peripheral t-cell lymphomas (ptcl) specified and...
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Peripheral T-cell lymphomas (PTCL)Specified and Unspecified
Eric Van Den Neste
Cliniques universitaires Saint-Luc
Bruxelles
BHS seminar 12, 07 March 2015
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Peripheral T-cell lymphomas (PTCL)Specified and Unspecified
1. Physiopathology, epidemiology, diagnosis, prognosis – key points summary
2. Treatment – general recommendations
3. Treatment – disease-adapted recommendations
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T-cell ontogenesis
Cellular differentiation
Self-Ag recognition
MHC recognition
Pos- & neg-selection
TCR() receptor
Immature T-cell malignancies
(Thymic, TdT+)
T-ALL
T-LBL
Fetal liver
BM
Thymus Peripheral lymphoid organs
CD4+
CD8+
Malignant counterpart
Mature T-cell malignancies
(Post-Thymic, TdT-)
PTCL
Lymphoid
progenitors
NK
T
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APC
PTCL: pathophysiology of T-cell subsets
T/NK T
Innate immune system Adaptive immune system
Apoptotic/necrotic cell death
(not MHC restricted or limited
repertoire)
cytokines
chemokines
complement
CD4+ cells: regulatory
CD8+ cells: cytotoxic
(MHC restricted, greater specificity)
antigen
recognition
Pediatric/young T-cell lymphoma
Extranodal, CD4-/CD8-
Cytokine storm, HS
Ex: NK-cell lymphoma, ETTCL
Post-thymic
lymphocytes
Adult T-cell lymphoma
Nodal, predominantly CD4+
Ex: PTCL-NOS
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Simplified classification of PTCL10-15% of all lymphomas, 23 entities
• Common category
– Peripheral T-cell lymphoma, unspecified (PTCL-U/NOS) 34%
– Angioimmunoblastic T-cell lymphoma (AILT) 29%
– Extranodal NK/T-cell lymphoma, nasal type (NKTCL) 4%
– Enteropathy-type T-cell lymphoma (ETTCL) 9%
– Hepatosplenic T-cell lymphoma 2%
– Subcutaneous panniculitis-like T-cell lymphoma <1%
• Anaplastic large-cell lymphoma category
– ALK(-), systemic 9%
– ALK(+), systemic 6%
– cutaneous CD30+ 1%
For a complete classification, see WHO 2008 and Vose et al, JCO 2008
Europe
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Diagnosis of PTCL
• Multiparametric approach (clinical picture, phenotype, morphology, genetics), no specific markers
• Phenotypic profile:
– CD4/CD8 stain may indicate clonal restriction BUT double-neg and double-pos
– Frequent antigenic loss (« antigen-aberrancy »), ie CD5 and CD7
– TCR rearrangement pivotal, but germline in NK subtypes!
• Other markers
– Cytotoxic profile: granzyme, perforin
– NK markers
– CD30+: ALCL
– ALK+, t(2;5)
– EBV: nasal forms, aggressive behaviour
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PTCLPrognosis
Overall survival of 288 PTCL patients compared with 1,595
DLBCL patients
Gisselbrecht, Blood 1998
PTCL is a poor prognosis disease, except for some specific
entities (ie, ALCL ALK+, primary cutaneous ALCL, MF)
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PTCL, NOSPoor prognosis also explained by high IPI
Most PTCL patients
are advanced:
0/1: 28%
2-5: 72%
Weisenburgerr, Blood 2011
Factors included:
Age (<60y vs >60)
LDH (<NL vs >Nl)
ECOG PS (0-1 vs 2-4)
Stage (I/II vs III/IV)
EN involvement (<1 site vs >1)
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PTCLClinical characteristics
• Age > 50y, male, aggressive behavior, EN sites
• Potential association with hemophagocytic syndrome (HS)
• More « specific » clinical features
– AILT: fever, rash, polyclonal gammapathy, auto-immunity
– NKTCL: EBV-related, local nasal destruction, extensive necrosis
– Hepatosplenic : young men, liver/spleen, immune suppression, chronic antigen stimulation (SLE), i(7)(q10)
– ETTCL: jejunum/ileum, closely associated with celiac disease
– Panniculitis-like: subcutaneous nodules, HS often fatal
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PTCL – TreatmentCHOP is standard
Reviewed in Foss, Semin Hematol 2010
≈ 30%
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Weisenburger, Blood 2011
OS and FFS of 340 patients with PTCL-NOS (retrospective)
PTCL – TreatmentCHOP is disappointing
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PTCL - TreatmentHow to do better than CHOP? What has been tried?
