t- cell lymphomas - cme...
TRANSCRIPT
T- CELL LYMPHOMAS
JASMINE ZAIN, MD
CITY OF HOPE NATIONAL MEDICAL CENTER
DISCLOSURE
• Relevant Financial Relationship(s)
• Speakers bureau with Spectrum, Seattle
Genetics and Celgene. Also serve on the
advisory board for Celgene and Spectrum
• Off Label Usage
• Gemcitabine, Lenalidomide, Boretezomib,
Bendamsutine, Penotstatin, Mogamulizumab,
Belinostat, Alisertib, Rituximab
Blood. 2008;112:4384.
T - CELL DEVELOPMENT
WHO CLASSIFICATION OF MATURE TCELL AND NK/T
CELL LYMPHOMAS 2016
PRACTICAL CLASSIFICATION OF PTCL/NK-T CELL
LYMPHOMA
Nodal Cutaneous Extranodal Primary Leukemic Varied presentation
Peripheral T cell
lymphoma, not otherwise
sepcified (PTCL-nos)
Angioimmunoblasitc T
cell lymphoma (AITL)
Anaplastic large cell
lymphoma (ALCL) , alk+
Anaplastic large cell
lymphoma(ALCL) , alk-
Mycosis fungoides
Sezary syndrome
Primary cutnaeous
CD30-positive T cell
lymphoproliferative
disorders
-lymphomatoid papulosis
- Primary cutaneous
anaplastic large cell
lymphoma
Primary cutaneous ɣȢ T
cell lymphoma
Primary cutaneous CD8-
positive aggressive
epidermotropic cytotxic T
cell- lymphoma
Primary cutaneous CD4-
positive small medium T
cell- lymphoma
Extranodal NK/T cell
lymphoma, nasal type
Enteropathy associated
T- cell lymphoma
Hepatosplenic T-cell
lymphoma
Subcutaneous
panninculitis like T- cell
lymphoma
Seroma associated
ALCL of breast
Aggressive NK leukemia-
associated with
hemophagocytic
syndrome
T-cell prolymphocytic
leukemia
T – cell large granular
lymphocytic leukemia
Adult T cell leukemia
lymphoma
Chronic
lymphoproliferative
disorder of NK cells
Systemic EBV positive T
cell lymphoproliferative
disease of childhood
Hydroa vacciniforme like
lymphoma
Systemic EBV+ T cell
lymphoproliferative
disease- associated with
hemophagocytic
syndrome
Peripheral T-cell Lymphoma, PTCL Mature
“Usually Indolent CTCL”
Mycosis Fungoides
Sezary syndrome
Subcutaneous panniculitis-like
Primary cutaneous ALCL
Lymphomatoid papulosis
Primary cutaneous small /
medium CD4+ T-cell lymphoma
“Usually Aggressive Systemic
T-cell Lymphoma (PTCL)”
Peripheral T-cell lymphoma NOS*
Angioimmunoblastic T-cell lymphoma*
Anaplastic Large Cell-ALK-1 negative*
Anaplastic Large Cell-ALK-1 positive
Enteropathy-type intestinal lymphoma
Extranodal NK/T-cell lymphoma-nasal*
Adult T-cell leukemia / lymphoma*
Hepatosplenic T-cell lymphoma (may be
derived from an immature T-cell)
“Aggressive CTCL”
Cutaneous aggressive
epidermotropic CD8+
cytotoxic TCL
Cutaneous g/d TCL
*skin lesions are common in these entities
Lineage marker PTCL subtype Clinical features
TCR α/β( adaptive immunity) PTCL excluding NK/T cell
lymphomas
TCR ɣ/δ(innate immunity) Hepatosplenic TCL
Primary cutaneous ɣ/δ TCL
Non- HS TCL
Very aggressive, rare
Dx is by flow cytometry on fresh
tissue, or negativity of alpha/beta
by anti-bF1 antibody, monoclonal
antibodies to TCR ɣ or Ȣchains
available
Negative receptors NK/T cell lymphomas nasal and
extranasal type
Aggressive NK cell leukemia
EBV + by FISH or southern
blotting
Unique clinical features
T – CELL RECEPTOR GENE
REARRANGMENTS
FUNCTIONAL MARKERS IN
PTCL
BIOLOGIC MARKERS PTCL SUBTYPE DX AND CLINICAL
FEATURES Cytotoxic granules- perforin, TIA-
1,granzyme B ( NK cells, ϫ/ᴤT cells and
CD8+cytotoxic T cells)
• NKTCL( nasal type)
• EATL
• Subcutaneous panninculitis like
TCLprimary
• Cutnaneous CD30+ T cell
lymphoproliferative disorders
