Systemic T Cell Lymphomas

Massimo FedericoUniversity of Modena and Reggio Emilia

Città di Lecce Hospital - GVM Care & Research

My Disclosures

• Consultancy, Advisory Boards, Research funds

✓ Allos

✓ Spectrum

✓ Celgene

✓ Takeda

✓ Mundipharma

M. Federico, Kyiv, November 3-4, 2016

T-Cell LymphomasKey facts

• Orphan disease that needs more care

• Poor outcome

• (Too) Many different entities

• Uncertainity on standard treatment

Mature T- and NK- cell neoplasm (29

entities)

PTCLs: Epidemiology

• accounts for ~ 10% to 15% of all NHL

• rare in Western populations, prevalence slightly higher in Asia and Central–South America

• unique geographic distribution of different subtypes

• by some estimates, the incidence of PTCLs is growing significantly✓ may be driven by an aging population

✓ improvements in diagnosis techniques may also be driving the apparent growth in incidence

• Different clinical entities confirmed – fairly high rate of

different diagnosis on review

• Clinical outcomes different for subtypes; however many

have very poor outcomes with current therapies

• IPI or PIT may be helpful for prognosis and planning

• Outcomes not much different by anthracycline or

platinum agents used – alternative novel therapies needed

• Possible improvement by early intensive therapy – needs

confirmation with randomized clinical trials

Julie M. Vose

International Peripheral T-Cell Lymphoma ProjectCONCLUSIONS

www.tcellproject.orga project by the International T-Cell non-Hodgkin's Lymphoma Study Group

SouthAmerica

PTCL-NOS 41%AITL 8%ALCL,ALK- 26%ALCL,ALK+ 8%NKTCL 10%Extranodal PTCLs, other 4%Unclassifiable PTCLs 2%

North AmericaPTCL-NOS 35%AITL 21%ALCL,ALK- 13%ALCL,ALK+ 9%NKTCL 8%Extranodal PTCLs, other 11%Unclassifiable PTCLs 3%

Europe

Asia

PTCL-NOS 40%AITL 16%ALCL,ALK- 8%ALCL,ALK+ 13%NKTCL 11%Extranodal PTCLs, other 11%Unclassifiable PTCLs -

PTCL-NOS 37%AITL 21%ALCL,ALK- 14%ALCL,ALK+ 9%NKTCL 7%Extranodal PTCLs, other 9%Unclassifiable PTCLs 3%

Subtypes by geographic area(N=1391 validated Pts registered as of 30/04/2016)

PTCL-NOS 29%AITL 17%ALCL,ALK- 5%ALCL,ALK+ 5%NKTCL 29%Extranodal PTCLs, other 9%Unclassifiable PTCLs 6%

Middle East

CHOP, CHOP and once more CHO(E)P

Combination Chemotherapy in PTCL

Regimen Pts, n CR, % 5-yr OS, % Reference

CHOP 96144

-49

2632

RudigerLopez-Guillermo

ACVBP 228 49 35 Gisselbrecht

COPADEM-CYVE 77 52 40 Delmer

VACPE 27 77 48 Karakas

ESHAP 58 33 36 (2-yr) Bouabdallah

Meta-analysis of Frontline Anthracycline-Based Therapy for PTCL: overall survival

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

AITL Pautier et al, 1999Savage et al, 2004Sonnen et al, 2005Vose et al, 2008AITL summary estimate Fixed

Random

0.3600.3600.2800.3200.3210.321

0.217-0.5340.134-0.6720.155-0.4510.264-0.3810.272-0.3750.272-0.375

ALCL Gisselbrecht et al, 1998Savage et al, 2004 Sonnen et al, 2005 ALCL summary estimate Fixed

