Role of nuclear medicine in diagnosis and treatment of systemic lymphomas

1. Role of Nuclear Medicine in
Systemic Lymphomas

2. • Introduction
• Classification
• Staging and prognostication
• FDG PET/CT in lymphoma
• RadioImmunoTherapy (RIT)
• Atypical Presentations

3. Introduction
• Lymphomas are a diverse group of
lymphoproliferative malignancies
• Carry a broad spectrum of clinical presentation,
prognosis and survival rates depending upon the
specific immunophenotype
• The field of nuclear medicine is constantly
evolving in defining the various aspects of
management of systemic lymphomas

4. Classification

5. WHO Classification

9. False +ve PET/CT in Lymphomas
Second primary
Thyroid adenoma
Rebound thymic hyperplasia
Infectious process
Toxoplasmosis
Inflammatory lung process
Benign follicular lymph node hyperplasia
Unspecific lymphadenitis
Granulomatous lymphadenitis
Sarcoidosis and sarcoid-like reaction
Granulation tissue

10. Staging: The evolution

11. Rye Classification (1965)
I Disease limited to 1 anatomic region or to 2 contiguous anatomic regions
on the same side of the diaphragm
II Disease in more than 2 anatomic regions or in 2 noncontiguous regions on
the same side of the diaphragm
III Disease on both sides of the diaphragm, but not extending beyond the
involvement of lymph nodes, spleen, and/or Waldeyer's ring
IV Involvement of any tissue or organ in addition to lymph nodes, spleen, or
Waldeyer‘s Ring

12. Ann Arbor Staging (1971)

13. Modified Ann Arbor (Cotswolds)
(1988)

14. Staging: NCCN v2014

15. REVISION OF ANN ARBOR STAGING (Lugano
Guidelines) (2014)

16. Prognostication: IPI

18. Prognostication: Interim PET
• Strong prognostic indicator in HL and
aggressive NHL ( specially DLBCL )
• Outperform I.P.I
• Visual inspection of iPET - high NPV
• iPET uptake < Liver - Good prognosis
• Trials underway for PET-adapted therapy

19. Response Evaluation

20. Flashback
• International Working Group (IWG) published reponse
evaluation criteria for Chronic lymphomas in 1999

21. NCCN Response Evaluation Criteria
(Non-PET) 1999

22. • The original response evaluation criteria included
CRu (Complete Response uncertain)
• It was not possible to determine whether residual
masses on CT scan were residual lymphoma, scar
tissue or nonmalignant process
• Advent of PET in early 2000’s changed the
scenario

23. • PET/CT helped in omission of the concept of
CRu by being able to identify between residual
disease and scar tissue
• Guidelines revised and updated as 2007 IHP
(Int’l Harmonization Project) guidelines which
is currently followed in most response
evaluation criteria

24. Revised NCCN Response Evaluation
Criteria (PET-based) 2007

25. Deauville PET Criteria: NCCN 2014
NCCN modification of Deauville
criteria:
1 – 5a: previously known lesions
5b: appearance of new lesions likely
to be due to lymphoma

31. Deauville Criteria: Impact on Rx
• The current NCCN guidelines (2014) have included
Deauville criteria in their algorithms involving management
of lymphomas
Deauville 5a and 5b
Biopsy recommended
Biopsy +ve Biopsy -ve
Treat as refractory
disease
Short-term follow-up
•PET/CT q3-6mth until Deauville 1-2
•No progression for ≥ 12mth

32. PET/CT before Bone Marrow Bx
• PET/CT has high sensitivity
– Low PPV
– High NPV ( exception – DLBCL )
• Lugano Guidelines: Only do Biopsy if FDG-
PET/CT is positive for bone marrow
involvement
Any extra-nodal FDG uptake is highly
suggestive of involvement

33. RadioImmunoTherapy

34. RadioImmunoTherapy
• Use of biological products such as mAbs with
radioactive components (RadioImmunoConjugates) to
target malignant cells
• Has been valuable in management of aggressive
lymphomas that present in remission
• Zevalin: approved in 2002; currently in use
• Bexxar: approved in 2003; withdrawn/stopped
production in 2012

35. RIT: Principle
Initial ‘cold/naked’ Antibody dose
‘Warm’ Antibody dose
‘Hot’ Antibody dose
clears the body of normal
b-cells so that subsequent doses will be
more focused on tumor cells
likely has antitumor
effects, but also helps calculate the
optimal and safe final dose (Bexxar)
•most potent anti-tumor effects
•focused on tumor cells

36. Mechanism of Action
• Inducing apoptosis, triggered by the binding of the
antibody to the cell receptor.
• Complement-dependent cytotoxicity (CDC) - where
antibody leads to fixing of complement by the immune
system.
• Antibody-dependent cellular cytotoxicity (ADCC) - where
effector cells (immune cells) kill antibody-engaged tumor
cells.
• Ionizing radiation from the radioisotope damages the
tumor cells, leading to cell death.
• Possible vaccine-like effect - leading to adaptive immunity
against cells that may survive initial treatment
- not proven but suggested by
the time to optimal response – as long as two years

38. Clinical Indicaitons
• Treatment of relapsed or refractory low grade, follicular, or transformed B-
cell NHL
• As second primary treatment, particularly following a short or insufficient
response to prior treatment
• As an alternative to stem cell transplantation (SCT), particularly if SCT is
indicated, but not suitable because of age or other factors
• As part of the conditioning therapy of SCT: Myeloablative RIT
• As an alternative to maintenance Rituximab
• When transformation is suspected and patient is not a candidate for SCT,
or combination chemotherapy (R-CHOP)

