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

3. 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),
Commentaries and reviews associated with the indications [lymphoma]
Illustrations

4. 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),

5. 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

6. 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]

7. 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

8. Staging – activity of lymphomas
Most lymphomas are FDG avid
% HD
% Diffuse Large Cell B Lymphomas (DLBCL)
% 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 When should FDG-PET be used in the modern management of lymphoma? BJH 164:
Barrington et al 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):

9. 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 When should FDG-PET be used in the modern management of lymphoma? BJH 164:
Follows et al for the British Committee for Standards in Haematology Guidelines for the first line management of classical Hodgkin Lymphoma Br J Haematol 166(1):34-49)
Cheson et al Recommendations for Initial Evaluation, Staging, and Response Assessment of Hodgkin and Non-Hodgkin Lymphoma: The Lugano Classification. JCO 32(27):

10. 54 year old male; Stage I HL clinically and on CT
SG RA

11. SG RA

12. SG RA

13. 16 year old female; new diagnosis of Hodgkin Lymphoma
EP RA

14. EP RA

15. 20 year old female; new diagnosis of HL
RY RA

16. RY RA

17. 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 RA

18. 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

19. 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 When should FDG-PET be used in the modern management of lymphoma? BJH 164:

20. 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 When should FDG-PET be used in the modern management of lymphoma? BJH 164:
Follows et al for the British Committee for Standards in Haematology. Guidelines for the first line management of classical Hodgkin Lymphoma Br J Haematol 166(1):34-49
Barrington et al 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):

21. 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 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 When should FDG-PET be used in the modern management of lymphoma? BJH 164:

22. 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 When should FDG-PET be used in the modern management of lymphoma? BJH 164:

23. 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 When should FDG-PET be used in the modern management of lymphoma? BJH 164:
Barrington et al 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):

24. 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 When should FDG-PET be used in the modern management of lymphoma? BJH 164:

25. 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 Report on the first international workshop on interim-PET scan in lymphoma. Leukemia and Lymphoma

26. 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 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):

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

28. 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 Report on the first international workshop on interim-PET scan in lymphoma. Leukemia and Lymphoma
Barrington SF and Mikhael NG When should FDG-PET be used in the modern management of lymphoma? BJH 164:
Follows et al for the British Committee for Standards in Haematology. Guidelines for the first line management of classical Hodgkin Lymphoma Br J Haematol 166(1):34-49
Andre et al Interim FDG-PET Scan in Hodgkin’s Lymphoma: Hopes and Caveats. Advances in Haematology 2011:1-6
Barrington et al 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):

29. 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 When should FDG-PET be used in the modern management of lymphoma? BJH 164:

30. 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]

31. 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 When should FDG-PET be used in the modern management of lymphoma? BJH 164:

32. 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 When should FDG-PET be used in the modern management of lymphoma? BJH 164:
Follows et al for the British Committee for Standards in Haematology. Guidelines for the first line management of classical Hodgkin Lymphoma Br J Haematol 166(1):34-49
Cheson et al Recommendations for Initial Evaluation, Staging, and Response Assessment of Hodgkin and Non-Hodgkin Lymphoma: The Lugano Classification. JCO 32(27):

33. 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]

34. 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

35. 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

36. 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

37. 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

39. 39

40. 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:
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