MANAGEMENT OF PATIENTS WITH PERIPHERAL T …lymphomaforum.ch/docs/Luminari16Tcell.pdf · 06.12.2015 · MANAGEMENT OF PATIENTS WITH PERIPHERAL T-CELL LYMPHOMAS ... PTCL SUBTYPES.

MANAGEMENT OF PATIENTS WITH PERIPHERAL T-CELL LYMPHOMAS

DR. STEFANO LUMINARIASSOCIATE PROFESSOR OF MEDICAL ONCOLOGYUNIVERSITY OF MODENA AND REGGIO EMILIA

HEMATOLOGY, AZ. OSP. SANTA MARIA NUOVA REGGIO EMILIA,ITALY

Lyfe Forum of excellence 2016

What's new in Lymphoyd neoplasia?

IOSI course,

Bellinzona, 29-31 January 2016

F. D’amore et al. Ann Oncol (2015) 26 (suppl 5):v108-v115.

Peripheral T-cell lymphomas: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up†

https://annonc.oxfordjournals.org/content/26/suppl_5/v108.full

Peripheral T-cell Lymphomas

• Account for 10 to 15% of all NHL

• Differences in geographic distribution (AILT in Europe, NK in ASIA, alk- ALCL in South America)

• Clinically and biologically heterogeneous group of disorders

• Classification relies on

– Morphology/Immunophenotype/genetic (ALK)

– Clinical /anatomical presentation

Mature T-/NK-cells Neoplasm

Cutaneous

Mycosis Fungoides(MF)

Trasformed MF

Sézary Syndrome

Primay CutaneousCD30+ T-Cell Disorders

Primary CutaneousGamma/Delta TCL

Extranodal

NK/TCL Nasal Type

Entheropaty-associated TCL

Hepatosplenic TCL

SubcutaneousPanniculitis-like TCL

Nodal

Peripheral TCL NOS

Anaplastic Large CellLymphoma (ALK+/-)

Angioimmuno-blasticTCL

Leukemic

Adult T-cell LeukemiaLymnpoma

Aggressive NK-cellLeukemia

T-cell ProlymphocyticLeukemia

T-cell Large Granular Lymphocytic Leukemia

Grouping Aggressive Indolent

Adapted fromc Rodriguez et al, Crit Rev Onc Hematol, 2008

PTCL SUBTYPES

v

Adapted fromc O'Connor et al Clin Can Res 2014

International T-Cell Lymphoma Project: OS in PTCL

PTCL Subtypes

Alk+ ALCL Alk- ALCL PTCL-NOS AITL NK/TCL ATLL

5-yr OS, % 70 49 32 32 42 14

Majority of patients (> 85%) received an anthracycline-containing regimen

Vose J, et al. J Clin Oncol. 2008;26:4124-4130.

0 2 4 6 8 10 12 14 16 18

100

80

60

40

20P < .001

Ove

rall

Su

rviv

al (%

) Anaplastic large cell lymphoma, ALK+

Anaplastic large cell lymphoma, ALK-

All natural killer/T-Cell lymphomas

Peripheral T-cell lymphoma, not otherwise

specified

Angioimmunoblastic lymphoma

Adult T-cell leukemia/lymphoma

Yrs

Mak V, et al. J Clin Oncol. 2013;31:1970-1976.

Survival After First Relapse or Progression

of PTCL: Histologic Subtypes P

atie

nts

, %

100

80

60

40

20

0

Time (years)

0 5 10 15 20

PTCL-NOS

ALCL

AITL

P = .971

Pa

tie

nts

. %

100

80

60

40

20

0

Time (years)

0 5 10 15 20

PTCL-NOS

ALCL

AITL

P = .962

Progression-free Survival Overall Survival

Risk assessment in PTCL

Schmitz N et al. Blood 2010 Vose et al JCO; 2008

Variable IPI PIT IPTCLP mPIT AITL KPI EPI(*)

Age > 60 X X X X X X

ECOG ≥ 1 X X X X X

LDH (abn. values) X X X X X

Stage III-IV X X X X

ENS > 2 X X X

BM+ X

Plts < 150K X X

KI-67 ≥ 80% X

Anemia (M<13, F<11g/dl)

