PET-CT scanning in Haematological malignancy Haematology SSG November 3rd 2015

PET-CT scanning in Haematological malignancy Evidence based indications for the use of PET-CT in the UK 2013, Intercollegiate Standing Committee on Nuclear Medicine (Royal College of Physicians & Royal College of Radiologists), https://www.rcplondon.ac.uk/sites/default/files/pet-ct_guidelines_2013.pdf Commentaries and reviews associated with the indications [lymphoma] Illustrations

Evidence based indications for the use of PET-CT in the UK 2013; Myeloma Assessment of apparently solitary plasmacytoma with ambiguous lytic lesions on skeletal survey Suspected relapse in non-secretory myeloma or predominant extramedullary disease Evidence based indications for the use of PET-CT in the UK 2013, Intercollegiate Standing Committee on Nuclear Medicine (RCP & RCR), https://www.rcplondon.ac.uk/sites/default/files/pet-ct_guidelines_2013.pdf

Evidence based indications for the use of PET-CT in the UK 2013; Lymphoma Staging Hodgkin’s disease (HD/HL) Aggressive non-Hodgkin Lymphoma (NHL) Early stage follicular lymphoma (FL) considered for radiotherapy Interim treatment response assessment HD and aggressive NHL after two cycles (if complete metabolic response [CMR] = Deauville 1 or 2 [Need Deauville paper/ref]; no need for end of treatment scan) End of treatment response assessment HD and aggressive NHL [unless CMR after two cycles] Evaluation of symptomatic suspected relapse [in FDG avid lymphoma] Assessment of response to second line (and subsequent) treatment for FDG avid lymphoma [implies baseline PET prior to second line and subsequent treament] Staging of suspected post transplant lymphoproliferative disorder (PTLD) Prior to bone marrow transplant to assess volume of disease and suitability for transplant [how is suitability assessed] Determination of extent and identification of suitable site for biopsy in low grade lymphoma with suspected high grade transformation

Evidence based indications for the use of PET-CT in the UK 2013; Lymphoma Staging Hodgkin’s disease (HD/HL) Aggressive non-Hodgkin Lymphoma (NHL) Early stage follicular lymphoma (FL) considered for radiotherapy Suspected post transplant lymphoproliferative disorder (PTLD) Determination of extent and identification of suitable site for biopsy in low grade lymphoma with suspected high grade transformation Treatment response assessment Interim HD and aggressive NHL after two cycles (if complete metabolic response [CMR] = Deauville 1 or 2 no need for end of treatment scan) End of treatment HD and aggressive NHL [unless CMR after two cycles] Other situations Assessment of response to second line (and subsequent) treatment for FDG avid lymphoma [implies baseline PET prior to second line and subsequent treament] Prior to bone marrow transplant to assess volume of disease and suitability for transplant [how is suitability assessed] Evaluation of symptomatic suspected relapse [in FDG avid lymphoma]

Evidence based indications for the use of PET-CT in the UK 2013; Lymphoma Staging Hodgkin’s disease (HD/HL) Aggressive non-Hodgkin Lymphoma (NHL) Early stage follicular lymphoma (FL) considered for radiotherapy Staging of suspected post transplant lymphoproliferative disorder (PTLD) Determination of extent and identification of suitable site for biopsy in low grade lymphoma with suspected high grade transformation

Staging – activity of lymphomas Most lymphomas are FDG avid 97 - 100% HD 97 - 100% Diffuse Large Cell B Lymphomas (DLBCL) 91 - 100% FL 100% uncommon aggressive lymphoma – Burkitt Lymphoma, Mantle Cell Lymphoma, aggressive T cell lymphoma (94 – 100%) Minority of lymphomas have variable activity Small Lymphocytic Lymphoma (50 – 83%), Extranodal Marginal Zone Lymphoma (54 – 67%), Skin Lymphoma Barrington SF and Mikhael NG 2014. When should FDG-PET be used in the modern management of lymphoma? BJH 164:315-328 Barrington et al 2014. Role of Imaging in the Staging and Response Assessment of Lymphoma: Consensus of the International Conference on Malignant Lymphomas Imaging Working Group. JCO 32(27):3048-57