• Primary cutnaeous gamma /delta T
CL
• ALCL alk+ and alk-
Immunohistochemical stains
Possible associated with poor survival in
subsets of PTCL
NK- cell receptors (KIR) NK/T CL
T-LGL ( restricted KIR repertoire)
SS ( aberrant expression)
Immunophenotyping of cell surface
receptors
Restricted repertoire can help establish
clonality for NK/T cell lymphomas
Markers of Follicular helper T cells
(T-FH )-CXCL13, PD-1, ICOS,CD200,
BcL-6,c-MAF
• AITL
• PTCL-Fh
• Primary cutaneous CD4+
small/medium TCL
Helpful in diagnosis, therapeutic
significance
GENETIC AND CHROMOSOMAL
ABNORMALITIES
Alk rearrangements Alk+ ALCL Diagnosis , prognosis
ITS- SYK translocation Subset of PTCL-F Diagnosis, therapy with
fosamatinib
IRF4 or DUSP22
rearrangements
Subset of systemic and
cutaneous alk- ALCL
Diagnosis
STAT 3 mutations T-LGL, chronic NK-cell
LPD
Diagnosis, therapy
TET2, IDH2, DNMT3
mutations
AITL,PTCL-nos,T Fh-like Diagnosis, therapy with
hypomethylating agents
JAK3 mutations NKTCL Diagnosis , therapeutic
Gullard et al- Hematol Oncol 2013
JCO 2008;26:4124-4130
SUBTYPE DISTRIBUTION
DIAGNOSIS CAN BE A CHALLENGE
Diagnostic accuracy of a defined
immunophenotypic and molecular
genetic approach for PTCL/NK-T cell
lymphomas -A North American PTCL
Study Group Project Hsi, et al: Am J Surg path
2014
Distribution of PTNKCL diagnoses
that resulted from the review.
OUTCOMES
Hsi, et al: Am J Surg path
2014
GENOMIC SIGNATURE
Iqbal J, et al: Blood reviews 2015
Diagnostic pitfalls
• Review pathology. All biopsies performed outside to be reviewed. At least one
paraffin block representative of the tumor should be reviewed along with
biopsies of other sites that may be involved. Rebiopsy if enough tissue is not
available. Consent the patient for tissue collection protocols
• An FNA is not sufficient to make the diagnosis
• IHC panel- CD20, CD3, CD10,BCL-6, Ki-67, CD5, CD30, CD2, CD4, CD8,
CD56,CD57, CD21, CD23, EBER-ISH, ALK or
• Cell surface marker analysis by flow cytometry: kappa/ lambda, CD45, CD3,
CD5, CD19,CD20, CD30, CD4, CD8, CD7, CD2, TCRaB: TCRgamma
• Molecular analysis to detect T cell receptor gene rearrangements
• Additional immunohistochemical stains to establish the specific sybtype
diagnosis like CXCL13, BF1, TCR-C Myc
WORKUP FOR A PATIENT WITH PTCL
AT COH
• Physical examination, assess for performance status, B symptoms, extranodal sites of disease especially skin, and
any neurological symptoms. Establish risk factors for viral exposures like HTLV1, EBV..
• CBC with differential with attention to eosinophil count, lymphocyte percentage and presence of abnormal cells, LDH,
serologies for HIV, HTLV1, EBV, acute infectious hepatitis, comprehensive profile, uric acid. Send flow cytometry on
peripheral blood if lymphoctyosis or presence of atypical cells is noted
• Staging scans including PET/CT from head to toe to capture any skin or extranodal invovlment, MRI of brain and spine
if clinically indicated.
• Bone marrow biopsy and aspiration
• Consider biopsy of suspicious skin lesions
• MUGA scan
• CSF sampling if clinically indicated or if there is high risk of involvement of CNS
• Establish a prognostic score for each patient at diagnosis. IPI ( age,LDH, PS, Ann Arbor stage , extra nodal sites) PIT
( age> 60, LDH, PS, Bone marrow involvement) or modified PIT m- PIT( age,PS, LDH, Ki-67).
• Collect tissue samples for research and tissue banking including buccal swabs and blood samples.
