Nuevas recomendaciones para la estadificación y evaluación de la respuesta al tratamiento

de los linfomas: la clasificación de Lugano

Armando López-Guillermo Servicio de Hematología

Hospital Clínic Barcelona

VIII Curso GOTEL de formación en linfomas Málaga, 17-18 de abril de 2015

Diagnosis (histology, sometimes cytology) Staging Treatment (or not!) Re-assessment (“response to therapy”) Follow-up

Management of lymphomas

CLL/SL MALT LPL/Waldenström Follicular Mantle-cell Diffuse large B-cell Burkitt ALK+ ALCL Peripheral T-cell

Overall survival of patients with lymphoma

Clínic Barcelona, 2012

N=2012

Staging

Treatment Re-assessment

Anamnesis y exploración física Hemograma y estudio bioquímico del

suero (LDH y beta2-m) Biopsia medular Rx tórax TAC torácico, abdominal y pélvico PET/CT?

Linfomas

Estudio inicial

Response definitions

CR Disappearance of all evidence of disease

PR Regression of measurable disease and no new sites

SD Failure to attain CR/PR or PD

Relapsed disease or PD

Any new lesion or increase by >50% of previously involved sites from

nadir

Cheson et al, JCO 2007

Ann Arbor (1971) Cotswolds (1989) NCI criteria (1999) NCI criteria (PET/CT) (2007) Lugano classification (2014)

Staging in lymphomas

Purpose: “to modernize recommendations for evaluation, staging and response assessment of patients with lymphoma”

Authors: − Leading hematologists, oncologists, radiation oncologists,

pathologists, radiologists, and nuclear medicine physicians − Representing major international lymphoma clinical trials

groups and cancer centers

Development steps: − 11-ICML (2011) started the process − Clinical and imaging sub-committees worked during 2 years − Workshop at 12-ICML (2013) to present conclusions and

discuss main recommendations − Steering committee (lead by B. Cheson) wrote two

manuscripts (J Clin Oncol 2014;32:3048-67)

The Lugano classification: why, when and who?

Staging criteria − Imaging − Tumor bulk − Spleen and liver involvement − Bone marrow

Prognostic groups and treatment allocation Assessment of response Follow-up and outcome

Outline

Morphology, immunohistochemistry, flow cytometry, (and molecular studies when appropriate) reviewed by an experienced pathologist

Fine-needle aspirate inadequate for initial diagnosis

Incisional or excisional biopsy preferred; core-needle biopsy acceptable when not possible the others

Material for future research (with consent)

Diagnosis of lymphomas

Staging criteria − Imaging − Tumor bulk − Spleen and liver involvement − Bone marrow

Prognostic groups and treatment allocation Assessment of response Follow-up and outcome

Outline

Recommendations are for nodal lymphomas and all DLBCL (primary extranodal –CNS, skin- have specific guidelines)

Ann Arbor stage only as component of factors in prognostic indices

PET-CT for staging of routinely FDG-avid histologies (particularly in clinical trials) strongly recommended

CT preferred in FDG nonavid lymphomas All lymphomas are considered FDG-avid, except:

─ CLL/SLL ─ Lymphoplasmocytoid/Waldenström ─ Mycosis fungoides ─ Marginal zone lymphomas

Anatomic staging

SUV by histology

N SUV (mean) Burkitt 6 20.45 Diffuse large B-cell 48 15.55 Hodgkin 49 11.28 Peripheral T-cell 12 9.27 Mantle-cell 6 6.89 Follicular 43 7.47 CLL 22 2.60

Clínic Barcelona, 2008

Staging criteria − Imaging − Tumor bulk − Spleen and liver involvement − Bone marrow

Prognostic groups and treatment allocation Assessment of response Follow-up and outcome

Outline

A single nodal mass ≥10 cm or >1/3 of transthoracic diameter as determined by TAC is retained as definition of bulky disease for Hodgkin’s lymphoma

Chest x-ray not required

Variety of sizes have been suggested for non-Hodgkin’s lymphomas to define “bulky”

Recommendation: to record the longest measurement by CT

The term “X” no longer necessary

Tumor bulk

Staging criteria − Imaging − Tumor bulk − Spleen and liver involvement − Bone marrow

Prognostic groups and treatment allocation Assessment of response Follow-up and outcome

Outline

Criteria for involvement of site

Cheson BD, J Clin Oncol 2014;32:3059-67

Tissue site Clinical FDG avidity Test Positive finding Lymph nodes Palpable FDG-avid histologies

Nonavid disease

PET-CT CT

Increased FDG uptake Unexplained node enlargement

Spleen Palpable FDG-avid histologies Nonavid disease

PET-CT CT

Diffuse uptake, solitary mass, miliary lesions, nodules >13 cm vertical length, mass, nodules

Liver Palpable FDG-avid histologies Nonavid disease

PET-CT CT

Diffuse uptake, mass Nodules

CNS Signs, symptoms

CT MRI CSF ass.

