1. Assessing Response in Malignant Lymphoma Lieselot Brepoels Sigrid Stroobants UZ Gasthuisberg, Leuven, Belgium

2. Introduction  Wide range of pathobiologically distinct diseases (REAL/WHO classification) 1. Hodgkin’s disease/lymphoma 1. Hodgkin’s disease/lymphoma 2. Non-Hodgkin’s lymphoma 2. Non-Hodgkin’s lymphoma  Difficulties: Multiple sitesMultiple sites Different entities have different FDG avidity, different clinical behaviour, different treatment modalitiesDifferent entities have different FDG avidity, different clinical behaviour, different treatment modalities Working diagnosis -“Aggressive” subtypes - “Indolent” subtypes

3. Classification of lymphoma (WHO-classification) Hodgkin's Lymphoma (Hodgkin's Disease) (B Cell Origin) a.Nodular lymphocyte predominance Hodgkin's lymphoma b.Classical Hodgkin's lymphoma Nodular sclerosis Hodgkin's lymphoma Lymphocyte-rich classical Hodgkin's lymphoma Mixed cellularity Hodgkin's lymphoma Lymphocyte depletion Hodgkin's lymphoma B-Cell Neoplasms I. Precursor B-cell neoplasm: a. Precursor B-lymphoblastic leukemia/lymphoma II. Mature (peripheral) B-cell neoplasms a.B-cell chronic lymphocytic leukemia / small lymphocytic lymphoma small lymphocytic lymphoma b.B-cell prolymphocytic leukemia c.Lymphoplasmacytic lymphoma d.Splenic marginal zone B-cell lymphoma (+/- villous lymphocytes) e.Nodal marginal zone lymphoma (+/- monocytoid B-cells) f.Extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT) type mucosa-associated lymphoid tissue (MALT) type g.Hairy cell leuekmia h.Plasma cell myeloma/plasmacytoma i.Follicular lymphoma, follicle center j.Mantle cell lymphoma k.Diffuse large cell B-cell lymphoma Mediastinal large B-cell lymphoma Mediastinal large B-cell lymphoma Intravascular large B-cell lymphoma Intravascular large B-cell lymphoma Primary effusion lymphoma Primary effusion lymphoma l.Burkitt's lymphoma/Burkitt's cell leukemia B-cell proliferations of uncertain malignant potential Lymphomatoid granulomatosis Post-transplant lymphoproliferative disorder Childhood lymphoma lymphoblastic lymphoma (30%) Burkitt's lymphoma (40%) Anaplastic Large Cell Lymphoma (10%) large B-cell lymphoma (20%) T-Cell and Natural Killer Cell Neoplasms I. Precursor T cell neoplasm: a. Precursor T-lymphoblastic lymphoma/leukemia a. Precursor T-lymphoblastic lymphoma/leukemia b. Blastic NK lymphoma b. Blastic NK lymphoma II. Mature (peripheral) T cell and NK-cell neoplasms a. T cell prolymphocytic leukemia b. T-cell granular lymphocytic leukemia c. Aggressive NK Cell leukemia d. Adult T cell lymphoma/leukemia (HTLV1+) e. Extranodal NK/T-cell lymphoma, nasal type f. Enteropathy-type T-cell lymphoma g. Hepatosplenic gamma-delta T-cell lymphoma h. Subcutaneous panniculitis-like T-cell lymphoma i. Mycosis fungoides/Sézary's syndrome j. Primary Cutaneous Anaplastic large cell lymphoma T/null cell k. Peripheral T cell lymphoma, unspecified l. Angioimmunoblastic T cell lymphoma m.Primary Systemic Anaplastic large cell lymphoma, T/null cell T-cell proliferation of uncertain malignant potential Lymphomatoid papulosis Lymphomatoid papulosis Lymphomas by Location Central Nervous System (CNS) Lymphoma Lymphoma of Bone Eyelid Lymphoma (new) Digestive Tract Lymphoma Ocular (Eye) Lymphoma (new) Working diagnosis (NHL) -“Aggressive” subtypes: fast progression, potentially curable -“Indolent” subtypes: slow progression, considered incurable

4. Positron emission tomography 511 KeV 180 o + - 18 F > 60 min45 min Injection FDG fasting No glucose containing infuses start scan from pelvis upto head

