p eripheral t-c ell l ymphomas : h ow i m anage ptcl in the f rontline s etting professor of...

PERIPHERAL T-CELL LYMPHOMAS: HOW I MANAGE PTCL IN THE FRONTLINE

SETTING

Professor of Medicine and Experimental TherapeuticsDirector, Center for Lymphoid Malignancies

Columbia University Medical Center – College of Physicians and Surgeons

The New York Presbyterian HospitalNew York, N.Y.

Owen A. O’Connor, M.D., [email protected]

Center for Lymphoid Malignancies

PERIPHERAL T-CELL LYMPHOMAS: HOW I MANAGE FRONTLINE DISEASE

· Putting The T-cell Lymphomas in Context

· What Are the Optimal Upfront Treatment Considerations

· Bridging Patients with Relapsed or Refractory Disease with Novel Drugs

· Conclusion

MOST COMMON PTCL SUBTYPES

· PTCL-NOS is the most common subtype

· Anaplastic large cell lymphoma (ALCL) ALK+/- and angioimmunoblastic lymphoma are also common subtypes

1. Armitage J, et al. J Clin Oncol. 2008;26:4124–4130.

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

Peripheral T-cell lymphoma, not otherwise specified

Angioimmunoblastic T-cell lymphoma

Extranodal NK/T-cell lymphoma, nasal type

Adult T-cell leukemia/lymphoma

Anaplastic large cell lymphoma, ALK+

Anaplastic large cell lymphoma, ALK-

Enteropathy-associated T-cell lymphoma

Primary cutaneous anaplastic large cell lymphoma

Hepatosplenic T-cell lymphoma

Subcutaneous panniculitis-like T-cell lymphoma

Unclassifiable peripheral T-cell lymphoma

Other disorders

CLASSIFICATION OF PERIPHERAL T-CELL LYMPHOMA (PTCL)

· 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

1. Armitage JO, et al. Ann Oncol. 2004;15:1447–1449. 2. Adapted from Rodriguez J, et al. Crit Rev Oncol Hematol. 2008.3. Adapted from Swerdlow SH, et al. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. 2008.

Non-Hodgkins Lymphoma

Precursor Lymphoid

Neoplasms

T-Lymphoblastic Leukemia/Lymphoma

Cutaneous

Primary Cutaneous CD30+ T-cell

Disorders

Mycosis Fungoides (MF)

T-/NK-cell NeoplasmsB-cell Neoplasms

Extranodal

NK/TCL Nasal Type

Adult T-cell Leukemia/Lymphoma

T-cell Large Granular Lymphocytic

Leukemia

Subcutaneous Panniculitis-like TCL

Leukemic

Enteropathy- associated TCL

Hepatosplenic TCL

Aggressive NK-Cell Leukemia

T-cell Prolymphocytic Leukemia

Transformed MF

Mature T-/NK-cell Neoplasms

Primary Cutaneous Gamma/Delta TCL

Sézary Syndrome

Peripheral TCL-NOS

Nodal

Angioimmunoblastic TCL

Anaplastic Large Cell Lymphoma (ALK +/-)

20

08

WH

O C

las

sif

ica

tio

n

of

Ma

jor

Su

bty

pe

s2,

3

NH

L N

eo

pla

sm

G

rou

pin

g

Aggressive

NO IMPROVEMENTS IN SURVIVAL

Source: International T-Cell Lymphoma Project. J Clin Oncol. 2008;26:4124-4130 and courtesy of the T-Cell

Project Executive Committee, unpublished data.

PTCL PROGNOSIS

· Most PTCL subtypes have a worse prognosis than aggressive B-cell NHL– Median overall survival for most subtypes of PTCL is 1–3 years1,2

– 5-year overall survival is approximately 26%3

– ALK+ ALCL is an exception, with a 5-year survival of 65–90%2

Armitage JO, et al. Towards understanding the peripheral T-cell lymphomas. Ann Oncol. 2004;15:1447–1449. by permission of Oxford University Press.

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.

FIRST-LINE THERAPYClinical Trial Preferred

CHOP appropriate for ALCL alk+CHOEP, CHOP followed by ICE, CHOP followed by IVE

HyperCVAD

FIRST-LINE ConsolidationAll patients, except low risk IPI consider consolidation with high

dose therapy and stem cell rescue(ALCL ALK Positive is a subtype with good prognosis and dose not

need consolidative transplant if in remission

NCCN Practice Guidelines in Oncology v 3. 2011

NCCN- 2011 PTCL PRACTICE GUIDELINESFIRST LINE THERAPY





· Conclusion

Time

Pro

po

rtio

n

Anthracycline as part of initial tx CENSOR FAIL TOTAL MEDIANyes 98 173 271 2.1no 14 34 48 1.57

Test: p=0.14

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18

PTCL-NOS Cases by Anthracycline Initial Treatment

International T-cell Non-Hodgkin’s lymphoma Study Group, ASH 2005

OVERALL SURVIVAL BY INITIAL TREATMENT

Baseline with CHOP/CHOP-Like Therapy: PTCL-By IPI: Is there Favorable Risk Disease?