40. Eligibility Criteria
• resistant/refractory to
chemotherapy/immunochemotherapy
• no human anti-mAb Antibody (HAMA)
• positive CD20 malignant cells
• not more than 25% NHL involvement of the
bone marrow by biopsy

41. RIT: Exclusion Criteria
Patients with an increased likelihood of developing
hematological toxicity or patients with impaired bone
marrow reserve
• presence of > 25% infiltration of lymphoma cells within
the bone marrow
• prior history of EBRT to > 25% of the bone marrow
• baseline platelet counts < 100000/µl or neutrophil
counts < 1500/µl
Hypersensitivity to HAMA or chelating agents such as
tiuxetan

42. All patients require a bone marrow trephine
examination within 4–6 weeks prior to
treatment
• Patients with known active HIV infection, or
CNS lymphoma (insufficient data to confirm
safety of this approach)

43. • Patients who have progressed within 1 year of
radiation in a field that has previously been
irradiated
• Patients who are receiving other anticancer
drugs or biologics
• Prior chemotherapy must have been
discontinued for > 4 weeks

46. Expected Biodistribution
Count 1 (Day 0; within 1 hr of administration)
• Most of the activity is in the blood pool (heart and major
blood vessels).
• Uptake in normal liver and spleen is less than in the heart.
Count 2 (Day 2, 3, or 4) and Count 3 (Day 6 or 7)
• Activity in the blood pool decreases significantly.
• Decreased accumulation of activity in normal liver and
spleen
• Possible uptake present in thyroid, kidney, and urinary
bladder with minimal uptake in the lungs
• Possible increased intensity at known lymphoma sites

47. Altered Biodistribution
Count 1
• Blood pool is not visualized
• Diffuse, intense tracer uptake in the liver and/or spleen
• Uptake suggestive of urinary obstruction
• Diffuse uptake in normal lung > blood pool
Count 2 and Count 3:
• Uptake is suggestive of urinary obstruction
• Diffuse uptake in normal lung which is greater than that of
the blood pool
• Total body residence time is less than 50 hours
• Total body residence time is more than 150 hours

50. Therapy Dose Calculation
• Activity Hours: derived from patient mass and
reference tables
• Residence time: 37% of residual whole body
activity as derived from a semilog plot of
percent injected whole body activity

51. Zevalin
• 90Y-labeled ibritumomab tiuxetan (murine anti-
CD20 antibody)
• The radiometal and the mAb held together by an
acyclic bifunctional chelator viz DTPA
• 90Y: reactor produced
t1/2: 64hr
pure beta emitter; decays to 90Zr (Eβmax:
2.2 MeV)

52. 111In - Zevalin
• Chosen as surrogate to 90Y – Zevalin for
biodistribution and dosimetric purposes
• Comparable half-life (67 hr) and biodistribution
similar to 90Y-labelled molecule
• Decays by EC to 111Cd and emits principal
gamma photons of energies 173 keV (89%) and
247 keV (94%)

53. Zevalin

57. RIT: Results
ZEVALIN BEXXAR
ORR 73-83% 47-68%
CR 29-47% 20-33%
MEDIAN RESPONSE TIME 11-23mth 12-16mth

58. 90Y Epratuzumab: LymphoCide
• Currently in advanced clinical trials for treatment of
aggressive B-cell lymphomas in relapse
• 90Y-epratuzumab-(DOTA)-tetraxetan: targets CD22 on B-
cells
• Macrocyclic chelator (DOTA): more stable attachment;
enables administration of higher doses; prevents undue BM
toxicity
mAbs to CD22: internalized;
• Do not generate neutralizing Abs
• Improves tumor residence time of the nuclide

59. Lymphomas: Unusual Presentations

60. Neurolymphomatosis
• Uncommon syndrome of peripheral or cranial
nerve root dysfunction secondary to infiltration
by lymphoma
• Nearly always B-cell non-Hodgkin's lymphoma
• High index of suspicion is required as
presentation is varied (plexopathy, mononeuritis
multiplex, footdrop, radiculopathy and cranial
nerve palsies)

61. • conventional radiology has only modest
sensitivity, and pathological diagnosis is often
difficult
• PET/CT can play an important role in
diagnosing patients with high clinical suspicion
of NL when other conventional imaging
modalities are inconclusive

64. AIDS-related lymphomas
• Usually an AIDS-defining diagnosis in patients infected
with HIV
• Systemic lymphoma: 70 – 90 % (BL, DLBCL)
• Primary CNS lymphoma: 10 – 30 %
• Plasmablastic lymphoma and Primary Effusion
Lymphoma: more common in HIV + than HIV –
• PBL: oral cavity
• PEL: pleural, pericardial, peritoneal; HHV8 ± EBV

65. • Higher viral load and lower CD4 counts are
both risk factors for the development of NHL
• The risk of NHL substantial in patients with
- HIV RNA levels > 100,000 copies/mL
- CD4 counts < 50/mL (CNS lymphomas)

66. • PET/CT in conjunction with patient’s immunological
profile (viral load, CD4 count) helps to differentiate
between benign (HIV-associated) and malignant
(lymphomatous) LNP
• PET/CT may help guide treatment strategy and
minimize long-term toxicity in lymphoma patients with
HIV
• PET/CT can accurately depict the extent of lymphoma
in LNs of normal CT appearance (PET+/CT−)

67. CONCLUSION
• The role of diagnostic nuclear medicine is
currently constantly evolving in terms of
management of systemic lymphomas
• Nuclear medicine therapy with
radioimmunoconjugates has proven to be a
feasible option in treatment of aggressive
lymphomas that are refractory to
conventional treatment modalities

68. THANK YOU