novel treatment strategies in peripheral t-cell lymphomas · novel treatment strategies in...

Novel treatment strategies

in peripheral T-cell

lymphomas Prof. Paolo Corradini

Dept. of Hematology and Bone Marrow Transplantation

Chair of Hematology University of Milano,

Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy

Adapted from Vose JM, et al. J Clin Oncol. 2008;26:4124-‐30.

PTCL: Epidemiology

PTCL NOS

AILT

E NK/T

ATLL

ALCL, ALK+

ALCL, ALK-‐

ETTL

Other Disorders

Peripheral T-‐cell lymphoma -‐ NOS 25.9%

AngioimmunoblasNc 18.5%

Natural killer/T-‐cell lymphoma 10.4%

Adult T-‐cell leukemia/lymphoma 9.6%

AnaplasNc large cell lymphoma, ALK+ 6.6%

AnaplasNc large cell lymphoma, ALK-‐ 5.5%

Enteropathy-‐type T-‐cell 4.7%

Primary cutaneous ALCL 1.7%

Hepatosplenic T-‐cell 1.4%

Subcutaneous panniculiNs-‐like 0.9%

Unclassifiable PTCL 2.5%

Other disorders 12.2%

•  In a large internaNonal study, T-‐cell and NK-‐cell neoplasms accounted for only 12% of all non-‐Hodgkin lymphomas

Vose JM, et al. J Clin Oncol. 2008;26:4124-‐30.

Only 20% Long-‐term Survivors With Anthracycline-‐based Therapy

100

80

60

40

0 0 2 8 16 18

Time (years)

Overall Survival (%

)

20

4 6 14 10 12

Yes No

Anthracycline as part of iniNal treatment

p = 0.11

Treatment Guidelines for PTCL: SFll CHOP Based

NCCN. Clinical practice guidelines in oncology: non-Hodgkin’s lymphoma. v.1.2013.

First-‐line Therapy

  Clinical trial (preferred)   ALCL, ALK+ histology • CHOP-‐21 • CHOEP-‐21

  Other histologies (ALCL, ALK-‐; PTCL-‐NOS; AITL; EATL), regimens that can be used include: • CHOEP • CHOP-‐14 • CHOP-‐21 • CHOP followed by ICE • CHOP followed by IVE, alternaNng with intermediate-‐dose methotrexate (Newcastle regimen)

• Dose-‐adjusted EPOCH • HyperCVAD, alternaNng with high-‐dose methotrexate and cytarabine

First-‐line ConsolidaNon

All paNents except low risk (aaIPI) should be considered for high-‐dose therapy and stem cell rescue; ALCL, ALK+ is a subtype with good prognosis and does not need consolidaNve transplant if in remission

German High-‐Grade Lymphoma Study Group: T-‐Cell Lymphoma Cohort Analysis

•  320 paNents with mature nodal or extranodal T-‐cell or NK-‐cell lymphoma treated on 7 phase II or III studies (1993-‐2007)

•  ALK posiNve: 78 paNents (24.4%) •  ALK negaNve: 113 paNents (35.3%) •  Treated with CHOP ± etoposide: 100%

•  PaNents younger than 60 yrs of age with normal LDH •  AddiNon of etoposide to CHOP improved 3-‐yr EFS: 75% vs 51% with CHOP alone (p = 0.003)

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

ALK, anaplasNc large cell lymphoma kinase; CHOP, cyclophosphamide, doxorubicin, vincrisNne, prednisone; LDH, lactate dehydrogenase

Adding Etoposide to CHOP: German High-‐Grade NHL Study Group Analysis

PTCL Subtype n ALCL, ALK+ 78 ALCL, ALK-‐ 113 PTCL-‐NOS 70 AITL 28 Other 31 Total 320

EFS, aged < 60 yrs

YES

EFS, other subtypes

Probably NO

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

Months

Non-etoposide (n = 29)

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

100

80

60

20

0

40 Patie

nts

(%)

Etoposide (n = 69)

p = 0.057

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

100

80

60

20

0

40

Patie

nts

(%)

p = 0.003

6 x CHOP-14/21 (n = 41)

6 x CHOEP-14/21 (n = 42)

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

100

80

60

20

0

40

Patie

nts

(%)

p = 0.012

Non-etoposide (n = 12)

Etoposide (n = 34)

EFS, ALCL, ALK+

YES

AITL, angioimmunoblasNc T-‐cell lymphoma; LCL, anaplasNc large cell lymphoma; EFS, event-‐free survival; CHOEP, CHOP + etoposide

Autologous SCT in First Remission: ProspecFve Studies

Study Author (Yr) n Regimen Transplanted, % Outcomes, %

Corradini (2006) 62 Mitoxantrone/

melphalan or BEAM 74 12-‐yr EFS: 30 12-‐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: 30

4-‐yr OS: 39 Reimer (2009) 83 dexaBEAM or ESHAP ±

TBI 66 3-‐yr PFS: 36 3-‐yr OS: 48

d’Amore (2011) 160 CHO(E)P-‐14 x 6 ± BEAM/

BEAC 71 5-‐yr OS: 51 5-‐yr PFS: 44

Corradini P, et al. Leukemia. 2006;20:1533-8. Rodriguez J, et al. Eur J Haematol. 2007;79:32-8.

