Interferon-alpha for maintenance of follicular lymphoma

Interferon-alpha for maintenance of follicular lymphoma

(Review)

Baldo P, Rupolo M, Compagnoni A, Lazzarini R, Bearz A, Cannizzaro R, Spazzapan S,

Truccolo I, Moja L

This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library2010, Issue 1

http://www.thecochranelibrary.com

Interferon-alpha for maintenance of follicular lymphoma (Review)

Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

http://www.thecochranelibrary.com

T A B L E O F C O N T E N T S

1HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

3OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

3METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Figure 1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4

6RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Figure 2. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7

Figure 3. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8

Figure 4. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9

Figure 5. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10

Figure 6. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11

Figure 7. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11

Figure 8. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12

Figure 9. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12

Figure 10. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13

Figure 11. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14

14DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

15AUTHORS’ CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

16ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

16REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

20CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

28DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Analysis 1.1. Comparison 1 Interferon maintenance therapy versus other therapy, Outcome 1 Overall survival (HR,

random-effects model). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30

Analysis 1.2. Comparison 1 Interferon maintenance therapy versus other therapy, Outcome 2 Overall survival (HR, fixed-

effects model). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31

Analysis 1.3. Comparison 1 Interferon maintenance therapy versus other therapy, Outcome 3 Progression-free survival

(HR, fixed-effects model). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32

Analysis 1.4. Comparison 1 Interferon maintenance therapy versus other therapy, Outcome 4 Sensitivity analysis: Overall

survival (excluding Fisher 2000, fixed-effects model). . . . . . . . . . . . . . . . . . . . . 33

Analysis 1.5. Comparison 1 Interferon maintenance therapy versus other therapy, Outcome 5 Sensitivity analysis:

Progression-free survival (excluding Fisher 2000, fixed-effects model). . . . . . . . . . . . . . . 34

Analysis 1.6. Comparison 1 Interferon maintenance therapy versus other therapy, Outcome 6 Toxicity (any severity):

Leukocytopenia/ Granulocytopenia/ Neutropenia. . . . . . . . . . . . . . . . . . . . . . 35


Neurologic symptoms. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36

Analysis 1.8. Comparison 1 Interferon maintenance therapy versus other therapy, Outcome 8 Toxicity (any severity): Flu-

like symptoms. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37


Thrombocytopenia. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38

Analysis 1.10. Comparison 1 Interferon maintenance therapy versus other therapy, Outcome 10 Response to treatment:

Overall response. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39

Analysis 1.11. Comparison 1 Interferon maintenance therapy versus other therapy, Outcome 11 Toxicity WHO grade 3 or

4: Haematological toxicity. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39


4: Flu-like symptoms. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40


4: Neurologic symptoms. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41

iInterferon-alpha for maintenance of follicular lymphoma (Review)



4: Infection / fever. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41

Analysis 1.15. Comparison 1 Interferon maintenance therapy versus other therapy, Outcome 15 Drop-outs. . . . 42

42ADDITIONAL TABLES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

44APPENDICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

48WHAT’S NEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

48HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

48CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

49DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

49INDEX TERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

iiInterferon-alpha for maintenance of follicular lymphoma (Review)


[Intervention Review]

Interferon-alpha for maintenance of follicular lymphoma

Paolo Baldo1, Maurizio Rupolo2, Anna Compagnoni3 , Renzo Lazzarini4 , Alessandra Bearz2, Renato Cannizzaro5 , Simon Spazzapan2 ,

Ivana Truccolo6 , Lorenzo Moja7

1Pharmacy Unit, Drug Information Centre, CRO Aviano - Centro di Riferimento Oncologico IRCCS, Aviano (PN), Italy. 2 Department

of Medical Oncology, Centro di Riferimento Oncologico - CRO Aviano (PN) Italy, Aviano (PN), Italy. 3Laboratorio per la Ricerca

Clinica Oncologica, Instituto Mario Negri, Milan, Italy. 4Pharmacy Unit, CRO Aviano - Centro di Riferimento Oncologico IRCCS,

Aviano (PN), Italy. 5Gastroenterology, Centro di Riferimento Oncologico - CRO Aviano (PN) Italy, Aviano (PN), Italy. 6Library,

Centro di Riferimento Oncologico - CRO Aviano (PN) Italy, Aviano (PN), Italy. 7Italian Cochrane Centre, Mario Negri Institute for

Pharmacological Research, Milan, Italy

Contact address: Paolo Baldo, Pharmacy Unit, Drug Information Centre, CRO Aviano - Centro di Riferimento Oncologico IRCCS,

Via Franco Gallini, 2, Aviano (PN), Friuli-Venezia-Giulia, 33081, Italy. [email protected]. [email protected].

Editorial group: Cochrane Haematological Malignancies Group.

Publication status and date: New, published in Issue 1, 2010.

Review content assessed as up-to-date: 8 December 2008.

Citation: Baldo P, Rupolo M, Compagnoni A, Lazzarini R, Bearz A, Cannizzaro R, Spazzapan S, Truccolo I, Moja L. Interferon-

alpha for maintenance of follicular lymphoma. Cochrane Database of Systematic Reviews 2010, Issue 1. Art. No.: CD004629. DOI:

10.1002/14651858.CD004629.pub2.


A B S T R A C T

Background

Indolent non-Hodgkin’s lymphoma, in particular follicular lymphoma (FL), is characterized by multiple remissions and relapses. Several

studies have used interferon-alpha (IFN) to control this disease, both as induction and as maintenance therapy. It is not yet clear whether

IFN can be associated with a survival benefit although it may prolong progression-free survival.

Objectives

To determine the effects of IFN in the maintenance therapy of FL.

Search methods

We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, Issue 4, 2008), MEDLINE (1966

to 2008), DARE (1990 to 2008), SCOPUS (searched December 2008) and Current Contents (1975 to 2008). .

Selection criteria

Randomised controlled trials of IFN versus no intervention or placebo, or IFN plus chemotherapy versus chemotherapy alone, in a

maintenance setting in patients with non-Hodgkin’s FL. Primary outcomes were overall survival and progression-free survival.

Data collection and analysis

Three review authors independently assessed trial quality and extracted data. We contacted study authors for additional information.

We collected adverse events information from the trials.

1Interferon-alpha for maintenance of follicular lymphoma (Review)


mailto:[email protected]

mailto:[email protected]

Main results

We included eight trials (1563 patients). The drug was IFN alfa-2b in six trials and alfa-2a in two. Trials were heterogeneous in terms

of diagnosis of FL, using several classification systems. IFN had been compared with placebo/no intervention in five trials and other

chemotherapy in three. The effect of IFN was similar to that of placebo on overall survival (hazard ratio (HR) 0.90, 95% CI 0.61 to

1.34) whereas IFN was more effective when added to chemotherapy (HR 0.68, 95% confidence interval (CI) 0.52 to 0.90). Considering

IFN versus all comparators, IFN was effective in prolonging progression-free survival (HR 0.66, 95% CI 0.57 to 0.77) and overall

survival (fixed effects HR 0.79, 95% CI 0.67 to 0.94, I2 = 52%). After adjustment for heterogeneity this statistically significance

disappeared (random effects HR 0.82, 95% CI 0.63 to 1.08). Toxicity and patients lost to follow up were significantly higher in the

IFN groups.

Authors’ conclusions

There is evidence that addition of IFN as maintenance therapy for FL improves progression-free survival. A net benefit for overall

survival is less evident. In the included studies, IFN was associated with significant toxicities that may have a major impact on a patient’s

quality of life.

P L A I N L A N G U A G E S U M M A R Y

Interferon-alpha in the maintenance therapy of follicular non-Hodgkin’s lymphoma

The aim of this systematic review is to outline the possible benefits (i.e. prolonging survival) and also the disadvantages (adverse

events) of therapy with interferon-alpha, administered alone or in combination with other proven drug regimens (otherwise known

as chemotherapy) to patients affected by follicular non-Hodgkin’s lymphoma. Interferons are proteins secreted by vertebrate cells that

exhibit various biological actions. They confer resistance against many different viruses, inhibit proliferation of normal and malignant

cells, augment natural killer cell activity, and show several other immunomodulatory functions. Interferons, types alfa-2a or alfa-2b,

are usually administered in combination with other drugs to treat a variety of infective and neoplastic diseases. The results showed

a significant benefit in progression-free survival in patients treated with interferon-alpha alone or combined with chemotherapy as

compared with comparator therapies. There was, however, less evidence that interferon-alpha supported any benefit on overall survival.

Furthermore, the presence of relevant drug-related adverse events suggested that a careful analysis of the risks and benefits has to be

performed when making a specific clinical decision about this therapy.

B A C K G R O U N D

Non-Hodgkin’s lymphomas have increased dramatically over the

last decade. Follicular lymphoma (FL) is the second most com-

mon lymphoma, accounting for 20% to 30% of all non-Hodgkin

lymphomas (Armitage 1998). The peak incidence of FL occurs in

the sixth decade of life, with a slight female predominance. The

median overall survival is about seven to ten years (Bastion 1991).

FL is a lymphoma of follicle centre B cells, usually composed of a

mixture of centrocytes and centroblasts. The growth pattern may

be either nodular or diffuse. Grading and the aggressiveness of FLs

depend on the number of centroblastic cells per high-power field.

New information regarding the morphology, immunophenotype,

genetics, and clinical features of neoplasms of lymphoid cells has

led to the Revised European-American Classification of Lym-

phoid Neoplasms (REAL) (Harris 1994), a classification that has

been adopted by the World Health Organization (WHO) (Harris

2000). The REAL/WHO classification includes all the lymphoid

neoplasms and represents the first true international consensus on

the classification of haematologic malignancies.

Genetically, the majority of cases show translocation (Capaccioli

1996; Martinka 1997) and Bcl-2 gene rearrangement (Gaulard

1992; Lopez 1999; Matolcsy 1996; Matolcsy 1997).

Clinical presentation of FL is frequently as a widespread disease

with nodal, splenic, and bone marrow involvement as well as ex-

tranodal sites. Generally it is characterized by indolent behaviour

of the disease and occurrence of late relapses. After a long time

it can transform into intermediate or high-grade lymphoma with

an accelerated clinical course. The criteria used to define a high

tumour burden are the following:



• bulky disease (nodal or extranodal disease with maximum

diameter > 3 cm;

• presence of B symptoms;

• relevant splenomegaly;

• important pleural or peritoneal effusion;

• circulating lymphoma cells > 5 x 109/L, or neutrophils

count < 1 x 109/L, or platelets < 100 x 109/L.

The Follicular Lymphoma International Prognostic Index (FLIPI)

based on age, Ann Arbor stage, number of nodal area, haemoglobin

level and serum lactate dehydrogenase appeared more appropriate

to discriminate than the International Prognostic Index (Solal-

Céligny 2004). However other biological prognostic factors, as

the role of the microenvironment in FL are under study (De Jong

2009).

Several treatment options are available today. Management may

initially include a ’watch and wait’ approach: the disease may re-

main stable and the period of watchful waiting may be as long as 72

months. Chemotherapy-based treatment is advised in the presence

of high tumour burden and a negative prognostic index. CHOP (a

combination of cyclophosphamide, adriamycin, vincristine, and

prednisone) or CHOP-like regimens may be considered adequate

therapy, as well as other polychemotherapy regimens without an-

thracyclines (Brice 1997; Dana 1993). Fludarabine may be given

as an alternative second-line treatment, either as a single agent or

as part of a combination regimen (Lenz 2004). The availability of

novel biologic agents such as rituximab presents new, greatly im-

pacting therapeutic and maintenance opportunities for FL. Ritux-

imab is a murine genetically engineered human monoclonal anti-

body that binds to the antigen CD20, which is normally located

on pre-B and mature B lymphocytes, and is also expressed on more

than 90% of B-cell non-Hodgkin’s lymphomas. Adding rituximab

to chemotherapy treatment has been positively evaluated in a re-

cent systematic review (Schulz 2007). Based on available evidence,

rituximab has been recommended in recent guidelines (Cheung

2007; NICE TA110, 2006).