• HLA typing on patient and any siblings may be initiated if the patient has high risk disease
• Stem cell transplant consult
SUBTYPES OF PTCL
PTCL-NOS
• Most common
subtype of PTCL
in western
countries
• M>F at a ratio of
1.5
• Median age 61
• Present with high
IPI
• No clinical
differences in the
varied histolgies
ANGIOIMMUNOBLASTIC T-CELL LYMPHOMA
Nodal presentation , median age 64, M>F
Skin rashes, B symptoms, serositis and effusions, arthiritis,
polyclonal hyper gammaglobulinemia
Immunological dysfunction
T follicular helpher ( TFH ) phenotype and are positive for CD3,
CD4, CD10 and CD279 ( PD-1) and CXCL13, EBER+
Cytogenetic abnormality - trisomy 3,trsisomy 7 and additional X
chromosome
IDH2 gene mutations have been described in 20-40% of cases
HDACI are effective,, belinostat 66% in R/R
Rituximab, lenalidomide, cyclosporin, low dose methotrexate
can be effective in some cases
Alk expression (IHC)
Cytogenetics/molecualr markers
Clinical features Unique therapy prognosis
ALK+ ALCL Positive T(2,5)- classic- expression of
NPM/ALK Other translocations may partner with ALK
on ch 2
Median age -35 Extranodal features
Brentuximab vedotin targeting CD30,
Alk inhibitors like Crizotinib
Excellent
ALK- ALCL
Negative DUSP22 , TP63 affect prognosis, mutually exclusive with ALK
DUSP22 – outcome similar to ALK+ALCL
TP63- worse prognosis
Older age groups Brentuximab Vedotin targeting CD30
Intermediate between alk+ ALVL and PTCL-nos
Primary cutaneous ALCL
Negative Skin only presentation overlap with LyP
Skin directed therapies Low dose MTX
Radiation
Excellent 100% 5 year survival
Seroma associated ALCL of breast
Negative Associated with breast implants Median time to presentation is 8 years Arise in the seroma associated with the implant Can be aggressive and have invasive features
Remove the seroma and the implant Radiation or chemotherap based on extent of disease
Excellent if confined to the seroma
Savage K J et al. Blood 2008;111:5496-5504
HEPATOSPLENIC T CELL LYMPHOMA
• Rare form of PTCL arises from ɣȢ T cells of
the liver sinuses and splenic red pulp
hepatosplenomegaly without significant
adenopathy and pancytopenia
• Median age is 35
• More common in males
• Association with iatrogenic immunosuppresion
esp with Infliximab, purine analogues,
Crohn’s disease and recipients of solid organ
transplantationdisease
• Aggressive with a median survival of 16
months- early allogeneic stem cell transplant
• ICE or IVAC were more likely to lead to
remissions as a bridge to stem cell transplant
with a median PFS of 13.3 months and OS of
59 months of the 7/14 surviving patients;
Voss, M.H., et al.
• Cells are medium in size -marked pattern of
sinusoidal infiltration in the liver and spleen as well
as bone marrow
• Immunophenotypically the cells are positive for
CD56 or CD16 but negative for CD4,CD8 ( CD8 +
can be seen occasionally
• TIA-1 is usually positive but other cytotoxic
markers of activation like granzyme and perforin
are negative
• The most consistent chromosomal abnormality is
isochromosome 7q and trisomy
EATLI EATLII INDOLENT INTESINAL INVOLVMENT
OF PTCL-NOS, NK/T-cell
lymphoma, ɣȢ T- cell
lymphoma
Associated with celiac
disease
Anit gliadin antibody positive
No association with Celiac
disease
No association with Celiac
disease
Clinical features will support
the differential daignosis
Common in Northern Europe Common in Asia Intestinal involvement is
common in other types of
PTCL
αβ subtype-express mucosal
homing receptor CD103
(HML-1)
Invasion of intestinal mucosa
Villous atrophy of
surrounding tissue
Epitheliotropism,surrounding
mucosa intact .
ɣȢ origin ,CD8 and CD56
positive
small mature lymphoid cells
that are mostly CD8+ with no
evidence of STAT3 SH2
domain mutation
Pathologic features
consistent with diagnosis
EATL type I and II are aggressive and present with abdominal
symptoms and multifocal intestinal involvement that can lead
to perforation and other complications. Outcomes are poor
with 5 year survival of less than 20%
Indolent clinical course Treat as per primary
diagnosis
Upfront transplant in first remission after CHOEP - 5 yr PFS
38% and OS of 48%- D’Amore et al
IVE/MTX-ASCT - ORR 69%, PFS 52%, OS 60%
-Sieniawski et al 2010
Do not require aggressvie
therapy
High incidence of GIT bleed
and other complications
ENTEROPATHY ASSOCIATE T- CELL
LYMPHOMA
• Subcutaneous nodules - affect the extremities and
trunk - vary in size from 0.5 to several cm in size
• Atypical lymphoid cells that rim individual fat cells.
