Lyfe Forum of excellence 2016 What's new in Lymphoyd neoplasia? IOSI course, Bellinzona, 29-31 January 2016 LYMPHOMA PROGNOSTIC INDEXES AND EMERGING NEW BIOMARKERS DR. STEFANO LUMINARI ASSOCIATE PROFESSOR OF MEDICAL ONCOLOGY UNIVERSITY OF MODENA AND REGGIO EMILIA HEMATOLOGY, AZ. OSP. SANTA MARIA NUOVA REGGIO EMILIA, ITALY
Outline Definitions and methodology issues in prognostic studies Prognostic scores in malignant lymphoma Diffuse large B cell lymphomas Follicular lymphomas Will not discuss: Hodgkin lymphoma, Mantle cell Lymphomas (1), Other indolent lymphomas (2-4), Peripheral T-cell lymphomas (1):MIPI: Hoster et al Blood 2008; (2) SMZL-IPI Arcaini et al. Blood 2006;(3) MALT: Zucca et al. Blood 2004 (4) Morel et al blood 2009
Prognostic score/index To estimate a given risk by combining together single risk/prognostic factors, each independently correlated with that risk
Prognostic score/index A prognostic score defines, for each patient, a specific risk: To die for the disease To have a bad response to therapy To have a short DFS To stay free of therapy (W&W) To transfrom into aggressive NHL..
Utility of prognostic scores Improve knowledge Choose therapy Assess treatment activity Understand and compare results of clinical studies
A good prognostic score Easy to remember and to assess Mirror clinical practice Validated Stable under different conditions Be univocal in the allocation of risk Be clinically useful Low risk: less toxicity Intermediate risk: standard therapy High risk: investigational therapies
Prognosis is an «evolving» science Evolution of Classification systems Evolution of therapies. New drugs, new labels Identification of New prognostic factors (biomarkers)
Patient related prognostic factors Unrelated to lymphoma Age Sex Comorbidities Individual innate features Related to lymphoma B Symptoms Performance Status Serum albumin levels
Lymphoma related prognostic factors QUANTITY of disease Stage Disease sites (EN vs LN, n. of sites.) Tumor size (i.e. Bulky) Serum LDH or B2 microglobulin levels Cytopenias (Hb, WBC, Plt) QUALITY of disease Histology Grading Biology (tumor and microenvironement)
FDG-PET/CT metrics Tumor SUVmax of the patient Total Metabolic Tumor Volume (TMTV) TMTV = MTV of all lesions % SUVmax threshold methods (41% most used) absolute SUVmax threshold method Total Lesion Glycolysis (TLG) MTV x meansuv SUVmax % reduction patient tumor SUVmax (between PET baseline and PET after treatment)
TMTV0 in HL prediction PFS 4y PFS=85% TMTV0 225ml 4y PFS=42% P= 0.001 TMTV0 >225ml 57 HL patients Stage III/IV = 63%,MFu= 50 months Kanoun S et al, EJNM 2014, 41:1735-43
OS according to TMTV0 in DLBCL TMTV 550ml n=78 93% 84% 78% 59% TMTV>550ml n=36 P = 0.0003 3-y OS : 87% vs 60% P = 0.01 TMTV quartiles 114 pts DLBCL, 5 centers, 3 observers inclusions 2003-2010, med F-U 39 months Sasanelli, EJNMMI 2014
Baseline TMTV prognostic value Follicular Lymphoma n = 81 (fused PET-CT images) 2y PFS 83% 2y PFS 45% TMTV mean = 462 median = 303 range 1-2401 AUC 0.63 Cut-off TMTV >938cm 3 12/81 (15%) HR = 4 Population with SUV max >13.7 n=21 all had MTV <938cm 3 Of the 12 patients: 9 had stage IV disease 9 in int-high FLIPI group more nodal sites bulk >7cm % similar in both groups Trotman et al Menton 2014
PFS/OS according to TMTV0 in PTCL 2y PFS=71% 2y PFS=26% 2y OS=80% 2y OS=50% 108 patients PTCL-NOS, ALCL, AITL nodal presentation MFU=23 months AS.Cottereau 2016, Ann Oncol in pr
Pros Prognostic biomarkers Describe pathogenesis Are also targets of therapy «Drive» response to therapy Cons Low reproducibility/costs Pros and cons Are not stable with different therapies Most data still come from old therapies (no R) Once found they are used as targets to correct the adverse outcome (diagnostic Markers!!)
