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A Canadian Evidence-Based Guideline for the First-line Treatment of Follicular Lymphoma: Joint Consensus of the Lymphoma Canada Steering Committee

Clinical Lymphoma Myeloma and Leukemia

Abstract

Follicular lymphoma (FL) is the most common indolent non-Hodgkin lymphoma in North America. Due to the heterogeneity of the disease, treatment options vary from observation to aggressive therapies and/or stem cell transplantation. Although advances in treatment have improved outcomes, the disease remains largely incurable. In Canada, no unified national guideline exists for the front-line treatment of FL; provincial guidelines vary and are largely based on funding. There is therefore a need for evidence-based national treatment guidelines that are supported by Canadian hematologists to ensure that patients with FL have equitable access to the best available care. A group of experts from across Canada developed a national evidence-based treatment guideline to provide healthcare professionals with clear guidance on the first-line management of FL. Results of a systematic review of the literature are presented with consensus recommendations based on available evidence.

Introduction

Follicular lymphoma (FL) is the most common indolent (or low-grade) form of non-Hodgkin lymphoma (NHL) and the second most common form of all NHLs, comprising up to 35% of all cases in North America and 9% to 22% worldwide.1, 2, 3, 4, and 5 In Canada, NHL was estimated to account for 4.2% of all new cancer cases in 2013. 6 Furthermore, between 1998 and 2007, there was a significant increase in the incidence rate of NHL in males (by 0.8% per year) and a numeric (but not significant) increase in females (by 0.4% per year). 6 In Canada, the incidence and prevalence of FL specifically are >1500 cases and >20,000 cases per year, respectively. 7

FL is staged using the Ann Arbor classification, where stages I and II are considered as limited or localized disease, and stages III and IV as advanced disease. 8 For all stages, patients presenting with traditional B-symptoms (fever, night sweats, and weight loss) are considered symptomatic. 8 Other symptoms might include painful adenopathy/splenomegaly, or locally obstructing symptoms. However, many patients, even some with advanced stage disease, are asymptomatic. In addition to B-symptoms, the Groupe d’Etudes des Lymphomes Folliculaires (GELF) criteria are commonly used to define patients requiring immediate treatment.4 and 9

FL is further histologically classified into grades based on the World Health Organization (WHO) classification. 10 WHO categorizes FL into low grade (formerly grades 1 and 2) and high grade (previously grade 3A).4 and 10 Diffuse areas in any grade 3 FL (previously grade 3B) should be designated as diffuse large B-cell lymphoma (DLBCL) and is typically treated as such. Following diagnosis, the Follicular Lymphoma International Prognostic Index (FLIPI) and revised FLIPI2 may be determined for prognostic purposes.11 and 12

Due to the heterogeneity of this disease, treatment options for patients with FL tend to be controversial and vary from observation (or “watch and wait”) to stem cell transplantation (SCT).13 and 14 With advances in treatment, patients with FL have shown improved outcomes; however, a curative treatment is still not available, particularly for advanced-stage disease.4, 13, and 15 Accordingly, the overarching goal of treatment is to achieve effective and durable disease control (i.e., prolong overall survival [OS] and progression-free survival [PFS]) with minimal toxicity, while maintaining quality of life (QoL).4, 13, and 14

Several international guidelines exist for FL, including the National Comprehensive Cancer Network (NCCN), European Society for Medical Oncology (ESMO), British Committee for Standards in Haematology (BCSH), Italian (SIE/SIES/GITMO guidelines), and Spanish guidelines.16, 17, 18, 19, and 20 However, in Canada, there is no unified national guideline for FL. Although provincial guidelines exist, they differ across provinces and are primarily based on the availability of agents in the provincial formulary.21 and 22 Accordingly, there is a need for evidence-based national treatment guidelines that are supported by Canadian hematologists to ensure that patients with FL in Canada have equitable access to the best available care. 23 Therefore, a group of experts from across Canada, including representation from Ontario, Quebec, Nova Scotia, British Columbia, and Alberta, developed a national evidence-based treatment guideline, in association with Lymphoma Canada, to provide healthcare professionals with clear guidance on the first-line management of patients with FL.

Target Population

The current guideline is for the primary treatment of adult patients with FL. Any patients with DLBCL or any grade 3b FL should be treated as per DLBCL guidelines and a discussion of their treatment is beyond the scope of this guideline.

Guideline Questions

 

  • 1) What treatment options should be considered for localized FL?
  • 2) How should asymptomatic advanced-stage FL be managed?
  • 3) What treatment options should be considered for symptomatic, advanced-stage FL?
  • 4) In which patients should additional treatment be considered (i.e., maintenance, consolidation, SCT)?

Methodology

Where available, publications based only on phase III studies were included in the literature review. In cases where few randomized trials were identified, we considered prospective studies. In cases where few prospective studies were identified, we considered retrospective and institutional-level studies with a study sample of at least 20 patients. Publications in languages other than English were excluded. Relevant existing international practice guidelines from the NCCN, ESMO, BCSH, American College of Radiology (ACR), Italy (SIE/SIES/GITMO), and Spain, as well as those from the Alberta Health Services (AHS), British Columbia Cancer Agency (BCCA), Cancer Care Nova Scotia (CCNS), and Cancer Care Ontario (CCO), were also reviewed. Further details on methodology are included within each section of the guideline below.

The expert panel used the NCCN categories of evidence and consensus to grade the level of evidence supporting recommendations. 24 Details of the NCCN categories are presented in Table 1 .

Table 1 NCCN Categories of Evidence and Consensus

Category 1 Based upon high-level evidence, there is uniform consensus that the intervention is appropriate
Category 2A Based upon lower-level evidence, there is uniform consensus that the intervention is appropriate
Category 2B Based upon lower-level evidence, there is consensus that the intervention is appropriate
Category 3 Based upon any level of evidence, there is major disagreement that the intervention is appropriate

Adapted from the National Comprehensive Cancer Network, Accessed March 18, 2014

Question 1: What treatment options should be considered for localized follicular lymphoma?

Background

While the vast majority of patients are diagnosed with advanced FL, approximately 15−30% present with localized (stage I or II) disease.25, 26, and 27 Treatment of localized FL remains poorly defined and controversial due to a lack of randomized phase III trials in this uncommon subpopulation. Accordingly, based on data from retrospective series, radiotherapy (RT) is considered the standard of care for localized FL by North American and European guidelines, as well as provincial guidelines in Canada.16, 17, 18, 19, 20, 21, and 22 Alternative treatment options being examined in clinical trials include observation (i.e., watch and wait [WW]) and combined modality therapies, such as chemotherapy and/or immunotherapy with and without RT. Furthermore, to the best of our knowledge, no current guidelines or literature distinguish between asymptomatic and symptomatic localized FL, and therefore, it is unclear if both presentations should be treated similarly.

Methodology

A literature search was performed using the following terms: follicular, indolent, lymphoma, stage I, stage 2, localized, limited, first-line, front-line, primary, asymptomatic, and symptomatic. In cases where few randomized trials were identified, we considered prospective studies. In cases where few prospective studies were identified, we considered retrospective and institutional-level studies with a study sample of at least 20 patients. Studies including patients with histologies other than FL were eliminated from the literature review, with the exception of one study determined to be of key importance in determining the optimal dose of radiation therapy (RT). All searches were limited to years 2000 through 2014.