Other bio-modulating agents such as interferons have been used

for many years as maintenance therapy for non-Hodgkin’s lym-

phoma, but they are less frequently included in the maintenance

therapy options because of significant drug-related toxicities. In-

terferons are cytokines, proteins secreted by vertebrate cells in re-

sponse to a wide variety of inducers. They exhibit various bio-

logical actions (Ezaki 1996) that include inhibition of prolifera-

tion of normal and malignant cells, and complex immunomodula-

tory functions. The pharmaceutical agents actually used in therapy

are derived from recombinant DNA technology and the variants

(types alfa-2a, alfa-2b, alfa-2c) differ in the amino acid sequences.

Up to now, there are no reliable data supporting differences in the

action or the clinical efficacy of any particular type of interferon-

alpha. The FDA approved only interferon alfa-2b for the treat-

ment of FL.

There are no unequivocally convincing data showing that the in-

terferon-alpha used alone or in combination with other drug reg-

imens as maintenance therapy can prolong the overall survival

time in patients with non-Hodgkin’s FL (Brandt 2001; Rohatiner

2001). A previous meta-analysis by Allen 2001 did show a signif-

icantly increased progression-free survival rate in patients receiv-

ing interferon-alpha, both for induction and maintenance therapy

(Allen 2001) as opposed to other studies which did not confirm

a survival benefit (Arranz 1998; Hagenbeek 1998; Hiddemann

1998; Smalley 2001; Solal-Céligny 1998).

O B J E C T I V E S

To determine possible benefits or disadvantages derived from the

administration of interferon-alpha in the maintenance therapy of

non-Hodgkin’s FL.

M E T H O D S

Criteria for considering studies for this review

Types of studies

Randomised controlled trials on patients who had a diagnosed

FL were eligible for inclusion. Studies which included more than

one type of lymphoma, according to international classifications

(WHO, REAL, etc.), were excluded unless:

a) we were able to extract data specifically referring to FL patients,

or

b) FL patients were the majority (> 70%).

Types of participants

Inclusion criteria

Patients who had a documented histologically confirmed diagno-

sis of non-Hodgkin’s FL (WHO, REAL, etc). The criteria used

to distinguish between patients with FL and other subcategories

of low-grade or mantle cell lymphoma were based on classifica-

tion systems widely accepted: Kiel (Lennert 1978; Lennert 1992;

Stansfeld 1988), Rappaport (Rappaport 1966), Working Formu-

lation (NHCPLP 1982), REAL (Harris 1994), WHO (Harris

2000). A summary of the various classification systems for FL

is reported in Table 1. Definitions are reported in Appendix 2.

A schematic view of relationship between different B-cell lym-

phomas is presented in Figure 1.



Figure 1. The relationship between different B-cell lymphomas and the normal physiological compartments

of B-cell differentiation.ALL, acute lymphoblastic leukaemia (courteously from Dogan, 2005: Modernhistological classification of low-grade B-cell lymphomas, Best Practice & Research Clinical Haematology, 2005;

18 (1): pp 11-26).

Patients were included regardless of sex, age, pre or concomitant

therapy, and without a pre-set time limit on the duration of inter-

feron-alpha therapy.

Exclusion criteria

• Studies enrolling patients for which the non-Hodgkin’s

lymphoma disease classification was not clearly follicular

(according to the international classifications WHO, REAL, or

WHO/REAL). This criterion was not declared in the original

review protocol, but it was introduced as some studies also

reported a small number of patients having lymphomas classified

as low-grade or mantle cell. These studies were included because

results were sufficiently clear to extract data referring specifically

to FL patients.

Types of interventions

Interferon-alpha versus no intervention or placebo, or interferon-

alpha plus chemotherapy versus the chemotherapy alone, in main-

tenance setting (Berinstein 2006). Possible administration of in-

terferon-alpha included concomitance or subsequence to single

or combination chemotherapy (or between two or more cycles of

chemotherapy).

Comparisons were subgrouped for efficacy analyses with regard to

interventions and controls.

Possible single or combination chemotherapy regimens used as

control included:

• CEOP-Bleo (cyclophosphamide, epirubicin, vincristine,

prednisone, and bleomycin);

• CHOP (cyclophosphamide, doxorubicin, vincristine,

prednisone);

• CVP (cyclophosphamide, vincristine, and prednisone);

• chlorambucil;

• CHVP (cyclophosphamide, doxorubicin, teniposide, and

prednisone);

• ProMACE (prednisone, methotrexate, doxorubicin,

cyclophosphamide);



• MOPP (etoposide or mechlorethamine, vincristine,

procarbazine).

Definition of maintenance therapy

Maintenance therapy is defined as: “Treatment that is given to help

a primary (original) treatment keep working. Maintenance therapy

is often given to help keep cancer in remission” - National Cancer

Institute (NCI): dictionary of cancer terms (www.cancer.gov/dic-

tionary/ - accessed January 2009). Induction or upfront therapy

with interferon-alpha was excluded.

Types of outcome measures

Primary outcomes

Primary outcome measures to be evaluated were:

• overall survival;

• progression-free survival.

Secondary outcomes

Other outcomes considered were:

• adverse events and toxicity related to drug therapy;

• overall response to therapy;

• adherence and coping with therapy, expressed as number of

patients lost to follow up (drop outs);

• quality of life during treatment, as measured using any

previous validated scale;

• cost-effectiveness and costs per quality-adjusted life year.

Search methods for identification of studies

.

We searched the following databases:

• Cochrane Haematological Malignancies Group (CHMG)

Trials Register;

• Cochrane Central Register of Controlled Trials

(CENTRAL) (The Cochrane Library 2008, Issue 4) (see

Appendix 3);

• MEDLINE and PREMEDLINE, through the PubMed

interface (see Appendix 4) and OVID interface (see Appendix 5)

(January 1966 to December 2008);

• The Database of Reviews of Effectiveness (DARE) (January

1990 to December 2008);

• SCOPUS (no date limits, last accessed December 2008);

• Current Contents: Clinical Medicine and Life Sciences

(January 1975 to December 2008).

MEDLINE was searched using the search strategy (see Appendix

6) together with the optimally sensitive search strategy devel-

oped by the Cochrane Collaboration for the identification of ran-

domised controlled trials (Dickersin 1994). Detailed search strate-

gies were developed for each database (see Appendix 3, Appendix 4,

Appendix 5, Appendix 6). Handsearching was executed to retrieve

additional journal articles, eligible reports or documents from the

following conference proceedings.

We also searched for ongoing trials in:

• http://www.trialscentral.org/;

• www.controlled-trials.com;

• http://www.cancer.gov/search/clinical˙trials/;

• http://clinicaltrials.gov;

• http://clinicaltrials.nci.nih.gov/;

• http://doh.gov.uk/research/nrr.htm;

• http://www.centerwatch.com/.

Data collection and analysis

Study selection

Three review authors (PB, MR and AC) looked at every report

identified by the searches and made an assessment of their suitabil-

ity for inclusion in the review based on the criteria set out above.

Initially, the selection criteria were broad to avoid missing relevant

data. The review authors then awarded each study a grade for their

methodological quality. Any disagreements were resolved by dis-

cussion. The first authors of the original papers were contacted,

if necessary, for any clarifications (i.e. studies published only in

abstract form).

Quality assessment

The criteria for quality assessment were based on the recommenda-

tions of Cochrane Reviewers’ Handbook, Version 5.0.0 (Cochrane

Reviewers’ Handbook 2008). Evaluation of quality of reporting

of trials was based on the revised CONSORT statement (Consol-

idated Standards of Reporting Trials) (Moher 2001). The overall

quality of the studies was based on the following criteria.

Adequacy of the randomisation process and of allocation concealmentA - Adequate based on one or more of the following elements:

research methods and study design clearly defined; randomisation

by a central office; internal coherence between protocol, presenta-

tion of results, and outcomes.

B - Unclear: design method was less clear; apparently adequate

concealment but without other information in trial report.

C - Inadequate: not unconfounded; no evidence of internal co-

herence between protocol, presentation of results, and outcomes;

inadequate reporting.

Attrition biasA - Adequate: an intention-to-treat analysis was possible and drop-

out rate was less than 20% for all groups.

B - Unclear: drop-out rate was more than 20%, or observed het-

erogeneity in drop-out rate between groups.



C - Inadequate: lack of reporting on drop-out rates and intention-

to-treat analysis not possible.

Data extraction

Two review authors (PB and AC) independently extracted data ,

analysing each trial separately and using a standardized data ex-

traction form developed by the group. The form included all the

data referred to by the authors of the original trials, the source

and year of publication, the type of study, the characteristics of

patients, and the characteristics of the interventions (chemother-

apy regimen and dose, interferon-alpha or placebo use and dose,

timing, and where necessary notes on the different levels of effec-

tiveness of the various chemotherapy regimens), and the outcome

measures as specified above. Survival data relating to FL patients

were extracted directly from survival curves or from data tables.We

contacted the first author of papers in order to obtain missing data

. We resolved any differences or disagreements by discussion.

Data analysis

About efficacyThe hazard ratio (HR) and associated variances (or other measures

of dispersion) for overall survival and progression-free survival were

extracted directly from the trial publication(s). If not reported,

we obtained these data indirectly using the methods described

by Parmar 1998 either from other available summary statistics or

from data extracted from published Kaplan-Meier curves.

We obtained a pooled HR through the generic inverse variance

approach from the log HR and the standard error of the log HR,

using fixed-effect and random-effect models, along with assess-

ments of heterogeneity (Deeks 2001). The pooled HR represents

the overall risk of an event on chemotherapy regimens containing

interferon-alpha versus those not containing interferon-alpha.

We reported ratios of treatment effects for time-to-event outcomes

such that HRs less than 1.0 favour regimens containing interferon-

alpha and values greater than 1.0 favour regimens that do not con-

tain interferon-alpha. We used HR plots to show overall survival

and progression-free survival .

We assessed the degree of heterogeneity among the trials by us-

ing the I2− statistic for each outcome. An I2 value greater than

50% should be considered large (Cochrane Reviewers’ Handbook

2008). If statistical evidence exists for homogeneity of effect sizes,

the planned analysis will be to use a fixed-effect model. Where sig-

nificant heterogeneity exists clinically or statistically, careful clini-

cal review of the data for the source of such heterogeneity will oc-

cur. Based on this review, a decision will be made by the reviewers

to either: (1) redo the analysis using the homogenous subgroup

(only if a clear and compelling reason to exclude the heterogeneous

data can be made); (2) abandon statistical combining of the trials

in favour of a narrative review of the literature; or (3) redo the

analysis using the random-effects model (DerSimonian 1986).

Response rates were analysed as dichotomous variables (complete

or partial response versus stable disease or no response) and pooled

odds ratio were derived. Responses were reported on an intention-

to-treat basis. We have reported ratios of treatment effects for

response such that ORs less than 1.0 favour regimens containing

interferon-alpha and values greater than 1.0 favour regimens that

do not contain interferon-alpha.

About toxicityWe extracted toxicity data for leukocytopenia, granulocytopenia,

neutropenia, neurologic symptoms, flu-like symptoms, infection,

fever, other symptoms of any severity, thrombocytopenia, and

grade III or grade IV events of haematological toxicity.

The number needed to treat (NNT) (Table 2) has been calculated

when possible.

All statistical analyses were performed with Review Manager Ver-

sion 5.0.

R E S U L T S

Description of studies

See: Characteristics of included studies; Characteristics of excluded

studies.

