FOLLICULAR LYMPHOMA. BHS course: indolent lymphoma 7 th february Ann Janssens MD, PhD Hematology UZ Leuven

Transcription

1 FOLLICULAR LYMPHOMA BHS course: indolent lymphoma 7 th february 2015 Ann Janssens MD, PhD Hematology UZ Leuven

2 Non Hodgkin Lymphoma Epidemiology US Marginal Zone MALT 8 % Follicular 22 % 20% Incidence FL Europe 5-7/ % 10% Others 6 % SLL/ CLL type anaplastic T/null 8 % 5.3% 2 % 1.1% M age 67y M 52.5% B 83% T/ NK 5% NOS 12% Mantle Cell 6 % 4.8% Lyplasmocytic ly 1.4% DLBCL 35 % 39.2% T-AILD 0.8% Péripheral T cell 7 % 2% lymphoblastic 2 % Burkitt 1 % 2% Non Hodgkin s Lymphoma Classification Project, Blood 1997 Go et al. EHA 2014, abstract

3 WHO: B-cell neoplasms Precursor B-cell neoplasm B-ALL, lymfoblastenlymfoom Mature B-cell neoplasms B-cell chronic lymphocytic leukemia/small lymphocytic lymphoma B-cell prolymphocytic leukemia Lymphoplasmacytic lymphoma Splenic marginal zone B-cell lymphoma Hairy cell leukemia Plasma cell myeloma/plasmacytoma/mgus Extranodal marginal zone B-cell lymphoma (MALT) Nodal marginal zone B-cell lymphoma Follicular lymphoma Mantle cell lymphoma Diffuse large B-cell lymphoma Burkitt lymphoma/burkitt cell leukemia stage 3-4 at diagnosis 80% bone marrow invasion 50%

4 FL-cells are the malignant counterpart of normal germinal center B-cells

5 How to diagnose and stage a FL? Clinical data Personal history Clinical examination Blood examination Full blood count LDH 2 microglobulin HIV, hep B-C Histopathology Bone marrow/threphine Imaging

6 Diagnosis of FL on histopathology Lymph node biopsy Inguinal nodes not first choice due to reactive changes Cervical nodes are prefered A growing node is also prefered Fine needle aspiration DD reactive vs suspected H&N regio: DD epithelioma Core biopsy: no impression of Ln-strukture

7

8 FL immunohistochemistry CD20 Bcl-2 CD10

9 FL immunohistochemistry CD3 CD4 CD8

10 Follicular lymphoma: Grading Grade 1 Grade 2 Grade 3 Histological subtype Number of centroblasts/hpf Grade I 0 5 Grade II 6 15 Grade III > 15 Treat as a FL Grade IIIa Grade IIIb centrocytes still present centroblasts form solid sheets with no residual centrocytes Treat as a DLBCL

11 BONE MARROW EXAMINATION Bone marrow aspirate + biopsy + immunophenotyping + genetics For diagnosis or staging FL? Yes Unexplained cytopenia (disease related, autoimmune, drug related) Yes Confirming complete remission after treatment : Yes

12 Bone marrow infiltration in FL CD20

13 T(14;18) genetic hallmark of FL + additional genetic abnormalities

14 How to diagnose and stage CLL? Clinical data Personal history: most asympthomatic, only 5% reveal B-symptoms Clinical examination: 25% lymphadenopathies, 15% organomegaly Blood examination: leukocytosis due to a lymphocytosis Histopathology Bone marrow/threphine Imaging: - CT-scan neck, thorax, abdomen & pelvis - PET-CT

15 International prognostic index for follicular lymphoma ( FLIPI-index) Age :< of > 60 jaar Stage :I, II vs III, IV LDH :nl vs elevated Hb :> 12 vs <12 g/dl N of nodal sites :> 4 Number of Nodal sites > 4 LDH > normal Age > 60 N O L A S H Ann Arbor Stage III-IV Hemoglobin < 12

