PTCL update: Evidence for subtype-specifictreatment approaches

Francesco d’Amore, MD, DMScDept. of Hematology

Aarhus University HospitalAarhus, Denmark

May 3-4, 2019

7th TSH International SymposiumBangkok,

Disclosures

• Advisory boards: Nordic Nanovector, ServierPharmaceuticals, Takeda

• Speaker’s honoraria: Takeda, Servier Pharmaceuticals

• Research support: Sanofi/Genzyme, Takeda, Roche, CTI Life Sciences, Servier Pharmaceuticals

Structure of the talk

• Introduction

• Selected entities from the revised WHO classification

– TFH – selected updates on biology and and novel treatments

– GI TCL – WHO updates and some therapeutic considerations

– ALCL – selected updates on biology and therapy

– NK/T and HSTCL

• What about ‘the rest’? Role of SCT and experience from the large academic PTCL-specific trials run so far

• The ACT-1 trial

• Concluding remarks

PTCL IncidenceUS SEER registry (8802 pts)

Petrich et al. Br J Haematol 2014

PTCL subtypes

Laurent et al. J Clin Oncol 2017

PTCL: a rare and heterogeneous diseaseNordic Lymphoma Group

Updated Kiel Classification: the first major attempt to establisha specific classification for T-cell malignancies (J Clin Pathol 1987; 40, 995-1015)

T-cell lymphomas over the last 30 years

Suchi-Lennert Classification1987

Morphology, IH

REAL Classification

1994

Morphology, IH,

FISH,cytogenetics

WHO Classification2001

Morphology, IH,

FISH, cytogenetics,

mol. biol.

WHO Classification

2008

Morphology, IH,

FISH,cytogenetics,

mol. biol., GEP

WHO Classification2016/2017

Morphology, IH,

FISH,cytogenetics,

mol. biol., GEP, NGS,

Nanostring, RNA seq, high-throughput of FFPEs

WHO 2016: What is new in systemic PTCL?

AITL/ other TFH lymphomas Intestinal PTCL ALCL, ALK-negative

WHO 2016: AITL is a disease of GC-derived TFH cells

CD3+, CD10+, BCL-6+/-, PD1+, CXCL13+, CD21+ FDC meshwork;Both EBVpos and neg B cells;Often clonal B-cells

WHO 2016: Nodal PTCL of TFH cell origin

AITL

Follicularvariant

NodalPTCL-NOS

TFH cell

GEP and mutation analysis have helped to characterize the relationship between nodal PTCL entities og TFH origin

Nodal PTCL 2008-2016: subtype migration2008

AITL

T-zone variant

Follicular variant

Lymphoepithelioid variant(Lennert’s lymphoma)

PTCL-NOS

International T-cell Lymphoma Project, J Clin Oncol 2008

Nodal PTCL 2008-2016: subtype migration2016

T-zone variant

Follicular variant

Lymphoepithelioid variant(Lennert’s lymphoma)

PTCL-NOS

Nodal PTCL with TFH phenotype

AITL

Laurent et al. J Clin Oncol 2017

TFH-derived PTCL: Actionable mutations in epigenetic modifier and other genes

IDH2 and TET2 mutations are mutually exclusivein AML but co-occur in TFH-derived TCL

Sakata-Yanagimoto M, et al. Nat Gen 2014;46:171-5

PTCL, peripheral T-cell lymphoma; IDH, isocitrate dehydrogenase; BCL, B-cell lymphoma gene; CXCR, chemokine receptor; PD-1, programmed cell death; AITL, angioimmunoblastic T-cell lymphoma, NOS, not otherwise specified; TET2, ten-eleven translocation DNMT3A, DNA (cytosine-5) methyltransferase 3 alpha; AML, acute myeloid leukemia; TFH, T follicular helper; TCL, T-cell lymphoma; mIDH2, mutant IDH

PV ET MF CML Mastocytosis MPN-NOS Total

Chronic lymphocytic leukemia 8 6 2 1 - 14 31

Diffuse large B-cell lymphoma 8 2 2 2 1 5 20

Low grade lymphoma - NOS 4 - 3 - - 4 11

Peripheral T-cell lymphoma- ALCL ALK-neg- AITL

-2

-2

11

--

--

-3

18

Waldenström macroglobulinemia - 1 4 2 - 3 10

Lymphoblastic lymphoma - - - 5 - - 5

Marginal zone lymphoma - - 1 - - 4 5

Hodgkin’s lymphoma - 1 - 1 - - 2

Follicular lymphoma - 1 - 1 - - 2

Mantle cell lymphoma - - - - - 1 1

Primary CNS lymphoma - - - 1 - - 1

Total 22 13 14 13 1 34 97

Lymphoproliferative and myeloproliferative malignancies occurring in the same host: A nationwide discovery cohort

