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CD20 monoclonal antibody therapy for B-cell lymphona
van der Kolk, L.E.
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Citation for published version (APA):van der Kolk, L. E. (2001). CD20 monoclonal antibody therapy for B-cell lymphona.
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Download date: 17 Aug 2019
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Summaryy and General Discussion
Summaryy and General Discussion
Summary y
Nowadays,, chimeric CD20 monoclonal antibodies (rituximab) are widely used in the treatment
off relapsed low-grade non-Hodgkin's lymphoma (NHL). Although results with rituximab as
singlee agent therapy are encouraging with 48% of patients responding for >13 months,
responsee rates still might be improved.
Possiblee anti-tumor mechanisms of chimeric CD20 mAbs include the induction of antibody-
dependentt cellular cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC) and
apoptosis.. One possibility to augment the efficacy of chimeric CD20 mAbs in vivo might be
too increase the efficacy of effector cells involved in ADCC. Since granulocyte colony-
stimulatingg factor (G-CSF) is known to increase the cytotoxic capacity of neutrophils in
ADCC,, addition of G-CSF to rituximab treatment could theoretically enhance the efficacy of
rituximab. .
Chapterr 2 describes the results of a phase l/ll clinical trial evaluating the safety and efficacy
off the combination of rituximab and G-CSF in relapsed low-grade NHL patients. The
combinationn of rituximab and G-CSF appeared to be well tolerated. Side effects observed
inn the present study were comparable to side effects observed during rituximab monotherapy
andd consisted of fever, chills and allergic reactions, occurring mainly during the first infusion.
Thee efficacy of rituximab and G-CSF was comparable to the efficacy of rituximab
monotherapyy as well. However, although the overall response rate was similar, the number
off complete remissions was high and remission duration seemed to be longer than observed
afterr rituximab monotherapy. These results might suggest that the combination of rituximab
andd G-CSF is more efficient in eradicating minimal residual disease than rituximab
monotherapy.. However, more patients and longer follow-up duration are required to
substantiatee this finding.
Still,, the results on efficacy of the combination of rituximab and G-CSF were not as favorable
ass hoped for. Several possible explanations for these findings are discussed in chapter 2 as
well. .
Treatmentt with rituximab is generally well tolerated in patients with low numbers of
circulatingg tumor cells. However, side effects can be severe and life threatening in patients
withh high numbers of circulating CD20-positive B-cells.1;2 Therefore, we investigated the
mechanismm underlying these side effects (chapter 3). At multiple early time points during
thee first infusion of rituximab, complement activation products (C3b/c and C4b/c) and
cytokiness (tumor necrosis factor-a (TNF-a), interleukin-6 (IL-6) and IL-8) were measured in
fivee patients treated with the combination of rituximab and G-CSF.
Duringg the first infusion of rituximab, we observed rapid complement activation, followed
101 1
Chapterr 7
byy the release of TNF-cc, IL-6 and IL-8. Although the 5 investigated patients had very low
levelss of circulating B-cells and only mild side effects, the level of complement activation
wass correlated both with the number of circulating B-cells prior to the infusion and with the
severityy of the side effects. We conclude that complement activation plays an important
rolee in the side effects of rituximab treatment, and propose a mechanism explaining the
pathogenesiss of these side effects.
Alll measurements were performed in patients treated with rituximab and G-CSF. We did not
seee any influence of G-CSF administration on either complement activation products, cytokine
levelss or side effects. Therefore, a possible influence of G-CSF, although not excluded, is unlikely.
Complementt activation, in contrast to cytokine release, can not be prevented by
corticosteroids.3'44 It has been described that patients with high levels of circulating tumor
cellss may develop severe side effects during the first infusion of rituximab, despite
pretreatmentt with corticosteroids. This observation not only supports a role for complement
activationn products in the development of the side effects, but also forms a rationale for
studiess investigating the use of complement inhibitors during the first rituximab-infusion,
especiallyy in patients with high numbers of circulating tumor-cells who are at risk of severe
first-dosee side effects.
Inn chapter 4, the ability of G-CSF stimulated neutrophils to kill CD20-coated B-cells was
measuredd in vitro, by using ADCC-assays. For this purpose, G-CSF-stimulated neutrophils
weree derived from patients treated in the clinical trial, after three injections of G-CSF, i.e.
justt prior to the infusion of rituximab.
G-CSF-primedd neutrophils proved to be capable of functioning as effector cells in CD20-
dependentt ADCC. However, HLA class II mAbs were far more effective in inducing B-cell
lysis.. In chapter 4, possible explanations for the difference between CD20 mAbs and HLA
classs II mAbs in inducing neutrophil-mediated B-cell lysis are investigated and discussed.