OS (Yrs)

Cum

ulati

ve S

urvi

val

0

0.2

0.4

0.6

0.8

1.0

0 2 4 6 8 10 12 14 16

CR: 64%PFS: 24%

0, 1 (n = 36)

2, 3 (n = 54)

4, 5 (n = 27)

Courtesy British Columbia Cancer Agency

ARE ETOPOSIDE CONTAINING REGIMENS BETTER?

Blood 2010;116:3418-25

PTCL subtype

N pts

ALCL alk+ 78

ALCL alk- 113

PTCL-NOS

70

AITL 28

Other 31

Total 320

Breakdown by Subtype of T-Cell Lymphoma

COLLECTIVE T-CELL LYMPHOMA EXPERIENCEOVERALL SURVIVAL AS FUNCTION OF HISTOLOGICAL SUBTYPES (N=295)

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1

Pro

por

tion

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

Months

1: ALK+ (n= 73)

2: ALK- (n= 108)

3: PTCL (n= 68)

4: AILT (n= 28)

5: T/NK (n= 18)

p-values 2 3 4 5

1 <0.001 <0.001 0.001 <0.001

2 0.350 0.958 0.339

3 0.537 0.700

4 0.472

ALK+: 88.8% (95% CI: 80.8%-96.8%)ALK-: 63.3% (95% CI: 53.9%-72.7%)

PTCL: 52.9% (95% CI: 40.2%-65.6%)AILT: 65.9% (95% CI: 47.7%-84.1%)T/NK: 48.9% (95% CI: 25.4%-72.4%)

3-years OS-rate:

Schmitz et al., Blood 2010;116(18):3418

EVENT FREE SURVIVAL OF 320 PATIENTS WITH T-CELL LYMPHOMA

ACCORDING TO HISTOLOGIC SUBTYPE

Eve

nt

Fre

e S

urv

ivia

l %

0

10

20

30

40

50

60

70

80

90

100

Months

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

ALCL/ALK+ (n=78)

ALCL/ALK- (n=113)

PTCLU (n=70)

AITL (n=28)

Other (n=31)

Schmitz et al., Blood 2010;116(18):3418

%

0

10

20

30

40

50

60

70

80

90

100

Months

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

p=0.057

non Etoposide (n=29)

Etoposide (n=69)

PATIENTS WITH OTHER MAJOR SUBTYPES (PATIENTS WITH ALK+ OR ALCL EXLCUDED)

GERMAN HIGH-GRADE NHL STUDY GROUP (DSHNHL)

www.lymphome.de/en/Groups/DSHNHL

EFS OF YOUNGER PATIENTS (18-60 YEARS, LDH<=UNV) TREATED ON THE NHL-B1 OR HI-CHOEP

PHASE II/III TRIALS Schmitz et al., Blood 2010;116(18):3418

CHOEP-14d x 3

CR, PR SD,PD

CHOEP-14d x 3

(stem cell collection)

NLG-T-01: 2001-2007 Design and schedule

HDT (BEAM)

CR, PR SD,PD

Follow-up

Excluded: 1) Alk pos ALCL T/0 2) CTCL3) Leukemic T-

NHL

Nordic PTCL project

d’Amore et al EHA 2009: abs.#53

NLG-T-01

• Intention-to-treat

Population

• Only 50% of patients in CR 3 months post ASCT

• Higher fraction than expected made it to ASCT


Subtype, % OS PFS

3 Yrs 5 Yrs 3 Yrs 5 Yrs

PTCL-U (n = 62) 51 47 43 38

AILT (n = 30) 57 52 54 49

ALCL, ALK- (n = 31) 77 70 64 61

Enteropathy (n = 21) 52 48 47 38

d’Amore F, et al. European Hematology Association 2009. Abstract 53.d’Amore F, et al. J Clin Oncol. 2012;30:3093-3099.

