Acta Clin Croat 2017; 56:143-156 Review

doi: 10.20471/acc.2017.56.01.20

RITUXIMAB MAINTENANCE STRATEGY

IN ADVANCED FOLLICULAR LYMPHOMA:
FACTS AND CONTROVERSIES
Vibor Milunović1,2, Martina Bogeljić Patekar1, Karla Mišura Jakubac1, Inga Mandac Rogulj1,
Delfa Radić-Krišto1, Ana Planinc-Peraica1,3 and Slobodanka Ostojić Kolonić1,3

1
Division of Hematology, Merkur University Hospital, Zagreb, Croatia;
2
Lombardi Comprehensive Cancer Centre, Georgetown University, Washington D.C., USA;
3
School of Medicine, University of Zagreb, Zagreb, Croatia

SUMMARY – Rituximab is a chimeric monoclonal CD20 antibody used in the treatment of

CD20 positive non-Hodgkin lymphomas and has revolutionized treatment approach to these hema-
tologic malignancies in the last decade. The main aim of this review is to present data on the use of
rituximab in the treatment of follicular lymphoma (FL). We will focus on rituximab maintenance
strategies in the first and second line treatment. This approach has improved the outcome in FL pa-
tients with better progression-free survival in all patients and better overall survival in relapsed setting.
Regardless of good results, this strategy has generated controversies in medical community in the
range from the lack of overall survival benefit in first line setting, adverse effects of possible overtreat-
ment and toxicities to its unknown role in the era of novel agents. The existing data suggest that
rituximab maintenance should be a rational therapeutic option for all patients with FL responding to
first line therapy and transplant-ineligible patients responding to reinduction.
Key words: Rituximab; Lymphoma, non-Hodgkin – therapy; Lymphoma, follicular; Maintenance che-
motherapy; Treatment outcome

Introduction cently by the international NHL classification proj-

ect4. The histology of FL is characterized by germinal
Follicular lymphoma (FL) is one of the most com- centers of B lymphocytes, predominantly centrocytes
mon subtypes of non-Hodgkin lymphoma (NHL). A and centroblasts with follicular growth pattern2,5. They
recent survey in the United States that included harbor universal translocation t(14;18)(q32;q21) in-
596,476 patients with newly diagnosed NHL over a volving the rearrangement of BCL2 and IgH in most
period of 14 years demonstrated that FL was the sec- cases. Morphologically, four different grades are recog-
ond most common subtype of NHL, accounting for nized, based on the number or centroblasts per high
17.1% of cases1,2. In Croatia, the incidence of NHL is power field with FL grade 4b being a distinct entity
5.57 per 100,000 of men or women, as reported by No- due to different biological and clinical behavior2,6. It is
vak et al. for the 2005-2009 period3. FL accounts for also characterized by expression of BCL2, BCL6,
20.2% of NHL cases in Croatia as demonstrated re- CD20, CD19 and monoclonal immunoglobulin light
chain.
Correspondence to: Vibor Milunović, MD, Lombardi Comprehen- The course of the disease is marked by indolent
sive Cancer Centre, Georgetown University, 3970 Reservoir Road course, frequent relapses, ‘incurability’, and tendency
NW E501, 20007 Washington D.C., United States of America
(current address)
to transform into more aggressive NHL (diffuse large
E-mail: [email protected] B cell lymphoma). It is important to note that not all
Received February 10, 2015, accepted April 25, 2016 patients are treated initially due to the ‘watch and wait’

Acta Clin Croat, Vol. 56, No. 1, 2017 143

V. Milunović et al. Rituximab maintenance in follicular lymphoma

Table 1. GELF proposal as a reason to start treatment7 ROCARE 5 report13. A subanalysis for hematologic
malignancies was performed for 1997-2007 including
Reason to start treatment
32,110 FL cases14. Considerable improvement was re-
Involvement of 3 nodal sites (diameter ≥3cm) corded in 5-year OS of FL patients and in comparison
Any tumor mass greater than 7 cm to other lymphoid malignancies, rising from 58.9% in
B symptoms the 1997-1999 period to 74.3% in the 2006-2008 pe-
Pleural effusion or ascites riod. There are several reasons for this improvement in
Cytopenia (leukopenia, thrombocytopenia) outcomes, but for the purpose of this review we will
Leukemia (≥5x109 of malignant cells) state only two, i.e. the widespread introduction of
rituximab, a chimeric antiCD20 antibody, and im-
provement in autologous stem cell transplantation
Table 2. Risk stratification according to FLIPI-1 (ASCT).
and FLIPI-210,11 In the report of the European Society for Blood
Prognostic score and Marrow Transplantation (EBMT) study, which
included 693 patients followed-up for at least 15 years,
FLIPI-1* FLIPI-2**
the outcomes of ASCT for FL are presented15. The
Age ≥60 years Beta 2 microglobulin
median progression-free survival (PFS) at 5, 10 and 15
≥ULN
years was 41%, 28% and 26%, respectively, with a pla-
Ann Arbor stage III or IV Bone marrow involvement
teau in the survival curve indicating satisfactory dis-
Hemoglobin ≤120 g/L Age >60 years ease control in one-quarter of patients with relapsed or
Serum LDH ≥ULN Hemoglobin ≤120 g/L refractory FL. The median OS for ASCT at 5, 10 and
Number of nodal sites ≥5 Longest nodal diameter 15 years was 64%, 52% and 47%, respectively. In a
>6 cm study of 121 patients undergoing ASCT at second re-
*number of factors: 0-1 low risk group; 2 intermediate risk group; 3 mission or subsequent relapse, followed-up for at least
or more high risk group; **number of factors: 0 low risk group; 1-2 12 years, PFS was 55% at 5 year and 48% at 10 years16.
intermediate risk group; 3 or more high risk group; ULN = upper These results also show adequate tumor control, which
normal limit; LDH = lactate dehydrogenase
can be obtained by ASCT. The only factor associated
with longer OS was ASCT at 2nd complete remission
strategy. The most commonly used treatment criteria (CR). This treatment approach was also embraced of-
(GELF) are presented in Table 17. Controversies re- ficially by the leading international guidelines and sub-
main regarding treatment rationale in cases of low tu- sequently by the Croatian Society of Hematology and
mor mass8,9. Furthermore, newly diagnosed FL pa- Transfusion in the national lymphoma guidelines17-19.
tients should be stratified according to FLIPI-1 or Another important improvement in the treatment
FLIPI-2 criteria (Table 2) in order to predict the out- of FL patients was the introduction of rituximab. The
comes and overall survival (OS)10,11. pivotal study included 166 patients with relapsed FL
The main aim of this review is to analyze the exist- or other low grade NHL on infusion regimen with
ing data on the current treatment of FL with special 375 mg/m2 once weekly for 4 weeks20. The overall re-
emphasis on maintenance therapy. sponse rate (ORR) was 48% and PFS 13 months. Tox-
icities were mild and the efficacy was comparable to
the cyclophosphamide, doxorubicin, vincristine and
Historical Overview of Advances
prednisone (CHOP) chemotherapy regimen, then
in Follicular Lymphoma Therapy
considered as the gold standard for indolent lympho-
Prognosis in patients diagnosed with FL was poor. mas. This study led to approval of rituximab for re-
In a retrospective single-center analysis from the lapsed indolent NHL in 199721. With its impressive
1970s, the 5-year OS was 54%, deteriorating to 34% in activity and low toxicity profile, the question arose if
patients older than 5012. Disease-free survival after rituximab could be further combined with conven-
5-year follow up was only 18% of patients. However, tional chemotherapy to improve outcomes in these
these numbers improved as outlined by the recent EU- patients. Preliminary data on preclinical models sup-

