Follicular Lymphoma

Introduction

Non-Hodgkin lymphoma currently accounts about 5% of cancer diagnoses in males and 4% in females.¹ The incidence of this disease has been rising and it is estimated that 66,120 new cases will be diagnosed in the United States in 2008.

Non-Hodgkin lymphoma can be divided into a number of types of which follicular lymphomas represent 30-35% of cases.² Follicular lymphomas are defined as malignancies composed of follicular center cells, derived from the germinal B-cells centrocytes and centroblasts, and generally display a follicular growth pattern. These tumors are graded into three groups according to increasing number of centroblasts (large non-cleaved cells), and at one time were referred to as follicular small, cleaved cell, mixed cell and large cell types by the Working Formulation.

Although treatable by a number of modalities, follicular lymphomas are considered incurable with conventional therapy. Most behave as indolent lymphomas, though some, especially grade 3 tumors can have aggressive courses. Many will transform to higher grade and become less responsive over time.³

Over the years a number of prognostic systems have been described. The most recent is the Follicular Lymphoma International Prognostic Index (FLIPI) which divides patients into three risk groups.⁴ Variables include age >60, Stage III-IV, increased LDH, hemoglobin <12g/dl and nodal involvement at 5 or more sites. High beta-2 microglobulin and certain chromosomal abnormalities have also been shown to be associated with an increased risk of progression.

Methods

All cases of follicular lymphoma diagnosed or treated at the Susquehanna Cancer Center between January 1, 1999 and December 31, 2003 were identified through the electronic Tumor Registry database. Records were reviewed for demographics, grade, stage, and initial treatment. Five year survival curves were calculated and compared to benchmarks.

Results

45 patients were identified during the interval of 1999-2003 with an average of 9 cases per year. Table 1 displays the demographics of this group.

Table 1 Demographics

Age

Median

Range

65 years

19 – 85 years

Sex (male:female)

24:21 (53:47%)

Race (Caucasian)

45 (100%)

Stage I

Stage II

Stage III

Stage IV

12 (27%)

5 (11%)

10 (22%)

18 (40%)

Grade 1

Grade 2

Grade 3

27 (60%)

16 (36%)

2 ( 4%)

Although the median age was 65 years the range was quite wide between 19 and 85 years. 31% of patients were less than 60 years, while 33% were over 70 years and 9% were over 80 years.

All patients were Caucasian reflecting the demographics of this region. There was a slight predominance of males over females. Initial evaluation and staging studies are displayed in Table 2.

Table 2 Initial Evaluation & Staging

History & Physical	45	100%
CBC	45	100%
Biochemistry profile	44	98%
LDH	41	91%
Beta-2 microglobulin	2	4%
CT chest/abd/pelvis	44	98%
PET CT	8	18%
Gallium scan	24	53%
Any dynamic imaging	32	71%
Bone marrow	34	76%
Path report	45	100%
Immunophenotype	33	73%

All records contained a confirmatory pathology report and all or nearly all patients underwent a complete history and physical examination, CBC, Chemistry profile and CT scans of the chest, abdomen and pelvis. LDH was commonly obtained. Only three-quarters of patients had a nuclear medicine scan, bone marrow or immunophenotyping. Beta-2 microglobulin was rarely requested.

96% of these patients were found to have either grade 1 or 2 disease. Stage IV disease was identified in 40% of patients while 27% were Stage I. Stage and grade are contrasted in Tables 3 and 4.

Table 3 Stage by Grade

Grade 1

Stage I

Stage II

Stage III

Stage IV

27 cases (60%)

30%

11%

18%

41%

Grade 2

Stage I

Stage II

Stage III

Stage IV

16 cases (36%)

25%

13%

31%

Grade 3

Stage IV

2 cases (4%)

100%

Table 4 Grade by Stage

Stage I

Grade 1

Grade 2

Grade 3

12 cases (27%)

67%

33%

Stage II

Grade 1

Grade 2

Grade 3

5 cases (11%)

60%

40%

Stage III

Grade 1

Grade 2

Grade 3

10 cases (22%)

50%

Stage IV

Grade 1

Grade 2

Grade 3

18 cases (40%)

61%

28%

11%

As displayed in Table 5 radiotherapy was the most common treatment for Stage I disease being administered in one-half of those patients. One-quarter of Stage I patients were treated with chemotherapy alone. Stage II patients were nearly equally divided between chemotherapy and radiotherapy alone. Stage III and IV patients were nearly always treated with chemotherapy alone. Only one patient received combined modality therapy and one refused treatment. 4 were followed without initial treatment.

Table 5 Treatment by Stage

Treatment	I	II	III	IV
RadioRx alone	6	3	0	1
ChemoRx alone	3	2	9	15
Combined	1	0	0	0
Watch & Wait	1	0	1	2
Refused Rx	1	0	0	0
Totals	12	5	10	18

A variety of initial chemotherapy approaches were recorded during this time interval as shown in Tables 6 and 7. Multi-agent chemotherapy was the most frequent at 52% of cases with CVP the leading regimen. Chlorambucil was the most commonly employed single agent used in 14% of cases.