X

Serum IgA (>400 mg/dl) X

B symptoms X X

Regional Lymph nodes X

PTCL subset All PTCL-U PTCL-U PTCL-U AITL NK-TCL EATL(*)

Prognostic models in PTCL: clinical variables

Modified from: Gutierrez-Garcia: Ann Oncol. 2011; 22: 397–404

(*)de Baaij LR, Clin Can res 2015

Peripheral T-cell lymphomas in a large US multicenter cohort: prognostication in the modern era including impact of frontline therapy (N=341)

J. S. Abramson, et al. Ann Oncol. 2014 Nov; 25(11): 2211–2217

This analysis identifies early-stage disease and initial treatment response as dominant prognostic factors in PTCL.

ASCT vs CTOnly CR pts

ASCT vs CTAll pts

• N=130 (110 with baseline PET; 105 Pet+ at baseline)

• romidepsin at a dose of 14 mg/m2 on days 1, 8, and 15 of 28-day cycles

• With FDG-PET– 3/16 CR PR

– 9/14 PR/SD CR

S. Horwitz et al. Ann Oncol. 2015 Apr; 26(4): 774–779.

Utility of 18fluoro-deoxyglucose positron emission tomography for prognosis and response assessments in a phase 2 study of romidepsin in patients with relapsed or refractory peripheral T-cell lymphoma

Progression Free Survival

MODENA March 20-21, 2014

Comparison with retrospective IPTCLPPTCL-NOS

13

Weisenburger et al, 2011

5-yr OS Weisenburger et al 32%T-Cell Project 35%% (95% CI 29-42)

Weisenburger et al (N=340)

T-Cell Project (N=347)

Meta-analysis of Frontline Anthracycline-

Based Therapy for PTCL: OS

PTCL Subgroup Study, Yr 5-Yr OS Rate 95% CI 5-Yr OS Rate and 95% CI

AITL Pautier et al, 1999

Savage et al, 2004

Sonnen et al, 2005

Vose et al, 2008

AITL summary estimate Fixed

Random

0.360

0.360

0.280

0.320

0.321

0.321

0.217-0.534

0.134-0.672

0.155-0.451

0.264-0.381

0.272-0.375

0.272-0.375

ALCL Gisselbrecht et al, 1998

Savage et al, 2004

Sonnen et al, 2005

ALCL summary estimate Fixed

Random

0.640

0.430

0.610

0.573

0.565

0.512-0.751

0.275-0.600

0.394-0.790

0.479-0.662

0.428-0.692

Alk-neg ALCL Vose et al, 2008

Alk-neg ALCL summary estimate Fixed

Random

0.490

0.490

0.490

0.377-0.604

0.377-0.604

0.377-0.604

ETTL Savages et al, 2004

Vose et al, 2008

ETTL summary estimate Fixed

Random

0.220

0.200

0.203

0.203

0.055-0.577

0.118-0.318

0.125-0.312

0.125-0.312

Non-ALCL PTCL Gisselbrecht et al, 1998

Rudiger et al, 2002

0.350

0.260

0.291-0.414

0.182-0.357

PTCL-NOS Savage et al, 2004

Sonnen et al, 2005

Vose et al, 2008

0.350

0.450

0.320

0.269-0.440

0.338-0.567

0.273-0.371

PTCL combined Karakas et al, 1996

Kim et al, 2002

Reiser et al, 2002

0.480

0.526

0.550

0.303-0.663

0.415-0.633

0.429-0.665

0% 50% 100%

Induction therapy in PTCL

What's wrong with CHOP in PTCL?

Not evidence based!!

Used for all subtypes.

Activity of doxorubicin not confirmed

Vose et al JCO; 2008

PTCL-NOS AILT

EFS: age < 60 y, LDH ≤ UNL

Schmitz N et al. Blood 2010

Moving away from CHOP in PTCLThe german experience with CHOEP

CHOEP

CHOP

EFS: ALK +, age < 60 y, LDH ≤ UNL

Integrated management algorithm (according to, e.g. risk factors, stage and histological subtype) in the (A) front-line and (B) relapsed/refractory setting.

