what is the best approach to the initial therapy of...

What is the best approach to the initial

therapy of PTCL?

standards of treatment? Should all

Jia Ruan, M.D., Ph.D.

Center for Lymphoma and Myeloma

Weill Cornell Medical College

New York Presbyterian Hospital

10/24/2015

5-10% of all NHL in Western countriesMost common: PTCL-nos, angioimmunoblastic, and ALCL

Higher incidence, 15-20% of all lymphomas, in AsiaMost common: PTCL-nos, NK/TCL, and ATLL

PTCL: uncommon and heterogenous

J Clin Oncol 2008;26:4124-4130

J Clin Oncol 2008;26:4124-4130

PTCL: outcome varies by subtypes and IPI

5-yr OS

Diagnosis % IPI 0/1 IPI 4/5

PTCL-NOS 32% 50% 11%

AITL 32% 56% 25%

ALCL, ALK+ 70% 90% 33%

ALCL, ALK- 49% 74% 13%

ATLL 14% 28% 7%

NKTCL, nasal 42% 57% 0

NKTCL, extranasal 9% 17% 0

Enteropathy-type 20% 29% 14%

Hepatosplenic 7% 0 0

Subcutaneous panniculitis-like 64% 60% 0

Initial Treatment of PTCL

Other than ALK+ ALCL, no standard of care for most.

Clinical trial

ALK+ ALCL– CHOP-21

– CHOEP-21

Other PTCL histologies– CHOEP

– CHOP‐14 or 21

– Dose adjusted EPOCH

– CHOP followed by IVE or ICE

– HyperCVAD

Consider consolidation with SCT

NCCN Guidelines 2015

PTCL: Can we do better than CHOP?

Adding to the CHOP backbone

CHOP + alemtuzumab

CHOP + denileukin diftitox

CHOP + bortezomib

CHOP + etoposide

Alternative intensive regimens

Upfront SCT consolidation

Novel strategies

ORR 60-80+%, CR 30-40+%

Durable remissions <20-30%

Schmitz et al., Blood 2010;116:3418-25

DSHNHL Studies: CHOP vs CHOEP

Analysis of Younger Patients with Normal LDH

3-yr EFS

ALCL, ALK+3-yr EFS

Other subtypes

91.2% vs 57.1% 60.7% vs 48.3%

•7 trials: DSHNHL

(1993-2007)

•320 patients

•CHOP or CHOEP

56% ALCL

21% PTCL

9% AITL

Improving on CHOPUpfront ASCT for PTCL: NLG-T-01

D’Amore et al J Clin Oncol 30:3093-3099

Phase 2 study by the Nordic Lymphoma Group (NLG)

N=160, 156 evaluable

Induction regimen with dose dense biweekly CHOEP

ORR 82%, CR 51%, transplant rate 72%

5-yr OS 51%, 5-yr PFS 44%

US Multicenter Retrospective Study

341 newly PTCL patients from 2000 to 2011 in 10 centers

PTCL-NOS (31%), ALCL (26%), AITL (23%), NK/T-cell

lymphoma (7%), ATLL (6%), and other (7%)

Frontline therapy

• CHOP-like regimens (70%)

• hyperCVAD/MA (6%)

• Other chemo (18%)

• Palliation (7%)

• Consolidation XRT (21%)

• Consolidation SCT (10%, 26 auto, 7 allo)

ORR 73%, CR 61% (ORR 69%, CR 58% with CHOP-like)

Abramson et al, Annals of Oncology 25: 2211–2217, 2014

Abramson et al, Annals of Oncology 25: 2211–2217, 2014

Inferior survival compared to DLBCLAll patients

Patients w SCT

SCT Survival benefit disappeared in

MVA adjusting to treatment response

US Multicenter Retrospective Study

Swedish Lymphoma Registry Study

755 newly PTCL patients from 2000 to 2009, 7.4% NHL

PTCL-NOS (34%), ALCL (29%), AITL (14%), EATL (9%),

NK/T-cell lymphoma (4%), and other (10%)

Frontline therapy (n=594, 78%)

• CHOP-like regimens (n=499)

• Other intensive chemo (n=43)

• Response rate 70% (n=570)

• CHOP: ORR 65% (n=343)

• CHOEP: ORR 75% (n=156)

• Consolidation SCT

• AutoSCT: 104 (18%)

• AlloSCT: 5 (1%)

Ellin et al, Blood 2014 124:1570-1577

Swedish Lymphoma Registry Study

Ellin et al, Blood 2014 124:1570-1577

Multivariate Survival Analysis in 252 Patients Up to Age 70 Treated with CHOP/CHOEP

