What can a «solid-tumour» expert learn from lymphomas and myeloma management

Transcription

1 What can a «solid-tumour» expert learn from lymphomas and myeloma management Franco Cavalli M.D., F.R.C.P. Scientific Director Oncology Institute of Southern Switzerland (IOSI)

2 A bit of history (I) CT was discovered by accident because of haematoxicity of neurotoxic gas (byproduct of war!) Most of the chemotherapy agents successful in screening system which favored myelosuppressive compounds

3 A bit of history (II) Combination CT developed first in ALL and HL First success in precision medicine with imatinib in CHL (which led to wrong conclusion )

4 Are haematological tumors still today the model on which new treatment modalities are developed?

5 Topics Precise diagnosis: predictive/prognostic marker(s) Power of early/dynamic predictors of treatment benefits At the end. Surprise!

6 First steps (almost at the same time) Discovery B/T cells Discovery hormonal receptors (first biomakers!)

7 For BC it took longer to incorporate knowledge into diagnostic/therapeutic progress

8 Our trial ( !) R HT + CT HT 3 different CTs CT at PD F. Cavalli, Br Med J :5-8

9 Accepted as a specific subtype only in the 1990s germinocytoma (Lennert, late 1960s) centrocytic lymphoma (Lennert, 1973) lymphocytic lymphoma of intermediate differentiation (Berard and Dorfman, 1974) diffuse small-cleaved cell lymphoma (Working Formulation, 1982) mantle cell lymphoma (Banks, 1992) WHO 2001 and 2008: characterized by t(11;14)(q13;q32) and cyclin D1 overexpression Typical phenotype: CD5+, FMC7+, CD20+(bright), sig+ (moderate to bright), CD23-, CD10-

10 A molecular model of lymphoma development secondary genetic events are needed Jares, et al. Nature Rev Cancer, 2007

11 A new paradigm in the REAL and WHO Classifications of NHLs A large number of distinct diseases associated with distinctive epidemiology, morphology, immunophenotype, genetic features, clinical features.

12 The commonest non-hodgkin lymphomas N = 1993 Lymphoblastic 1% Anaplastic 1% Peripheral T-cell 2% Other 6% Follicular 19% Burkitt 2% Marginal 10% Lymphoplasmocytic 3% Diffuse large B-cell 35% Small lymphocytic 15% Mantel 6% IOSI NHL database IOSI Database

13 Chronic Lymphocytic Leukaemia (CLL) q Most common leukaemia in adults q Diagnosis straightforward CD19+/CD5+/CD23+ lymphocytosis q Molecular pathogenesis unresolved Microenvironmental stimulation B cell receptor signalling (antigenic drive) Genomic aberrations, mutations, epigenetics q Clinical course highly variable Survival times ranging from months to decades Wide range of treatments (watch & wait SCT) Zenz T. Nature Rev. Cancer; 2009

14 Monoclonal B-Cell lymphocytosis (MBL) x 5.1% of persons with normal blood count xx 13.9% of persons with lymphocytosis (> 4 K) x no follow-up (anonymous samples) xx after 6-7 year FU Ò 15% CLL MBL Ò 100x more frequent than CLL Ò characteristics like indolent CLL Ò only 1%/year MBL Ò CLL requiring treatment Rawstrom et al. NEJM 2008; 359:575-83

15 Genotype, Phenotype and Outcome 11q Deletion and Lymphadenopathy Overall survival (n=300) mutated IGHV p- 11q- unmutated IGHV Months Stilgenbauer et al. PNAS 1996; Döhner et al. Blood 1997 Kröber et al. Blood 2002

16 Expected survivalof CLL patients stratified accordingto the integrated mutationaland cytogenetic model and compared to the matched general population. Expected survivalis calculated at ten years Foà R et al., Haematologica, 2013; 98(5):

17 PreviouslyuntreatedCLL requiring therapy No significant co-morbidity FCR Significantco-morbidity alkylating agents (+/- anti CD20 MoAb) 17p deleted p53 mutated Ibrutinib Idealisib

18 Immunophenotype Cytogenetic Next generation sequencing (NGS) MZL CD20+ CD19+ CD79a+ CD5- CD23- CD10-CD43v BCL2+ Matutes Score < 3 7q (del) 45% +3/+3q MALT L. : t(11;18), t(14;18), t(1;14), t(3;14) Splenic MZL NOTCH2 30% LPL/Waldenström CD22+f CD25+ CD103- del6q MYD88 L265P 90% Hairy cell leukemia CD103 CD11c CD25 (HC-2/) CD123 (=IL-3R) Score RMN 3 ou 4 / 4 5q13 +5 del(5) del(7)(q32) del(17)(q25) t(11;20) t(2;8) BRAF V600E 100% Absent in HCL-V and HCL IGHV4-34 CD20+ 13q(del) 60% LLC/ SLL CD5+ CD23+ CD43+ CD10- FMC7- CD79b % 11q (del) 30% - Matutes Score 4 ou 5 / 5 17pdel 2-30% Swerdlow SH. et al. IARC 2008; Kiel et al. 2012; Rossi D et al. 2012; Tiacci E et al. 2011; Treon SP. et al.