We found 116 studies, of which 27 were eligible to be consid-

ered for inclusion (see Figure 2). Eight trials (Aviles 1996; Aviles

2004; Fisher 2000; Hagenbeek 1998; Neri 2001; Rohatiner 2001;

Smalley 2001; Solal-Céligny 1998) met the criteria to be included

in the meta-analyses (see diagram in Figure 2). Solal-Céligny 1993

presented an interim analysis about the same patients included in

Solal-Céligny 1998. Two publications, Cole 1998 and Wirt 2001,

respectively refer to patients’ quality of life and cost-effectiveness

analyses based on data from Solal-Céligny 1998. These studies

were included in this review and described qualitatively. All the in-

cluded studies are described in Characteristics of included studies.

Reasons for exclusion of trials are described in Characteristics of

excluded studies. One study (Rohatiner 2001) performed a se-

quential double randomisation using interferon-alpha as initial

and maintenance therapy. We considered in the analyses only pa-

tients included in the maintenance setting. In total, this review

analysed 1563 patients.



Figure 2. Progress for the evaluation and inclusion of trials in this review



In six of the eight included studies interferon type was alfa-2b,

and in two studies was alfa-2a. Diagnosis of non-Hodgkin’s lym-

phoma, follicular type, was performed across the studies according

to: Working Formulation (Aviles 1996; Fisher 2000; Hagenbeek

1998), REAL (Neri 2001), WHO (Aviles 2004), Rappaport

(Smalley 2001) or Kiel (Rohatiner 2001) . In Solal-Céligny 1998

the diagnosis of FL was confirmed by a panel of three haemato-

pathologists by mean of histologic review, but authors did not refer

to any classification system. In any case, in all the included studies

FL patients were in the majority (> 70%). A summary of the trials

included in the meta-analysis is given in additional Table 3.

Risk of bias in included studies

In general, the methods used in the studies support the conclu-

sions. Randomisation was performed in all of the eight studies

which provided data for this review. Only Aviles 1996 reported the

method of allocation concealment in details (although the method

of coded envelopes used could be potentially open to abuse). All

studies were well balanced: treatment and control groups had com-

parable baseline characteristics. Four studies provided complete in-

formation about patients who withdrew and reasons (Fisher 2000,

Rohatiner 2001, Hagenbeek 1998, Solal-Céligny 1998); one study

(Smalley 2001) provided only the percentage of withdrawals but

not reasons; three reports (Solal-Céligny 1993, Neri 2001 and

Aviles 2004) presented unclear information about withdrawals;

one study clearly reported that there were no dropouts (Aviles

1996). One study lost between 10% and 20% patients during

the post-treatment follow up (Solal-Céligny 1998). Intention-to-

treat analysis was performed in four of eight trials (Fisher 2000;

Hagenbeek 1998; Neri 2001; Solal-Céligny 1998 ).

Effects of interventions

Primary outcomes

Overall survival (OS)

Interferon versus placebo or no intervention

Five trials including 1100 patients (Aviles 1996; Aviles 2004;

Fisher 2000; Hagenbeek 1998; Rohatiner 2001) provided data for

the analysis comparing interferon-alpha as maintenance therapy

with placebo or no therapy. Overall, there was no difference in the

risk for all-cause mortality between interferon and placebo or no

intervention (HR 0.90; 95% CI 0.61 to 1.34) (Figure 3). There

was statistical evidence of heterogeneity (P = 0.03, I2 = 63%).

Figure 3. Forest plot of comparison: 1 Interferon maintenance therapy versus not, outcome: 1.1 Overall

Survival (HR, Random effects model).



Interferon plus chemotherapy versus chemotherapy

alone

Three trials including 463 patients contributed data for the anal-

ysis comparing interferon plus chemotherapy versus chemother-

apy alone (Neri 2001; Smalley 2001; Solal-Céligny 1998). When

compared to chemotherapy alone, interferon plus chemotherapy

resulted in a significantly decreased risk for mortality (HR 0.68

95% CI 0.52 to 0.90) (Figure 4). There was no heterogeneity (P

= 0.39, I2 = 0%).

Figure 4. Forest plot of comparison: 1 Interferon maintenance therapy versus not, outcome: 1.2 Overall

Survival (HR, fixed effects model).

Interferon versus any control

There was not a statistically significant difference (interaction test

P=0.17) between studies exploring interferon versus placebo or no

intervention compared to chemotherapy (Figure 4). Considering

all eight trials including 1563 patients, overall interferon did im-

prove OS when compared to any control (HR 0.79; CI 0.67 to

0.94), using fixed-effect models (Figure 4). There was marginally

significant statistical heterogeneity between the trials (P=0.04, I2

= 52%). This effect was not maintained using the random-effects

model which presents wider confidence intervals around a similar

effect (HR 0.82; 95% CI 0.63 to 1.08) (Figure 3).

Progression-free (PFS) survival

Interferon versus placebo or no intervention

Three trials including 894 patients (Aviles 2004; Fisher 2000;

Hagenbeek 1998) contributed to this analysis. PFS was signifi-

cantly better for interferon therapy compared to placebo or no

intervention (HR 0.74;95% CI 0.61 to 0.91) (Figure 5). There

was no significant heterogeneity (P = 0.97, I2 = 0%).



Figure 5. Forest plot of comparison: 1 Interferon maintenance therapy versus not, outcome: 1.3

Progression-free survival (HR, fixed effects model).

Interferon plus chemotherapy versus chemotherapy

alone

Three trial involving 463 patients (Neri 2001; Smalley 2001;

Solal-Céligny 1998) explored the role of interferon plus chemo-

therapy versus chemotherapy alone. PFS was significantly better

for interferon plus chemotherapy (HR 0.56; 95% CI 0.45 to 0.71).

There was moderate heterogeneity among studies (P = 0.13, I2 =

51%).

Interferon versus any control

Studies exploring interferon versus placebo or no intervention

compared to chemotherapy held positive results although studies

exploring interferon associated with chemotherapy resulted in an

increased magnitude of effect (interaction test P=0.08). Consider-

ing all six trials including 1357 patients, overall interferon signif-

icantly improved PFS when compared to any control (HR 0.66;

95% CI 0.57 to 0.77), using fixed-effects model (Figure 5). There

was no statistical heterogeneity between trials (P=0.20, I2 = 31%).

Secondary outcomes

Toxicity

Leukocytopenia or granulocytopenia or neutropenia (Any

severity)

This analysis involved five trials (Aviles 1996; Fisher 2000;

Rohatiner 2001; Neri 2001; Solal-Céligny 1998 ) with 797 pa-

tients (Figure 6). There was evidence of heterogeneity across all

studies (P=0.008, I2 = 71%). We used a random-effects model.

Results studies showed a significantly higher risk of toxicity in

patients treated with interferon (relative risk (RR) 5.68; 95% CI

1.28 to 25.18).



Figure 6. Forest plot of comparison: 1 Interferon maintenance therapy versus not, outcome: 1.6 Toxicity

(any severity): Leukocytopenia/Granulocytopenia/Neutropenia.

Infection, fever (WHO Grade 3 or 4)

Two trials (Neri 2001; Solal-Céligny 1998) were involved in this

analysis. There was no heterogeneity (P = 0.43, I2 = 0%) nor

significant evidence of a higher risk of toxicity in patients treated

with interferon-alpha (RR 2.26; 95% CI 0.34 to 15.01).

Neurologic symptoms

These analyses involved two trials (Neri 2001; Solal-Céligny 1998)

with 323 patients. Results demonstrated a significantly higher risk

of neurologic symptoms in patients treated with interferon (RR

1.83; 95% CI 1,06 to 3.15 ) (Figure 7). However, the same toxicity

restricted to WHO grades 3 or 4 showed no significant evidence

in patients treated with interferon (RR 1.61; 95% CI 0.41 to

6.38) (Figure 8). There was no evidence of heterogeneity in either

analyses (I2=0%).


(any severity): Neurologic symptoms.




WHO grade 3 or 4: Neurologic symptoms.

Flu-like symptoms

Any severity

This analysis involved two trials (Aviles 1996; Solal-Céligny 1998).

Results did not reach a significant increased risk of toxicity for

patients treated with interferon (RR = 8.49; 95% CI 0.85 to 84.75)

although the point estimate suggests an appreciable harm (Figure

9).


(any severity): Flu-like symptoms.

Severity WHO grade 3 or 4

Only Solal-Céligny 1998 reported on this outcome. There was

no significant evidence of an increased risk of toxicity in patients

treated with interferon (RR 2.91; 95% CI 0.12 to 70.86).

Thrombocytopenia

Three trials (Neri 2001; Solal-Céligny 1998 ; Aviles 1996) con-

tributed to this analysis. Results showed a significantly higher risk

of thrombocytopenia for patients treated with interferon-alpha

(RR 5.78; 95% CI 2.17 to 15.41).



Response to therapy

Patients achieving complete or partial remission (overall

response)

Three trials (Hagenbeek 1998; Neri 2001; Solal-Céligny 1998 )

with 449 patients contributed data to this analysis. There was

evidence of heterogeneity (P = 0.02, I2=75%). Results did not

show a significant difference in response to treatment for patients

given interferon-alpha and patients not treated (RR = 1.12; 95%

CI 0.95 to 1.33) (see Figure 10).

Figure 10. Forest plot of comparison: 1 Interferon maintenance therapy versus not, outcome: 1.11

Response to treatment: Not achieving complete or partial remission (CR or PR).

Number of patients lost to follow up (drop outs)

This analysis involved four trials (Fisher 2000; Hagenbeek 1998;

Rohatiner 2001; Solal-Céligny 1998) with 860 patients (Figure

11). There was significant heterogeneity between trials (P = 0.06,

I2 = 59%). Results showed a significant greater risk to drop out

in patients treated with interferon (RR=5.63; 95% CI 1.06 to

29.94).



Figure 11. Forest plot of comparison: 1 Interferon maintenance therapy versus not, outcome: 1.17 DROPS-

OUT number.

Number needed to treat (NNT) and to harm (NNH)

All efficacy and safety results are summarised as NNT and NNH

in Table 2.

Quality of life (QoL) and cost-effectiveness evaluation

Two additional studies (Cole 1998; Wirt 2001) were included in

this review to assess the advantages of administering interferons

in a therapeutic maintenance setting in terms of QoL. The paper

by Cole (Cole 1998) was based on the patients and data from

Solal-Céligny 1998. A ’quality-adjusted time without symptoms

of toxicity’ (Q-TWIST) analysis, based on the method developed

by Gelber et al. (Gelber 1995), was applied to evaluate the clinical

benefits of interferon-alpha with reference to the increased risk of

toxicity or adverse events . Q-TWIST was applied to 242 patients

randomised to receive a chemotherapy regimen alone (119 pa-

tients) or CHVP plus interferon alfa-2b (123 patients). The study

was based on the definition of four clinical states, useful for the

Q-TWIST analysis:

1. the time spent with toxicity derived from the chemotherapy

treatment alone; or

2. the time spent with toxicity derived from chemotherapy

plus interferon;

3. the time period without symptoms or without disease

progression and without toxicity, and

4. the period following disease progression.

A quality of life-adjusted survival model was applied with the use of

utility coefficients to represent the value of time in the four health

states (Earle 2000, Pettengell 2008). CHVP chemotherapy plus

interferon-alpha provided an average gain of 7.8 quality-adjusted

months as compared with chemotherapy alone.

The paper of Wirt (Wirt 2001) was based on the same 242 patient

data from Solal-Céligny 1998 but was a cost-effectiveness analysis.

The study used a Markov model based on the natural history of ad-

vanced follicular non-Hodgkin’s lymphoma as altered by therapy.

Results showed that interferon-alpha concomitant therapy added

9.9 quality-adjusted months at a cost of USD 13,900 (at a mar-

ginal cost-effectiveness value of USD 16,900 per quality-adjusted

life-year (QALY) , that is below the conventional threshold of USD

50,000 per QALY in the USA (Evans 2004). Authors concluded

that the addition of low-dose interferon-alpha to CHVP chemo-

therapy in a maintenance setting was cost effective in reference to

increasing PFS time.