F. d'Amore et al. Ann Oncol 2015;26:v108-v115

© The Author 2015. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected].

…although the role of anthracyclines in PTCL is still debated, anthracycline void

regimens have, so far, failed to demonstrate their superiority to

CHOP/CHOEP.(2015 ESMO guidelines statetment)

Evidence for BMT is PTCL 1st line

Prospective PTCL restricted studies

Encouraging results!!... However…Not randomized. Some are very small series; Tx rate varies from 41 to 74%.

~ 20 % relapse within the first year after ASCT, + ~10% by 2years post ASCTCHOP was not used!!

CHOEP14 x 6 + BEAM-ASCT

D’Amore F et al. J Clin Oncol 2012

XIII ICML Abs 74. D'Amore et al. The 10-year OS, and PFS for the whole ITTP were 41%, and 38%ALK- ALCL and female had the best outcome

What does reallymake BMT effective?

• High dose chemotherapy itself

• Patient selection (risk groups)

• How the patients gets to BMT

– Quality of response (CR vs < CR; FDG PET?)

– Quantity of responding patients (Tx rate)




Phase II Trial of Reduced-Intensity Conditioning Followed by Allo-

SCT in PTCL

• Relapsed/refractory

PTCL/AITL/ALCL

• N = 17 (8 prev ASCT)

• Median age: 41 yrs

(range: 23-60)

• Time from diagnosis: 5-8 mos

to 5 yrs

• Median follow-up: 28 mos

• Nonrelapse mortality at 2 yrs:

6%, later updated to: 12%

• 2/4 patient responses to DLI

Corradini P, et al. J Clin Oncol. 2004;22:2172-2176.

PFS: 64%

OS: 80%P

FS

(%

)

100

75

50

25

00 10 20 30 40 50 60 70

Mos

OS

(%

)

100

75

50

25

00 10 20 30 40 50 60 70

Mos

XIII ICML Abs 033 N. Schmitz, et al Ph III AUTO vs ALLO 1st line: no significant differences in survival for pts randomized to autoSCT or alloSCT. Most importantly, >30% of pts randomized to ASCT or alloSCT did not make it to transplantation mostly because of early lymphoma progression. DSMC decided to prematurely stop patient accrual.

Strategies to improve outcome of PTCL patients

• New old drugs– L-asparaginase (SMILE rx in ENK/TL). Yamaguchi JCO 2011

– Bendamustine (BENTLY trial in R/R PTCL). Damaj JCO 2013.

– Pralatrexate (PROPEL Trial) O'Connor JCO 2011.

• Target therapies

– Monoclonal antibodies– Alemtuzumab, Brentuximab vedotin, Mogamulizumab (anti CCR4)

– Histone deacetilase Inh.– Romidepsin, Vorinostat, Belinostat

– Tyrosine kinase inh.– IPI-145, Crizotinib, Sorafenib

– Miscellaneous– Lenalidomide, alisertib, anti PD1

Prospective Trial: First-line Alemtuzumab+ CHOP in PTCL (N = 24)

• IPI score

– 0-1: 33%

– 2-3: 58%

– 4-5: 8%

• CR: 71%

– PTCL-U: 50%

– AITL: 100%

• Grade 4 infection: 17%

– Sepsis, aspergillosis, JC virus, PCP

Gallamini A, et al. Blood. 2007;110:2316-2323.