Radiotherapy

A total of one prospective and ten retrospective studies examining RT in localized FL were found ( Table 2 ).25, 26, 27, 28, 29, 30, 31, 32, 33, 34, and 35 In identified studies, the median age of patients with localized FL generally ranged from 50 to 64 years. Although a few studies reported that age was an independent prognostic factor of outcome, with younger age being more favourable, none assessed the long-term risks of RT in young patients.25, 27, and 31

Table 2 Studies of radiation therapy in localized follicular lymphoma

Reference Treatment (Dose/

Field)
N NHL Type/

Stage I/ II/III (%)
Median follow-up (years) OS Remission duration CSS/DSS Response rates
Prospective studies
Lowry et al. (2011)36 a

[Multicentre (BNLI & NCRI)]
40−45 Gy vs. 24 Gy for indolent NHL

IFRT
Total: 1001 (WHO diagnosis: 765) Any NHL

FL grade 1/2: 171
5.6 5-yr OS: 74% for 24 Gy, 73% for 40-45 Gy (p = 0.84) 5-yr FFLP: 75.6% for 24 Gy, 78.9% for 40-45 Gy (p = 0.59) NG ORR: 92% for 24 Gy, 93% for 40-45 Gy (p = 0.72)

CR: 82% for 24 Gy, 79% for 40-45 Gy

PR: 10% for 24 Gy, 14% for 40-45 Gy

SD/PD: 8% for 24 Gy, 7% for 40-45 Gy
Ha et al. (2003) 30

[single centre (University of Texas M. D. Anderson Cancer Center)]
30−30.6 Gy

CLI
47 FL

10.6/29.8/59.6
4.5

(in 45/47 surviving patients)
5-yr: 94%

(Stage I/II/III: 100%/100%/91%; p = 0.56)
5-yr FFP: 53%

(Stage I/II/III: 33%/72%/50%; p = 0.77)
NG CR: 98%

PD: 2%
Retrospective studies
Frank et al. (2001) 29

[single centre]
25.5−50 Gy

IFRT/EFRT/

TLI/TNI:

n = 19/13/11/3

n = 1 for local therapy
47 FL

46.8/29.8/23.4
6.58 Stage I/II

5-yr: 85% for EFRT/TLI, 83% for IFRT (NS)

Stage III

5-yr: 73%
Stage I/II

5-yr RFS: 73% for EFRT/TLI, 61% for IFRT (NS)

Stage III

5-yr FFP: 27%
NG CR: 96%
Wilder et al. (2001) 28

[single centre (University of Texas M. D. Anderson Cancer Center)]
26.2−50.0 Gy

IFRT/IRRT/EFRT: 9%/54%/37%
80

RT alone
FL

41/59/0
19

(of 20 surviving patients)
15-yr: 43%

(Stage I vs. II: 44% vs. 43%; p = 0.67;

IFRT/IRRT vs. EFRT: 40% vs. 49%; p = 0.51)
15-yr PFS: 41%

(Stage I vs. II: 66% vs. 26%; p = 0.006)
15-yr CSS: 87% vs. 54%

(Stage I vs. II; p = 0.01; IFRT/IRRT vs. EFRT: 72% vs. 59%; p = 0.36)
NG
Guadagnolo et al. (2006) 31

[multicentre (Boston)]
30−42 Gy

IFRT/IRRT/EFRT/TBI
Total: 106

(RT alone:

n = 79; of which, IFRT/

IRRT:

n = 75)
FL

74/26/0
12 10-yr:

RT alone: 74%; IFRT/IRRT: 72%;

15-yr:

RT alone: 62%; IFRT/IRRT: 59%
FFTF:

10-yr:

RT alone: 47%; IFRT/IRRT: 46%;

15-yr:

RT alone: 43%; IFRT/IRRT: 42%
NG NG
Campbell et al. (2010) 27

[BCCA Lymphoid Cancer Database]
20−40 Gy

IRRT/INRT≤5 cm
Total: 237

(IRRT: 142; INRT≤5 cm: 95)
FL

76/24/0
7.3 5-yr: 85%

10-yr: 66% (IRRT vs. INRT≤5 cm: 71% vs. 59%; p = 0.013)

15-yr: 46%

Median: 80 months
PFS:

5-yr: 66%

10-yr: 49%

(IRRT vs. INRT≤5 cm: 48% vs. 50%; p = 0.498)

15-yr: 43%

Median: 51 months
DSS:

5-yr: 92%

10-yr: 82%

(IRRT vs. INRT≤5 cm: 85% vs. 78%; p = 0.142)

15-yr: 68%

20-yr: 62%
NG
Pugh et al. (2010) 25

[SEER Database]
35−50 Gyb Total: 6568

(RT alone: 2222)
FL

67/33/0

(RT alone: 77/23/0)
5.5 5-yr: 81%

10-yr: 62%

15-yr: 45%

20-yr: 35%

(All data for RT alone)
NG DSS:

5-yr: 90%

10-yr: 79%

15-yr: 68%

20-yr: 63

(All data for RT alone)
NG
Guckenberger et al. (2012) 32

[single centre]
25−50 Gy and 12.6−45 Gy a median of 30 days later

EFRT/TNI
Total: 107 FL

46.7/33.6/19.6
10 (all); 14 (living) 10-yr: 64%

15-yr: 50%

(Stage I/II/III: 51%/45%/54%; NS; EFRT/TNI: 34%/65%)
FFP:

5-yr: 76%

10-yr: 58%

(Stage I/II/III: 74%/40%62%; I vs. II

p =0.001;

EFRT/TNI: 54%/62%; NS)

15-yr: 56%
NG NG
Fakhrian et al. (2012) 33

[single centre]
26−56 Gy

IFRT/EFRT
Total: 50 FL

60/30/10
8 2-yr: 96%

(Stage I vs. II: 100% vs. 93)

5-yr: 90% (Stage I vs. II: 100% vs. 69%)

10-yr: 70% (Stage I vs. II: 87% vs. 52%; IFRT vs. EFRT: 71% vs. 68%; p = 0.19)

Median: 18 yrs
EFS:

2-yr: 90%

5-yr: 70%

10-yr: 38% (Stage I vs. II: 36% vs. 37%; IFRT vs. EFRT: 23% vs. 43%; p = 0.84)

Median: 7 yrs
NG CR: 78%

PR: 18%
Friedberg et al. (2012) 35

[National LymphoCare Database]
RT b,c Total: 206

(RT only: 56)
FL

100/0/0
4.75 NG PFS:

4.75-yr: 68%

Median: 6 yrs
NG NG
Ahmed et al. (2013) 34

[single centre (Manitoba Cancer Registry)]
15−48 Gy

IFRT/EFRT
40 FL

65/35/0
6.9 5-yr: 86%

10-yr: 59%

Median: 13 yrs
PFS:

5-yr: 67%

10-yr: 54%

EFS:

5-yr: 60%

10-yr: 22%

Median: 6.5 yrs
NG CR: 100%
Michallet et al. (2013) 26 40−50 Gy

IFRT/EFRT
Total: 145

(RT alone: 21; IFRT: 16; EFRT: 5)
FL

57.9%/42.1%/0% (total); 90.5%/

9.5%/0% (RT alone)
7.1 7.5-yr: 66% (RT alone) 7.5-yr PFS: 19% (RT alone) NG CR: 80.9%

PR: 9.5%

SD: 0%

PD: 9.5%

(All data for RT alone)

Abbreviations: BCCA = British Columbia Cancer Agency; BNLI = British National Lymphoma Investigation; CLI = central lymphatic irradiation; CR = complete response/remission; CT = chemotherapy; CSS = cause-specific survival; DFS = disease-free survival; DSS = disease-specific survival; EFRT = extended field radiotherapy; EFS = event-free survival; FFP = freedom from progression; FFTF = freedom from treatment failure; FFLP = freedom from local progression; FL = follicular lymphoma; IFRT = involved field radiotherapy; INRT(≤5 cm) = involved node radiotherapy (with margins up to 5 cm); IRRT = involved regional radiotherapy; NCRI = National Cancer Research Institute; NG = not given; NHL = non-Hodgkin lymphoma; NS = not significant; OS = overall survival; PD = progressive disease; PFS = progression-free survival; PR = partial response/remission; RFS = relapse-free survival; RR = response rate; RT = radiation therapy; SD = stable disease; SEER = Surveillance Epidemiology and End Results; STLI = subtotal lymphoid irradiation; TBI = total body irradiation; TLI = total lymphoid irradiation; TNI = total nodal irradiation

a Despite including histologies other than FL, this study was included based on its importance in determining the optimal dose of RT;

b Did not specify field size

c Did not specify radiation dose

Data reported from existing studies show RT confers excellent local tumour control (i.e., overall response rate [ORR] and local control >90%), however the 10–20 year PFS/relapse-free survival (RFS) rate is approximately 50%, resulting in 10-year OS rates of approximately 50−75%. While nearly half of patients relapse within 10 years, relapse rates appear to plateau after 10 years, suggesting that not only is the risk of relapse beyond 10 years low, but also that RT is potentially curative ( Table 2 ).

