Non-Hodgkin Lymphoma (NHL) in children and adolescents. W. Woessmann

Transcription

1 Non-Hodgkin Lymphoma (NHL) in children and adolescents W. Woessmann

2 WHO Classification antigen independent ( precursor cells ) B cells precursor-b lymphoblastic lymphoma (pb-lbl) 5% T cells precursor-t lymphoblastic lymphoma (T-LBL) 15% antigen dependent ( mature cells ) Mature B-NHL: Burkitt-45%, DLBCL-10%, rare 55-60% Mature T-NHL: ALCL-13% PTCL-2% 15%

3 NHL in children and adolescents Pathogenesis, clinical presentation, therapy Lymphoblastic lymphoma Mature B cell lymphoma Anaplastic large cell lympoma Rare NHL-Subtypes: PMLBL Pediatric type follicular lymphoma Marginal zone lymphoma PTCL

4 Lymphoblastic lymphoma (LBL)

5 Lymphoblastic lymphoma: Immunology + genetics Immunology: markers of immature cells; marker for a lineage T-LBL pb-lbl TdT + (>90%), CD34+ TdT + (>90%), CD34+ CD7, cycd3 + CD19, CD79a, Pax5 + scd3, CD5, CD2 CD20 ±, CD10 ± CD1a (cortical) sig neg NOTCH1, FBXW7 mutations (60%) rarely detectable (few 11q23; BCR-ABL)

6 T LBL: localisation + clinical presentation

7 pb-lbl: localisation and clinical presentation

8 Lymphoblastic lymphoma: Localisation, stage distribution T-LBL Mediastinal mass (Thymus) 90% pb-lbl Cutaneous or subcutaneous (soft tissue) infiltrates 25% Cervical Lymph nodes 50% Bone 30% Liver, spleen 20% Cervical Lymph nodes 50% BM 20% BM 30% Stage T-LBL pb-lbl I 1% 10% II 2% 25% III 77% 27% IV 20% 38%

9 Lymphoblastic lymphoma or ALL? precursor B- and T-cell neoplasia with BM-involvement 0% - <5% BM involvement: lymphoblastic Lymphoma 25% BM involvement: Acute lymphoblastic leukemia 5% - <25% BM involvement: lymphoblastic Lymphoma stage IV

10 Lymphoblastic lymphoma: symptoms T-LBL Coughing Dyspnoe Superior vena cava syndrome Stridor Lymph node swelling Reduced general condition pb-lbl Cutaneous or subcutaneous infiltrates Bone pain Lymph node swelling

11 LBL therapy NHL-BFM90 stage I+II Induction Prot. M Maintenance 6-MP/MTX Cranial RT 12 Gy III+IV Induction Prot. M Re-Induction maintenance Woche

12 LBL Induction (protocol I) NHL-BFM90 PRED p.o. 60 mg/m 2 /d VCR i.v. 1.5 mg/m 2 DNR i.v. (1h) 30 mg/m 2 L-ASP i.v. 10,000 U/m 2 CPM i.v mg/m 2 ARA-C i.v. 75 mg/m 2 /d 6-MP p.o. 60mg/m 2 /d MTX i.th. * CNS positive pts only ( )* ( )* Day

13 T-LBL: pefs (5 y) in NHL-BFM 90 P , SE= All patients (N=129, 16 events) years (Reiter, Blood 00 )

14 T-LBL: prophylactic cranial irradiation? pdfs stage III/IV, CNS negative P , SE=.02.88, SE=.03 NHL 86/90 (N=165, 15 events) NHL V95/95 (N=156, 17 events) Log-Rank p = years (Burkhardt, JCO 06)

15 T-LBL: Euro-LB02 Steroid?, maintenance therapy? Induction Consolidation Re-Induction (not stage I+II) Maintenance 24 mnths I/1-PRED 6-MP/MTX P Random 1 I/2 M Prot. II Random 2 I/1-DEXA 6-MP/MTX 18 months Precursor-T-cell-LBL: Randomisation 1+2 Precursor-B-LBL: Reference arm

16 (Landmann et al., Haematologica 2017) Euro-LB02: pefs (5 y) N=319 years

17 Euro-LB02: Events protocol patients n=319 % Nonresponse Relapse/Progression Toxic death Second Malignancy (Landmann et al., Haematologica 2017)

18 Euro-LB02: pefs (5 y) acc to subtype (Landmann et al., Haematologica 2017)

19 Euro-LB02 - T-LBL: pefs (5 y) acc to steroid (Landmann et al., Haematologica 2017)

20 Treatment results in LBL trial age stage treatment No. of pts pefs reference LMT81 9y (0.9-16) I-IV mod. LSA2-L ±3% Patte et al CCG502 9y (0.5-19) I-IV mod. LSA2-L2 vs ADCOMP POG y (5-15) III/IV L-Asp vs L-Asp % 64% 64±6% 78±5% Tubergen et al Amylon et al NHL-BFM90 9y (1-16) I-IV ALL-BFM % Reiter et al NHL-BFM95 8y (0.2-19) III/IV BFM ±3% Burkhardt et al EORTC y (0-16) I-IV BFM ±3% Uyttebroeck et al COG Pilot n.d. III/IV mod. LSA2-L ±5% Abromowitch et al LNH92 8y (0-<16) I-IV mod. LSA2-L ±6% Pillon et al St. Jude 13 n.d. III//V T-ALL 41 83±6% Sandlund et al pb EORTC 7y I-IV mod. LMT, BFM 53 82% Ducassou et al POG % < 10y III/IV mod. DFCI ALL with HDMTX w/o HDMTX ±5% 88±4% Asselin et al A y (1-25) I/II CCG BFM 56 90% Termuhlen et al EURO-LB 02 I-IV BFM randomized Dex (10mg/m²) vs. Pred (60mg/m²) EORTC I-IV mod. BFM Dexa (6mg/m²) Pred (60mg/m²) 319 (all) % 84% 84% 81% 89% Landmann et al Uyttebroeck et al [Abstract NY] COG A y III/IV NHL-BFM95 MTX w/o HDMTX intensification w/o intensification total ±4% 83±4% 83±4% 83±4% LNH97 9y mod. LSA2-L ±4% (7y) Termuhlen et al Pillon et al. 2015

