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Maintenance and Consolidation Strategies in Non-Hodgkins

Lymphoma: A Review of the Data

Fredrick B. Hagemeister

Published online: 4 September 2010# Springer Science+Business Media, LLC 2010

Abstract Results of treatment for patients with non-

Hodgkins lymphomas have significantly improved overthe last decade, especially following the discovery that anti-

CD20 antibody therapy can significantly change the

outlook for patients with both aggressive and indolent

lymphomas. Although investigators have previously

attempted to prevent relapses by intensifying chemotherapy

programs for patients with poor-risk disease, further

improvements in treatment will require development of

biologic agents that can be added to current programs and

exploitation of currently available drugs that can prevent

recurrence of these diseases with good tolerability. This

review analyzes currently available plans that can be used

to maintain responses or consolidate initial responses to

therapy, programs that may prevent relapse and potentially

cure more patients with lymphomas, with a review of

current ongoing trials designed along these lines.

Keywords Lymphoma . Rituximab . Maintenance .

Radioimmunotherapy

Introduction

Therapy for patients with lymphomas has seen significant

improvements in results over the last decade, especially

since the discovery and easy clinical usage of monoclonal

antibodies and other biologic therapies that have been

developed within the last few years. Rituximab itself has

improved results of treatment for patients with not only

aggressive but also indolent non-Hodgkins lymphomas(NHLs), and the success of this drug spurred investigators

to develop newer antibodies that might improve upon those

results [1]. However, to date, none of these have been

better than rituximab at improving progression-free survival

(PFS) results, and investigators have turned to development

of biologic agents other than monoclonal antibodies to

improve responses with standard regimens, hoping for

minimal added toxicity, especially protein inhibitors and

immunomodulators [28]. Other investigators have turned

to efforts at consolidation of initial response in order to

prevent relapses, including high-dose therapy followed by

stem cell rescue (SCT), although it remains unclear that

such therapy improves overall survival (OS) results for any

lymphoma when administered as part of initial therapy.

Finally, others have developed therapies much more

tolerable than SCT in an attempt to prolong PFS and OS

results. In this report, we review results of consolidation

and maintenance therapies, and describe newer agents in

clinical trials that might improve results for patients with

these diseases.

Indolent NHL

Rituximab as Maintenance Therapy

This anti-CD20 chimeric antibody induced a 48% response

rate in patients with relapsed indolent NHLs and was

approved by the US Food and Drug Administration (FDA)

in 1997 for treatment of these diseases [1]. Multiple

investigators have subsequently studied this drug as initial

therapy for indolent NHLs, and in combination with

chemotherapy or following chemotherapy as initial therapy

F. B. Hagemeister (*)

Department of Lymphoma/Myeloma,

M. D. Anderson Cancer Center,

1515 Holcombe, Unit 429,

Houston, TX 77030, USA

e-mail: [email protected]

Curr Oncol Rep (2010) 12:395401

DOI 10.1007/s11912-010-0128-x


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or for relapses of indolent NHLs [9, 10, 1117, 1823,

24,25]. In four randomized phase 3 trials of initial therapy

and in two randomized trials of therapy for relapsed

disease, rituximab plus chemotherapy for patients with

follicular lymphomas (FL) resulted in better PFS and OS

rates than did chemotherapy alone [9, 10, 1115]. In a

recent meta-analysis of these studies, Schultz et al. [16]

found that combined immunochemotherapy with rituximabappeared to improve survival in treatment of patients with

these diseases. Because of these trials, investigators agree

that rituximab should now be included as part of initial

therapy for all patients with indolent lymphomas. However,

the use of this drug as maintenance or consolidation has

been controversial.