Despite the positive outcomes reported, the majority of identified studies are not only complicated by their retrospective nature, but also by the varied doses and fields of RT that were used. Radiation doses generally ranged from 15 Gy to 56 Gy, and only one study had compared low versus high radiation doses ( Table 2 ). A phase III trial in the U.K. compared 24 Gy to 40–45 Gy in patients with indolent and aggressive lymphoma. 36 Results demonstrated no difference in ORR between the standard-dose and lower-dose arms (93% vs 92%, respectively), and no significant difference in local control, remission duration, or OS. Among 248 patients who received radical RT as first-line therapy, there was no difference in PFS between the 24 Gy and 40-45 Gy arms. Consequently, except in unusual cases, doses of 24-30 Gy in 1.5-2 Gy fractions are typically recommended. 37

A variety of different radiation field sizes have been reported in patients with localized FL. Radiation field sizes include, in order from largest to smallest volume, total body irradiation (TBI), total/central lymphoid irradiation (TLI/CLI), total nodal irradiation (TNI), extended field radiotherapy (EFRT), involved regional radiotherapy (IRRT), involved field radiotherapy (IFRT), and involved nodal radiotherapy (INRT). Retrospective studies comparing various field sizes in patients with localized FL have found no significant differences in PFS or OS.27, 28, 29, 32, and 33 Given that the use of larger field sizes has not been found to improve OS and there are concerns of radiation-induced toxicity and secondary malignancy, IFRT has been considered the standard field size in clinical practice.16, 17, 18, 19, and 20

Despite being considered the standard of care, RT for localized FL is greatly underutilized in the U.S. A large, Surveillance, Epidemiology, and End Result (SEER) database analysis of 6568 patients with low-grade, localized FL in the U.S. found that RT was associated with significantly improved OS compared with non-RT approaches (p <0.0001); however, only a third of the patients received upfront RT over the 30-year study period. 25 Few studies to date have comparatively evaluated the varied treatment approaches used for localized FL. In a retrospective analysis of the LymphoCare database, less than one third of patients (27%) with stage I FL were treated with RT. 35 The other first-line treatment strategies included rituximab plus chemotherapy (R-chemotherapy; 28%), observation (17%), rituximab monotherapy (12%), and combined modality with RT (13%), with the latter subgroup being more likely to have B-symptoms and grade 3 histology. After a median follow-up of 4.75 years, there were no differences in OS between the various approaches. However, after adjusting for tumour grade, lactate dehydrogenase (LDH), and the presence of B-symptoms, PFS was significantly improved with either chemoimmunotherapy or combined modality with RT versus RT alone. Another recent retrospective study divided patients into six groups according to their initial treatment: observation, RT alone, chemotherapy, RT with chemotherapy, rituximab monotherapy, and chemoimmunotherapy. 26 Similar to the findings of the LymphoCare database analysis, OS did not differ between treatments at 7.5 years, whereas PFS at 7.5 years was significantly higher with chemoimmunotherapy versus all other treatments (p = 0.00135). 26 Accordingly, while these studies challenge the use of RT alone as the standard of care for localized FL, they are limited by their retrospective design and small numbers of patients.

Combined modality therapies

Radiotherapy plus chemotherapy

Despite the fact that RT alone results in durable in-field tumour control rates of >90%, relapse in new and out-of-field sites is the main cause of treatment failure.38 and 39 Accordingly, the addition of chemotherapy to first-line RT may be an attractive alternative approach. A total of four studies evaluating the combination of chemotherapy with radiation in the rituximab era were identified ( Table 3 ).26, 31, 35, and 40 With the exception of one prospective study, most studies were retrospective, generally included few patients, and demonstrated conflicting results. In the relatively large, non-randomized, prospective study of 85 patients with localized FL who were treated with chemotherapy (i.e., 10 cycles of cyclosphosphamide, vincristine, prednisone, and bleomycin with or without doxorubicin [CHOP/CVP plus bleomycin]) and IFRT (30−40 Gy), the 10-year time to treatment failure (TTF) and OS rates were 72% and 80%, respectively, and 99% of patients achieved complete remission. 40 While these outcomes suggest a benefit of combining chemotherapy with RT compared with RT alone, there are no definitive data demonstrating a survival advantage. In light of the limited promising data, a randomized controlled phase III trial comparing IFRT versus IFRT plus chemotherapy (i.e., CVP) with rituximab in patients with localized FL was initiated in 2000 by the Trans-Tasman Radiation Oncology Group and the Australian Leukaemia and Lymphoma Group (NCT00115700). This trial is currently ongoing and estimated to be completed in late 2022.

Table 3 Combined modality therapy in localized follicular lymphoma

Reference Treatment N NHL Type/

Stage I/II (%)
Median follow-up (years) OS Remission duration Response rates
Prospective studies
Seymour et al. (2003) 40

[single centre (University of Texas M. D. Anderson Cancer Center)]
COP-Bleo/

CHOP-Bleo + RT

(30−40 Gy)
Total: 102 (FL only: 85) FL

45/55
10 5-yr: 91%(FL only)

10-yr: 80% (FL only; Stage I vs. II:

71% vs. 87%;

p = 0.02)
TTF:

5-yr: 80%

(FL only)

10-yr: 72% (FL only; Stage I vs. II:

73% vs. 70%;

p = 0.7)
CR/CRu: 99%

(n = 77/78)
Retrospective studies
Guadagnolo et al. (2006) 31

[Multicentre (Boston)]
CHOP/

CHOP + CVP/

CVP/CP/

CMOPP/

M-BACOD/

M-ACOD + RT (30−42 Gy)
Total: 106 (RT + CT: 27) FL

74/26
12 10-yr: 78%

15-yr: 57% (Data are for RT + CT)
FFTF:

10-yr: 46%

15-yr: 31%

(Data are for

RT + CT)
NG
Friedberg et al. (2012) 35

[National LymphoCare Database]
RT + CT (R-CHOP/R-CVP);

R; or

R-CT

(R-CHOP/

R-CVP)
Total: 206

(RT + CT: 26;

R: 25;

R-CT: 57)
FL

100/0
4.75 NG 4.75-yr PFS:

RT + CT: 96%;

R: 76%;

R-CT: 84%
NG
Michallet et al. (2013) 26 RT + CT (CHOP and CHOP-like regimens);

R-CT;

CT;

R
Total: 145 (RT + CT: 19;

R-CT: 36; CT: 26;

R: 7)
FL

57.9/42.1
7.1 7.5-yr:

67%

(RT + CT); 74% (R-CT); 74% (CT);

100% (R)
7.5-yr PFS:

26% (RT + CT);

60% (R-CT);

23% (CT);

N/A (R)
CR: 94.7%, PR: 5.3%

(RT + CT);

CR: 75%,

PR: 16.7%

(R-CT);

CR: 69.2%,

PR: 19.2% (CT);

CR: 57.1%,

PR: 42.9% (R)