21 Current therapy of LBL

22 High-dose MTX for LBL? COG A5971 CCG-modified BFM regimen 254 randomised pts (2x2 design with intensification) (Termuhlen et al., BJH 2013)

23 High-dose MTX for LBL? COG A5971 (Termuhlen et al., BJH 2013)

24 Current therapy of LBL

25 T-LBL: survival after relapse NHL-BFM 90 and 95 EURO-LB 02 P , SE=0.08 Log-Rank p = T-LBL (N= 31, 22 events) years Burkhardt et al., J Clin Oncol 2009 Landmann et al., Haematologica 2017

26 LBL: current status and future vision ALL-type therapy reaches pefs of 80% HD-MTX necessary? Survival in relapse 20-30% Intensification? - no new drugs for T-LBL - toxicity limits escalation - osteonecroses as late effects Prognostic factors needed!

27 T-LBL: prognostic factors? Burkhardt B et al.,br J Haematol., 2016

28 P Common analysis of AIEOP, NHL-BFM und SFCE: NOTCH1 and FBXW7 pefs (5y) 0.89, SE= , SE=0.05 Log-Rank p = < years other (N=108, 33 events) NOTCH1/FBXW7 mut. (N=159, 19 events) P pos (5y) 0.90, SE= , SE= Log-Rank p = years Other (N=108, 27 events) NOTCH1/FBXW7 mut. (N=159, 15 events) 0.4 cum. incidence of relapse (5y) 0.3 P p(gray)=.0001 years Other 0.27, SE=0.04 Events/N 29/108 NOTCH/FBXW7 mut. 0.10, SE=0.02 Events/N 15/159 Burkhardt B et al., manuscript in preparation

29 LBL 2018 proposal Standard consolidation Standard-risk pb-lbl stage I/II protocol Ib protocol M maintenance T-LBL N/F mut protocol Ib protocol M protocol II maintenance R1 protocol Ia- Pred protocol Ia- Dexa Standard consolidation High-risk T-LBL N/F WT pb-lbl stage III/IV all CNS positive patients R2 protocol Ib protocol Ib* protocol M modified protocol M protocol II maintenance Intensified consolidation

30 NHL in children and adolescents Pathogenesis, clinical presentation, therapy Lymphoblastic lymphoma Mature B cell lymphoma Anaplastic large cell lympoma Rare NHL-Subtypes: PMLBL Pediatric type follicular lymphoma Marginal zone lymphoma PTCL

31 Mature B-NHL Burkitt-Lymphoma/B-AL DLBCL, PMLBL

32 Mature B-NHL: Immunology + genetics Burkitt DLBCL stary sky proliferation 100% CD20, CD19, sig, CD10 pos CD20, CD19 pos, sig±, CD10± t(8;14), t(2;8), t(8;22)? (IRF4) gene expression: GCB-type

33 Burkitt Lymphoma: localisation + clinical presentation

34 Sono Pascal Baum

35 Burkitt Lymphoma: localisation + clinical presentation

36 Burkitt Lymphoma: localisation + clinical presentation

37

38 Burkitt Lymphoma: localisation + clinical presentation

39

40 Burkitt leukemia (B-AL, FAB L3)

41 Mature B-NHL: symptoms Burkitt DLBCL Abdominal pain Lymph node swelling Irregular defacation, Ileus Abdominal mass Bone pain Invagination Lymph node swelling tonsillitis (one-sided) General symptoms Reduced general condition

42 Maure B-NHL: Localisation, stage Burkitt Abdomen 70% (LN, intestinal wall, ascites) DLBCL cervical lymph nodes 55% Cervical lymph nodes 40% abdominal lymph nodes 40-50% Tonsils (asymmetric) Bone 10% BM 25% (B-AL 20%) (more variable!) Stage Burkitt DLBCL I 10% 25% II 20% 40% III 40% 34% IV 30% 1%

43 Pathogenesis of BL / B-AL: the balance between proliferation and apoptosis cell cycle regulation pro-apoptotic signaling Proliferation Apoptosis

44 Pathogenesis of Burkitt - Lymphoma translocation t(8;14)(q24;q32) t(2;8)(p11;q24) t(8;22)(q11:q24) involved genes c-myc - IgH Ig - c-myc c-myc - Ig cell cycle regulation pro-apoptotic signaling Proliferation Apoptosis???

45 Burkitt-Lymphoma: more than Myc Burkitt-translocation alone is not enough to produce a lymphoma (Adams JM et al, Nature 1985) More recurrent genetic lesions of the coding genome have been detected by deep genomic sequencing.* * Schmitz et al, Nature 2012, Love C. et al, Nature Genetics 2012, Richter J, Nat Genet 2012

46 International Cancer Genome Consortium (ICGC) Determining Molecular Mechanisms in Malignant Lymphoma by Sequencing (Germinal Center Derived B-Cell Lymphoma) (ICGC MMML-Seq) Richter J* et al. for the ICGC MMML-Seq Project, Nature Genetics, 2012

47 Mutations in ID3-TCF3-CCND3 pathway In children with Burkitt / B-AL (NHL-BFM) Rohde et al., Haematologica, 2017

48 Pathogenesis of Burkitt Lymphoms / B-AL translocation t(8;14)(q24;q32) t(2;8)(p11;q24) t(8;22)(q11:q24) involved genes c-myc - IgH Ig - c-myc c-myc - Ig EBV in endemic BL ID3, p53 in sporadic BL cell cycle regulation pro-apoptotic signaling Proliferation Apoptosis aggressive NHL Proliferation rate

49 Therapy of B-NHL / B-AL historical perspective LBL ALL-type therapy ( continuous, 6 months + maintenance) CNS-irrad. In CNS-pos Induction consolidation Re-Induction maintenance months 2, Mature B cell lymphoma / B-AL - pulse-type therapy BFM V AA BB CC AA BB weeks CC Number of courses risk-adapted (2, 4, 6) LMB / FAB COP COPAD (M) COPAD (M) CYM CYVE CYM CYVE m m Number of courses risk-adapted weeks 15 (Anderson et al., NEJM 1983, Müller-Weihrich et al., Klin Padiatr 1982, 1984 ; Patte, Blood 2001, Reiter, Blood 1999)