Surrounding infiltrate can have reactive histiocytes
and can show vascular invasion, necrosis and
karyorrhexis
• Immunophenotyping shows the cells to be positive
for CD8 and they are of the αβ type.
• ɣȢ subtype is a primary cutaneous ɣȢ T cell
lymphoma- the median age at presentation is 30
years but can be seen in children as well.
• Associated with a hemophagocytic syndrome that
confers a poor prognosis and can occur either
before, concurrent with or even after the disease
has been treated
SUBCUTANEOUS PANNINCULITIS LIKE T- CELL
LYMPHOMA
ATLL • HTLVI virus is endemic in Japan
Carribean , parts of Africa – prevelence is 6-37%
• Vertical transmission , cell to cell contact
• HTLV1 encodes 3 structural gene (pol, gag and tax) and 2 regulatory genes (tax and rex)-drive pathogeneis
• 2.5 % will develop ATLL
• Median age is 45 years
• Prognosis is poor for acute ATLL, allogeneic transplant early
• Mogamolizumab approved in Japan for R/R disease
ADULT T CELL LEUKEMIA/
LYMPHOMA SUBTYPES
Healthy carrier Smoldering
ATLL
Chronic ATLL Acute ATLL ATLL
lymphoma
Anti HTLV-1
serology
+ + + + +
Clonal
integration of
provirus
-
(blood)
+
(blood)
+
(blood)
+
(blood)
+
(lymph nodes)
Lymphocyte
count
Normal Normal
Elevated Elevated
Elevated
Abnormal cells
(%)
<5% >5% >5% >5% <1%
Hypercalcemia - - - + +
LDH Normal <1.5N <2N >2N >2N
Skin and lung
involvement
- + + + +
BM or spleen - - + + +
Bone, GI or
CNS +
- - - + +
Suzuki et al: Curr Ocol rep 2012 14: 395-402
NK/T CELL LYMPHOMAS- NASAL
TYPE
EBV associated, common in Asia,
Central and South America as well as
Native American populations
Median age – 50
Nasal or midline facial lesion ,skin, GIT,
upper respiratory tract or other organs.
Hemophagocytic syndrome -negative
prognostic value
CD2, cytoplasmic CD3, CD7,CD56, TCR
–ve, cytotoxic granules+, EBV+
Somatic activating mutations of JAK3
gene have been identified in 35% of
cases of NK/T cell lymphoma
•Express MDR associated p-glycoprotein
– MTX and asparaginase effective
•Radiation sensitive
TREATMENT
WHY SHOULD PTCL BE TREATED
DIFFERENTLY
Armitage JO, et al. Ann of Oncol. 2004;15:1447–1449.
UPFRONT THERAPY FOR PTCL
WHAT WE KNOW SO FAR Regimen N RESPONSE
Refractory % ASCT
CHOEP q 14 < 60
CHOP-14 >60
D’Amore et al
Prospective
160 ORR 82%
CR 50%
16% 72%
CHOP +/- etoposide Schmitz et al
Retrospective
Pts < 60 vs >60 3 EFS/OS
75.8% /89.8%- alk+ALCL
45%/62%- alk-ve ALCL
50/67%- AITL
41/53%– PTCL-nos
Younger patients with normal LDH addition of etoposde improved EFS
but not OS
NA NA
Some had transplant
VIP-rABVD vs
CHOP/21
Simon et al
randomized
95 No difference
ORR 62%/ 39% - higher for ALCL
2 year EFS 45%/41%
5 yr EFS 32%
CyclOBEAP
Cytoxan, vcr,
bleomycin,
etoposdie,
doxorubacin, pred
Niitsu et al
Prospective
84 all < 60
PTCL,AILT,
ALCL,
CR- 92%, PR%
Median fu 84 months
5 yr OS 72% , PFS 62%- higher for ALCL
Grade 3 and 4 hematologicl toxicity
No TRM
NA NME1 (cytoplasmic
expression)
identified as a prognostic
marker
ACVBP vs CHOP Tilly et al
Randomized
98 total No difference between the 2 arms
CR- 56-58%, TRM 13% in ACVBP and 7% in CHOP arm
5 yr EFS 39% and 29% in CHOP arm
NA
PEGS Mahadevan et al
Prospective
20 ORR 39%
CR 24%
NA NA
hyper-fraction-
ated
cyclophosphamide,
vincristine,
pegylated liposomal
doxorubicin and
dexamethasone
alternating with
methotrexate/cytara
bine (HCVIDD/MA
Chihara et al
Prospective
53
Excluding alk+
ALCL
ORR-66%/CR 57%
Median PFS 7 5 months.