Abbreviations: CHOP = cyclophosphamide, doxorubicin, vincristine, and prednisone; CHOP-Bleo = cyclophosphamide, doxorubicin, vincristine, prednisone, and bleomycin; CMOPP = cyclosphosphamide, nitrogen mustard (mechlorethamine), vincristine, procarbazine, and prednisone; COP-Bleo = cyclophosphamide, vincristine, prednisone, and bleomycin; CR = complete response/remission; CRu = complete response/remission unconfirmed; CT = chemotherapy; CSS = cause-specific survival; CVP = cyclophosphamide, vincristine, and prednisone; DFS = disease-free survival; FL = follicular lymphoma; FFTF = freedom from treatment failure; M-ACOD = methotrexate, doxorubicin, cyclophosphamide, vincristine, and dexamethasone; M-BACOD = methotrexate, bleomycin, doxorubicin, cyclophosphamide, vincristine, and dexamethasone; NHL = non-Hodgkin lymphoma; NS = not significant; ORR = overall response rate; OS = overall survival; PD = progressive disease; PFS = progression-free survival; PR = partial response/remission; R = rituximab; RR = response rate; RT = radiation therapy; SD = stable disease; TTF = time to treatment failure

Chemotherapy and/or immunotherapy

Despite the fact that FL is very radiosensitive, chemotherapy or immunotherapy without RT is used in around 40% of patients with localized disease, according to the U.S. LymphoCare database data from 2004 to 2007. 35 In addition, a recent Surveillance, Epidemiology, and End Results Program (SEER) database analysis demonstrated that only 34% of patients in the U.S. with early-stage FL were treated with RT. 35

Only two retrospective studies assessing chemotherapy, immunotherapy, or both in patients with localized FL were identified ( Table 3 ).26 and 35 No significant differences in OS were reported; however, in both studies, patients who received chemoimmunotherapy fared better than those who received RT alone in terms of PFS. These findings should be interpreted with caution as these studies were retrospective and involved small numbers of patients.

Observation

While observation is a common and reasonable approach used in patients with asymptomatic, advanced FL (described later), its use in localized disease is controversial because no prospective randomized controlled studies have been conducted in this population. Three retrospective studies investigating observation as the first-line approach in localized FL were identified ( Table 4 ).26, 35, and 41 A retrospective analysis of 43 patients with low-grade, asymptomatic, localized FL in whom treatment was deferred for at least three months reported 5-, 10-, 15-, and 20-year OS rates of 97%, 85%, 58%, and 22%, respectively. 41 After a median follow-up of 7.2 years, over half of the patients (63%) did not require treatment, suggesting that deferred therapy may be an acceptable approach in asymptomatic, localized FL. 41 Reasons for no initial therapy included concerns for potential complications of RT, patient or physician preference, and advanced age or comorbidities. In two recent retrospective studies of patients with localized FL treated with variable treatment options, including observation, no differences in OS were reported, suggesting that observation may be a reasonable strategy in the first-line setting in selected cases.26 and 35

Table 4 Studies of observation (watch and wait) in localized follicular lymphoma

Reference Treatment N NHL Type/

Stage I/II (%)
Median follow-up (years) OS Remission duration
Advani et al. (2004) 41

[Retrospective; Stanford University Lymphoma Database]
No initial therapy 43 FL

26/74
7.2 5-yr: 97%

10-yr: 85%

15-yr: 58%

20-yr: 22%
NG
Friedberg et al. (2012) 35

[Retrospective; National LymphoCare Database]
Observation Total: 206 (WW only: 35) FL

100/0
4.75 NG 4.75-yr PFS: 74%
Michallet et al. (2013) 26

[Retrospective]
Observation Total: 145 (WW only: 36) FL

61.1/38.9
7.1 7.5-yr: 72% (WW only) 7.5-yr PFS: 26% (WW only)

Abbreviations: NG = not given; NHL = non-Hodgkin lymphoma; OS = overall survival; PFS = progression-free survival; WW = watch-and-wait.

Recommendation 1: While RT is considered the standard of care, it is difficult to claim that RT is better than other therapies because there is a lack of prospective randomized controlled trials justifying high-level evidence-based recommendations. However, in light of the indolent nature of FL, and thereby the inherent necessity of a long-term follow-up, as well as the relative rarity of localized FL, it should be kept in mind that randomized phase III trials are difficult to conduct in this population. Accordingly, RT should be considered as the preferred treatment for localized FL. (Level of evidence: Category 2A)

Recommendation 2: Outside of clinical trials, lower doses, 24-30 Gy in 1.5-2 Gy fractions, and smaller field sizes for RT are most appropriate given the potential for long-term toxicity. (Level of evidence: Category 1)

Recommendation 3: Although emerging data using combined modality treatments are promising, existing data are limited and there are no randomized phase III trials. If outcomes from randomized studies prove positive, combined modality treatments may present additional options for patients with localized disease. (Level of evidence: Category 2B)

Recommendation 4: In cases where either the potential toxicity of RT outweighs the potential benefits or the patient refuses RT, observation alone may be a reasonable alternative. (Level of evidence: Category 2B)

Question 2: How should asymptomatic, advanced-stage follicular lymphoma be managed?

Background

Canadian provincial guidelines for the treatment of asymptomatic, advanced-stage disease FL are available for Alberta and British Columbia (B.C.). The Alberta guidelines recommend the initiation of systemic treatment in patients with stage III/IV or bulky stage I/II disease that have symptoms (e.g., fever, night sweats, weight loss, malaise, pain, nausea); significant lymphadenopathy (e.g., >7 cm mass, >3 sites and >3cm, rapidly progressive); splenomegaly >6 cm below costal margin, or hypersplenism, or pain; impending organ compromise (e.g., compression, pleural/pericardial effusions, ascites); cytopenias secondary to bone marrow infiltration; or according to patient preference because of anxiety and poor QoL without treatment. 21 International guidelines similarly recommend the initiation of systemic treatment upon identification of symptoms such as B-symptoms, hematopoietic impairment, bulky disease, vital organ compression, ascites, pleural effusion or rapid lymphoma progression.16, 17, 18, 19, and 20

Both the Alberta and B.C. guidelines state that close follow-up under continued observation (WW) is appropriate for patients without requirement for systemic treatment.21 and 22 In addition, the Alberta guidelines recommend that in the absence of symptoms, patients may choose systemic treatment based on anxiety or poor QoL. The B.C. guidelines also state that patients with asymptomatic, advanced stage FL without requirement for systemic therapy within six months of diagnosis are eligible to receive rituximab monotherapy.

Methodology

We performed a systematic literature search including the search terms watch, wait, and follicular lymphoma; and asymptomatic, watch, and wait. The search included only randomized studies, and only published studies were included in the pre-rituximab era. However, in the rituximab era, we included one abstract in our report due to the importance of this study in the discussion of this topic.

Pre-rituximab era

A total of three published randomized trials were found that compared first-line treatment with chemotherapy versus WW alone at diagnosis in asymptomatic patients ( Table 5 ).42, 43, and 44 The Groupe pour l’Etude de Lymphome Folliculaire (GELF) and the British National Lymphoma Investigation (BNLI) used defined criteria for patients in whom immediate therapy was not felt to be indicated ( Table 6 ). No trials showed a significant difference in OS between WW groups and those given early treatment ( Table 5 ).

Table 5 Randomized studies comparing treatment to observation in asymptomatic, advanced-stage follicular lymphoma

Reference N Treatment groups Median follow-up

(years)
Efficacy results
Pre-rituximab era
Young et al. (1988) 44

[NCI]
104 Arm 1 (n = 44): WW

Arm 2 (n = 60; 15 not randomly assigned): ProMACE-MOPP + TNI
5 FFT: 56% in WW arm

Median time to crossover: 34 months
Brice et al. (1997) 43

[GELF]
193 Arm 1 (n = 66): WW

Arm 2 (n = 64): Prednimustine (200 mg/m2/day)

Arm 3 (n = 63): Interferon (5 MU for 3 months)
3.75 Arm 1 vs. 2. vs. 3: FFT/FFTF: 24 vs. 40 vs. 35 months (NS)

5-yr OS: 78% vs. 70% vs. 84% (NS)
Ardeshna et al. (2003) 42

[BNLI]
309 Arm 1 (n = 151): WW

Arm 2 (n = 158): Chlorambucil (10 mg/day)
16 Median OS (Arm 1 vs. 2): 6.7 vs. 5.9 years (NS)
Rituximab era
Ardeshna et al. (2014) 46 463 Arm 1 (n = 187): WW