Mercadal S, et al. Ann Oncol. 2008;19:958-63. Reimer P, et al. J Clin Oncol. 2009;27:106-13.

d’Amore F, et al. Blood. 2011;118:abstract 331.

BEAC, BiCNU, etoposide, Ara-‐C, cyclophosphamide; BEAM, BiCNU, etoposide, ara-‐C, melphalan; ESHAP, etoposide, methylprednisolone, ara-‐C and cisplaNn; IFE, ifosfamide, etoposide; TBI, total body irradiaNon

NLG-‐T-‐01: Flow chart

160 pts confirmed diagnosis

156 pts Evaluable response

90 pts CR/CRu 3 mo post Tx

115 pts transplanted

131 pts CR/PR after 6xCHOEP

4 pts not evaluable response

25 pts primary refractory

16 pts PD/tox/mobilisation failure/other before Tx

25 pts PR/PD/tox

166 pts enrolled

6 pts inclusion criteria not fulfilled

ORR pre-Tx 131 (82%)

CR/CRu 82 (51%)

PR 49 (31%)

% Tx 115 (72%)

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

Intention-to-treat population

d'Amore F, et al. J Clin Oncol. 2012;30:3093-9.

OS (A) and PFS (B) for the Entire NLG-T-01 Cohort and OS (C) and PFS (D) for the 4 Largest Histologic Subtypes (CHOEP-14 and Auto-sct)

d'Amore F, et al. J Clin Oncol. 2012;30:3093-9.

51% at 5 yrs

1.0

0.8

0.6

0.4

0 0 12 48

Time (months)

Overall Survival

(propo

rUon

)

0.2

24 36 60 72

95% CI Survivor funcNon

Log-‐rank test p = 0.21

1.0

0.8

0.6

0.4

0 0 12 48

Time (months)

Overall Survival

(propo

rUon

)

0.2

24 36 60 72

PTCL-‐NOS AILT Alk-‐negaNve ALCL EATL

Log-‐rank test p = 0.26

1.0

0.8

0.6

0.4

0 0 12 48

Time (months)

0.2

24 36 60 72

Progression-‐free Survival

(propo

rUon

)

PTCL-‐NOS AILT Alk-‐negaNve ALCL EATL

A B

C D

44% at 5 yrs

1.0

0.8

0.6

0.4

0 0 12 48

Time (months)

0.2

24 36 60 72

95% CI Survivor funcNon

Progression-‐free Survival

(propo

rUon

)

The novel gold standard ?

EATL, enteropathy-‐associated T cell lymphoma.

Intensive Chemo-‐immunotherapy as First-‐line Treatment in Adult PaFents With PTCL -‐ GITIL and IIL naFonal cooperaFve study (2006) -‐

AIM OF THE STUDY: A “global” approach to improve the outcome of PTCLs reducing the primary

refractory and early PD paUents

1.  Inclusion of alemtuzumab at diagnosis 2.  HD chemo before transplant with drug crossing

the blood-‐brain barrier 3.  First study with allogeneic SCT frontline

Corradini P Leukemia 2014.

Outline of Clin A Study Alemtuzumab-‐CHOP X 2 courses

1 cycle HyperCHidam

2 cycle HyperCHidam

Auto-‐SCT Allo-‐SCT (HLA-‐idenUcal sibling or one anUgen

mismatched unrelated donor)

Stem cell harvest

PD or SD salvage GeneNc straNficaNon

Start donor search

HyperCHidam, HyperfracNonated cyclophosphamide with high-‐doses of arabinosylcytosine and methotrexate EudraCT Number 2006-‐004234-‐33

Clin A – Survival Outcomes

65%

OS

PFS

44%

Time (months)

Prob

abili

ty

0 6 12 18 24 30 36 42 48 0.0

0.2

0.4

0.6

0.8

1.0

Time (months)

Prob

abili

ty

0 6 12 18 24 30 36 42 48 0.0

0.2

0.4

0.6

0.8

1.0

Time (months)

Prob

abili

ty

0 6 12 18 24 30 36 42 48 0.0

0.2

0.4

0.6

0.8

1.0

DFS

•  Median follow-‐up: 40 months

•  8 of 61 paUents died for treatment-‐related causes with a cumulaUve incidence of non-‐relapse mortality of 13%.