Value of PET in staging lymphoma Higher sensitivity (small active nodes) and specificity (mildly enlarged indeterminate inactive nodes) than CT More accurate than CT for involved node and involved site RTC More often identifies extranodal disease than CT within bone, bone marrow, liver, spleen and occasionally peritoneum More sensitive for the detection of focal bone marrow activity than bone marrow biopsy in HD and aggressive NHL Baseline scans improve accuracy of subsequent response assessment (in 19 – 34% of cases) and reporter agreement Recommended routinely for staging FDG avid lymphomas Barrington SF and Mikhael NG 2014. When should FDG-PET be used in the modern management of lymphoma? BJH 164:315-328 Follows et al for the British Committee for Standards in Haematology 2014. Guidelines for the first line management of classical Hodgkin Lymphoma 2014. Br J Haematol 166(1):34-49) Cheson et al 2014. Recommendations for Initial Evaluation, Staging, and Response Assessment of Hodgkin and Non-Hodgkin Lymphoma: The Lugano Classification. JCO 32(27):3059-65

54 year old male; Stage I HL clinically and on CT SG RA76465706

SG RA76465706

SG RA76465706

16 year old female; new diagnosis of Hodgkin Lymphoma EP RA77454645 22 12 10

EP RA77454645 22 12 10

20 year old female; new diagnosis of HL RY RA77356427 14 11 08

RY RA77356427 14 11 08

Conclusion, this is hyperplastic and reactive haematopoietic tissue. Cellularity of the haematopoietic tissue is increased. There are increased number of megakaryocytes seen, which show normal morphology and distribution. There is increased myeloid activity present. Erythroid colonies are seen. There is no evidence of infiltration by Hodgkin lymphoma. Conclusion, this is hyperplastic and reactive haematopoietic tissue. RY RA77356427 14 11 08

Evidence based indications for the use of PET-CT in the UK 2013; Lymphoma Treatment response assessment Interim HD and aggressive NHL after two cycles If complete metabolic response (CMR) no need for end of treatment scan End of treatment HD and aggressive NHL (unless CMR after two cycles) Other situations Assessment of response to second line (and subsequent) treatment for FDG avid lymphoma Prior to bone marrow transplant to assess volume of disease and suitability for transplant

Value of interim PET (iPET) in lymphoma (post 2 or 3 cycles) Metabolic changes precede changes in tumour size hence PET allows earlier response assessment than CT Rapid reduction in activity associated with good prognosis in HL 5 year progression free survival (PFS) 92% with minimal residual activity/uptake (MRA/MRU) cf 39% with positive scan Does response enable decision to de-escalate or escalate treatment? Barrington SF and Mikhael NG 2014. When should FDG-PET be used in the modern management of lymphoma? BJH 164:315-328

Value of interim PET in lymphoma (post 2 or 3 cycles) Currently insufficient evidence to change standard treatment on the basis of an interim PET Useful to confirm response (cf poor or absent response early) May replace CT if a mid-treatment scan is indicated If complete metabolic response (CMR) there is no need to repeat at the end of treatment if the clinical course is uncomplicated Should always be interpreted in the context of the clinical situation, anticipated course of the disease and treatment regime ideally in a multidisciplinary setting Barrington SF and Mikhael NG 2014 . When should FDG-PET be used in the modern management of lymphoma? BJH 164:315-328 Follows et al for the British Committee for Standards in Haematology. Guidelines for the first line management of classical Hodgkin Lymphoma 2014. Br J Haematol 166(1):34-49 Barrington et al 2014. Role of Imaging in the Staging and Response Assessment of Lymphoma: Consensus of the International Conference on Malignant Lymphomas Imaging Working Group. JCO 32(27):3048-57

Value of interim PET in lymphoma (post 2 or 3 cycles) Interim and end of treatment PET potentially unhelpful following treatment with Rituximab 48 treated aggressive NHL, 9 post treatment PET +ve of which 8 were false +ve’s (1 LM –ve, 7 repeat scans –ve over 1 – 24/12). Positive areas require biopsy prior to further treatment; Rituximab appears to provoke non-specific PET +ve inflammatory changes in residual masses Han et al 2009. High incidence of false-positive PET scans in patients with aggressive non-Hodgkin’s lympoma treated with rituximab-containing regimens. Annals of Oncology 20(2):309-18 ? correct for this by measuring the change in SUV measured in the most active lesion before and after treatment > 66% after two (or 76 or 92%) defined as response some studies show correlation, others do not very sensitive to timing of post treatment scan and requires identical machine and calibration and patient state Barrington SF and Mikhael NG 2014 . When should FDG-PET be used in the modern management of lymphoma? BJH 164:315-328