Arm 2 (n = 84): Rituximab (375 mg/m2/week) (study arm was closed early)

Arm 3 (n = 192): Rituximab (375 mg/m2/week) + R-maintenance (every 2 months for 2 years)
3.8 3-yr PNRNT (Arm 1 vs. 2 vs. 3): 46% vs. 78% vs. 88% (Arm 1 vs. 3 and Arm 1 vs. 2: p <0.0001; Arm 2 vs. 3: p = NS)

3-yr PFS (Arm 1 vs. 2 vs. 3): 36% vs. 60% vs. 82% (Arm 1 vs. 3: p <0.0001; Arm 2 vs. 3: p = 0.011; Arm 1 vs. 2: p = 0.0034)

3-yr OS (Arm 1 vs. 2 vs. 3): 94% vs. 96% vs. 97%:

p = NS, between groups

QoL: Arm 3 vs. Arm 1 superior Mental Adjustment to Cancer scale score (p = 0.0004), and Illness Coping Style score (p = 0.0012) between baseline and month 7. Difference between Arm 1 vs. Arm 2: p = NS.
Kahl et al. (ASH 2011) 45

[ECOG Abstract] a
384 In patients responding to rituximab (375 mg/m2/week) induction (n = 274):

Arm 1 (n = 140): R-maintenance (every 3 months)

Arm 2 (n = 134): R-retreatment at progression
3.8 TTF: 3.9 vs. 3.6 years (NS)

QoL: At 12 months post randomization, no difference between arms

a Included in abstract form due to potential importance of full final results that are not currently available.

Abbreviations: BNLI = British National Lymphoma Investigation; FFT = freedom from treatment; FFTF = freedom from treatment failure; GELF = Groupe D’Etude des Lymphomes Folliculaires; NCI = National Cancer Institute; NS = not significant; OS = overall survival; PFS = progression-free survival; PNRNT = patients not receiving next therapy; ProMACE-MOPP = prednisone, methotrexate, doxorubicin, cyclophosphamide, etoposide, mechlorethamine, vincristine, procarbazine, prednisone; R-maintenance = rituximab maintenance; TNI = total nodal irradiation; TTF = time to treatment failure ;WW = watch and wait

Table 6 Criteria for initiating treatment of FL

Groupe pour l’Etude de Lymphome Folliculaire (GELF)18 and 43 Any of the following: a
  • A tumor >7 cm in diameter
  • 3 nodes in 3 distinct areas each >3 cm in diameter
  • Symptomatic spleen enlargement >16 cm on CT
  • Organ compression
  • Ascites or pleura effusion
  • Presence of systematic symptoms
  • Serum lactacte dehydrogenase or B2-microglobulin level above normal
  • Hb ≤100 g/L, neutrophil count ≤1.5 x 109/L, platelet count ≤100 x109/L
British National Lymphoma Investigation (BNLI) 42 Any of the following:
  • B-symptoms or pruritus
  • Rapid generalized disease progression in the preceding 3 months
  • Marrow compromise (Hb <100 g/L, WBC count <3.0 x 109/L, or platelet count <100 x 109/L)
  • Life-threatening organ involvement
  • Renal infiltration
  • Bone lesions
  • Macroscopic liver involvement

a LDH and β2 microglobulin within normal range were later added to GELF criteria

Abbreviations: Hb = hemoglobin; WBC = white blood cell; CT = computed tomography; LDH = lactate dehydrogenase

Rituximab era

For the rituximab era, there were no studies found examining early treatment with rituximab plus chemotherapy. Results from one published study and one abstract examining early treatment with rituximab monotherapy are reported in Table 5 .45 and 46 One published randomized study by Ardeshna et al. (2014) compared rituximab to WW in asymptomatic patients. 46 Around 95% of patients had low tumour burden (GELF criteria); the other 5% had raised LDH but fulfilled the remaining GELF criteria. Preliminary results showed significantly fewer patients required further treatment, and longer PFS was reported in those initially treated with rituximab ( Table 5 ). Additionally, an improvement in the Mental Adjustment to Cancer scale score and Illness Coping Style score was demonstrated in patients given rituximab versus those in the WW arm. 46 An abstract by Kahl et al. (2011) included low tumor burden FL (GELF) patients given rituximab induction and randomized (for those responding to induction) to rituximab maintenance (R-maintenance) or rituximab retreatment at progression. Time to treatment failure (TTF) was 3.6 years in the rituximab retreatment and 3.9 years in the R-maintenance arm, with no statistical difference between groups.

Recommendation 1: Criteria for initiation of chemoimmunotherapy should be based on the identification of symptoms as defined by the GELF or BNLI criteria. (Level of evidence: Category 2A)

Recommendation 2: In asymptomatic, advanced FL, we do not recommend the use of chemo-immunotherapy or chemotherapy alone as early treatment due to the lack of published randomized studies. We therefore recommend observation alone in patients who do not fulfill the indications for treatment with chemoimmunotherapy. (Level of evidence: Category 1)

Recommendation 3: Ongoing randomized studies are examining early treatment with rituximab with or without rituximab maintenance in asymptomatic patients; one such study by Ardeshna et al. (2014) has been published. 46 Should the positive outcome noted in the Ardeshna et al. (2014) study be subsequently confirmed, early treatment with single-agent rituximab may change current practice based on its ability to substantially reduce the risk of relapse. (Level of evidence: Category 2B)

Question 3: What treatment options should be considered for symptomatic, advanced-stage follicular lymphoma?

Background

International guidelines generally recommend the addition of rituximab to standard chemotherapy for the first-line treatment of FL, with no recommendation of one chemotherapy regimen over another.16, 17, 18, 19, and 20 Canadian provincial guidelines for the treatment of FL are available for Alberta and B.C. The Alberta guidelines recommend giving six courses of bendamustine and rituximab (BR) or six to eight courses of R-CVP, followed by 2 years of rituximab maintenance, with the preference being for BR as initial treatment given its increased PFS and lower toxicity. 21 The BCCA also recommends giving BR as a first-line treatment, followed by rituximab maintenance. 22

Methodology

In comparing first-line regimens for the treatment of FL, we performed a literature search that included all phase III comparative studies. The following search terms were used: lymphoma, treatment, symptomatic, first-line, upfront, and untreated. The search included published randomized comparative studies only. In the chemoimmunotherapy combination section, only studies including rituximab-containing regimens were included.

Rituximab monotherapy

Initially studied in relapsed or refractory FL, rituximab monotherapy administered weekly for 4 weeks, produced a response rate of 48% and a median duration of response (DOR) of 13 months. 47 More recently, rituximab (375 mg/m2 weekly for 4 weeks) followed by rituximab maintenance (375 mg/m2 weekly for 4 weeks at 6-month intervals for a maximum of 4 courses or until progression) has been studied in untreated FL. 48 Complete restaging was performed at 6-month intervals before each scheduled maintenance course of rituximab. Restaging included physical examination, complete blood counts, chemistry profile, and repeat computed tomography scanning of all areas of previous lymphoma involvement. Results demonstrated an ORR of 47% at 6 weeks, with an ORR after continued maintenance of 76% and a median PFS of 34 months.

Addition of rituximab to chemotherapy

Although the efficacy of rituximab was initially demonstrated as monotherapy, the main benefits of rituximab have been shown when combined with chemotherapy. Four randomized studies were identified comparing rituximab plus chemotherapy (R-chemotherapy) with chemotherapy alone ( Table 7 ).49, 50, 51, 52, 53, and 54 The use of chemoimmunotherapy produced ORRs of 81–96% and median remission duration of around 27–66 months. Although not supported in head-to-head studies, the response to chemoimmunotherapy appears to be superior to that of rituximab monotherapy.

Table 7 Phase III studies examining rituximab plus chemotherapy versus chemotherapy alone in untreated, advanced-stage FL

Reference N Treatment Median follow-up

(years)
ORR OS Remission duration
Bachy et al. (2013) 49

Salles et al. (2008) 54
358 R-CHVP + IFN (n = 175) vs.

