstrated that none of these factors had a statistically
significant effect upon the outcome of treatment (all
Ps 
.05).
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The current estimations for the median duration of response and time to
progression for the 17 responders, as determined by Kaplan-Meier
analysis, are 22.3 months and 25.2 months, respectively, but final
values have not yet been reached. These data are summarized in Table 4
. The Kaplan-Meier curve of TTP in
evaluable responders in this current study as well as the Kaplan-Meier
curve of TTP obtained from a previous Phase III single-agent rituximab
trial are presented in Fig. 2
. In the
Phase III trial, rituximab (375 mg/m2) was given
in the same course and schedule (weekly times four) to 166 patients
with relapsed or refractory, low-grade or follicular, NHL who were
selected by the same inclusion/exclusion study criteria. A comparison
of the TTPs achieved in the two trials indicated that the increase in
TTP observed in the combination trial has not yet reached statistical
significance (P =0.4704 determined by log-rank statistics).
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DISCUSSION |
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TopABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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has pleiotropic effects on the immune system, including
increased expression of the MHC class I antigen, cellular adhesion
molecules and other tumor antigens, increased production of, and
sensitivity to, other cytokines, as well as augmentation of the
cytotoxic activity of NK cells, an integral part of ADCC (56
, 57)
. Although the predominant mechanism of action of rituximab
in vivo is not known, the antibody is able to mediate both
complement and antibody-mediated cell killing (ADCC; Ref.
10
). Evidence that IFN- could stimulate the ability of
NK cells to mediate ADCC (58)
suggests that simultaneous
treatment with IFN- and antibody may augment efficacy. The regimen
used in this trial provided tolerable dosing of IFN- before, during,
and after rituximab therapy to maximize any synergistic activity.
The safety and efficacy of rituximab and IFN-, given as single
agents, were demonstrated previously in patients with relapsed or
refractory, low-grade or follicular NHL (7
, 8
, 35
, 36
, 38
, 39
, 43
, 45 , 59)
. This trial demonstrated that rituximab treatment
(375 mg/m2, i.v., once weekly times four) given
in combination with IFN--2a (5 MIU, s.c., three times a week for 12
weeks) in patients with relapsed or refractory, low-grade or follicular
NHL was active, safe, and well tolerated.
There were no unexpected events resulting from the combination
treatment. Most related adverse events were attributed to IFN--2a
treatment (395 of 734 events; 54%), with few being attributed to the
combination therapy (61 of 734; 8%). The majority of adverse events
were grade 1 or 2; none were grade 4. The hematological or
immunological adverse event profile did not appear to significantly
differ from that observed in single-agent rituximab trials
(4, 5, 6, 7, 8, 9)
. Most hematological events were mild and transient.
B cells were transiently depleted and recovered within 6–9 months, the
same time frame observed in rituximab single-agent trials. T-cell and
NK-cell counts remained relatively stable throughout the study
(4, 5, 6, 7, 8, 9)
. There were no significant abnormalities of grade 2
or greater in laboratory values during the study. In addition, no
patients developed a HACA response, clear evidence that IFN--2a
therapy does not promote humoral responses against the chimeric
antibody.
The overall response rate was similar to that observed in single-agent studies of patients with relapsed or refractory low-grade or follicular NHL. The response rate of 45% (95% CI, 29–61%) is similar to the 50% overall response rate (95% CI, 42–58%) seen in the pivotal trial of rituximab given as a single agent (7 , 8) and compares favorably with the 36% response rate determined by a 10-year literature review of IFN single-agent trials (45) . As has been observed in rituximab single-agent trials, lesion size decreased in responders until it stabilized between approximately 4–7 months after study entry (9) . No statistically significant relationship between various prognostic factors at baseline and response was identified. This is in contrast to a significant relationship (univariate analysis; P < 0.05) between response and histological type, prior ABMT therapy, baseline bcl-2 status, number of relapses, and bone marrow involvement identified in the rituximab single-agent pivotal trial (9) . Although responders were found to have higher serum levels of rituximab compared with nonresponders, this difference did not achieve statistical significance, as had been observed in previous trials (9 , 60) .