NLG STUDY: AUTOLOGOUS BMT IN FIRST REMISSION (MEDIAN F/U: 45 MOS)

Mos

OS

(%

)

10

80

60

40

20

0

PTCL-NOSAILTALCL, ALK-EATL

0 12 24 36 48 60 72

Log-rank test P = .21

Mos

PF

S (

%)

10

80

60

40

20

0

PTCL-NOSAILTALCL, ALK-EATL

0 12 24 36 48 60 72

Log-rank test P = .26

AUTOLOGOUS STEM CELL TRANSPLANTATION (AUTOSCT) AS FIRST-LINE THERAPY IN PERIPHERAL T-CELL

LYMPHOMAS (PTCL):RESULTS OF A PROSPECTIVE MULTICENTER STUDY

STUDY DESIGN

PTCL

Collection of stem cells

Cyc 120mg / kg+ TBI AutoSCT

CH

OP

-21

CH

OP

-21

CH

OP

-21

CH

OP

-21

CH

OP

-21

CH

OP

-21

De

xa

BE

AM

/ E

SH

AP

De

xa

BE

AM

/ E

SH

AP

PR/CR PR/CR PR/CR

Reimer et al., 2009

PTCL

n= 83

DeadCompleteRemission

Alive with Disease

n= 17n= 6n= 32

No autoSCT

n= 28


LYMPHOMAS (PTCL): OUTCOME

AutoSCT

n= 55

DeadComplete Remission

Alive with Disease

n= 23n= 2n= 3

N = 24 progressive disease

N = 2 patient request

N = 2 other

Reimer et al., 2009, JCO 27(1): 106-113

GERMAN PROSPECTIVE STUDY: OS AFTER ASCT IN FIRST REMISSION

• PIT group 1: 0 risk factors• PIT group 2: 1 risk factor• PIT group 3: 2 risk factors• PIT group 4: 3-4 risk factors

• N = 83• CHOP x 4-6• If ≥ PR, dexaBEAM or ESHAP• dexaBEAM or ESHAP ± TBI• Median follow-up: 33 mos

Reimer P, et al. J Clin Oncol. 2009;27:106-113.

Nontransplanted patients did poorly

Poor-risk patients did poorlyPro

po

rtio

n A

ch

iev

ing

OS

1.0

0.8

0.6

0.4

0.2

00 12 24 36 48 60

Mos

P < .001

Transplanted (n = 55)

Nontransplanted (n = 28)

Pro

po

rtio

n A

ch

iev

ing

OS

1.0

0.8

0.6

0.4

0.2

00 12 24 36 48 60

Mos

P = .0414

PIT group 2 (n = 34)

PIT group 4 (n = 3)PIT group 3

(n = 21)

PIT group 1 (n = 25)

ASCT 1st line in PTCLOS + PFS in the two largest PTCL-restricted ASCT trials

OS NLG-T-01(EHA 09)

Reimer et al(JCO 09)

3-yrs 57% 48%

5-yrs 50% 40%

PFS NLG-T-01(EHA 09)

Reimer et al(JCO 09)

3-yrs 49% 36%

5-yrs 43% n.d.

InductionConditioning

regimen

Nordic trial CHOEP-14 x6 BEAM

German trial

CHOP-21 x4-6+ DexaBEAM (mobilizing)

HdCy+TBI

Differences in treatment schedule

NLG-T = Etoposide in Induction vs Reimer = No Etoposide in Induction

AUTOLOGOUS STEM CELL TRANSPLANT IN FIRST REMISSION – PROSPECTIVE DATA

Study Author(Yr)

n Regimen Transplanted, % Outcomes, %

Corradini(2006) 62 Mitoxantrone/

melphalan or BEAM 73 12-yr EFS: 3012-yr OS: 34

Rodriguez(2007) 26 MegaCHOP ± IFE 73 3-yr PFS: 56

3-yr OS: 84

Mercadal(2008) 41 High-dose

CHOP/ESHAP 41 4-yr PFS: 304-yr OS: 39

Reimer(2009) 83 dexaBEAM or ESHAP

± TBI 66 3-yr PFS: 363-yr OS: 48

d’Amore(2011) 160 CHO(E)P-14 x 6 ±

BEAM/BEAC 71 5-yr OS: 515-yr PFS: 44

Corrandini P, et al. Leukemia. 2006;20:1533-1538. Rodriguez J, et al. Eur J Haematol. 2007;79:32-38.Mercadal S, et al. Ann Oncol. 2008;19:958-963. Reimer P, et al. J Clin Oncol. 2009;27:106-113. d’Amore F,

et al. ASH 2011. Abstract 331.