CHVP + IFN (n = 183)
8.3 94% vs. 85%

(p <0.001)
8-yr: 78.6% vs. 69.8%

(p = 0.076)
EFS:

8-yr: 44.1% vs. 27.9%

Median: 5.5 vs. 2.8 years (p = 0.0004)
Marcus et al. (2005, 2008)50 and 51 321 R-CVP (n = 159) vs.

CVP (n = 162)
4.4 81% vs. 57%

(p <0.0001)
4-yr: 83% vs. 77%

(p = 0.029)
Median TTF:

27 vs. 7 months

(p <0.0001)
Hiddemann et al. (2005) 52 428 R-CHOP (n = 223) vs. CHOP (n = 205) 1.5 96% vs. 90%

(p = 0.011)
2-yr: 95% vs. 90%

(p = 0.016)
1.5-yr TTF: 87% vs. 70%

(p <0.001)
Herold et al. (2007) 53 358; 201 with FL R-MCP (n = 105) vs.

MCP (n = 96)
4.1 vs. 3.5 92% vs. 75%

(p = 0.0009)
4-yr: 87% vs. 74%

(p = 0.0096)
4-yr PFS: 71% vs. 40% (p <0.0001)

Abbreviations: CHVP = cyclophosphamide, adriamycin, etoposide, prednisolone; CHOP = cyclophosphamide, doxorubicin, vincristine, prednisone; CVP = cyclophosphamide, vincristine, prednisone; EFS = event-free survival; IFN = interferon; MCP = mitoxantrone, chlorambucil, prednisone; NG = not given; ORR = overall response rate; OS = overall survival; PFS = progression-free survival; R = rituximab; TTF = time to treatment failure; yr = year

In all studies, the addition of rituximab to chemotherapy significantly increased ORRs, with a difference between groups of 6% to 24% ( Table 7 ). Additionally, rituximab significantly improved the DOR in all studies and improved OS in three of four studies. Based on the results of these randomized studies, it appears that the efficacy of chemoimmunotherapy is superior to chemotherapy alone.

Chemo-immunotherapy Combinations

Given the improvement in ORRs and DOR with the addition of rituximab to chemotherapy, only studies including rituximab-containing regimens were included in the literature search. A total of three phase III comparative studies were retrieved examining the first-line treatment of FL with chemoimmunotherapy ( Table 8 ).55, 56, and 57

Table 8 Phase III comparative chemoimmunotherapy studies for first-line treatment of FL

Reference Treatment Patient population N Median

follow-up
Response rates OS Remission duration Toxicity
Federico et al. (2013) R-CVP vs.

R-CHOP vs.

R-FM;

No maintenance treatment
Grade 1, 2, 3a FL; Ann Arbor stage II to IV; ECOG PS 0 to 2; active disease R-CVP: 178

R-CHOP: 178

R-FM:

178
34 months ORR:

88% vs. 93% vs. 91%;

p = 0.247
3-yr: 95% 3-yr TTF: 46% vs. 62% vs. 59%;

R-CHOP vs. R-CVP: p = 0.003; R-FM vs. R-CVP: p = 0.006

3-yr PFS: 52% vs. 68% vs. 63%;

p = 0.011
Grade 3/4 neutropenia (%):

28 vs. 50 vs. 64;

p <0.001

Second malignancies: 4 vs. 5 vs. 14 patients
Rummel et al. (2013) BR vs.

R-CHOP;

No maintenance treatment
Age ≥18 years; WHO PS ≤2; histologically confirmed MCL, iNHL (FL grade 1

and 2, Waldenstrom’s macroglobulinaemia); small lymphocytic; and marginal-zone

lymphoma
BR:

274

R-CHOP: 275
45 months ORR:

93% vs. 91%; NS

CR:

40% vs. 30%;

p = 0.021
43 vs. 45 patients died; NS Overall median PFS: 69.5 vs. 31.2 months;

HR = 0.58;

p <0.0001

Median PFS for FL: NR vs. 40.9 months;

HR = 0.61;

p = 0.0072

Median TTNT: NR vs. 42.3 months;

HR = 0.52;

p <0.0001
All grades:

Alopecia (%):

0 vs. 100;

p <0.0001

Hematological (%):

30 vs. 68;

p <0.0001

Infections (%):

37 vs. 50;

p = 0.0025

Skin reactions (%):

16 vs. 9;

p = 0.024
Flinn et al. (2014)

[BRIGHT Study]
BR vs.

R-CHOP/

R-CVP;

No maintenance treatment
Age ≥18 years; histologically confirmed CD20+ iNHL or MCL; ECOG PS 0 to 2; Ann Arbor stage ≥2; Adequate renal, hepatic, hematologic function BR:

224

R-CHOP: 104

R-CVP: 119
NG ORR:

97% vs. 91% ; Superiority: p = 0.0102

CR:

31% vs. 25%; Non-inferiority: p = 0.0225; Superiority: NS
NG NG All grades:

BR vs. R-CHOP; BR vs. R-CVP: Nausea (%):

63 vs. 58, NS;

63 vs. 39,

p <0.01

Vomiting (%):

29 vs. 13,

p <0.01;

25 vs. 13,

p <0.05

Neuropathy (%):

9 vs. 44,

p <0.0001;

14 vs. 47,

p <0.0001

Alopecia (%):

4 vs. 51,

p <0.0001;

3 vs. 21,

p <0.0001

Infections (%):

55 vs. 57, NS;

53 vs. 50, NS

Abbreviations: BR = bendamustine, rituximab; CR = complete response; CRu = complete response unconfirmed; ECOG = Eastern Cooperative Oncology Group; EFS = event-free survival; IFN = interferon; MCP = mitoxantrone, chlorambucil, prednisone; NG = not given; NS = not significant; ORR = overall response rate; OS = overall survival; PFS = progression-free survival; PS = performance status; R = rituximab; R-CHOP = rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone; R-CVP = rituximab, cyclophosphamide, vincristine, prednisone; R-FM = rituximab, fludarabine, mitoxantrone; TTF = time to treatment failure; TTNT = time to next treatment; WHO = World Health Organization; yr = year

A phase III study by Federico et al. (2013) compared the efficacy of three standard treatments: eight doses of rituximab plus six cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP), eight doses of rituximab plus eight cycles of cyclophosphamide, vincristine, and prednisone (R-CVP), and eight doses of rituximab plus six cycles of fludarabine and mitoxantrone (R-FM) for the treatment of indolent lymphomas. 55 Three-year TTF and PFS were greater with R-CHOP and R-FM than with R-CVP (p <0.05). In addition, R-CHOP demonstrated lower toxicity than R-FM, with a superior risk-benefit ratio ( Table 8 ). Results of this study demonstrated that R-CHOP is an effective option for the treatment of FL.

Bendamustine is a cytotoxic bifunctional alkylating agent that is highly effective as monotherapy or combined with rituximab in relapsed and refractory lymphoid malignancies.35, 58, 59, and 60 Although bendamustine has been used for more than 20 years in Germany, it only gained approval for the management of lymphoid malignancies in the U.S. in 2008 and the E.U. in 2010, with approval in Canada in August 2012. Given the long-term experience with bendamustine in Germany, Rummel et al. (2013) compared the efficacy and safety of BR versus R-CHOP in untreated indolent NHL and mantle cell lymphoma patients. 56 Results of this phase III study demonstrated an improvement in the primary outcome, PFS, in the BR group (FL subgroup: NR vs. 40.9 months; HR = 0.61; p = 0.0072). There was also an improvement in the time to next treatment with BR, as compared to R-CHOP (NR vs. 42.3 months; HR = 0.52; p <0.0001). Furthermore, the safety profile was improved with BR, with lower rates of alopecia, hematological toxicity, and infections as compared to R-CHOP; however, rates of skin reactions were increased (p <0.05) ( Table 8 ). The improved efficacy of BR versus R-CHOP, as well as lower toxicity, suggests BR should be the preferred treatment standard versus R-CHOP in FL.