Of the five patients with prior ABMT, only one experienced a serious
adverse event. This grade 3 febrile neutropenia occurred 6 months
after therapy and resolved within 1 week. Three patients had dose
reductions of IFN. One of these five patients responded with a response
duration of 7 months.
When response rate is assessed by histological type and compared with response of the population as a whole, patients with type A histology had a lower ORR (0 responders of 2 patients), patients with type B had a higher ORR (12 of 22; 54%), patients with type C had a similar ORR (4 of 9; 44%), and patients with type D had a higher ORR (2 of 3; 67%). Although the ORR was higher in the patients with types B and D histology and lower in patients with type A histology, the small population size precludes definitive conclusions.
The Kaplan-Meier estimate for median TTP in responders of 25.2 months
compares favorably with the 13.1-month median TTP observed in the
pivotal single-agent rituximab trial that used the same dose and
schedule in a similar patient population (9)
. These
efficacy results are consistent with combination trials of IFN and
chemotherapy in patients with relapsed or refractory, low-grade NHL in
which IFN demonstrated a prolongation of TTP without necessarily
increasing the response rate (38
, 42
, 44)
. The potential
10.1-month increase in TTP observed with combination therapy, compared
with the TTP observed with single-agent rituximab treatment, is not
currently statistically significant. Definitive conclusions regarding
the potential benefit of combination therapy require a randomized trial
investigating single-agent therapy versus combination
therapy. Nonetheless, this trial indicates that it is safe and feasible
to combine rituximab and IFN--2a for the treatment of NHL, and that
combination treatment may prolong the TTP. We believe this result
justifies further evaluation of this regimen.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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1 Supported by clinical grants from the NIH and
IDEC Pharmaceuticals Corporation. 
2 To whom requests for reprints should be
addressed, at Investigational Drug Branch Cancer Therapy Evaluation
Program, National Cancer Institute, Executive Plaza North 715, 6130
Executive Boulevard, Rockville, MD 20852. Phone: (301) 435-9134; Fax:
(301) 402-0428.
3 The abbreviations used are: NHL, non-Hodgkin’s
lymphoma; ORR, overall response rate; TTP, time to progression; IWF,
International Working Formulation; MIU, million units; AST, aspartate
aminotransferase; ALT, alanine aminotransferase; ANC, absolute
neutrophil count; CR, complete response; PR, partial response; SD,
stable disease; HACA, human anti-chimeric antibody; NK, natural killer;
ADCC, antibody-dependent cellular cytotoxicity; ABMT, autoimmune bone
marrow transplantation.
Received 1/ 6/00; revised 4/ 3/00; accepted 4/ 3/00.