Failure-Free Survival2 yrs: 48%

2-Yr OS: 53%C

um

ula

tive

Pro

po

rtio

n

Surv

ivin

g

1.0

0.8

0.6

0.4

0.2

0

Yrs From Diagnosis0 1 2

*Censored observations

* ***** ** * **

Cu

mu

lati

ve P

rop

ort

ion

Su

rviv

ing

1.0

0.8

0.6

0.4

0.2

0.0

Yrs From Diagnosis

0 1 2

*Censored observations

***** **

** **

3

**

CHOP-

14

HDT

The ACT trial after the dose/age amendment

CHOP-14

CHOP-14

CHOP-14

CHOP-14

CHOP-14

CHOP-14

A30 - CHOP-14

A30 - CHOP-14

A30 - CHOP-14

A30 - CHOP-14

HDT

R

CHOP-14

CHOP-14

CHOP-14

CHOP-14

CHOP-14

CHOP-14

A30 - CHOP-14

A30 - CHOP-14

A30 - CHOP-14

A30 - CHOP-14

CHOP-

14

R

18 yrs

60 yrs

80 yrs

CHOP-

14

CHOP-

14

D’Amore F: Blood (ASH Annual Meeting Abstracts) 2012 120: Abstract 57

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

Reprinted with permission. © 2012 American Society of Clinical Oncology. All rights reserved.

Phase II Study of Brentuximab Vedotin in Patients with R/R sALCLMaximum tumour reduction by IRF

(data cut off: Jan 2011)

Ch

an

ge f

rom

baselin

e in

tum

ou

r siz

e (

%)

*One patient did not have a post-baseline assessment

Subgroup

ALK-negative (n=42) ORR / CR, % 88 / 52

ALK-positive (n=16) ORR / CR, % 81 / 69

Combination treatment

• Patients: 26 patients received combined treatment

– 23/26 (88%) received all 6 cycles

– 21 patients had maintenance treatment with brentuximab vedotin

– Median DOT (including maintenance): 13 (range, 3-16)

• Safety

• MTD: 1.8 mg/kg (DLT = Gr 3 rash)

• SAEs occurring in >1 pt: febrile neutropenia (31%), pyrexia (8%) and cardiac failure (8%)

Median observation time: 21.4 months

• Estimated 1-yr PFS 71% (95% CI 49, 85)

• Estimated 1-yr OS 88% (95% CI 68, 96)

SGN35-011: Phase 1 study of frontline brentuximab vedotin plus multi-agent chemotherapy in ALCL and CD30-positive mature T-cell and NK-cell lymphomas - Response

Fanale M et al. JCO 2014

• Clinical Response

Sequential treatment• Patients: 13 patients received sequential treatment:

– All completed initial 2 cycles of brentuximab vedotin

– 11/13 completed subsequent 6 cycles of CHOP

– 12/13 patients had maintenance treatment with brentuximab vedotin

• Safety

• Febrile neutropenia was the only SAE occurring in more than 1 patient (2 patients)

Median observation time: 23.8 months

• Estimated 1-yr PFS 77% (95% CI 44, 92)

• Estimated 1-yr OS 85% (95% CI 51, 96)

SGN35-011: Phase 1 study of frontline brentuximab vedotin plus multi-agent chemotherapy in ALCL and CD30-positive mature T-cell and NK-cell lymphomas - Response

• Clinical Response

Fanale M et al. JCO 2014

Brentuximab Vedotin in Relapsed or Refractory Mature

T-/NK-Cell Lymphomas

Horwitz et al, Blood 2014

N= 35; BV at 1,8 mg/Kg q3w until toxicity or PG

Brentuximab Vedotin in Relapsed or

Refractory Mature T-/NK-Cell Lymphomas

Horwitz et al, Blood 2014

Response to BV is not predicted by level of CD30 expression

Epigenome as a target in PTCL

"Epigenetics are the processes that ensure that the right genes are expressed at the right time, in the right quantity and in the right place"


Epigenome as a target in PTCL

- Mutations in epigenetic genes are present in PTCL-NOS, and AITL (TET2, IDH2, and DNMT3A)

- Epigenetic therapy is active in PTCL throughHDAC inhibition. Three approved drugs

- Vorinostat: CTCL Duvic et al. Blood 2007

- Belinostat: CTCL and PTCL Foss et al. BJH 2014

- Romidepsin: CTCL and PTCL Coiffier et al. JCO 2012

- HDAC inibition has a more complex MoA thansimply altering gene transcription (proliferation, angiogenesis,…)


Study Schema

Eligibility (n = 131)Confirmed PTCLFailed at least one prior systemic therapyMeasurable diseasePrimary endpoint: Complete response by Independent Review Committee

Romidepsin 14 mg/m2 IV over 4 hoursDays 1, 8 and 15 of a 28-day cycle x 6 cyclesResponding patients could continue to receive treatment beyond 6 cycles at discretion of patient and investigator

Coiffier B et al. Proc ASH 2010;Abstract 114.