5-year PFS/OS 21/48%
PFS and overall survival (OS) were 21% and 48%, Shorter PFS- 2.4
months for NK/T cell
UPFRONT THERAPIES- CANNOT
ACHIEVE CURE IN MOST CASES
Br. J of hematology 2010
Br J or hematology 2011
HCVIDD/MA Br. J of hematology 2015
• High dose therapy and ASCT- phase 2 data
• Consolidate remission state with a finite number of
cycles of novel targeted agents like pralatrexate,
brentuximab vedotin, romidepsin , campath,
lenalidomide- data is emerging
HOW TO IMPROVE OUTCOME CONSOLIDATION / MAINTAINENCE THERAPY
AUTOLOGOUS STEM CELL TRANSPLANT AS
CONSOLIDATION THERAPY - INTENT TO TREAT
n % ASCT CR/PR % OS % PFS %
d’Amore et al 166 69 90/166 51% at 5 years
(ALCLalk- best) 44% at 5 years
Corradini et al 62 74 56/16 34
(12 yrs)
30
( 12 yrs )
Reimer et al 65 65 47/26 50
( 3 yrs ) N/A
D’ Amore et al 121 73 50/35 67
( 3 yrs ) N/A
Rodriguez et al 26 77 61/ 16
75
( 3 yrs )
53
( 3 yrs )
Mercadal et al 41 41 49/10 39
( 4 yrs )
30
(4 yrs )
ALCL
ALK+
ALCL
ALK-
PTCL-NOS AITL NK/T
5 yr OS
rate%- Int T
cell Project
70 49 32 32 32
5 year OS
rate %
Abouyabis
et al
56 ( all
subtypes
34 36 48
3 year OS
Schmitz et al
88.8 63 53 56 49
5 year OS %
D’Amore et
al
Not included 70 47 52 44
EFFECT OF UPFRONT TRANSPLANT IN PTCL
PATIENTS WHO DO NOT BENEFIT FROM
UPFRONT AUTO BMT
• IPI- Strongest predictor
– OS in AITL
– PFS in AIT , PTCL
ALCL histology was favorable
- all ALK-ve
No difference between AITL
and PTCL
Adverse factors by
multivariate analysis
BM involvement
PS>2 D’Amore et al JCO 2012
TARGETED AGENTS IN UPFRONT THERAPY CAN IMPROVE
OUTCOME
• BV+CHP; 6 cycles q 3 wk
• Patients with PR could receive 10 additional cycles of BV
• systemic ALCL (n=19; 3 ALK+, 16 ALK-), peripheral T-cell lymphoma-NOS (n=2),
angioimmunoblastic T-cell lymphoma (n=2), adult T-cell leukemia/lymphoma (n=2), and
enteropathy-associated T-cell lymphoma (n=1).
• ORR 100% and CR 88%
• 3 year OS is 80%, median PFS not reached, No SCT
Horowitz et al : abstract 1537
Belinostat in combination with CHOP in PTCL
Phase 1 study
Belinostat approved for R/R PTCL –
ORR 25.8%
Belinostat and each component of
CHOP targets a different aspect of cell
cycle – there is potential for synergy in
a Bel-CHOP regimen
primary objective – MTD of Bel-
CHOP
Secondary end points- safety,
tolerability, ORR and PKs
3x3 design with cohort expansion at
MTD
Johnston et al :Abstract # 253
BEL- CHOP
MTD- Belinsotat 1000mg/m2
days 1-5 with standard dose
CHOP q 21 days
DLT- Nausea / vomiting
Main toxicity was hematologic
in nature
ORR- 89%, CR 72%
• Prospective multicenter phase II trial
• CHOP/CHOEP induction with alemtuzumab consolidation for CR/PR
• n=41, only 29 got alemtuzumab
• Grade 3-4 toxicities - infections and neutropenia and 1 TRM
• CR=58.5% PR 2.4%
• PD= 29.3%
• At 3 years, EFS = 32.3%, OS = 62.5% (ITT)
• Patients receiving alemtuzumab, EFS 42.4%, OS 75.1%
• Phase III study is underway
Binder et al: Ann Hematol
Aug 24 2013
ALEMTUZUMAB CONSOLIDATIONS
AFTER CHO(E)P
RELAPSED DISEASE
APPROVED AGENTS FOR R/R
PTCL AGENT N HISTOLOGICAL
subtypes
n
MEDIAN
PRIOR
THERAPIE
S
ORR/CR RESPONSE BY
HISTOLOGY
ORR/CR
DOR COMMENTS
