Signification clinique du dosage des chaines légères libres et des chaines lourdes sériques dans les LDGCB

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1 Signification clinique du dosage des chaines légères libres et des chaines lourdes sériques dans les LDGCB Réunion du CNO, axe 2, le 6 avril 2012 Fabrice Jardin

2 κ Samples λ Concentration (mg/l)

3 κ/λ κ Samples λ Concentration (mg/l)

4 κ/λ κ Samples λ Concentration (mg/l)

5 Signification clinique des FLC dans les hémopathies lymphoïdes B Valeur pronostique et diagnostique Pathologies plasmocytaires: myélome, amylose AL Valeur pronostique LLC Dans les LNH / LH?

6 n = 66 AIDS NHL (vs 225 contrôles) (K/L > EPP)

7 2 cohortes N0489: RCHOP + epratuzumab MER : cohorte SPORE «off study patients»

8 N = 17

9 N = 100

10 Dosage des chaines lourdes/légères HevyLite assay

11 Rationnel / But de l étude Freelite: technique sensible et valeur pronostique dans les hémopathies B matures Valeur des dosages HevyLite dans les DLBCL? Cellules clonotypiques circulantes dans tous les DLBCL et MdH Lien entre Ig/FLC circulante et biologie de la tumeur

12 Matériels et méthodes (1) Patients Patients inclus dans le programme 03B avec DLCBL (6 essais) serums au diagnostic (2) Serums Dosages freelite Dosages hevylite Centralisés (Binding site compagny) GEP (Affy U133+2): GCB/ABC Corrélations biologiques: albuminémie, lymphocytes, créatinémie

13 Description de la cohorte (1) 466 dosages réalisés > 409 retenus pour l analyse 03-7B 7% 05-1B 1% 03-1B 14% 03-6B 41% 03-2B 26% 03-39B 4% 03-3B 7%

14 Description de la cohorte (2) R-Mini-CHOP21 7% R-CHOP14 20% R-ACVBP 27% R-ACVBP+ASCT 4% ACVBP 8% R-CHOP21 34%

15 Median age (range) n (%) n (%) n (%) Age > 60 years 195 (79.9) 3 (1.8) 198 (48.6) Male sex 129 (52.9) 95 (58.3) 224 (55.0) IPI 0 2 (0.8) 55 (33.7) 57 (13.9) 1 45 (18.3) 48 (29.4) 93 (22.7) 2 42 (17.2) 39 (23.9) 81 (19.8) 3 70 (28.5) 16 (9.8) 86 (21.0) 4 59 (24.0) 5 (3.1) 64 (15.6) 5 28 (11.4) (6.8) Age-adjusted IPI RCHOP / R-miniCHOP (n = 246) RACVP / ACVBP (n = 163) Total (n = 409) 70 (26-93) 47 (18-63) 59 (18-93) 0 8 (3.3) 59 (36.2) 67 (16.4) (43.5) 58 (35.6) 165 (40.3) 2 94 (38.2) 40 (24.5) 134 (32.8) 3 37 (15.2) 6 (3.7) 43 (10.5) Stage I-II 52 (21.1) 89 (54.6) 141 (34.5) III-IV 194 (78.9) 74 (45.4) 268 (65.5) Performance Status (ECOG) 0 90 (36.1) 94 (57.7) 184 (45.0) (43.1) 58 (35.6) 164 (40.1) 2 49 (19.9) 8 (4.9) 57 (13.9) 3 1 (0.4) 3 (1.8) 4 (1.0)

16 LDH > Normal 162 (65.9) 71 (43.6) 233 (57.0) Extra-nodal sites RCHOP / R-miniCHOP (n = 246) RACVP / ACVBP (n = 163) Total (n = 409) n (%) n (%) n (%) <= (54.1) 128 (78.5) 261 (63.8) > (45.9) 35 (21.5) 148 (36.2) Bone marrow involved 42 (17.1) 11 (6.7) 53 (13.0) Mass > 10 cm 49 (20.2) 37 (22.7) 86 (21.2) B symptoms 90 (36.6) 56 (34.6) 146 (35.8) Beta 2 microglobulin (>= 3 mg/l) 91 (42.7) 20 (14.5) 111 (31.6) Albumin (g/l) <=35 g/l 60 (28.6) 22 (15.0) 82 (23.0) Arm of Treatment R-ACVBP (27.5) R-ACVBP+ASCT - 18 (4.4) ACVBP - 33 (8.1) R-CHOP (33.9) - R-CHOP14 80 (19.2) - R-Mini-CHOP21 28 (6.9) (39.9) 246 (60.1)

