Lymphoma Update 2018

Transcription

1 Lymphoma Update 2018 Sonali M. Smith, MD Elwood V. Jensen Professor of Medicine Section of Hematology/Oncology Director, Lymphoma Program The University of Chicago April 18, 2018

2 Disclosure Information 23 rd Annual Developmental Therapeutics Symposium Sonali Smith I have the following significant financial relationships to disclose: Consultant for: Celgene Speaker s Bureau for: none Grant/Research support from: Celgene Stockholder in: none Honoraria from: none Employee of: none - I will discuss the following off label use and/or investigational use in my presentation: Lenalidomide 2

3 There are nearly 100 types of lymphoma Goals of therapy vary by histology and expected clinical behavior: Curative intent Palliative intent WHO Classification of Lymphoid Malignancies 2008, 2016 update

4 Diffuse Large B-cell Lymphoma Most common non-hodgkin lymphoma 40% of global NHL burden is DLBCL Approximately 25-30K new cases per year in US All ages Increases with age Both genders All races All socioeconomic classes Can manifest in nearly any organ or body part Variable cure rate: 30-90%

5 DLBCL: a study in heterogeneity Neoplasm of large B lymphoid cells with a diffuse growth pattern Clinicopathologic subtypes Genomic variants Morphologic variants Gene expression profiling subtypes Altered protein expression

6 Retrospective data identifies high-risk groups unlikely to be cured with R-CHOP SUBSET FREQ R-CHOP CR PFS OS ABC DLBCL 30-50% NR 2-yr 28% 2-yr 46% Double hit lymphoma Dual expression of MYC/BCL2 3-12% 40% 1-yr % <1yr 21% NR 5-yr 27% 5-yr 30% Elderly DLBCL>60y 50% 70-80% 5-yr 50% 5-yr 58% High IPI 45% NR 4-yr 53% 4-yr 55% *DPL: dual protein expression of MYC and BCL2 Ref: Aukema Blood 2011) Hu Blood 2013; Oki 2014, Maurer 2014, Feugier 2005, Sehn 2005; Nowakowski 2014; Johnson JCO 2012.

7 Clinical impact of heterogeneity on Low IPI Low stage GC phenotype curative potential R-CHOP Time to move beyond R- CHOP for all High IPI Elderly Non-GC phenotype Double hit lymphoma Double protein lymphoma

8 CAN WE MOVE BEYOND R-CHOP?

9 Wilson JCO 2008 Challenging R-CHOP

10 CALGB 50303: R-CHOP vs. DA-EPOCH-R Event Free Survival* Overall Survival *Primary endpoint Wilson and Bartlett, et al.., ASH 2016

11 GOYA: R-CHOP vs. obinutuzumab-chop No difference in PFS

12 GOYA: R-CHOP vs. obinutuzumab-chop No difference in OS: 81% in both arms

13 Consolidative transplant benefits a small portion of patients All patients with IPI > 3 All patients with IPI 5 PFS OS Stiff N Engl J Med 2013; 369:

14 Summary of approaches to improve upon R-CHOP for DLBCL Augmenting the chemotherapy backbone Replacing rituximab with second generation antibody Shortening cycle length Post-remission autologous stem cell transplant Post-remission novel agents 2018: R-CHOP-21 remains the standard of care Pfreundschuh Lancet Oncology 2008; Pfreudschuh Blood 2004; Coiffier NEJM 2002, Fisher NEJM 1995; Cunningham Lancet 2013

15 Possible reasons for equivalent outcomes Trials enrolled all-comers with DLBCL Not stratified for GC and non-gc Inadvertent inclusion of double hit lymphomas Mixture of DEL and non DEL Not powered to detect differences based on outcomes of subgroups Unexpectedly good outcomes for the control arm

16 MOVING BEYOND R-CHOP REQUIRES BIOLOGIC RISK STRATIFICATION

17 Cell-of-origin (COO) model as a prognostic tool in DLBCL Two molecular subtypes with disparate outcomes Lenz et al. N Engl J Med. 2008;359:

18 Lenz et al. N Engl J Med. 2008;359: ; Dunleavy and Wilson Oncology 2014 ; Dunleavy et al. Blood : ; Hernandez et al. Cancer 2011 Nov 15; ; Wilson et al. Nature Med 2015 Aug;21:922-6 GC and ABC-DLBCL rely on distinct pathogenetic mechanisms for survival ABC-DLBCL BCL2 amp Increased NFkB (increased STAT3,IRF4, SPIB) 19q gain or amp Trisomy 3 (increased FOXP1) INK4A-ARF del Increased AID GC-DLBCL BCL2 translocation mir am (mtor activation) PTEN deletion ING1 deletion MDM2 gain/amp P53 mut Bortezomib, lenalidomide, ibrutinib 5-azacytidine?

19 DLBCL: GOING BEYOND COO

20 Frequency of MYC and BCL2-rearrangements in DLBCL: double hit lymphoma (DHL) Ref. N Subtype MYC rearr. MYC and BCL2 rearr. Comments Barrans 245 R-CHOP 35 (14%) 19 (7.7%) MYC as sole abnl was rare (2%) BCCA 135 R-CHOP 12 (9%) 3 (2%) Japan 394 DLBCL 24 (6%) 19 (4.8%) Only looked at pts with cytogenetic abnl MYC proliferation + BCL2 = DOUBLE HIT LYMPHOMA Antiapoptosis Barrans JCO 2010; Savage Blood 2009; Niitsu

21 Frequency of MYC and BCL2 overexpression via IHC: dual expressor lymphoma (DEL) Ref. N Subtype MYC rearr MYC IHC BCL2 rearr BCL2 IHC BCL2 and MYC IHC Horn 2013 Johnson 2012 Johnson DLBCL (RICOVER) 167 DLBCL (training) 140 DLBCL (validation) Hu DLBCL (training) 8.8% 32% (>40%) 11% 29% (>40%) 13% 37% (>40%) NR 64% (>40%) 13.5% 80% (>0%) 18% 44% 18% overall (vs. 30% 62% 5% with DHL) NR 50% (>70%) 34% (vs. 3% with DHL) Approximately 25-30% of DLBCL has dual protein expression Johnson JCO 2012; Horn Blood 2013; Hu Blood 2013

22 Prognosis of DHL vs. DEL OS and PFS for classic DHL (MYC/BCL2 rearranged) OS and PFS for DPL 30% 75% 27% 73% Hu Blood 2013

23 Definitions Double-hit lymphoma High grade B-cell lymphoma with translocations of MYC, BCL2, +/- BCL6 Accounts for 5-7% of all DLBCL New category: 2016 WHO category: High grade B-cell lymphoma, with rearrangements of MYC and BCL2 and/or BCL6 Majority are germinal center DLBCL Outcome poor with standard therapies Double-expressing lymphomas Not a distinct entity but an adverse prognostic factor Accounts for 20-30% of all DLBCL DLBCL with immunohistochemical expression of MYC ( 40%) and BCL2 ( 50% recommended in 2016 WHO revision) in the absence of translocations Majority are non-germinal center DLBCL Outcome inferior to other DLBCLs treated with R-CHOP, but not as poor as DHL Slide modified from Jeremy Abramson

24 PHASE I/II TRIAL OF LENALIDOMIDE PLUS DA-EPOCH-R (PCCCC)

25 Study Plan Double hit or dual expressing aggressive B-cell lymphoma One cycle of anthracyclinebased chemo allowed DA-EPOCH-R plus lenalidomide x 6 Lenalidomide maintenance x 12 cycles 25

26 Phase I Len/EPOCH-R: Results 26

27 Phase I Len/EPOCH-R: Results Grade 3/4 Toxicity and/or AE s of interest: Hypokalemia 14% Hypotension 14% Sepsis 14% Anemia 71% Neutropenia 64% Thrombocytopenia 43% Phase II is ongoing!! Thromboembolic events occurred in 4 patients despite aspirin One patient in phase I portion with t-mds (prior history of methotrexate for autoimmune disease) 27

28 T-CELL LYMPHOMAS: MOVING TOWARDS TARGETED APPROACHES

29 Peripheral T-cell lymphomas account for 10-15% of NHL in NA PTCL is a heterogeneous group of aggressive mature T-/NK-cell lymphomas 1 PTCL does not refer to anatomic sites, but rather to the involvement of more mature (post-thymic) T cells vs pre-thymic or immature T cells 1 1. Armitage J, et al. J Clin Oncol. 2008;26: Source: Armitage J, et al. J Clin Oncol. 2008;26:p4125. Reprinted with permission American Society of Clinical Oncology. All rights reserved.

