Role of Nuclear Medicine in Systemic Lymphomas

• Introduction

• Classification

• Staging and prognostication

• FDG PET/CT in lymphoma

• RadioImmunoTherapy (RIT)

• Atypical Presentations

Introduction

• Lymphomas are a diverse group oflymphoproliferative malignancies

• Carry a broad spectrum of clinical presentation,prognosis and survival rates depending upon thespecific immunophenotype

• The field of nuclear medicine is constantlyevolving in defining the various aspects ofmanagement of systemic lymphomas

Classification

WHO Classification

False +ve PET/CT in Lymphomas

Second primaryThyroid adenomaRebound thymic hyperplasiaInfectious processToxoplasmosisInflammatory lung processBenign follicular lymph node hyperplasiaUnspecific lymphadenitisGranulomatous lymphadenitisSarcoidosis and sarcoid-like reactionGranulation tissue

Staging: The evolution

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

Ann Arbor Staging (1971)

Modified Ann Arbor (Cotswolds) (1988)

Staging: NCCN v2014

REVISION OF ANN ARBOR STAGING (LuganoGuidelines) (2014)

Prognostication: IPI

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

Response Evaluation

Flashback • International Working Group (IWG) published reponse

evaluation criteria for Chronic lymphomas in 1999

NCCN Response Evaluation Criteria (Non-PET) 1999

• 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, scartissue or nonmalignant process

• Advent of PET in early 2000’s changed the scenario

• PET/CT helped in omission of the concept ofCRu by being able to identify between residualdisease and scar tissue

• Guidelines revised and updated as 2007 IHP(Int’l Harmonization Project) guidelines whichis currently followed in most responseevaluation criteria

Revised NCCN Response Evaluation Criteria (PET-based) 2007

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

Deauville Criteria: Impact on Rx

• The current NCCN guidelines (2014) have includedDeauville criteria in their algorithms involving managementof 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

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

RadioImmunoTherapy

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

RIT: Principle

Initial ‘cold/naked’ Antibody dose

‘Warm’ Antibody dose

‘Hot’ Antibody dose

clears the body of normalb-cells so that subsequent doses will bemore focused on tumor cells

likely has antitumoreffects, but also helps calculate theoptimal and safe final dose (Bexxar)

•most potent anti-tumor effects •focused on tumor cells

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

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)

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

RIT: Exclusion Criteria

Patients with an increased likelihood of developinghematological toxicity or patients with impaired bonemarrow reserve

• presence of > 25% infiltration of lymphoma cells withinthe 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 astiuxetan

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)

• 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

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

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

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

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 producedt1/2: 64hrpure beta emitter; decays to 90Zr (Eβmax: 2.2 MeV)

111In - Zevalin

• Chosen as surrogate to 90Y – Zevalin forbiodistribution and dosimetric purposes

• Comparable half-life (67 hr) and biodistributionsimilar to 90Y-labelled molecule

• Decays by EC to 111Cd and emits principalgamma photons of energies 173 keV (89%) and247 keV (94%)

Zevalin

RIT: Results

ZEVALIN BEXXAR

ORR 73-83% 47-68%

CR 29-47% 20-33%

MEDIAN RESPONSE TIME 11-23mth 12-16mth

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

Lymphomas: Unusual Presentations

Neurolymphomatosis

• Uncommon syndrome of peripheral or cranialnerve root dysfunction secondary to infiltrationby lymphoma

• Nearly always B-cell non-Hodgkin's lymphoma

• High index of suspicion is required aspresentation is varied (plexopathy, mononeuritismultiplex, footdrop, radiculopathy and cranialnerve palsies)

• conventional radiology has only modestsensitivity, and pathological diagnosis is oftendifficult

• PET/CT can play an important role indiagnosing patients with high clinical suspicionof NL when other conventional imagingmodalities are inconclusive

AIDS-related lymphomas

• Usually an AIDS-defining diagnosis in patients infectedwith HIV

• Systemic lymphoma: 70 – 90 % (BL, DLBCL)• Primary CNS lymphoma: 10 – 30 %

• Plasmablastic lymphoma and Primary EffusionLymphoma: more common in HIV + than HIV –

• PBL: oral cavity• PEL: pleural, pericardial, peritoneal; HHV8 ± EBV

• 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)

• PET/CT in conjunction with patient’s immunologicalprofile (viral load, CD4 count) helps to differentiatebetween benign (HIV-associated) and malignant(lymphomatous) LNP

• PET/CT may help guide treatment strategy andminimize long-term toxicity in lymphoma patients with

HIV

• PET/CT can accurately depict the extent of lymphomain LNs of normal CT appearance (PET+/CT−)

CONCLUSION

• The role of diagnostic nuclear medicine iscurrently constantly evolving in terms ofmanagement of systemic lymphomas

• Nuclear medicine therapy withradioimmunoconjugates has proven to be afeasible option in treatment of aggressivelymphomas that are refractory toconventional treatment modalities

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