Ghielmini and colleagues [17, 18] first studied mainte-

nance therapy with rituximab following induction with

rituximab versus observation alone; in this trial, at long-

term follow-up of these patients, those who received

prolonged rituximab therapy enjoyed an event-free survival

(EFS) rate that was almost double that reported for thosewho were on the observation arm. Remarkably, 25% of

those with previously untreated disease who received

maintenance rituximab were still free of progression at

8 years of follow-up [18]. Since this first report, multiple

investigators have found that retreatment with maintenance

rituximab is an effective way to prolong the duration of

remission achieved with induction therapy, although, until

recently, the results have only been reported from trials

testing rituximab maintenance versus observation in thera-

py of patients who had received rituximab or chemotherapy

alone as induction therapy [19]. In a phase 3 trial conducted

in a group of 331 treatment-nave patients with indolent

NHL s, 282 of who m had FL, tho se who received

maintenance rituximab following induction with CVP

chemotherapy (cyclophosphamide, vincristine, prednisone)

had a median PFS rate of 52 months from the start of

rituximab therapy compared to only 16 months for those

who were randomized to observation alone (P


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include varying dosing schedules of rituximab following

single-agent rituximab or rituximab and bendamustine;

however, because the drug is well tolerated, it is likely that

many schedules of therapy will work, and the decision to

use one over the other may be one of convenience.

Radioimmunotherapy

These drugs, 131I tositumomab (Tos) and 90Y ibritumomab

(Ibr), have demonstrated effectiveness in treatment of

patients with relapsed indolent NHLs [25,26]. Following

approval of these drugs in the United States, investigators

have found that they can be effective in therapy of patients

with rituximab-refractory disease, can induce long-term

remissions, appear more effective if used earlier in the

treatment plan rather than later, can be combined with

SCT therapy, and are associated with low rates of long-

term complications [2736]. However, these drugs have

also been used in phase 2 trials as consolidation therapy

for patients induced into first remission by chemotherapyor chemoimmunotherapy [3745]. The Southwest Oncol-

ogy Group recently completed a study that treated patients

with newly diagnosed FL on a randomized trial of CHOP-

R, using the original design formulated by Czuczman,

versus CHOP followed by Tos, based on a phase 2 study

of CHOP followed by Tos, conducted by Press and

colleagues [45]. In that phase 2 trial, 96% had stage III

to IV disease, and bulky tumor greater than 10 cm was

noted in 23%. The CR rate after six cycles of CHOP was

44%, but after Tos, it increased to 74%; at 5 years, the PFS

and OS rates for all patients were 67% and 87%,

respectively. The FLIPI score appeared to play some role

in the outcomes; patients who had high FLIPI scores had

52% PFS and 79% OS rates at 5 years. Reports from the

randomized trial will be particularly important because no

rituximab was administered to those patients on the latter

arm of this study. More importantly, Morschhauser and

colleagues [46] have reported results of the FIT trial, a

study in which patients who entered first remission with

chemotherapy or rituximab plus chemotherapy were

enrolled and received randomized therapy with Ibr or

underwent observation. In this trial, there was a significant

improvement in the failure-free survival rate for those who

received radioimmunotherapy (RIT) consolidation; how-

ever, this difference was seen mainly in those who had

received induction therapy with only chemotherapy. Using

an intent-to-treat analysis, no significant differences were

observed between the consolidation and observation arms

for those patients who had received rituximab as part of

induction therapy, due to low enrollment numbers.

Nonetheless, RIT may play an important role in consol-

idation of responses in FL, and further studies are

warranted.

Vaccines

Three trials have been recently completed using different

anti-Id vaccines as prevention of relapse of FLs. Levy and

colleagues [47] treated 287 patients with newly diagnosed

FL with CVP chemotherapy for 21 weeks, followed by

vaccine therapy versus observation. Median PFS results

were 19.1 months for the vaccine group versus 23.3 monthsfor the controls; further studies with this drug were

abandoned. In a second trial with a different vaccine,

Freedman and colleagues [48] reported no differences in

time to progression (TTP) results for patients with initially

diagnosed FL who received the vaccine versus placebo

following induction therapy with rituximab alone. TTP

results were 11.9 months versus 17.2 months, respectively;

for those with relapsed FL, results following the vaccine

were actually inferior; no future trials with this agent are

planned. More recently, Shuster and colleagues [49]

presented their results of a phase 3 randomized trial, in

which PACE (cyclophosphamide, doxorubicin, etoposide,prednisone) chemotherapy was used to induce CR, and then

within the next 12 months the patients received either

vaccine therapy or placebo. Of the 234 patients enrolled on

trial, only 66% maintained CR for at least 6 months, and

were able to undergo randomization. Median disease-free

survival (DFS) results for those receiving vaccine and

control were 44.2% and 30.6%, respectively (P=0.045),

although OS results were similar for the two arms.