17 Résultats des dosages FLC / HLC FLC / HLC Measurements n (%) Mean measurement (Range) FLC (n = 408) Elevated FLC kappa 68 (16.7) mg/l (0-656) Elevated FLC lambda 25 (6.1) mg/l (1-2130) Elevated FLC kappa and Lambda 17 (4.2) Elevated FLC Kappa or Lambda 76 (18.6) Abnormal FLC ratio 38 (9.3) 1.33 (0-68) IgA (n = 409) Low IgA Kappa Low IgA lambda (16.3) (15.8) Elevated IgA Kappa Elevated IgA Lambda 38 7 (9.3) (1.7) 1.2 mg/l (0-20) 0.85 mg/l (0-3) Abnormal IgA K/IgAL ratio 12 (2.9) 1.55 (0-74) IgM (n = 408) Low IgM Kappa Low IgM lambda (11.2) (15.5) Elevated IgM Kappa Elevated IgM lambda (6.9) (5.4) 0.71 mg/l (0-13) 0.39 mg/l (0-4) Elevated IgM lambda or IgM Kappa 38 (9.3) Abnormal IgM K/IgM L ratio 78 (19.1) 2.37 (0-49) IgG (n = 409) Low IgG Kappa Low IgG lambda (21.0) (13.4) Elevated IgG Kappa Elevated IgG lambda 5 7 (1.2) (1.7) 5.55 mg/l (0-16) 3.22 mg/l (0-12) Abnormal IgG K/IgG L ratio 26 (6.4) 1.84 (0-18)

18 Corrélation cliniques avec les dosages FLC / HLC (1) K/L FLC ratio IgM K/IgM L ratio abnormal normal abnormal normal n (%) n (%) χ2 n (%) n (%) χ2 Population Age > 60 years 27 (71.1) 170 (46.3) P = (74.4) 140 (42.7) P = <0.001 IPI [0-2] 12 (31.5) 218 (59.1) P = (32.0) 205 (62.1) P = <0.001 [3-5] 26 (68.5) 151 (40.9) 53 (68.0) 125 (37.9) Age-adjusted IPI [0-1] 13 (34.2) 218 (59.1) P = (35.9) 203 (61.6) P = <0.001 [2-3] 25 (65.8) 151 (40.9) 50 (64.1) 127 (38.4) Ann arbor stage I-II 4 (10.5) 137 (37.1) 15 (19.2) 126 (38.2) P = P = III-IV 34 (89.5) 232 (62.9) 63 (80.8) 204 (61.8) Performance Status (ECOG) [0-1] 30 (79.0) 316 (85.6) P = (80.8) 284 (86.1) P = [2-3] 8 (21.0) 53 (14.4) 15 (19.2) 46 (13.9) LDH > Normal 27 (71.1) 205 (55.5) P = (70.5) 178 (53.9) P = Nb of extra-nodal sites <= 1 19 (50.0) 241 (65.3) P = (53.8) 218 (66.1) P = Bone marrow biopsy Involved 12 (31.6) 40 (10.8) P = < (20.5) 37 (11.2) P = Mass > 10 cm Yes 8 (21.1) 78 (21.1) P = (23.4) 68 (20.7) P = B symptoms Present 21 (55.3) 125 (33.8) P = (39.7) 115 (35.0) P = Beta 2 microglobulin >= 3 mg/l 21 (65.6) 90 (28.4) P = < (56.7) 73 (25.8) P <0.001 Albumin (g/l) <= 35 g/l 10 (28.6) 72 (22.5) P = (29.9) 62 (21.5) P = Creatinine (µmol/l) Médiane [range] 85 [39-151] 79 [30-221] p =0.074 a 88 [38-159] 78 [30-221] p <0.001 a

19 Corrélation cliniques avec les dosages FLC / HLC (2) FLC rate (K or L) IgM rate (IgM K or IgML) elevated non elevated elevated non elevated n (%) n (%) χ2 n (%) n (%) χ2 Population Age > 60 years 17 (22.4) 192 (58.0) P < (60.5) 176 (47.6) P = IPI [0-2] 29 (38.1) 201 (60.7) P < (39.5) 215 (58.1) p = [3-5] 47 (61.8) 130 (39.2) 23 (60.5) 155 (41.9) Age-adjusted IPI [0-1] 32 (42.1) 199 (60.1) p = (44.7) 214 (57.8) p = [2-3] 44 (57.8) 132 (39..9) 21 (55.3) 156 (42.1) Ann arbor stage I-II 16 (21.1) 125 (37.8) 11 (28.9) 130 (35.1) P = P = 0.48 III-IV 60 (78.9) 206 (62.2) 27 (71.1) 240 (64.9) Performance Status (ECOG) [0-1] 18 (23.6) 288 (87.0) P = (86.8) 314 (84.8) p= 1.00 [2-3] 58 (76.3) 43 (13.0) 5 (13.1) 56 (15.1) LDH > Normal 49 (64.5) 183 (55.3) P = (57.9) 211 (57.0) P = 1 Nb of extra-nodal sites <= 1 47 (61.8) 213 (64.4) P = (55.3) 239 (64.6) P = Bone marrow biopsy Involved 11 (14.5) 41 (12.4) P = (15.8) 47 (12.7) P = Mass > 10 cm Yes 9 (11.8) 77 (23.5) P = (73.7) 291 (79.3) P = B symptoms Pres ent 32 (42.1) 114 (34.5) P = (39.5) 131 (35.5) P = Beta 2 microglobulin >= 3 mg/l 39 (60.0) 72 (25.4) P = < (38.7) 99 (31.0) P=0.42 Albumin (g/l) <= 35 g/l 25 (37.3) 57 (19.8) P = (30.3) 72 (22.3) P=0.28 Creatinine (µmol/l) Médiane [range] 91 [39-159] 78 [30-221] p <0.001 a 76 [46-126] 79 [30-221] p = 0.96 a