In order to confirm results of the Rummel et al. (2013) study in North America, a phase III study (BRIGHT) examined the efficacy and safety of BR, R-CHOP, and R-CVP. 57 Results showed that the CR rate for BR is statistically noninferior to that of R-CHOP/R-CVP (p = 0.0225). Safety results show that all three treatment regimens have distinct toxicity profiles. Nausea, vomiting, and drug hypersensitivity occurred more frequently with BR, while constipation, neuropathy, and alopecia occurred more frequently with R-CHOP and R-CVP ( Table 8 ). The BRIGHT study supports the results of the Rummel et al. (2013) study, demonstrating that BR is at least noninferior to R-CHOP/R-CVP. However, use of CR rate is not an appropriate primary endpoint for efficacy in FL and is therefore a major weakness of the study.

Recommendation 1: Chemoimmunotherapy should be used in preference to rituximab monotherapy for the first-line treatment of symptomatic advanced stage FL, except in cases where chemotherapy is contraindicated, based on the observed lower response to rituximab monotherapy shown in clinical trials. (Level of evidence: Category 2A)

Recommendation 2: Given the improved ORR and PFS demonstrated with the addition of rituximab to a number of chemotherapy combinations, rituximab should be added to chemotherapy in the first-line treatment of symptomatic advanced stage FL. (Level of evidence: Category 1)

Recommendation 3: We currently recommend BR as the preferred chemoimmunotherapy for the first-line treatment of symptomatic advanced stage FL, given the superior efficacy and favourable tolerability of this regimen versus R-CHOP in two randomized trials. Based upon high-level evidence, there is uniform consensus that the intervention is appropriate. (Level of evidence: Category 1)

Question 4: In which patients should additional treatment be considered following first-line induction?

Background

To reduce the risk of relapse, additional strategies have been sought to either maintain or improve the initial response achieved with first-line induction therapy. The goal of maintenance therapy is to sustain the best initial response achieved with first-line induction, whereas consolidation therapy aims to improve the quality of the response, preferably via eradication of minimal residual disease (MRD). 61

Prior to rituximab, maintenance therapy using interferon has been attempted; however, since the introduction of rituximab, most guidelines recommend rituximab maintenance (R-maintenance) based on positive outcomes in phase III trials.16, 17, 18, 19, and 20 In Canada, the Alberta guidelines recommend giving R-maintenance every 3 months for a total of 2 years (375 mg/m2 intravenous single dose every 3 months for a total of eight doses) if a PR or CR has been achieved following induction. 21 The BCCA also recommends giving rituximab as maintenance if at least a PR is achieved following induction. 22

Radioimmunotherapy (RIT) and high-dose therapy (HDT) with autologous stem cell transplantation (ASCT) are two types of consolidation strategies investigated in the first-line setting. With the exception of the NCCN guidelines, all European guidelines do not recommend RIT consolidation as there are insufficient data in patients receiving RIT consolidation after rituximab-containing induction therapy, as well as a lack of phase III trials comparing RIT consolidation with R-maintenance.16, 17, 18, 19, and 20 In terms of ASCT, all European guidelines strictly do not recommend ASCT in first-line therapy for FL outside of the clinical trials setting, and the NCCN guidelines do not even discuss ASCT for first-line therapy.16, 17, 18, 19, and 20 In Canada, none of the provincial guidelines available mention either RIT or ASCT consolidation in the first-line setting.21 and 22

Methodology

In examining maintenance treatment following first-line induction in FL, we performed a literature search of all phase III studies. The following search terms were used: follicular, lymphoma, and maintenance. Additionally, a literature search was performed to identify all phase III trials of consolidation therapy following first-line induction in FL. The following search terms were used: follicular, lymphoma, consolidation, radioimmunotherapy, transplantation, first-line, initial, front-line, and primary. Our literature search was restricted to published studies using rituximab plus chemotherapy as induction.

Maintenance therapy

A total of two randomized studies have compared maintenance to observation following first-line treatment with rituximab plus chemotherapy in FL ( Table 9 ).62 and 63 Both studies gave R-maintenance, resulting in improved CR rates that ranged from 71.5% to 80%. The study by Salles et al. (2011) additionally reported an improved PFS of 74.9% at three years. 63 Although there was a numeric increase in PFS in the study by Vitolo et al., the difference between groups did not reach significance. 62 In the latter study, both treatment arms were given rituximab consolidation, which may explain the higher PFS shown in both groups. 62 Although the benefit of R-maintenance following BR was not examined in a phase III trial, R-maintenance has shown improvements in CR rates following a number of rituximab-based chemotherapies. It is therefore reasonable to conclude that R-maintenance would also improve outcomes following first-line treatment with BR.

Table 9 Phase III studies examining maintenance following first-line induction in FL

Reference Treatment N Median follow-up Maintenance schedule Patient population Efficacy Safety
Published studies
Vitolo et al. (2013) 62 [R-FND + R-consolidation] +

R-Maintenance (n = 101)

vs.

Observation

(n = 101)
Total: 234;

202
34 months Consolidation: Rituximab once weekly for 4 weeks

Maintenance: For 8

months, rituximab once every 2 months for a total of 4 doses
Age: 60 to 75 years

FL grade 1, 2, 3a

Stage II, III, IV disease

>50% FLIPI ≥3
At 18 months (3 months after end of maintenance): Patients in CR/CRu:

87% vs. 71%;

p = 0.006

Converted from PR to CR/CRu:

60% vs. 15%;

p = 0.008

2-year PFS: 81% vs. 69%;

HR = 0.74;

p = 0.226

OS: NS

between arms
Grade 3/4 neutropenia:

14% vs. 1%

Grade 3/4 infections: 3% vs. 1%
Salles et al. (2011) 63

(PRIMA)
Induction:[R-Chemo (R-CVP, R-CHOP, or R-FCM)] +

R-Maintenance (n = 505)

vs.

Observation

(n = 513)
Total:

1217;

ITT: 1018
36 months Single dose of rituximab every 2 months for 2 years Age >18 years

FL grade 1, 2, 3a

ECOG ≤2
At end of maintenance:

CR/CRu:

71.5% vs. 52.2%; p = 0.0001

Converted from PR to CR/CRu at 2 years:

52% vs. 30%;

p = 0.0001

3-yr PFS:

74.9% vs. 57.6%; HR = 0.55;

p <0.0001

OS: NS

between groups
Any AE:

56% vs. 37%;

p <0.0001

Any grade 3/4 AE: 24% vs. 17%;

p = 0.0026

Grade 3/4 neutropenia:

4% vs. 1%

Grade 2-4 infections: 39% vs. 24%;

p < 0.0001

AEs leading to treatment discontinuation:

4% vs. 2%; p = 0.029

Abbreviations: AE = adverse event; CHOP = cyclophosphamide, doxorubicin, vincristine, prednisone; CR = complete response; CRu = complete response unconfirmed; CVP = cyclophosphamide, vincristine, prednisone; ECOG = Eastern Cooperative Oncology Group; FL = follicular lymphoma; FLIPI = follicular lymphoma international prognostic index; HR = hazard ratio; ITT = intention to treat; NS = not significant; OS = overall survival; PFS = progression-free survival; PR = partial response; R = rituximab; R-CHOP = rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone; R-FCM = rituximab, fludarabine, cyclophosphamide, mitoxantrone; R-FND = rituximab, fludarabine, mitoxantrone, and dexamethasone

The addition of R-maintenance significantly increased the overall number of adverse events in both studies, with slightly higher rates of neutropenia and infections reported ( Table 9 ). However, R-maintenance was generally well tolerated, with few patients withdrawing due to treatment-related toxicities. 63

Maintenance schedule

A number of maintenance schedules of rituximab have been used following treatment with rituximab plus chemotherapy in front-line and relapsed FL.63, 64, 65, and 66 The duration of R-maintenance used in clinical trials has varied from a minimum of two courses of four doses per week to a maximum of 2 years or until disease progression. In addition, the frequency of treatment with rituximab varies in clinical trials and has been given every 2 months;62 and 63 every 3 months; 64 every 6 months; 65 or four times weekly. 66 However, no randomized studies have compared the duration or frequency of R-maintenance following induction with rituximab plus chemotherapy.