1 8 15 22 1

Week 1Cycle 1

Week 2 Week 3 Week 4 Week 1Cycle 2

Romidepsin Romidepsin Romidepsin Romidepsin

Romidepsin Response and PFS

in R/R PTCL

Coiffier B et al. JCO 2012;30:631-636

©2012 by American Society of Clinical Oncology

OR rate 26%CR rate 13%

Treatment-Emergent Adverse Events (TEAEs)

At least one TEAE

Nausea

Infection

Fatigue

Vomiting

Thrombocytopenia

Diarrhea

Pyrexia

Neutropenia

Constipation

Anorexia

Anemia

Dysgeusia

0 10 20 30 40 50 60 70 80 90 100

Percentage(%)

Overall

≥ Grade 3

Coiffier B et al. J Clin Oncol 2012

Ro-CHOP Phase III Study

Phase I/II trial Pts ≥18 yrs ≤ 65 yrs

Phase I : Romidepsin 8, 10,

12, 14 mg/sqm; starting

with 12 mg/sqm

Phase II: Romidepsin at

MTD*romidepsin provided free by

Celgene

Ro-CHOEP21 x 3

Response Evaluation

<PR CR or PR

Ro-CHOEP21 x 3

PR CR PD or SD

ALLO - SCT AUTO - SCT Other treatments (investigators’ choice)

Other treatments

(investigators’

choice)

For PR

start donor search

DHAP – Stem Cell Harvest

Follow-up

Response Evaluation

Clinical Activity of IPI-145 in Patients With B-Cell

and T-Cell Lymphomas

*15 iNHL patients treated at ≤ 25 mg twice daily.

• Responses occurred early with 20 of 21 responses by first assessment

(~ 2 mos)

Population

Patients, n Best Observed Response, n (%) Median Time to Response, Mos

(Range)Treated/Evaluable

ORR CR PR SD PD

iNHL 26/19* 13 (68) 3 (16) 10 (53) 4 (21) 2 (11) 1.8 (1.7-4.1)

MCL 9/6 4 (67) 1 (17) 3 (50) 1 (17) 1 (17) 1.8 (1.6-1.9)

T-cell 17/9 3 (33) 1 (11) 2 (22) 2 (22) 4 (44) 1.9 (1.7-2.7)

HL 3/3 1 (33) 1 (33) 0 1 (33) 1 (33) 1.7

aNHL 13/10 0 0 0 4 (40) 6 (60) N/A

Horwitz S, et al. ASCO 2013. Abstract 8518.

Potent oral inhibitor of PI3K-δ and PI3K-γ isoforms

Targeting ALK tyrosine kinase: crizotinib

• Crizotinib (PF-02341066) is an

ALK tyrosine kinase inhibitor that

has demonstrated activity in lung

cancers1,2

• In two case studies of patients

with relapsed ALCL, both patients

showed complete regression at 1

month; this persisted to 6 months

in one patient2

• Pilot study3 on 11 pts with RR

ALCL ALK+

• ORR in 10 of 11 (90.9%; 95% CI

58.7% to 99.8%)

• CR in 9 cases, 4 ongoing

• Safe toxicity profile

Images obtained before and after crizotinib

therapy in a patient with ALK-positive ALCL2

1. Kwak EL, et al. N Engl J Med 2010;363:1693–703.

2. Gambacorti-Passerini C, et al. N Engl J Med 2011;364:775–6.

3. Gambacorti-Passerini C, et al. INCI 2014

Images obtained before and after

crizotinib therapy in a patient with ALK-

positive ALCL2

Presentation at the 57th ASH Annual Meeting and Exposition on December 6, 2015.