Overall survival curve based on lymphoma associated macrophage content P Farinha et al., 2005
Prognostic role of Macrophage content in patients with FL treated with R-CHOP Taskinen, M. et al. Clin Cancer Res 2007;13:5784-5789 Copyright 2007 American Association for Cancer Research
Treatment related prognostic factors Drugs Available drugs/combinations Approved labels Response to therapy FDG/PET scan Molecular response
Response to therapy as prognostic factor This is not a typical prognostic factor With the use of FDG/PET, early metabolic changes were associated with different outcome in most lymphomas (HL, DLBCL, FL,..) The early use of FDG/PET for response assessment makes the assessment of prognosis a dynamic process
DIFFUSE LARGE B-CELL LYMPHOMA
International Prognostic Index (IPI) All ages Age >60 years PS 2 LDH elevated >1 extranodal site Ann Arbor stage III-IV Patients 60 years (IPI ageadjusted) PS 2 LDH elevated Ann Arbor stage III-IV All ages Low 0-1 Low-intermediate 2 High-intermediate 3 High 4-5 Patients 60 years (IPI ageadjusted) Low 0 Low-intermediate 1 High-intermediate 2 High 3 Shipp. N Engl J Med. 1993
DLCBL: treatment by prognostic group aa IPI 0-1 aa IPI 2-3 Young low-risk high-risk Elderly 60 yrs > 60 yrs
IPI
IPI
0-1 2 3 4-5 0 1-2 3-5 Outcome according to IPI A: PFS B:OS Outcome according to R-IPI A: PFS B:OS
Zhou Z et al. Blood 2014;123:837-842 27
NCCN IPI vs IPI in risk stratification in the NCCN DLBCL training cohort. Zhou Z et al. Blood 2014;123:837-842
Rosenwald et al. NEJM 2002 Rosenwald et al. J Exp Med 2003 DLBCL is far from being a single entity, but a heterogeneous disease with at least 3 molecular subtypes Cell of origin (COO) Clinical relevance independently of the IPI Distinct genetic features & oncogenic pathways
Survival model and IPI N Engl J MED. G. Lenz et al. 2008; Suppl. to 359 (22): 2313-23
2011 by American Society of Clinical Oncology Meyer P N et al. JCO 2011;29:200-207
Overall survival of patients with diffuse large B-cell lymphoma according to immunophenotype by each algorithm. Hans Tally Meyer P N et al. JCO 2011;29:200-207 2011 by American Society of Clinical Oncology
DLBCL Genetic heterogeneity and impact on prognosis
Progression-free survival (%) Reporting interim PET by Integrative SUVmax more predictive of outcome than scoring residual activity at one step of the kinetics (DS) DLBCL Deauville < 4 (n = 63) SUV > 66% (n = 89) PFS=81% Deauville 4 (n = 51) PFS= 79% PFS=59% SUV 66% (n = 25) P = 0.003 2 = 8.58 P = 0.0002 2 = 13.69 PFS= 44% IVS: 114 pts, 5 centers, 3 observers, PET 2 cycles; med FU 39 months Itti, 2013, Eur J Nucl Med Mol Imaging
Combining GCB/ABC subtypes and ΔSUVmax Fast /GCB Fast /ABC DLBCL 57 patients PET 3-4 cycles ΔSUV>70% Good risk group Fast / GCB slow /ABC Poor risk group Slow GCB and ABC slow /GCB Lanic, Jardin 2011, Leuk Lymphoma
Follicular Lymphomas
Validation of IPI in indolent lymphomas Auth. year Pts Histology Study findings Lopez-G 1994 125 Low-grade Good discrimination Aviles 1994 238 Low-grade Doesn't work Hermans 1995 744 LG, IG, HG Better discrimination for IG and HG Foussard 1994 182 LG St III-IV Good discrimination ILSG 1997 REAL No for MZL e SLL Stelitano 2000 137 WF-A Improved by symptoms International Prognostic Index (Shipp et al Nejm 1993) Età, LDH, ECOG PS, Stadio, Sedi EN
Follicular Lymphoma International Prognostic Index (FLIPI) Solal-Celigny (Blood. 2004;104:1258-1265) Parameter Adverse factors Age 60 years Ann Arbor Stage III-IV Hemoglobin level < 12 g/dl Serum LDH level > ULN Number of nodal sites > 4 Risk group Number of factors Low 0-1 Intermediate 2 High 3
Background FLIPI Solal-Celigny et al Blood 2004 Registered 5120 Analyzed 4520 With adeq. FLUP 4167 With complete data 1795 (35%)
The changing face of LF 1. Excellent response to immunoct (ORR 90%) 2. Response duration can be prolonged with mintenance R and/or salvage therapies (med PFS > 80m) 3. Risk of transformation into aggressive LNH (10%) 4. Death for lymphoma is becoming a late event 5. Disease is potentially curable.