50 Therapy of B-NHL / B-AL historical perspective NHL-BFM90 LMB89 (Patte, Blood 2001, Reiter, Blood 1999)

51 B-NHL / B-AL: therapeutic strategy BFM course A B C A B C week Dexamethasone 10 mg/m²/d Ifosfamide 800 mg/m² Ara C 150 mg/m² i.v. 1h Etoposide 100 mg/m² i.v. 2h Methotrexate 1 (5) g/m² MTX / ARA-C / PRED intrathecal x x Day

52 B-NHL: pefs NHL-BFM 90 P , SE= Pat. at risk years All Patients (N=413, 43 events) (Reiter, Blood 99)

53 B-NHL: pefs LMB89 (Patte, Blood 01)

54 Stratification of treatment intensity stage, LDH, resection status (localised lymphomas), BM-, CNS - involvement Definition pts (%) courses R1 Completely resected R2 not resected, LDH < 500 U/L R3 LDH < 1000 U/L R4 LDH > 1000 U/L +/or CNS pos

55 NHL-BFM95 and FAB/LMB96: De-escalation of treatment intensity? BFM95: MTX-question (randomised): - infusion time: 4h versus 24h (dose: 1g/m 2 in R1/2, 5g/m 2 in R3/4) FAB-LMB96: - IR: CP / m1-question (randomised, 2x2): CP x0.5 in COPADM 2, no m1 - HR: mini-cyve + m1 versus CYVE+ m2-m4 (Patte, Blood 2007, Cairo, Blood 2007, Woessmann, Blood 2005)

56 NHL-BFM95 and FAB/LMB96: De-escalation of treatment intensity? Low and intermediate risk: de-escalation possible toxicity, EFS and OS = High risk (R3/4; group C): de-escalation EFS and OS (Patte, Blood 2007, Woessmann, Blood 2005)

57 NHL-BFM95 and FAB/LMB96: De-escalation of treatment intensity? Low and intermediate risk: de-escalation possible (EFS and OS =) High risk (R3/4; group C): de-escalation toxicity, but EFS and OS! (Cairo, Blood 2007, Woessmann, Blood 2005)

58 B-NHL: stratification of treatment intensity acc to the results of NHL-BFM 95 Risk group Patients Therapy courses MTX (g/m 2 ) pefs Mucositis 3 +4 Toxic death R1 10% 2 1, 4h 96% <10% 0 R2 45% 4 1, 4h 95% <10% 0 R3 17% 5 5, 24h 87% 50% 3% R4 28% 6 5, 24h 84% 50% 4%

59 Current standard BFM-type therapy for mature B-NHL (Burkitt + DLBCL) R1 A 4 B 4 R2 V A 4 B 4 A 4 B 4 R3 V AA 24 BB 24 CC AA 24 BB 24 R4 V AA 24 BB 24 CC AA 24 BB 24 CC R4 CNS+ VZ AAZ1 BBZ1 CC AAZ2 BBZ2 CC

60 B-NHL R3 + R4: EFS (3y) acc. to CNS-involvement P years CNS neg. R3 0.86, SE= 0.04 (N= 93, 13 events) CNS neg. R4 0.84, SE= 0.03 (N=166, 26 events) ICM/CNP 0.89, SE= 0.07 (N= 19, 2 events) CSF Blasts BM< 25% 0.91, SE= 0.06 (N= 23, 2 events) CSF Blasts BM>=25% 0.61, SE= 0.08 (N= 40, 15 events) (Lisfeld et al., unpublished)

61 Pediatric mature B-NHL: Role of Rituximab?

62 B-NHL: Rituximab Window study (Meinhardt et al., JCO 2010)

63 Response to Rituximab aim mg/m % (95% CI 35 63%) 700 mg/m % 20% 40% 60% 80% 100% responder non-responder (Meinhardt ea., JCO 2010; Lisfeld et al, Abstract, NY 2012)

64 B-NHL BFM Rituximab: Event free survival (2 y) matched pair analysis (B-NHL BFM 04) P , SE= , SE=0.02 No Rituximab (N=432, 60 events) Rituximab (N=183, 10 events) Log-Rank p = years NHL-BFM, unpublished

65 COG: FAB + Rituximab: Event free survival (2 y) retrospective comparison (Goldman et al., Leukemia 2012)

66 Inter-B-NHL Ritux-2010 study (Minard et al., ASCO 2016)

67 Inter-B-NHL Ritux-2010 study Addition of Rituximab to LMB-type chemo: Improvement of EFS of HR-pts? Pts: stage III, LDH >2x ULN; stage IV; B-AL LMB-type chemotherapy +/- Rituximab (6 x 375mg/m 2 ) 310 pts randomised (155 each arm) EFS (1y): chemo: 81.5% ( ) chemo + Rit 94.2% ( ) (p<.006) (Minard et al., ASCO 2016)

68 B-NHL 2013: study for B-NHL und B-AL R1 R A 4 b 4 R2 stage I/II R P A 4 b 4 A 4 b 4 R2 stage III P IT A 4 B 4 A 4 B 4 R I R P A 4 B 4 A 4 B 4 R3, R4 R II R P (IT) AA(Z1) 24** BB(Z1) 24 CC AA(Z2) 24 BB(Z2) 24 CC only in R4 R P (IT) RR-AA(Z1) 24** RR-BB(Z1) 24 R-CC R-AA(Z2) 24 BB(Z2) 24 CC only in R4 * * * * * * * * lymphocyte subpopulations, immunoglobulin levels and infections: prior treatment, before prephase, 2nd course and 6, 12, 18 and 24 months after start of treatment and where applicable continued in 6-monthly intervals until normalization R randomization; R: rituximab 375 mg/m² ; P (IT) : prephase with intrathecal triple for CNS positive pts; AA(Z1) 24 etc in CNS positive pts Primary endpoints: EFS and immunreconstitution NHL-BFM and NOPHO, unpublished