J.M.Holst, T.L.Plesner, M.B.Pedersen, H.Frederiksen, M.B.Møller, M.R.Clausen, M.Ludvigsen, P.Nørgaard, P.Johansen, T.Ramm-Eberlein, B.K.Mortensen, G.Mathiasen, A.Øvlisen, R.Wang, W.Tam, WC Chan, G.Inghirami, F.d’Amore

Holst J et al. Blood 2017 130:1525

Exp%: 3% >> Obs%: 12,5%4-5 fold

AITL: expected occurrence among NHL (i.e. without CLL and HL) => 3% of 64 = ca 2 => observed: 8 = 12,5%

Clinical case 2 points: (i) ET/AITL; (ii) Mutational status

• 45 y/o man with known JAK2+ ET develops fever, fatigue, drenching sweats, PS 3

• Multiple supra- and infradiaphragmaticLN involvement and BM infiltration

• Cervical LN biopsy showed AITL • Elevated LDH (770 U/l)• Mutations: TET2+, IDH2+, JAK2+

CD3 CD4 CD10 EBER CXCL-13 PD1

at Dx

PTCL subtype Pralatrexate Romidepsin BelinostatBrentuximabvedotin

All subtypes 29 25 26 ---

PTCL-NOS 31 29 23 33

AITL 8 30 46 54

ALCL 29 24 15 86

Subtype-specific responses (%) in FDA approved PTCL

PTCL subtype IDH2R140 IDH2R172 TET2

PTCL-NOS 0/43 0/43 22/58 (40%)

(FH 58% non-FH 24%)

AITL 25/101 (25%) 1/101 40/86 (47%)

ALCL 0/50 0/50 0/18

Mutations in epigenetic regulators are more frequent in TFH- derived PTCL

HdAc inhibitors: Best effect in PTCL with highest frequency of mutations in epigenetic modifier genes

Romidepsin-CHOP vs CHOP

➢ Romidepsin MTD (phase 1b): 12mg/m2 x6 d1+8 at each cycle of CHOP

➢ Target population: 420 pts

➢ Enrolled pr Feb 2015: 108 pts

➢ 1st interim analysis at 84 events (30% of the total expected)

ICML, Lugano 2013: Median Follow-up: 10 months➢ n=27 evaluable➢ CR 15/27 (55.6%)➢ ORR 20/27 (74%)

Dupuis J, et al. Lancet Haematol 2015;2:e160-5

Delarue R, et al. ICML 2013;abstract OT02;

Randomized Phase 3 Study Evaluating the Efficacy and the Safety of Oral Azacitidine (CC-486) Compared to Investigator's Choice Therapy in Patient With Relapsed or Refractory

Angioimmunoblastic T Cell Lymphoma

The ORACLE trial

Sponsor: LYSARC – PI: R.DelarueExternal partnership: CelgeneEudraCT number: 2017-003909-17 European centersAsian centersNLG participates with 4 centers: Aarhus, Copenhagen, Lund, Helsinki

Summary -1

• Better definition of TFH derived lymphomas (prototype AITL), whichmay gradually become a more frequent diagnosis than PTCL-NOS

• Frequent mutations in epigenetic modifier genes, already described inmyeloid diseases, where they are mutually exclusive, while they can co-exist in AITL (TFH-TCL). These mutations can be targeted therapeutically(e.g. 5-Azacytidine, HdACi).

• AITL is the lymphoma subtype with the highest occurrence of associatedMPNs (in the same host). Common early pathogenetic events can behypothesized.