Althoughh our data demonstrate that rituximab is capable of inducing ADCC with G-CSF-
primedd neutrophils as effector cells, NK cells are more potent inducers of CD20-dependent
cytotoxicity.. Thus, stimulating the effector function of NK cells might also form a possibility
too enhance the efficacy of rituximab therapy. A recent clinical trial investigated the
combinationn of rituximab with IFN-a, which is known to stimulate NK-cell function.5
Interestingly,, results were similar to results of rituximab and G-CSF, i.e. the response rate
afterr rituximab + IFN-a was comparable to the response rate of rituximab monotherapy
whereass the response duration appeared to be longer. These results strengthen the
suggestion,, that responses induced by rituximab monotherapy might be improved by an
adjuvantt stimulating the anti-tumor mechanism of ADCC. However, randomized trials should
bee performed to validate these findings.
Inn chapter 5, the effect of rituximab treatment on the primary and secondary humoral
102 2
Summaryy and General Discussion
immunee response was investigated. Treatment with rituximab leads to a rapid depletion of
BB cells from the peripheral blood, lasting for 9-12 months after completion of treatment.
Clinically,, this sustained B-cell depletion neither leads to a decrease in immunoglobulin levels,
norr to an increase in the number of infectious complications. However, it is not unlikely that
rituximabb treatment influences the humoral immune responsiveness. Therefore we
investigatedd the effect of rituximab treatment on the primary and secondary humoral immune
response,, by immunizing patients both before and after rituximab treatment with two
primaryy antigens (keyhole limpet hemocyanin and hepatitis A) and two recall antigens
(tetanuss toxoid and poliomyelitis vaccine).
Somewhatt unexpectedly, none of the patients mounted a response to either primary antigen,
neitherr before, nor after rituximab treatment. Therefore, our study does not allow a conclusion
ass to the influence of rituximab on the primary immune response.
Interestinglyy though, after rituximab treatment, the response to the recall antigens was
decreasedd when compared to the response before treatment. This might be due to a decrease
inn the amount of memory B-cells after rituximab treatment. The possible implications of this
findingg for the use of rituximab as maintenance therapy and for the use of rituximab in the
treatmentt of antibody-mediated autoimmune diseases are discussed in chapter 5.
Inn chapter 6, we investigated the intracellular pathways of CD20-induced apoptosis. We
foundd that chimeric CD20 mAbs only induce apoptosis after crosslinking (CD20XL).
Furthermore,, we found that CD20XL-induced apoptosis is independent of the Fas/FasL
apoptosiss pathway, is not inhibited by overexpression of Bcl-2 and is only partially dependent
onn active caspases. Most chemotherapeutic drugs require the activation of caspases to
exertt their cytotoxicity, and chemoresistance may be caused by a defect in apoptosis-
inducingg pathways, leading to the inability of drugs to activate caspases. Therefore, these
dataa imply that CD20XL-induced apoptosis may circumvent important causes of
chemoresistance. .
B-celll lymphomas are known to become increasingly chemoresistant after being treated
withh multiple chemotherapy regimens. However, in clinical trials evaluating the efficacy of
rituximabb in B-cell lymphomas, it was observed that the number of prior chemotherapy
regimenss did not influence the response to rituximab. This suggests that the chemoresistance
off the tumor did not influence the response to rituximab, thus supporting our in vitro data
onn CD20-induced apoptosis.
Ass mentioned, chimeric CD20 mAbs require crosslinking in order to induce apoptosis. In
vitro,vitro, goat-anti-human antibodies have been used as crosslinking antibodies. Furthermore, it
hass been demonstrated in vitro that FcyR-expressing cells were able to provide functional
crosslinkingg of CD20 mAbs and thereby induce apoptosis in target cells. Thus, FcyR-expressing
cellss might play a role in vivo not only by inducing ADCC, but also by inducing apoptosis.
103 3
Summaryy and General Discussion
Generall discussion
Inn the present studies, several aspects of the combination of rituximab and G-CSF were
evaluated.. The main goal of this study was to increase the efficacy of rituximab treatment
viaa the addition of G-CSF. Although the overall response rate of the combination of rituximab
andd G-CSF was comparable to rituximab monotherapy, we observed a high percentage of
completee remissions and a remarkably long duration of response. A randomized trial,
comparingg rituximab monotherapy with the combination of rituximab and G-CSF should
bee conducted in order to validate this finding.