Random

0.6400.4300.6100.5730.565

0.512-0.7510.275-0.6000.394-0.7900.479-0.6620.428-0.692

Alk-neg ALCL Vose et al, 2008 Alk-neg ALCL summary estimate Fixed

Random

0.4900.4900.490

0.377-0.6040.377-0.6040.377-0.604

ETTL Savages et al, 2004 Vose et al, 2008 ETTL summary estimate Fixed

Random

0.2200.2000.2030.203

0.055-0.5770.118-0.3180.125-0.3120.125-0.312

Non-ALCL PTCL Gisselbrecht et al, 1998 Rudiger et al, 2002

0.3500.260

0.291-0.4140.182-0.357

PTCL-NOS Savage et al, 2004 Sonnen et al, 2005 Vose et al, 2008

0.3500.4500.320

0.269-0.4400.338-0.5670.273-0.371

PTCL combined Karakas et al, 1996 Kim et al, 2002Reiser et al, 2002

0.4800.5260.550

0.303-0.6630.415-0.6330.429-0.665

0% 50% 100%

▪ 31 studies: 2815 Pts; 5-yr OS (all PTCL): 38.5%

CHOP remains the standard of care for both PTCL-NOS and AITL

• VIP-rABV: etoposide, ifosfamide, cisplatin alternating with adriamycin, bleomycin, vinblastine, and dacarbazine

• PEGS: cisplatin, etoposide, gemcitabine, and methylprednisolone

• CHOP-EG: CHOP + etoposide e gemcitabine

Schmitz N & de Leval L, 2016

Is there something better than CHOP?

CHOP vs CHOEP

EFS of Pts <60 years and with normal LDH(NHL-B1 and HiCHOEP phase II/III trials)

▪ The addition of etoposide to CHOP (CHOEP) improves the EFS of young Pts with normal LDH, but not OS (P=0.176)

▪ In Pts >60 years neither shortening the time interval (CHOP-21 vs CHOP-14), number of cycles (8 vs 6 CHOP-14), or the addition of etoposide (CHOEP) yielded any advantage, mainly due to added toxicities

2010

▪ In patients > 60 years 6 courses of CHOP administered

every 3 weeks remains the standard therapy

▪ Patients with ALK-neg ALCL, PTCLU, or AITL presenting

with IPI > 1 have a poor prognosis and should be considered

candidates for novel treatment strategies

2010

•Role of HDT ASCT

Treatment of PTCLsOpen questions

Authors N° Pts Regimen TX rate CR rate PFS OS

Rodriguez2007

26 Mega CHOP+/- IFEBEAM ASCT

73% 89% 53 % ( 3yrs) 73% (3yrs)

Corradini2006

62 HDS or MACOP-B + Mito- AracMito/ Alk or BEAM ASCT

74% 66% 30 % (12yrs) 34 % ( 3yrs)

Mercadel2008

41 Mega CHOP/ESHAPBEAM ASCT

70% 51% 30 % ( 3yrs) 39 % ( 3yrs)

Reimer2008

83 CHOP CTX-TBI ASCT

66% 58% 36 % ( 3yrs) 48 % ( 3yrs)

D’ Amore2011

160 CHOEP14-BEAM ASCT 71% 56% 44 % ( 5yrs) 51 % ( 5yrs)

Sieniawsky2010

26* IVE/MTXMito /Melph TBI or BEAM-ASCT

53% 65% 52 % ( 5yrs) 60 % ( 5yrs)

Corradini 2014

61 A-CHOP + HyperCHIDAMASCT (14) Allo ASCT (23)

60% 54% 44 % ( 4yrs) 49 % ( 4yrs)

*All patients with diagnosis of EATL

First line chemotherapy and ASCT in PTCL:prospective phase II studies

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

60 mo median follow-up

160 patients

PLHSL T/NK

EATL

ALCL

AILTNOS

ORR pre-Tx 131 (82%)

CR/CRu 82 (51%)

PR 49 (31%)

% Tx 115 (72%)

CR/CRu 100d post-Tx 90 (56%)

5 yrs PFS 44%

5 yrs OS 51%

2012

21

Second PFS and OS of Patients with PTCL Treated at time of Relapse or Progression

31(16):1970-1976,2013

V. Mak et al.

22

Dismal outcome of t-cell lymphoma patients failing

first-line treatment: results of a population-based

study from the Modena Cancer Registry.

33: 147-151,2015

✓TCL failing first line systemic therapy

✓Diagnosis between 1997 and 2010

✓53 cases

Survival after relapse

median SAR 2.5 mo

3-yr SAR 19%

Survival after relapse according to

performance status and type of failure

In conclusion …..