69 B-NHL - current status and outlook Pathogenesis of BL/B-AL: MYC-Rearrangement + mutation in ID3-pathway EFS with BFM- or LMB-type chemotherapy: - low stage, low LDH: limited therapy: 95% - advanced stage, LDH: intensive ther.: 85% - CNS+ 80% Addition of Rituximab to high risk pts (R3, R4): improvement of EFS to 94% Acute toxic death rate in R3/R4: 3-4% Survival in relapse: Burkitt 20%, DLBCL 50%

70 B-NHL Subtypes, molecular mechanisms and targets Lange J, Lenz G and Burkhardt B, Expt Rev Hematol, 2017

71 NHL in children and adolescents Pathogenesis, clinical presentation, therapy Lymphoblastic lymphoma Mature B cell lymphoma Anaplastic large cell lympoma Rare NHL-Subtypes: PMLBL Pediatric type follicular lymphoma Marginal zone lymphoma PTCL

72 anaplastic large cell Lymphoma (ALCL)

73 ALCL: molecular pathogenesis Genetics: t(2;5)(p23;q35) with NPM-ALK zentromer telomer Promotor recombination Promotor transcription / translation NPM-ALK fusion protein

74 NPM ALK P P P P P P P P P P Oligomerisation SHC IRS Grb2/Sos1 PLC Src NIPA PI3-K JAK3? JAK2? Ras DAG AKT STAT3 STAT5 Raf-1 PKC BAD Mek-1 ERK Bcl-XL PD-L1 (Chiarle et al., Nat Rev Ca 2008, Marzek et al, PNAS 2008) Cell growth Apoptosis Immune escape

75 Common Small cell lymphohistiocytic mixed

76 (Brugieres, Blood 98, Seidemann, Blood 01, Williams BJH 02, Mori BJH 03, Rosolen Cancer 05, Brugieres, JCO 09, Lamant JCO 10, Perkins BJH 05, Damm-Welk Blood 07, BJH 09, Abramov Haematol 13) ALCL: histopathology in children Histology common 65% small cell 6% ly-hist 2-3% mixed (sc/lh) 25% rare (HL, giant) 1-2% ALK-positivity 95% NPM-ALK (% ALK+) 90% 1 T cell marker >>95% Perforin, Granzyme B 95%

77 (Reiter, JCO 94, Brugieres, Blood 98, Seidemann, Blood 01, Woessmann, 03, Williams BJH 02, Mori BJH 03, Rosolen Cancer 05, Lowe PBC 09, Brugieres, JCO 09) ALCL: characteristics in children Age 10 y (0.3 18) Sex girls 40% boys 60% Stage I 5-10% (St Jude) II 20% III 60-65% IV 10% 30% 70%

78 (Reiter, JCO 94, Brugieres, Blood 98, Seidemann, Blood 01, Woessmann, 03, Williams BJH 02, Mori BJH 03, Rosolen Cancer 05, Lowe PBC 09, Brugieres, JCO 09) ALCL in children: involved sites Lymph nodes % Mediastinum % Skin % Bone % Lung % HSM / liver 20-30% Spleen 15-20% Soft tissue 10-20% Bone marrow 5-15% CNS 1-3 % B-symptoms %

79 (Reiter, JCO 94, Brugieres, Blood 98, Seidemann, Blood 01, Woessmann, 03, Williams BJH 02, Mori BJH 03, Rosolen Cancer 05, Lowe PBC 09, Brugieres, JCO 09) ALCL in children: involved sites Lymph nodes % Mediastinum % Skin % Bone % Lung % HSM / liver 20-30% Spleen 15-20% Soft tissue 10-20% Bone marrow 5-15% CNS 1-3 % B-symptoms % extranodal ~60% Fever 60%

80

81

82 BFM strategy: basic therapy plan 5-day courses, month of therapy P A B A B A B drugs Kumulative Dosis Dexamethasone 350 mg/m 2 Cyclophosphamide / Ifosfamide 3.4 / 12 g/m 2 MTX 6 x 3 g/m 2 over 3h Doxorubicine 150 mg/m 2 Ara C 12 x 150 mg/m 2 Etoposide 600 mg/m 2 (Reiter, JCO 1994, 1995, Seidemann, Blood 2001)

83 NHL-BFM 90: pefs (5 y.) (Seidemann, Blood 01)

84 Chemotherapy for ALCL Improvement by intensification? NHL-BFM 95 ALCL99 ANHL0131

85 NHL-BFM 95: Risk groups Branch Stage/resection HR* Therapy K1 I, II, complete - V-A-B-A K2 II incompl., III - V-A-B-A-B-A-B 45% of all pts K3 IV and/or + V-AA-BB-CC-AA-BB-CC *HR, involvement of skin or lung or lymphohistiocytic subtype or secondary ALCL

86 EFS (3y): HR-patients in NHL-BFM 95 versus 90 P , SE= , SE= NHL 90 (N= 36, 17 events) 0.1 NHL 95 (N= 42, 18 events) years

87 ALCL99 Basis: NHL-BFM 90 Stratification acc to clinical risk factors 2 questions: 1. MTX question (R1): 1 g/m 2, 24h + i.th. versus 3 g/m 2, 3h - i.th. 2. VBL questions (R2) for HR-pts: VBL 6 mg/m 2 per course + maintenance vs no VBL

88 ALCL99 R1: OS and EFS (2 y.) (Brugieres, JCO 09)

89 ALCL99 R1: pefs acc to therapy arm (Brugieres, JCO 09)

90 ALCL99 R2: pefs acc to therapy arm (LeDeley, JCO 10)

91 COG: ANHL0131 (Alexander, PBC 14)

92 ANHL0131: pefs acc to therapy arm (Alexander, PBC 14)

93 ALCL therapeutic strategies international Protocol Pts Courses (N) duration (mnths) CP/Ifo g/m 2 Doxo mg/m 2 drugs Eto g/m 2 (Lavers, JCO 05; Lowe, PBC 09; Brugieres, Blood 98, JCO 09, Pillon, PBC 12, Rosolen, Cancer 05; Seidemann, Blood 01, Williams, BJH 02, Alexander, PBC 14) MTX g/m 2 HM 90/ ,3 / ,2 3 (x6) BFM ,4 / ,6 0.5 (x6) ALCL ,4 / ,6 3 (x6) POG / LD CCG ,4 / ,8 1 (x7) ANHL In / LD LNH92 34 n.a. 24 7,5 / ,3 2,7 2 (x2)