Mass lession/s Leptomeningeal inv., mass Cytology, flow cytometry

Other Site dependent

PET-CT, biopsy

Lymphoma involvement

Staging criteria − Imaging − Tumor bulk − Spleen and liver involvement − Bone marrow

Prognostic groups and treatment allocation Assessment of response Follow-up and outcome

Outline

BM biopsy has been the gold-standard for decades

High sensitivity of PET/CT for BM involvement

Hodgkin’s lymphoma: 18% focal skeletal lesions by PET/CT with only 6% BM infiltration by BM biopsy, in all cases with disseminated disease by PET/CT

DLBCL: ─ PET/CT more sensitive than biopsy ─ 27% of BM+, including 94% by PET/CT and 40% by biopsy ─ Discordant histologies issue?

Insufficient data in other histologies

Bone marrow (BM)

BM biopsy has been the gold-standard for decades

High sensitivity of PET/CT for BM involvement

Hodgkin’s lymphoma: 18% focal skeletal lesions by PET/CT with only 6% BM infiltration by BM biopsy, in all cases with disseminated disease by PET/CT

DLBCL: ─ PET/CT more sensitive than biopsy ─ 27% of BM+, including 94% by PET/CT and 40% by biopsy ─ Discordant histologies issue?

Insufficient data in other histologies

Bone marrow (BM)

Recommendation: If a PET/CT is performed, a BM biopsy in no longer indicated for HL; A BM biopsy is only needed for DLBCL if the PET is negative and identifying a discordant histology is important for patient management

BMO negativa

Patrón difuso: (definir umbral) PET + si la captación del patrón difuso > hígado

Salaun PY; EJNM 2009;36:1813-21

Estandarizar la valoración de PET + o – en la médula ósea

Patrón Focal

PET/TC en la médula ósea

• 454 ptes EH (BMO y PET/TC) • BMO + 27 ptes (6%) Bibliografía 4-16%

– PET + 23 (85) – PET – 4 (15%) FN (estadios avanzados / BMO no cambió tto)

• BMO – 427 ptes – Todos los ptes en estadío I – II por PET (BMO -) – PET + focal 59 ptes (PET>BMO)

• EH – BMI > focal PET > BMO • Menton: EH estadificada con PET – BMO no necesaria • EH: patrón difuso asociado a hipereplenismo:

– Hiperplasia/infiltrado inflamatorio asociado a la EH y no infiltración por EH

2012

PET vs BMO en LDCG ?? Meta-análisis y revisión sistemática del EJNM

Estudios Nº Ptes Sensibilidad (%) Especificidad (%)

Kahn (2013) 130 94 100

Cortés (2013) 84 95 100

Berthet (2013) 133 94 99

Hong (2012) 89 70 100

Pelosi (2011) 120 84 100

Ribrag (2008) 43 89 100

GLOBAL 654 88 99

PET – BMO + = 3.1 % FN PET + BMO - = 12.5 %

PET - descarta infiltración de MO BMO podría evitarse Eur J Nucl Med 2013

LDCG controversia

• Clasificación histológica concordante o discordante • PET – Infiltración MO < 10% - 20% • Valor pronóstico BMO

– Khan et al. Blood 2013.

• Menton: – BMO si en LDCG – BMO L indolentes

PET BMO

BM biopsy has been the gold-standard for decades

High sensitivity of PET/CT for BM involvement

Hodgkin’s lymphoma: 18% focal skeletal lesions by PET/CT with only 6% BM infiltration by BM biopsy, in all cases with disseminated disease by PET/CT

DLBCL: ─ PET/CT more sensitive than biopsy ─ 27% of BM+, including 94% by PET/CT and 40% by biopsy ─ Discordant histologies issue?