▪ The outcome of PTCL continues to be dismal in the majority of cases

▪ No improvement in OS compared to older series

▪ Treatment remains challenging

▪ New therapies are welcome !

Therapeutic Options for T-Cell Lymphomas

Monotherapy with Biological Agents in R/R PTCL

Compound ORR

Monoclonal antibodies

Alemtuzumab (CD52) 36%1

Siplizumab (CD2) 31%2

Zanolimumab (CD4) 26%3

Mogamulizumab 34%4

HDAC inhibitors

Belinostat 26%5 (approved US)

Romidepsin 25%6 (approved US)

Antifolate

Pralatrexate 29%7 (approved US)

Biologic response modifiers

Denileukin Diftitox 40%8

Compound ORR

Antibody drug conjugates

Brentuximab vedotin (CD30)

86%9 (ALCL, approved US,EU)

Kinase inhibitors

Alisertib 24%10

Duvelisib 47%11

Crizotinib 90%12 (ALK+ ALCL)

Sorafenib 42%13

Farnesyltransferase inhibitor

Tipifarnib 50%14

Organic arsenic compound

Darinaparsin 28.6%15

References: 1. Enbald G. et al. Blood. 2004;103:2920-2924. 2. O’Mahony D. et al. CCR. 2009; 15:2514-2522. 3. d’Amore F. et al. BJH. 2010; 150:565-573. 4. Ogura M. et al. J Clin Oncol. 2014; 32:1157-1163. 5. O’Connor O.A. et al. J Clin Oncol. ASCO 2013; abstract 8507. 6. Coiffier B. et al. J Clin Oncol. 2012; 30:631-636. 7. O’Connor O.A. et al. J Clin Oncol. 2011; 29:1182-1189. 8. Foss F. et al. ASCO 2010; abstract 8045. 9. Pro B. et al. J Clin Oncol. 2012; 30:2190-2196. 10. O’Connor O.A. et al. ASH 2015; abstract 341. 11. Horwitz S. et al. ASH 2014; abstract 803. 12. Gambacorti Passerini C. et al. JNCI. 2014; 106:djt378. 13. Gibson J.F. et al. Br J Haematol. 2014;167(1):141–4. 14. Witzig T.E. et al. Blood. 2011;118(18):4882–9. 15. Hosein P.J. et al. Am J Hematol. 2012;87(1):111–4.

26

Response Rates Based on Overall IRC andInvestigators’ Assessments

Coiffier et al., JCO 2012 FDA APPROVAL

27

Romidepsin: Trials are examining in combination

✓First-line patients – In combination with chemotherapy

• Ro-CHOP

• Ro-CHOEP

• Ro-DHAP

– Maintenance

✓Relapsing patients– In combination with chemotherapy

• With bendamustine

• With gemcitabine

• Ro-ICE

RoCHOP Trial

• Open-label, randomized, phase 3 trial in 420 patients with untreated PTCL

Delarue R et al. J Clin Oncol. 2013;31 (suppl; abstr TPS8616).

Primary endpoint: PFS

Select secondary endpoints: OS, response rate, duration of response, safety, QoL

Randomizat ion

Romidepsin CHOP Q3 wk

CHOP Q3 wk

Romidepsin: 12 mg/m2 dosed days 1 and 8 of each CHOP cycle (6 cycles)Dose reductions allowed to 10 and 8 mg/m2

Treatment Phase

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

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

Response Evaluation

DHAP – Stem Cell Harvest

Follow-up

ORR: 26% (n 31; CR: 13; PR: 18)

These results have led to FDA and EMAapproval of belinostat for this indication

31

Pralatrexate—PROPEL Data

70% of responders did so in cycle 1 Central Review

n = 109

Investigator

Assessment n = 109

Best response n % n %

CR+CRu*PR 32 29% 43 39%

CR 11 10% 17 16

CRu 1 1% 3 3%

PR 20 18% 23 21%

Med DOR 10.1 months

Med PFS 3.5 months

Med OS 14.5 months

• Most common AEs:

• Mucositis (71%), nausea (41%),

thrombocytopenia (41%), and

fatigue (36%)

• Most common grade 3-4 AEs:

• Thrombocytopenia (33%),

mucositis (22%), neutropenia

(22%), and anemia (18%)AEs, adverse events; CR, complete response; CRu, CR

unconfirmed; DOR, duration of response; OS, overall survival; PFS,

progression-free survival; PR, partial response

O‘Connor OA, et al. J Clin Oncol. 2011;29(9):1182-1189.