Both of these studies (Cole 1998; Wirt 2001) are based on only

one trial (Solal-Céligny 1998), the one with most positive findings

favouring interferon.

D I S C U S S I O N

Summary of main results

Eight eligible trials were conducted between 1993 and 2004. In-

terferon as a maintenance therapy for FL, after or concomitant



with chemotherapy, significantly improved PFS. Impact on over-

all survival was less straightforward: results were fairly heteroge-

neous and inconsistent, the random-effects meta-analysis did not

reach statistical significance providing evidence for imprecision.

Although emphasis on P values and the dichotomization of results

based on arbitrary thresholds ( P <0.05) would be inappropriate

(Goodman 1999), our results suggest that the survival benefit is

still uncertain given the low quality of evidence. Toxicity was in

general higher with the interferon chemotherapy regimens. There

was insufficient evidence to assess whether there was any benefit

from interferon chemotherapy in terms of symptom control or

QoL compared with chemotherapy alone because the two studies

which explored QoL were based on only one trial.

Overall completeness and applicability ofevidence

The randomised trials were heterogeneous in terms of concomi-

tant chemotherapies and interferon dosages. For instance, in the

UK the most frequently used initial treatment was chlorambu-

cil, in Europe it was CVP and in the USA it was CHOP. Trials

used administration schedules of interferon-alpha with a total dose

greater than 36 million of international units (MIU) monthly or

less than 36 MIU monthly. The low number of included studies

made it difficult to explore these differences in subgroup analyses.

Median overall survival of FL is about seven to 10 years. Against

this background a novel drug should prolong life in order to be

considered as first choice treatment for maintenance therapy of FL.

Over the past years other novel drugs such as fludarabine-contain-

ing regimens, anti-C20 containing treatments, radioimmunother-

apy and high dose chemotherapy treatments with stem-cell res-

cue (i.e. carmustine, carboplatin, etoposide, cyclophosphamide,

cytarabine and melphalan in several combination regimens), have

been introduced in clinical practice based on evidence about bene-

fits on overall survival. Recently a novel biologic agent, rituximab,

has been adopted as therapeutic and maintenance treatment for

non-Hodgkin’s lymphoma patients (Vidal 2009). Rituximab is a

well-tolerated agent and it has a great activity in relapsing patients

(Coiffier 2007). In combination with chemotherapy, rituximab al-

lowed for the longest PFS and OS described in FL (Coiffier 2007).

Given the toxicity of interferon-alpha and the uncertainty about

survival benefits, it is hard to hypothesize that interferon could

be incorporated into these new therapeutic approaches (Feuerlein

2009, Sebban 2008). These novel agents - and particularly the

monoclonal antibody rituximab - decreased the interest of investi-

gators in understanding the real advantages of interferon in terms

of OS over control chemotherapies.

Agreements and disagreements with otherstudies or reviews

The use of interferon-alpha as an additive therapy for the treat-

ment of FL has been investigated in another systematic overview

(Brandt 2001), and two meta-analyses (Allen 2001; Rohatiner

2005). The systematic overview (Brandt 2001) did not include a

meta-analysis; it was based essentially on 31 randomised studies,

38 prospective studies, and 18 retrospective studies all involving

patients with indolent NHL, predominantly FL. The review did

not distinguish between initial (induction) interferon therapy and

maintenance therapy. The results suggested that addition of inter-

feron to initial combination chemotherapy may increase the re-

sponse rate and significantly prolong remission duration but pro-

longed survival had not been unequivocally proven. The meta-

analysis published by Allen (Allen 2001) selected 25 articles, of

which eight studies met all the criteria for inclusion and six used

interferon-alpha as maintenance therapy. Results of this review in-

dicated that patients who received interferon-alpha (“as either in-

duction or maintenance therapy”) had significantly increased five-

year survival, and approximately 20% increased progression-free

survival rates at three and five years when compared with controls.

Following the authors conclusions the advantages were greater

in patients who received interferon-alpha with an anthracycline-

containing chemotherapy regimen. The authors expressed caution

about the possible literature biases and heterogeneity of the in-

cluded studies. The meta-analysis published by Rohatiner et al

(Rohatiner 2005) included 10 phase III studies, evaluating a total

of 1922 patients with FL. Six studies correspond with studies in-

cluded in this review (ECOG study (Smalley 2001), GELA study

(Solal-Céligny 1993; Solal-Céligny 1998), SWOG study (Fisher

2000), Mexican study (Aviles 1996), UK study (Rohatiner 2001)

and the EORTC study (Hagenbeek 1998)). Four studies (Arranz

1998; Chisesi 1991; Peterson 1997; Unterhalt 1996) included in

the Rohatiner 2005 meta-analysis were considered for inclusion

in our review but were excluded (see Characteristics of excluded

studies). The results of the Rohatiner meta-analysis showed that

addition of interferon-alpha to conventional chemotherapy did

not improve response rate (Rohatiner 2005). However, authors

concluded that interferon therapy may prolong remission dura-

tion and survival under specific circumstances (i.e. chemotherapy

used and intensity of dose).

A U T H O R S ’ C O N C L U S I O N S

Implications for practice

Interferon as a maintenance therapy for FL, after or concomitant

with chemotherapy, significantly improved PFS. Impact on sur-

vival was less certain because of the low quality of evidence due

to heterogeneity, inconsistency and imprecision. There is an in-

creased incidence of adverse events related to the concomitant ad-

ministration of interferon-alpha to chemotherapy. There was in-

sufficient evidence to assess whether there was any benefit from



interferon chemotherapy in terms of symptom control or QoL

compared with chemotherapy alone.

Implications for research

The availability of novel and efficacious biologic agents makes

unlikely that new resources will be invested in interferon-alpha

as a maintenance agent. If any, future research should pay greater

attention to the QoL and related factors for evaluating the trade-

off between progression-free survival and severity and duration of

adverse events.

A C K N O W L E D G E M E N T S

This review has been undertaken within the collaboration of :

• the Cochrane Haematological Malignancies Group, a

specialised group of researchers and consumer representatives

that belong to The Cochrane Collaboration.

• the Cochrane Working Group of the “Centro di

Riferimento Oncologico” - CRO Aviano (Italy), which is a team

working specially in the field of the best drug treatment for

cancer patients and evidence-based oncology. Members: Paolo

Baldo, Maurizio Rupolo, Alessandra Bearz, Renato Cannizzaro,

Antonella Bertola, Simon Spazzapan, Ivana Truccolo, Luigino

Dal Maso, Giuseppe Toffoli, Simona Scalone, Vincenzo

Canzonieri.

R E F E R E N C E S

References to studies included in this review

Aviles 1996 {published data only}

Aviles A, Duque G, Talavera A, Guzmàn R. Interferon

alpha 2b as maintenance therapy in low grade malignant

lymphoma improves duration of remission and survival.

Leukemia and Lymphoma 1996;20:495–9.

Aviles 2004 {published data only}

Aviles A, Neri N, Huerta-Guzman J, Pèrez F, Sotelo L.

Interferon alpha 2b as maintenance therapy improves

outcome in follicular lymphoma. Leukemia and Lymphoma2004;45(11):2247.

Cole 1998 {published data only}

Cole BF, Solal-Céligny P, Gelber RD, Lepage E, Gisselbrecht

C, Reyes F, et al.Quality-of-life adjusted survival analysis

of interferon alfa-2b treatment for advanced follicular

lymphoma: an aid to clinical decision making. Journal ofClinical Oncology 1998;16:2339–44.

Fisher 2000 {published and unpublished data}∗ Fisher RI, Dana BW, LeBlanc M, Kjeldsberg C, Forman

JD, Inger JM, et al.Interferon alfa consolidation after

intensive chemotherapy does not prolong the progression-

free survival of patients with low-grade non-Hodgkin’s

lymphoma: results of the Southwest Oncology Group

randomized phase III study 8809. Journal of ClinicalOncology 2000;18(10):2010–6.

Hagenbeek 1998 {published data only}

Hagenbeek A, Carde P, Meerwaldt JH, Somers R, Thomas

J, De Back R, et al.Maintenance of remission with human

recombinant Interferon Alfa-2a in patients with stages III

and IV low-grade malignant non-Hodgkin’s lymphoma.

Journal of Clinical Oncology 1998;16(1):41–7.

Neri 2001 {published data only}∗ Neri N, Aviles A, Cleto S, Diaz N, Talavera A, Garcia

EL, et al.Chemotherapy plus interferon-alpha 2b versus

chemotherapy in the treatment of follicular lymphoma.

Journal of Hematotherapy and Stem Cell Research 2001;10:

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Rohatiner 2001 {published data only}

Price CGA, Rohatiner AZS, Steward W, Deakin D, Bailey

N, Norton A, et al.Interferon-alfa 2b in the treatment

of follicular lymphoma: Preliminary results of a trial in

progress. Annals of Oncology 1991;2 Suppl 2:141–5.

Rohatiner A, Radford J, Deakin D, Earl H, Love SB, Price

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85(1):29–35.

Smalley 2001 {published data only}

Smalley RV, Andersen JW, Hawkins MJ, Bhide V,

O’Connell MJ, Oken MM, et al.Interferon alfa combined

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P, Haioun C, et al.Doxorubicin-containing regimen with

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Solal-Céligny 1993 {published data only}

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Wirt 2001 {published data only}

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effectiveness of interferon alfa-2b added to chemotherapy

for high-tumor-burden follicular non-Hodgkin’s lymphoma.

Leukemia and Lymphoma 2001;40(5-6):565–79.

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Arranz 1998 {published data only}

Arranz R, Garcia-Alfonso P, Sobrino P, Zamora P, Carrion

R, Garcia-Larana J, et al.Role of interferon alfa-2b in

the induction and maintenance treatment of low-grade

non-Hodgkin’s lymphoma: results from a prospective,

multicenter trial with double randomization. Journal of

Clinical Oncology 1998;16(4):1538–46.

Brice 1997 {published data only}

Brice P, Bastion Y, Lepage E, Brousse N, Haioun C,

Moreau P, et al.Comparison in low-tumor-burden follicular

lymphomas between an initial no-treatment policy,

prednimustine, or interferon alfa: A randomized study from

the Groupe D’etude des Lymphomes Folliculaires. Journalof Clinical Oncology 1997;15(3):1110–7.

Chisesi 1987 {published data only}

Chisesi T, Capnist G, Vespignani M, Cetto G. Interferon

alfa-2b and chlorambucil in the treatment of non-Hodgkin’s

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Chisesi 1991 {published data only}

Chisesi T, Congiu M, Contu A, Coser P, Moretti L,

Porcellini A, et al.Randomized study of chlorambucil (CB)

compared to interferon (alfa-2b) combined with CB in low-

grade non-Hodgkin’s lymphoma: an interim report of a

randomized study. Non-Hodgkin’s Lymphoma Cooperative

Study Group. European Journal of Cancer 1991;27 Suppl 4:

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Davis 2000 {published data only}

Davis TA, Maloney DG, Grillo-Lopez AJ, White CA,

Williams ME, et al.Combination immunotherapy of

relapsed or refractory low-grade or follicular non-Hodgkin’s

lymphoma with rituximab and interferon-a-2a. Clinical

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Giles 2000 {published data only}

Giles FJ, Shan J, Advani SH, Akan H, Aydogdu I, Aziz Z,

et al.A prospective randomized study of chop versus chop

plus alpha-2b interferon in patients with intermediate and

high grade non-Hodgkin’s lymphoma: the International

Oncology Study Group NHL1 study. Leukemia andLymphoma 2000;40(1-2):95–103.

Herold 2007 {published data only}

Herold M, Haas A, Srock S, Neser S, Al-Ali KH, Neubauer

A, et al.Rituximab added to first-line mitoxantrone,

chlorambucil, and prednisolone chemotherapy followed by

interferon maintenance prolongs survival in patients with

advanced follicular lymphoma: an East German Study

Group Hematology and Oncology Study. Journal of Clinical

Oncology 2007;25(15):1986–92.