20 Valeur pronostique (PFS/OS) des dosages FLC/HLC Elevated IgM κ or IgM λ Elevated FLC (κ or λ) Abnormal κ/λ FLC ratio Abnormal IgMκ / IgM λ ratio Abnormal IgGκ / IgGλ ratio Hypogammaglobulinemia Pop. Totale ACVBP / R-ACVBP R-CHOP / R-miniCHOP

21 Abnormal IgMκ/ IgMλ ratio Normal IgMκ/ IgMλ ratio

22 Abnormal κ/λ FLC ratio Normal κ/λ FLC ratio

23 Abnormal FLC Normal FLC

24 Valeur pronostique des dosages FLC/HLC. Analyse Univariée PFS Patients Hazard Ratio 95% CI p Hazard Ratio 95% CI p Univariate models Overall cohort Elevated IgM kappa or IgM lambda Elevated FLC (Kappa or Lambda) Abnormal K/L FLC ratio Abnormal IgM K/IgM L ratio Abnormal IgG K/IgG L ratio Hypogammaglobulinemia R-ACVBP/ACVBP cohort Elevated IgM kappa or IgM lambda (-) Elevated FLC (Kappa or Lambda) Abnormal K/L FLC ratio Abnormal IgM K/IgM L ratio Abnormal IgG K/IgG L ratio (-) (-) hypogammaglobulinemia R-CHOP/R-mini-CHOP cohort Elevated IgM kappa or IgM lambda Elevated FLC (Kappa or Lambda) Abnormal K/L FLC ratio Abnormal IgM K/IgM L ratio Abnormal IgG K/IgG L ratio Hypogammaglobulinemia S

25 Valeur pronostique des dosages FLC/HLC. Analyse Multivariée PFS Patients Hazard Ratio 95% CI p Hazard Ratio 95% CI p Mutlivariate models (overall cohort) Elevated IgM kappa or IgM lambda Elevated FLC (Kappa or Lambda) Abnormal K/L FLC ratio Abnormal IgM K/IgM L ratio Abnormal IgG K/IgG L ratio Hypogammaglobulinemia aaipi < <.0001 Abnormal IgM K/IgM L ratio Age (> 60 y) LDH (> normal) Performance Status (ECOG)> Ann arbor stage III-IV Nb of extra-nodal sites > Abnormal IgM K/IgM L ratio S

26 Diagramme de Venn Abnormal IgMκ/IgMλ ratio 48 Abnormal κ/λ FLC ratio Elevated FLC 261

27 Dosages FLC/HLC et GEP 16 IgMκ/IgMλ 4 GCB 12 ABC/unclassified

28 Dosages FLC/HLC et GEP

29 Conclusion Première analyse FLC / HLC dans les DLBCL FLC (polyclonal - K/L), IgMK/L, IgGK/L, Hypogammaglobulinemie = valeur pronostique défavorable Association ++ avec IPI, créatinémie Multivariée (1): FLC / IgMK/L Multivariée (2): facteurs non indépendant de l IPI IgMK/IgML : reflet de la biologie tumorale > Expression d une IgM. Lien avec ABC à confirmer

30 Discussion (1) Valeur pronostique de l isotype > IgM /ABC IHC ++ À réaliser

31 Discussion (2) Mayo GELA n Treatment R-CHOP + anti-cd22 + R-CHOP / R-ACVBP Follow-up (months) Age > 60y 59% 48% Renal insuffisancy 14% 5% Elevated FLC 31.9% 18.8% Abnormal K/L FLC 14% 9.4% Prognostic value Multivariate Univariate

32 Discussion (3) «secreting lymphoma» B-cell lymphoma 16% (64) 25% 3% (14) 75% (303) 5% (23)

33 Discussion (4) Proposition d une classification «immunobiochimique» des DLBCL Type I: dosages FLC / HLC normaux Type II: dosages «polyclonaux» (élévation des taux FLC, HLC) Inflammation, microenvironnement, rein Type III: dosages «clonaux» (ratio K/L FLC ou HLC) (COO, différenciation plasmocytaire?) Type IV: hypogammaglobulinemie («immunoparesis») Pronostic type I > types II-IV

34 Remerciements Sami Boussetta / LYSARC Anne-Laure Borrel Binding Site compagny Investigateurs des essais 03.