Lymphoma Update 2018

Sonali M. Smith, MDElwood V. Jensen Professor of Medicine

Section of Hematology/OncologyDirector, Lymphoma Program

The University of ChicagoApril 18, 2018

Disclosure Information23rd Annual Developmental Therapeutics Symposium

Sonali Smith

• I have the following significant financial relationships to disclose:Consultant for: Celgene Speaker’s Bureau for: noneGrant/Research support from: Celgene Stockholder in: noneHonoraria from: noneEmployee of: none

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• I will discuss the following off label use and/or investigational use in my presentation:

Lenalidomide

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There are nearly 100 types of lymphoma

WHO Classification of Lymphoid Malignancies 2008, 2016 update

Goals of therapy vary by histology and expected clinical behavior: Curative intentPalliative intent

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%

DLBCL: a study in heterogeneity

Clinicopathologicsubtypes Gene expression

profiling subtypesGenomic variants

Altered protein expressionMorphologic variants

Neoplasm of large B lymphoid cells with a

diffuse growth pattern

Retrospective data identifies high-risk groups unlikely to be cured with R-CHOP

SUBSET FREQ R-CHOPCR PFS OS

ABC DLBCL 30-50% NR 2-yr 28% 2-yr 46%Double hit lymphoma

3-12% 40% 1-yr % <1yr

Dual expression of MYC/BCL2

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.

Clinical impact of heterogeneity on curative potential

High IPIElderlyNon-GC phenotypeDouble hit lymphomaDouble protein lymphoma

R-CHOP

Low IPILow stageGC phenotype

Time to move beyond R-CHOP for all

CAN WE MOVE BEYOND R-CHOP?

Challenging R-CHOP

Wilson JCO 2008

CALGB 50303: R-CHOP vs. DA-EPOCH-R

Wilson and Bartlett, et al.., ASH 2016

Event Free Survival* Overall Survival

*Primary endpoint

GOYA: R-CHOP vs. obinutuzumab-CHOP

No difference in PFS

GOYA: R-CHOP vs. obinutuzumab-CHOP

No difference in OS: 81% in both arms

Consolidative transplant benefits a small portion of patients

All patients with IPI > 3

OS

PFS

All patients with IPI 5

Stiff N Engl J Med 2013; 369:1681-1690

Summary of approaches to improve upon R-CHOP for DLBCL

Augmenting the chemotherapy backboneReplacing rituximab with second generation antibodyShortening cycle lengthPost-remission autologous stem cell transplantPost-remission novel agents

Pfreundschuh Lancet Oncology 2008; Pfreudschuh Blood 2004; Coiffier NEJM 2002, Fisher NEJM 1995; Cunningham Lancet 2013

2018: R-CHOP-21 remains the standard of care

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

MOVING BEYOND R-CHOP REQUIRES BIOLOGIC RISK STRATIFICATION

Cell-of-origin (COO) model as a prognostic tool in DLBCL

Lenz et al. N Engl J Med. 2008;359:2313-2323.

Two molecular subtypes with disparate outcomes

GC and ABC-DLBCL rely on distinct pathogeneticmechanisms for survival

Lenz et al. N Engl J Med. 2008;359:2313-2323; Dunleavy and Wilson Oncology 2014 ; Dunleavy et al. Blood 2009 113:6069-6076; Hernandez et al. Cancer 2011 Nov 15;1175058-66; Wilson et al. Nature Med 2015 Aug;21:922-6

GC-DLBCL• BCL2

translocation• miR-17-92 am

(mTORactivation)

• PTEN deletion• ING1 deletion• MDM2

gain/amp• P53 mut

ABC-DLBCL• BCL2 amp• Increased NF-

kB (increased STAT3,IRF4, SPIB)

• 19q gain or amp• Trisomy 3

(increased FOXP1)

• INK4A-ARF del• Increased AID

Bortezomib, lenalidomide, ibrutinib

5-azacytidine?

DLBCL: GOING BEYOND COO

Frequency of MYC and BCL2-rearrangements in DLBCL: double hit lymphoma (DHL)

Ref. N Subtype MYC rearr.

MYC andBCL2 rearr.