AutoSCT

Superior OS and PFS

5-yr OS 51%, 5-yr PFS 44%

PFS benefit w adding etoposide in patients ≤ 60

Incorporating novel agents in

frontline therapies in PTCL

Novel Agents with Indications in TCL

Drugs Class Indications

Pralatrexate Antifolate FDA:PTCL (2009)

Romidepsin HDAC inhibitor FDA: CTCL (2009), PTCL

(2011)

Brentuximab

vedotin

Anti-CD30 ADC FDA: ALCL (2011)

Belinostat HDAC inhibitor FDA: PTCL (2014)

Mogamulizumab

(KW-0761)

Anti-CCR4 mAb Japan: CCR4 ATLL (2012)

Chidamide HDAC inhibitor China: PTCL (2014)

1 2 3 4 5 8 9 10 11 12 13 15 16 17 18 19 20 22 236 24 25 26 2714 217 28

Cycle 1 Cycle 2 Cycle 3 Cycle 4

Weeks

•Antifolate

•30 mg/m2 IV push × 6 weeks

•109 people treated, many types of T-cell lymphoma

•On average 3 prior treatment regimens

•ORR 29%, CR 11%, median DOR 10 months

•Common A/E: mucositis, thrombocytopenia, and fatigue

•FDA approval for relapsed / refractory PTCL in 2009

Antifolate: Pralatrexate

O’Connor et al J Clin Oncol 2011;29:1182-1189

Phase 2 Study of CEOP + Pralatrexate

University of Nebraska / NCI: NCT01336933

Newly Diagnosed

PTCL

Part A: CEOP D1-5

Part B: Pralatrexate D15,

D22, D29

q42D, 6 cycles

A

S

S

E

S

S

*: Consolidative ASCT permitted per investigator discretion.

*

Phase 2 Study of CEOP + Pralatrexate

1-yr PFS: 50%

2-yr PFS: 34%

1-yr OS: 64%

2-yr OS: 64%

33 evaluable patients, median age 62 years

Median 4 cycles of treatment

ORR 70% with CR 52%

15 patients (45%) went on to ASCT

A/Es included cytopenias, mucositis, sepsis

Advani et al, ASH2013 abstract 3044

Antibody-Drug Conjugates: Brentuximab Vedotin

Responses

Overall response rate (95% CI) 86% (75, 94)

Complete remission 57%

Partial remission 29%

•58 patients with relapsed systemic ALCL

•Brentuximab vedotin 1.8 mg/kg IV over 30 min every 21 days

•Maximum 16 cycles

•A/E: peripheral neuropathy, neutropenia, and thrombocytopenia

•FDA approval for sALCL in 2011

J Clin Oncol. 2012 Jun 20;30(18):2190-6

Brentuximab Vedotin: Phase II study in sALCL

•NCT01421667

•35 patients with PTCL enrolled: AITL (13) and PTCL-NOS (22)

•Median age 64

•CD30 expression ranged from 5-100%

•Brentuximab vedotin 1.8 mg/kg IV over 30 min every 21 days

•34 evaluable: ORR 41% (8 CR, 6 PR)

•Subset in AITL: ORR 54% (5 CR, 2 PR), median PFS 6.7 mon

•Safety data consistent with profile of BV

•No correlation of response to CD30 expression level

Brentuximab Vedotin: Phase II study in CD30+ TCL

Blood2014;123:3095-3100

Phase 1: Brentuximab Vedotin in Frontline Therapy

for CD30+ PTCL

BV 2 cycles

CHOP 6 cycles

BV 8 cycles

BV + CHP 6 cycles

BV 10 cycles

A

S

S

E

S

S

CR

PR

I

II

Group I: Sequential Therapy, n=13 (sALCL)

Group II: Combination Therapy, n=26 (sALCL 19, non-sALCL 7)

Fanale et al. J Clin Oncol 32:3137-3143

Phase 1: Brentuximab Vedotin in Frontline Therapy

for CD30+ PTCL

Fanale et al. J Clin Oncol 32:3137-3143

Combination Therapy (n=26)

ORR: 100%; CR 88%

Median PFS: NR

1-yr PFS 71%;1-yr OS 88%

Sequential Therapy (n=13)

ORR: 85%; CR 62%

Median PFS: 22.1 months

1-yr PFS 77%; 1-yr OS 85%

Phase 3 Study of Brentuximab Vedotin + CHP vs CHOP

ECHELON -2 Study (NCT01777152)