FDA APPROVAL

Pralatrexate + Romidepsin: a well tolerated and effective combination for PTCL

Patients with PTCL 13

Patients dosed at the MTD (P 25 mg/m2 & R 12mg/m2 QOW) did not experience any toxicities

ORR 77%

CR 31%

DoR 6.55 months (range 1.6 – 26.5+)

Mean PFS 6.13 months (range 1.5 – 30.2+)

Amengual et al.ASH 2016; abs 1824; poster

33

Phase II Study of Brentuximab Vedotin in Patients

with R/R sALCL: Response and Outcomes

Pro B et al, 2012

IRF (N=58)

ORR, % (95% CI) 86 (74.6, 93.9)

CR, % (95% CI) 57 (43.2, 69.8)

PR, % 29

SD, % 3

PD, % 5

Histologically ineligible, % 3

NE, % 2

Median duration of OR, months (95% CI) 12.6 (5.7, NE)

Median duration of response in patients with CR, months (95% CI)

13.2 (10.8, NE)

Median PFS, months (95% CI) 13.3 (6.9, NE)

Median OS, months (95% CI) NR (14.6, NE)

12-mo OS, % 70

34

Phase II Study of Brentuximab Vedotin in

Patients with R/R sALCL

Pro B et al, 2012

97% of patients achieved tumour reduction

Long-Term Survival Data from Pivotal

Phase 2 Clinical Trial of BV in R/R sALCL

• Estimated Five-Year Overall Survival Rate was 60

Percent and Five-Year Progression-Free Survival

Rate was 39 Percent

• In the 66 Percent of Patients who Achieved

Complete Remission, Both Median Overall Survival

and Progression-Free Survival Not Yet Reached

• “Publication of the five-year follow up results

represents a significant milestone for the sALCL

community by demonstrating that treatment with

single-agent BV resulted in high response rates and

durable, long-term remissions

35October 3, 2017 (Press release)

36

2014

37

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

Primary objectives:

▪ Safety profile

▪ Determine recommended dose of brentuximabvedotin in combination with CHP

Secondary objective:

▪ Antitumor activity

Eligibility:

▪ CD30+ MTCL including sALCL

Fanale M et al. ASH 2013, New Orleans, LA, USA (Abstract 4386)

38

ECHELON-2: Phase III trial of brentuximab vedotin and CHP

vs. CHOP in frontline CD30+ mature T-cell lymphomas

Endpoints:• Primary: PFS per IRF

• Secondary:

- PFS per IRF for patients with sALCL

- Others: CR rates per IRF following completion of treatment, Overall survival, ORR

per IRF, Safety and tolerability

Study Design: Patients with newly diagnosed CD30+ MTCL

Brentuximab Vedotin

1,8 mg/kg q3w

+

CHP

21-day cycles

CHOP

21-day cycles

R

A

N

D

O

M

I

Z

E

E

V

A

L

U

A

T

I

O

N

39

Brentuximab vedotin or physician's choice in CD30-positive

cutaneous T-cell lymphoma (ALCANZA): an international,

open-label, randomised, phase 3, multicentre trial

Inclusion:

• Diagnosis of CD30-positive

MF or pcALCL

– ≥10% CD30-positive on either

neoplastic cells or lymphoid

infiltrate by central review of

≥1 biopsy (≥2 required for MF)

• MF patients with ≥1 prior

systemic therapy

• pcALCL patients with prior

radiotherapy or ≥1 prior

systemic therapy

Exclusion:

• Progression on both prior

methotrexate and bexarotene

Screening*

Ran

do

miz

ati

on

Methotrexate: 5–50 mg PO, weekly

or

Bexarotene: 300 mg/m² (target dose)

PO, daily

Brentuximab vedotin:

1.8 mg/kg IV, every 3 weeks

Up to 48 weeks (16 x 21-day cycles)End of

treatment

visit

Post-

treatment

follow-up

Every 12

weeks for

2 years

and then

every 6

months

thereafter

30 days

after last

dose of

study drug

*within 28 days of randomization

• Methotrexate or bexarotene was managed as standard of care, targeting maximum tolerated effective dose

• International study of 52 centers, 13 countries

Prince HM, Kim YH, et al. Lancet June 2017.

