Nuevas recomendaciones para la estadificación y evaluación de la respuesta al tratamiento de los linfomas: la clasificación de Lugano

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

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

Overall survival of patients with lymphoma N=2012 CLL/SL MALT LPL/Waldenström Follicular Mantle-cell Diffuse large B- cell Burkitt ALK+ ALCL Peripheral T-cell Clínic Barcelona, 2012

Staging Treatment Re-assessment

Linfomas Estudio inicial 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?

Response definitions CR PR SD Disappearance of all evidence of disease Regression of measurable disease and no new sites 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

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

The Lugano classification: why, when and who? 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)

Outline Staging criteria Imaging Tumor bulk Spleen and liver involvement Bone marrow Prognostic groups and treatment allocation Assessment of response Follow-up and outcome

Diagnosis of lymphomas 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)

Anatomic staging 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

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

Tumor bulk 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

Criteria for involvement of site Tissue site Clinical FDG avidity Test Positive finding Lymph nodes Palpable FDG-avid histologies PET-CT Increased FDG uptake Nonavid disease Spleen Palpable FDG-avid histologies Nonavid disease Liver Palpable FDG-avid histologies CT PET-CT CT PET-CT Unexplained node enlargement Diffuse uptake, solitary mass, miliary lesions, nodules >13 cm vertical length, mass, nodules Diffuse uptake, mass Nonavid disease CT 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 Cheson BD, J Clin Oncol 2014;32:3059-67

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) BM biopsy has been the gold-standard for decades High sensitivity of PET/CT for BM involvement Recommendation: Hodgkin s lymphoma: 18% focal skeletal lesions by PET/CT with only 6% BM infiltration by BM biopsy, in If a PET/CT all cases is with performed, disseminated a BM disease biopsy in by no PET/CT longer indicated DLBCL: for HL; PET/CT more sensitive than biopsy 27% of BM+, including 94% by PET/CT and 40% by biopsy Discordant histologies issue? A BM biopsy is only needed for DLBCL if the PET is negative and identifying a discordant histology is important Insufficient for patient data in management other histologies

PET/TC en la médula ósea Estandarizar la valoración de PET + o en la médula ósea BMO negativa Patrón Focal Patrón difuso: (definir umbral) PET + si la captación del patrón difuso > hígado Salaun PY; EJNM 2009;36:1813-21

2012 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

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

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

Bone marrow (BM) BM biopsy has been the gold-standard for decades High sensitivity of PET/CT for BM involvement Recommendation: Hodgkin s lymphoma: 18% focal skeletal lesions by PET/CT with only 6% BM infiltration by BM biopsy, in If a PET/CT all cases is with performed, disseminated a BM disease biopsy in by no PET/CT longer indicated DLBCL: for HL; PET/CT more sensitive than biopsy 27% of BM+, including 94% by PET/CT and 40% by biopsy Discordant histologies issue? A BM biopsy is only needed for DLBCL if the PET is negative and identifying a discordant histology is important Insufficient for patient data in management other histologies

Prognostic groups 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, 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 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 Single E lesions without nodal involvement Stage I or II nodal extend with limited contiguous E involvement n/a n/a Cheson BD, J Clin Oncol 2014;32:3059-67

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

Assessment of response (end-of-treatment) 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% Cheson BD, J Clin Oncol 2014;32:3059-67

Interpretation of PET/CT scans 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 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

Interpretation of PET/CT scans 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 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 CMR PET final tto CD 1,2,3 No mas tratamiento CMRr CD 1,2,3 Con masa residual PMR CD 4,5 Con masa residual No nuevas lesiones PMD CD 4,5 Mayor uptake Nuevas lesiones Biopsia PET en 3 meses PET Dual Point Biopsia si accesible Más tratamiento

CMR Cortesía del Dr. X. Setaín

FDG uptake < liver CMRr (retroperitoneal) Cortesía del Dr. X. Setaín

FDG inguinal > liver PMR Cortesía del Dr. X. Setaín

Menton 2012 Interim PET Validado para uso clínico Enfermedad de Hodgkin 400 ptes (IVS) 260 LDCG - B Criterios Deauville 5-PS Criterios Deauville 5-PS Negativo Positivo Negativo Positivo 1,2,3 4,5 Lesión < hígado Lesión > hígado 1,2,3 4,5 Lesión < hígado Lesión > hígado SUV > 66% SUV < 66%

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 CD 1,2,3 PMR CD 4,5 Uptake inferior al PET basal NMR/PMD CD 5 No cambios de uptake Nuevas lesiones CMRr CD 1,2,3 Con masa residual PMR CD 4,5 Con masa residual No nuevas lesiones PMD CD 4,5 Mayor uptake Nuevas lesiones

Cortesía del Dr. X. Setaín Varón de 68 a. LDCG-B estadio III-A masa voluminosa abdominal Tratamiento con R-CHOP x 6 PET inicial PET interim SUV PET inicial 12.5 SUV interim PET 2.6

Cortesía del Dr. X. Setaín PET inicial PET interim SUV interim PET lesión 2.6 SUV interim PET mediastino 2.2 Lesión > Mediastino Interim PET positivo No respondedor Mal pronóstico

Cortesía del Dr. X. Setaín PET inicial PET interim PET final QMT

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

SUV PET inicial 12.5 SUV interim PET 2.6 SUV 79% > 66% Interim PET negativo Respondedor Buen pronóstico Cortesía del Dr. X. Setaín

Follow-up and outcome 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 (falsepositive 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 Cheson BD, J Clin Oncol 2014;32:3059-67

Clasificación de Lugano: modificaciones más significativas 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