144 Acta Clin Croat, Vol. 56, No. 1, 2017

V. Milunović et al. Rituximab maintenance in follicular lymphoma

ported in vivo synergistic effects of rituximab with cy- er toxicity, primary cytopenias and cardiotoxicity,
totoxic drugs22. However, it took years to translate which limit its application. The use of R-CHOP or
these findings into clinical reality. The first pivotal ran- R-CVP currently depends on the experts’ judgment
domized trial published in 2005 compared cyclophos- until the large observational trials such as RE-
phamide, vincristine and prednisone (CVP) with FLECT-1 provide answer to this question29.
rituximab-CVP (R-CVP)23. It included 321 patients First line therapy including rituximab has achieved
with stage III or IV FL. Primary objective was time to excellent tumor control and reduction, but the ques-
treatment failure (TTTF). TTTF was significantly tion remains if additional benefit of rituximab may be
longer in R-CVP group as compared with CVP group exploited to reduce relapses and prolong PFS without
(27 months vs. 7 months). ORR rates were 81% and the need for further cytotoxic treatment.
57%, respectively, indicating superior tumor control in
rituximab group with prolonged duration of response
The Rationale for Rituximab
(35 months vs. 14 months). Concerning toxicity pro- as Maintenance Therapy
file, the addition of rituximab resulted in infusion reac-
tions that were manageable and higher rates of neutro- After encouraging results of the pivotal study on
penia but without any clinical repercussion. The au- rituximab, additional analysis was conducted based on
thors conclude that R-CVP represents a novel, im- the pharmacokinetics and response20,30. Overall, ritux-
proved standard of care in FL, which was recognized imab serum concentrations increased and accumulated
by regulatory agencies24. The results of this study were after each infusion with slow clearance during post
updated with a longer follow up of 53 months showing treatment follow up. Additionally, the authors found
the superiority of R-CVP with OS benefit (83% vs. that serum concentration of rituximab was significant-
77%)25. Subsequently, additional improvements of the ly higher in responders when compared to non-re-
first line rituximab-containing regimen were explored. sponders, especially during follow up. Additional pa-
Rituximab was also included in the anthracycline- rameters associated with elevated rituximab concen-
based CHOP regimen in a trial including 428 high tration were B-cell depletion, reduction of the largest
tumor burden FL patients26. Better ORRs, longer time tumor diameter, and the sum of diameter of six largest
to treatment failure (60% TTTF reduction) and dura- tumor lesions. The authors conclude that this may rep-
tion of response, and better 2-year OS rates (95% vs. resent additional antitumor activity of rituximab and
90%) were achieved with R-CHOP as compared to that higher concentrations may have a beneficial clini-
CHOP. This study added to the on-going heated dis- cal effect. These findings were further clinically con-
cussion whether to use anthracyclines in the frontline firmed in a randomized control trial by Ghielmini et
therapy for better tumor control in FL. A meta-analy- al.31. In 185 treatment naïve or relapsed FL patients,
sis that included four clinical trials was performed to rituximab was administered once weekly for four
answer this review question27. Therapy with R-CVP weeks. After induction, they were randomized to re-
enabled higher CRs while R-CHOP was associated ceive additional four doses of rituximab every 8 weeks
with better ORRs. However, the pitfall of this system- (‘prolonged phase’) or had no additional therapy. Pri-
atic review was not analyzing long term FL outcomes, mary outcome of the study was EFS which was sig-
and the authors conclude that the choice of the regi- nificantly longer in ‘prolonged’ group (23.2 months vs.
men should be decided individually based on the need 11.8 months). Overall, the risk of disease related event
to avoid anthracycline cardiotoxicity in older patients decreased by 60%. The prolonged treatment was not
or in young patients where salvage therapy followed by associated with any clinically relevant toxicity. In con-
ASCT is planned in the future. A recent Cochrane clusion, prolonged rituximab exposure is associated
meta-analysis including 8 randomized control trials with beneficial effects in FL with more favorable out-
investigated the effect of adding anthracycline in treat- comes. This trial provided evidence to further explore
ing FL on long term outcomes28. No OS benefit was if rituximab could be used as maintenance therapy for
recorded while PFS was in favor of anthracycline us- reducing the relapse rates and the need for additional
age. However, anthracycline was associated with high- chemotherapy.

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V. Milunović et al. Rituximab maintenance in follicular lymphoma

Maintenance with Rituximab CHOP regimens, for the first time showing that
in Relapsed Follicular Lymphoma maintenance strategy following the standard of care
improved outcomes in these patients. Furthermore,
The first randomized phase III trial explored ritux- PFS translated in OS benefit with 3-year OS rate was
imab maintenance in 176 patients with relapsed or re- 85.1% in maintenance group as compared with 77.1%
fractory FL or mantle cell lymphoma32. Reinduction in observation group. Additional safety risks arose in
was induced with fludarabine, cyclophosphamide and patients in the maintenance group being more prone
mitoxantrone (FCM) with or without rituximab. Ow- to neutropenia (10.8%) and infections (9%). This tox-
ing to the more favorable ORRs in R-FCM group, icity was manageable and no death related to treat-
first randomization was stopped and additionally re- ment was recorded. EORTC trial has demonstrated
cruited patients were allocated to R-FCM group. Sec- major improvements in care for relapsed or refractory
ond randomization of responding patients involved FL patients, leading to approval of rituximab mainte-
rituximab maintenance (2 courses of 4-times-weekly nance for this indication20. Long term follow up (me-
doses at 3rd and 9th month) and observation. Primary dian 6 years) of the trial was published, again demon-
objective of the study was response duration, which strating better PFS in maintenance group as compared
was not reached in maintenance group vs. 17 months to observation group (3.7 years vs. 1.7 years)34. How-
ever, the benefit in OS was lost probably due to the
in observation group after median follow up of 26
bias produced by consequent retreatment regimens
months. When analyzing for the subtypes of NHLs,
containing rituximab. Subsequent meta-analysis in-
difference persisted in FL patients. Regarding toxicity,
cluded 6 randomized controlled trials including 909
only one discontinuation occurred due to severe infu-
patients with relapsed or refractory FL35. Improved
sion reactions, but lymphocytopenia was most pro- OS was seen in maintenance group with hazard-ratio
nounced without infections. of death estimated to 0.72. Therefore, current evidence
A rituximab maintenance study in relapsed and re- shows not only PFS, but also OS benefit in this sub-
fractory FL patients was carried out by EORTC group of patients (Table 3). Accordingly, the Croatian
group, involving 456 patients randomized at 1:1 ratio national guidelines for lymphoma diagnostics and
to receive either R-CHOP or CHOP as reinduction management have included rituximab maintenance in
therapy33. Second randomization included rituximab second CR or partial remission in transplant ineligible
maintenance administered once in 3 months for 2 patients19.
years or observation. As expected, the addition of
rituximab to CHOP regimen resulted in better ORRs Rituximab Maintenance as Part of First Line
and PFS. Promising disease control, defined as PFS of Therapy of Follicular Lymphoma
51.5 months was achieved as compared to only 14.9
months in observation arm for the whole group. PFS Preliminary results of rituximab maintenance ther-
remained significant when adjusting for R-CHOP or apy after rituximab induction at four weekly doses

Table 3. Summary of selected phase III randomized control trials on maintenance therapy in relapsed or refractory
follicular lymphoma
Study N Reinduction Primary objective Overall survival
32*
Forstpointner et al. 176 R-FCM Response duration: median 77% vs. 57%****
not reached vs. 17 months
van Oers et al.33** 456 R-CHOP PFS: 51.5 months vs. 14.9 months 85.1% vs. 77.1%
CHOP
van Oers et al.34*** 456 R-CHOP PFS: 3.7 years vs. 1.7 years 74.3% vs. 64.7%****
CHOP
*follow up 26 months, 3-year OS rate; **follow up 33.3 months, 3-year OS rate; ***follow up 6 years, 5-year OS rate; ****nonsignificant; OS
= overall survival; R-FCM = rituximab, fludarabine, mitoxantrone, cyclophosphamide; R-CHOP = rituximab, cyclophosphamide,
doxorubicin, vincristine, prednisone; CHOP = cyclophosphamide, doxorubicin, vincristine, prednisone