Enteropathy-associated TCL 2008-20162008

EATL type I

Usually TCR αβ rearranged, CD8+, CD56-

Coeliac disease associatedNorthern European

EATL type II

Usually TCR γδ rearranged, CD8+,CD56+

EpitheliotropicNot associated with enteropathy

Asian, Hispanic

γδ

Enteropathy-associated TCL 2016

EATL type I

Usually TCR αβ rearranged, CD8+, CD56-

Coeliac disease associatedNorthern European

Monomorphic epitheliotropic TCL

Usually TCR γδ rearranged, CD8+,CD56+, SETD2 mut. in 90% of pts

EpitheliotropicNot associated with enteropathy

Asian, Hispanic

Indolent T-cell lymphoproliferative disease of the GI tract (provisional entity)

(Perry et al, Blood 2013)

• Adults, rare <20 yrs; M=F• Oral cavity, stomach, small intestine, colon• Diarrhea, pain, rectal bleeding• Chronic, indolent course• Usually no dissemination outside the GI-tract• Chemotherapy not useful

Summary -2

• ‘Type-2 enteropathy-associated TCL’ is renamed ‘momonorphicepitheliotropic intestinal TCL’ (MEITL) due to the absence of enteropathyin these pts

• As opposed to type-1 EATL, MEITL is often CD56+ and has a mutatedSETD2 gene in 90% of the pts.

• Clinicians should be aware of the presence of these indolent GIT CD8+TCL, which rarely metastasize outside the GI tract, are often localized andchemoresistent. These pts should not be treated with combinationchemotherapy and/or stem cell transplant.

Anaplastic Large Cell Lymphomas

• ALCL, ALK-positive• ALCL, ALK-negative (no longer provisional entity, but a definit entity)

o Differential diagnostic criteria vs CD30+ PTCL-NOS have been clarifiedo Should have similar morphology and phenotype as ALK+ALCL

• Primary cutaneous ALCL, Lymphomatoid papulosis• Breast-implant associated ALCL (now entered as provisional entity)• A majority of these tumors show activation of the JAK-STAT pathway

ALK +

ALK - CD30+ EMA+

de Leval et al, Histopathology, 2011

Actionable mutations in sALCL within the JAK/STAT pathway

Crescenzo R, et al. Cancer Cell 2015;27:516-32

• Co-occurring somatic mutations and TF/TK fusions in STAT3+JAK1 in syst alk-ALCL>>oncogenic• JAK/STAT pathway inhibitors showed therapeutic efficacy in pre-clinical models• Phase 2 Ruxolitinib trial is ongoing

Breast implant associated ALCLClinicopathological features

Molecular features

Seroma and cellular infiltrate

Treatment approaches

Prognostic impact of ALK, DUSP22 and TP63 rearrangements in adult systemic ALCL

Parilla Castellar ER, et al. Blood 2014;124:1473-80

ALK, anaplastic lymphoma kinase; DUSP, dual specificity phosphatase; TP63, transformation-related protein 63; ALCL, anaplastic large cell lymphoma

Parrilla Castellar et al (Blood 2014)

ALCL, only

• N=105 – 32 ALK positive (30%)

– 73 ALK negative (70%)

• ALK negative• N= 22 DUP22+ (30%)

• N= 6 TP63+ (8%)

• N= 45 -/-/- (62%)

Pedersen et al (Blood 2017)

PTCL-NOS, AITL, ALCL

• N= 138 – ALCL N=40

– 13 ALK positive (32%)

– 27 ALK negative (68%)

• ALK negative• N= 5 DUP22+ (21 %)

• N= 2 TP63+ (7%)

• N= 20 -/-/- (74 %)

DUSP22/TP63/triple neg: Comparison of frequency, subtype distribution and outcome

Upfront HDT/ASCT and genetic subtype

+ HDT/ASCT (n=13)

- HDT/ASCT (n=5)

P=0.74n=18

+ HDT/ASCT (n=7)

- HDT/ASCT (n=21)

P=0.25n=28

- HDT/ASCT (n=6)

DUSP22+ ALK+ ALCL

TP63+ PTCL-/-/-

n=7

- HDT/ASCT (n=1)

(Pedersen et al, ASH abstr. Blood 2017 130:822)

n=152 P=0.036

low IPI high IPI

P=0.13 P=0.007

- HDT/ASCT

+ HDT/ASCT- HDT/ASCT

+ HDT/ASCT

Greatest benefit seems to be in high IPI pts

Upfront HDT in triple negative ALCL

- HDT/ASCT (n=73)

+ HDT/ASCT (n=79)

Report on DUSP22 rearranged ALK-neg ALCL with less favorable outcome

Hapgood G, et al. BJH (corr) 2019, doi:10.1111/bjh.15860

5y PFS and OS: 40%

Targeting CD30: Brentuximab vedotin in R/R ALCL

Tum

ou

r si

ze(%

ch

ange

fro

m b

ase

line

)