ICE and Planned ASCT for Relapsed/Refractory T-cell Lymphoma: PFS from ICE

ALL, N=40 Rel, N=22

Ref, N=18

Horwitz et al, ASH 2005

Response to ICE 70% (28/40) Received ASCT 68% (27/40)

0 12 24 36 48 60 72 84 96 108 120 132

PFS ICE months

0.0

0.2

0.4

0.6

0.8

1.0

%

Progress Free Survival

0 12 24 36 48 60 72 84 96 108 120 132

PFS ICE months

0.0

0.2

0.4

0.6

0.8

1.0

%

PFS: Relapsed versus Refractory

PTCL is Not DLBCL





· Conclusion

70% of responders did so in Cycle 1

Central Review(N=109)

InvestigatorAssessment

(N=109)

n Percent n Percent

Best Response

CR+CRu+PR 32 29% 43 39%

CR 11 10% 17 16%

CRu 1 1% 3 3%

PR 20 18% 23 21%

SD 21 19% 22 19%

PD 40 37% 40 37%

UE 2 2% 0 0%

ND: off-treatment in Cycle 1 14 13% 5 5%

SUMMARY OF RESPONSEPROPEL

O. A. O’Connor et al., JCO, 2011; 29(9): 1182-1189

CASE MATCHING PROCEDURES USING 4 DATABASES FROM 3 CONTINENTS

MSKUNMCGELASMCTotalTimeframe1997-20111984-20101997-20081995-20071984-2011

N17176117504868

Patients with: Relapsed/refractory PTCL Appropriate histology

No pralatrexate

Matched by:(1) Histology(2) No. therapies(3) Age ranges(4) Gender

Medical review

1:1 match

Historical control

N

PralatrexateN

868 -

390 109

280 75

92 75

66 66MSK UNMC GELA SMC22 13 22 9

Very Closely Matched Patients Populations

Courtesy Charlie Morris

SIGNIFICANT IMPROVEMENT IN OS VERSUS MATCHED CONTROLS

Pralatrexate

Matched Controls

Hazard Ration = 0.394 (95% CI: 0.259, 0.600)

Courtesy Charlie Morris

PROPEL: AS 2ND LINE THERAPY AFTER CHOP FAILURE

15/109 had previously received CHOP as their first-line therapy

11/15 had a prior response to CHOP (7 CR, 4 PR)

2/15 remained on treatment at the time of data cut-off (12.9 and 18.5 months)

2 patients proceeded to SCT after response to pralatrexate (censored at 2.3 and 3.3 months)

Remain in CR and disease free at publication (20.1 and 21.7 months)

Shustov, et al, Blood (ASH Annual Meeting Abstracts) 2010 116: Abstract 4882

PROPEL: SUMMARY OF EFFICACY AS SECOND-LINE TREATMENT FOLLOWING

CHOP FAILURE

*ND- not determined, as there were insufficient events at the time of last follow-up; **per a Kaplan-Meier estimateCR=complete response; CRu=complete response unconfirmed; PR=partial response; SD=stable disease; PD=progressive disease; DoR=duration of response; PFS=progression-free survival; OS=overall survival.

Shustov, et al, Blood (ASH Annual Meeting Abstracts) 2010 116: Abstract 4882

Efficacy Assessments Central Review Assessment (n=15), %

Investigator Assessment (n=15), %

Tumour ResponseORR (CR+CRu+PR) 7 (47) 6 (40)CR 3 (20) 4 (27)CRu 0 (0) 1 (7)PR 4 (27) 1 (7)SD 4 (27) 4 (27)PD 4(27) 4 (27)Not Evaluable 0 (0) 1 (7)

Median DoR ND* 12.5 mthsMedian by PFS** 8.1 mths 7.4 mthsMedian OS ND* ND*

SINGLE-AGENT ROMIDEPSIN IN RELAPSED PERIPHERAL T-CELL LYMPHOMA: EFFICACY

• Responses reported in PTCL (not otherwise specified) (29%), angioimmunoblastic TCL (33%), and ALK1– ALCL (24%)

• Similar response rates in patient subgroups according to number of prior therapies (< 3 vs. ≥ 3), prior SCT (yes vs. no), and refractory to most recent therapy (yes vs. no)

Coiffier et al. JCO, 2012; Jan. 23 (epub ahead of print)

ResponseIndependent Review

Committee Analysis (n = 130)

Overall Response Rate 34 (26%)

Complete response 10 (8%)

Unconfirmed complete response 7 (5%)

Duration of Response Median (Range)

Overall 12 (< 1.0-26.0+) months

Complete response/unconfirmed complete response

Not reached (< 1.0-26.3+) months)

International PTCL Study

Subtype (n) CD30 Expression (%)

0-5% 6-49% 50-80% >80%

PTCL-NOS (168) 54 32 7 7

AITL (167) 55 42 2 1

EATL (27) 74 11 4 11

ATLL (120) 50 37 8 5

Nasal NK/T (73) 53 34 6 7

Extranasal NK/T (30)

27 27 23 23

Courtesy Dennis Weisberger, University of Nebraska

REDUCED-INTENSITY ALLOGENEIC BMT IN RELAPSED PTCL: RETROSPECTIVE DATA

• 52 patients; 12 had DLI for relapse• Chemosensitive patients (n = 39) did better • Patients who had > 2 previous regimens (n = 13) had inferior outcomes

Dodero A, et al. Leukemia. 2012;26:520-526.

