Grade 3 Follicular Lymphoma: Outcomes in the Rituximab Era

Background: Follicular lymphoma (FL) is a heterogeneous disease commonly graded as 1, 2, 3A and 3B based on percentage of large cells. While FL grade 3A is often considered as an indolent disease and grouped with grades 1-2, data suggest that FL grade 3B has clinical behavior similar to diffuse large B-cell lymphoma (DLBCL) so is approached as an aggressive lymphoma.  At the Cleveland Clinic, we reviewed a large series of patients (pts) diagnosed with FL grade 3A, 3B and FL grade 3 with areas of DLBCL and reported characteristics and outcomes in the rituximab era.

Methods:

Patients:  We performed a retrospective IRB-approved analysis of patients diagnosed with FL 3A, 3B, or FL3 with concomitant areas of DLBCL. 72 subjects were identified with FL grade 3; including: 3A, 3B, FL 3/DLBCL, or unclassified FL3.  We excluded subjects who had no follow-up data or diagnosed as unclassified FL 3, thus we analyzed a cohort of 46 patients. These 46 were divided into two groups. The aggressive lymphoma group (n=21) included subjects diagnosed with FL3B (n=11) and FL3 (A or B) with concomitant areas of DLBCL (n=10) (termed aggFL).  The indolent lymphoma group (n=25) included subjects diagnosed with FL3A. All patients started their 1^st treatment between 1998-2014.  The aim of this study was to assess the clinical outcomes by comparing the progression free survival (PFS) and overall survival (OS) between the two groups.

Results:  Of the 46 patients, 25 (54%) had FL 3A, 11 (24%)  FL 3B, and 10 (22%) FL3/DLBCL. Thus, the aggressive group (aggFL) had 21 patients (46%). For the entire cohort, 37 (49%) were male and 35 (51%) female; 78% were Caucasian. Table 1 compares FL 3A and combined 3B and FL 3/DLBCL cohorts.

With median follow-up of 54 and 62 months for FL3A and aggFL, respectively; 75% of FL 3A and 86% of aggFL patients were alive. Among the FL3A and combined aggFL groups, 23 of 25 (92%) and 18 of 21patients (85%) received R-CHOP, respectively. There was no statistical difference in PFS between the 2 groups, and each group has apparent PFS plateau after ~ 3 years (Figure2). Similarly, we found that no statistical difference in Overall Survival between the groups of indolent FL (F3A) and aggFL (FL3B or FL3/DLBCL) lymphoma.

Conclusion: The outcomes of the 1st large series of FL grade 3 patients in the rituximab era, primarily treated with R-CHOP, show no statistically significant difference in PFS or OS between FL 3A vs. aggFL with predominantly large cells (FL 3B/DLBCL). As expected, aggFL, FL3B and FL3/DLBCL, showed a plateau confirming that these pts should be treated with curative intent. Surprisingly, FL3A pts mainly managed with R-CHOP also show a plateau in survival; however, indicating the possibility of long term unmaintained remission in this histology and raising the issue of potential under-treatment with less aggressive regimens.

Table1: Clinical and Demographic Characteristics

	FL 3A		FL 3b                                                     FL 3/ DLBCL
	N=25	%	N=21	%	P
Age					0.45*
Mean+ SD	61 ± 15.6		58  ± 11
Range	65 (19- 85)		55 (39-80)
Gender					0.56**
Male	14	54%	9	43%
Female	12	46%	12	57%
ECOG Performance Status					1**
Good (ECOG     0,1)	18	72%	17	81%
Poor (ECOG   >1)	2	8%	1	5%
Unknown	5	20%	3	14%
B Symptoms					0.74**
Present	8	32%	5	24%
Not Present	17	68%	16	76%
BM Involvement					0.47**
Involved	6	24%	3	14%
Not Involved	16	64%	16	76%
Unknown	3	12%	2	10%
Stage					0.76**
I, II, III	17	68%	13	62%
IV	8	32%	8	38%
1st Line Regimen					1**
R-CHOP)	22	88%	18	85%
Other	3	12%	2	9%
Median/Average        Follow-up (Months)
From DX	54/60		62/65		0.68*
From TX	55/58		59/56		0.91*
* Anova
** Fisher's Exact