146 Acta Clin Croat, Vol. 56, No. 1, 2017

V. Milunović et al. Rituximab maintenance in follicular lymphoma

showed improved PFS, as described previosly31. An- It should be stressed that one study did not find
other study explored this strategy in rituximab-naïve benefit of maintenance therapy in FL. This trial was
patients36. The study enrolled 387 patients suffering conducted in elderly, untreated patients (N=234) using
from indolent NHL, most of them FL. The induction rituximab, fludarabine, mitoxantrone and dexametha-
regimen was CVP. Patients were then randomized ei- sone (R-FND). Patients were randomized in ritux-
ther to maintenance therapy (four doses of rituximab imab maintenance (one dose every four months, total
monthly at 6-month intervals, 4 courses) or observa- of four doses) or observation arm. Primary endpoint of
tion arm. Three-year PFS was 68% in maintenance the study was 2-year PFS reaching 81% in rituximab
group versus 33% in observation group. PFS advantage group versus 69% in maintenance group. However, this
did not significantly translate into OS rates. More im- difference was not statistically significant (p=0.226)39.
portantly, the study has reported conversion to better There may have been several reasons, e.g., short follow
response to CVP during rituximab phase in 22% of up, limited rituximab exposure, small sample under-
patients compared with only 7% in observation group, powered to detect difference and use of non-standard
indicating that not only rituximab maintenance im- immunochemotherapy regimen in the first line setting.
proved outcomes in terms of PFS, but could addition- An updated meta-analysis has consistently shown im-
ally improve ORRs to prior induction regimen. No provement in PFS across various studies (N=5), but
data on toxicity were provided in the study. These stud- again without translation in OS35. Data on rituximab
ies used historical regimens (CVP, rituximab 4 doses in first line maintenance therapy treatment of FL are
weekly) and the need arose to explore maintenance summarized in Table 4.
strategy in contemporary setting. In one of the largest
trials to date, PRIMA, which enrolled 1217 patients
suffering from untreated high burden FL, newer treat- Controversies Surrounding Maintenance Therapy
ment regimens were used37. All patients were treated in Advanced High Burden Follicular Lymphoma:
with one of the following chemotherapy regimens: R- to Maintain or not to Maintain?
CHOP, R-CVP or R-FCM. After the end of treat-
So far, we have described relevant clinical trials of
ment, 1019 patients were randomized into rituximab
maintenance group (rituximab therapy once in two maintenance strategy in FL and several controversies
months for two years) or observation group. Primary have arisen. This will be discussed regarding routine
endpoint was PFS. The 3-year PFS rate was 74.9% in clinical practice.
rituximab group as compared with 57.6% in observa-
The role of autologous stem cell transplantation
tion group, with median follow up of 36 months. Fur-
for relapsed follicular lymphoma in rituximab era
thermore, as shown by previous study, this strategy
may contribute to conversion to optimal response, i.e. One of the few clinical trials examining ASCT and
72 patients with PR were converted to CR during the conventional therapy (N=89) showed OS and PFS
maintenance phase. Once again, PFS did not translate benefit, but was performed before the advent of ritux-
into OS benefit. Results with a longer follow up (me- imab40. The largest data set on ASCT comes from
dian 6 years) have been reported38. The 6-year PFS rate various retrospective series (e.g., EBMT), while data
was 59.2% for maintenance group versus 42.7% in ob- on ASCT during rituximab availability are scarce15,41.
servation group. Time to next lymphoma treatment or In a retrospective analysis by the French GELA group,
chemotherapy was significantly longer in the mainte- 254 patients with relapsed FL were included42. Pa-
nance group. The maintenance strategy did not affect tients treated with rituximab-based regimen had sig-
second line treatment of FL with CRs being similar nificantly better outcomes (OS and EFS) than those
between the groups. However, no significant difference treated with ASCT, but adding rituximab to salvage
in OS has been reported. Based on the results of PRI- regimen followed by ASCT resulted in the most effi-
MA trial, rituximab was approved by regulatory agen- cient disease control (OS and EFS not reached). Ac-
cies for another indication as first line maintenance cording to the Croatian national guidelines, salvage
therapy in previously untreated FL responding to in- chemotherapy containing rituximab followed by
duction therapy24. ASCT is recommended for young, fit patients without

Acta Clin Croat, Vol. 56, No. 1, 2017 147

V. Milunović et al. Rituximab maintenance in follicular lymphoma

Table 4. Data from selected phase III randomized controlled trials on rituximab maintenance following first line
therapy in high burden follicular lymphoma
Study N Induction Primary objective Overall survival
Ghielmini et al.31* 64 Rx4 EFS: 36 vs. 19 months Not reported
Hochster et al.36** 288 CVP PFS: 68 vs. 33 months 92% vs. 86%******
Salles et al.37*** 1217 R-CVP PFS:74.9 vs. 57.6% months No significant reduction in hazard
R-CHOP ratio for death
R-FCM
Salles et al.38**** 1217 R-CVP PFS: 59.2 vs. 42.7% 84.7% vs. 88.7*****
R-CHOP
R-FCM
Vitolo et al.39***** 234 R-FND PFS: 81% vs. 69% ****** Not reported for groups
*median follow up 35 months; **median follow up 3.7 years, 3-year survival rates; ****median follow up 3 years, 3-year survival rates;
*****median follow up 6 years, 6-year survival rates; ******median follow up 2 years, 3-year survival rates; ******nonsignificant; R = rituximab;
CVP = cyclophosphamide, vincristine, prednisone; CHOP = cyclophosphamide, doxorubicin, vincristine, prednisone; FCM = fludarabine,
mitoxantrone, cyclophosphamide; FND = fludarabine, mitoxantrone, dexamethasone; EFS = event-free survival; PFS = progression-free
survival

significant comorbidities19. The issue of possible omis- surrogate endpoints such as response rates with suffi-
sion of ASCT in FL must be resolved in the context of cient duration (i.e. pathologic complete response to
randomized clinical trial examining ASCT compared neoadjuvant therapy in breast cancer) or molecular re-
to rituximab maintenance approach. To our knowl- missions (e.g., tyrosine kinase inhibitors for chronic
edge, no such trial has been performed. As stated pre- myelogenous leukemia), evidence for clear PFS benefit
viously, in transplant non-eligible patients, rituximab by rituximab maintenance in FL might be considered
post-reinduction maintenance approach is a standard sufficient ground for inclusion in routine protocols45.
of care since benefits are recorded in both PFS and
OS17,18,35. To retreat or to maintain?
Rituximab has been established as maintenance
Is progression-free survival a valid endpoint
therapy, but its possible role in retreatment was also
in follicular lymphoma?
assessed. The first phase II randomized controlled trial
One of the main criticisms of rituximab mainte- included 114 rituximab naïve and previously relapsed
nance therapy in high tumor burden FL is the fact that patients with indolent NHLs46. Subjects first received
improvement in PFS has not yet translated in OS ben- 4 weekly rituximab infusions followed by maintenance
efit by clinical trials and meta-analyses31,35-39,43. Several (four courses of 4 doses of rituximab every 6 months)
factors affecting OS in FL should be taken into ac- or reinduction with rituximab after disease progres-
count. First, FL is characterized by an indolent course sion. Primary objective was duration of rituximab
leading to high OS rates and front-line rituximab con- benefit, which was 31.3 months in maintenance
tributed to 74.3% of 5-year OS rate1,14. A follow up group versus 27.4 months in observation group.
longer than 5 years would provide information if PFS However, although the difference in primary outcome
will translate in OS. Second, for relapsed patients the was not statistically significant, PFS was significantly
established second line rituximab regimens and ASCT longer in the maintenance group (31.7 vs. 7.4 months)
may result in additional OS interpretation bias due to with a higher rate of CRs and continuous remissions.
long term remissions, which directly influences the OS When analyzing the results, we must take in account
curve. In a recent review by Korn and Crowley, PFS that this trial was designed in the era when rituxi-
was highlighted as a powerful endpoint in clinical tri- mab was only approved for relapsed FL. Further bias
als to be included in future studies44. In the time of when interpreting the results may be due to short
accelerated approvals of cancer drugs on the basis of follow up and unbalanced numbers across the groups