Hiddeman 1998 {published data only}

Hiddeman W, Unterhalt M, Herrmann R, Woltjen HH,

Kreuser ED, Trumper L, et al.Mantle-cell lymphomas

have more widespread disease and a slower response to

chemotherapy compared with follicle-center lymphomas:

results of a prospective comparative analysis of the German

low-grade Lymphoma Study Group. Journal of Clinical

Oncology 1998;16(5):1922–30.

McLaughlin 1993 {published data only}

McLaughlin P, Cabanillas F, Hagemeister FB, Swan Jr F,

Romaguera JE, Taylor S, et al.CHOP-bleo plus interferon

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Morris 2004 {published data only}

Morris GJ, Millenson MM, Padavic-Shaller K, Wang H,

Rogatko A, Clyde J, et al.Phase II study of fludarabine and

alpha-interferon in patients with low-grade non-Hodgkin’s

lymphoma. Haematologica 2004;89(12):1484–91.

Peterson 1993 {published and unpublished data}

Peterson BA, Petroni GR, Oken MM, Johnson JL,

Barcos M, MR Copper. Cyclophosphamide versus

cyclophosphamide plus interferon alfa-2b in follicular low-

grade lymphomas: .a preliminary report of an intergroup

trial (CALGB 8691 and EST 7486). Proceeding of ASCO.

1993; Vol. 12:366.

Peterson 1997 {published and unpublished data}

Peterson BA, Petroni GR, Oken MM, Johnson JL,

Barcos M, MR Copper. Cyclophosphamide versus

cyclophosphamide plus interferon alfa-2b in follicular low-

grade lymphomas.an intergroup phase III trial (CALGB

8691 and EST 7486). Proceedings of ASCO, Abstract 48.

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Salles 2008 {published data only}

Salles G, Mounier N, de Guibert S, Morshhauser F, Doyen

C, Rossi JF, et al.Rituximab combined with chemotherapy

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Sebban 2006 {published data only}

Sebban C, Mounier N, Brousse N, Belanger C, Brice P,

Haioun C, et al.Standard chemotherapy with interferon

compared with CHOP followed by high-dose therapy

with autologous stem cell transplantation in untreated

patients with advanced follicular lymphoma: the GELF-94

randomized study from the Groupe d’Etude des Lymphomes

de l’Adulte (GELA). Blood 2006;108(8):2540–4.

Unterhalt 1996 {published data only}

Unterhalt M, Herrmann R, Tiemann M, Parwaresch R,

Stein H, Trumper L, et al.Prednimustine, mitoxantrone

(PmM) vs cyclophosphamide, vincristine, prednisone

(COP) for the treatment of advanced low-grade non-

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Zinzani PL, Bendandi M, Magagnoli M, Rondelli D, De

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patients with chronic lymphocytic leukemia and low-

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Armitage JO, Weisemburger DD. New approach to

classifying non-Hodgkin’s lymphomas: clinical features of

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Bastion 1991

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C H A R A C T E R I S T I C S O F S T U D I E S

Characteristics of included studies [ordered by study ID]

Aviles 1996

Methods Parallel randomised controlled trial; method of randomisation: coded envelopes

Participants 98 patients affected by low-grade malignant lymphoma in complete remission after a conventional che-

motherapy regimen and radiotherapy, if necessary. Most patients had follicular mixed or follicular small

cell histology

Interventions Induction therapy consisted of two cycles of two low doses of methotrexate with leucovorin, followed by

two cycles of CEOP-Bleo (cyclophosphamide, epirubicin, vincristine, prednisone and bleomycin), given

every three weeks and followed by six cycles of CVP (cyclophosphamide, vincristine and prednisone),

given monthly. Patients in complete response (98) were randomised to receive: interferon alfa-2b, 5.0

MIU, three times a week for one year, as maintenance therapy, or no further treatment (control group)

Outcomes Overall survival, progression-free survival, quality of life, treatment-related toxicity

Notes

Risk of bias

Item Authors’ judgement Description

Allocation concealment? Yes A - Adequate

Aviles 2004

Methods Parallel randomised controlled trial; method of randomisation not declared

Participants 384 patients affected by follicular lymphoma (according to REAL/World Health Organization Classifi-

cation), in complete response after 6 cycles of chemotherapy (CEOP-Bleo) and adjuvant radiotherapy if

necessary

Interventions Initally, the patients received the same chemotherapy regimen (CEOP-Bleo, cyclophosphamide, epiru-

bicin, vincristine, prednisone and bleomycin at standard doses) and adjuvant radiotherapy if necessary.

Patients in complete response were randomised to receive: interferon alfa-2b, 5.0 MIU three times a

week or no treatment (control group). Complete response was defined as disappearance of all detectable

evidence of the progression

Outcomes The primary end-points were overall survival (OS), event-free survival (EFS). Toxicity was reported only

in relation to total number of cycles, and not referred to individual patient treatment-related toxicity

Notes Data about treatment-related toxicity (table II of the original paper) were not usable for the purpose of

the review

Risk of bias



Aviles 2004 (Continued)


Allocation concealment? No C - Inadequate

Cole 1998

Methods A quality of life-adjusted survival analysis based on the data of GELF 86 multi-centre trial (Groupe

D’Etude Des Lymphomes Folliculaires) (see Solal-Céligny 1998).

Participants Analysis based on 242 patients who had advanced follicular lymphoma

Interventions Two arms of patients randomised to receive a chemotherapy regimen (CHVP, cyclophosphamide, dox-

orubicin, teniposide and prednisone) alone or CHVP plus interferon alfa-2b, 5 MIU three times weekly

for 18 months

Outcomes To estimate health-state durations and to evaluate the trade off of toxicity versus improved clinical outcome

achieved with concomitant administration of interferon therapy

Notes

Risk of bias


Allocation concealment? Unclear B - unclear

Fisher 2000

Methods Parallel randomised clinical trial.

Participants 268 eligible patients; 86% had follicular lymphoma, and only 14% had working formulation (WF) type

A

Interventions Two arms of patients, randomised to receive interferon alfa-2b consolidation (maintenance) therapy

(2 MIU three times a week for two years) or observation alone. Induction therapy consisted of six to

eight cycles of chemotherapy (ProMACE, prednisone, methotrexate, doxorubicin, cyclophosphamide

at day 1, and MOPP, etoposide/mechlorethamine, vincristine, procarbazine, and prednisone at day 8)

or chemotherapy plus radiotherapy. Responding patients were randomised to observation alone or to

interferon alfa-2b maintenance therapy, given at 2 MIU/m2 three times weekly for 2 years.

Outcomes Overall survival (OS) and progression-free survival (PFS).

Notes

Risk of bias




Fisher 2000 (Continued)

Allocation concealment? Unclear B - Unclear

Hagenbeek 1998

Methods Parallel randomised controlled clinical trial.

Participants 242 patients with stages III and IV low-grade malignant NHL (predominantly follicular)

Interventions Two arms of patients randomised to receive: interferon alfa-2a, 3.0 MIU, three times a week or no further

therapy (control group)

Outcomes Overall survival (OS), time to progression (TTP), treatment-related toxicity

Notes

Risk of bias



Neri 2001


Participants 55 patients with follicular NHL lymphoma, stages I or II (according to REAL classification)

Interventions Two arms of patients randomised to receive: chemotherapy COPP (cyclophosphamide, vincristine, pred-

nisone and procarbazine) plus interferon alfa-2b (5.0 MIU three times a week) or chemotherapy COPP

alone

Outcomes Overall survival, event-free survival (EFS), treatment-related toxicity

Notes

Risk of bias





Rohatiner 2001

Methods Parallel randomised controlled clinical trial (sequential).

Participants 231 patients affected by stage III or IV follicular lymphoma. We considered in the analyses only patients

included in the second randomization group (maintenance setting, N = 108)

Interventions Two arms of patients randomised to receive either chlorambucil 10 mg daily in a specific schedule) or

the same therapy given concurrently with interferon alfa-2b (3 MIU three times a week) for 18 weeks.

Responding patients were then randomised to receive maintenance interferon therapy at the same dose

for six months or no further therapy (control group)

Outcomes Evaluation of the clinical course of patients with follicular lymphoma, complete and partial remission,

survival time, time of remission, treatment-related toxicity

Notes

Risk of bias


Allocation concealment? Yes A - Adequate

Smalley 2001

Methods Randomised controlled clinical trial.

Participants 249 eligible patients who had low-grade or intermediate-grade NHL. Only patients with FL were included

in the analysis for this systematic review (N= 166)

Interventions Two arms of patients, randomised to receive a chemotherapy regimen including cyclophosphamide, vin-

cristine, doxorubicin and prednisone given with or without (control group) the concomitant administra-

tion of interferon alfa-2a (6 MIU/m2 on days 22-26, for 8-10 cycles).

Outcomes Overall survival, time to treatment failure (TTF).

Notes

Risk of bias





Solal-Céligny 1998

Methods Final analysis derived from Solal-Céligny 1993.

Participants 242 patients who had small-cell or mixed-cell follicular lymphoma

Interventions Two arms of patients, randomised to receive a chemotherapy regimen including cyclophosphamide,

teniposide, doxorubicin and prednisone (CHVP) given with or without (control group) the concomitant

administration of interferon alfa-2b (5 MIU/m2 three times weekly for 18 months).

Outcomes Overall survival, progression-free survival (PFS), response to treatment and toxicity related to drug therapy

Notes

Risk of bias



Solal-Céligny 1993


Participants 242 patients who had small-cell or mixed-cell follicular lymphoma

Interventions Two arms of patients, randomised to receive a chemotherapy regimen including cyclophosphamide,

teniposide, doxorubicin and prednisone (CHVP) given with or without (control group) the concomitant

administration of interferon alfa-2b (5 MIU/m2 three times weekly for 18 months).

Outcomes Overall survival, progression-free survival (PFS), response to treatment and toxicity related to drug therapy

Notes The 1993 paper contains some data on patient compliance, and toxicity (not extractable from Solal-Céligny

1998).

Risk of bias



Wirt 2001

Methods A cost-effectiveness analysis based on the data of GELF 86 multi-centre trial (Groupe D’Etude Des

Lymphomes Folliculaires) (see Solal-Céligny 1998).

Participants Analysis based on 242 patients who had advanced follicular lymphoma



Wirt 2001 (Continued)

Interventions Two arms, patients randomised to receive chemotherapy (CHVP, cyclophosphamide, doxorubicin, teni-

poside and prednisone) alone or CHVP plus interferon alfa-2b, 5 MIU three times weekly for 18 months

Outcomes To estimate the cost-effectiveness of interferon therapy added to a regimen of chemotherapy in the

treatment of advanced follicular lymphoma

Notes

Risk of bias


Allocation concealment? Unclear D - Not used

Characteristics of excluded studies [ordered by study ID]

Study Reason for exclusion

Arranz 1998 The study also admitted patients with lymphoma in marginal areas (mucosa-associated lymphoid tissue (MALT)

and monocytoids) and patients with mantle-cell lymphoma

Brice 1997 The study included a treatment arm in which interferon alfa-2b was used as induction therapy

Chisesi 1987 This pilot study (not randomised) enrolled patients with clinically incurable diffuse poorly differentiated lym-

phocytic NHL (DPDL) and patients with diffuse mixed NHL (DM)

Chisesi 1991 Interferon was used in all patients as induction therapy.

Davis 2000 Interferon was used in all patients as induction therapy.