40

Youn H Kim et al.

• 131 pts (97 MF, 31 pcALCL, 3 excluded)

BV = 64 (1.8 mg/Kg IV, once every 3 weeks),

PC = 64:- MTX (5-50mg PO weekly)- Bex (300mg/m2 PO daily) for up to 16x 3 week cycles

41

Youn H Kim et al.

Endpoint BV N = 64

PCN = 64

Differences BetweenArms (95% CI)

Statistical Significance

Primary endopoint

ORR4, n (%) 36 (56.3%) 8 (12.5%) 43.8% (29.1, 58.4) p<0.0001

Key secondary endopoints

CR, n (%) 10 (15.6%) 1 (1.6%) 14.1 (-4.0, 31.5) p=0.0046 (adj)

Median PFS, months

16.7 3.5 p<0.0001 (adj)HR=0.270

(95% CI: 0.169, 0.430)

Mean maximumreduction in Skindex-29 symptom

domain, points

-27.96 -8.62 -18.9 (-26.6, -11.2) p<0.0001 (adj)

▪ Results at median follow-up 17.5 months

42

Brentuximab vedotin or physician's choice in CD30-positive

cutaneous T-cell lymphoma (ALCANZA): an international,

open-label, randomised, phase 3, multicentre trial

Prince HM, Kim YH, et al. Lancet June 2017 .

• Phase 3 Lumière trial of alisertib versus investigator’s choice (pralatrexate,

gemcitabine, romidepsin) in R/R PTCL (NCT01482962)1

Alisertib (Aurora A Kinase Inhibitor)

Comparator

Response Alisertib(n=96)

All pts (n=85) Pralatrexate (n=45) Gemcitabine (n=22)

Romidepsin (n=18)

ORR 36% 46% 44% 36% 61%

CR 19% 28% 29% 23% 33%

PR 17% 18% 16% 14% 28%

SD 30% 20% 24% 14% 17%

PD 34% 34% 31% 50% 22%

References: 1. O’Connor O.A. et al. ASH 2015; abstract 341. 2. Friedberg J.W. et al. J Clin Oncol. 2014; 32(1):44-50. 3. Barr P.M. et al. J Clin Oncol. 2015; 33(21):2399-2404.

Ongoing Clinical Trials

Agent Targeting site Phase ClinicalTrial.gov ID

Endostar Angiogenesis inhibitor II NCT02520219

Selinexor Selective inhibitor of nuclear export II NCT02314247

Tipifarnib Farnesyltransferase inhibitor II NCT02464228

Darinaparsin Organic arsenic compound INCT01435863

NCT01689220

Ixazomib Proteasome inhibitor II NCT02158975

Denileukin diftitox Interleukin fusion protein IINCT00050999

NCT00051012

Forodesine PNP inhibitor I/II NCT01776411

Ruxolitinib JAK inhibitor II NCT01431209

Temsirolimus mTOR inhibitor I NCT01614197

Carfilzomib Proteasome inhibitor I NCT01336920

Panobinostat Pan-deacetylase inhibitor II NCT01261247

Clofarabine DNA synthesis inhibitor I/II NCT00644189

MK2006 AKT inhibitor II NCT01258998

Sorafenib Multikinase inhibitor II NCT00131937

Alefacept Immunosuppressive dimeric fusion protein I NCT00438802

Pembrolizumab PD-1 antibody II NCT02535247

References: 1. Zhang Y. et al. J Hematol Oncol. 2016 Apr 12;9:37.

45

In conclusion …..

▪The outcome of PTCL continues to be dismal in the majority of cases;

▪Limited improvement in OS compared to older series;

▪Treatment remains challenging;

▪New therapies are welcome!

THE (TRUE) END