Given the lack of head-to-head studies comparing the duration and frequency of R-maintenance, there is currently insufficient evidence to make recommendations on the maintenance schedule of rituximab.

Recommendation: Given the improved response with R-maintenance versus observation in two randomized trials, maintenance rituximab is recommended following first-line treatment of FL. (Level of evidence: Category 1)

Note: There is currently insufficient evidence to determine the optimal frequency and duration of maintenance rituximab following first-line treatment of FL.

Consolidation therapy

Radioimmunotherapy

No published randomized studies were found examining the use of RIT following first-line therapy with only rituximab-based chemotherapy given as induction. However, one published randomized study included a subgroup of patients (n = 59/414) that were given rituximab-based chemotherapy as induction.67 and 68 The study evaluated the efficacy and safety of consolidation with yttrium-90 (90Y)–ibritumomab tiuxetan in patients with advanced-stage FL. 90Y-ibritumomab tiuxetan consolidation significantly prolonged median PFS (after a median observation time of 3.5 years) in all patients (36.5 vs. 13.3 months; p <0.0001), regardless of FLIPI subgroup. In addition, the final CR rate was 87% and 77% of patients in PR converted to CR/CRu. However, in the subgroup of patients given rituximab-based chemotherapy as induction, response improvement (conversion from PR to CR/CRu) was not significantly greater in the 90Y-ibritumomab tiuxetan consolidation arm (41.7% vs. 71.4%; p = 0.34). Given the small number of patients that had been given rituximab-based chemotherapy as induction, it is difficult to interpret the results of this study. There is therefore not sufficient evidence to currently support the use of this strategy following first-line treatment of FL.

High-dose therapy and autologous stem cell transplantation

Only one published, randomized trial comparing HDT and ASCT to conventional therapy following first-line treatment with rituximab-based chemotherapy was identified ( Table 10 ). 69 In this study, six courses of R-CHOP were compared with rituximab-supplemented high-dose sequential chemotherapy with autografting (R-HDS) to assess the value of intensified chemotherapy as a first-line treatment for FL. After a median follow-up of 4.25 years, disease control and the 4-year event-free survival (EFS) were significantly improved in the R-HDS arm versus R-CHOP arm (CR/CRu: 85% vs. 62%; 4-year EFS: 61% vs. 28%; p <0.001 for both); however, there was no OS advantage of HDT with ASCT. 69 Secondary malignancies and treatment-related mortality (TRM) were numerically higher in the R-HDS arm ( Table 10 ). The cumulative incidence of myelodysplastic syndrome/acute myeloid leukemia (MDS/AML) at 4 years was 6.6% for R-HDS and 1.7% for R-CHOP (p = 0.111). For solid tumours, the cumulative incidence at 4 years was 1.5% for both arms.

Table 10 Phase III trials of high-dose therapy and autologous stem cell transplantation in the first-line setting

Reference Treatment N Median follow-up (years) OS Duration of response Response rates Safety
Ladetto et al. (2008)

(GITMO/

IIL)
R-CHOP (comparator):
  • Initial: 6 courses CHOP followed by 4 infusions rituximab (375 mg/m2)
  • If PR or PCR positivity at treatment cessation: 2 additional infusions rituximab
  • Radiotherapy: 30-36 Gy on bulky sites or residual masses ∼2 mo after treatment cessation
R-HDS:
  • Initial: 2 courses of APO (doxorubicin 75 mg/m 2 on d 1 and d 22, vincristine 1.2 mg/m2 on d 1 and d 15, and prednisone 50 mg/m 2 on d 1-22). If no CR, then 2 courses of DHAP (cisplatin 100 mg/m 2 on d 1, Ara-C 4 g/m 2 on d 2, and dexamethasone 40 mg on d 1-4).
  • Mobilization: Etoposide (VP16) 2 g/m2 and 2 courses of rituximab (375 mg/m2). After 40 d, 7 g/m2 cyclophosphamide, followed by in vivo purging with 2 courses of rituximab (375 mg/m2)
  • HDT: mitoxantrone 60 mg/m 2 on d -5 and melphalan 180 mg/m 2 on d -2.
  • Radiotherapy: 30-36 Gy on bulky sites or residual masses ∼2 mo after ASCT
  • If PR or PCR positivity at treatment cessation: 2 additional infusions of rituximab
134 4.25 R-CHOP vs. R-HDS:

4-yr: 80% vs. 81%, p = 0.96
R-CHOP vs. R-HDS:

4-yr EFS: 28% vs. 61%, p <0.001

4-yr PFS: 31% vs. 68%, p <0.001

4-yr DFS: 45% vs. 76%, p <0.001
R-CHOP vs. R-HDS:

CR/CRu: 62% vs. 85%, p <0.001

PR: 8% vs. 5%

PD or SD: 30% vs. 10%
TRM:

R-CHOP: n = 1

R-HDS: n = 4

Secondary Malignancies:

R-CHOP: MDS/AML, n = 1 (fatal); solid tumours, n = 3

R-HDS: MDS/AML, n = 5 (3 fatal); solid tumours, n = 1

Abbreviations: AML = acute myeloid leukemia; ASCT = autologous stem cell transplantation; CR = complete response; CRu = unconfirmed complete response; d = day; DFS = disease-free survival; DHAP = dexamethasone, cytarabine, cisplatin; EFS = event-free survival; FL = follicular lymphoma; HDT = high dose therapy; MDS = myelodysplastic syndrome; OS = overall survival; PCR = polymerase chain reaction; PD = progressive disease; PFS = progression-free survival; PR = partial response; R-CHOP = rituximab, cyclophosphamide, doxorubicin, vincristine, prednisolone; R-HDS = rituximab-supplemented high-dose sequential chemotherapy with autografting; SD = stable disease; TRM = treatment-related mortality; yr = year

Updated results were presented at the ASH 2013 Annual Meeting in abstract form. 70 After a median follow-up of 9.5 years, the superior disease control achieved with R-HDS compared to R-CHOP was reaffirmed (CR: 83% vs. 57%; p <0.001), but did not translate into either a 5- or 10-year OS advantage. Additionally, it was reported that achieving either a CR or molecular remission (MR) was associated with a significantly prolonged 10-year OS (CR vs. no CR: 80% vs. 43%; p <0.001; MR vs. no MR: 83% vs. 57%; p = 0.03).

Recommendation: We do not recommend HDT followed by ASCT as part of front-line treatment of FL given the lack of a survival benefit and potential toxicity of this approach. (Level of evidence: Category 1)

Note: There is no evidence to support the use of RIT following first-line treatment of FL.

Acknowledgements

The authors would like to acknowledge the financial support of Lymphoma Canada at all stages of the development of this guideline, including medical writing support provided by Anna Christofides and Marina Komolova of New Evidence.

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Footnotes

1 Assistant Professor of Medicine, University of Toronto, Hematologist, Princess Margaret Hospital, Toronto, Ontario

2 Assistant Professor of Medicine, McGill University, Hematologist, Jewish General Hospital, Montreal, Quebec

3 Associate Professor of Medicine, University of Toronto, Radiation Oncologist, Princess Margaret Hospital, Toronto, Ontario

4 Assistant Professor of Medicine, Dalhousie University, Hematologist, Queen Elizabeth II Health Sciences Centre, Halifax, Nova Scotia

5 Professor, Departments of Oncology and Medicine, University of Calgary and Tom Baker Cancer Centre, Calgary, Alberta

6 Senior Medical Writer and Managing Director, New Evidence, Toronto, Ontario

7 Medical Writer, New Evidence, Toronto, Ontario

8 Professor of Medicine, University of British Columbia, Hematologist, BC Cancer Agency, Vancouver, British Columbia