100

75

50

25

0

Su

rviv

al

(%)

Yrs After Transplantation

120 1 2 3 4 5 6 7 8 9 10 11

50%

40%

OSPFS

100

75

50

25

0

PF

S (

%)


120 1 2 3 4 5 6 7 8 9 10 11

51%

8%

SensitiveRefractory

P < .0001

100

75

50

25

0P

FS

(%

)


120 1 2 3 4 5 6 7 8 9 10 11

54%

16%

≤ 2 previous regimens> 2 previous regimens

P < .0026

100

75

50

25

0

OS

(%

)


120 1 2 3 4 5 6 7 8 9 10 11

PTCL-NOSAILDALCLOthers

P = NS

Confirm Hematopathology : CD30, CD52 Expression

Baseline CT/PET and Bone Marrow Biopsy, full skin exam with punch biopsy of suspicious lesions; HLA Typing, viral studies including HTLV-1, HIV

Combination Chemotherapy: EPOCH / CHOEP x 6 – 8 cycles

Complete Remission

Autologous Stem Cell Transplant

Partial Remission or Worse

PralatrexateRomidepsinBrentuximabGemcitabine

Partial Remission or Worse

Consider Allogeneic Stem Cell TransplantPalliative Care

AN ALGORITHM FOR THE MANAGEMENT OF PTCL-NOS UPFRONT

Relapse

Complete Remission

Peripheral T-Cell Lymphomas: How I Manage Frontline Disease

• CHOP clearly inferior, but is a regulatory standard. Integrating

etoposide may provide advantage?

• Caution removal of doxorubicin based upon the T-cell Lymphoma

Project

• Consolidation with ASCT probably beneficial, and more so then in the

relapsed or refractory setting

• Allogeneic stem cell transplant should be considered in eligible patients with

R/R disease

• USE NEWER FDA APPROVED DRUGS earlier in the natural history of

the disease.

• Many new studies emerging as CHOP additions (Pralatrexate,

Romidepsin, Brentuximab vedotin, Belinostat)

THANK YOU



· Defining ‘Standards of Care’ for Upfront Treatment (won’t take long)

· Newly Emerging Options for Advanced (R/R) Disease: Is combination the right way to go?

- Pralatrexate in Relapsed/Refractory PTCL

- Targeting the Epigenome in PTCL

- Targeting CD30+ T-cell Malignancies

· Conclusion

NCCN GUIDELINESFOR RELAPSED OR REFRACTORY PTCLSA

CLINICAL TRIAL IS RECOMMENDED FIRST!

a Reproduced from NCCN Practice Guidelines in Oncology – v.2.2009.b See suggested regimens (TCEL-B).

Clinical trial preferred for 1st and 2nd relapse; no therapies other than clinical trial described

for 2nd relapse

Relapsed/ refractory disease

Relapsed/Refractory

disease

Clinical trialpreferred

-or-Second-line

therapyb

Clinical trial preferred-or-

Second-line therapyb

-or-Palliative RT

Completeresponse

-or-Partial

response

No response

Clinicaltrial-or-

Auto- orallo- SCT

Clinical trial

Clinical trial-or-

Best supportive care-or-

Palliative RT

Candidate for high-dose

therapy

Non-candidatefor high-dose

therapy

Relapse #2 or greater

Consolidation/ additional therapy

Response#2

Additional therapy

MECHANISM OF ACTION AND BIOMARKER DISCOVERY RFC-1; FPGS; DHFR; GARPH; OTHER?

RFC-1

Cell membrane

Extracellular

Cytosol

Pralatrexate >> > Methotrexate

DNA

10-formyl

THF

5.10-methenyl

THF

Pralatrexate

THF

Folate

DHF

PRPP

GARFT

Pralatrexate-Glu(n)

IMP

AICARFT

AMP

GMP

dUMP

dTMP

DHFR

RNADNA

TS

FPGS

RFC-1

Adapted from Jaffe et al. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. 2001.