94 ALCL therapeutic strategies: EFS Protocol Pts pefs/pfs (2-5y) HM 90 / ± 10% NHL-BFM ± 5% UKCCSG ± 12% ALCL ± 4% POG ± 6% CCG ± 11% ANHL0131 (COG) ± 7% LNH92 (AIEOP) ± 8% CHO(E)P (DSHNHL) ± 10% LNH87, 93, 98 (GELA) %xxx (Brugieres, Blood 98, JCO 09, Lavers, JCO 05; Lowe, PBC 09; Pillon, PBC 12, Rosolen, Cancer 05; Schmitz, Blood 10, Seidemann, Blood 01, Sibon, JCO 12, Williams, BJH 02, Alexander, PBC 14)

95 Summary chemotherapy for ALCL every aggressive regimen: pefs 65-75% independently of - duration - drugs - drug doses Current standard : ALCL99 (cumulative drug doses, shortest duration)

96 Summary chemotherapy for ALCL every aggressive regimen: pefs 65-75% Current standard : ALCL99 (cumulative drug doses, shortest duration) No improvement by intensification (BFM95, ALCL99, COG) OS 90% independently of front-line strategy

97 Conclusions chemotherapy pefs 65-75% with any chemotherapy Standard established (ALCL99: cumul doses, shortest time) Intensification w/o benefit (BFM95, ALCL99, ANHL0131) OS 90% independently of front-line strategy 30% inherent chemoresistance: new therapeutic modalities! 70% cure by toxic multiagent chemother. development of less toxic regimen.

98 New therapeutic options for ALCL? Lessons from ALCL-relapse therapies Lessons from phase I/II

99 ALCL: survival (5 y.) after relapse (NHL-BFM) (Woessmann et al., JCO 11)

100 Allogeneic SCT for consolidation in relapse? SFCE (93-11) allo-sct progr. TRM DFS/ EFS 34 18% (6) 24% (8) 58% (20) Japan (90-10) 24 28% 25% (5) 50% BFM (90-03) 21 10% (2) 15% (3) 75% (16) CIBMTR (90-05) 12 20% 34% 46% (Strullu et al, BMT 15, Mori et al, BJH 06, Fukano et al., BJH 15, Gross et al., BBMTR 10, Woessmann et al, BJH 06, JCO 11)

101 P Survival (5y) of ALCL relapse patients after allogeneic SCT ALCL-Relapse study, Progression during therapy or CD3-positive relapse 72±7% (N=45, 12 events) years (eicnhl, unpublished)

102 83% CR Vinblastine for ALCL relapse a French retrospective analysis CR 31 Pat. Vinblastine 36 Pat. (SFOP ) Nonresponse 5 Pat. VBL only (Median 14 m) 25 Pat. CCR 9 Pat. CCR 6 Pat. (Brugieres et al., JCO 09) relapse 16 Pat. VBL (Median 30 m) 7 Pat. SCT 6 Pat.

103 P EFS (5 y) of ALCL-relapse patients: Vinblastine monotherapy ALCL-Relapse study, Relapsed CD3 neg ALCL 1 year after dg 85±8% (N=21, 3 events) years (eicnhl, unpublished)

104 ALK-Inhibitor Crizotinib in a pt with ALCL Respons to Critzotinib in a 20y old man with refractory ALCL (Gambacorti ea, NEJM 11)

105 Crizotinib: best response in 26 children with relapsed ALK-positive ALCL (Mosse et al, Lancet Oncol 13; JCO 2017)

106 New therapeutic options Vinblastine ALK-Inhibitors Brentuximab Vedotin (immunotherapy)

107 Conclusions chemotherapy pefs 65-75% with any chemotherapy Standard established (ALCL99: cumul doses, shortest time) Intensification w/o benefit (BFM95, ALCL99, ANHL0131) OS 90% independently of front-line strategy 30% inherent chemoresistance: new therapeutic modalities! 70% cure by toxic multiagent chemother. development of less toxic regimen.

108 ALCL prognostic factors Clinical risk factors Histology Antibody titers against ALK Minimal disseminated disease (MDD) Minimal residual disease (MRD)

109 DFS (5y) acc to ALK-antibody titers (AIEOP + BFM) (n=128) (Mussolin et al., Leukemia 13)

110 EFS (5 y) acc to MDD (BM/PB-PCR for NPM-ALK) P (AIEOP + BFM, n=271) 0.83 ± 0.04 (N=118, 18 events) 0.55 ± 0.04 (N=153, 66 events) BM / PB PCR negative BM or PB PCR positive Log-Rank p = < years (AIEOP + BFM, update, unpublished)

111 MRD? qualitative PCR for NPM-ALK in BM/PB AIEOP + BFM ( ) NPM-ALK pos ALCL therapy P A B A B A B MDD (BM/PB) positive MRD vor Kurs 2 (BM/PB) (Damm-Welk et al, Blood 2014)

112 P EFS (5 J) acc to MRD before course 2 (AIEOP + BFM).81 ±.05 (n= 80, 13 events).69 ±.09 (n=26, 8 events) MDD-negative MDD-positive / MRD-negative MDD-positive / MRD-positive.19 ±.08 (n=26, 21 events) p: < years (Damm-Welk et al, Blood 2014)

113 ALCL studies Summary background EFS 65-75% with chemotherapy No improvement by intensification New therapeutic options: - ALK kinase inhibitors - Vinblastin ( new backbone ) - Brentuximab Vedotin Importance of ALK-Immunresponse for control Stratification in risk groups possible

114 Stratification acc to MDD Design of ALCL-studies for children and adolescents ALCL-VBL SR (40%) Vinblastine 24mo. Prephase VBL+Dex HR (60%) ALCL-ALK-I R ALCL 99 ALCL 99 + ALK-Inhibitor 24mo.