Current and expected changes in FL Effects on prognostic assessment New therapies Manitenance with Rituximab R-bendamustine R-Lenalidomide BCR pathway (Ibrutinib, Idelalisib, ) New prognostic tools (who is the high risk patient?)
Kaplan Meier (K M) survival functions for OS, PFS, and time to next treatment (TTNT) by the FLIPI risk group. All tx +Rituximab OS PFS TTNT Nooka A K et al. Ann Oncol 2013;24:441-448 The Author 2012. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com
Which endpoint should be used for studying prognosis in FL? Overall survival and progression-free survival of 832 patients used for Follicular Lymphoma International Prognostic Index 2 development. Federico M et al. JCO 2009;27:4555-4562
FLIPI2 results from the multivariate analysis of PFS HR P B2M 1.47 0.004 Hb 1.55 0.003 Age 1.43 0.005 BM 1.56 0.001 LoDLIN a 1.43 0.007 a LoDLIN: longest diameter of largest lymph node ( 6 cm). Federico M, et al. J Clin Oncol. 2009;27(27):4555-4562.
Estimated hazard of progression for the (A-C) National LymphoCare Study and (D) University of Iowa and Mayo Clinic Molecular Epidemiology Resource validation cohorts. Carla Casulo et al. JCO doi:10.1200/jco.2014.59.7534 2015 by American Society of Clinical Oncology
(A) Overall survival (OS) from a risk-defining event after diagnosis in patients who received rituximab with cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) chemotherapy in the National LymphoCare Study group. Carla Casulo et al. JCO doi:10.1200/jco.2014.59.7534 2015 by American Society of Clinical Oncology
Log (HR) on PFS CR30 for PFS in FL: Results 0.5 Log(HR PFS ) = -0.093 0.636 x log(or CR30 ) CR30 rate met prespecified surrogacy qualification criteria for PFS 0.0-0.5 R 2 WLS: 0.88 (95% CI: 0.77-0.96) R 2 Copula: 0.86 (95% CI: 0.72-1.00) Correlation similar for induction vs maintenance trials and R vs non-r trials -1.0-1.5-0.5 0.0 0.5 1.0 1.5 2.0 Log (OR) on CR30 Object size is proportional to sample size Surrogate threshold suggests that observed OR 1.56 in an ongoing trial will predict nonzero PFS treatment effect At individual pt level, overall global OR 11.84 shows CR30 associated with greatly reduced odds of progression Sargent DJ, et al. ASCO 2015. Abstract 8504. Reprinted with permission.
How is response assessed in FL -1 CT: Difficult assessment (sum of the product of transverse diameters of 6 largest nodes) Cheson 2007 Limited capacity to assess extranodal disease Only one study demonstrated an OS impact of CR/CRu over PR Bachy 2009 CT based CR vs PR not so important in the postinduction setting (PR to CR conversion) Salles Lancet Oncology 2010
How is response currently assessed in FL -2 Molecular remission (PCR for FL marker t(14;18)) Is prognostic, and independent of therapy but Is not an universal marker (~50%) Ladetto, M. et al. Blood 2008;111:4004-4013 Reproducibility and standardization issues Timing of MRD is uncertain
FDG-PET is prognostic after induction therapy Both PET cutoffs predictive of PFS Score 3 (Mediastinum) Score 4 (Liver) PET+ve 17% PET+ve 27% HR 3.9 (95% CI 2.5 5.9, P <.0001) Median PFS: 16.9 (10.8 31.4) vs 74.0 mo (54.7 NR) Trotman J, et al. Lancet Hematol. 2014; 1(1)
Postinduction PET status (cutoff 4) and Overall Survival 97% 87% Trotman J, et al. ASCO 2014: Abstract 8502. HR 6.7, 95% CI 2.4 18.5, P = 0.0002 Median OS: 79 months vs NR
Failure free survival (FFS) Pastore et al., Lancet Oncology 2015
Clinicogenetic risk model: m7-flipi Pastore et al., Lancet Oncology 2015
Failure free survival Pastore et al., Lancet Oncology 2015
CONCLUSIONS Prognostic indexes provide useful data to understand and manage patients with lymphoma We now have vlidated indexes for the most frequent Lymphoma subtypes (IPI, MIPI, FLIPI, IPS) The clinical utility of Prognostic scores is still limited (IPI) Several biomarkers have been suggested with a potential role in the definition of prognosis Metabolic response to treatment is also identiified as a substantial prognostic factor (FL, HL) and is currently investigated in the context of response adapted therapies New drugs and new effective therapies make it mandatory to keep prognostic studies updated