16 Follicular Lymphoma Survival according FLIPI-index 10 y OS 71% 51% 36% N= 1795 Solal-Celigny, P. et al. Blood 2004;104: Factors, n Risk Patients, % 5-Yr OS, % 10-Yr OS 0-1 Good Intermediate Poor

17

18 M, 51y, new diagnosis FL Male <60j Stage 4 Bone marrow + LDH nl Hb >12 B2 elevated T(14;18)+ FLIPI: 2 FLIPI2: 2

19 M, 60y, relapsing FL Male 60y Stage 4 Bone marrow + LDH nl Hb >12 B2 nl New Ln biopsy: FL grade 1-2 T(14;18)pos FLIPI: 2 FLIPI2: 1

20 Follicular lymphoma: Disease transformation Transformation to aggressive lymphoma in ±37% of patients in the 15y following diagnosis Lister, JCO, 2007

21 Probability of survival (%) Survival Patterns are Different for Indolent and Aggressive NHL 100 Indolent NHL (e.g. Follicular lymphoma) Aggressive NHL (e.g. Diffuse large B-cell lymphoma) Years The Non-Hodgkin s Lymphoma Classification Project. Blood 1997;89:

22 Treatment options for FL Radiotherapy Watchful waiting Chlorambucil, Cyclophosphamide High-dose therapy Kinase inhibitors Lenalidomide. Treatment modalities CIT= chemo + Mo Ab CVP CHOP Flu-combinations Bendamustine Monoclonal Ab

23 Follicular Lymphoma: Treatment stage I en II ( <3 nodi): involved field irradiation Stad III-IV: >60j en asymptomatisch Watch and wait 50% nood aan behandeling binnen de 24m 80 à 90% behandeld eerste 5 j ± 20% spontane remissies! Stad III-IV: <60j en >60j met symptomen Chlorambucil, CVP, CHOP, a-interferon Fludarabine en combinaties Rituximab, R-CVP of R-CHOP of R-FCM, Rituximab onderhoud Zevalin consolidatie Autologe transplantatie als consolidatie Allogene transplantatiediagnose

24 Radiotherapy for localised FL Involved field radiotherapy 37% relapse free at 20y (Macmanus et al) 50% stage I cured, 25% stage II (MDACC) PFS influenced by tumor size < or > 3 cm and stage I vs II Relapses possible even after 30y, however rare > 10y 2% in-field failure-rate at 20 years 85% of failures in out-of-field nodal sites Extended field radiotherapy-tli (stage III-IV) (excessive toxicity, > secondary cancers) IFRT with chemotherapy (eradication occult disease) + Chl, CVP, CHOP, TROG/ALLLG trial ongoing: Involved field RT Gy with or without R-CVP x 6 ( ongoing till 2022)

25 Treatment guidelines: stage 1-2 RT preferred treatment of localized FL (36) Gy (no difference between 24-45Gy), involved field No data that show that RT is better than other treatment modalities, also not observation (no prospective trials, only retrospective data, data acquired before the R-era) If RT toxicity outweights the potential benefits then observation is a reasonable alternative Hiddemann et al, Leukemia, 2014 Dreyling et al, ESMO guidelines, Ann Oncol 2014 Kuruvilla et al, Canadian guidelines FL 1st line, Clin Lymph Myeloma Leuk 2015

26 LymphoCare database FL stage 1: 27% IFRT 28% CIT 12% R 23% Other R+ IFRT N= 471 Only 206 staged with a bone marrow Friedberg JW et al., JCO, 2009 and

27 Follicular Lymfoma Treatment stage I en II ( <3 nodi): involved field bestraling Stage III-IV: asymptomatic or/and low tumor burden Watch and wait 50% in need for treatment <24mo 80 à 90% treated in the coming 5y ± 20% spontaneous remissions! Stage III-IV: <60j en >60j met symptomen Chlorambucil, CVP, CHOP, a-interferon Fludarabine en combinaties Rituximab, R-CVP of R-CHOP of R-FCM, Rituximab onderhoud Zevalin consolidatie Autologe transplantatie als consolidatie Allogene transplantatiediagnose

28 Wait and see if No systemic symptoms < 3 nodal sites no bulky nodes No splenomegaly >16cm No effusions No compressive symptoms No circulating lymphoma cells No cytopenia No rapid disease progression No renal infiltration No bone lesions No life treatening organ involvement Impairment of qol Induction of myelosuppression, fatigue, secondary leukemia Impairment of collection of stem cells Induction of tumor resistance? Increasing risk of transformation????