Unfortunately, no patient in this trial had received ritux-

imab; therefore, these findings may not play an important

role in therapy administered in clinical practice today, in

which patients with FL almost universally receive ritux-

imab as part of induction therapy, and a significant number

receive maintenance therapy. There is an ongoing trial of a

plant-based vaccine in patients with relapsed FL, although

induction for these patients does not include rituximab [50].

Further studies are needed to confirm the value of this

therapeutic approach in patients receiving rituximab with

untreated and relapsed disease.

Aggressive NHL

Certain problems hamper development of agents that might

prolong PFS for aggressive lymphomas, represented by the

most common of these, diffuse large B-cell lymphoma

(DLBCL). First, with R-CHOP therapy, approximately 50%

of patients who develop disease progression will do so

during or shortly after therapy, signifying resistance to both

chemotherapy and rituximab. By definition, these patients

have diseases considered refractory to initial standard

chemotherapy, often have poor responses to therapy for

relapse, and may not be the best candidates for consolida-

Curr Oncol Rep (2010) 12:395401 397


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tion or maintenance strategies. Second, older patients have

worse outcomes with standard R-CHOP therapy than do

younger patients, and would be the ideal candidates for

consolidation or maintenance therapies because of higher

rates of relapse. However, many of these may be ineligible

for investigational trials due to comorbid illnesses, or may

have social issues that prohibit their enrollment in studies.

Finally, randomized trials are necessary to demonstrate thebenefit of maintenance therapies, and patients may be

reluctant to enroll in such trials that would include a

placebo arm. Nonetheless, there are three drugs currently

being tested as maintenance therapy in the treatment of

DLBCL: enzastaurin, lenalidomide, and everolimus.

Enzastaurin

This drug is an oral, serine threonine kinase inhibitor that

targets the PKCBeta and PI3/AKT signaling pathways,

suppressing tumor cell proliferation, inducing cell death, and

causing tumor-induced angiogenesis. PKCBeta was identifiedby gene-expression profiling and other preclinical studies as a

rational target in DLBCL, and the drug has been granted

orphan drug status by the FDA for treatment of DLBCL. In

one clinical trial of 55 patients with relapsed disease, three

entered CR, and the drug was well tolerated [51]. The

PRELUDE trial (Preventing Relapse in Lymphoma Using

Daily Enzastaurin) is a randomized, placebo-controlled study

in older patients at high risk of relapse following CR

induction with initial therapy; the primary end point of the

study is DFS, and the trial is enrolling at more than 100 sites

worldwide [52].

Lenalidomide

This analogue of thalidomide is active in therapy of lympho-

proliferative malignancies. The drug is classified as an

immunomodulatory agent, and has significant effects on the

normalcells in the tumor microenvironment, besides having

some effects on tumor cells themselves [53, 54]. Some of

these effects include inhibition of binding of tumor cells to

the tumor bed, inhibition of release and activity of cytokines

associated with tumor cell proliferation, suppression of

tumor-induced angiogenesis, and activation of natural killer

cells and macrophages, although its major mechanisms of

action in patients with lymphoproliferative diseases are still

uncertain. It is currently approved in the United States for

treatment of patients with relapsed myeloma in combination

with dexamethasone and in therapy of myelodysplastic

syndrome with 5q deletion with or without other cytogenetic

abnormalities. However, investigators have discovered that

this drug also demonstrates significant activity in therapy of

relapsed indolent and aggressive NHLs, and may even play

an important role in initial therapy of these diseases [5460].