148 Acta Clin Croat, Vol. 56, No. 1, 2017

V. Milunović et al. Rituximab maintenance in follicular lymphoma

due to early progressions prior to starting maintenance were observed38. Safety of rituximab maintenance
therapy. treatment was investigated in MAXIMA, a phase IIIb
The groundbreaking trial was the RESORT trial trial, including 545 patients with previously untreated
including 289 treatment naïve low burden FL pa- or relapsed FL50. Hematologic adverse events equal
tients47. After 4 weeks of rituximab induction, the sub- and greater than 3 occurred in 4.4% of subjects with
jects were randomized to either receive single ritux- the most prominent event being neutropenia (2.4%),
imab infusion every 13 weeks (maintenance group) or but only 4 cases of febrile neutropenia were recorded.
reinduction in case of progression (retreatment group). Concerning infections, 4.3% of events equal or greater
The study had two primary objectives, i.e. TTTF and than 3 were recorded, with pneumonia as the most fre-
time to first cytotoxic therapy. TTTF did not statisti- quent one. Infections of grade 1 or 2 were more com-
cally differ between the groups being 3.9 years in re- mon, including nasopharyngitis (7.1%), bronchitis
treatment group versus 4.3 years in maintenance group. (4.7%) and sinusitis (4.3%). Grade 3 or 4 hypoimmu-
Time to first cytotoxic therapy was significantly longer noglobulinemia developed in 4 patients, and in 32 pa-
in maintenance group as compared to retreatment tients hypoimmunoglobulinemia was of prolonged
group. The authors concluded that the retreat scheme duration, but this event was self-limiting and did not
was as efficacious as maintenance strategy, therefore require intervention in most cases.
reducing overtreatment in this group. The results of In a systematic review of rituximab maintenance
this study were greeted with great enthusiasm by therapy that included 11 clinical trials and 1009 pa-
maintenance opponents as the ‘final nail in mainte- tients suffering from FL or MCL, suppression of bone
nance coffin’48,49,53. Still, great care should be exercised marrow and infections were most common toxicities,
regarding extrapolation of these results to treatment of with 24% of patients experiencing grade 3 or 4 toxici-
advanced FL. Considering the relatively short EFS of ty51. Significantly less toxicity was found in the regi-
11.8 months in first line rituximab induction therapy men of 4 weekly rituximab infusions every 6 months
without extended use, retreatment strategy may not be compared to PRIMA schedule (once in two months
as effective in high tumor burden FL, but this pre- for 2 years), i.e. 12% and 35%, respectively. The system-
sumption was not analyzed. Although the retreatment atic review also included MCL patients, which prob-
option with rituximab may be attractive due to the ac- ably affected the results, as MCL patients are treated
ceptable toxicity profile and probable cost-effective with more aggressive therapy in first line treatment
benefit, in the absence of data for advanced FL, stan- (high doses of cytarabine with cumulative toxicity).
dard maintenance therapy should represent good clin- Rituximab maintenance therapy is associated with few
ical practice. side effects, which are tolerable and mostly do not
cause discontinuation. While PRIMA schedule should
Toxicity of rituximab maintenance remain the standard of care, in specific patient popula-
tions (elderly, unfit, and those prone to infectious com-
Concerning the safety profile of rituximab mainte-
plications) alternative approach with rituximab (four
nance, the largest set of data comes from the PRIMA
weekly doses every 6 months for four cycles) may be a
trial37. The frequency of adverse events equal and
sound option.
greater than 3 occurred in 24% of patients in mainte-
nance group as compared to 17% events in observation
Rituximab maintenance therapy and quality of life
group. The most common events were new malignancy
(4%), neutropenia (4%) and infections (4%). Discon- The World Health Organization defines the qual-
tinuation rate due to adverse events was 4% in mainte- ity of life (QoL) as the “individuals’ perception of their
nance group. Continuous rituximab exposure can position in life in the context of the culture and value
cause low plasma immunoglobulins, but no significant systems in which they live and in relation to their
decrease in immunoglubulins A, M and G was found goals, expectations, standards and concerns”53. QoL as
in either group. Also, the incidence of transformation an important medical issue has substantial impact on
to aggressive diffuse large B cell lymphoma did not designing of clinical trials, mostly as self-reported sec-
differ between the groups and no other safety risks ondary endpoint. Two different QoL questionnaires

Acta Clin Croat, Vol. 56, No. 1, 2017 149

V. Milunović et al. Rituximab maintenance in follicular lymphoma

were applied in PRIMA trial and no difference was progression group associated with higher cost of care
found between maintenance and observation group37. and its impact on healthcare system. This study indi-
This has led to criticism that QoL is not improved in rectly provides the rationale that the prolongation of
these patients, thus failing in secondary endpoint43. PFS in FL patients is associated with lower healthcare
This is apparently conflicting, but the treatment did burden and costs, and provides evidence that mainte-
not further deteriorate QoL. Also, patients were cen- nance therapy can indeed be cost-effective. One of
sored at the time of progression, so prospective data on earlier cost-effectiveness studies of rituximab mainte-
the possible deterioration in QoL during relapse and nance comes from the Swedish group56. They based
the true impact of maintenance strategy on QoL will their financial model on the phase III trial in relapsed
remain unknown. It is important to note that relapsed setting conducted by EORTC group33. Incremental
FL patients experience a rapid decline in QoL, as cost per quality-adjusted life-years (QALY) was esti-
demonstrated in a series of 222 patients during differ- mated to 12,600 € for rituximab group, while the cost
ent disease states, but in relapsed setting53. The im- per life-years-gained (LYG) was 11,200 €. In all of the
provement in QoL as a valid surrogate outcome of simulations, rituximab maintenance was associated
treatment was recently raised by a prospective clinical with incremental costs which were less than 25,400 €.
trial including 379 asymptomatic, low tumor burden With regard to willingness-to-pay value in Sweden of
FL patients9. The main question of the trial was com- up to 54,000 € per intervention, rituximab mainte-
parison of outcomes between the ‘watch and wait’ nance in relapsed setting was cost-effective. Recently, a
strategy versus rituximab treatment. By randomizing Dutch population-based study used registry data com-
patients into three groups (‘watch and wait’, rituximab prising 3581 patients with relapsed FL undergoing
induction, and rituximab maintenance), the authors maintenance therapy57. The incremental cost-effective-
showed the expected improvement in time to next ness ratio (ICER) was 11,254 € per QALY and 10,591
therapy in rituximab groups. Interestingly, the second € per LYG. ICERs slightly differed in two studies
main endpoint was improvement in QoL. The active (EORTC trial and matched-real world scenarios), but
approach, i.e. rituximab maintenance, significantly im- in conclusion rituximab maintenance in relapsed pa-
proved QoL in these patients, indicating that active tients was found to be cost-effective and in line with
approach towards illness improves many lifestyle as- Dutch healthcare policy makers. Similar results were
pects, including coping mechanisms and emotional obtained by a French economic analysis based on
status. QoL as primary endpoint has its drawbacks due EORTC trial estimating ICER of 7612 € per LYG
to the existence of various, more cost-effective inter- and 8729 € per QALY33,58. These data demonstrate that
ventions in this group such as psychotherapy54. In con- rituximab maintenance is cost-effective in relapsed FL
clusion, it is hard to extrapolate the findings of these setting and its ICER is well below willingness-to-pay
studies, whether maintenance therapy improves QoL value for oncologic drug.
of FL patients indeed, but it is important to note that The earliest data on rituximab maintenance cost-
this strategy does not have negative impact, thus sug- effectiveness in first line setting come from US group
gesting another argument for the validity of this ap- based on the results of PRIMA trial37,59. Total cost of
proach. maintenance therapy was estimated to be 38,545 USD
with ICERs being 31,394 and 34,842 USD for LYG
The cost-effectiveness of rituximab maintenance and QALY, respectively. The majority of US studies
The cost of rituximab maintenance strategy is an use ICER per QALY threshold as 50,000 USD, this
important issue43. In a recent retrospective health eco- approach seems to be cost-effective from US point of
nomics US study that included 1002 patients with FL view60. In Europe, only one health economics study
from MEDICARE database, the cumulative one-year from the UK National Institute for Health and Care
cost for patients that progressed was 30,890 USD Excellence examined rituximab maintenance61. Most
(N=268) versus only 8704 USD for those in observa- of ICERs per QALY were under 30,000 GBP, as re-
tion group (N=734)55. The outpatients, inpatients, che- ported by the manufacturer, while Evidence Review
motherapy and acute care visits were more frequent in Group estimated ICERs per QALY to range between