29 Before R era: W&W vs Chl 3 trials W &W vs Promace-MOPP W & W vs predimustin W&W vs IFN-a No gain in OS mttt: 2.6y At 10y: 19% not treated ( 40% of >70y) Higher risk of transformation if W&W??? Ardeshna et al, Lancet 2003

30 R-era: W&W vs R stage II-IV, non-bulky ( ) Ardeshna et al, Lancet Oncol, 2014

31 R-era: W&W vs R stage II-IV, non-bulky ( ) OS 3y W&W 94% R + MR 97% Will early treatment impair further treatment wit R or R- chemo? Improved psychological well-being in the R arms Time to chemo- or radiotherapy longer in the R-arm Ardeshna et al, Lancet Oncol, 2014

32 R-era: R with maintenance or retreatment Median follow-up: 4.5 y Till progression Kahl, JCO, 2014 Time to treatment failure identical

33 Low tumor burden GELF No systemic symptoms < 3 nodal sites of > 3cm no bulky nodes (< 7) No splenomegaly >16cm No vital organ compression No compressive symptoms > 5000 clonal lymphocytes No cytopenia Hb <10, plt <100000, PMN <1500 FLIPI low 17%, intermediate 47%, high 36% Kahl, JCO, 2014 GELF: Groupe pour l etude de lymphome folliculaire

34 2014 by American Society of Clinical Oncology Kahl B S et al. JCO 2014;32:

35 Treatment guidelines low tumor burden FL Observation if not fulfilling criteria for starting treatment according GELF-BLNI criteria If results of Ardeshna should be confirmed, R immediately as risk of relapse is reduced??? Hiddemann et al, Leukemia, 2014 Dreyling et al, ESMO guidelines, Ann Oncol 2014 Kuruvilla et al, Canadian guidelines FL 1st line, Clin Lymph Myeloma Leuk 2015

36 Follicular Lymphoma Treatment stad I en II ( <3 nodi): involved field bestraling ( relapsen mogelijk zelfs na 30j) Stad III-IV: >60j en asymptomatisch Watch and wait 50% nood aan behandeling binnen de 24m 80 à 90% behandeld eerste 5 j ± 20% spontane remissies! Stage III-IV: symptomatic and/or high tumor burden Chlorambucil, CVP, CHOP, a-interferon Fludarabine en combinaties, bendamustine Rituximab-chemo Rituximab maintenance Radio-immunotherapy (Zevalin) Autologeous transplantation Allogeneic transplantation

37 Marcus-trial: R-CVP vs CVP - PFS R-chemo is the standard of care for high tumor burden FL

38 Is one chemotherapeutic regimen better than another? R- CVP R- CHOP R-FM R- Benda

39 Primary Rituximab and MAintenance Study An intergroup international study co-ordinated by Untreated follicular NHL R-CVP 8 or R-CHOP 6 + 2R or R-FCM 6 + 2R or R-MCP 6 + 2R R A N D O M I Z E Rituximab maintenance 1 dose every 8 weeks for 24 months CR/PR Observation R-CHOP 74% R-CVP 23% R-FCM 3,5% PDs/SDs off study Salles G et al., JCO, 2011