Giles 2000 The study admitted patients with different classifications of lymphoma, not only or prevalently in the follicular

form

Herold 2007 The study compared two treatment regimens not including interferon (mitoxantrone, chlorambucil, pred-

nisolone (MCP) with rituximab or MCP alone). All patients achieving a complete or partial remission were

treated with interferon alfa-2a until relapse, but no data about efficacy of interferon therapy were reported

Hiddeman 1998 The study compared patients with follicle-centre lymphoma or with (FCLs) and mantle-cell lymphomas (MCLs)

McLaughlin 1993 The study evaluated the integration of interferon alfa-n1 into a conventional chemotherapy regimen (CHOP-

bleo) was not a randomised control trial

Morris 2004 The study was not a randomised clinical trial; furthermore, the study enrolled patients who had prior treatment

(with one to three different chemotherapy regimens) and patients who had no prior treatment



(Continued)

Peterson 1993 Data from this study, the preliminary data of the same study reported in American Society of Clinical Oncology

(ASCO) proceedings 1997 (Peterson 1997), were only reported as an abstract presented at ASCO in 1993, and

published in the proceedings of ASCO Vol 12 (n. *1240 pag 366); the paper evaluated the efficacy of interferon

alfa-2b administered as induction therapy

Peterson 1997 Data from this study were only reported as an abstract presented at American Society of Clinical Oncology

(ASCO) in 1997, and published in the proceedings of ASCO Vol 16 (n. *48 pag 14a); and evaluated the efficacy

of interferon alfa-2b administered as induction therapy

Salles 2008 Interferon was used in all patients as induction therapy.

Sebban 2006 Interferon was used in all patients as induction therapy.

Unterhalt 1996 The study compared patients with centroblastic-centrocytic (Kiel classification) or with follicle centre lymphoma

(REAL classification) or with mantle cell lymphoma. In the study tables CB-CC (centroblastic-centrocitic

lymphoma) were presented in the same group as FCL (follicle centre) patients, and the former were 81% against

19% of the FCL

Zinzani 1997 The study enrolled patients affected by B-cell chronic lymphocytic leukemia (B-CLL)



D A T A A N D A N A L Y S E S

Comparison 1. Interferon maintenance therapy versus other therapy

Outcome or subgroup titleNo. of

studies

No. of

participants Statistical method Effect size

1 Overall survival (HR,

random-effects model)

8 1563 Hazard Ratio (Random, 95% CI) 0.82 [0.63, 1.08]

1.1 Studies evaluating

Interferon therapy vs no further

therapy



Interferon therapy plus CT vs

CT alone


2 Overall survival (HR,

fixed-effects model)

8 1563 Hazard Ratio (Fixed, 95% CI) 0.79 [0.67, 0.94]



therapy




CT alone


3 Progression-free survival (HR,





therapy




CT alone


4 Sensitivity analysis: Overall

survival (excluding Fisher

2000, fixed-effects model)




therapy




CT alone


5 Sensitivity analysis:

Progression-free survival

(excluding Fisher 2000,





therapy






CT alone


6 Toxicity (any severity):

Leukocytopenia/

Granulocytopenia/

Neutropenia

5 797 Risk Ratio (M-H, Random, 95% CI) 5.68 [1.28, 25.18]


Neurologic symptoms

2 323 Risk Ratio (M-H, Fixed, 95% CI) 1.83 [1.06, 3.15]


Inteferon therapy plus CT vs

CT alone


8 Toxicity (any severity): Flu-like

symptoms




therapy




CT alone



Thrombocytopenia


10 Response to treatment: Overall

response


11 Toxicity WHO grade 3 or 4:

Haematological toxicity



Flu-like symptoms



Neurologic symptoms



Infection / fever


15 Drop-outs 4 860 Risk Ratio (M-H, Random, 95% CI) 5.63 [1.06, 29.94]



CT alone




therapy




Analysis 1.1. Comparison 1 Interferon maintenance therapy versus other therapy, Outcome 1 Overall

survival (HR, random-effects model).

Review: Interferon-alpha for maintenance of follicular lymphoma

Comparison: 1 Interferon maintenance therapy versus other therapy

Outcome: 1 Overall survival (HR, random-effects model)

Study or subgroup Interferon therapy Control log [Hazard Ratio] Hazard Ratio Weight Hazard Ratio

N N (SE) IV,Random,95% CI IV,Random,95% CI

1 Studies evaluating Interferon therapy vs no further therapy

Aviles 1996 48 50 -0.891 (0.481) 6.2 % 0.41 [ 0.16, 1.05 ]

Aviles 2004 191 193 -0.474 (0.184) 17.9 % 0.62 [ 0.43, 0.89 ]

Fisher 2000 144 124 0.0198 (0.209) 16.4 % 1.02 [ 0.68, 1.54 ]

Hagenbeek 1998 122 120 0.271 (0.272) 13.0 % 1.31 [ 0.77, 2.23 ]

Rohatiner 2001 60 48 0.405 (0.362) 9.3 % 1.50 [ 0.74, 3.05 ]

Subtotal (95% CI) 62.9 % 0.90 [ 0.61, 1.34 ]

Heterogeneity: Tau2 = 0.12; Chi2 = 10.87, df = 4 (P = 0.03); I2 =63%

Test for overall effect: Z = 0.50 (P = 0.62)

2 Studies evaluating Interferon therapy plus CT vs CT alone

Neri 2001 28 27 0.113 (0.659) 3.7 % 1.12 [ 0.31, 4.07 ]

Smalley 2001 78 88 -0.234 (0.21) 16.3 % 0.79 [ 0.52, 1.19 ]

Solal-C ligny 1998 123 119 -0.562 (0.199) 17.0 % 0.57 [ 0.39, 0.84 ]

Subtotal (95% CI) 37.1 % 0.68 [ 0.52, 0.90 ]

Heterogeneity: Tau2 = 0.0; Chi2 = 1.88, df = 2 (P = 0.39); I2 =0.0%


Total (95% CI) 100.0 % 0.82 [ 0.63, 1.08 ]



0.2 0.5 1 2 5

Favours interferon Favours control



Analysis 1.2. Comparison 1 Interferon maintenance therapy versus other therapy, Outcome 2 Overall

survival (HR, fixed-effects model).



Outcome: 2 Overall survival (HR, fixed-effects model)


N N (SE) IV,Fixed,95% CI IV,Fixed,95% CI


Aviles 1996 48 50 -0.891 (0.481) 3.4 % 0.41 [ 0.16, 1.05 ]

Aviles 2004 191 193 -0.474 (0.184) 23.1 % 0.62 [ 0.43, 0.89 ]

Fisher 2000 144 124 0.0198 (0.209) 17.9 % 1.02 [ 0.68, 1.54 ]

Hagenbeek 1998 122 120 0.271 (0.272) 10.5 % 1.31 [ 0.77, 2.23 ]

Rohatiner 2001 60 48 0.405 (0.362) 6.0 % 1.50 [ 0.74, 3.05 ]

Subtotal (95% CI) 60.8 % 0.87 [ 0.70, 1.09 ]

Heterogeneity: Chi2 = 10.87, df = 4 (P = 0.03); I2 =63%



Neri 2001 28 27 0.113 (0.659) 1.8 % 1.12 [ 0.31, 4.07 ]

Smalley 2001 78 88 -0.234 (0.21) 17.7 % 0.79 [ 0.52, 1.19 ]

Solal-C ligny 1998 123 119 -0.562 (0.199) 19.7 % 0.57 [ 0.39, 0.84 ]

Subtotal (95% CI) 39.2 % 0.68 [ 0.52, 0.90 ]

Heterogeneity: Chi2 = 1.88, df = 2 (P = 0.39); I2 =0.0%


Total (95% CI) 100.0 % 0.79 [ 0.67, 0.94 ]



Test for subgroup differences: Chi2 = 1.85, df = 1 (P = 0.17), I2 =46%

0.2 0.5 1 2 5




Analysis 1.3. Comparison 1 Interferon maintenance therapy versus other therapy, Outcome 3 Progression-

free survival (HR, fixed-effects model).



Outcome: 3 Progression-free survival (HR, fixed-effects model)




Aviles 2004 191 193 -0.315 (0.168) 21.4 % 0.73 [ 0.53, 1.01 ]

Fisher 2000 144 124 -0.248 (0.215) 13.1 % 0.78 [ 0.51, 1.19 ]

Hagenbeek 1998 122 120 -0.311 (0.161) 23.3 % 0.73 [ 0.53, 1.00 ]

Subtotal (95% CI) 57.8 % 0.74 [ 0.61, 0.91 ]




Neri 2001 28 27 -1.822 (0.707) 1.2 % 0.16 [ 0.04, 0.65 ]

Smalley 2001 78 88 -0.429 (0.167) 21.7 % 0.65 [ 0.47, 0.90 ]

Solal-C ligny 1998 123 119 -0.659 (0.177) 19.3 % 0.52 [ 0.37, 0.73 ]

Subtotal (95% CI) 42.2 % 0.56 [ 0.45, 0.71 ]


Test for overall effect: Z = 4.80 (P < 0.00001)

Total (95% CI) 100.0 % 0.66 [ 0.57, 0.77 ]




0.2 0.5 1 2 5




Analysis 1.4. Comparison 1 Interferon maintenance therapy versus other therapy, Outcome 4 Sensitivity

analysis: Overall survival (excluding Fisher 2000, fixed-effects model).



Outcome: 4 Sensitivity analysis: Overall survival (excluding Fisher 2000, fixed-effects model)




Aviles 1996 48 50 -0.891 (0.481) 4.1 % 0.41 [ 0.16, 1.05 ]

Aviles 2004 191 193 -0.474 (0.184) 28.1 % 0.62 [ 0.43, 0.89 ]

Hagenbeek 1998 122 120 0.271 (0.272) 12.8 % 1.31 [ 0.77, 2.23 ]

Rohatiner 2001 60 48 0.405 (0.362) 7.3 % 1.50 [ 0.74, 3.05 ]

Subtotal (95% CI) 52.3 % 0.82 [ 0.63, 1.06 ]




Neri 2001 28 27 0.113 (0.659) 2.2 % 1.12 [ 0.31, 4.07 ]

Smalley 2001 78 88 -0.234 (0.21) 21.5 % 0.79 [ 0.52, 1.19 ]

Solal-C ligny 1998 123 119 -0.562 (0.199) 24.0 % 0.57 [ 0.39, 0.84 ]

Subtotal (95% CI) 47.7 % 0.68 [ 0.52, 0.90 ]



Total (95% CI) 100.0 % 0.75 [ 0.62, 0.91 ]



Test for subgroup differences: Chi2 = 0.86, df = 1 (P = 0.35), I2 =0.0%

0.2 0.5 1 2 5

Favours treatment Favours control



Analysis 1.5. Comparison 1 Interferon maintenance therapy versus other therapy, Outcome 5 Sensitivity

analysis: Progression-free survival (excluding Fisher 2000, fixed-effects model).



Outcome: 5 Sensitivity analysis: Progression-free survival (excluding Fisher 2000, fixed-effects model)




Aviles 2004 191 193 -0.315 (0.168) 24.6 % 0.73 [ 0.53, 1.01 ]

Hagenbeek 1998 122 120 -0.311 (0.161) 26.8 % 0.73 [ 0.53, 1.00 ]

Subtotal (95% CI) 51.5 % 0.73 [ 0.58, 0.92 ]




Neri 2001 28 27 -1.822 (0.707) 1.4 % 0.16 [ 0.04, 0.65 ]

Smalley 2001 78 88 -0.429 (0.167) 24.9 % 0.65 [ 0.47, 0.90 ]

Solal-C ligny 1998 123 119 -0.659 (0.177) 22.2 % 0.52 [ 0.37, 0.73 ]

Subtotal (95% CI) 48.5 % 0.56 [ 0.45, 0.71 ]



Total (95% CI) 100.0 % 0.64 [ 0.55, 0.76 ]




0.1 0.2 0.5 1 2 5 10




Analysis 1.6. Comparison 1 Interferon maintenance therapy versus other therapy, Outcome 6 Toxicity (any

severity): Leukocytopenia/ Granulocytopenia/ Neutropenia.