• Consolidation with upfront ASCT
• Consolidation with upfront allogeneic transplantation
• Addition of etoposide: CHOEP
• New CHOP-X combinations
No proof of superiority, sometimes looks better but not demonstrated in randomized trials
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PTCLRole of high-dose therapy and ASCT in consolidation
Rodriguez, Ann Oncol 2004
BUT
-median age 46y
-Only 14% PIT 3-4
-ALCL included (ALK
status not known)
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Le Gouill, JCO 2008
Patient characteristics (n=77):
18-60 years, LDH ≤ UNV
35% ALCL, 35% PTCL-NOS, 14% AITL
All pretreated (25% ASCT)
74% myeloablative, TBI 66%, RIC 26%
PTCLRole of allogeneic translantation
BUT
-Survivals given AFTER
transplantation
-Many patients do not achieve
transplant eligibility at any time!
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PTCLRole of addition of etoposide (retrospective)
Schmitz et al, Blood 2010
ALCL, ALK-positive Other subtypes
Benefit in young mainly, risk of toxicity in elderly
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PTCL – TreatmentNew CHOP-X combinations
• CHOP-alemtuzumab (closed study)
• CHOP-rhomidepsin (ongoing study)
• CHOP alternating with BV (brentuximab vedotin) or CHP-BV for CD30+ malignancies
• Maintenance pralatrexate after CHOP
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PTCLTreatment recommendations
• Start with an anthracyclin-containing regimen
• CHOP21/14, CHOEP…
• If NO/SLOW response (role of Pet?), try to convert into CR
• ESHAP, DHAP, IFE (IFO-VP16), gemcitabine-containing…
• Consider upfront HDT and ASCT
• in young patients with initial int/high IPI (majority)
• and/or with HS
• and chemosensitive (in 1st CR)
• HDT and ASCT (or allogenic Tx?) in relapse
• if not transplanted upfront
• and chemosensitive (in 2nd or higher CR)
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PTCLBelgian treatment recommendations (van Obbergh et al, BJH 2013)
Overallrecommendations Category*
· Inclusioninaclinicaltrialisadvisedgiventhedisappointingresultsofstandardmanagement
· CHOP-basedtreatments1remainstandard
· 4-6cyclesconsolidatedbylocoregionalRTinlocalizeddisease(stagesIorII)withIPI0or1
· 6-8cycles+/-RTinadvanceddisease(stagesIII,IV)orlocalizeddiseasewithIPI2or3
2A
· ConsiderconsolidationwithHDT/ASCTinfirstlineifrespondingpatientsandinthepresenceofriskfactors2
2B
· In refractory/relapsing patients, use non cross-resistant (mainlyplatinum-orgemcitabine-based)regimens3andconsiderpatientforASCTifnotperformedpreviously,orallogeneictransplantation,ornewdrug
2A
· Incaseofallogeneictransplantation,considerRICbecauseofthetoxicityofmyeloablativeconditionings
2B
· CNSprophylaxisasinDLBCL 2B
* Grade of recommendation based on NCCN categories of evidence and consensus1 Potential regimens: CHOP-21, CHOP-14, CHOEP-21, CHOEP-14…2 IPI 2 or 3, presence of HPS3 DHAP, ESHAP, gemcitabine-containing (GDP, GemOX), ICE, pralatrexate, romidepsin, alemtuzumab, bortezomib…
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Low-IPI PTCLs: more conservative approach?
18/02/2014 19/06/201422/08/2014
08/10/2014
IPI=0 Metabolic CR?
6xCHOP, planned for RT
Facial palsy Systemic relapse
MTX IT and systemic
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PTCLTreatment recommendations by NCCN version 1.2015
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PTCLTreatment recommendations by NCCN version 1.2015
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PTCLTreatment recommendations by ESMO 2013
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PTCL« How I treat the PTCLs » by Moskowitz et al, Blood 2014
• General approach
– « Outside of a clinical trial, we most frequently use the treatment approach evaluated in the Nordic study with 6 cycles of CHOEP-14 followed by consolidation with ASCT as this is the largest dataset with the best phase II outcomes »
• Is there a favorable risk PTCL who should be treated differently?