Pralatrexate 109
PTCL-nos -59
sALCL—17. AITL--- 13,
tMF—12 other ---10
3 (1-12) 29%/11% PTCL- nos 32%,
sALCL- 35%, AITL-
8%, tMF- 25%’
other – 38%
10.1
months (
,1-22.1)
Numbers are small to
make individual
deductions about
histological subtypes
Romidepsin 130 PTCL- nos – 69, AITL-
27, ALK-ve ALCL -21,
Other -13
2 (1-8) 25%/15% PTCL- nos—29/14,
AITL- 30/19, Alk-ve
ALCL -24/19, Other
0/0
28
months (
1-48)
Median OS 11.3
months
Median duration of
response not
reached for CR
patients
Time to CR is 3.7
months
Belinostat 129 PTCL-nos 77, AITL –
22,ALCL- 15,EATL –
2,NK/T- 2, HSTCL- 2
2(1-8) 26%/11% PTCL-nos-
23%,AITL,46%/18%,
ALCL- 15%,EATL-
0,ENKTCL-50%,
HSTCL-0
13.6 9
4.5- 29.4)
Seems to have a
higher response rate
in AITL
Brentuximab
Vedotin
58 sALCL 2 (1-6) 86%/59% 13.2 (5.7-
26.3)
Medain OS not
reached
1 year:70%, 3
year:63%, 4year:
64%)
Mogamulizumab] 27 ATLL 1-3 50/31 Median
PFS 5.2
months
Median OS 13.7
ORR % FOR FDA APPROVED
AGENTS FOR PTCL Pralatrexate romidepsin Belinostat Brentuximab
vedotin
All 29 25 26
PTCL-nos 31 29 23 33
AITL 8 30 46 54
ALCL 29 24 15 86
R/R PTCL AGENT N HISTOLOGIC
AL subtypes
n
MEIDAN
PRIOR
THERAPIES
ORR/CR Response by
histology
ORR/CR
DOR/PFS COMMENTS
Brentuximab
vedotin
35 PTCL-nos
22,AITL n- 13
2 ( 1-9) 41%/24% PTCL-nos
33/14
AITL54/38
PTCL-nos- 7.6
AITL- 5.5
ICE 40 PTCL 1 70/35 Median PFS 6
months
68% went to
transplant 83%
relapsed at 3
years
ESHAP 22 All PTCL 1 32/18 Median PFS 2.5
months
Bendamsutine 58 AITL- 32,
PTCL- nos 23,
ALCL- 2, EATL-
1
1 91-3) 50/28 Median DOR
3.5 ( 1-21)
Median OS 6.3
months
Alemtuzumab 14 PTCL-nos 10,
AITL – 4
2(1-4) 36/21
Crizotinib 9 Alk+ ALCL 89/78 NR
Lenalidomide 50 AITL- 26,
PTCL-nos- 20,
ALCL- 3,
ENKTCL- 1
3 (1-11) 22/11 AITL-31/15
PTCL-nos 20
Gem/Dex/Cispl
atin
51 PTCL 69/19 Median PFS 4
months
72% went to
auto or allo
transplant
Author Agent N RR
Dearden et al 1991 Pentosatin 6 0/6
Zinzani et al1998 Gemcitabine 8 5/8
Enblad et al
2004 Alemtuzumab 15 4/14
Dang et al
2006
Denileukin diftitox
27 13/27
Zinzani et al 2007 Boretezomib 2 1/2
Reiman et al 2007 Lenalidomide 10 4/10
Czuczman et al
2007
Nelarabine
8 1/8
SINGLE AGENTS FOR R/R PTCL
PTCL AND CNS DISEASE
PTCL patients have a higher incidence of
extranodal presentation at the time of diagnosis
including CNS disease
Exact incidence of CNS disease is unknown
1 study reported that a high LDH and paranasal
sinus involvement predicts for CNS involvement -
Yi et al - 2011
High suspicion for CNS involvement is warranted
STEM CELL TRANSPLANTATION FOR
RELAPSED PTCL
Number Clinical setting Results
Rodriguez et al 29 Salvage 3 yr OS 36%
3 yr PFS 28%
Blystad et al 40 First line CR/
Salvage
3 yr OS 58%
3 yr PFS 48%
Song et al 36 Salvage 3 yr OS 48%
3 yr PFS 37%
Jantunen et al 19 Front line CR/ salvage 5 yr OS 45%
5 yr PFS 28%
Kewalramani et al 24 Salvage 5 yr OS 33%
5 yr DFS 24%
Smith et al 32 Salvage 5 yr OS 34%
5 yr DFS 18%
Feyler et al 33 Salvage 2 yr OS 49%
2 yr PFS 49%
Rodriquez et al 123 Salvage 5 yr OS 45%
5 yr PFS 34%
STUDIES OF ASCT IN PTCL
ALLOGENIC TRANSPLANTS FOR
PTCL HISTOLOGY DZ STATUS N CONDITIONING RESPONSE
Perales et al
