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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

C h a p p

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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