– Low IPI patients: « Clearly, even for these more favorable patients, reduced therapy is not validated »
– ALK-positive: « We generally treat these patients as we treat the less favorable diseases with induction chemotherapy and ASCT consolidation »
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PTCL« How I treat the PTCLs » by Moskowitz et al, Blood 2014
• Relapsed/refractory (R/R) disease
– « We typically aim for allogeneic stem cell transplant (alloSCT) in fit patients, as in our experience this has been more reliably curative than ASCT in the relapsed setting »
• Categories of R/R patients
– Transplant soon: fit, donor+
Multiagent chemotherapies (IFO, CARBO or CDDP) before Tx
– Transplant never: age, co-morbidities, lack of donor, choice…
– Transplant unclear: to be valuated for Tx
Experimental or single-drug more tolerable
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PTCL – TreatmentRecommendations by disease subtypes
• ALCL ALK+, systemic
• Primary cutaneous ALCL
• Extranodal NK/T, nasal type
• Enteropathy-type (EATL)
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PTCL - ALCL category (CD30+)ALK+ systemic vs ALK- systemic
ALK+
ALK-
PTCL vs DLBCL ALCL ALK+ vs ALK-
ALK+ (ALKoma) systemic ALCL:
Men, < 35y
Chromosome translocation t(2;5), resulting in the fusion protein NPM-ALK
CHOP-type treatment, no upfront HDC-SCT (at relapse)
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PTCL - ALCL category (CD30+)ALK+ systemic, ALK- systemic, Cutaneous
Features
ALK+ systemic
ALCL
ALK-systemic
ALCL
Primary cutaneous
ALCL
T-cell phenotype CD4 CD4 CD4
ALK protein + - -
CD30 + + +
Median age <30 >50 >50
5-y OS 65-90% 30-40% >90%
Treatment Chemo Chemo conservative
Transplantation NO (2A) YES (2B) NO
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PTCL - ALCL category (CD30+)ALK+ systemic, ALK- systemic, Cutaneous
Cutaneous ALCLPrimary cutaneous ALCL:
Localized nodules, spontaneous regression 25%
Spot radiation, surgical excision, interferon + bexarotene
CHOP-type treatment only advanced cases
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Extranodal NK/TCL, nasal typeClinical presentation
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Extranodal NK/TCL, nasal typeMainstays of treatment
• Avoidance of anthracyclins
• Radiotherapy (> 50 Gy)
• L-asparaginase
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Extranodal NK/TCL, nasal typeMainstays of treatment
Localized disease*
* Definition: stage IE disease, potentially stage IIE
Radiotherapy (concurrent, sequential, or in sandwich at > 50 Gy) combined with chemotherapy (L-asparaginase-containing)
Advanced disease
AspaMetDex followed by BEAM and ASCT
(Jaccard, Blood 2011)
SMILE followed by BEAM/ASCT or allogenic Tx
(Yamaguchi, JCO 2011)
See also « How I treat NK/T-cell lymphomas », Tse & Kwong, Blood 2013
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Smile1 Smile2 BEAM+
ASCT
Extranodal NK/TCL, nasal typeSMILE regimen
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PTCLNew drugs
• Pralatrexate
– Novel antifolate, ORR 29%
– In combination? Maintenance?
• Romidepsin
– HDACi, ORR 30%
• Bendamustine
• Brentuximab vedotin
– Anti-CD30 antibody-drug conjugate
– ALCL (ALK+ and ALK-): ORR 87%, 57% CR
– Active in systemic CD30+ PTCLs: 33-54% ORR
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New drugs: alisertib (Aurora-kinase inhibitor)
07/08/14 07/10/2014 02/12/2014 10/02/2015
Courtesy by Dr Philippe d’Abadie, nuclear medicine, UCL Saint-Luc
PTCL NOSRelapse 6 months
after 6xCHOP14
Alisertib2 months
Alisertib4 months
Alisertib6 months
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PTCLConclusions
• CHOP remains the (poor) platform to build on, but beware of additional toxicity of CHOP-X
• Limited number of patients who can be treated less intensively must be identified, but beware of under-treatment
• More targeted approaches eagerly awaited