2012 PTCL Relapsed 34 TBI based 47%, RIC38%
2 yr OS 61%
,ki-67<25% and
CR at time of
transplant
Dodero et al
2012 PTCL Relapsed 52
RIC
DLI in 8/12 relapsed pts
5 yr OS 50%
5 yr PFS 40%
Zain et al
2010 PTCL/CTCL Relapsed 38
Ablative and non-
myeloablative
5 yr OS is 54.4%
, PFS = 46.5%
Le Gouill et al 2008 PTCL Multiply relapsed 77 2/3 ablative
1/3 RIC
5 yr OS 57%
5 yr DFS 53%
TRM 33%
Corridiani et al PTCL Relapsed/
refractory 17
RIC/ Thiotepa/Flu/Cy
3 yr OS
81%,DFS 62%,
5 yr survival for
CR is 75%
Rodrigues et al
2006 T cell NHL Multiply relapsed 11
7 RIC
4 CMR
2 yr F/u
OS 57%
Copyright © American Society of Clinical Oncology
n=77 Plateau on the curve at about
1 to 2 years
Numbers still small, but
suggest promising graft
versus TCL effect
Differences seen based on
histology
Numbers are small to
evaluate the effect of
intensity of conditioning
Is this curative therapy?
ALLOGENEIC STEM CELL TRANSPLANT IN T-CELL NHL
Le Gouill et al 2008
ALLOGENEIC TRASNPLANTS FOR PTCL AT CITY
OF HOPE - FINAL OUTCOME
Zain et al Leuk Lymphoma.
2011 Aug;52(8):1463-73.
•Median f/u of 20
months for all patients
•30% of pts have
relapsed
•20 pts are alive, 18
dead
•TRM was 55.6%
•Acute GVHD was
seen in 51% of pts-
68% grade III/IV
•Ch GVHD seen in
82% of pts
•78% of the pts had
some form of acute or
chronic GVHD
OUTCOMES OF AUTO VS ALLO
TRANSPLANTS FOR PTCL
• CIBMTR data
• 115 autos and 126 allos
• Auto CR1 ( 35%) and allo CR1 (14%)
Smith et al: J clin Oncol July 2013
ALLOGENEIC SCT FOR CR1
• Retrospective study from France
• 16 patients <70 yrs (median 54),
excluding CTCL or alk + ALCL,
• IPI of >2 at dx, at least a PR with
primary therapy, suitable donor
• AITL n=8, PTCL nos n=4, alk-
ALCL n=3, hepatosplenic TCL n=1,
• Median time to transplant was 6
months from diagnosis
Median fu is 38 months
3 year OS and DFS is 87% (+/- 8%)
Acute GVHD 37%, ch GVHD 20%
No TRM
Robles et al: Bone Marrow
Transplantation June 2013
CITY OF HOPE ALGORITHIM FOR TREATING PTCL/EXCLUDING NK/T CELL
LYMPHOMA
CITY OF HOPE ALGORITHIM FOR NK/T
CELL LYMPHOMA
NOVEL COMBINATIONS
NOVEL A GENTS AND STRATEGIES
PATIENT SELECTION FOR APPRIATE
TARGETED AGENTS
IMMUNOTHERAPY
NEW AND EMERGING THERAPIES FOR PTCL
ALISERTIB N=83 COMPARATOR
Response TYPE PERCENTAGE All (n=80) Pralatrexate (n=40) Romidepsin (n=17) Gemcitabine
(n=23)
ORR 27 (33%) 34 (43%) 16 (40%) 10 (59%) 8 (35%)
Complete response 13 (16%) 20 (25%) 10 (25%) 5 (29%) 5 (22%)
Partial response 14 (17%) 14 (18%) 6 (15%) 5 (29%) 3 (13%)
Stable disease 26 (31%) 18 (23%) 13 (33%) 2 (12%) 3 (13%)
Progressive
disease 30 (36%) 27 (34%) 11 (28%) 4 (24%) 12 (52%)
LUMIERE TRIAL
RANDOMIZED PHASE III IN R/R PTCL AFTER FAILING 1 LINE OF THERAPY
A PHASE I/II TRIAL OF THE COMBINATION OF ROMIDEPSIN AND
LENALIDOMIDE IN PATIENTS WITH RELAPSED/REFRACTORY LYMPHOMA-
• 21 pts with TCL (10 CTCL, 11 PTCL) were enrolled with 15 treated at
the MTD ( romi 14mg/m2 dasy 1,8,15 and len 25mg day 1-21
• ORR in PTCL 56% (5/9, 2 CR, 3 PR)
• CR was seen in transformed MF (1), and Sezary syndrome (1)
• The median time to response was 7.3 w (range: 2.8-16.9 w)
• Median OS was not reached.