19 Routine molecular profilingof pts with advanced NSCLC: Results of 1- year nationwideprogram of the French cooperative thoraric intergroup N = patients The presence of a genetic alteration affected first-line treatment in ~ 50% of cases F. Barlesi et al. Lancet 2016; 387:

20 Oral drugs = better quality of life?

21 New frontiers Chemofree treatments Liquid biopsy

22 Tissue biopsy is the gold standard for lymphoma genomic studies Tissue biopsy: Not always easily accessible Discomfort for patients Does not allow real time monitoring Does not represent the entire tumor

23 Liquid biopsy is a source of tumor DNA for lymphoma genotyping Plasma: Easily accessible Low disconfort for patients Real time monitoring Representative of the tumor Plasma cell free DNA

24 Longitudinal plasma cfdna genotyping in DLBCL allows to recover in real time tumor genotype and treatment-associated clonal evolution Pre-treatment Remission Mutated molecules per ml of plasma ID1 Mutated molecules per ml of plasma Remission ID7 PIM1 PIM1 Remission Pre-treatment Remission (cycle 4) (post-therapy) RCHOP Months 0 Months BIRC3 BIRC3 Pre-treatment Refarctoriness Mutated molecules per ml of plasma ID13 ID12 Mutated molecules per ml of plasma Refractoriness FU RCHOP 5 Relapse PIM1 PIM1 Pre-treatment RCHOP Months 0 Refractoriness RCHOP 5 Months 0 5

25 Minimally invasive genomic and transcriptonomic profiling of visceral cancers by next-generation sequencing of circulating exosomes «Liquid biopsies using shed exosomes has the potential.. for diagnosis, stratification and treatment monitoring» F.A. San Lucas et al. Ann Oncol 2016; 27:

26 Topics Precise diagnosis: predictive/prognostic marker(s) Power of early/dynamic predictors of treatment benefits At the end. Surprise!

27 Early predictors MRD, e.g. in ALL, CML PET!

28 Hodgkin s Lymphoma: Incidence and Mortality in the US

29 Approximate cumulative risk of recurrent HL, second malignant conditions, and cardiovascular events among patients receiving both radiotherapy and chemotherapy for early-stage HL Armitage JO. NEJM;2010;363:

30 But not (yet?) in solid tumors The risk of solid cancers has not changed ( ; 77-88; ) and remains elevated up to 40 years after treatment M. Schaapuld et. al, NEJM, 2015;373:2499

31 Today s issues in HL Avoid useless treatment with long-term toxicity Give just enough treatment to cure In other words: How many cycles of chemo? ABVD or BEACOPP? Who needs readiotheray, and how much?

32 HL: limited stages (NA definition) q Vancouver = 142 pts q Rapid (UK) PET â 2 ABVD à Θ (82%) à + 2 ABVD Å (18%) à IFRT PET â 3 ABVD à Å (20%) à IFRT IFRT Ø Θ (80%) R J. Connors, Hematology, 2011 J. Radford et. Al, NEJM 2015, 372:1598

33 Stage II (adverse),iii,iv, IPS 0-7 Over 18 PS 0-3 PET 2 +ve PET 1(Staging) 2 cycles ABVD Full dose, on schedule PET2 RATHL Study (CRUK/07/033) PET 2 -ve 4 cycles BEACOPP-14 or 3 ebeacopp Randomise PET3 4 cycles ABVD 4 cycles AVD PET 3 +ve PET 3 -ve RT or salvage regimen 2 cycles BEACOPP-14 or 1 ebeacopp No RT Follow-up (no RT)

34 Hodgkin s Lymphoma - The great Teacher After ABVD failure, 60% of patients relapsing and 30% refractory can be cured with HDCT à Secondary treatment and long-term toxic effects impact on the choice of primary treatment in all stages of HL Connors J: NEJM 2011; 365: Results of ABVD only have clearly improved in the last 20 years Connors J. Ultman Lecture, ICML 2013

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36 PET/CT surveillance versus neck-dissection in advanced head and neck cancer N = 564 pts N 2 or N 3 Chemoradiotherapy Planned neck dissection (ND) PET/CT -> ND only by incomplete response Fewer ND: 54 vs. 221 OS: Very similar (trend better for PET/CT)

37 PD-1 Blockade with Nivolumab in RR HL 23 patients Heavily pre-treated: 80% BV and/or ABMT 1/3 each 3/4-5/ 6 previous therapies 17% CR 70% PR at 24 weeks 11 continue treatment early for assessing PFS Toxicity manageable Ansell SM et al. NEJM. 2015;372:

38 Teaching role of haemato-oncology today Somewhat decreasing, although still easier to measure Remains important to understand biology of tumors and haematological SAEs of treatments Ansell SM et al. NEJM. 2015;372:

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41 Perspectives on Cost and Value in Cancer Care Editorial L. B. Saltz, JAMA Oncology 2016; 2:19-22