5. Metabolic imaging: FDG tumor model Glucose 6-phosphatase Glucose 6-phosphatase Hexokinase Glycolytic pathway FDG D-glucose G6P FDG-6-P Glucose 6-phosphatase Glucose 6-phosphatase Hexokinase Glycolytic pathway G6P FDG-6-P Normal cell Tumor cell (inflammatory cells) standardized uptake value (SUV)= FDG-uptake/g in a lesion Injected dose/weight

6. Indication for FDG-PET in Lymphoma  Staging and restaging after treatment Revised reponse criteria IWC+PET Revised reponse criteria IWC+PET  PET as a prognostic marker early during treatment

7.  Residual masses at the end of therapy are frequent (70% HD, 50% NHL) (70% HD, 50% NHL) but only a minority of pts relapse (<20% HD, 25% NHL)  late toxic effects of treatment are increasingly recognized  Patients in apparent complete remission also relapse  Early treatment of residual disease may improve survival End-of-treatment PET in Lymphoma Need for an accurate and sensitive tool to detect residual disease

8. AuthorYearNumbersensitivityspecificityaccuracyPPVNPVMedian follow-up of patients%%%(months) Naumann 20014310093 2510035 Heultenschmidt 200147958991869620 Spaepen 20016050100921009132 Dittman 2001248894928894>6 Weihrauch 200128678076608428 de Wit 200137916974469626 Lavely 200320 ns8136 Guay 200348799792 16 Jerusalem 200336100818310094>36 Friedberg 200432808584509624 Panizo 20042910085907510028 Rigacci 20052810083865010045 Abbreviations: PPV: positive predictive value; NPV: negative predictive value PET for evaluation of residual disease in Hodgkin’s Lymphoma

9. Systematic review Zijlstra et al, Haematologica 2006 NHL sub-analysis, n=201 End-of-treatment PET in NHL

10. New Revised Response Criteria in Lymphoma  Aim = Revision of the 1999 guidelines (CT-based) for response assessment and outcome measurements 1. Standardization of PET-response 2. Update of CT-based guidelines 3. Combination of PET and CT-results International Harmonisation Working Group Juweid et al, JCO February 2007 Bruce Cheson et al., JCO February 2007

11. PET in Lymphoma standardization and interpretation  Image acquisition for PET and PET/CT  Image interpretation PET+ = uptake > local background and incompatible with normal anatomy/physiology PET+ = uptake > local background and incompatible with normal anatomy/physiology Exception: Exception: residual mass > 2 cm, uptake ≤ mediastinal BG = PET negativeresidual mass > 2 cm, uptake ≤ mediastinal BG = PET negative additional guidelines additional guidelines Liver and SpleenLiver and Spleen Diffuse uptake in spleen is positive if > liver uptake Diffuse uptake in spleen is positive if > liver uptake Focal lesions > 1.5 cm must appear photopenic to be PET negative Focal lesions > 1.5 cm must appear photopenic to be PET negative Bone marrowBone marrow Focal higher than BG (no BMB+ necessary to confirm involvement) Focal higher than BG (no BMB+ necessary to confirm involvement) Juweid et al, JCO February 2007

12. Positivity on PET? residual mass > 2 cm residual mass > 2 cm uptake ≤ mediastinal BG = PET negative = PET negative residual mass < 2 cm uptake > local BG = PET positive

13. AB C D Increased FDG-uptake in the spleen in 4 patients with Hodgkin’s Lymphoma (HL). While patient A is a classical example of diffusely increased FDG-uptake in an enlarged spleen, patient B presented with a normal sized spleen with only slightly increased FDG-uptake compared to liver uptake. Both patients had diffuse splenic involvement by HL. Focal lesions in the spleen were seen in patient C, which were caused by lymphoma involvement. Although patient D was initially thought to have residual disease in the spleen based on a heterogenous uptake, microscopic examination showed only arguments for extramedullary hematopoiesis. Assessment of splenic involvement

14. Combination of PET and CT IWC+PET criteria PR if > 50% reduction in SPD SD if < 50% reduction in SPD PD or Relapse if new lesion or > 50% increase of a known lesion Only adviced for end-of-treatment evaluation in routinely FDG-avid and potentially curable lymphoma ! CR regardless of response on CT CT + - PET Cheson et al, JCO February 2007 IWC Cheson et al. JCO 1999 CRu if > 75% reduction in SPD