Comments

Barrans 245 R-CHOP 35 (14%) 19 (7.7%) MYC as sole abnlwas 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 BCL2

proliferation Anti-apoptosis

+ = “DOUBLE HIT LYMPHOMA”

Barrans JCO 2010; Savage Blood 2009; Niitsu

Frequency of MYC and BCL2 overexpression via IHC: dual expressor lymphoma (DEL)

Ref. N Subtype MYC rearr

MYCIHC

BCL2 rearr

BCL2 IHC

BCL2 andMYC IHC

Horn 2013

442 DLBCL (RICOVER)

8.8% 32%(>40%)

13.5% 80%(>0%)

Johnson 2012

167 DLBCL(training)

11% 29%(>40%)

18% 44% 18% overall (vs. 5% with DHL)

Johnson 2012

140 DLBCL(validation)

13% 37%(>40%)

30% 62%

Hu 2013 466 DLBCL (training)

NR 64% (>40%)

NR 50% (>70%)

34% (vs. 3% with DHL)

Johnson JCO 2012; Horn Blood 2013; Hu Blood 2013

Approximately 25-30% of DLBCL has dual protein expression

Prognosis of DHL vs. DEL

OS and PFS for classic DHL (MYC/BCL2 rearranged)

OS and PFS for DPL

Hu Blood 2013

75%

30%

73%

27%

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

PHASE I/II TRIAL OF LENALIDOMIDEPLUS DA-EPOCH-R (PCCCC)

Study Plan

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Double hit or dual expressing aggressive

B-cell lymphoma One cycle of

anthracycline-based chemo

allowed

DA-EPOCH-R plus lenalidomide x 6

Lenalidomidemaintenance x

12 cycles

Phase I Len/EPOCH-R: Results

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Phase I Len/EPOCH-R: Results

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Grade 3/4 Toxicity and/or AE’s of interest: Hypokalemia 14% Hypotension 14% Sepsis 14% Anemia 71% Neutropenia 64% Thrombocytopenia 43%

Thromboembolic events occurred in 4 patients despite aspirin One patient in phase I portion with t-MDS (prior history of methotrexate for

autoimmune disease)

Phase II is ongoing!!

T-CELL LYMPHOMAS: MOVING TOWARDS TARGETED APPROACHES

Peripheral T-cell lymphomas account for 10-15% of NHL in NA

1. Armitage J, et al. J Clin Oncol. 2008;26:4124–4130. Source: Armitage J, et al. J Clin Oncol. 2008;26:p4125.Reprinted with permission. © 2008 American Society of Clinical Oncology. All rights reserved.

PTCL is a heterogeneous group of aggressive mature T-/NK-cell lymphomas1

– 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 cells1

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;15:1447–1449.2. Savage KJ. Blood Rev. 2007;21:201–216.3. Rüdiger T, et al. Ann Oncol. 2002;13:140–149.

Emerging concept: molecular subtypes in T-NHL (WHO 2016)

Some T-NHL have stronger epigenetic signatures (AITL, PTCL-NOS)

Iqbal, et al., Blood. 2014 May 8;123(19):2915-23. doi: 10.1182/blood-2013-11-536359.O’Connor, et al., Clin Cancer Res. 2014 Oct 15;20(20):5240-54. doi: 10.1158/1078-0432.CCR-14-2020Blood. 2016 May 19;127(20):2375-90. doi: 10.1182/blood-2016-01-643569. Epub 2016 Mar 15

TFH phenotype as a distinct subset

Defining T(FH) phenotype

PD1

ICOS

CXCL13

BCL6

CD10

CCR5

SAP

Follicular helper T-cell lymphomaAITLPTCL with T(FH)

phenotype

2-3 markers

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. 2010 Mar;95(3):432-9

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!!

COMING TO YOU…

The University of Chicago: Hoogland Lymphoma Biobank

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

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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 Cells1*

– Saliva1*

– Urine1*

– Fecal Matter Sample2*

– Future Studies – Hospital information/medical records

1Not currently being collected or only being collected at University of Chicago. 2 Treatment naïve patients only* Kits will be provided for sample collection

Hoogland Lymphoma Biobank by the Numbers

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Data as of 4/19/2018Blood, tissue ,bone marrow and fecal samples are the number of collected samples out of total patients listed.

269

568

899

11401176

188

347

551

815859

75150

250

387 414

2 24 40 62 6612 30

2014 2015 2016 2017 2018

total patients blood tissue bone marrow fecal matter

www.chicagolymphoma.comMay 4-5th, 2018

Kimpton Gray Hotel

NEW: Nursing/pharmacy session on Friday

morning

The University of Chicago Lymphoma Program

Not pictured: James Godfrey MD Andrew Hantel MD Jon Trujillo, MD PhD

Thank you