Consolidative ASCT permitted per investigator discretion

1o objective: PFS

2o objective: Response rates; OS; safety

Estimated enrollment: 450

Newly Diagnosed

CD30+ PTCL CHOP

6-8 cycles

BV + CHP 6-8 cycles

A

S

S

E

S

S

R

A

N

D

O

M

I

Z

E

*

*

JCO 2012;30:631-636

ASCO2013, abstract 8507; ICML2013, abstract 153

Histone Deacetylase (HDAC) Inhibitors

Agents Romidepsin Belinostat

Drug class Class I HDACi Class I&II HDACi

Dosing 14 mg/m2 IV 4h, weekly 3

of 4 wks

1000 mg/m2 IV 30min,

daily x 5, every 3 wks

PTCL subtypes PTCL PTCL AITL

Pt number 130 129 22

ORR 25% 26% 45%

CR 15% 10% 18%

TTR 1.8 months 5.6 wk

DOR 28 months 8.3 months 7.5 months

PFS 4 months N/A 5.8 months

OS 11.3 months N/A 9.2 months

Thrombocytopenia (gr 3/4)

Neutropenia (gr 3/4)

Anemia (gr 3/4)

24%

20%

11%

13%

13%

10%

Phase Ib/II Study of Romidepsin(Ro)-CHOP

The Lymphoma Academic Research Organisation (LYSARC)

NCT01280526

Newly Diagnosed

PTCLCHOP D1

Ro 12 mg/m² IV, D1, 8

8 cycles

CHOP D1

Ro (8-14) mg/m² IV, D1, 8

8 cyclesA

S

S

E

S

S

Ph1b

N=18

Ph2

N=19

Phase Ib/II Study of Romidepsin(Ro)-CHOP

Safety

25 (68%) of 37 patients had SAEs

Common grade 3-4 A/Es: febrile neutropenia (14%), physical

deterioration (14%), lung infection (11%), and vomiting (8%),

neutropenia (89%), and thrombocytopenia (78%).

Efficacy

ORR 68%: CR 51%, PR17%

18-month PFS 57%; 18-month OS 76.5%

Dupuis et al. Lancet Haematol 2015;2:e160

Phase 3 Study of Romidepsin(Ro)-CHOP vs CHOP

The Lymphoma Academic Research Organisation (LYSARC)

NCT01796002

Newly Diagnosed

PTCL

CHOP 6 cycles

Ro + CHOPRo 12 mg/m² IV, D1, 8

6 cycles

A

S

S

E

S

S

R

A

N

D

O

M

I

Z

E

1o objective: PFS


Phase 2 Study of Romidepsin Maintenance Following AutoSCT

Romidepsin

Maintenance

1o objective: 2-yr PFS post-transplant

2o objective: safety, 2-yr OS


NCT01908777MSKCC, U Washington, Weill Cornell

Newly

Diagnosed

PTCL

CHOP-based

AutoSCT+

A

S

S

E

S

S

CR1

PR1

Phase 1 Dose Finding Study of Belinostat (Bel)-CHOP

NCT01839097

Newly Diagnosed

PTCL

CHOP D1

Belinostat dose escalation

q21D, 6 cycles

A

S

S

E

S

S

*: 3+3 design to assess MTD of belinostat in combination with CHOP.


*

•MTD: romidepsin 14 mg/m2 and lenalidomide 25 mg

•Median dose: romidepsin 8 mg/m2 and lenalidomide 15 mg

•ORR 53% (10/19; CR 2, PR 8)

•Common A/E: cytopenias and fatigue

Phase I/II Study of Romidepsin and Lenalidomide

Mehta-Shah et al, Lugano 2015, abstract 016

Study Design: NCT01755975

Week 1

Cycle 1

Week 2 Week 3 Week 4 Week 1

Cycle 2

D1 D8 D15 D22

Lenalidomide, D1-21

Romidepsin Romidepsin Romidepsin

Results in 21 R/R TCL patients

NCT02232516

Newly Diagnosed

PTCL

Romidepsin D1, 8, 15

Lenalidomide D1-21

q28D, up to 1 year

A

S

S

E

S

S

*: 1o objective: efficacy

2o objective: safety; delay to cytotoxic chemotherapy


*

Phase II Upfront Study of Romidepsin and Lenalidomide

CCR2014;20:5240-54

Potential Molecular Therapeutic Insights

Management for T-cell lymphoma is challenging

Rare incidence and heterogenous biology

Standard of care should be clinical trial when possible

CHOP is inadequate as initial therapy for most

Addition of etoposide and consolidation SCT for fit patients

Novel agents alone / in combination are promising

HD consolidation vs maintenance strategies

Summary

Concerted efforts in research to improve

diagnostic precision and identify disease-

specific therapeutic targets.

Thank you!

Center for Lymphoma and Myeloma

Meyer Cancer Center

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