Insufficient data in other histologies

Bone marrow (BM)

Recommendation: If a PET/CT is performed, a BM biopsy in no longer indicated for HL; A BM biopsy is only needed for DLBCL if the PET is negative and identifying a discordant histology is important for patient management

Staging criteria − Imaging − Tumor bulk − Spleen and liver involvement − Bone marrow

Prognostic groups and treatment allocation Assessment of response Follow-up and outcome

Outline

Ann Arbor staging less relevant in directing treatment

Specific prognostic scores for different histologies: IPI, FLIPI, MIPI, …

Prognostic groups

Ann Arbor staging less relevant in directing treatment

Specific prognostic scores for different histologies: IPI, FLIPI, MIPI, …

Prognostic groups

Revised staging system for primary nodal lymphomas Stage Involvement Extranodal (E) status

Limited I II

One node or a group of adjacent nodes 2 or more nodal groups on the same side of the diaphragm

Single E lesions without nodal involvement Stage I or II nodal extend with limited contiguous E involvement

II bulky II as above with “bulky” disease n/a

Advanced III IV

Nodes on both sides of diaphragm; nodes above diaphragm with spleen involvement Additional noncontiguous extralymphatic involvement

n/a n/a

Cheson BD, J Clin Oncol 2014;32:3059-67

Staging criteria − Imaging − Tumor bulk − Spleen and liver involvement − Bone marrow

Prognostic groups and treatment allocation Assessment of response Follow-up and outcome

Outline

Non Hodgkin’s lymphoma

CR[u]

“A large abdominal or mediastinal mass that undergoes greater than 50% reduction in size and remains stable for 2 to 4 months should not prevent classification as a CR given the absence of all other measurable disease.”

Coiffier, JCO 1989

End-of-treatment assessment is more accurate with PET/CT, especially in CRu or PR patients in HL, DLBCL and FL

PET/CT criteria eliminate CRu

PET/CT in HL: ─ Negative predictive value: 95-100%

─ Positive predictive value: >90%

PET/CT in DLBSL: ─ Negative predictive value: 80-100%

─ Positive predictive value: 50-100%

Assessment of response (end-of-treatment)

Cheson BD, J Clin Oncol 2014;32:3059-67

Five-point scale is recommended for reporting PET/CT; results should be interpreted in context of anticipated prognosis, clinical findings and other markers of response

Scores 1 and 2 represent complete metabolic response (CMR)

Score 3 also probably represents CMR in patients receiving standard treatment

Scores 4 or 5 with reduced uptake from baseline likely represents partial metabolic response, but at the end of treatment represents residual metabolic disease

Increase in FDG uptake to score 5, score 5 with no decrease in uptake, and new FDG-avid foci consistent with lymphoma represent treatment failure and/or progression

Interpretation of PET/CT scans

Barrington SF, J Clin Oncol 2014;32:3048-58

Guy’s and St Thomas’ Hospital, London

Criterios Deauville’s 5-PS: 1. No uptake 2. Uptake ≤ mediastinum 3. Uptake > mediastinum but ≤ liver 4. Uptake moderately more than liver, at any

site 5. Markedly increased uptake at any site and

new sites of disease

Five-point scale is recommended for reporting PET/CT; results should be interpreted in context of anticipated prognosis, clinical findings and other markers of response

Scores 1 and 2 represent complete metabolic response (CMR)

Score 3 also probably represents CMR in patients receiving standard treatment

Scores 4 or 5 with reduced uptake from baseline likely represents partial metabolic response, but at the end of treatment represents residual metabolic disease

Increase in FDG uptake to score 5, score 5 with no decrease in uptake, and new FDG-avid foci consistent with lymphoma represent treatment failure and/or progression

Interpretation of PET/CT scans

Barrington SF, J Clin Oncol 2014;32:3048-58

Criterios Deauville 5 PS CD 1,2,3 < hígado y CD 4,5 > hígado

Final tratamiento

Valoración PET final tto

CMR CMRr

CD 1,2,3 CD 1,2,3 Con masa residual

No mas tratamiento

PMR CD 4,5 Con masa residual No nuevas lesiones

Biopsia PET en 3 meses PET Dual Point

PMD CD 4,5 Mayor uptake Nuevas lesiones

Biopsia si accesible Más tratamiento

CMR

Cortesía del Dr. X. Setaín

Criterios Deauville 5 PS CD 1,2,3 < hígado y CD 4,5 > hígado

Final tratamiento

Valoración PET final tto

CMR CMRr

CD 1,2,3 CD 1,2,3 Con masa residual

No mas tratamiento

PMR CD 4,5 Con masa residual No nuevas lesiones

Biopsia PET en 3 meses PET Dual Point

PMD CD 4,5 Mayor uptake Nuevas lesiones

Biopsia si accesible Más tratamiento

FDG uptake < liver CMRr (retroperitoneal)