Severall other strategies have been developed in order to increase the efficacy of rituximab
treatment,, not only by combining rituximab with an immunologic adjuvant (e.g. IFN-a56,
IL-1277 or IL-28), but also by coupling CD20 mAbs to a radioisotope or toxin. In general, the
dataa obtained in different studies combining rituximab with IL-2, IL-12 or IFN-a are too
preliminarypreliminary to allow conclusions as to their additional value. However, one study has a
longerr follow up.5 In this study, treatment of patients with the combination of rituximab
andd IFN-a resulted in a similar response rate as obtained with rituximab monotherapy. Here
too,, the response duration appeared to be longer than observed with rituximab
monotherapy.. Thus, these results resemble those obtained in our study.
Off specific interest are the results obtained with iodine 131iodine (131l) labeled murine CD20
mAbss (tositumomab, mlgG2a; Bexxar) and ̂ yttrium ("Y) labeled CD20 mAbs (ibritumomab
tiuxetan,, mlgGI; Zevalin). In 59 patients with either low-grade or transformed low-grade
NHLL (n=42) or de novo intermediate- or high-grade NHL (n=17) who were treated with 1311
tositumomabb (75 cGy), an overall response rate (ORR) of 7 1 % with a complete remission
(CR)) rate of 34% was reported.9 Comparable results were obtained with Zevalin (0.4 mCi/
kg,, maximum 32 mCi): in 143 patients with either relapsed or refractory low-grade NHL or
transformedd low-grade NHL, who were randomized between treatment with Zevalin or
withh rituximab monotherapy, the ORR in the Zevalin group was 80% (30% CR), versus 56%
(4%% CR) in the rituximab group.10 Furthermore, in 54 follicular lymphoma patients refractory
afterr rituximab therapy treatment with Zevalin resulted in an ORR of 74% (15% CR).11 Thus,
responsee rates with radiolabeled CD20 mAbs exceed those obtained with rituximab
monotherapy. .
ToxicityToxicity was primarily hematologic and although grade IV thrombocytopenia and/or
neutropeniaa were observed in approximately 20% of the patients, hematologic toxicity
wass always transient and reversible, not requiring stem cell support.^10
13111 tositumomab has also been applied in conjunction with stem cell rescue.12'14 In this
phasee l/lI study, 29 patients were treated with myeloablative doses of 131l tositumomab.
Thee response rate was 86% (79% CR) and the time to treatment failure was 37 months.
105 5
Chapterr 7
Besidess the expected severe myelosuppression after treatment with 131l tositumomab,
cardiopulmonaryy toxicity was found to be the dose limiting toxicity. Thyroid dysfunction
hass been the most common late complication, occurring in 60% of patients. None of the
299 patients has developed myelodysplasia or acute leukemia during the follow up period
off (median) 47 months.
Otherr applications of rituximab include its use in combination with chemotherapy, which is
beingg investigated in indolent as well as in aggressive lymphomas. Because of their non-
overlappingg toxicities, these two treatment modalities may be safely combined. In elderly
patientss with diffuse large cell lymphoma (n= 400), addition of rituximab to CHOP
chemotherapyy resulted in a significantly higher response rate and, after a median follow up
periodd of 12 months, a significant prolongation of event-free survival and overall survival,
withoutt significant additional toxicity.15 The combination of CHOP and rituximab in low-
gradee or follicular lymphoma was well tolerated and resulted in a response rate of 100%
withh a median duration of response of 39+ months after a median follow up period of 41
months.166 Conversion of Bcl-2 positivity to negativity in 7/8 patients tested.17 Although the
resultss of these studies are promising, long-term follow up is required in order to determine
thee value of the addition of rituximab to CHOP chemotherapy.
Thee conversion of Bcl-2 from positive to negative in bone marrow and peripheral blood
afterr treatment with the combination of CHOP and rituximab has not been observed after
CHOPP alone, suggesting that rituximab might effectively clear minimal residual disease (MRD).
Too investigate the application of rituximab in MRD, the efficacy of rituximab as maintenance
therapyy in B-cell malignancies is currently being investigated {no studies published yet).
Furthermore,, rituximab is currently been applied in combination with high dose chemotherapy
beforee stem-cell harvest {'in vivo purging')18 and after stem<ell transplantation, in order to
eradicatee minimal residual disease.19 The complete molecular responses observed in these
studiess has lead to speculations that addition of rituximab to (high dose) chemotherapy
mightt form a curative treatment option.