In a recent update of the current knowledge regarding this

agent in management of aggressive NHLs, Witzig and

colleagues [57] reported results of therapy for 217 patients

with aggressive NHLs, 108 of whom had DLBCL. Other

histologies included mantle cell lymphoma, transformed

lymphoma, and FL, grade 3. The median number of prior

therapies for these patients was three, 44% were considered to

have disease refractory to their last therapy, and 34% hadpreviously undergone SCT. Overall, 13% of the patients in

this analysis demonstrated CR, and the OR and median PFS

rates for those with DLBCL were 28% and 2.3 months,

respectively, with a median duration of response of

4.5 months. The drug was only modestly myelosuppressive,

with grades 2 to 3 neutropenia and thrombocytopenia in 41%

and 18%, respectively. Because of this activity, investigators

have begun to combine lenalidomide with R-CHOP in

therapy of previously untreated large-cell lymphomas [60].

More recently, investigators have also suggested that germi-

nal center B-cell lymphomas may not respond as well to

therapy with this agent as do non-germinal B-cell lympho-mas, a provocative finding that is the subject of a large

international trial to more precisely define the true benefit of

this drug in treatment of aggressive lymphomas [61]. For this

reason, investigators in the Group Etudes de Lymphome de

lAdulte are conducting a trial testing the value of this agent

as a maintenance agent in treatment of patients with high-risk

aggressive lymphomas.

Everolimus

The mammalian target of rapamycin (mTOR) is a key tyrosine

kinase in the PI3K/Akt pathway, regulating growth factor

signaling and intracellular nutrients, and activation of this

kinase promotes cell growth, cell growth and proliferation,

angiogenesis, and cellular metabolism [6264]. Inhibition of

mTOR slows G1-S transition, and inhibits proliferation of

lymphoma cell lines [65, 66]. Therefore, investigators have

developed inhibitors to this important target, temsirolimus

and everolimus, and have studied these drugs in a variety of

tumor types. In 2007, temsirolimus was approved by the

FDA in the United States for initial therapy of advanced

renal cell carcinoma, and in 2009, everolimus was approved

to treat patients with relapsed renal cell carcinoma following

failure of sorafenib or sunitinib [67, 68]. These drugs are

also known to have activity in therapy of relapsed NHLs,

and in vitro studies suggest synergism with standard agents

known to be active in lymphoma therapy [6971]. Witzig

and colleagues [71] presented results of everolimus therapy

for 143 patients with a wide variety of relapsed or refractory

lymphomas, 47 of whom had DLBCL. The median number

of prior therapies was four (range 115). Grades 3 to 4

hematologic toxicities included anemia (16%), neutropenia

(17%), and thrombocytopenia (35%). Nonhematologic tox-

398 Curr Oncol Rep (2010) 12:395401


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icities included hypercholesterolemia, hyperglycemia, and

hypertriglyceridemia. The OR and CR rates for all patients

were 43% and 3.5%, respectively; corresponding results for

those with DLBCL were 30% and 2%. For all patients, the

median TTP was 4.3 months, and the duration of remission

for 48 responders was 6.8 months. The drug is currently in

trials in combinations with panobinostat and bortezomib for

relapsed lymphoma; however, a trial is also underway toexplore the value of this drug as maintenance in patients

with large-cell lymphoma [72].

Conclusions

Therapy for patients with NHLs has become more

successful over the last 10 years, mainly because of the

development of the monoclonal antibody, rituximab. A few

studies have suggested that results could be further

improved by the use of consolidation therapy, consisting

of high-dose therapy followed by SCT, but this mode oftreatment has not gained popularity among clinicians and

patients alike because of expense and tolerability issues.

However, a number of promising trials have suggested that

more tolerable treatments might also improve results, and

one of these, the addition of maintenance rituximab

following induction immunochemotherapy, has recently

been reported for patients with previously untreated FL.

Other trials have been reported with vaccine therapies and

RIT, and have met with mixed opinions, mainly because

most of these trials have not been conducted with patients

receiving immunochemotherapy, which has become a

standard for many patients with NHLs. For aggressive

NHLs, a variety of protein inhibitors are being studied as

maintenance therapy for patients who have been induced

into remission with immunochemotherapy.

Acknowledgment The author wishes to recognize the expert

technical assistance of Thao Phan in the preparation of this

manuscript.

Disclosure No potential conflict of interest relevant to this article

was reported.

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