T-/NK-cell neoplasms

Extranodal Leukemic

Mature T-/NK-cell neoplasms

NodalCutaneous

Precursor lymphoid

neoplasms

Blastic NK lymphoma

Precursor T/NK neoplasms

Mycosis fungoides (MF)

Transformed MF Sézary Syndrome Primary cutaneous

CD30+ disorders: ALCL and lymphomatoid papulosis

T/NK-cell lymphoma – nasal

Enteropathy-type intestinal lymphoma

Hepatosplenic T-cell lymphoma

SubcutaneouspanniculitisT-cell lymphoma

Peripheral T/NK-cell lymphoma unspecified

PTCL –unspecified

Anaplastic large-cell lymphoma, primary systemic type

Angioimmuno-blastic T-cell lymphoma

Adult T-celllymphoma/ leukemia (HTLV1+)

T/NK-cell leukemia/ lymphoma

T-cell prolymphocytic leukemia (T-PLL)

T-cell large granular lymphocytic leukemia

ELIGIBLE HISTOLOGIESPROPEL

PROPEL

N=111

Number of Regimens n Percent

1 23 21%

2 30 27%

3 23 21%

4 14 13%

≥ 5 21 19%

Median (range) 3.0 (1-12)

53% of patients had no evidence of response tothe most recent line of prior therapy

25% of patients had no evidence of response toany prior therapy

NUMBER OF PRIOR SYSTEMIC REGIMENS


PROPEL

Parameter Category IWC Response Rate 95% CI

RegionNorth America

Europe27 / 85 (32%)5 / 24 (21%)

(22%, 43%)(7%, 42%)

Histology

PTCL NOSAnaplastic LC

AngioimmunoblasticTransformed MF

Other

19 / 59 (32%)6 / 17 (35%)1 / 13 (8%)

3 / 12 (25%)3 / 8 (25%)

(21%, 46%)(14%, 62%)(0%, 36%)(5%, 57%)(9%, 76%)

Prior transplantYesNo

6 / 18 (33%)26 / 91 (20%)

(13%, 59%)(20%, 39%)

RESPONSE BY KEY SUBSETS

OO. A. O’Connor et al., JCO, 2011; 29(9): 1182-1189

RESPONSE BY PRIOR TREATMENTPROPEL

Parameter Category Response Rate 95% CI

Prior systemictherapy

1 regimen2 regimens

> 2 regimens

8 / 23 (30%)7 / 29 (24%)

17 / 57 (30%)

(16%, 57%)(10%, 44%)(18%, 43%)

Best Response to Any Prior Therapy

CR / PRSD / PD / Unknown

25 / 83 (30%)5 / 26 (19%)

(21%, 41%)(7%, 39%)

Response to Most Recent Therapy

CR / PRSD / PD

Unknown

13 / 40 (32%)14 / 57 (25%)3 / 12 (25%)

(19%, 49%)(14%, 38%)(5%, 57%)

Prior Methotrexate

YesNo

5 / 21 (24%)25 / 88 (28%)

(8%, 47%)(19%, 39%)


DURATION OF RESPONSE BY CENTRAL REVIEWPROPEL

1.00

0.75

0.50

0.25

00 3 6 9 12 15 18

Months

Pro

po

rtio

n

Number of Responders = 30Median duration = 10.1 months

Permanently censored (eg, transplant) (n = 8)

Continue in follow-up for response (n=7)

Follow-up exceeds 6 months for all patients who continue in follow-up for response

SCT

SCT

SCTSCT


Updated

GPI 06-0002 RegistrationTrial

Romidepsin14 mg/m2

days 1,8,15of a 28 day cycle

OBJECTIVE

Response Rate

Response Duration

Safety

Patient Criteria:PTCLRelapsed orprogressive

>1 prior systemic therapy

NCI Trial (NCI 1312)

Romidepsin14 mg/m2

days 1,8,15of a 28 day cycle

OBJECTIVE

Response Rate

Response Duration

Safety

Patient Criteria:PTCLRelapsed orprogressive

>1 prior “chemotherapy”

ROMIDEPSINONGOING STUDIES IN PTCL

PHASE 2 ROMIDEPSIN IN PTCL

RESPONSE RATES

All Pts N=48

Pts ≥ 2 cycles**N=34

ORR (CR+PR), n (%) 15 (31%) 15 (44%)

CR*, n (%) 4 (8%) 4 (12%)

PR, n (%) 11 (23%) 11 (32%)

SD, n(%) 7 (15%) 7 (21%)

s Piekarz et al., Blood, 2011; 117(2):5827-5834

Overall Response Rates

PHASE 2 ROMIDEPSIN IN PTCL RESPONSE DATA

Duration of Response (DOR) &Time to Disease Progression (TTP)

Median time to first response was 1.8 (1-6) months

Population N*Median (range) DOR

in monthsMedian (range) TTP

in months

ORR (CR & PR) 15 9 (2 – 61+) 12 (4 – 63+)

CR 4 34 (3 – 61+) NR (14 – 63+)

PR 11 8 (2 – 41+) 10 (4 – 42+)

SD 7 – 9 (3 – 26+)

PD 19–

1.4 (.2– 4)

*7 patients were not evaluable; NR, median not yet reached; + denotes continuing responsePiekarz et al., Blood, 2011; 117(2):5827-5834