15. Patiënt 1 Patiënt 2 PR (SPD – 55%) CRu (SPD – 84%)

16. IWC+PET in Hodgkin’s Lymphoma Brepoels, Stroobants et al. 2007 Data Spaepen, Br J Haematol. 2001 Updated and IWC + PET response in 56 pts with Hodgkin’s lymphoma PET at the end of first line R/ (after additional radiotherapy)

17. IWC+PET in Aggressive NHL CR CRu PR SD PD IWC PR IWC+PET CR SDPD Brepoels, Stroobants et al., 2007 Data Spaepen, JCO 2000 PET after first line R/ Updated and IWC + PET response in 55 pts with routinely FDG-avid and potentially curable (aggressive) NHL

18. No additional value of IWC+PET in Indolent NHL ? Brepoels, Stroobants et al., 2007 Data Spaepen, JCO 2000 PET after first line R/ Updated and IWC + PET response in 14 pts with not-routinely FDG-avid and incurable NHL (8 FL, 4 MCL, 2 MZL)

19. FDG uptake and grading Schöder et al. JCO 2005 Aggressive N=63 DLBCL 55 FL gr III 7 PTCL 1 Indolent N=28 FL gr I 11 FL gr II 4 MZL 4 small cell 8 13

20. FDG uptake and grading Schöder et al. JCO 2005 MCL: -Tendency to relapse - PET presentation as indolent - agressive disease course

21. MCL-BV (median SUV 16.88) versus common MCL (median 6.79) (p=0.00006). Staging of Mantle cell lymphoma

22. Response criteria in MCL? CT-based criteria (IHP) CR: disappearance of all detectable disease PR: decrease > 50% SPD SD: decrease < 50% SPD PD: new lesion or >50% SPD PET-based criteria (EORTC) CMR: PET negative PMR: SUV decrease > 25% SMD: SUV decrease < 25% PMD: SUV increase >25% or new lesion IWC+PET criteria CR: everything if PET negative PR/SD/PD idem as CT-based criteria if PET is positive

23. Additional value of IWC+PET in MCL ? Different response categories have different prognosis No prognostic difference between responders Non-responders are the same as with CT alone

24. Additional value of IWC+PET in MCL ?

25.  Use of IWC+PET criteria  essential at the end of treatment in routinely FDG-avid and potentially curable lymphoma (DLBCL and HD)  Limitations  Only recommended for end-of-treatment evaluation  value has to be established in the other histological subtypes, no encouraging results in Mantle cell lymphoma  Only assessment of negative or positive on PET, no quantitative evaluation of response ! Revised Response Criteria in Lymphoma

26. PET as a prognostic marker early during therapy  A substantial number of patients are not cured with standard chemotherapy  early change of therapy might improve outcome  Late treatment related morbidity and mortality especially after combination chemoradiation  reduce therapy without compromising outcome Individualized patient management - risk adapted - response adapted

27. 4x CHOP-R 8 x CHOP-R prior 1x CHOP-R Early Response Assessment

28. Early PET in HL Hutchings et al, Blood 2005 Prospective study, 77 pts, 48 stage I/II PET after 2 cycles

29. Prognostic value of PET for early response assessment during first line or induction treatment AuthorYearNumberhistologytiming PETsensitivityspecificityaccuracyPPVNPVFollow-up of patients (cycles)%%%(months) Jerusalem200028NHL2-542100731006717 Mikhaeel200023NHL2-410094968810024 Mikhaeel200232HD2-375100941009236 Kostakoglu200230HD/NHL187 19 Spaepen200270NHL3-485100911008436 Zijlstra200326NHL264756975 25 Torizuka200420HD/NHL1-2875080875024 Friedberg200422HD3809491809424 Haioun200590NHL2637168557724 Mikhaeel2005121NHL2-3 5-year PFS of 16.2% when PET+, 88.8% when PET-, 59.3% for MRU Hutchings200585HD2-3 5-year PFS of 38.5% when PET+, 91.5% when PET-, MRU considered PET- Hutchings200677HD2799290699523 Gallamini2006108HD2869895909720 Abbreviations: PPV: positive predictive value; NPV: negative predictive value, HD: Hodgkin's disease; NHL: Non-Hodgkin's lymphoma; PFS: progression- free survival; PET+: PET positive; PET-: PET negative; MRU: minimal residual uptake Early Response Assessment by PET Optimal timing? Definition of PET response (quantification)?