30 PTCL: Defining Features Uncommon and heterogeneous Aggressive Worse outcome compared to B-NHL 5-yr PFS < 24% No therapeutic standard of care Few prospective trials 1. Armitage JO, et al. Ann Oncol. 2004;15: Savage KJ. Blood Rev. 2007;21: Rüdiger T, et al. Ann Oncol. 2002;13:

31 Emerging concept: molecular subtypes in T-NHL (WHO 2016) TFH phenotype as a distinct subset Some T-NHL have stronger epigenetic signatures (AITL, PTCL-NOS) Iqbal, et al., Blood May 8;123(19): doi: /blood O Connor, et al., Clin Cancer Res Oct 15;20(20): doi: / CCR Blood May 19;127(20): doi: /blood Epub 2016 Mar 15

32 Defining T(FH) phenotype PD1 BCL6 CCR5 ICOS CD10 CXCL13 SAP 2-3 markers Follicular helper T-cell lymphoma AITL PTCL with T(FH) phenotype

33 ICOS (inducible T-cell costimulator) Present on normal T follicular helper (T(FH)) cells Member of the CD28/B7 family Regulates balance between immune response and inhibition of autoimmunity Regulates B-cell response in germinal center Expressed on nearly 100% of AITL and T(FH)-PTCL Aliases: CD278, CVID1 AITL PTCL-NOS NCI9930 Protocol; Marafioti Haematologica Mar;95(3):432-9

34 Phase I Trial of MEDI-570 in Rel/Ref PTCL Follicular Variant and AITL: NCI 9930 Human afucosylated IgG1k monoclonal antibody against ICOS-L IV infusion every 21 days (current dose level is 0.1mg/kg) Correlative studies: CD4+ lymphocytes subsets ICOS expression in tumor and CD4+ T-cells PK Anti-MEDI-570 antibodies Key eligibility criteria: PTCL or AITL refractory to > 1 line of treatment CTCL relapsed after at least one prior systemic treatment NO ALCL or NK-cell lymphomas Phase I is ongoing!!

35 The University of Chicago: Hoogland Lymphoma Biobank COMING TO YOU

36 Background There is a relative dearth of data regarding the link between epidemiological data/factors and prognosis Linking epidemiologic risk factors to lymphoma is essential to understanding how lifestyle, occupation, environment and genes affect lymphoma Lymphoma Tissue is precious! Often the only tissue for lymphoma cases comes from the diagnostic tissue Unlike many other cancers, surgery is not normally part of the treatment plan for lymphoma patients We don t get a second chance 36

37 Patient Consent to Study Overview Our protocol is designed to ask patients to consent to the following: Questionnaires Blood* Blood at initial diagnosis and at the time of relapse is preferred Blood at any time is also acceptable Malignant tissue Bone Marrow* Buccal Cells 1* Saliva 1* Urine 1* Fecal Matter Sample 2* Future Studies Hospital information/medical records 1 Not currently being collected or only being collected at University of Chicago. 2 Treatment naïve patients only * Kits will be provided for sample collection 37

38 Hoogland Lymphoma Biobank by the Numbers total patients blood tissue bone marrow fecal matter Data as of 4/19/2018 Blood, tissue,bone marrow and fecal samples are the number of collected samples out of total patients listed. 38

39 NEW: Nursing/pharmacy session on Friday morning May 4-5 th, 2018 Kimpton Gray Hotel

40 The University of Chicago Lymphoma Program Not pictured: James Godfrey MD Andrew Hantel MD Jon Trujillo, MD PhD

41 Thank you