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Immunotherapy for Non-Hodgkin’s Lymphoma

Immunotherapy for Non-Hodgkin’s Lymphoma

ABSTRACT: The first attempt at using monoclonal antibodies in lymphoma therapy, reported in 1980, was unsuccessful. Since that time, several immunotherapeutic approaches to treating non-Hodgkin’s lymphoma have been developed, with varying degrees of success. These approaches are largely based on the fact that each lymphoma is a clone of identical cells with a unique immunoglobulin on its surface. This unique portion of the immunoglobulin—the idiotype—is an ideal target for therapy. Clinical trials with antibodies have mostly targeted CD20, which is present on 95% of all B-cell lymphomas, as well as CD19 and CD22. This concept of using the idiotype to broaden the antilymphoma effect and to use it as a vaccine model has recently been evaluated. This approach would theoretically produce an active immunization with induction of humoral and cellular responses that would be longer acting than passive antibodies alone. The response is heterogeneous and polyclonal, which may be an advantage. Studies of these approaches will be outlined in this article. [ONCOLOGY 15(2):141-155, 2001]


Monoclonal antibodies are the
first example of successful
therapy for lymphoma using our knowledge of the immune system. In 1975, Kohler
and Milstein[1] discovered that the antibody-producing cells from a mouse spleen
could be immortalized by fusion with myeloma cells. These fused cells
(hybridoma) were able to live indefinitely and produce antibodies that provided
the reagents and systems for further experiments. The first attempt at using
monoclonal antibodies in lymphoma therapy was reported by Nadler et al[2] in
1980. In that study, a transient decrease in the white blood cell count was
observed following each treatment; however, no significant antitumor effect was
noted—perhaps due to the presence of a soluble antigen in the serum that
blocked the antibody.

Each lymphoma is a clone of identical cells, all of which
possess the same immunoglobulin on their surface. Each B cell’s immunoglobulin
is unique. The idiotype—the unique portion of the immunoglobulin—is an ideal
target for therapy. Early studies targeted the idiotype with individual
monoclonal antibodies designed for that patient’s lymphoma. In many patients,
such therapy produced direct antilymphoma responses that lasted for several
years, with very limited toxicity.[3] In an attempt to create a more generic
antilymphoma antibody, molecules found on many B-cell lymphoma cells became
targets for antibodies. Clinical trials with antibodies have mostly targeted
CD20, which is present on 95% of all B-cell lymphomas, as well as CD19 and CD22.

This concept of using the idiotype to broaden the antilymphoma
effect and to fashion a vaccine model has recently been evaluated. This approach
would theoretically produce an active immunization, inducing humoral and
cellular responses that would be longer acting than passive antibodies alone.
The response is heterogeneous and polyclonal, which may be an advantage.
Individual studies utilizing both of these approaches will be outlined in this

Unconjugated Antibodies

Rituximab for Indolent
Non-Hodgkin’s Lymphoma

The most extensively studied and clinically used unconjugated
monoclonal antibody is the chimeric anti-CD20 monoclonal antibody rituximab
(Rituxan). This antibody consists of the murine variable regions of the parent
2B8 murine anti-CD20 grafted onto a human immunoglobulin G1-constant
region.[4] The CD20 antigen is an excellent target for immunotherapy because it
is found only on mature B cells and not on precursor B cells (which would lead
to long-term depletion), and the antigen is not shed, internalized, or modulated
to any great extent once antigen-antibody binding has occurred.[5] Apoptosis
also appears to be triggered by this antibody-antigen binding motif.[6]

Pivotal Trial: Initial phase I studies of the rituximab
anti-CD20 antibody used a bolus of the antibody that was repeated weekly in
patients with relapsed CD20-positive non-Hodgkin’s lymphoma (NHL).[7] Multiple
phase II studies enrolled many patients with relapsed, indolent CD20-positive
NHL. Patients received a dose of 375 mg/m2 of rituximab weekly for 4 weeks. The
pivotal trial showed a 6% complete response rate and a 42% partial response
rate, for an overall response rate of 48% in this patient population with
relapsed, indolent NHL.[8]

In this trial, patients had received a median of two prior
chemotherapy regimens before being treated with rituximab. Patients who were
tested before and after therapy with rituximab could clear a detectable bcl-2
rearrangement (by polymerase chain reaction [PCR] analysis for the t[14;18]
translocation) in the blood and marrow compartments. However, some of these
patients still had bcl-2-positive lymph nodes.[9] Median time to progression
for the responders in the pivotal trial was 13 months (Figure 1). Relapses
with a CD20-negative lymphoma have now been reported, although these represent a
minority of such cases.[10]