PHASE II TRIAL OF ROMIDEPSIN IN RELAPSED OR PROGRESSIVE PERIPHERAL T-CELL

LYMPHOMA FOLLOWING PRIOR SYSTEMIC THERAPY

• Patient population: – 131 enrolled– 130 with confirmed PTCL– Failed ≥ 1 prior systemic therapy

• Treatment regimen: romidepsin 14 mg/m2, days 1, 8, and 15 q 28 days × 6 cycles; continued beyond 6 cycles in responding patients at investigator and patient discretion

• Primary endpoint: CR/CRu by independent review• Secondary endpoints including: ORR, duration of response,

TTP, tolerability, and safety

Coiffier et al. JCO, 2012; Jan. 23 (epub ahead of print)



· Defining ‘Standards of Care’ for Upfront Treatment (won’t take long)

· Newly Emerging Options for Advanced (R/R) Disease: Is combination the right way to go?

- Pralatrexate in Relapsed/Refractory PTCL

- Targeting the Epigenome in PTCL

- Targeting CD30+ T-cell Malignancies

· Conclusion

CD30 Expression in in Non-Lymphoma Tumors

Acute Myeloid Leukemia/Granulocytic Sarcoma– M Fickers 1996, J Clin Pathol 49: 762-

3; R Horie 1999, Am J of Path. 155: 2029-41

ALL and AML – Gattei 1997, Blood 89: 2048-59

Bone sarcomas – G Mechtersheimer 1990, Cancer 66:

1732-37 Lung (Adenocarcinoma)

M Garcia-Prats 1998, Histopathology 32: 462-472

Mastocytosis Sotlar 2010, Modern Pathology, 1-11

Mesothelioma– M Garcia-Prats 1998, Histopathology

32: 462-472; C Dunphy 2000, Arch Pathol Lab Med 124: 1077-79

Melanoma– Internal data on file

Nasopharyngeal carcinoma Kneile 2006, Histopathology 48: 855-

861 Testicular embryonal carcinoma

– J Ferreiro 1994, Hum. Pathol. 25:522-524; K Iczkowski 2008, Hum. Pathol. 39: 275-281

Thyroid Carcinoma (Medullary, Papillary)– M Trovato 2001, Thyroid 11: 621-8

Cervical, Head and Neck SCC (Viral-associated cancers), Lung, Breast, Endometrial, Ovarian,Prostate, & Melanoma– Human protein atlas

(http://www.proteinatlas.org/ENSG00000120949/cancer)

CD30 Expression in DLBCL

Citation CD30+ High CD30+

Stein et al., 1985 4% (2/45) 0% (0/45)

Norton et al., 1987 11% (3/28) 7% (2/28)

Hall et al., 1988 10% (6/60) 2% (1/60)

Schwarting et al., 1989 29% (35/121) 9% (11/121)*

Miettinen, 1992 38% (14/37) 11% (4/37)

Noorduyn et al., 1994 40% (36/91) 23% (21/91)

Eow et al., 2006 4% (3/67) 0% (0/67)

Total 22% (99/449) 9% (39/449)

Courtesy Dennis Weisberger, University of Nebraska

Anaplastic Large cell Lymphoma: A Unique Entity Among PTCL

• sALCL is a CD30-positive aggressive subtype of peripheral T-cell lymphoma

• 4065% of patients develop recurrent disease after initial multiagent chemotherapy1

• To improve OS, durable responses must be attained – few therapies available for this unmet need

1 Savage et al, 20082 Data provided by J. Connors, BC Cancer Agency

Sur

viva

l

Time (years)

Median = 3.3 monthsN = 61

Overall Survival After Failure of Primary Therapy2

BRENTUXIMAB VEDOTIN MECHANISM OF ACTION

Brentuximab vedotin (SGN-35) ADCmonomethyl auristatin E (MMAE), potent antimicrotubule agent

protease-cleavable linker

anti-CD30 monoclonal antibody

ADC binds to CD30

MMAE disruptsmicrotubule network

ADC-CD30 complex traffics to lysosome

MMAE is released

Apoptosis

G2/M cellcycle arrest

DEMOGRAPHICS AND BASELINE CHARACTERISTICS

N=58

Age* 52 yr (1476)

Gender 33 M / 25 F

ECOG status

0 33%

1 66%

2 2%

ALCL confirmed by central pathology 97%

ALK-negative 72%

Refractory to frontline therapy 62%

Refractory to most recent treatment 50%

No response to any prior treatment 22%

Prior chemotherapy regimens* 2 (16)

Prior radiation 45%

Prior ASCT 26%

* Median (range)

R. Advani, ASH Abstract 443, 2011

KEY RESPONSE RESULTS SUMMARY

N=58

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

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

CR rate (95% CI) 57% (43, 70)