Cortesía del Dr. X. Setaín

Criterios Deauville 5 PS CD 1,2,3 < hígado y CD 4,5 > hígado

Final tratamiento

Valoración PET final tto

CMR CMRr

CD 1,2,3 CD 1,2,3 Con masa residual

No mas tratamiento

PMR CD 4,5 Con masa residual No nuevas lesiones

Biopsia PET en 3 meses PET Dual Point

PMD CD 4,5 Mayor uptake Nuevas lesiones

Biopsia si accesible Más tratamiento

FDG inguinal > liver PMR

Cortesía del Dr. X. Setaín

Criterios Deauville 5 PS CD 1,2,3 < hígado y CD 4,5 > hígado

Final tratamiento

Valoración PET final tto

CMR CMRr

CD 1,2,3 CD 1,2,3 Con masa residual

No mas tratamiento

PMR CD 4,5 Con masa residual No nuevas lesiones

Biopsia PET en 3 meses PET Dual Point

PMD CD 4,5 Mayor uptake Nuevas lesiones

Biopsia si accesible Más tratamiento

Menton 2012 Interim PET Validado para uso clínico

Enfermedad de Hodgkin 400 ptes (IVS) – 260 Criterios Deauville 5-PS Negativo Positivo 1,2,3 4,5 Lesión < hígado Lesión > hígado

∆SUV > 66% ∆SUV < 66%

LDCG - B Criterios Deauville 5-PS Negativo Positivo 1,2,3 4,5 Lesión < hígado Lesión > hígado

Criterios Deauville 5 PS CD 1,2,3 < hígado y CD 4,5 > hígado

Interim (2 ciclos) Final tratamiento

Valoración Interim PET Valoración PET final tto

CMR CD 1,2,3 CMR CMRr

CD 1,2,3 CD 1,2,3 Con masa residual

PMR CD 4,5 Uptake inferior al PET basal

PMR CD 4,5 Con masa residual No nuevas lesiones

NMR/PMD CD 5 No cambios de uptake Nuevas lesiones

PMD CD 4,5 Mayor uptake Nuevas lesiones

SUV PET inicial 12.5 SUV interim PET 2.6

PET inicial PET interim

Varón de 68 a. LDCG-B estadio III-A masa voluminosa abdominal Tratamiento con R-CHOP x 6

Cortesía del Dr. X. Setaín

SUV interim PET lesión 2.6 SUV interim PET mediastino 2.2 Lesión > Mediastino Interim PET positivo No respondedor Mal pronóstico

PET inicial PET interim

Cortesía del Dr. X. Setaín

PET inicial

PET final QMT

PET interim

Cortesía del Dr. X. Setaín

SUV interim PET lesión 2.6 SUV interim PET hígado 2.8 Lesión < Hígado Interim PET negativo Respondedor Buen pronóstico

Cortesía del Dr. X. Setaín

SUV PET inicial 12.5 SUV interim PET 2.6

∆ SUV 79% > 66% Interim PET negativo Respondedor Buen pronóstico

Cortesía del Dr. X. Setaín

Staging criteria − Imaging − Tumor bulk − Spleen and liver involvement − Bone marrow

Prognostic groups and treatment allocation Assessment of response Follow-up and outcome

Outline

Good clinical judgment, a careful history, and physical examination are the cornerstone of patient follow-up

Specific guidelines available for the follow-up of the different lymphoma subtypes

Published studies fail to support routine surveillance scans (false-positive rate with PET is >20%)

RECOMMENDATIONS

─ Surveillance scans after remission are discouraged, especially for DLBCL and HL, although a repeat study may be considered after equivocal findings after treatment

─ Judicious use of follow-up scans may be considered in indolent lymphomas with residual intra-abdominal or retroperitoneal disease

Follow-up and outcome

Cheson BD, J Clin Oncol 2014;32:3059-67

“Simplificación “ de Ann Arbor

La biopsia medular deja de ser imprescindible en el estudio de extensión del linfoma de Hodgkin y el linfoma difuso de células grandes

PET/CT como prueba estándar para la mayoría de linfomas (excepto LLC, Waldenström, micosis fungoides y linfomas marginales)

El sistema de 5 puntos de Deauville como criterio estándar de valoración de respuesta

Clasificación de Lugano: modificaciones más significativas