Value of end of treatment PET in lymphoma To avoid false positives due to post-treatment inflammation do not scan until more than: 10/7 post chemotherapy 2/52 post GSF 3/12 after RTC Barrington SF and Mikhael NG 2014 . When should FDG-PET be used in the modern management of lymphoma? BJH 164:315-328

Value of end of treatment PET in lymphoma End of treatment scan to confirm remission is becoming standard of care in FDG avid lymphomas Assessment of residual soft tissue masses to confirm remission (-ve, hence avoiding eg consolidation radiotherapy) Direct biopsies (+ve areas) and potential further treatment (eg consolidation radiotherapy) Barrington SF and Mikhael NG 2014 . When should FDG-PET be used in the modern management of lymphoma? BJH 164:315-328 Barrington et al 2014. Role of Imaging in the Staging and Response Assessment of Lymphoma: Consensus of the International Conference on Malignant Lymphomas Imaging Working Group. JCO 32(27):3048-57

Value of end of treatment PET in lymphoma What is meant by –ve and +ve scans? More of a spectrum -ve MRU (MRA) +ve Defined using the Deauville scale (recommended) Barrington SF and Mikhael NG 2014 . When should FDG-PET be used in the modern management of lymphoma? BJH 164:315-328

Deauville criteria to describe interim PET appearances 1 No uptake 2 Uptake <= mediastinal blood pool 3 Uptake > mediastinum, <=liver 4 Uptake ‘moderately’ > liver 5 Uptake ‘markedly’ increased and/or new sites of disease Meignan et al 2009. Report on the first international workshop on interim-PET scan in lymphoma. Leukemia and Lymphoma 2009 1-4

5-PS after Deauville criteria to describe end of treatment and interim PET appearances 1 No uptake 2 Uptake <= mediastinal blood pool 3 Uptake > mediastinum, <=liver 4 Uptake ‘moderately’ > liver 5 Uptake ‘markedly’ increased and/or new sites of disease X New foci of activity unlikely to be related to the lymphoma Barrington et al 2014. Role of Imaging in the Staging and Response Assessment of Lymphoma: Consensus of the International Conference on Malignant Lymphomas Imaging Working Group. JCO 32(27):3048-57

Deauville (5-PS) scale 1-2 = -ve 4-5 = +ve 3 = MRU (MRA) Meignan et al 2009. Report on the first international workshop on interim-PET scan in lymphoma. Leukemia and Lymphoma 2009 1-4 Barrington SF and Mikhael NG 2014 . When should FDG-PET be used in the modern management of lymphoma? BJH 164:315-328 Follows et al for the British Committee for Standards in Haematology. Guidelines for the first line management of classical Hodgkin Lymphoma 2014. Br J Haematol 166(1):34-49

Deauville scale Significance of MRU (MRA, 3 on Deauville scale ie activity between mediastinal blood pool and liver) varies with different subtypes and stages Limited stage aggressive NHL and HL – PFS with –ve and MRU is similar (with standard treatment – ie no de-escalation) In advanced stage NHL – PFS worse with MRU than –ve Meignan et al 2009. Report on the first international workshop on interim-PET scan in lymphoma. Leukemia and Lymphoma 2009 1-4 Barrington SF and Mikhael NG 2014 . When should FDG-PET be used in the modern management of lymphoma? BJH 164:315-328 Follows et al for the British Committee for Standards in Haematology. Guidelines for the first line management of classical Hodgkin Lymphoma 2014. Br J Haematol 166(1):34-49 Andre et al 2011. Interim FDG-PET Scan in Hodgkin’s Lymphoma: Hopes and Caveats. Advances in Haematology 2011:1-6 Barrington et al 2014. Role of Imaging in the Staging and Response Assessment of Lymphoma: Consensus of the International Conference on Malignant Lymphomas Imaging Working Group. JCO 32(27):3048-57

Confounding factors on post treatment PET scans (potential false positives) Infection Inflammation Granulomatous disease Synchronous malignancy Physiological variants (thymus, brown fat, marrow hyperactivity) Artefacts of treatment (GSF, rituximab) Barrington SF and Mikhael NG 2014 . When should FDG-PET be used in the modern management of lymphoma? BJH 164:315-328