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

13.2 mo (10.8, )

Median PFS (95% CI) 13.3 mo (6.9, )

Median OS Not reached


Maximum Tumor Reduction

97% of patients achieved tumor reduction

Individual Patients (n=57)

Tum

or S

ize

(% C

hang

e fr

om B

asel

ine)

Complete remission


PFS by Disease Response

Median PFS(months)

CR 14.6PR 4.2SD 2.7PD 1.2HI*

Time (months)

% P

atie

nts

Fre

e of

PD

or

Dea

th

* Histologically ineligible


PFS: Brentuximab Vedotin vs. Last Prior Therapy

91% of the most recent prior therapies were multiagent chemotherapy or ASCT

Time (months)

% P

atie

nts

Fre

e of

PD

or

Dea

th

* Investigator-assessed

PFS brentuximab vedotin*; median = 14.3 monthsPFS last prior therapy; median = 5.9 monthsHR=0.48 (p=0.001)


STRATEGIES TO IMPROVE UPFRONT THERAPY FOR PTCL

CHOP based

+ Etoposide- CHOEP, EPOCH

+ Alemtuzumab+ Pralatrexate+ anti CD4+ anti CXC4+ lenalidomide+ Brentuximab vendotin

Novel combinations

PEGS (cisplatin, etoposide, gemcitabine,

methylprednisolone)

Pralatrexate + Bortez + SAHA

Pralatrexate + Romidepsin

Novel targeted agents + monoclonal antibodies

Thank You


LYMPHOMAS (PTCL): IMPROVED OVERALL SURVIVAL WITH ASCT

Overall Survival(IPI: high/intermediate high vs. low/intermediate low)

0

0,2

0,4

0,6

0,8

1

0 12 24 36 48 60

Time (months)

IPI: high/intermediate high (n=42) IPI: low /intermediate low (n=41)

p= 0,1799p= 0,1799

Overall survival

IPI: high / interm.high vs. low / interm.low

high / interm.high (n= 42) low / interm.low (n= 41)

Overall Survival(Transplanted vs. non-transplanted)

0

0,2

0,4

0,6

0,8

1

0 12 24 36 48 60

Time (months)

non-transplanted (n=28) transplanted (n=55)

p< 0.001p< 0.001

Overall survival

Transplanted vs. non-transplanted

time (months)

transplanted (n= 55) non-transplanted (n= 28)

estimated 3-year OS: 71% vs. 11%

Reimer et al., 2009, JCO 27(1): 106-113

NLG-T-01: OS + PFS (Med follow-up 45 mos)Subtype Analysis

0.00

0.20

0.40

0.60

0.80

1.00

0 12 24 36 48 60 72analysis time

rhistdia = ptcl, nos rhistdia = aildrhistdia = alcl, alk neg

OS : ALCL, AIL, PTCL-NOS

0.00

0.20

0.40

0.60

0.80

1.00

0 12 24 36 48 60 72analysis timerhistdia = ptcl, nos rhistdia = aild

rhistdia = alcl, alk neg

PFS : ALCL, AIL, PTCL-NOS

OS PFSSubtype 3-yr 5-yr 3-yr 5-yrPTCLu (n=62) 51% 45% 43% 34%

AIL (n=30) 57% 50% 54% 47%

ALCL alk-neg (n=31) 77% 73% 64% 64%

Enteropathy (n=21) 52% 44% 47% 40%


PROPEL: PRIOR ICE

20/109 had previously received ICE-based regimen 2nd line

ORR to ICE-based regimens was 25% (3 CR, 2 PR)

Median duration on treatment for responders was <1 month

9/20 received an ICE-based regimen immediately before pralatrexate

Of those 9, 2 did not respond to the ICE-based regimen, but did respond to pralatrexate (1 CR, 1 PR)

Goy A, et al, Blood (ASH Annual Meeting Abstracts) 2010 116: Abstract 1753

PROPEL: PRIOR ICE (N=20)

• ORR (CR + PR): 40% • CR: 25% by Investigator Assessment• Median Duration of Response: 16.2 months by Investigator

Assessment

Efficacy AssessmentsCentral Review Assessment

(n=20), %Investigator Assessment

(n=20), %Tumor Response

ORR (CR+PR) 8 (40) 8 (40)

CR 5 (25) 3 (15)

PR 3 (15) 5 (25)

SD 5 (25) 2 (10)

PD 6 (30) 4 (20)

Not Evaluable 1 (5) 6 (30)

Median DoR 16.2 mths 13.1 mths

Goy A, et al, Blood (ASH Annual Meeting Abstracts) 2010 116: Abstract 1753

p eripheral t-c ell l ymphomas : h ow i m anage ptcl in the f rontline s etting professor of...

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