40 pat enrolled National LymphoCare Study 80% at non academic sites Median age 61y F 52%, whites 91% Grade 1: 43%, grade 2: 29%, grade 3: 19% Stage I 17%, II 15%, III 29%, IV 37% Friedberg JW et al., JCO, 2009 and Initial Treatment Clincal trial 6% WW 18% Other 1% R-mono 14% XRT 5% Chemo 3% 500 pat grade 3: PFS & OS not significantly different between R-CHOP and R-CVP (median follow-up: 4.5 yrs) R-Chemo 53% R-CHOP 55% R-CVP 23.1% R-F 15.5% Other 6.4%

41 PFS in FL after 1st line treatment

42 Responses in FL according to 1 st line N= 534 M age 56 y treatment R-FM: more myelotoxicity and secondary malignancies TTF 3y OS R-CVP 46% 98% R-CHOP 64% 95% R-FM 61% 93% Federico, JCO, 2013

43 The Bright trial: BR vs RCVP/RCHOP in inhl and MCL Excluded: transformed disease, CLL-SLL, grade 3 FL Median age y inhl: BR 213, RCVP/CHOP 206 MCL BR 37, RCHOP 37% BR RCHOP RCVP ORR 97% 90% 83% CR 31% 23% 23% CR for BR or R-CVP/CHOP non inferior More nausea and emesis for BR, antiemetics equal Less neuropathy for BR Neutropenia > CHOP although more G-CSF use Lymphopenia > BR: 66 vs 33% Efficacy equal Toxicity different Flinn, ICML 2013, abstract 084

44

45

46

47

48 Treatment guidelines for FL with high tumor burden CIT except when chemotherapy is contraindicated F-based regimen no 1st line treatment due to toxicities No preference between R-CHOP, R-benda vs R- CVP Hiddemann et al, Leukemia, 2014 Dreyling et al, ESMO guidelines, Ann Oncol 2014 Kuruvilla et al, Canadian guidelines FL 1st line, Clin Lymph Myeloma Leuk 2015

49 after induction treatment consolidation maintenance? Radioimmunotherapy autosct R- maintenance

50 Median follow-up: 73 mo PFS 6y favors R-arm: 59.2 vs 42.7% (p<0.0001) Benefits seen in all 3 FLIPI groups, CR increased after 2y of maintenance No difference in OS Salles et al, Lancet, 2011

51 Maintenance after 1st line R new standard of maintenace after induction when >PR Expensive Toxic. More infections More neutropenia maintenance Re-treatment

52 Rituximab maintenance in FL Infection-related adverse events in patients with follicular lymphoma treated with rituximab maintenance compared with observation Hazard ratio 1.99 ( CI ) Vidal et al, JNCI 2009 Van Oers: gr 3-4 infections: 9.7% vs 2.4%

53 Duration of remission in patients with indolent NHL No Curative treatment available for advanced stages First course Second Third Fourth course Goal of treatment: effective and durable disease control (OS-PFS) with minimal toxiciy and maintaining qol Johnson et al. J Clin Oncol. 1995;13: Years Treatment No. Treated RR, % Duration, Yrs Survival, Yrs First Second Third Fourth

54 Maintenance R in folliculair lymfoom na tweede respons op CHOP of R-CHOP Van Oers et al., Blood, 2006

55 Considerations for subsequent therapy Age Comorbidities Candidate for transplant? Previous treatment(s) Period of previous remission Refractory to R-monotherapy or R-chemo Tolerance of previous treatments Fit or unfit? Patient s preference

56 But not all patients respond to R or R-chemo 1 st line R SD and/or progression R (Gela phase 2) 27% R (Ardeshna) 27% 25% 1st line R-chemo SD and/or progression R-CVP 20% R-CHOP < 10% R-MCP 10% R-Benda < 10% 15% >2nd line R-chemo SD and/or progression R-CHOP 30% R-FCM 30% 30%

57 And some relapse or progress during maintenance R + R maintenance 1st line 20% SD and/or progression R-CHOP + IFNa 20% EORTC 20981: R/3m/24m 30% at <2.5y GLSG: R/6m 20% at <15m 25% during upfront and 1th relapse treatment approximately 70% of patients with inhl become refractory to rituximab