Evidence based indications for the use of PET-CT in the UK 2013; Lymphoma Treatment response assessment Other situations Assessment of response to second line (and subsequent) treatment for FDG avid lymphoma [implies baseline PET prior to second line and subsequent treatment] Prior to bone marrow transplant to assess volume of disease and suitability for transplant [how is suitability assessed] Evaluation of symptomatic suspected relapse [in FDG avid lymphoma]

Value of PET in pre-transplant assessment Following salvage treatment for refractory or relapsed disease: -ve scan (CMR) 71 – 82% PFS after autologous stem cell transplant (ASCT) +ve scan 23 – 41% PFS after ASCT hence may guide choice of treatment eg in HL patient with +ve scan might be offered allograft if suitable donor Barrington SF and Mikhael NG 2014 . When should FDG-PET be used in the modern management of lymphoma? BJH 164:315-328

Value of PET in surveillance No clear evidence to support use currently Risk of false positives (in excess of 20%) Effective radiation dose of PET-CT (low dose CT) 11 – 17 mSv c. 5 – 8 years background radiation c. same as diagnostic contrast CT (quoted as 16 mSv) Barrington SF and Mikhael NG 2014 . When should FDG-PET be used in the modern management of lymphoma? BJH 164:315-328 Follows et al for the British Committee for Standards in Haematology. Guidelines for the first line management of classical Hodgkin Lymphoma 2014. Br J Haematol 166(1):34-49 Cheson et al 2014. Recommendations for Initial Evaluation, Staging, and Response Assessment of Hodgkin and Non-Hodgkin Lymphoma: The Lugano Classification. JCO 32(27):3059-65

Evidence based indications for the use of PET-CT in the UK 2013; Lymphoma Staging Hodgkin’s disease (HD/HL) Aggressive non-Hodgkin Lymphoma (NHL) Early stage follicular lymphoma (FL) considered for radiotherapy Suspected post transplant lymphoproliferative disorder (PTLD) Determination of extent and identification of suitable site for biopsy in low grade lymphoma with suspected high grade transformation Treatment response assessment Interim HD and aggressive NHL after two cycles (if complete metabolic response [CMR] = Deauville 1 or 2 no need for end of treatment scan) End of treatment HD and aggressive NHL [unless CMR after two cycles] Other situations Assessment of response to second line (and subsequent) treatment for FDG avid lymphoma [implies baseline PET prior to second line and subsequent treament] Prior to bone marrow transplant to assess volume of disease and suitability for transplant [how is suitability assessed] Evaluation of symptomatic suspected relapse [in FDG avid lymphoma]

PET scanning in Lymphoma: Summary Pre-treatment Staging of FDG avid lymphomas To direct biopsy of suspected transformation in low grade lymphomas May avoid bone marrow biopsy in HL and DLBCL Radiotherapy planning in HL and DLBCL – better definition of radiotherapy volume, essential for techniques less than IFRT

PET scanning in Lymphoma: Summary During treatment (iPET) In HL and DLBCL more accurate monitoring of response than CT No evidence to modify treatment as yet, but useful to detect poor or no response early

PET scanning in Lymphoma: Summary Post-treatment End of treatment assessment in HL, DLBCL and FL (unless mid-treatment PET showing CMR) To confirm disease remission or to direct biopsy if residual disease is suspected

PET scanning in Lymphoma: Summary Post-treatment Not recommended for routine surveillance Evaluation of symptomatic suspected relapse [in FDG avid lymphoma] pre-transplant assessment in patients undergoing ASCT with HL or DLBCL – more accurate and prognostic than CT Staging and treatment response in second line (and subsequent) treatment in FDG avid lymphoma

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Value of PET in staging lymphoma – avoidance of marrow biopsy? HL 454 patients No stage I or II upstaged on Bx 83 PET +ve for marrow involvement 27 Bx +ve 22 – extranodal disease elsewhere on PET 5 – upstaged III – IV but no change in management Therefore biopsy did not change treatment in any patients El-Galaly et al 2012 JCO 30:4508-4514 Aggressive NHL 130 patients 33 PET +ve for marrow involvement 14 Bx +ve No patient classified as IV on Bx alone Therefore biopsy did not change stage in any patients Kahn et al 2013 Blood 122:61-67