30. Baseline PET-CT PET-CT after 1 cycle CHOP-R Timing of early PET?? Need for quantification The patient with DLBCL obtained a complete remission on PET after 3 cycles of CHOP and is still progression free after 16 months follow-up  very early after initiation of therapy: need for quantification???  very early after initiation of therapy: need for quantification???

31. Baseline PET-CT Timing of early PET?? Need for quantification The patient became clinical progressive during treatment and died of lymphoma only 3 months after initial diagnosis.  very early after initiation of therapy: need for quantification???  very early after initiation of therapy: need for quantification??? PET-CT after 1 week CHOP-R

32. Cycles of chemo Chemosensitivity Chemoresistance Number of malignant cells Time Time of diagnosis Start chemotherapy Symptoms Death PET-detection

33. Quantification of early PET?   Hutchings, Blood 2005 SUVmax = 4 is optimal? HD after 2-3 cycles  Kostakoglu, Cancer 2006 SUVmax = 1.75 (sens 92%, spec 84%) SUVmax = 1.75 (sens 92%, spec 84%) HD/DLBCL after 1 cycle  Torizuka, EJNM 2004 Decrease SUV of -60% Decrease SUV of -60% HD/NHL after 1-2 cycles

34. PET after 1 week CHOP-R in DLBCL (29 patients)  Prospective study Newly diagnosed DLBCL Newly diagnosed DLBCL PET after 7 days CHOP-R PET after 7 days CHOP-R  12 patients negative on early PET  12/12 disease free after a median follow- up of 19 months Figure V.1. Complete remission on early FDG-PET. (A) Pretreatment PET/CT shows an intense FDG-avide lesion left hilair. (B) Early PET/CT shows a slighly increased FDG-uptake but not exceeding mediastinal blood pool uptake. Also an important response is seen on CT. (C) Interim and (D) end-of-treatment PET/CT show persistent complete remission. This patient is in sustained complete remission after 30 months follow-up

35. PET after 1 week CHOP-R in DLBCL (29 patients)  17 patients positive on early PET  2/17 refractory disease  2/17 relapsed (12, 23 mts) Residual FDG-uptake on early PET Patient A never obtained a complete remission and refractory disease was histologically proven based on end- of-treatment PET/CT

36. PET after 1 week CHOP-R in DLBCL (29 patients)  17 patients positive on early PET  13/17 disease free after a median follow- up of 20 months  Quantification???? No significant difference in absolute uptake values No significant difference in absolute uptake values High variability in percentage decrease High variability in percentage decrease (B) Despite a significant residual uptake on early PET, this patient obtained a complete remission at interim PET, and is still disease free after a follow-up of 29 months

38. PET after 1 week of therapy  early PET: sensitivity 100%, specificity 48%, NPV 100%, PPV 24% sensitivity 100%, specificity 48%, NPV 100%, PPV 24%  Negative on early PET: excellent prognosis, reduction of therapy?  Positive on early PET: low specificity, quantification not better than visual interpretation

39.  Persistent FDG uptake after 2-3 cycles of chemo is associated with a high probability of relapse at the end of treatment Early PET response is a stronger predictor of PFS than IPI or IPS  Optimal timing? Definition of PET response (quantification)? PET for Early Therapy response: Conclusion

40. Conclusions  PET for RESIDUAL DISEASE in aggressive NHL and HL  IWC+PET for end-of-treatment evaluation  Persistent FDG uptake after a 2-3 cycles of chemo is associated with a high probability of relapse  PET for measuring CHEMOSENSITIVITY in the other histological subtypes: IWC+PET criteria not recommended in MCL  Early PET at more early time points and Optimal timing? Definition of PET response (quantification)?  Will PET-adapted treatment improve overall survival? (Dann, Blood 2007, PET after 2 cycles in HL, reduction of cumulative dose of chemotherapy without impairment of outcome.) !!!! Need for prospective trials !!!! Need for prospective trials Baseline PET Early PET Chemo A Chemo B PFS & OS