115 COG: ANHL12P1 (Lowe, 2014)

116 studies for children with ALCL Relapse Crizotinib (COG phase I/II closed) Brentuximab Vedotin (phase I/II closed) ITCC: Vinblastine + Crizotinib (2018) Nivolumab (start late 2018) Allogeneic SCT after reduced conditioning

117 ALCL - current status and outlook Standard ALCL99 chemotherapy: EFS 70% Front-Line trials in initiation: Vinblastine monotherapy (LR); ALK-inhibition + chemotherapy (HR) Relapse trials: VBL + Crizotinib; Nivolumab Importance of ALK-Immunresponse for control

118 Future vision: ALCL-therapy 2037 Safe debulking by Vinblastine / BV Induction of a deep remission by an ALK-inhibitor Consolidation according to individual immune response + MRD: - Vaccination with ALK-peptides - Patients without immune response: allogeneic SCT after reduced conditioning (alternative: PD1 inhibition?)

119 NHL-BFM study center B. Burkhardt S. Müller U. Meyer others NHL-BFM Laboratory C. Damm-Welk V. Singh F. Knoerr S. Stadler technicians Thank you for your attention Patients, parents, physicians, nurses, data managers of the of the NHL BFM study centers! Statistics: M. Zimmermann Reference Pathology: Hematopathology Kiel W. Klapper, I. Oschlies Other reference pathologists AIEOP: L. Mussolin, M. Pillon Forschungshilfe Peiper

120 NHL in children and adolescents Pathogenesis, clinical presentation, therapy Lymphoblastic lymphoma Mature B cell lymphoma Anaplastic large cell lympoma Rare NHL-Subtypes: PMLBL Pediatric type follicular lymphoma Marginal zone lymphoma PTCL

121 NHL in children and adolescents: Subtypes ped. type follicular Lymphoma 2% ALCL 12% PTCL 2% Marginal zone Lymphoma 3% Other 4% N= 1070 Burkitt Lymphoma/ Leukemia 36% T-LBL - 14% pb-lbl - 4% PMLBL 4% DLBCL 12% (NHL-BFM , unpublished) Mature B-NHL 6%

122 NHL in children and adolescents: Subtypes ped. type follicular Lymphoma 2% ALCL 12% PTCL 2% Marginal zone Lymphoma 3% Other 4% N= 1070 Burkitt Lymphoma/ Leukemia 36% T-LBL - 14% pb-lbl - 4% PMLBL 4% DLBCL 12% (NHL-BFM , unpublished) Mature B-NHL 6%

123 PMLBL - Introduction Histology: extensive sclerosis Immunohistochemistry: CD20, CD79a & Pax5 positive, (negative: CD15) often positive: CD23 (67%), CD30 (77%), Bcl-6 (97%) Molecular features: 9p- und 2p-aberrations in >40% Unique transcriptional signature (but smilarities to classical Hodgkin) Constitutive activation of NFkB + JAK-STAT-pathway Oschlies et al. 2011

124 PMLBL clinical characteristics adolescents + young adults girls > boys Mediastinal tumor! Typical localisations: thoracical: mediastinum, lung, pericardial-/ pleural effusion abdominal: kidney, liver/spleen, pancreas Oschlies et al. 2011

125 PMLBL Diagnosis Histopathology: PMLBL + Localisation: Thymus

126 PMLBL: EFS (5y) with BFM-type B-NHL therapy (Seidemann et al., Blood 2003)

127 PMLBL: EFS (5y) with LMB-type B-NHL therapy (Gerrard et al., Blood 2013)

128 DA-EPOCH-R (scheme) Dunleavy et al., Blood (ASH Annual Meeting) 2009

129 DA-EPOCH-R in adults Phase II-Studie: 51 erwachsene Pat. mit PMLBL (med. Alter 30y) 6 (-8) Kurse DA-EPOCH-R tolerable Toxizität, keine kardialen Spätfolgen bisher pefs 93% / pos 97% (med. follow-up 5y, range mo.) 2 Pat. wurden lokal bestrahlt retrospektive Studie (Stanford): 16 pts mit PMLBL und DA-EPOCH-R (med. Alter 33y), keine lokale Radiotherapie med. follow-up 37 Monate EFS und OS 100% Dunleavy et al., NEJM 2013

130 PMLBL: Therapy in the BFM-group : BFM-type therapy primär mediastinale B-NHL: Therapieplan LDH (U/l): < 500 MTX 1 g/m 2 über 24h V A 24 B 24 A 24 B 24 A 24 B 24 LDH (U/l): > 500 MTX 5 g/m 2 über 24h V AA 24 BB 24 CC AA 24 BB 24 CC BB 24 from 2010: DA-EPOCH-R Dunleavy et al., Blood (ASH Annual Meeting) 2009, NEJM 2013

131 PMLBL : EFS acc to treatment (BFM vs EPOCH-R) P , SE= , SE= 0.09 No EPOCH (N= 31, 13 events) EPOCH (N= 32, 4 events) Log-Rank p = years

132 PMLBL current status + outlook Diagnosis: Reference pathology + tumor within the thymus! DD: grey zone lymphoma, DLBCL, Hogdkin Current therapy in BFM: 6x DA-EPOCH-R Remnant post therapy: common, PET-positive; short-term follow-up necessary Relapse after EPOCH-R: PD1-blockage?