• Median event free survival was 30.0 w
• most common side -being neutropenia (48%), thrombocytopenia
(38%), anemia (33%), electrolyte abnormalities (K, Phos, glucose, Mg)
(43%)
Mehta et al: ASCO 2015
• PTCL – not a single disease
• Treatments are now being defined for specific subtypes
• Current upfront treatments are not curative
• Need for consolidation/maintainence approaches including stem
cell transplant
• Improved molecular pathology will define specific subtypes that
can benefit from unique therapeutic approaches
• Single agents have limited efficacy and combination therapies
will likely improve outcome
• Continued need for collaboration and well designed clinical trials
to make progress
CONCLUSIONS
THANKYOU
•Diagnosis
•Treatment - front line
•Treatment -relapsed disease
•Stem cell transplant
•Novel therapies
OBJECTIVES
SIGNALLING PATHWAYS
NF-kB ATLL, NKTCL,Cutaneous
TCL,PTCL- nos, AITL,
ALK-ALCL
High expression
associated with poor
outcome – therapy with
proteosome inhibitors?
SYK Majority of PTCL, subset
of CD30+ PTCL
Therapy with fosamatinib
PDGFRa PTCL-NOS, AITL, NKTCL ? Therapy with imatinib
Gullard et al- Hematol Oncol 2013
CHALLENGES IN UNDERSTANDING
T/NK CELL LYMPHOMAS
• PTCL cell of origin is poorly characterized
• T cell differentiation system is complex - innate
and adaptive immunity
• Marked functional diversity of effector cells
• Overlap and plasticity of T cells and NK cells
subsets
MOLECULAR GENETIC ANALYSIS OF T-CELL CLONALITY
•PCR methods to assess clonality at the TCR gamma locus on tissue samples has high sensitivity of over 90% to detect a malignant T cell clone
•False positives (monoclonal or oligoclonal) can occur in benign reactive conditions
•PCR for TCR beta is more specific but less sensitive and more challenging due to the large number of v and J segments
•Southern blotting remains cumbersome and is less sensitive and specific
•Newer methods using flow cytometry are under investigation
Schematic representation of the human TCR gamma
and beta locus
Cho-Vega et al: annals of diagnostic
pathology
STRATEGIES TO IMPROVE UPFRONT THERAPIES FOR PTCL
CHOP BASED
Etoposide- CHOEP,
EPOCH
+Alemtuzumab
•+Brentuximab vendotin
•+Pralatrexate
+anti CD4
+anti CXC4
+lenalidomide
NOVEL COMBINATIONS
Pralatrexate + HDACI
Novel targeted agents + monoclonal antibodies
Lenalidomide+romidepsin
CHOEP+lenalidomide
USEFUL CELL SURFACE
MARKERS
Marker Functional
significance
PTCL subtype Therapeutic
potential
CD30 • TNF family
• Signal transduction
via NF-kB and
MAPK growth and
differentiation
• Activated B and T
lymphocytes
ALCL alk+/alk-
Subset of PTCL-nos
Primary cutaneous
CD30+ T cell
lymphoproliferative
disorders
Targeted therapy with
brentuximab vedotin
CD52 • Cell surface
glycoprotein
• Most B and T cells,
monocytes and
macrophages
Subsets of AITL,PTCL-
nos, NKTCL,ATLL,
minority of ALCL
• Targeted therapy with
alemtuzumab
• Very few studies
have correlated the
expression of CD52
with response
CCR-4 Chemokine marker High expression in ATLL,
subsets of CTCL, PTCL-
nos
Targeted therapy with
KW-0761
Gullard et al- Hematol Oncol 2013