Molecular landscape of distinct follicular lymphoma histologic grades: Insights from genomic and transcriptome analyses.

Abstract

7002 Background: The 2022 World Health Organization Classification of Hematologic Malignancies classifies follicular lymphoma grades 1-2 (FL1-2) and grade 3A (FL3A) as classical follicular lymphoma (cFL) and reclassifies grade 3B (FL3B) as follicular large B-cell lymphoma (FLBL), without addressing cases of patients with concurrent FL and DLBCL. However, genetic information of FL histologic grading remains limited, and the latest classification lacks sufficient evidence to resolve whether these subgroups represent single or multiple distinct biological entities. Methods: This study analyzed clinical data from 831 patients, whole-exome sequencing (WES) from 149 patients, and transcriptome sequencing from 63 patients to explore differences among FL1-2, FL3A, FL3B, and FL/DLBCL. Results: A total of 1006 patients were initially identified. After excluding those under 18 years of age, those with histological transformation, and those with incomplete clinical information, 831 patients remained. Among them, 588 (71%) had FL1-2, 84 (10%) had FL3A, 67 (8%) had FL3B, and 92 (11%) had FL/DLBCL. Baseline clinical and tumor characteristics are summarised in table. The Kaplan-Meier survival analysis was performed on 477 FL patients who received R-CHOP treatment. Age > 60, spleen involved, elevated serum LDH, elevated β2-MG and grade 3B were associated with inferior PFS and OS; while ECOG 3-4 and Ann Arbor stage III/IV disease were associated with inferior PFS. Factors that retained significance on multivariable analysis for PFS were grade 3B (HR 2.08, 95% CI 1.22-3.56, p = 0.0076) , ECOG 3-4 (HR 2.49, 95% CI 0.98-6.32, p = 0.05) and elevated serum LDH (HR 1.68, 95% CI 1.05-2.69, p = 0.03), while for OS, it was only grade 3B (HR 4.67, 95% CI 1.95-11.15, p < 0.001). Genomics showed that FL3B and FL/DLBCL lack mutations in epigenetic regulators CREBBP and KMT2D but exhibit additional copy number variations, such as 1p36.32 losses and 3p21.1 gains, which are linked to poor prognosis. Transcriptomics revealed that with increasing histologic grade, immune-related pathway activity decreases, whereas metabolic pathway activity increases, which may be associated with the upregulation of MYC, IRF4, and BATF expression. Conclusions: In summary, these findings define FL3B and FL/DLBCL as biologically and clinically distinct B-cell lymphomas, differing from traditional FL. FL1-2 and FL3A differ in their tumor microenvironments rather than genetic profiles. Clinical and genetic characteristics among four subgroups. Clinical characteristics FL1-2 (%) FL3A (%) FL3B (%) FL/DLBCL (%) P No. of patients 588 (71) 84 (10) 67 (8) 92 (11) AgeMedian years (range)< 60 years≥60 years 52 (24-87)439 (75)149 (25) 56.5 (28-82)48 (57)36 (43) 56 (24-78)36 (54)31 (46) 60 (27-87)43 (47)49 (53) <0.0001 ECOG performance status< 2≥2Missing 549 (93)8 (1)31 (5) 82 (98)0 (0)2 (2) 60 (90)3 (4)4 (6) 79 (86)4 (4)9 (10) 0.029 B symptomsYesNoMissing 75 (13)482 (82)31 (5) 18 (21)64 (76)2 (2) 10 (15)52 (78)5 (7) 17 (18)66 (72)9 (10) 0.110 Ann Arbor stageI–IIIII–IVMissing 98 (17)445 (76)45 (8) 19 (23)58 (69)7 (8) 20 (30)39 (58)8 (12) 25 (27)51 (55)16 (17) 0.001 POD24YesNoMissing 97 (16)436 (74)55 (9) 8 (10)65 (77)11 (13) 17 (25)46 (69)4 (6) 18 (20)60 (65)14 (15) 0.078 Lymph nodes <5YesNoMissing 208 (35)371 (63)9 (2) 34 (40)49 (58)1 (1) 37 (55)25 (37)5 (7) 54 (59)35 (38)3 (3) <0.0001 Marrow involvedYesNoMissing 80 (14)504 (86)4 (1) 16 (19)63 (75)5 (6) 4 (6)60 (90)3 (4) 3 (3)88 (96)1 (1) 0.003 Spleen involvedYesNoMissing 139 (24)407 (69)42 (7) 25 (30)54 (64)5 (6) 14 (21)47 (70)6 (9) 15 (16)65 (71)12 (13) 0.295 FLIPI0-123-5Missing 141 (24)220 (37)183 (31)44 (7) 18 (21)22 (26)37 (44)7 (8) 24 (36)10 (15)24 (36)9 (13) 24 (26)19 (21)31 (34)18 (20) 0.269 FLIPI20-123-5Missing 398 (68)100 (17)64 (11)26 (4) 51 (61)16 (19)13 (15)4 (5) 39 (58)9 (13)10 (15)9 (13) 51 (55)19 (21)11 (12)11 (12) 0.316 LDH(u/L)>UNLYesNo 88 (15)500 (85) 26 (31)58 (69) 23 (34)44 (66) 44 (48)48 (52) <0.0001 β2-MG≤3mg/LYesNoMissing 411 (70)172 (29)5 (1) 61 (73)23 (27)0 (0) 46 (69)20 (30)1 (1) 64 (70)28 (30)0 (0) 0.943 Genetic alterations No. of patients 99 22 10 18 KMT2D mutationCREBBP mutationSTAT6 mutation1p36.32 alteration6p22.1 alteration7q22.3 alteration3p21.1 alteration 50 (51)39 (39)21 (21)21(21)27(27)8(8)19(19) 8(36)7 (32)2 (9)3(14)11(50)3(14)7(32) 2 (20)0 (0)0 (0)5(50)3(30)7(70)4(40) 1 (6)2 (11)0 (0)6(33)11(61)10(56)9(50) p<0.001 p<0.001 p=0.045 p=0.096 p= 0.016 p<0.0001 p<0.0001 Note: Differences in patient/disease characteristics among groups (FL1-2, FL3A, FL3B and FL/DLBCL respectively) were analyzed using Fisher’s exact test for discrete variables and the Kruskal-Wallis H test for continuous variables. DLBCL, diffuse large B cell lymphoma; ECOG, Eastern Cooperative Oncology Group; POD24, progression of disease within 2 years; FLIPI, Follicular Lymphoma International Prognostic Index; HGB, hemoglobin; LDH, lactate dehydrogenase; CRP, C-reactive protein; β2-MG, β2-macroglobulin.