150 Acta Clin Croat, Vol. 56, No. 1, 2017

V. Milunović et al. Rituximab maintenance in follicular lymphoma

24,600 and 35,000 GBP based on the scenario. The maintenance still plays a role in this setting. Rituximab
review group has concluded that rituximab mainte- maintenance following B-R induction is being evalu-
nance is cost effective for the National Health System ated in the ongoing MAINTAIN study67. Preliminary
resources, which evaluate ICER per QALY as 30,000 results have shown feasibility of the approach, but we
GBP. Data were from primary PRIMA study with a will have to wait if difference in PFS will be achieved
short follow up, which possibly influenced the results. between maintenance arms and observation arm.
Future studies including real-world data are needed to The greatest challenge to rituximab maintenance
address this issue. poses the relatively new introduction of B-cell receptor
(BCR) pathway inhibitors into the field of NHLs68.
Rituximab maintenance at the dawn of new drugs These agents have rapidly changed therapy approach
for indolent non-Hodgkin lymphoma: still necessary? as tyrosine kinase inhibitors. In indolent NHLs, the
most important member of the class is currently idelal-
The past several years have certainly been exciting
isib, a phophatidylinositol-3 kinase δ inhibitor. Based
for indolent NHLs, particularly FL with the introduc-
on the preliminary data on its activity in indolent
tion of new drugs possibly changing treatment op-
NHLs, a randomized, clinical trial was performed on
tions. The first drug of interest is certainly bendamus-
125 heavily pretreated patients with indolent NHLs69.
tine (B), an ‘old’, but new drug in the field. Bendamus-
Idelalisib has shown satisfactory activity with ORR of
tine acts as a potent alkylating agent, indeed more
57% and median duration of response of 12.5 months,
potent than cyclophosphamide62, which also is not
which was granted by FDA approval for refractory and
cross-resistant with other members from the group.
relapsed indolent NHLs70. Although this agent alone
The activity of bendamustine was demonstrated in
cannot produce durable CRs, its low toxicity in re-
early clinical trials in refractory or relapsed indolent
lapsed setting and new mechanism of action make ide-
NHLs resulting in high ORRs and durable remissions
lalisib a preferable target for various combinations.
as a single agent or in combination therapy resulting in
Recently, a great setback has occurred with idelalisib71.
FDA approval for rituximab-resistant indolent
The interim safety analysis of trials exploring idelalisib
NHLs63. However, the true value of bendamustine was
recognized in first line therapy of iNHLs. First ran- in combinations with cytotoxic drugs has shown infe-
domized clinical trial compared bendamustine in rior OS due to toxicity profile (Pneumocystis jirovecii
combination with rituximab (R-B) to standard R- infections, cytomegalovirus reactivation, high rates of
CHOP therapy in indolent and mantle cell lympho- transaminitis and pneumonitis), which led to suspen-
mas64. This combination resulted in improved PFS sion of RCTs in first line setting. Other BCR pathway
when compared to standard arm across all NHLs his- inhibitors for indolent NHLs, such as venetoclax, are
tology. Also, its toxicity was more tolerable with fewer explored in phase I/II trials and proper introduction of
hematologic and other adverse events (mostly infec- these agents in real time clinical practice will not occur
tions). The results of this trial produced the hype that soon.
the era of R-CHOP had ended65. However, despite
the non-inferiority design, BRIGHT study compared Conclusion
R-B to R-CHOP or R-CVP and did not demonstrate
superiority in terms of ORRs, while PFS was not re- The existing data indicate that rituximab mainte-
ported70. Adverse events included more hypersensitiv- nance in advanced high tumor FL is efficient for:
ity reactions, vomiting and nausea, and infection rate 1. prolonged PFS
was not reduced. These results sparked doubt on the 2. prolonged OS in relapsed FL
role of bendamustine in first line treatment and on- 3. optimization of response
going controversy whether B-R regimen should re- 4. low toxicity profile
place current standard regimens in FL and has not 5. adequate cost-benefit profile
been granted universal approval for this indication. 6. no negative interference with QoL
Nevertheless, ever more patients are being treated with Recommended treatment algorithms are presented
B-R regimen questioning appropriateness of which in Figures 1 and 2. Rituximab maintenance may be
has led to the question whether subsequent rituximab used in first and second line treatment of advanced

Acta Clin Croat, Vol. 56, No. 1, 2017 151

V. Milunović et al. Rituximab maintenance in follicular lymphoma

*Maintenance in case of complete or partial remission, dosing schedule according to PRIMA study37

Fig. 1. Preferred treatment algorithm for previously untreated advanced high tumor burden follicular lymphoma72.

*include rituximab if first remission is longer than 6 months19; **proceed to ASCT in case of complete or partial remission in transplant-
eligible patient; ***rituximab maintenance in case of complete or partial remission in transplant-ineligible patient, use EORTC dosing
schedule33

Fig. 2. Preferred treatment algorithm for relapsed advanced stage high tumor burden follicular lymphoma.

high tumor burden FL according to the national guide- gitudinal analysis of the National Cancer Data Base from 1998
lines for lymphoma diagnosis and treatment19. Despite to 2011. Am J Hematol. 2015;90:790-5. https://doi.org/10.
1002/ajh.24086
current controversies surrounding this strategy, current
2. Jaffe ESHN, Stein H, Vardiman JW, editors. World Health
data suggest that rituximab maintenance may and need
Organization Classification of Tumours: Pathology and Ge-
to be employed in modern treatment of FL. netics of Tumours of Haematopoietic and Lymphoid Tissues.
Lyon: IARC Press; 2001.
Acknowledgment. 3. Novak I, Jakšić O, Kuliš T, Batinjan K, Znaor A. Incidence and
mortality trends of leukemia and lymphoma in Croatia, 1988-
We thank Professor Vesna Kušec for help with
2009. Croat Med J. 2012;53:115-23.
preparation of the manuscript.
4. Dotlic S, Perry AM, Petrusevska G, Fetica B, Diebold J, Ma-
cLennan KA, et al. Classification of non-Hodgkin lymphoma
in south-eastern Europe: review of 632 cases from the interna-
References
tional non-Hodgkin lymphoma classification project. Br J
1. Al-Hamadani M, Habermann TM, Cerhan JR, Macon WR, Haematol. 2015;171:366-72. https://doi.org/10.1111/bjh.13586
Maurer MJ, Go RS. Non-Hodgkin lymphoma subtype distri- 5. Xerri L, Dirnhofer S, Quintanilla-Martinez L, Sander B, Chan
bution, geodemographic patterns, and survival in the US: a lon- JK, Campo E, et al. The heterogeneity of follicular lymphomas:

