1. Revised Response Criteria for Malignant Lymphoma
Bruce D. Cheson, Beate Pfistner, Malik E. Juweid, Randy D. Gascoyne, Lena Specht, Sandra J. Horning,
Bertrand Coiffier, Richard I. Fisher, Anton Hagenbeek, Emanuele Zucca, Steven T. Rosen, Sigrid Stroobants,
T. Andrew Lister, Richard T. Hoppe, Martin Dreyling, Kensei Tobinai, Julie M. Vose, Joseph M. Connors,
Massimo Federico, and Volker Diehl
JOURNAL OF CLINICAL ONCOLOGY
VOLUME 25 NUMBER 5 FEBRUARY
R3 Lee Jae Yeon

2. INTRODUCTION International Working Group response criteria
(Cheson et al, J Clin Oncol 17:1244, 1999)
- Guidelines for response assessment and outcomes measurement
- limitations :
considerable inter- and intraobserver variation
Recommend technologies, such as gallium scans
misinterpretation, esp. application of
complete remission/unconfirmed (CRu)
not include assessment of extranodal disease
increased use of PET, immunohistochemistry(IHC),
flow cytometry

3. MODIFICATIONS OF THE IWG CRITERIA
International Harmonization Project was initiated by
the German Competence Network Malignant Lymphoma
1. PET
2. BM assessment

4. PET (1) using [18F] fluorodeoxyglucose (FDG)
Advantage
: ability to distinguish between viable tumor and necrosis or fibrosis
in residual mass present after treatment
Juweid et al
Integrated PET into the IWG criteria ,retrospective ,54 pts with DLBL NHL Tx with an anthracycline-based regimen
Increased num. of CR
eliminated the CRu category
enhanced the ability to discern the difference in PFS between CR and PR pts
 provided rationale for incorporating PET into revised criteria

5. PET (2) false positive vs false negative
rebound thymic hyperplasia, infection, inflammation, sarcoidosis, or brown fat
Diffusely increased bone marrow uptake
 often observed after Tx of hematopoietic growth factors
false-negative
d/t resolution of the equipment, technique
variability of FDG avidity among histologic subtypes

6. PET (3) Recommendations for the use of PET or PET/CT
curable
incurable

7. PET (4) PET for the post-treatment assessment
- DLBCL & HD  because CR required
- Incurable histologies ,
only if PET positive before Tx
if response rate ; primary end point of a clinical study
Timing of PET scans after Tx
- should not be performed for at least 3 weeks
- preferably 6 to 8 wks, after completion of Tx
 d/t Post-therapy inflammation:
CTx – 2wks , RTx/ CTx+RTx - >2~3 mon

8. PET (5) Definition of a positive PET Exceptions
; focal or diffuse FDG uptake above background in a location incompatible with normal anatomy or physiology,
without a specific standardized uptake value cutoff
Exceptions
mild and diffusely increased FDG uptake at the site of moderate- or large-sized masses with an intensity that is lower than or equal to the mediastinal blood pool
hepatic or splenic nodules 1.5 cm with FDG uptake lower than the surrounding liver/spleen uptake
diffusely increased bone marrow uptake within weeks after treatment

9. Bone Marrow Assessment
Restaging bone marrow exam
common, assess response to Tx
usual approach relies on morphologic assessment of the BM biopsy, and clot section
immunohistochemistry, flow cytometry, and polymerase chain reaction methodology
 largely ignored or underused
Recommendation for bone marrow response
: histologically normal bone marrows with a small (2%)
clonal B-cell population detected by flow cytometry
should be considered normal

10. Kappa & lambda light chains
Bone Marrow Assessment Immunohistochemistry has a clear role in the assessment of the bone marrow at diagnosis and restaging after therapy
Immunohistochemistry
Role in disease
CD 20+,CD3+
and morph nl BM
Harbor disease
CD5, cyclin D1, CD23, CD10, DBA44
Kappa & lambda light chains
Increase sencitivity of occult BM disease
- splenic marginal zone B-cell lymphomas
- subtypes of DLBCL (ie, intravascular LBCL
and HIV-related DLBCL)
CD5 , CD23
Indolent B-cell lymphomas and CLL
difficult distinction from reactive lymphoid aggregates and nodular partial remission
( because of the frequent admixture of reactive T cells )
Cyclin D1
Recognize subtle BM inv. of mantle-cell lymphoma
CD10
Recognize subtle BM inv. of follicular lymphoma

11. Bone Marrow Assessment Caution with Immunohistochemistry and flow cytometry when interpreting biopsies post-therapy for residual disease
Rituximab
: may lead false-negative interpretation of residual B-cell disease,
commercial anti-CD20 (L26) recognizes a cytoplasmic epitope of CD20, in contrast to the surface epitope recognized by rituximab.
use of another pan–B-cell antibody, CD79a recommended
Similar caution is required when interpreting CD20 flow
cytometric data for several months after therapy with rituximab, given that surface epitopes may be blocked

12. REVISED RESPONSE CRITERIA

13. CR Variably FDG-avid lymphomas/FDG avidity unknown :
all lymph nodes and nodal masses must have regressed on CT to nl size
- >1.5 cm before Tx  ≤1.5 cm greatest transv. diameter
~ 1.5 cm long axis & >1.0 cm short axis before Tx
 <1.0cm short axis after Tx
Splenic involvement : not always reliable
- spleen considered normal in size may still contain lymphoma
- an enlarged spleen d/t other cause ; variations in anatomy, blood vol.,
use of hematopoietic growth factors, or causes other than lympoma
(-) immunohistochemistry / (+) small population of clonal lymphocytes by
flow cytometry : will be considered a CR until data become available
demonstrating a clear difference in patient outcome

14. CRu
use of REVISED RESPONSE CRITERIA the above definition for CR and that below for PR eliminates the category of CRu

15. PR SPD : sum of the product of the diameters Nodes ;
- measurable in at least 2 perpendicular dimensions
- from disparate regions of the body
- include mediastinal and retroperitoneal areas of disease
whenever these sites are involved
Pt with CR and persistent morphologic BM involvement
 considered PR

16. Stable Disease

17. Relapsed Disease (after CR) /Progressive Disease(after PR, SD)
Abnormal LN : long axis >1.5cm ,regardless of the short axis
long axis 1.1 ~ 1.5 cm, if its short axis >1.0cm
LNs ≤1.0 * ≤ 1.0cm
 not considered as abnormal for relapse or progressive disease
new lung nodules in CT~ mostly benign.
therapeutic decision should not be made solely on the basis of
the PET without histologic confirmation
spleen  considered nodal disease

18. Fallow-Up evaluation
Good clinical judgment & careful history and physical examination are the most important
National Comprehensive Cancer Network recommendations for f/u of Pt with Hodgkin’s and NHL
Hodgkin’slymphoma in an initial CR
: every 2 to 4 months for 1 to 2 yrs
every 3 to 6 months for the next 3 to 5 yrs
annual after 5 yars
Follicular or other indolent histology lymphoma in a CR
: every 3 months for a year  every 3 to 6 months
DLBCL NHL: every 3 months for 2 yrs
 every 6 months for 3 yrs

19. END POINTS
PFS : - preferred in lymphoma clinical trials, esp.incurable histologic subtypes
- reflects tumor growth, interpretable earlier than overall survival
Event-free survival : useful in evaluating highly toxic Tx

20. Clinical benefits revised guidelines
 improve comparability among studies
 facilitate new agent development
 improved therapies for patients with lymphoma