Table 6 Chemotherapy Regimen Types

Chemotherapy
Single agent	4	14%
Multi-agent	15	52%
Rituximab alone	3	10%
Rituximab-Chemo	7	24%

Regimens employing Rituximab were used in 34% of treated patients with R-CHOP the most common combination. Rituximab was used as a single agent in 10%.

Table 7 Chemotherapy Regimens

CVP	8	28%
R-CHOP	6	21%
Chlorambucil	4	14%
Mitoxantrone based	4	14%
CHOP	3	10%
Fludarabine based	2	7%

45% of patients received a regimen containing an anthracycline. Only 7% of patients received initial fludarabine.

Survival curves for this group of patients are displayed in Appendix 1. The median survival of the overall group has not yet been reached at 5 years of minimum follow up.

92% of our stage I patients survived 5 years compared to 55% of similarly staged patients in the Pennsylvania Registry. Stage II, III and IV patients also exceeded the reference 5 year survival at 60% vs. 48%, 70% vs. 54% and 61% vs. 46% respectively.

Grade 1 patients seen here achieved an 81% 5 year survival compared to 50% in the State Registry. Grade 2 and 3 patients were similar to the reference range at 56% vs. 54% and 50% vs. 47% respectively.

A single patient in our series under 40 years survived over 5 years. But, the 40 – 65 year old and > 65 year old groups survival at 5 years of 82% and 57% exceeded the National Cancer Database of 59% and 42%.

Discussion

Follicular lymphoma is the second most common form of Non-Hodgkin lymphoma following only diffuse large-cell, B-cell lymphoma.³ It is reported most often among the middle aged and advanced aged patients as were our patients in this study. The slight male predominance seen among our patients is also typical.

Grade 1 disease is expected to constitute 55-65% of follicular lymphomas. The 60% incidence in our series is consistent. However, the 36% grade 2 is above the more typically reported 15-30% and the 4% grade 3 is lower than the reported 8-15%.

Stage I disease is generally reported in 15-20% of grade 1 cases. The 30% Stage I among our grade 1 patients is certainly higher than expected. As grade increases, the incidence of higher stage has been reported to decrease. With only 2 grade 3 cases among our patients, comparisons for that group are limited.

The optimal treatment of follicular lymphomas is not yet defined.^{2-3, 5-6}Treatment is most often initiated for patients with symptomatic or bulky disease or those with marrow compromise or rapid progression. Enrolment of these patients on clinical trials is frequently advocated.⁵

There is sufficient evidence to support treatment of Stage I and II, grade 1-2 follicular lymphoma patients with involved field radiotherapy. Studies report up to 95% control rates and 5 year survivals of 79%. Nine of our 17 (53%) stage I and II patients received primary radiotherapy. Some authors also advocate the addition of chemotherapy to radiotherapy which was performed in one of our stage I patients. The 82% 5 year survival in our combined Stage I and II patients (graph not shown) is comparable.

“Watch and wait” remains a common strategy for patients with more advanced stage disease. Clinical trials have demonstrated equivalent survival for early or delayed treatment among these patients.^2-3 This approach however has become less acceptable to patients and oncologists. It was employed in only four patients (9%) in our series.

Chemotherapy with or without immunotherapy is commonly undertaken in patients with advanced stage disease. The choice of agent or agents remains an area of great controversy. Single vs. multi-agent regimens, alkylator vs. fludarabine based, with or without an anthracycline, with or without rituximab or rituximab alone are all debated.

Some advocate alkylator therapy rather than fludarabine to preserve stem cells for later treatments.⁵ The majority of our chemotherapy treated patients received an alkylator with only 7% receiving fludarabine.

No randomized trials have shown a survival benefit for the initial use of anthracyclines in follicular lymphoma yet they are noted to be heavily favored in clinical practice in the United States.⁵ 45% of the patients treated in our series received an anthracycline.

In the most recent years the use of rituximab in the treatment of follicular lymphoma has been said to change our paradigm.⁶ The addition of rituximab to chemotherapy of any regimen has been superior to that regimen alone in terms of progression free survival. Long term follow up of those studies will be necessary to determine if there is also a survival advantage. Although 1999-2003 is early in the implementation of rituximab, a full 34% of our follicular lymphoma patients received that agent in their initial treatment.

Survival among follicular lymphoma patients treated at Susquehanna Cancer Center exceeded that of comparable benchmarks when evaluated by age, stage and grade. The relatively small sample size of our patients may account some of this difference. Additionally among any selected group of follicular lymphoma patients the natural history and biology may be heterogeneous.

This review of follicular lymphoma patients treated at Susquehanna Cancer Center between 1999 and 2003 demonstrates that these patients underwent appropriate evaluation and management. The survival of this selected group of patients exceeded that of comparable State and National benchmarks.
Appendix 1 Survival Curves