152 Acta Clin Croat, Vol. 56, No. 1, 2017

V. Milunović et al. Rituximab maintenance in follicular lymphoma

from early development to transformation. Virchows Arch. 17. Zelenetz AD, Gordon LI, Wierda WG. NCCN Clinical Prac-
2015; 468:127-39. https://doi.org/10.1007/s00428-015-1864-y tice Guidelines in Oncology (NCCN Guidelines) Non-Hodg-
6. Freedman A. Follicular lymphoma: 2014 update on diagnosis kin’s Lymphomas Version 2/2015. Accessed 11/17/2015 http://
and management. Am J Hematol. 2014;89:429-36. https://doi. www.nccn.org/professionals/physician_gls/pdf/nhl.pdf
org/10.1002/ajh.23674 18. Dreyling M, Ghielmini M, Marcus R, Salles G, Vitolo U,
7. Solal-Céligny P, Lepage E, Brousse N, Tendler CL, Brice P, Ladetto M. Newly diagnosed and relapsed follicular lympho-
Haïoun C, et al. Doxorubicin-containing regimen with or ma: ESMO Clinical Practice Guidelines for diagnosis, treat-
without interferon alfa-2b for advanced follicular lymphomas: ment and follow-up. Ann Oncol. 2014;25:iii76-82. https://doi.
final analysis of survival and toxicity in the Groupe d’Etude des org/10.1093/annonc/mdu200
Lymphomes Folliculaires 86 Trial. J Clin Oncol. 1998;16:2332- 19. Aurer I, Gasparov S, Kralik M, Balenović A, Huić D, Santek F,
8. https://doi.org/10.1200/JCO.1998.16.7.2332 et al. Lymphoma diagnosis and treatment – second Croatian
8. Hagemeister FB. ‘Watch and wait’ as initial management for consensus. Lijec Vjesn. 2013;135:63-76. (in Croatian)
patients with follicular lymphomas: still a viable strategy? Bio- 20. McLaughlin P, Grillo-López AJ, Link BK, Levy R, Czuczman
Drugs. 2012;26:363-76. https://doi.org/10.2165/11634320- MS, Williams ME, et al. Rituximab chimeric anti-CD20
000000000-00000 monoclonal antibody therapy for relapsed indolent lymphoma:
9. Ardeshna KM, Qian W, Smith P, Braganca N, Lowry L, Pat- half of patients respond to a four-dose treatment program.
rick P, et al. Rituximab versus a watch-and-wait approach in J Clin Oncol. 1998;16:2825-33. https://doi.org/10.1200/
patients with advanced-stage, asymptomatic, non-bulky follic- JCO.1998.16.8.2825
ular lymphoma: an open-label randomised phase 3 trial. Lancet
21. Grillo-López AJ, White CA, Varns C, Shen D, Wei A, Mc-
Oncol. 2014;15:424-35. https://doi.org/10.1016/S1470-2045
Clure A, et al. Overview of the clinical development of ritux-
(14)70027-0
imab: first monoclonal antibody approved for the treatment of
10. Solal-Céligny P, Roy P, Colombat P, White J, Armitage JO, lymphoma. Semin Oncol. 1999;26:66-73.
Arranz-Saez R, et al. Follicular lymphoma international prog-
22. Demidem A, Lam T, Alas S, Hariharan K, Hanna N, Bonavida
nostic index. Blood. 2004;104:1258-65. https://doi.org/10.
B. Chimeric anti-CD20 (IDEC-C2B8) monoclonal antibody
1182/blood-2003-12-4434
sensitizes a B cell lymphoma cell line to cell killing by cyto-
11. Federico M, Bellei M, Marcheselli L, Luminari S, Lopez- toxic drugs. Cancer Biother Radiopharm. 1997;12:177-86.
Guillermo A, Vitolo U, et al. Follicular lymphoma internation- https://doi.org/10.1089/cbr.1997.12.177
al prognostic index 2: a new prognostic index for follicular lym-
phoma developed by the international follicular lymphoma 23. Marcus R, Imrie K, Belch A, Cunningham D, Flores E, Ca-
prognostic factor project. J Clin Oncol. 2009;27:4555-62. talano J, et al. CVP chemotherapy plus rituximab compared
https://doi.org/10.1200/JCO.2008.21.3991 with CVP as first-line treatment for advanced follicular lym-
phoma. Blood. 2005;105:1417-23. https://doi.org/10.1182/
12. Qazi R, Aisenberg AC, Long JC. The natural history of nodular
blood-2004-08-3175
lymphoma. Cancer. 1976;37:1923-7.
24. Storz U. Rituximab: how approval history is reflected by a cor-
13. De Angelis R, Sant M, Coleman MP, Francisci S, Baili P, Pier-
responding patent filing strategy. MAbs. 2014;6:820-37. https:
annunzio D, et al. Cancer survival in Europe 1999-2007 by
//doi.org/10.4161/mabs.29105
country and age: results of EUROCARE-5 – a population-
based study. Lancet Oncol. 2014;15:23-34. https://doi.org/ 25. Marcus R, Imrie K, Solal-Celigny P, Catalano JV, Dmoszynska
10.1016/S1470-2045(13)70546-1 A, Raposo JC, et al. Phase III study of R-CVP compared with
14. Sant M, Minicozzi P, Mounier M, Anderson LA, Brenner cyclophosphamide, vincristine, and prednisone alone in pa-
H, Holleczek B, et al. Survival for haematological malignan- tients with previously untreated advanced follicular lymphoma.
cies in Europe between 1997 and 2008 by region and age: J Clin Oncol. 2008;26:4579-86. https://doi.org/10.1200/
results of EUROCARE-5, a population-based study. Lancet JCO.2007.13.5376
Oncol. 2014;15:931-42. https://doi.org/10.1016/S1470-2045 26. Hiddemann W, Kneba M, Dreyling M, Schmitz N, Lengfelder
(14)70282-7 E, Schmits R, et al. Frontline therapy with rituximab added to
15. Montoto S, Canals C, Rohatiner AZ, Taghipour G, Sureda A, the combination of cyclophosphamide, doxorubicin, vincris-
Schmitz N, et al. Long-term follow-up of high-dose treatment tine, and prednisone (CHOP) significantly improves the out-
with autologous haematopoietic progenitor cell support in 693 come for patients with advanced-stage follicular lymphoma
patients with follicular lymphoma: an EBMT registry study. compared with therapy with CHOP alone: results of a prospec-
Leukemia. 2007;21:2324-31. https://doi.org/10.1038/sj.leu. tive randomized study of the German Low-Grade Lymphoma
2404850 Study Group. Blood. 2005;106:3725-32. https://doi.org/10.
16. Rohatiner AZ, Nadler L, Davies AJ, Apostolidis J, Neuberg D, 1182/blood-2005-01-0016
Matthews J, et al. Myeloablative therapy with autologous bone 27. Siddhartha G, Vijay P. R-CHOP versus R-CVP in the treat-
marrow transplantation for follicular lymphoma at the time of ment of follicular lymphoma: a meta-analysis and critical ap-
second or subsequent remission: long-term follow-up. J Clin On- praisal of current literature. J Hematol Oncol. 2009;2:14.
col. 2007;25:2554-9. https://doi.org/10.1200/JCO.2006.09.8327 https://doi.org/10.1186/1756-8722-2-14