Due to concerns about penetration of the antibody in large
masses, a separate study was also performed in patients with bulky disease. In
this trial, patients with masses > 10 cm with relapsed or refractory indolent
NHL received rituximab for four doses as per previous trials. The overall
response rate in this population was 43%, with a median time to progression of 8

More recently, studies of rituximab in previously untreated
patients have been evaluated. Gutheil et al[12] reported on 20 patients with
previously untreated indolent lymphoma who received rituximab in a phase II
trial. An overall response rate of 50% was reported in these patients, with the
follow-up currently too short to obtain a median time to relapse.

Combination Therapy: In addition to the single-agent use of
rituximab for indolent lymphoma, it has also been combined with conventional
chemotherapy. This combination therapy is based on the in vitro study that
demonstrated synergism with the anti-CD20 antibody and chemotherapy in
sensitizing previously chemotherapy-resistant cell lines.[13]

In the first combination study, reported by Czuczman et al,[14]
38 patients with indolent lymphoma (31 previously untreated) were treated with
rituximab and CHOP (cyclophosphamide [Cytoxan, Neosar]/doxorubicin
HCl/vincristine [Oncovin]/prednisone). The response rate was 100%, including a
66% complete response rate. With no comparison other than a historical one, it
is difficult to know whether an improvement in event-free survival will be shown
over CHOP alone. A prospective, randomized trial will be needed for this

Ongoing trials are studying combinations of rituximab with
fludarabine (Fludara), CVP (cyclophosphamide/vincristine/prednisone), and FND
(fludarabine/mitoxantrone [Novantrone]/dexamethasone), among other regimens.

Rituximab for Aggressive NHL

With respect to aggressive NHL, only a few trials have been
published. Coiffier et al[15] evaluated 54 patients with relapsed diffuse, large
cell or mantle cell lymphoma who received rituximab for eight weekly doses. A
total of 5 complete responses and 12 partial responses were observed, for an
overall response rate of 31%. Another study, by Foran et al,[16] evaluated 120
patients with newly diagnosed or recurrent mantle cell lymphoma, immunocytoma,
or small lymphocytic lymphoma, who received rituximab for four weekly infusions.
The overall response rate in these patients was 30% (36 out of 120 patients). A
total of 10 patients (all with mantle cell lymphoma) achieved a complete
response with this therapy.

Combination Therapy: With respect to combination therapy for
aggressive NHL, the most mature study is a phase II trial, in which 33 patients
with newly diagnosed diffuse, large B-cell NHL received rituximab at
375 mg/m2 on day 1 of each cycle, followed by CHOP on day 3 of each cycle.
The complete response rate in this trial was 61%, and the partial response rate
was 35%, for an overall response rate of 97%.[17] All patients were able to
receive all cycles of therapy, with a 27% rate of neutropenia and < 1%
incidence of thrombocytopenia. With a minimum follow-up of 24 months, 29 of 33
patients (88%) are alive and disease free following this therapy.

Recently, the preliminary results of a large prospective
randomized trial evaluating the addition of rituximab to CHOP as initial therapy
for aggressive NHL have been presented.[18] In this trial, patients with diffuse
large B-cell NHL who were ³ 60 years of age were randomized to receive either 6
cycles of CHOP alone or rituximab combined with CHOP. There were 159 patients in
the CHOP alone arm and 169 patients in the combination arm. The combination
regimen had a CR rate of 76% compared with 60% for the CHOP alone arm (P =
.004). In addition, the event-free survival rate was 69% in the combination arm
compared to 49% in the CHOP alone arm (P < .0005). The overall survival was
also improved in the combination arm—83% at 1 year, compared to 68% at 1 year
in the CHOP alone arm (P < .01). Another confirmatory trial is currently
close to finishing accrual in the ECOG study group.

The combination of CHOP plus rituximab has also been evaluated
in patients with newly diagnosed mantle cell lymphoma. A report from the
Dana-Farber Cancer Institute evaluated 40 patients who received this
regimen.[19] The complete response rate was 33%, the unconfirmed complete
response rate was 15%, and the partial response rate was 49%, for an overall
response rate of 98%. The median progression-free survival rate was 16 months—no
different from similar historical control patients receiving CHOP alone.
Although 11 of the 23 patients with detectable bcl-1 rearrangements became
PCR-negative, this did not correlate with the overall response to therapy.