49 %

New agents in the Front-‐Line Treatment in

PTCL

Brentuximab VedoUn in the Front-‐Line Treatment of PaUents With CD30+ Peripheral T-‐Cell Lymphomas: Results of a Phase I Study •  39 treatment-‐naive paNents with a diagnosis of CD30 +

PTCL (≥ 1% CD30 expression in malignant cells) •  Two strategies for incorporaNng BV into treatment were examined:

•  SequenUal treatment, in which sALCL paNents received 2 cycles of 1.8 mg/kg BV followed by 6 cycles standard-‐dose CHOP

•  CombinaUon treatment, in which paNents with PTCL, including those with sALCL, received 6 cycles of BV in combinaNon with CHP (VincrisNn was omiled to eliminate the potenNal for addiNonal neurotoxicity).

Fanale et al, J Clin Oncol. 2014 Aug 18.

CharacterisUc sALCL ALK posiUve (n=6)

sALCL ALK negaUve (n=26)

Non-‐ALCL (n=7)

Total (n=39)

Median age, years (range)

35 (21-‐62)

60 (25-‐82) 55 (37-‐74) 57 (21-‐82)

Desease diagnosis

ATLL -‐ -‐ 2 2

ALCL 6 26 -‐ 32

AITL -‐ -‐ 2 2

EATL -‐ -‐ 1 1

PTCL NOS -‐ -‐ 2 2

Baseline IPI score

0-‐1 0 13 0 13

2-‐3 6 7 6 19

4-‐5 0 6 1 7 ATLL: Adult T-‐cell leukemia/lymphoma; AITL: AngioimmunoblasNc T-‐cell lymphoma; EATL: Enteropathy-‐associated T-‐cell lymphoma

Amer a median observaNon Nme of 21.4 months: •  Median PFS had not been reached

•  The esUmated 1-‐year PFS rate was 71%

Of note, no paNents went on to receive consolidaNve ASCT or allogeneic SCT

Fanale et al, J Clin Oncol. 2014 Aug 18.

CombinaUon ORR 100% CR 88%

SequenUal ORR 95% CR 62%

Trials NCT Title Seing

ECHELON-‐2 01777152 A Comparison of Brentuximab VedoUn and CHP With Standard-‐of-‐care CHOP in the Treatment of PaNents With CD30-‐posiNve Mature T-‐cell Lymphomas

InducNon

Ro-‐CHOP 01796002 Phase 3 MulN-‐center Randomized Study to Compare Efficacy and Safety of Romidepsin CHOP (Ro-‐CHOP) Versus CHOP in PaNents With Previously Untreated Peripheral T-‐Cell Lymphoma

InducNon

A-‐CHOP-‐14 00725231 Immunotherapy in Peripheral T Cell Lymphoma -‐ the Role of Alemtuzumab in AddiNon to Dose Dense CHOP

InducNon

Pralatrexate 01420679 Study of Pralatrexate Versus ObservaNon Following CHOP-‐based Chemotherapy in Previously Untreated Peripheral T-‐cell Lymphoma PaNents

Maintenance

Ongoing phase III inducUon/maintenance clinical trials in treatment-‐naïve PTCL

Protocol FIL_PTCL13

Principal InvesNgator: Prof. Paolo Corradini

Romidepsin in combinaUon with CHOEP as

first line treatment before hematopoieUc

stem cell transplantaUon in young paUents

with nodal peripheral T-‐cell lymphomas: a

phase I-‐II study

Phase I/II Trial of Ro-‐CHOEP: PaFents ≥18 yrs ≤ 65 yrs

Phase I : Romidepsin D1&8 8, 10, 12, 14 mg/m2;

starting with 12 mg/m2 Phase II: Romidepsin at MTD

Ro-CHOEP21 x 3

Response Evaluation

<PR CR or PR

Ro-CHOEP21 x 3

PR Donor: yes no CR PD

ALLO - SCT AUTO - SCT Other treatments

(investigators’ choice)

Other treatments (investigators’

choice)

For PR start donor search

Pre SCT Response Evaluation followed by one DHAP course and Stem Cell Harvest

Follow-up

Conclusions •  There is a clear unmet clinical need for PTCL paNents

•  Disease biology and classificaNon have to be improved •  Long-‐term survival is poor (20 -‐25% with anthracyclin-‐based treatment)

• Current treatment guidelines are sNll CHOP-‐based

• Up-‐front autologous transplantaNon has improved PFS in responding paNents

• Ongoing studies invesNgate combinaNons with romidepsin and CHOP/CHOEP, or BV or Pralatrexate

New agents in relapsed/refractory PTCL

•  The historical outcomes for paNents with relapsed disease have been especially dismal

•  In a recent retrospecNve study on 153 paNents with relapsed or refractory PTCLs who did not undergo transplant , the reported median OS was only 5.5 months and the PFS 3.1 months (1)

•  These data do not capture possible gains from novel agents, since paNents included in the study had been diagnosed prior to 2010, before the approval of the new drugs.