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TopABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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 D. G. Maloney Immunotherapy for Non-Hodgkin's Lymphoma: Monoclonal Antibodies and Vaccines J. Clin. Oncol., September 10, 2005; 23(26): 6421 - 6428. [Abstract] [Full Text] [PDF]
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B. Jahrsdorfer, L. Muhlenhoff, S. E. Blackwell, M. Wagner, H. Poeck, E. Hartmann, R. Jox, T. Giese, B. Emmerich, S. Endres, et al. B-Cell Lymphomas Differ in their Responsiveness to CpG Oligodeoxynucleotides Clin. Cancer Res., February 15, 2005; 11(4): 1490 - 1499. [Abstract] [Full Text] [PDF]
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N. Niitsu, M. Khori, M. Hayama, K. Kajiwara, M. Higashihara, and J.-i. Tamaru Phase I/II Study of the Rituximab-EPOCT Regimen in Combination with Granulocyte Colony-Stimulating Factor in Patients with Relapsed or Refractory Follicular Lymphoma Including Evaluation of Its Cardiotoxicity Using B-Type Natriuretic Peptide and Troponin T Levels Clin. Cancer Res., January 15, 2005; 11(2): 697 - 702. [Abstract] [Full Text] [PDF]
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J. W. Friedberg, H. Kim, M. McCauley, E. M. Hessel, P. Sims, D. C. Fisher, L. M. Nadler, R. L. Coffman, and A. S. Freedman Combination immunotherapy with a CpG oligonucleotide (1018 ISS) and rituximab in patients with non-Hodgkin lymphoma: increased interferon-{alpha}/{beta}-inducible gene expression, without significant toxicity Blood, January 15, 2005; 105(2): 489 - 495. [Abstract] [Full Text] [PDF]
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M. S. Czuczman, R. Weaver, B. Alkuzweny, J. Berlfein, and A. J. Grillo-Lopez Prolonged Clinical and Molecular Remission in Patients With Low-Grade or Follicular Non-Hodgkin's Lymphoma Treated With Rituximab Plus CHOP Chemotherapy: 9-Year Follow-Up J. Clin. Oncol., December 1, 2004; 22(23): 4711 - 4716. [Abstract] [Full Text] [PDF]
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G. Cartron, H. Watier, J. Golay, and P. Solal-Celigny From the bench to the bedside: ways to improve rituximab efficacy Blood, November 1, 2004; 104(9): 2635 - 2642. [Abstract] [Full Text] [PDF]
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N. Niitsu, M. Hayama, M. Okamoto, M. Khori, M. Higashihara, J.-i. Tamaru, and M. Hirano Phase I Study of Rituximab-CHOP Regimen in Combination with Granulocyte Colony-Stimulating Factor in Patients with Follicular Lymphoma Clin. Cancer Res., June 15, 2004; 10(12): 4077 - 4082. [Abstract] [Full Text] [PDF]
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W. L. Gluck, D. Hurst, A. Yuen, A. M. Levine, M. A. Dayton, J. P. Gockerman, J. Lucas, K. Denis-Mize, B. Tong, D. Navis, et al. Phase I Studies of Interleukin (IL)-2 and Rituximab in B-Cell Non-Hodgkin's Lymphoma: IL-2 Mediated Natural Killer Cell Expansion Correlations with Clinical Response Clin. Cancer Res., April 1, 2004; 10(7): 2253 - 2264. [Abstract] [Full Text] [PDF]
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 J. Boye, T. Elter, and A. Engert An overview of the current clinical use of the anti-CD20 monoclonal antibody rituximab Ann. Onc., April 1, 2003; 14(4): 520 - 535. [Abstract] [Full Text] [PDF]
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 H. Ben-Bassat, Z. Hartzstark, R. Levitzki, B. Y. Klein, Z. Shlomai, A. Gazit, and A. Levitzki Tyrosine Kinase Inhibitors Suppress the Growth of Non-Hodgkin B Lymphomas J. Pharmacol. Exp. Ther., October 1, 2002; 303(1): 163 - 171. [Abstract] [Full Text] [PDF]
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 B. Jahrsdorfer, R. Jox, L. Muhlenhoff, K. Tschoep, A. Krug, S. Rothenfusser, G. Meinhardt, B. Emmerich, S. Endres, and G. Hartmann Modulation of malignant B cell activation and apoptosis by bcl-2 antisense ODN and immunostimulatory CpG ODN J. Leukoc. Biol., July 1, 2002; 72(1): 83 - 92. [Abstract] [Full Text] [PDF]
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J. M. Vose, B. C.-H. Chiu, B. D. Cheson, J. Dancey, and J. Wright Update on Epidemiology and Therapeutics for Non-Hodgkin's Lymphoma Hematology, January 1, 2002; 2002(1): 241 - 262. [Abstract] [Full Text]
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O. W. Press, J. P. Leonard, B. Coiffier, R. Levy, and J. Timmerman Immunotherapy of Non-Hodgkin's Lymphomas Hematology, January 1, 2001; 2001(1): 221 - 240. [Abstract] [Full Text] [PDF]
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