133 New options for PMLBL relapse? 9p-aberrations with PDL1-overexpression Phase 1 study of Pembrolizumab in 18 r/r PMLBL Zinzani et al., Blood 2017

134 NHL in children and adolescents: Subtypes ped. type follicular Lymphoma 2% ALCL 12% PTCL 2% Marginal zone Lymphoma 3% Other 4% N= 1070 Burkitt Lymphoma/ Leukemia 36% T-LBL - 14% pb-lbl - 4% PMLBL 4% DLBCL 12% (NHL-BFM , unpublished) Mature B-NHL 6%

135 Pediatric type follicular lymphoma (Oschlies et al., Haematologica 10)

136 Pediatric type follicular lymphoma BCL2 typical histopathology FL grade 3, high proliferation, less BCL2 typical genetic features no Translocation t(14;18) (IGH;BCL2). Alterations in TNFRSF14, 1p36, EZH2, MAP2K**, low genomic complexity. (Oschlies et al., Haemtologica 2010, Martin-Guerrero I. et al, Haematologiac 2013; Attarbaschi A. et al, Ann Hematol 2013 Schmidt J et al, Blood 2016; Louissant A. et al, Blood 2016, Swerdlow et al, Blood 2016)

137 Pediatric type follicular lymphoma (Attarbaschi et al., Ann Hematol 13)

138 Pediatric type follicular lymphoma (Attarbaschi, Ann Hematol 2013)

139 Pediatric type follicular lymphoma: New therapeutic recommendations Central Review after biopsy/surgery B-NHL BFM therapy Stage I Stage >I chemotherapy residual tumor chemotherapy B-NHL BFM therapy no yes Exceptions: pfl with IGH-, BCL2-, BCL6-, MYC- Transloctations DLBCL components additional surgery complete resection no wait and see yes

140 NHL in children and adolescents: Subtypes ped. type follicular Lymphoma 2% ALCL 12% PTCL 2% Marginal zone Lymphoma 3% Other 4% N= 1070 Burkitt Lymphoma/ Leukemia 36% T-LBL - 14% pb-lbl - 4% PMLBL 4% DLBCL 12% (NHL-BFM , unpublished) Mature B-NHL 6%

141 Marginal zone lymphoma in children/adolescents Extranodal: comparable to adults (MALT, glands) Pediatric nodal: 80% boys, 70-80% stage I/II (head + neck ) NHL-BFM (31 pts, 17 nodal, 11 extranodal 7 typical MALT): 23 pts with event or follow-up 24 months: 16 patients (70%) no systemic treatment after surgery 6 patients NHL-BFM therapy for mature B-NHL 1 patient rituximab monotherapy 4 relapses: all four patients are free of disease Tadesse-Heath et al., Am J Surg Path 2003, Rizzo et al, PBC 2010, Makarova et al., BJH 2017

142 Marginal zone lymphoma in children: EFS (5y) 100 (N=23) Event-free survival Years Makarova et al., BJH 2017

143 Marginal zone lymphoma in children: Survival (5y) 100 (N=23) Overall survival Years Makarova et al., BJH 2017

144 Summary: Pediatric nodal MZL 80% boys Mostly stage I/II in head + neck area Excellent outcome with chemotherapy, w&w after surgery with few relapses Future therapy? - w&w after complete surgery - rituximab monotherapy for relapse? - Chemotherapy only for stage III/IV

145 NHL in children and adolescents: Subtypes ped. type follicular Lymphoma 2% ALCL 12% PTCL 2% Marginal zone Lymphoma 3% Other 4% N= 1070 Burkitt Lymphoma/ Leukemia 36% T-LBL - 14% pb-lbl - 4% PMLBL 4% DLBCL 12% (NHL-BFM , unpublished) Mature B-NHL 6%

146 PTCL in children / adolescents Rare (2% of NHL) Subtypes: PTCL NOS 50-60% > NKT 20-30% > HSTCL 10-15% > SCPLTCL 10-15% (Hutchinson et al., PBC 08; Winsor et al, PBC 08, Kobayashi et al., PBC 10, Kontny et al., BJH 15)

147 NHL-BFM: ALCL-like therapy for PTCL Since

148 Event-free Survival (probability) NHL-BFM: EFS (5y) PTCL , SE=0.08 (N=38, 18 events) Time (years) Kontny et al, Brit J Haematol 2015

149 Overall Survival (probability) NHL-BFM: survival (5y) PTCL , SE=0.09 (N= 38, 15 events) Time (years) Kontny et al, Brit J Haematol 2015

150 Event-free Survival (probability) NHL-BFM: EFS (5y) of PTCL-NOS , SE=0.11 (N= 18, 7 events) Time (years) Kontny et al, Brit J Haematol 2014

151 PTCL in children / adolescents Rare (2% of NHL) Subtypes: PTCL NOS 50-60% > NKT 20-30% > HSTCL 10-15% > SCPLTCL 10-15% major DD: ALCL, ALPS, benign cutaneous lympho. Optimal first-line therapy not yet defined (ALL-type, ALCL-type?; NKT: SMILE) EFS and OS with chemo dependend on subtype: PTCL NOS 60% / 65% NKT / HSTCL 20% / 35% ( allosct in CR1) SCPLTCL 80% / >80% (Hutchinson et al., PBC 08; Winsor et al, PBC 08, Kobayashi et al., PBC 10, Kontny et al., BJH 15)

152 NHL-BFM study center B. Burkhardt S. Müller U. Meyer others NHL-BFM Laboratory C. Damm-Welk V. Singh F. Knoerr S. Stadler technicians Thank you for your attention Patients, parents, physicians, nurses, data managers of the of the NHL BFM study centers! Statistics: M. Zimmermann Reference Pathology: Hematopathology Kiel W. Klapper, I. Oschlies Other reference pathologists AIEOP: L. Mussolin, M. Pillon Forschungshilfe Peiper

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158 NHL - Therapie NHL-Subtypen + Therapiegruppen Therapiegruppe I: LBL Therapiegruppe II: B-NHL Therapiegruppe III: ALCL Adoleszente

159 100% 80% 60% 40% 20% histologische Subtypen nach Alter other ALCL PMLBL DLBCL-CB Burkitt/B-A pb-lbl 0% <15 years >= 15 years n = n = 218 T-LBL

160 EFS (5y) nach Alter + histologischem Subtyp 100% 80% 60% 40% 20% 0% T-LBL pb-lbl Burkitt / B-AL DLBCL- CB PMLBL <15 years >=15 years ALCL

161 DLBL: Risiko junge Frauen > 15 J. (pefs) P 1.0 male.95, SE= female.50, SE= Log-Rank p = male (N= 19, 1 event) years female (N= 10, 5 events)

162 EFS (5y) nach Alter + histologischem Subtyp 100% 80% 60% 40% 20% 0% T-LBL pb-lbl Burkitt / B-AL DLBCL- CB PMLBL <15 years >=15 years ALCL