Rituximab Plus High-Dose Therapy/Stem Cell Transplant

Because rituximab has been shown to "clear" bcl-2-positive
cells from the blood and marrow, it has recently been tested in the transplant
setting as an additive therapy. A few preliminary studies have now been
presented in abstract form.

Salles et al[20] evaluated 26 patients—with follicular
lymphoma (n = 17), mantle cell lymphoma (n = 4), or marginal zone or small
lymphocytic lymphoma (n = 5)—who were treated with rituximab prior to
hematopoietic stem cell harvest. Patients received four doses of rituximab at
375 mg/m2. Mobilization was attempted with high-dose cyclophosphamide,
etoposide, and granulocyte colony-stimulating factor (G-CSF [Neupogen]) at 4
weeks after the administration of rituximab. Of the 26 patients, 3 failed to
mobilize and the remainder received stem cell transplants. Among patients with
adequate follow-up (minimum 1 year) 10 of 11 were alive and in complete
remission. The PCR analysis in the stem cell product demonstrated PCR negativity
in 6 of 7 patients with follicular lymphoma, while 2 patients with mantle cell
lymphoma and 1 patient with small lymphocytic lymphoma showed residual
PCR-positive cells.

Another trial, by Flinn et al,[21] evaluated 40 patients with
follicular lymphoma (n = 19), mantle cell lymphoma (n = 9), or small
lymphocytic, marginal zone, or lymphoplasmacytic disease (n = 12), who were
receiving autologous transplantation. Patients received rituximab, 375 mg/m2, on
day 1 of mobilization, followed by cyclophosphamide and G-CSF or
granulocyte-macrophage colony-stimulating factor (GM-CSF [Leukine]). The last 15
patients were also selected for CD34 positivity. Preliminary results
demonstrated that 7 of the patients with unmanipulated grafts had a PCR-positive
product, whereas none of the CD34-positive-selected grafts did. Final results
from both of these trials are pending.

At the University of Nebraska Medical Center, we recently
completed a trial of 30 chemotherapy-sensitive patients with follicular or
mantle cell lymphoma. In this study design, patients received rituximab with the
BEAM transplant regimen (carmustine [BiCNU]/etoposide/cytarabine
[Ara-C]/melphalan [Alkeran]). Patients were given one dose of rituximab prior to
initiation of the BEAM regimen and at 30 and 60 days posttransplant. With very
early follow-up, 29 of 30 patients are alive following the transplant, with a
complete response rate of 88%. No additional toxicity was seen with the
supplemental rituximab, and engraftment results were identical to those seen in
patients receiving BEAM alone.

Our newest study uses the principles outlined above to take
advantage of rituximab premobilization to clear the blood: Rituximab is
administered during the regimen to sensitize the lymphoma cells, and another
four doses are given at 6 months posttransplant when the B cells begin to
recover (Figure 2). Quantitative bcl-2 assays will also be performed on these

Rituximab for Posttransplant Lymphoproliferative Disorder

In patients who have received solid organ or bone marrow
transplants, posttransplant lymphoproliferative disorder (PTLD) can be a serious
complication. The problem is believed to result from the rapid proliferation of
Epstein-Barr virus-transformed B cells in the setting of T-cell deficiency, a
phenomenon that occurs in immunosuppressed patients. The first line of therapy
for PTLD is typically a reduction of the immunosuppression. However, this does
not succeed in all patients, and further therapy is often necessary.

Several pilot studies have evaluated the use of rituximab for
the treatment of PTLD. In a study by Milpied et al,[22] 32 patients with PTLD
received rituximab at 375 mg/m2 for four weekly doses. Of the 32 patients, 26
had solid organ transplants and 6 had bone marrow transplants. The overall
response rate was 69%, with 63% of patients having a complete response and 6%
experiencing a partial response. Median time to response was 54 days (range: 11
to 148 days). Of the responding patients, 59% were still in remission at a
median follow-up of 10 months posttreatment.

Several other small investigations of rituximab for the
treatment of PTLD have been published in abstract form.[23,24] Since many of
these patients are quite ill at the time that PTLD is diagnosed, a therapeutic
intervention with a less toxic agent is ideal in this clinical situation.


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