Acta Clin Croat, Vol. 56, No. 1, 2017 153

V. Milunović et al. Rituximab maintenance in follicular lymphoma

28. Itchaki G, Gafter-Gvili A, Lahav M, Vidal L, Raanani P, 37. Salles G, Seymour JF, Offner F, López-Guillermo A, Belada D,
Shpilberg O, et al. Anthracycline-containing regimens for Xerri L, et al. Rituximab maintenance for 2 years in patients
treatment of follicular lymphoma in adults. Cochrane Database with high tumour burden follicular lymphoma responding to
Syst Rev. 2013;7:CD008909. https://doi.org/10.1002/146518 rituximab plus chemotherapy (PRIMA): a phase 3, randomised
58.CD008909.pub2 controlled trial. Lancet. 2011;377:42-51. https://doi.org/10.
29. Hoffmann-La Roche. Rituximab therapy in follicular lympho- 1200/JCO.2008.17.1561
ma in combination with chemotherapy – REFLECT 1. In 38. Salles G, Seymour JF, Feugier P, Offner F, Lopez-Guillermo A,
Clinical Trials.gov [Internet]. Bethesda (MD): National library Belada D, et al. Updated 6 year follow-up of the PRIMA study
of Medicine. 2013. [cited 20 Nov 2015] Available from URL: confirms the benefit of 2-year rituximab maintenance in fol-
https://clinicaltrials.gov/ct2/show/NCT02461290?term=follic licular lymphoma patients responding to frontline immuno-
ular+lymphoma&rank=107 NLM identifier: NCT02461290 chemotherapy. Blood. 2013;122:509.
30. Berinstein NL, Grillo-López AJ, White CA, Bence-Bruckler I, 39. Vitolo U, Ladetto M, Boccomini C, Baldini L, De Angelis F,
Maloney D, Czuczman M, et al. Association of serum ritux- Tucci A, et al. Rituximab maintenance compared with observa-
imab (IDEC-C2B8) concentration and anti-tumor response in tion after brief first-line R-FND chemoimmunotherapy with
the treatment of recurrent low-grade or follicular non-Hodg- rituximab consolidation in patients older than 60 years with
kin’s lymphoma. Ann Oncol. 1998;9:995-1001. advanced follicular lymphoma: a phase III randomized study
31. Ghielmini M, Schmitz SF, Cogliatti SB, Pichert G, Hummer- by the Fondazione Italiana Linfomi. J Clin Oncol. 2013;
johann J, Waltzer U, et al. Prolonged treatment with rituximab 31:3351-9.
in patients with follicular lymphoma significantly increases 40. Schouten HC, Qian W, Kvaloy S, Porcellini A, Hagberg H,
event-free survival and response duration compared with the Johnsen HE, et al. High-dose therapy improves progression-
standard weekly x4 schedule. Blood. 2004;103:4416-23. free survival and survival in relapsed follicular non-Hodgkin’s
https://doi.org/10.1182/blood-2003-10-3411 lymphoma: results from the randomized European CUP trial. J
32. Forstpointner R, Unterhalt M, Dreyling M, Böck HP, Repp R, Clin Oncol. 2003;21:3918-27. https://doi.org/10.1200/JCO.
Wandt H, et al. Maintenance therapy with rituximab leads to a 2003.10.023
significant prolongation of response duration after salvage 41. Hamadani M. Reappraising the role of autologous transplanta-
therapy with a combination of rituximab, fludarabine, cyclo- tion for indolent B-cell lymphomas in the chemoimmunother-
phosphamide, and mitoxantrone (R-FCM) in patients with apy era: is it still relevant? Bone Marrow Transplant. 2013;
recurring and refractory follicular and mantle cell lymphomas: 48:1013-21. https://doi.org/10.1038/bmt.2012.182
results of a prospective randomized study of the German Low
42. Sebban C, Brice P, Delarue R, Haioun C, Souleau B, Mounier
Grade Lymphoma Study Group (GLSG). Blood. 2006;108:
N, et al. Impact of rituximab and/or high-dose therapy with
4003-8. https://doi.org/10.1182/blood-2006-04-016725
autotransplant at time of relapse in patients with follicular lym-
33. van Oers MH, Klasa R, Marcus RE, Wolf M, Kimby E, Gas- phoma: a GELA study. J Clin Oncol. 2008;26:3614-20. https://
coyne RD, et al. Rituximab maintenance improves clinical out- doi.org/10.1200/JCO.2007.15.5358
come of relapsed/resistant follicular non-Hodgkin lymphoma
43. Haines I. Rituximab maintenance therapy for follicular lym-
in patients both with and without rituximab during induction:
phoma. Lancet. 2011;377:1151-2. https://doi.org/10.1016/
results of a prospective randomized phase 3 intergroup trial.
S0140-6736(11)60459-5
Blood. 2006;108:3295-301. https://doi.org/10.1182/blood-
2006-05-021113 44. Korn RL, Crowley JJ. Overview: progression-free survival as an
34. van Oers MH, Van Glabbeke M, Giurgea L, Klasa R, Marcus endpoint in clinical trials with solid tumors. Clin Cancer Res.
RE, Wolf M, et al. Rituximab maintenance treatment of re- 2013;19:2607-12. https://doi.org/10.1158/1078-0432.CCR-
lapsed/resistant follicular non-Hodgkin’s lymphoma: long- 12-2934
term outcome of the EORTC 20981 phase III randomized 45. Johnson JR, Ning YM, Farrell A, Justice R, Keegan P, Pazdur
intergroup study. J Clin Oncol. 2010;28:2853-8. https://doi. R. Accelerated approval of oncology products: the Food and
org/10.1200/JCO.2009.26.5827 Drug Administration experience. J Natl Cancer Inst. 2011;
35. Vidal L, Gafter-Gvili A, Salles G, Dreyling MH, Ghielmini 103:636-44. https://doi.org/10.1093/jnci/djr062
M, Hsu Schmitz SF, et al. Rituximab maintenance for the 46. Hainsworth JD, Litchy S, Shaffer DW, Lackey VL, Grimaldi
treatment of patients with follicular lymphoma: an updated M, Greco FA. Maximizing therapeutic benefit of rituximab:
systematic review and meta-analysis of randomized trials. J maintenance therapy versus re-treatment at progression in pa-
Natl Cancer Inst. 2011;103:1799-806. https://doi.org/10.1093/ tients with indolent non-Hodgkin’s lymphoma – a randomized
jnci/djr418 phase II trial of the Minnie Pearl Cancer Research Network. J
36. Hochster H, Weller E, Gascoyne RD, Habermann TM, Gor- Clin Oncol. 2005;23:1088-95.
don LI, Ryan T, et al. Maintenance rituximab after cyclophos- 47. Kahl BS, Hong F, Williams ME, Gascoyne RD, Wagner LI,
phamide, vincristine, and prednisone prolongs progression-free Krauss JC, et al. Rituximab extended schedule or re-treatment
survival in advanced indolent lymphoma: results of the ran- trial for low-tumor burden follicular lymphoma: Eastern Co-
domized phase III ECOG1496 study. J Clin Oncol. 2009; operative Oncology Group protocol e4402. J Clin Oncol. 2014;
27:1607-14. https://doi.org/10.1200/JCO.2008.17.1561 32:3096-102.