1) Mak et al. J Clin Oncol 2013 Jun 1;31(16):1970-‐6

Agents PaUents ORR CR PFS (months)

DOR (months)

OS (months)

Brentuximab VedoUn 1

34 41% 24% 2.6 7.6 NA

BendamusUne 2 60 50% 28% 3.6 3.5 6.2 Pralatrexate 3 111 29% 11% 3.5 10.1 14.5 Romidepsin 4 130 25% 15% 4 17 11.3 Belinostat 5 129 26% 10% NA 8.3 NA

1) Horwitz et al. Blood 2014 May 15;123(20):3095-‐100 2) Damaj et al. J Clin Oncol 31:104-‐110 3) O’Connor et al. J Clin Oncol 2011 Mar 20;29(9):1182-‐9 4) Coiffier B et al, J Clin Oncol 2012 Feb 20;30(6):631-‐6 5) O’Connor et al, J Clin Oncol 2013; 31 (Suppl 15): 8507 ABSTRACT

Studies in relapsed/refractory PTCL

The PROPEL Trial •  111 paNents with independently confirmed R/R PTCL received PRALATREXATE IV at 30 mg/m2/wk for 6 weeks in 7-‐week cycles, unNl progression or unacceptable toxicity

•  ORR 29% (CR 11%) • Median DoR 10.1 months • Median PFS 3.5 months • Median OS 14.5 months

•  Most common grade 3 to 4 adverse events: thrombocytopenia (32%), mucosiNs (22%), neutropenia (22%)

O’Connor et al. J Clin Oncol 2011 Mar 20;29(9):1182-‐9.

Results From a Pivotal, Open-‐Label, Phase II Study of Romidepsin in Relapsed or Refractory Peripheral T-‐Cell Lymphoma Aner Prior Systemic Therapy

•  130 paNents with histologically confirmed R/R PTCL received ROMIDEPSIN at 14 mg/m2 as IV infusion on days 1, 8, and 15 every 28 days, for up to 6 cycles

• ORR 25% • CR/CRu 15% • Median DoR 17 months •  The most common grade 3 adverse events were thrombocytopenia (24%), neutropenia (20%), and infecNons (all types, 19%). Coiffier B et al, J Clin Oncol 2012 Feb 20;30(6):631-‐6.

The BENTLY Trial •  60 paNents with histologically confirmed peripheral T-‐cell lymphoma or cutaneous T-‐cell lymphoma ,who progressed amer one or more lines of prior chemotherapy, received BENDAMUSTINE at 120 mg/m2 per day on days 1 -‐ 2 every 3 weeks for six cycles.

•  In the intent-‐to-‐treat populaNon: •  ORR 50% •  CR 28% •  DoR 3.5 months •  PFS 3.6 months; OS 6.2 months

•  The most frequent grade 3 to 4 adverse events were neutropenia (30%), thrombocytopenia (24%), and infecNons (20%).

Damaj et al. J Clin Oncol 31:104-‐110

ObjecUve responses in relapsed T-‐cell lymphomas with single-‐agent brentuximab

This phase 2, open-‐label, mulNcenter study was iniNated to evaluate the efficacy and safety of single-‐agent BV in R/R T cell lymphomas •  Brentuximab vedoNn 1.8 mg/kg was administered every 3 weeks unNl progression or unacceptable toxicity.

Inclusion criteria: •  Histologically confirmed mature T-‐cell lymphoma with any detectable CD30 expression per insNtuNonal laboratory using IHC

•  PaNents who have had at least one prior systemic therapy

Horwitz et al. Blood 2014 May 15;123(20):3095-‐100

CharacterisUcs AITL (n=13) PTCL (n=22) All paUents (n=35)

Median age, years (range) 64 (55-‐79) 64.5 (33-‐83) 64 (33-‐83)

CD30 expression per central laboratory, n (%)

PosiNve 9 (69) 17 (77) 26 (74) NegaNve 2 (15) 4 (18) 6 (17) Missing or NA 2 (15) 1 (5) 3 (9) Disease status relaUve to front-‐line therapy, n(%)

Refractory 9 (69) 17 (77) 26 (74) Relapsed 4 (31) 5 (23) 9 (26) Median number of prior cancer-‐related therapy (range)

3 (1-‐4) 2 (1-‐9) 2 (1-‐9)


Amer a median follow up from first dose of 2.7 months: •  Median PFS 2.6 months

Median PFS for AILT: 6.7 months

Median PFS for PTCL: 1.6 months


For all paUents ORR 41% CR 24%

There was no apparent correlaNon between response and CD30 expression:

•  64% of ORR in the 14 paNents with ≤ 15% CD30 expression by central review.


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