Peripheral T-cell lymphomas (PTCL) Specified and Unspecified. Eric Van Den Neste Cliniques universitaires Saint-Luc Bruxelles

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1 Peripheral T-cell lymphomas (PTCL) Specified and Unspecified Eric Van Den Neste Cliniques universitaires Saint-Luc Bruxelles BHS seminar 12, 07 March 2015

2 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

3 T-cell ontogenesis Fetal liver Thymus Peripheral lymphoid organs CD8+ BM Lymphoid progenitors Cellular differentiation Self-Ag recognition MHC recognition Pos- & neg-selection TCR ( ) receptor CD4+ T NK Malignant counterpart Immature T-cell malignancies (Thymic, TdT+) T-ALL T-LBL Mature T-cell malignancies (Post-Thymic, TdT-) PTCL

4 PTCL: pathophysiology of T-cell subsets Innate immune system Adaptive immune system Post-thymic lymphocytes T /NK T cytokines chemokines complement antigen recognition APC Apoptotic/necrotic cell death (not MHC restricted or limited repertoire) Pediatric/young T-cell lymphoma Extranodal, CD4-/CD8- Cytokine storm, HS Ex: NK-cell lymphoma, ETTCL CD4+ cells: regulatory CD8+ cells: cytotoxic (MHC restricted, greater specificity) Adult T-cell lymphoma Nodal, predominantly CD4+ Ex: PTCL-NOS

5 Simplified classification of PTCL 10-15% 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% Europe 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

6 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

7 PTCL Prognosis Overall survival of 288 PTCL patients compared with 1,595 DLBCL patients PTCL is a poor prognosis disease, except for some specific entities (ie, ALCL ALK+, primary cutaneous ALCL, MF) Gisselbrecht, Blood 1998

8 PTCL, NOS Poor prognosis also explained by high IPI 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) Most PTCL patients are advanced: 0/1: 28% 2-5: 72% Weisenburgerr, Blood 2011

9 PTCL Clinical 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

10 PTCL Treatment CHOP is standard 30% Reviewed in Foss, Semin Hematol 2010

11 Weisenburger, Blood 2011 PTCL Treatment CHOP is disappointing OS and FFS of 340 patients with PTCL-NOS (retrospective)

12 PTCL - Treatment How 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

13 PTCL Role of high-dose therapy and ASCT in consolidation BUT -median age 46y -Only 14% PIT 3-4 -ALCL included (ALK status not known) Rodriguez, Ann Oncol 2004

14 PTCL Role of allogeneic translantation Patient characteristics (n=77): years, LDH UNV 35% ALCL, 35% PTCL-NOS, 14% AITL All pretreated (25% ASCT) 74% myeloablative, TBI 66%, RIC 26% BUT -Survivals given AFTER transplantation -Many patients do not achieve transplant eligibility at any time! Le Gouill, JCO 2008

15 PTCL Role of addition of etoposide (retrospective) ALCL, ALK-positive Other subtypes Benefit in young mainly, risk of toxicity in elderly Schmitz et al, Blood 2010

16 PTCL Treatment New 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

17 PTCL Treatment recommendations Start with an anthracyclin-containing regimen CHOP 21/14, 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)

18 PTCL Belgian treatment recommendations (van Obbergh et al, BJH 2013) Overall recommendations Category* Inclusion in a clinical trial is advised given the disappointing results of standard management CHOP-based treatments 1 remain standard 2A 4-6 cycles consolidated by locoregional RT in localized disease (stages I or II) with IPI 0 or cycles +/- RT in advanced disease (stages III, IV) or localized disease with IPI 2 or 3 Consider consolidation with HDT/ASCT in first line if responding patients 2B and in the presence of risk factors 2 In refractory/relapsing patients, use non cross-resistant (mainly 2A platinum- or gemcitabine-based) regimens 3 and consider patient for ASCT if not performed previously, or allogeneic transplantation, or new drug In case of allogeneic transplantation, consider RIC because of the toxicity 2B of myeloablative conditionings CNS prophylaxis as in DLBCL 2B * Grade of recommendation based on NCCN categories of evidence and consensus 1 Potential regimens: CHOP-21, CHOP-14, CHOEP-21, CHOEP-14 2 IPI 2 or 3, presence of HPS 3 DHAP, ESHAP, gemcitabine-containing (GDP, GemOX), ICE, pralatrexate, romidepsin, alemtuzumab, bortezomib

19 Low-IPI PTCLs: more conservative approach? 18/02/ /06/ /10/ /08/2014 IPI=0 Metabolic CR? Facial palsy Systemic relapse 6xCHOP, planned for RT MTX IT and systemic

20 PTCL Treatment recommendations by NCCN version

21 PTCL Treatment recommendations by NCCN version

22 PTCL Treatment recommendations by ESMO 2013

23 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»

24 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

25 PTCL Treatment Recommendations by disease subtypes ALCL ALK+, systemic Primary cutaneous ALCL Extranodal NK/T, nasal type Enteropathy-type (EATL)

26 PTCL - ALCL category (CD30+) ALK+ systemic vs ALK- systemic PTCL vs DLBCL ALCL ALK+ vs ALK- ALK+ 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)

27 PTCL - ALCL category (CD30+) ALK+ systemic, ALK- systemic, Cutaneous Features ALK+ systemic ALCL ALKsystemic ALCL Primary cutaneous ALCL T-cell phenotype CD4 CD4 CD4 ALK protein CD Median age <30 >50 >50 5-y OS 65-90% 30-40% >90% Treatment Chemo Chemo conservative Transplantation NO (2A) YES (2B) NO

28 PTCL - ALCL category (CD30+) ALK+ systemic, ALK- systemic, Cutaneous Primary cutaneous ALCL: Cutaneous ALCL Localized nodules, spontaneous regression 25% Spot radiation, surgical excision, interferon + bexarotene CHOP-type treatment only advanced cases

29 Extranodal NK/TCL, nasal type Clinical presentation

30 Extranodal NK/TCL, nasal type Mainstays of treatment Avoidance of anthracyclins Radiotherapy (> 50 Gy) L-asparaginase

31 Extranodal NK/TCL, nasal type Mainstays 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

32 Extranodal NK/TCL, nasal type SMILE regimen Smile1 Smile2 BEAM+ ASCT

33 PTCL New 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

34 New drugs: alisertib (Aurora-kinase inhibitor) 07/08/14 07/10/ /12/ /02/2015 PTCL NOS Relapse 6 months after 6xCHOP 14 Alisertib 2 months Alisertib 4 months Alisertib 6 months Courtesy by Dr Philippe d Abadie, nuclear medicine, UCL Saint-Luc

35 PTCL Conclusions 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