Althoughh initial studies primarily focussed on the use of rituximab in low-grade NHL, rituximab
hass also been applied in various other CD20-positive B-cell malignancies (table 1). The efficacy
off rituximab in aggressive lymphomas is less favorable than in low-grade lymphomas. Several
groupss have studied the efficacy of rituximab in mantle cell lymphoma, and response rates
weree -35%, which was comparable in the different studies. The response rate of patients
withh diffuse large cell lymphoma treated with rituximab was 39%. In contrast, post-transplant
lymphomass were found to be highly sensitive to rituximab treatment (table 1). In several
reportss on patients with post-transplant lymphoproliferative disease (PT-LPD) treated with
rituximab,, response rates were >80%.
Rituximabb has also been applied in patients with plasma cell dyscrasias, including multiple
106 6
Summaryy and General Discussion
Tablee 1. Use of rituximab* in various CD20-positive B-cell malignancies
histology** *
follicularr lymphoma (FL) smalll lymphocytic lymphoma (SLL)
diffusee large cell lymphoma (DLCL)
mantlee cell lymphoma (MCL)
MCL1 1 MCL2 2 immunocytoma a smalll lymphocytic lymphoma
MCL1 1 MCL2 2
PT-LPD D EBVV positive (22/266 cases tested)
PT-LPD D EBVV negative
PT-LPD D EBVV positive
number r of f patients s
n=118 8 n=30 0
n=30 0
n=13 3
n=34 4 n=40 0 n=28 8 n=29 9
n=37 7 n=50 0
n=32
ORR R (CR***) )
60% % 13% %
37% %
33% %
38% % 37% % 28% % 14% %
34%% (14%)
69%% (63%)
83%% (83%)
85%% (53%)
comments s
assessablee patients
3755 mg/m2 x8 or 375mg/m2x11 + 5000 mg/m2 x7; noo difference between treatmentt arms
noo difference between MCL11 and MCL2
solidd organ transplantationn n=26, RRR 65%; bonee marrow transplantationn n=6, RRR 83%
CRR n=4, SD n=2
3755 mg/m2 x7-11
ref f
29 9
30 0
31 1
32 2
33 3
34 4
35 5
*regimen:: 375 mg/m2 weekly x4, unless indicated otherwise; **relapsed lymphoma unless indicated otherwise;; ***CR rate is given if known. In 2 patients and 6 patients, rituximab was used as first-linee therapy (000unknown). Abbreviations: ORR = overall response rate, on intent-to-treat basis; CR == complete remission; SD - stable disease; MCL1= MCL, newly diagnosed; MCL2= MCL, previously treated;; PT-LPD = post-transplant lymphoproliferative disease; EBV - Epstein Barr virus.
myelomaa (MM)20 and Waldenstrom's macroglobulinemia (WM).21;22 Analysis of 7 (previously
treated)) WM patients treated with rituximab showed that 3 of them achieved a partial
responsee upon rituximab treatment.22 Although CD20 is expressed on the monoclonal B-
celll population of most WM patients, CD20 expression on plasma cells of most MM patients
iss either weak or absent. However, CD20-positive clonotypic B-cells have been detected in
patientss with MM, and these cells may function as myeloma precursor cells. Furthermore,
experimentss have been conducted to search for agents that might increase the CD20-
107 7
Chapterr 7
expressionn on plasma cells (e.g. IFN-y23). In initial clinical studies it was suggested that certain
MMM patients may benefit from rituximab therapy.20;24
Finally,, promising results have been described on rituximab in antibody-mediated
autoimmunee diseases.2"8 Of 10 patients with chronic idiopathic thrombocytopenic purpura
(ITP)) treated with rituximab 375 mg/m2 weekly x4, 6 patients responded. The duration of
responsee varied from > 3 months to > 14 months.26 Evidently, these studies need to be
extended.. Furthermore, it will be interesting to determine the exact mechanism of action
off rituximab in antibody-mediated autoimmune diseases.
Inn conclusion, chimeric CD20 mAbs are safe and well tolerated. The efficacy of rituximab in
relapsedd low-grade NHL has already been established. However, many other B-cell
malignancies,, especially the post-transplant lymphoproliferative diseases, are effectively
treatedd by rituximab. Preliminary data on the combination of rituximab with (high-dose)
chemotherapyy even suggest that this combination might form a curative treatment option.
Moreover,, rituximab might be a valuable treatment option for antibody-mediated
autoimmunee diseases. Thus, although the optimal use of rituximab in the treatment of the
variouss B-cell malignancies and other potential fields remains to be determined, many
patientss have already benefited of this safe and efficient treatment modality, and future
prospectss are highly encouraging.
108 8
Summaryy and General Discussion
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