ORR 86% in R/R ALCL

Pro B, et al. J Clin Oncol 2012;30:2190-6

BV, brentuximab vedotin; R//R, relapsed/refractory; ALCL, anaplastic large cell lymphoma; ORR, overall response rate

CD

30

sta

inin

g

ECHELON-2 Study Design (NCT01777152)

Key Eligibility Criteria

• Age ≥18 years

• CD30-expression (≥10% cells)

• Previously-untreated PTCL:

oSystemic ALCL (sALCL)*

including ALK(+) sALCL with

IPI ≥2, ALK(-) sALCL

oPTCL-NOS, AITL, ATLL,

EATL, HSTCL

Stratification Factors

• IPI score (0-1 vs. 2-3 vs. 4-5)

• Histologic subtype (ALK-positive

sALCL vs. all other histologies)

R

(1:1)

N=226

N=226

EOT

PET

A+CHP

(A) brentuximab vedotin 1.8 mg/kg +

(C) cyclophosphamide 750 mg/m2 +

(H) doxorubicin 50 mg/m2 +

(P) prednisone 100 mg (Days 1-5)

Q3W for 6 to 8 cycles

CHOP

(C) cyclophosphamide 750 mg/m2 +

(H) doxorubicin 50 mg/m2 +

(O) vincristine 1.4 mg/m2 +

(P) prednisone 100 mg (Days 1-5)

Q3W for 6 to 8 cycles

*targeting 75% (±5%) ALCL

AITL, angioimmunoblastic T-cell lymphoma; ALCL, anaplastic large-cell lymphoma; ALK, anaplastic lymphoma kinase ATLL, adult T-cell leukaemia/lymphoma; EATL, enteropathy-associated T-cell lymphoma; EOT, end of treatment; HSTCL, hepatosplenic T-cell lymphoma; IPI, international prognostic index

Baseline Characteristics

A+CHP

(N=226)

CHOP

(N=226)

Male, n (%) 133 (59) 151 (67)

Age in years,

median (range)58 (18-85) 58 (18-83)

IPI score*, n (%)

0-1 53 (23) 48 (21)

2-3 140 (62) 144 (64)

4-5 33 (15) 34 (15)

A+CHP

(N=226)

CHOP

(N=226)

Stage III/IV

disease, n (%)184 (81) 180 (80)

Disease diagnosis, n (%)

sALCL 162 (72) 154 (68)

ALK+ 49 (22) 49 (22)

ALK- 113 (50) 105 (46)

PTCL-NOS 29 (13) 43 (19)

AITL 30 (13) 24 (11)

ATLL 4 (2) 3 (1)

EATL 1 (0) 2 (1)

PFS and OS

3-yr PFS

57%44%

Events HR (95% CI) P

A+CHP 95 (42%) 0.71(0.54, 0.93) 0.011

CHOP 124 (55%)

Median PFS (95% CI)

48.2 mo (35.2, NE)20.8 mo (12.7, 47.6)

Deaths HR (95% CI) P

A+CHP 51 (23%) 0.66(0.46, 0.95) 0.0244

CHOP 73 (32%)

Prespecified Subset Analyses: PFS

Would like to know from the ECHELON-2 data set

• Distribution of DUSP22+ cases

• Outcome for DUSP22 rearranged, ALK-neg ALCL

• Outcome for TP63 rearranged, ALK-neg ALCL

• Outcome for triple neg ALCL

• Outcome for ALK-neg ALCL adjusted for DUSP22 and TP63

• Outcome for TFH derived TCL (AITL + PTCL-NOS with TFH phenotype)

Crizotinib – ALK inhibitor

Parameter N

N 11

type R/R ALCL ALK+

Med prior lines of therapy

3

ORR 10/11 (91%)

2 yr OS and PFS 73% and 64%

Ph 1-2 in combination with chemotherapy–> only ALK+ ALCL

Gambacorti-Passerini C, et al. JNCI 2014; 106:2:djt378. doi: 10.1093/jnci/djt378

R/R ALCL ALK+: t(2;5) (NPM/ALK)Crizotinib monotherapy

ALK, anaplastic lymphoma kinase; R/R, relapsed/refractory; ALCL, anaplastic large cell lymphoma; NPM, nucleophosmin; med, median; ORR, overall response rate; yr, year; OS, overall survival; PFS, progression free survival; ph, phase

Summary -3

• ALK-neg ALCL is no longer a provisional entity, but a definite one

• BIA-ALCL has been introduced as a provisional entity

• Genetic abnormalities in the JSAK/STAT pathways are often present in all subgroups of ALCL, inkl. BIA-ALCL. Clinical trial with JAK inhibitors are ongoing.