154 Acta Clin Croat, Vol. 56, No. 1, 2017

V. Milunović et al. Rituximab maintenance in follicular lymphoma

48. Friedberg JW. End of rituximab maintenance for low-tumor 60. Chhatwal J, Mathisen M, Kantarjian H. Are high drug prices
burden follicular lymphoma. J Clin Oncol. 2014;32:3093-5. for hematologic malignancies justified? A critical analysis.
https://doi.org/10.1200/JCO.2005.12.191 Cancer. 2015;121:3372-9.
49. Cheson B. Reason to RESORT to rituximab maintenance? 61. Greenhalgh J, Bagust A, Boland A, Blundell M, Oyee J, Beale
Accessed online 12/2/2015 http://www.medscape.com/view- S, et al. Rituximab for the first-line maintenance treatment of
article/756805 follicular non-Hodgkin’s lymphoma: a NICE single technolo-
gy appraisal. Pharmacoeconomics. 2013;31:403-13. https://
50. Witzens-Harig M, Foá R, Di Rocco A, van Hazel G, Cham-
doi.org/10.1007/s40273-013-0043-8
one DF, Rowe JM, et al. Maintenance with rituximab is safe
and not associated with severe or uncommon infections in pa- 62. Darwish M, Bond M, Hellriegel E, Robertson P Jr, Chovan JP.
Pharmacokinetic and pharmacodynamic profile of bendamus-
tients with follicular lymphoma: results from the phase IIIb
tine and its metabolites. Cancer Chemother Pharmacol.
MAXIMA study. Ann Hematol. 2014;93:1717-24. https://doi.
2015;75:1143-54. https://doi.org/10.1007/s00280-015-2727-6
org/10.1007/s00277-014-2103-3
63. Tageja N, Nagi J. Bendamustine: something old, something
51. Nabhan C, Ollberding NJ, Villines D, Chiu BC, Caces DB,
new. Cancer Chemother Pharmacol. 2010;66:413-23. https://
Valdez TV, et al. A systematic review of comparative schedule- doi.org/10.1007/s00280-010-1317-x
related toxicities with maintenance rituximab in follicular and
64. Rummel MJ, Niederle N, Maschmeyer G, Banat GA, von
mantle cell lymphomas. Leuk Lymphoma. 2014;55:1288-94.
Grünhagen U, Losem C, et al. Bendamustine plus rituximab
https://doi.org/10.3109/10428194.2013.839787
versus CHOP plus rituximab as first-line treatment for patients
52. The World Health Organization Quality of Life assessment with indolent and mantle-cell lymphomas: an open-label, mul-
(WHOQOL): position paper from the World Health Organi- ticentre, randomised, phase 3 non-inferiority trial. Lancet.
zation. Soc Sci Med. 1995;41:1403-9. 2013;381:1203-10. https://doi.org/10.1016/S0140-6736(12)
53. Pettengell R, Donatti C, Hoskin P, Poynton C, Kettle PJ, Han- 61763-2
cock B, et al. The impact of follicular lymphoma on health-re- 65. Jacobson CA, Freedman AS. First-line treatment of indolent
lated quality of life. Ann Oncol. 2008;19:570-6. https://doi. lymphoma: axing CHOP? Lancet. 2013;381:1163-5. https://
org/10.1093/annonc/mdm543 doi.org/10.1016/S0140-6736(12)61965-5
54. LeBlanc T, Kamal A, Abernethy A. Rituximab for follicular 66. Flinn IW, van der Jagt R, Kahl BS, Wood P, Hawkins TE,
lymphoma: watch and wait, watch and worry, or watch and Macdonald D, et al. Randomized trial of bendamustine-ritux-
live? Lancet Oncol. 2014;15:e251-2. https://doi.org/10.1016/ imab or R-CHOP/R-CVP in first-line treatment of indolent
S1470-2045(14)70215-3 NHL or MCL: the BRIGHT study. Blood. 2014;123:2944-
52. https://doi.org/10.1182/blood-2013-11-531327
55. Beveridge R, Satram-Hoang S, Sail K, Darragh J, Chen C, For-
syth M, et al. Economic impact of disease progression in fol- 67. Rummel MJ, Viardot A, Greil R, et al. Bendamustine plus
licular non-Hodgkin lymphoma. Leuk Lymphoma. 2011; rituximab followed by rituximab maintenance for patients with
52:2117-23. https://doi.org/10.3109/10428194.2011.592623 untreated advanced follicular lymphomas. Results from the
StiL NHL 7-2008 Trial (MAINTAIN trial) (ClinicalTrials.
56. Kasteng F, Erlanson M, Hagberg H, Kimby E, Relander T, gov Identifier: NCT00877214). Blood 2014;124:3052.
Lundkvist J. Cost-effectiveness of maintenance rituximab
68. Sawas A, Diefenbach C, O‘Connor OA. New therapeutic tar-
treatment after second line therapy in patients with follicular
gets and drugs in non-Hodgkin‘s lymphoma. Curr Opin He-
lymphoma in Sweden. Acta Oncol. 2008;47:1029-36. https://
matol. 2011;18:280-7. https://doi.org/10.1097/MOH.0b013e
doi.org/10.1080/02841860802120028
328347786d
57. Blommestein HM, Issa DE, Pompen M, Ten Hoor G, Hogen-
69. Gopal AK, Kahl BS, de Vos S, Wagner-Johnston ND, Schuster
doorn M, Joosten P, et al. Cost-effectiveness of rituximab as SJ, Jurczak WJ, et al. PI3Kδ inhibition by idelalisib in patients
maintenance treatment for relapsed follicular lymphoma: re- with relapsed indolent lymphoma. N Engl J Med. 2014;370:
sults of a population-based study. Eur J Haematol. 2014;92:398- 1008-18. https://doi.org/10.1056/NEJMoa1314583
406. https://doi.org/10.1111/ejh.12264
70. Miller BW, Przepiorka D, de Claro RA, Lee K, Nie L, Simpson
58. Deconinck E, Miadi-Fargier H, Pen CL, Brice P. Cost effec- N, et al. FDA approval: idelalisib monotherapy for the treat-
tiveness of rituximab maintenance therapy in follicular lym- ment of patients with follicular lymphoma and small lympho-
phoma: long-term economic evaluation. Pharmacoeconomics. cytic lymphoma. Clin Cancer Res. 2015;21:1525-9. https://
2010;28:35-46. https://doi.org/10.2165/11314070-000000000 doi.org/10.1158/1078-0432.CCR-14-2522
-00000 71. European Medicines Agency. EMA reviews cancer medicine
59. Hornberger J, Chien R, Friedmann M, Han L, Shewade A, Zydelig. Accessed online 14/4/2015 from http://www.ema.eu-
Satram-Hoang S, et al. Cost-effectiveness of rituximab as ropa.eu/ema/index.jsp?curl=pages/news_and_events/news/2016
maintenance therapy in patients with follicular non-Hodgkin /03/news_detail_002487.jsp&mid=WC0b01ac058004d5c1
lymphoma after responding to first-line rituximab plus che- 72. Hiddemann W, Cheson BD. How we manage follicular lym-
motherapy. Leuk Lymphoma. 2012;53:2371-7. https://doi.org phoma. Leukemia. 2014;28:1388-95. https://doi.org/10.1038/
/10.3109/10428194.2012.694429 leu.2014.91

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V. Milunović et al. Rituximab maintenance in follicular lymphoma

Sažetak

ODRŽAVANJE RITUKSIMABOM U UZNAPREDOVALOM FOLIKULARNOM LIMFOMU:

KONTROVERZIJE

V. Milunović, M. Bogeljić Patekar, K. Mišura Jakubac, I. Mandac Rogulj, D. Radić-Krišto,

A. Planinc-Peraica i S. Ostojić Kolonić

Rituksimab je kimerično antiCD20 protutijelo koje se koristi u liječenju CD20 pozitivnih ne-Hodgkinovih limfoma te
je promijenilo paradigmu liječenja ovih hematoloških neoplazma u prošlom desetljeću. Glavni cilj ovoga preglednog rada je
predstaviti njegovu primjenu u folikularnom limfomu (FL) s naglaskom na terapiju održavanja. Ova strategija doprinijela je
boljem preživljenju bez progresije bolesti u prvoj i drugoj liniji terapije, odnosno boljem ukupnom preživljenju u bolesnika s
relapsom FL-a. No, usprkos dobrim rezultatima, održavanje rituksimabom je doprinijelo kontroverzi u medicinskoj zajed-
nici. Navedene nedoumice potječu od nedostatka poboljšanja ukupnog preživljenja u prvoj liniji terapije, moguće toksičnosti
do nepoznate uloge u eri novih lijekova za liječenje FL-a. Prema postojećim podacima zaključujemo da terapiju održavanja
rituksimabom treba ponuditi bolesnicima s FL-om koji su odgovorili na prvu liniju terapije te bolesnicima s relapsom FL-a
koji su odgovorili na reindukciju, a nisu kandidati za liječenje autolognom transplantacijom matičnih stanica.
Ključne riječi: Rituksimab; Limfom, ne-Hodgkinov – terapija; Limfom, folikularni; Terapija održavanja; Ishod liječenja

156 Acta Clin Croat, Vol. 56, No. 1, 2017