58 Treatment options for rituximab refractory inhl Radioimmunotherapy Monoclonal antibodies Hematopoietic transplantation Chemotherapy: bendamustine New drugs??? Immunomodulatory agents B-cell receptor signalling inhibitors mtor pathway inhibitors Proteasoom inhitors Histose deacetylase inhibitors Apoptosis inducing agents BH3mimetics

59 RIT in R-refractory inhl 90 Y 90 Y 9o Y-ibrutumomab (Zevalin) N= 57 (54 FL) M age: 54y Median number of previous R/: 4 (1-9) 76% resistant to last chemo All no reponse or relapse <6m to R monotherapy 90 Y ORR (FL) 74% CR 15% TTP 6.8m TTP for responders 8.7m Witzig et al, JCO 2002, 20:

60 Bendamustine (Levact): active in R-refractory patients Relapsed/refractory indolent lymphoma 120 mg/m² d1-2 (n= 52) ORR 73%, CR 11%, remission duration 16m Relapsed/refractory indolent lymphoma: (n= 76), Refractory to R (61% FL ) ORR 77% CR 34%, response duration 9m (indolent) Alkylator refractory OR 66% R refractory indolent NHL (n=100) ( FL 62%) ORR 84% CR 32%, Respons duration 9.3m Cheson et al., JCO 2009

61 Autologeous stem cell transplantation Improve disease control with no impact on OS In RCT s longer PFS compared to control arm postremission IFN) but OS not changed ( chemo, Outcomes comparable if R before autotransplant Low transplant related mortality Transplant contamination by lymphoma (in vivo or ex vivo purging give better outcomes) 10-20% secondary malignancies ( 10% t-mn) Indications for autotx:??? go go patients (<70y without comorbidity) at first (???) relapse relapse within 24m after an anthracycline containing regimen No data on autotx in R-refractory patients If relapse <1y after treatment: dismal prognosis, candidate for allotx

62 Allogeneic stem cell transplantation The only curative treatment option for inhl! Advantages: Stem cells free of lymphoma and prior chemotherapy induced DNA damage Lower relapse rate Lower rate of secondary malignancies Graft vs lymphoma effect Plateau in relapses (20% at 3à 5y posttx) Disadvantages: Requirement of a HLA- matched donor TRM >20% (higher if chemo-r disease) cgvhd 50% RIC: better outcome >50y and more comorbidities Indications for allo Tx: No CR to upfront treatment Duration of response <2y Relapse after autologeous Tx, if bone marrow burden is high and disease is refractory but Better outcome if chemosensitive No data on allo Tx in R-refractory patients

63 Chemo-free treatment for FL Kinase inhibitors lenalidomide Monoclonals Optimize dose and shedule of rituximab Other anti-cd20 monoclonals Combine anticd20 with anticd22, 80, 74, 37 Combine with G- or GM-CSF, IL2, IL-12, IFN-a Lenalidomide Combine with rituximab ( more CR, more neutropenia) Combine with GA-101 (GALEN phase 1b) Target PD1-PDL1: pidilizumab ORR 19/35 with CR 14 Target CD137 (T), Kir (NK), CD47 (phagocytosis) Bcl2-inhibitors Kinase inhibitors: Idelalisib in double Refr FL: ORR 57%, mdor 12.5 mo Ibrutinib R/R FL: ORR 56%, PFS 1y 50%, with R, with BR Bcl-2 antagonists Monoclonal antibodies Educational session FL EH 2014, G. Salles,

64 Overall Survival (%) Improving Survival of Follicular NHL: Impact of Antibody-Based Therapy OS by Treatment 1990s-2000s s Year N Death Estimate CHOP + Mab % ProMace % CHOP % Years After Registration Reprinted with permission American Society of Clinical Oncology. All rights reserved. Fisher RI, et al. J Clin Oncol. 2005; 23: s

65 FOLLICULAR LYMPHOMA Easy to treat. difficult to cure