• Approx. 20-30% of all ALK-neg ALCL are DUSP22 rearranged. If this is the sole abnormality, pts haveoften a good prognosis with conventional approaches. However, cases with more aggressive clinicalbehaviour may occur.

• Approx. 7-8% of all ALK-neg ALCL are TP63 rearranged. These pts have often a very poor prognosis.

• Triple neg ALCL seem to benefit of upfront HDT, particularly those with high risk IPI.

• The ECHELON-2 trial has shown a significant outcome benefit of adding BV to a CHOP backbone inCD30+ PTCL. The benefit is primarily evident in ALCL. No information on DUSP22, TP63 and triple negstatus is currently provided.

• ALK inhibitors (e.g. crizotinib) have shown good efficacy in r/r ALK-pos ALCL. A ph 1-2 clinical trialwhere crizotinib is given in combination with chemotherapy is ongoing.

Epidemiological and clinical features

Frequency North America andEurope: 1-5%Asia/Central-South America: >20%

Most common site

Nasal cavity/rhinopharynx

Less common Waldeyer ring, tonsils, sinuses

Other sites Skin, GIT, testes, sal.glands

EBV Stronglyassociated/driven

Quantitative p-EBVDNA is prognostic (PINK-E index, Lancet Oncol2016)

NK/T, natural killer T-cell lymphoma; p-EBVDNA, Epstein Barr Virus deoxyribose nucleic acid; PINK-E, prognostic index of natural killer lymphoma plus EBV DNA data; GIT, gastrointestinal tract; sal, salivary Kim SJ, et al. Lancet Oncology 2016;17:389-400

Extranodal NK/T cell lymphoma, nasal type

L-asparaginase in ENKTCL: The SMILE regimen

1-yr OS 3-yr OS 3-yr PFS

All pts 55% 50% 45%

79%

Yamaguchi M, et al. J Clin Oncol 2011;29:4410-6ENKTCL, extranodal natural killer T-cell lymphoma; d, day; G-CSF, granulocyte colony-stimulating factor; SMILE, dexamethasone, methotrexate, ifosamide, L-asprarginase, etoposide; CR, complete response; PR, partial response; NR, non responder; PD, progressive disease; ED, early death; OS, overall survival; PFS, progression free survival, pts, patients

ENKTL – CD38

• Short DoR

• Loss of target

• Maybe useful to improve QoR in

combination regimens within a

‘bridging-to-allo’ strategy

CD38 bright

CD56 bright

Lancet Oncology 2016

➢PINK• Age >60• St III-IV• Distant l.nodes• Non-nasal sites

➢PINK-E• PINK factors• p-EBV DNA detectable

PINK-E: OS pr N of factors PINK-E: OS pr risk group

Kim SJ, et al. Lancet Oncology 2016;17:389-400PINK, prognostic index of natural killer lymphoma; PINK-E, prognostic index of natural killer lymphoma plus EBV DNA data; OS, overall survival; pr N, prognostic number; HR, hazard ratio; CI, confidence interval; St, stage; l.nodes, lymph nodes; EBV, Epstein Barr Virus

HSTCL• Younger males• Often prior IBD and immunosuppression• Very aggressive clinical course• Marked hepato-splenomegaly• Bone marrow infiltration • Strong elevation of LDH and LFT’s• Isochromosome 7Int TCL Project J Clin Oncol 2008

• N=25• Allo SCT N=18 >> 3-yrs PFS: 48%• Auto SCT 5 of 7 relapsed

• ICE/IVAC induction preferred (MSKCC)• Median follow-up 5.5 yrs• Median PFS 13.3 mos• Median OS 59 mos

silencing

activatingactivatingactivating

McKinney M, et al Cancer Discovery 2017; doi:10.1158/2159-8290Tanase A, et al. Leukemia 2015

Voss MH, et al. Clin Lymph Myeloma Leuk 2013

The Genetic Basis of HSTCL

Summary -4

• NK/T extranodal: improtance of L-asparaginase and EBV-DNA

• Novel therapeutic strategies are emerging (e.g.checkpoint proteininhibition, CD38 targeting)

• HSTCL is still an often refractory disease, but, if the pt is Tx eligibleand chemosensitive, upfront allo is recommended

Ph 2 CEOP+Pralatrexate 2y PFS: 39%No obvious improvement on

historical CHOP dataAdvani et al.