Outcome: 6 Toxicity (any severity): Leukocytopenia/ Granulocytopenia/ Neutropenia

Study or subgroup Interferon therapy Control Risk Ratio Weight Risk Ratio

n/N n/N

M-H,Random,95%

CI

M-H,Random,95%

CI

Aviles 1996 5/48 0/50 14.7 % 11.45 [ 0.65, 201.60 ]

Fisher 2000 46/144 0/124 15.2 % 80.17 [ 4.99, 1287.64 ]

Neri 2001 3/28 4/27 25.1 % 0.72 [ 0.18, 2.93 ]

Rohatiner 2001 5/60 0/48 14.7 % 8.84 [ 0.50, 155.93 ]

Solal-C ligny 1998 49/136 10/132 30.4 % 4.76 [ 2.52, 8.99 ]

Total (95% CI) 416 381 100.0 % 5.68 [ 1.28, 25.18 ]

Total events: 108 (Interferon therapy), 14 (Control)



0.001 0.01 0.1 1 10 100 1000





severity): Neurologic symptoms.



Outcome: 7 Toxicity (any severity): Neurologic symptoms

Study or subgroup Interferon Therapy Control Risk Ratio Weight Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI

1 Studies evaluating Inteferon therapy plus CT vs CT alone

Neri 2001 4/28 2/27 11.8 % 1.93 [ 0.38, 9.68 ]

Solal-C ligny 1998 28/136 15/132 88.2 % 1.81 [ 1.01, 3.23 ]

Total (95% CI) 164 159 100.0 % 1.83 [ 1.06, 3.15 ]

Total events: 32 (Interferon Therapy), 17 (Control)



0.05 0.2 1 5 20





severity): Flu-like symptoms.



Outcome: 8 Toxicity (any severity): Flu-like symptoms


n/N n/N

M-H,Random,95%

CI

M-H,Random,95%

CI


Aviles 1996 17/48 0/50 35.0 % 36.43 [ 2.25, 589.34 ]

Subtotal (95% CI) 48 50 35.0 % 36.43 [ 2.25, 589.34 ]


Heterogeneity: not applicable



Solal-C ligny 1998 24/136 6/132 65.0 % 3.88 [ 1.64, 9.19 ]

Subtotal (95% CI) 136 132 65.0 % 3.88 [ 1.64, 9.19 ]




Total (95% CI) 184 182 100.0 % 8.49 [ 0.85, 84.75 ]




0.001 0.01 0.1 1 10 100 1000





severity): Thrombocytopenia.



Outcome: 9 Toxicity (any severity): Thrombocytopenia



Neri 2001 2/28 2/27 44.7 % 0.96 [ 0.15, 6.37 ]

Solal-C ligny 1998 18/136 2/132 44.6 % 8.74 [ 2.07, 36.91 ]

Aviles 1996 6/48 0/50 10.8 % 13.53 [ 0.78, 233.82 ]

Total (95% CI) 212 209 100.0 % 5.78 [ 2.17, 15.41 ]




0.001 0.01 0.1 1 10 100 1000




Analysis 1.10. Comparison 1 Interferon maintenance therapy versus other therapy, Outcome 10 Response

to treatment: Overall response.



Outcome: 10 Response to treatment: Overall response


n/N n/N

M-H,Random,95%

CI

M-H,Random,95%

CI

Hagenbeek 1998 110/122 108/120 42.0 % 1.00 [ 0.92, 1.09 ]

Neri 2001 25/28 20/27 22.7 % 1.21 [ 0.93, 1.56 ]

Solal-C ligny 1993 104/123 82/119 35.3 % 1.23 [ 1.06, 1.41 ]

Total (95% CI) 273 266 100.0 % 1.12 [ 0.95, 1.33 ]




0.5 0.7 1 1.5 2

Favours Control Favours interferon

Analysis 1.11. Comparison 1 Interferon maintenance therapy versus other therapy, Outcome 11 Toxicity

WHO grade 3 or 4: Haematological toxicity.



Outcome: 11 Toxicity WHO grade 3 or 4: Haematological toxicity


n/N n/N

M-H,Random,95%

CI

M-H,Random,95%

CI

Neri 2001 5/28 6/27 47.5 % 0.80 [ 0.28, 2.33 ]

Solal-C ligny 1998 48/136 9/132 52.5 % 5.18 [ 2.65, 10.12 ]

Total (95% CI) 164 159 100.0 % 2.14 [ 0.34, 13.47 ]




0.1 0.2 0.5 1 2 5 10





WHO grade 3 or 4: Flu-like symptoms.



Outcome: 12 Toxicity WHO grade 3 or 4: Flu-like symptoms



Solal-C ligny 1998 1/136 0/132 100.0 % 2.91 [ 0.12, 70.86 ]

Total (95% CI) 136 132 100.0 % 2.91 [ 0.12, 70.86 ]




0.001 0.01 0.1 1 10 100 1000





WHO grade 3 or 4: Neurologic symptoms.



Outcome: 13 Toxicity WHO grade 3 or 4: Neurologic symptoms



Neri 2001 4/28 2/27 66.7 % 1.93 [ 0.38, 9.68 ]

Solal-C ligny 1998 1/136 1/132 33.3 % 0.97 [ 0.06, 15.36 ]

Total (95% CI) 164 159 100.0 % 1.61 [ 0.41, 6.38 ]




0.01 0.1 1 10 100



WHO grade 3 or 4: Infection / fever.



Outcome: 14 Toxicity WHO grade 3 or 4: Infection / fever



Neri 2001 1/28 1/27 66.7 % 0.96 [ 0.06, 14.65 ]

Solal-C ligny 1998 2/136 0/132 33.3 % 4.85 [ 0.24, 100.16 ]

Total (95% CI) 164 159 100.0 % 2.26 [ 0.34, 15.01 ]




0.001 0.01 0.1 1 10 100 1000




Analysis 1.15. Comparison 1 Interferon maintenance therapy versus other therapy, Outcome 15 Drop-outs.



Outcome: 15 Drop-outs


n/N n/N

M-H,Random,95%

CI

M-H,Random,95%

CI


Solal-C ligny 1998 (1) 28/123 16/119 42.1 % 1.69 [ 0.97, 2.96 ]

Subtotal (95% CI) 123 119 42.1 % 1.69 [ 0.97, 2.96 ]





Fisher 2000 5/144 0/124 19.1 % 9.48 [ 0.53, 169.80 ]

Hagenbeek 1998 14/122 0/120 19.7 % 28.53 [ 1.72, 472.91 ]

Rohatiner 2001 5/60 0/48 19.2 % 8.84 [ 0.50, 155.93 ]

Subtotal (95% CI) 326 292 57.9 % 13.54 [ 2.61, 70.33 ]


Heterogeneity: Tau2 = 0.0; Chi2 = 0.43, df = 2 (P = 0.80); I2 =0.0%


Total (95% CI) 449 411 100.0 % 5.63 [ 1.06, 29.94 ]




0.002 0.1 1 10 500


(1) Drops out numbers for Solal-C ligny 1998 were extracted in reference to the preliminary data reported also in Solal-C ligny 1993

A D D I T I O N A L T A B L E S

Table 1. Additional table 1. Definitions for follicular lymphomas in the different classification systems.

ICD-O code Kiel (1992) REAL (1994) WHO (2001)

B-cell lymphomas B-cell neoplasms B-cell neoplasms

9690/3 Centroblastic-centrocytic

lymphoma,

follicular, follicular and diffuse

Follicle centre lymphoma, follicular Follicular lymphoma



Table 1. Additional table 1. Definitions for follicular lymphomas in the different classification systems. (Continued)

- with an increased number of cen-

troblasts

Centroblastic lymphoma, follicularGrade I Grade 1

Grade II Grade 2

Grade III Grade 3a

Grade 3b

Centroblastic-centrocytic

lymphoma, diffuse

Follicle centre lymphoma, diffuse,

small cell

Diffuse follicle centre lymphoma

9673/3 Centrocytic (mantle cell) lymphoma

Centroblastic lymphoma, centrocy-

toid

Mantle cell lymphoma Mantle cell lymphoma

Comparison of definitions for follicular lymphomas in the different classification systems. Note that in the Kiel classification, tumours

with a follicular growth pattern or a follicular component were not regarded as a separate entity. ICD-O code = International

Classification of Disease for Oncology codes; WHO = World Health Organization.

Table 2. Additional table 2. Summary of NNT/NNH by outcome.

Analysis ref. number Outcome NNT/NNH

1.1 Overall survival (random-effects model) NS

1.2 Overall survival (fixed-effects model), best scenario /

worst scenario

34 / 14

1.3 Progression-free survival (fixed-effects model), best

scenario / worst scenario

16 / 7

1.6 Toxicity (any severity): leukocytopenia/granulocy-

topenia/neutropenia

5

1.7 Toxicity (any severity): neurologic symptoms 12

1.8 Toxicity any severity: flu-like symptoms 6

1.9 Toxicity any severity: thrombocytopenia 10

1.13 Toxicity WHO grade III - IV: haematological toxicity 5

1.14 Toxicity WHO grade III - IV: flu-like symptoms 136



Table 2. Additional table 2. Summary of NNT/NNH by outcome. (Continued)

1.15 Toxicity WHO grade III - IV: neurologic symptoms 87

1.16 Toxicity WHO grade III - IV: infection/fever 84

1.17 Tolerability - Number of patients withdrawing from

treatment for any reason

16

Number needed to treat (NNT) by outcome. For overall survival (OS), using fixed-effects model, best scenario: 5-years survival = 0.85

(Aviles 2004); estimated pooled HR = 0.79; 95%CI 0.67 to 0.94, NNT= 34; 95% CI 21 to 120; worst scenario: 5-years survival

= 0.56 (Solal-Céligny 1998), estimated pooled HR = 0.79; 95%CI 0.67 to 0.94, NNT = 14; 95% CI 9 to 51. For progression-

free survival, fixed-effects model, best scenario: 5-years survival = 0.80 (Neri 2001); estimated pooled HR = 0.66; 95% CI 0.57 to

0.77, NNT = 16; 95% CI 12 to 24; worst scenario: 5-years survival = 0.20 (Solal-Céligny 1998); estimated pooled HR = 0.66; 95%

CI 0.57, 0.77, NNT = 7; 95% CI 5 to 11. Numbers were calculated following the methodology showed by Altman et al (Altman

1999). For adverse events/toxicity numbers needed to harm (NNH) were calculated.

Table 3. Additional table 3. Summary of studies included in meta-analysis.

Study name Publication status Patients: total enrolled/

measured

Treatment arm Control arm

Aviles 1996 full paper 98/98 48 50

Aviles 2004 full paper 384/384 191 193

Fisher 2000 full paper 571/268 144 124

Hagenbeek 1998 full paper 347/242 122 120

Neri 2001 full paper 55/55 28 27

Rohatiner 2001 full paper 126/108 (patients from sec-

ond randomisation only)

60 48

Smalley 2001 full paper 291/166 78 88

Solal-Cèligny 1998 full paper 273/242 123 119



A P P E N D I C E S

Appendix 1. Clarification of terms

CONSORT: Consolidated standards of reporting trials

A statement that was developed to help authors improve the reporting of a randomised clinical trial by using a checklist and flow

diagram; it also enables readers to understand a trial’s conduct and to assess the validity of the results.

Fixed-effect model:

A statistical model that stipulates that the units under analysis (e.g. people in a study in a meta-analysis) are the ones of interest, and

thus constitute the entire population of units. Only within-study variation is taken to influence the uncertainty of results (as reflected

in the confidence interval) of a meta-analysis using a fixed effect model. Variation between the estimates of effect from each study

(heterogeneity) does not affect the confidence interval in a fixed effect model. (see also: random-effects model).

FLIPI: Follicular lymphoma international prognostic index.