BACKGROUND AND RATIONALE

AAK, Aurora A kinase; NHL, non-Hodgkin lymphoma; ORR overall response rate; PTCL, peripheral T-cell lymphoma; R/R, relapsed/refractory

1. Vose JM, et al. J Clin Oncol 2008;26:4124–30

2. Gallop-Evans E. Future Oncol 2015;11:2515–24

3. Niu H, et al. Front Oncol 2015;5:189

4. Nikonova AS, et al. Cell Mol Life Sci 2013;70:661–87

5. Zullo KM, et al. CCR 2015; 21 (18); 4097–4109

6. Friedberg JW, et al. J Clin Oncol 2014 ;32:44–50

7. Barr PM, et al. J Clin Oncol 2015;33:2399–404

Alisertib:

Preclinical

findings:

Phase 2 data:

Investigational, oral, selective inhibitor of Aurora A kinase, a

key mitotic regulator overexpressed or amplified in various

cancers2–4

Antitumor activity of alisertib as a single agent and

synergistic partner in combination therapies5

Support antitumor activity and favorable tolerability for

single-agent alisertib in R/R NHL and PTCL6,7

– ORR of 27% in R/R NHL and 30% in R/R PTCL subtypes


LUMIERE STUDY DESIGN

*Stratified by:

• Nodal vs extranodal disease

• IPI score (0/1/2 vs 3/4/5)

• Region (North America + EU vs Rest of World)†Crossover to alisertib after comparator arm was not permitted.

BID, twice daily; CR, complete response; DOR, duration of response; ECOG PS, Eastern Cooperative Oncology Group performance status; ECT, enteric-coated

tablet; IPI, International Prognostic Index; IRC, independent review committee; IV, intravenous; IWG, International Working Group; OS, overall survival; PFS,

progression-free survival; PR, partial response; SD, stable disease; WHO, World Health Organisation

Arm A: Alisertib

• 50 mg BID ECT

• Days 1–7; 21-day cycles

Gemcitabine (currently not approved for

use in hematologic malignancy)

• 1000 mg/m2 via IV over 30 minutes

• Days 1, 8, and 15; 28-day cycles

Romidepsin• 14 mg/m2 via IV infusion over 4 hours

• Days 1, 8, and 15; 28-day cycles

Arm B: Single-agent comparator

(investigator choice) †

Primary:

• ORR (CR+PR)

• PFS (IRC)

Secondary:

• OS (key)

• CR rate

• DOR

• Safety

Treatment

until disease

progression

or unacceptable

toxicity

(Patients

achieving ≥SD

could continue

treatment for

up to 2 years)

Eligibility

• Age ≥18 years

• R/R PTCL (WHO criteria)

after ≥1 prior conventional

systemic cytotoxic therapy

• Measurable disease

(2007 IWG criteria)

• Tumor biopsy for central

review

• ECOG PS 0–2

• No prior treatment with

study drugs

Pralatrexate• 30 mg/m2 via IV push (3–5 minutes)

• Once weekly for 6 weeks; 7-week cycles

• Vitamin B12 + folic acid supplements

Ra

nd

om

iza

tio

n 1

:1*


BEST OVERALL RESPONSE RATE*

*Response-evaluable population, excluding tMF

CI, confidence interval; OR, odds ratio; PD, progressive disease; tMF, transformed mycosis fungoides

35%

46%

19%

28%

17% 18%

30%

20%

Response, n (%)

Comparator

Alisertib (n=96) All (n=85) Pralatrexate (n=45) Gemcitabine (n=22) Romidepsin (n=18)

ORR (CR + PR) 34 (35) 39 (46) 20 (44) 8 (36) 11 (61)

CR 18 (19) 24 (28) 13 (29) 5 (23) 6 (33)

PR 16 (17) 15 (18) 7 (16) 3 (14) 5 (28)

SD 29 (30) 17 (20) 11 (24) 3 (14) 3 (17)

PD 33 (34) 29 (34) 14 (31) 11 (50) 4 (22)

ORR (Alisertib vs Comparator): 35% vs 46%

Odds Ratio 0.65 (95% CI: 0.36, 1.18) p=0.077

ORR CR PR SD ORR CR PR SD

Alisertib Comparator


PROGRESSION-FREE SURVIVAL BY IRC (ITT)