Br J Haem 2015

Ph 2 R CHOP vs GEM-P

EOT-CR:CHOP 53%

GEM-P 47%(p=0.24)

1) No efficacy difference2) GEM-P: higher rate of

study withdrawals

Gleeson et al. Lancet Haematol

2018

What about ‘the rest’? CHOP/CHOEP (+/-HDT)

Design Regimen Outcome Comments Reference

Ph 2 CHOEP-14x6+ASCT 5y PFS: 44%No alk+ ALCL included

Best 5y PFS in alk-ALCL (61%)d’Amore et al.

JCO 2012

Other backbones?

Nordic Lymphoma Group

CHO(E)P-14d x 3

CHO(E)P-14d x 3

(stem cell collection)

HDT (BEAM)

Follow-up

Excluded:

• Precursor TCL

• alk+ ALCL

• CTCL

• Primary leukemic PTCL

CHO(E)P :

18-60 yrs: CHOEP-14 (n=118)

61-67 yrs: CHOP-14 (n=42)

CR, PR NC,PD

CR, PR NC,PD

JCO 2012;30(25):3093-9

60 mo median follow-up

N evaluable pts: 160

NLG-T-01: Subtype-specific outcome (N=160)

d’Amore et al, JCO 2012

p=0.21 (logrank test)

0.0

0.4

0.2

0.6

0.8

1.0

0 12 24 36 48 60 72months

PTCL-NOS AILTAlk-negative ALCL EATL

OS, 4 major subtypes

p=0.26 (logrank test)

0.0

0.2

0.4

0.6

0.8

1.0

0 12 24 36 48 60 72months

PTCL-NOS AILTAlk-negative ALCL EATL

PFS, 4 major subtypes

Histology 5-yr OS 95% CI 5-yr PFS 95% CI

ALCL 70% 50%-83% 61% 42%-76%

AILT 52% 33%-69% 49 % 30%-65%

EATL 48% 26%-67% 38 % 18%-57%

PTCL-NOS 47% 34%-59% 38 % 25%-50%

German auto vs allo trial (AATT)

Schmitz N, et al. ICML 2015;abstract 33

Trial cohort

All Auto Allo

Randomized (tot) 104 --- ---

Interim analysis 58 30 28

Efficacy

All Auto Allo

ORR 51% 53% 50%

1y EFS 41% 48% 48%

1y OS 69% 61% 55%

This analysis showed no significant differences in survival for pts randomized to autoSCT or alloSCT.After interim futility analysis,…the DSMB/PIs decided to prematurely stop patient accrual.

ALLOGENEIC OR AUTOLOGOUS TRANSPLANTATION AS FIRSTLINE THERAPY FOR YOUNGER PATIENTS WITH PERIPHERAL T-CELL LYMPHOMA—RESULTS OF THE INTERIM ANALYSIS OF THE AATT TRIAL

Authors’ statement

Main problems: 1) 38% not reaching consolidative SCT2) GvL-effect of allo counterbalanced by high TRM

AATT, autologous allogeneic, transplantation trial; auto, autologous; allo, allogeneic; tot, total; ORR, overall response rate; y, year; EFS, event free survival; OS, overall survival; SCT, stem cell transplantation; GvL, graft verses lymphoma; TRM, treatment related mortality; pts, patients; DSBM, Data and Safety Monitoring Board, PI, principal investigators

Horwitz S, et al. ASH 2018, abstr. #997d’Amore F, et al. ASH 2018;abstr. #998

Trümper L, et al. ASCO 2016; abstr.#7500 d’Amore F, et al. J Clin Oncol 2012;30:3093-9