163 Treatment Burden : Lymphoblastische Lymphome (Studie NHL-BFM 95) Patienten >15 Jahre (N = 35) Risiko- Pat. Cyc Ifo Doxo Eto LRT CRT Allo-HSCT gruppe % g/m² g/m² g/m² g/m² % Pat % Pat. % Pat SR MR % 0 HR % 0 LRT, Lokale Radiotherapie; CRT, Schädelbestrahlung

164 Treatment Burden : B-NHL/B-ALL (Studie NHL-BFM 95) Patienten >15 Jahre (N = 86) Pat. % Risikogruppe Ther- Kurse MTX g/m² Cyc g/m² Ifo g/m² Doxo g/m² Eto g/m² Auto-HSCT % Pat R x ,2 0 R x1 2, ,4 0 R x5 2, ,9 0 R x5 2, ,4 0

165 Treatment Burden : ALCL (Studie NHL-BFM 90) Patienten >15 Jahre (N = 86) Risiko Pat. Cyc Ifo Doxo Eto LRT CRT Auto-HSCT gruppe % g/m² g/m² g/m² g/m² % Pat % Pat. % Pat K1 10 1, , K2 73 3, , K3 17 2, ,3 0 1 % 0

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168 NHL-BFM Registry 2012 (06/ /2016) Follikuläres Lymphom 2% ALCL 12.5% PTCL 3% Marginalzonen Lymphom 3% Andere 3% NHL-BFM Registry 06/ /2016 N= 763; Burkitt Lymphom/ Leukämie 36% T-LBL - 14% pb-lbl - 4% PMLBL 4% DLBCL 11.5% Reifes B- NHL 6.5%

169 PMLBL Diagnose Histopathologie: PMLBL + Lokalisation: vorderes oberes Mediastinum = Thymusloge

170 PMLBL: Therapy in the BFM-group : BFM-type therapy primär mediastinale B-NHL: Therapieplan LDH (U/l): < 500 MTX 1 g/m 2 über 24h V A 24 B 24 A 24 B 24 A 24 B 24 LDH (U/l): > 500 MTX 5 g/m 2 über 24h V AA 24 BB 24 CC AA 24 BB 24 CC BB 24 from 2010: DA-EPOCH-R Dunleavy et al., Blood (ASH Annual Meeting) 2009, NEJM 2013

171 PMLBL : EFS acc to treatment (BFM vs EPOCH-R) P , SE= , SE= 0.09 No EPOCH (N= 31, 13 events) EPOCH (N= 32, 4 events) Log-Rank p = years

172 NHL-BFM Registry 2012 (06/ /2016) Follikuläres Lymphom 2% Marginalzonen Lymphom 3% Andere 3% N= 763; NHL-BFM Registry 06/ /2016 ALCL 12.5% PTCL 3% Burkitt Lymphom/ Leukämie 36% T-LBL - 14% pb-lbl - 4% PMLBL 4% DLBCL 11.5% Reifes B- NHL 6.5%

173 Pediatric type follicular lymphoma (Oschlies et al., Haematologica 10)

174 Pediatric follicular lymphoma BCL2 Typical Histopathology FL grade 3, high proliferation, less BCL2 Typical genetic features no Translocation t(14;18) (IGH;BCL2). Alterations in TNFRSF14, 1p36, EZH2, MAP2K**, low genomic complexity. (Oschlies et al., Haemtologica 2010, Martin-Guerrero I. et al, Haematologiac 2013; Attarbaschi A. et al, Ann Hematol 2013 Schmidt J et al, Blood 2016; Louissant A. et al, Blood 2016, Swerdlow et al, Blood 2016)

175 Pediatric follicular lymphoma (Attarbaschi et al., Ann Hematol 13)

176 Pediatric follicular lymphoma (Attarbaschi, Ann Hematol 2013)

177 WHO Klassifikation 2016

178 B-NHL - Stand + Ausblick EFS: R1/R2 95%, R3/R4 85%, ZNS 75%: - Einführung von Rituximab in R3/R4 - Ersatz von Chemotherapie durch Rituximab in R1/R2 Überleben im Rezidiv: Burkitt 20%, DLBCL 50% - Test neuer Substanzen (Ibrutinib) internat. Therapie für kleine Subgruppen: PMLBL (4%): DA-EPOCH-R pädiatr. follikuläre Lymphome: watch + wait

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180 T-LBL pb-lbl Burkitt DLBCL ALCL Zytologie Histologie Immunphänotyp Precursor T-Zellen (ca. 80%) Precursor B-Zellen (ca. 20%) Reife B-Zellen, Leichtkettenrestriktion κ/λ Reife B-Zellen Reife T-Zellen TdT CD20 - ± CD sig ± - CD10 ± ± + ± - CD ± + ALK Genetik p15/p16 NOTCH1 FBXW7 LOH6q t(8;14)(q24;q32) t(2;8)(p11;q24) t(8;22)(q24;q11) t(2;5)(p23;q35) t(1;2)(q21;p23) Zusätzlich seltenere Translokationen 2p23 betreffend

181 pb-lbl T-LBL Burkitt DLBCL PMLBL ALCL Typische Präsentation Lymphknotenschwellung, Hautpapel, Knochenlymphom Mediastinaltumor mit Einflussstauun g und/oder Luftnot Abdominaltumor, Darmwandtumor, einseitige Tonsillenhyperplasie Lymphknotenschwellung, Knochenlymphom, Abdominaltumor Mediastinaltumor Lymphknotenschwellung, Haut-befall, Knochenlymphom Befall von Körperregion (%) Kopf/Hals Mediastinum Abdomen Organbefall (%) ZNS KM Knochen Weichteile Haut Lunge Leber Milz Nieren B-Symptome (%) Stadien (%) I II III IV

182 Pädiatrische follikuläre Lymphome B-NHL BFM therapy Central Review after biopsy/operation Stage I Stage >I chemotherapy residual tumor chemotherapy B-NHL BFM therapy no yes Exceptions: pfl with IGH-, BCL2-, BCL6-, MYC- Transloctations DLBCL components additional surgery complete resection no wait and see yes