Alisertib vs Comparator:

Median PFS 115 vs 104 days

HR 0.87 (95% CI: 0.64, 1.16)

p=0.177

Su

rviv

al p

rob

ab

ility

1.0

0.8

0.6

0.4

0.2

0

0 60 120 180 240 300 360 420 480 540 600 660 720 780 840 900 960

Survival time (days)

133

138

65

84

35

46

26

33

20

23

10

15

9

12

4

6

4

5

3

4

3

4

3

2

1

1

1

1

0

1

0

1

0

0

Censored

PFS is defined as the time from the date of randomization to the date of first documentation of PD or death due to any cause,

whichever occurs first.

Lenalidomide in T-Cell Non-Hodgkin’s Lymphoma

• Phase II multicenter study for relapsed/refractory T-cell

lymphomas

– 39 eligible patients (14 PTCL-NOS, 9 AITL, 10 ALCL)

– Schedule: lenalidomide 25 mg on Days 1-21 every 28 days

• ORR: 26% (10/39); 3 CRs

– Responses in PTCL, AITL, and ALCL patients

• Median PFS: 4 mos (1 to 50+)

• Median OS: 12 mos ( 1 to 69+)

• Most common grade 3/4 AEs: thrombocytopenia (21%), pain

NOS (21%) and neutropenia (13%)

Toumishey E, et al. Cancer 2014.

PhI/II Combination with romidepsin: ORR 53% (10/19; CR 2, PR 8),Abs #16 @ICML N. Mehta-Shah et al. From MSKCC

The PD-1 immune checkpoint pathway may be co-opted by

tumors to evade immune attack.

Nivolumab is a fully human anti-PD1 IgG4 mAb which can

restore anti-tumor immune activity.

Nivolumab displays clinical activity across a number of solid

tumors; PD-L1 expression enriches for responders.

Background

MHC

PD-L1

PD-1PD-L2

T cell

Tumor cellNivolumab

T-cellreceptor

Topalian, et al. J Clin Oncol. 2014, McDermott, et al. J Clin Oncol. 2015

+

Wilcox et al, Blood 2009

Pre-clinical rationale for PD-1/PD-L1 blockade

PD-L1 expression on tumor cells (15%) or infiltrating macrophages (41%)

T cell lymphomas

Tumor Type#

ptsORR CR PR SD

Hodgkin Lymphoma 23 20 (87) 6 (26) 14 (61) 3 (13)

B-Cell Non-Hodgkin Lymphoma 31 8 (26) 3 (10) 5 (16) 16 (52)

Diffuse Large B-Cell 11 4 (36) 2 (18) 2 (18) 3 (27)

Follicular 10 4 (40) 1 (10) 3 (30) 6 (60)

Mantle Cell 4 0 0 0 3 (75)

Primary Mediastinal B-Cell 2 0 0 0 2 (100)

Other B-NHL (SLL n=3, MZL n=1) 4 0 0 0 2 (50)

T-Cell Non-Hodgkin Lymphoma 23 4 (17) 0 4 (17) 10 (43)

CTCL/MF 13 2 (15) 0 2 (15) 9 (69)

Peripheral T-Cell 5 2 (40) 0 2 (40) 0

Other T-NHL 5 0 0 0 1 (20)

Multiple Myeloma 27 1 (4) 1 (4) 0 17 (63)

Best Response




Peripheral T- cell Lymphoma

Conclusions

• PTCL is one of the most difficult lymphoma to diagnose and to treat

• Current approach is not based on evidences at all

• The "One therapy fits all" approach doesn't work in PCTL

• There are already data suggesting that a "personalized" approach in PTCL might work

• We need to enroll pts in clinical trials to learnmore about new drugs and therapies

MANAGEMENT OF PATIENTS WITH PERIPHERAL T …lymphomaforum.ch/docs/Luminari16Tcell.pdf · 06.12.2015 · MANAGEMENT OF PATIENTS WITH PERIPHERAL T-CELL LYMPHOMAS ... PTCL SUBTYPES.

Documents