4Schmitz N, et al. ICML 2015;abstract 33

Largest prospective upfront trials in PTCL

Study Type Design N pts Reference

ECHELON-2 (CHOP +/- BV ) CIS Ph 3 452 Final analysis ASH 2018

Nordic ACT-1 (younger) (CHOP+/- ALZ) IIS Ph 3 131 Final analysis ASH 2018

German ACT-2 (elderly) (CHOP+/- ALZ) IIS Ph 3 116 Final analysis ASCO 2016

Nordic NLG-T-01 (CHOEP+auto) IIS Ph 2 160 J Clin Oncol 2012

German (allo vs auto) IIS Ph 3 104 Stop at 1st interim-ICML 2015

Nordic Lymphoma Group

CIS= company-initiated studyIIS= investigator-initiated study

2 yr

12%

7-10 yrs

Refractory Chemosensititve, but eventually relapsing

Long-term remission

18%

~40%

~30%

End of induction,

consolidation7 yrDiagnosis

d’Amore F, et al. J Clin Oncol 2012;30:3093-9 d’Amore F, et al. Ann Oncol 2015; 26 Suppl 5:v108-15

Response patterns in PTCL after 1st line treatmentNordic Lymphoma Group

Summary - 5

• Auto Tx: The role of upfront ASCT in PTCL is debated. However,while new treatments are being developed it is still recommendedin chemosensitive patients particularly those with high risk IPI.

• Allo Tx: Good GvL effect, but still burdened by toxicity problems.Recommended upfront in very aggressive subtypes such as HSTCL.Otherwise, useful tool in relapsed Tx eligible pts.

• What have we learned from the large PTCL IITs? 1/3 of pts relapsesearly, some due to refractory disease, others due to frailty andsubsequent dose erosion. 1/3 completes induction in remission,but relapses either early (<2y=20%) or late (>2y=10%). The lastthird will be in long term CR.

New drugs

Improve PS

MRD, consolidate/maintain

MRD, consolidate/maintain

Ref Compound ORR Approved Upfront ph3 trials

Enblad, Blood 2004 Alemtuzumab (CD52) 36% - ALZ-CHOP

O’Mahony, CCR 2009 Siplizumab (CD2) 31% -

O’Connor, ASCO 2013 Belinostat 26% US

d’Amore, BJH 2010 Zanolimumab (CD4) 26% -

O’Connor, JCO 2011 Pralatrexate 29% US

Coiffier, JCO 2012 Romidepsin 25% US RO-CHOP

Foss, ASCO 2010 Denileukin Diftitox 40% -

Pro, JCO 2012 Brentuximab vedotin (CD30) 86% (ALCL) US, EU CH[O]P+/-BV

Ogura, JCO 2014 Mogamulizumab (CCR4) 34% -

O’Connor, JCO in press Alisertib 24% -

Horwitz, ASH 2014 Duvelisib 47% -

Passerini, JNCI 2014 Crizotinib 90% (alk+ALCL) US (BTD)

Novel agents tested as monotherapy in R/R PTCL Nordic Lymphoma Group

ACT-1

RANDOMIZATION

6 x CHOP-14+ autoSCT

6 x CHOP-14with ALZ

+ autoSCT

RANDOMIZATION

6 x CHOP-146 x CHOP-14

with ALZ

ACT-2

Trümper et al. ASCO 2016

Trial designNordic Lymphoma Group

ALCL, regardless of alk status, NOT included!

Slow accrual (N=136 pts, 44% of planned sample)

CR and PD ratesNordic Lymphoma Group

CR rate PD rate

CHOP 42 42

ALZ+CHOP 52 23

0

10

20

30

40

50

60

%

Months

Pro

po

rtio

n

0 10 20 30 40 50 60 70 80 90 100 110

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

6 x CHOP-14

(n=66)

6 x CHOP-14 + A

(n=65) p=0.448

Primary endpoint: EFSNordic Lymphoma Group

RNA seq analysis revealed molecularfeatures predictive for ALZ response

(next talk)

Summary of subtype specific treatment featuresEntity/subtype Subtype-specific treatment feature

AITL/TFH 5-aza, HdAC

BIA-ALCL Do not omit surgical implant removal

ALK+ALCL @CD30, crizotinib

ALK-ALCL @CD30, DUSP22, TP63, JAK/STAT

ALCL triple neg CHOEP+HDT, @CD30

NK/T L-asparaginase

HSTCL alloTx upfront in eligible pts

PAR+ PTCL Low-dose ALZ+CHOP schedule

PAR: Predictor for alemtuzumab response; 5-aza: 5-azacytidine; HDT: High-dose therapy; BIA: Breast implant associated