The prognosis of follicular lymphomas (FL) is heterogeneous and numerous treatments may be proposed. A validated prognostic index

(PI) would help in evaluating and choosing these treatments.

HR: Hazard ratio

The hazard ratio represents the overall reduction in the risk of death on treatment compared to control over the period of follow-up

of patients. This is one of the statistical methods that should improve the efficiency and reliability of meta-analyses of the published

literature with survival-type endpoints.

IPD: Individual patient data

In systematic reviews this term refers to the availability of raw data for each participant in each included study, as opposed to aggregate

data (summary data for the comparison groups in each study). Reviews using individual patient data require collaboration of the

investigators who conducted the original trials, who must provide the necessary data.

ITT: Intention to treat

An intention-to-treat analysis is one in which all the participants in a trial are analysed according to the intervention to which they

were allocated, whether they received it or not. Intention-to-treat analyses are favoured in assessments of effectiveness as they mirror

the noncompliance and treatment changes that are likely to occur when the intervention is used in practice, and because of the risk of

attrition bias when participants are excluded from the analysis.

Mantel-Haenszel Method (or test)

A summary Chi2 test for stratified data and used when collecting for confounding. In meta-analyses, the Mantel-Haenszel test is used

to analyse data stratified (grouped) by study.

Meta-analysis

Meta-analyses are statistical techniques that provide a full and comprehensive summary of related studies which have addressed a similar

question.

Sometimes used as synonym for systematic reviews, where the review includes these techniques.

MIU: Million of International Units

Symbol for one million international units. It represents a measure of the potency or the biological effect expected with a dose of 1 IU.

NNT: Number needed to treat

It is the number of patients who need to be treated to prevent one outcome. Statistically, it is the inverse of the risk difference.

QUALY: Quality-adjusted life year

A measurement index derived from a modification of standard life-table procedures and designed to take account of the quality as well

as the duration of survival. This index can be used in assessing the outcome of health care procedures or services and is often applied

in ’cost-utility’ analyses (CUA), in the field of Pharmacoeconomics.

QUOROM: Quality of reporting of meta-analyses

A statement that was developed to help authors improve the quality of reporting of meta-analyses of clinical randomised controlled

trials (RCTs) by using a checklist and a flow diagram. The flow diagram provides information about the numbers of RCTs identified,

included and excluded and the reasons for exclusion of trials.

Random-effects model:

A statistical model sometimes used in meta-analysis in which both within-study sampling error (variance) and between-studies variation

are included in the assessment of the uncertainty (confidence interval) of the results of a meta-analysis. If there is significant heterogeneity

among the results of the included studies, random effects models will give wider confidence intervals than fixed effect models (see also:

fixed-effects model).

Randomised controlled trial (RCT) (Synonym: randomised clinical trial, also typed as ’randomized’)



A clinical experiment in which investigators randomly allocate eligible people into intervention groups to receive or not to receive one

or more interventions that are being compared. The results are assessed by comparing outcomes in the treatment and control groups.

REAL: Revised European-American classification of lymphoid neoplasms

A list of lymphoid neoplasms as recognized by the International Lymphoma Study Group (see text of the background)

SMD: Standardised mean difference

The difference between two means divided by an estimate of the within-group standard deviation. When an outcome (such as pain)

is measured in a variety of ways across studies (using different scales) it may not be possible directly to compare or combine study

results in a systematic review. By expressing the effects as a standardised value the results can be combined since they have no units.

Standardised mean differences are sometimes referred to as a d index.

WHO: The World Health Organization

the United Nations specialized agency for health, that was established on 7 April 1948.

WMD: Weighted mean difference (in meta-analysis)

A method of meta-analysis used to combine measures on continuous scales (such as weight), where the mean, standard deviation and

sample size in each group are known. This method assumes that all of the trials have measured the outcome on the same scale.

Appendix 2. Definitions for non-Hodgkin’s lymphoma

Follicular lymphoma (FL)While the older classification systems grouped the neoplasms according to histological or morphological criteria (Kiel classification)

or according to their aggressiveness (Working Formulation), REAL and WHO classification systems provide definitions of neoplasms

on the basis of morphological, phenotypic, genotypic, and clinical data. (see Table 1). FL is a neoplasm of follicle centre B cells and is

composed of a mixture of centrocytes (cleaved follicle centre cells) and centroblasts that are arranged, at least partly, into a follicular

structure defined as a lymphoma of follicle centre B cells (DeVita 2005). A graphical representation of neoplasm subtypes and cell

transformation patterns can be seen in Figure 1 (courteously provided by Dogan 2005). The proportion of centroblasts and centrocytes

varies from tumour to tumour, and often within follicles of the same tumour. This has lead to a variety of grading systems to quantify

the number of centroblasts. The most widely used is the WHO classification system, for FL based on Berard’s criteria (Mann 1982).

FL are subgrouped according to the counts of centroblasts (CB) in 10 neoplastic follicles with 40 x high-power field magnification

(hpf ), into Grade 1 (0 to 5 CB/hpf ), Grade 2 (6 to 15 CB/hpf ), or Grade 3 (> 15 CB/hpf ) tumours. WHO classification additionally

distinguishes between Grade 3a (centroblasts intermingled with centrocytes) and Grade 3b (presence of solid sheets of centroblasts).

Although FLs are commonly regarded as indolent lymphomas (Ott 2002) the histological grading can provide predictive factors, Grade

1 and 2 being indolent but mainly incurable, while Grade 3 is aggressive but potentially curable.

Mantle cell lymphoma

Mantle cell lymphoma is a B-cell lymphoma composed of a monomorphical, uniform, small to medium sized lymphocytes reminescent

of centrocytes or mantle zone small B-cells, or both. Unlike other low-grade lymphomas, large transformed cells such as centroblasts

are absent. Mantle cell lymphoma (MCL) is characterized by the t(11;14)(q13;q32) translocation (Hankin 1999; Bentz 2004) which is

associated with cyclin D1 hyper-expression. This abnormality, which is characteristic of mantle cell lymphoma, can be demonstrated in

virtually all cases by using cytogenetics or fluorescent in situ hybridisation (FISH) for detecting t(11;14) translocation. The prognosis

of mantle cell lymphoma is much poorer than for FL, and this has been associated with pathological features such as high mitotic

activity and an over-expression of proteins associated with cell proliferation (Rosenwald 2003).

Other low-grade lymphoma subcategories

The WHO classification includes entities that were originally classified as low-grade B-cell lymphomas in the Kiel classification, or as

low-grade or intermediate-grade in the Working Formulation classification system. A list of the subcategories considered by WHO as

low-grade B-cell lymphoma, and the relative proportion of all non-Hodgkin’s lymphomas (NHL), are reported below.

Types of low-grade B-cell lymphoma in the WHO*classification: frequency (% of all NHL)

• Follicular lymphoma: 22%

• Extranodal marginal zone lymphoma of MALT**: 8%

• Small lymphocytic lymphoma: 7%



• Mantle cell lymphoma: 6%

• Nodal marginal zone lymphoma: 2%

• Splenic marginal zone lymphoma: < 1%

• Lymphoplasmacitic lymphoma: 2%

• Prolymphocytic leukaemia: < 1%

• Hairy cell leukaemia: < 1%

* WHO, World Health Organization; ** MALT, mucosa-associated lymphoid tissue.

Appendix 3. CENTRAL search strategy

1.Lymphoma Follicular [MESH]

2.(Lymphoma* near follicular) or (lymphoma* near nodular)

3.Lymphoma Non Hodgkin [MESH]

4.Nonhodgkin*

5.(Non next Hodgkin*)

6.bcl-2*

7.#1 or #2 or #3 or #4 or #5 or #6

8.Interferon Type I [MESH]

9.interferon*

10.IFN

11.#8 or #9 or #10

12.#7 and #11

Appendix 4. MEDLINE search strategy (PubMed)

Specific Medline search in PubMed:

Search (“Interferon-alpha”[Mesh] AND “Lymphoma, Follicular”[Mesh]) OR (“Lymphoma,

Follicular/drug therapy”[Mesh] OR (“Lymphoma, Follicular/immunology”[Mesh] OR

“Lymphoma, Follicular/therapy”[Mesh] OR “Lymphoma, Follicular/drug therapy”[mesh])

AND (“Antineoplastic Agents”[Mesh] OR “Antineoplastic Combined Chemotherapy

Protocols”[Mesh]) AND interferon[tw]) OR (lymphoma*[tw] AND follicular[tw] AND interferon

[tw] AND mainten*[tw])

Appendix 5. MEDLINE search strategy through OVID

1.exp Lymphoma, Follicular/

2.brill symmer$.tw.

3.(lymphoma$ adj5 (follicular or nodular)).tw.

4.Lymphoma, Non-Hodgkin/

5.non hodgkin$.tw.

6.nonhodgkin$.tw.

7.gene$ bcl-2.tw.

8.or/1-7

9.exp Interferon Type I/

10.interferon$.tw.

11.IFN.tw.

12.or/9-11

13.8 and 12



Appendix 6. MEDLINE RCT filter

14.randomized controlled trial.pt.

15.controlled clinical trial.pt.

16.randomized controlled trials/

17.random allocation/

18.double blind method/

19.single blind method/

20.or/14-19

21.animal/ not (animal/ and human/)

22.20 not 21

23.clinical trial.pt.

24.exp clinical trials/

25.(clinic$ adj25 trial$).tw.

26.cross-over studies/

27.(crossover or cross over or cross-over).tw.

28.((singl$ or doubl$ or trebl$ or tripl$) adj25 (blind$ or mask$)).tw.

29.placebos/

30.placebo$.tw.

31.random$.tw.

32.research design/

33.or/23-32

34.33 not 21

35.22 or 34

36.13 and 35

W H A T ’ S N E W

Last assessed as up-to-date: 8 December 2008.

Date Event Description

26 May 2008 Amended Converted to new review format.

H I S T O R Y

Protocol first published: Issue 1, 2004

Review first published: Issue 1, 2010



C O N T R I B U T I O N S O F A U T H O R S

• Baldo P: planning of the review, contacts, methods of the review, selection of studies, extraction of data, writing of the full review

• Lazzarini R: searching for studies, evaluation of included trials at the early stage and data extraction

• Cannizzaro R: concept, draft text, literature search

• Bearz A: evaluation of methodological quality, evaluation of experimental design of trials

• Compagnoni A: data extraction, statistical analysis, performing of all statistical tests

• Moja L: general methodological quality of review, concept, statistical analysis and RevMan5 support

• Rupolo M: evaluation of study quality, writing of the clinical discussion

• Spazzapan S: writing of background section, evaluation of study design

• Truccolo I: literature search strategy, handsearching, primary selection of studies

Members of the Cochrane Working Group of the “Centro di Riferimento Oncologico” - CRO Aviano (Italy)

The other members of the Cochrane Working Group of the “Centro di Riferimento Oncologico”, Aviano, Italy who contributed to

the review:

• Canzonieri V: evaluation of the diagnostic criteria for FL in the patients of the studies extracted by the whole search strategy for

the review; quality of the studies

• Di Lauro V: primary selection of studies, methods of the review

• Bertola A: primary selection of studies, methods of the review, English language

• Scalone S: written description of studies, methods of the review

• Toffoli G: evaluation of outcomes measures and pharmacoeconomic search

• Dal Maso L: contribution to the extraction of data, statistical analysis, evaluation of heterogeneity and of individual patient data

D E C L A R A T I O N S O F I N T E R E S T

None known

I N D E X T E R M SMedical Subject Headings (MeSH)

Antineoplastic Agents [adverse effects; ∗therapeutic use]; Disease-Free Survival; Interferon-alpha [adverse effects; ∗therapeutic use];

Lymphoma, Follicular [∗drug therapy]; Quality of Life; Randomized Controlled Trials as Topic; Recombinant Proteins



MeSH check words

Humans



Interferon-alpha for maintenance of follicular lymphoma

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