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1 T- CELL LYMPHOMAS TREATMENT STRATEGIES AND PITFALLS Jasmine Zain, M.D. Director, T Cell Lymphoma Program Associate Clinical Professor, Dept. of Hematology & Hematopoietic Cell Transplantation Click to edit Master Presentation Date

2 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

3 OBJECTIVES New 2016 WHO classification Insights into pathogenesis Prognostic models what we know Upfront treatment, relapsed disease Stem cell transplant New treatment e t approaches

4 T - CELL DEVELOPMENT Blood. 2008;112: :4384

5 WHO CLASSIFICATION OF MATURE TCELL AND NK/T CELL LYMPHOMAS 2016

6 UNIQUE GEP SIGNATURE FOR MAJOR SUBTYPES OF PTCL GEP performed on 372 pretreatment biopsies cryopreserved tissue Unique signature for different subtypes of PTCL Javeed Iqbal et al. Blood 2014;123:

7 Unique GEP signatures for ALCL Javeed Iqbal et al. Blood 2014;123:

8 MAJOR CHANGES IN THE CLASSIFICATION ENTITY T cell large granular lymphocytic leukemia CHANGE New subtypes STAT3 and STAT 5 mutations in a subset associated with aggressive dz Systemic EBV+ T cell lymphoma of childhood Hydroa vacciniforme like lymphoproliferative disorder Enteropathy associated T cell lymphoma (EATL) Monomorphic epitheliotropic intestinal T cell lymphoma Indolent T cell lymphoproliferative disorders of the GIT tract Distinguish from ch active EBV infection Variable clinical spectrum Formerly known as EATL1 associated with celiac disease Formerly EATL II no association with celiac dz New entity, monoclonal T cell infiltrate, some cases show progression Lymphamatoid papulosis Primary cutaneous γδ T cell lymphoma Primary cutaneous acral CD8+ T cell lymphoma Primary cutaneous CD4+ small/ medium T cell lymphoproliferative disorder Peripheral T cell lymphoma (PTCL), NOS Nodal T cell lymphomas with T follicular helper phenotype (TFH) phenotype ALK ALCL Breast implant associated ALCL New subtype atypical histologic /immunophenotypic features Exclude other disorders of γδ T c ells like MF oy LyP Indolent entity originally described as originating in the ear Limited clinical risk localized dz and similar to clonal drug reaction Subsets based on phenotypic and molecular abnormalities that may have clinical implications but not routine practice AITL, folliculart cell lymphoma, PTCL with TFH phenotype New definite entity that have cytogenetic subsets with prognostic implications (IRF4/DUSP22, p63) New provisional entity.non invasive dz associated with excellent prognosis

9 T-FOLLICULAR HELPER CELLS TFH is a CD4+ cells that promotes and regulate T cell dependent B cell responses Cytokine secretion, CXCL13 (plasma cell expansion),angiogeneic mediators Neoplasms derived from TFH cells maintain these features AITL, FTCL, PTCL of TFH origin

10 NODAL T CELL LYMPHOMAS TFH PHENOTYPE Mostly CD4+, frequent aberration or downregulation of pan T cell markers CD20 positive in B-cell blasts or neoplastic cells, CD21 positive in AITL CD30 maybe positive on tumor cells of B cell blasts Neoplastic cells should express at least 2 or 3 TFH related antigens- CD279/PD1,,CD10, BCL6, 6,CXCL13, C ICOS,SAP and CCR5 Cytotoxic markers negative in neoplastic cells. EBV positive in B- ITK-SYK ( rare) blasts CD28 fusion (CD28-CLA4) and others Gene rearrangements of TCR + RHOA % Gene rearrangements of TET % immunoglobulin li genes + in 30% DNMT3: 20-30% IDH2: 20-30% (AITL only) PLCG1,CD28and TCR signaling -50%

11 PTCL-NOS Cells are pleomorphic with a variable reactive component CD4+/CD8-, a subset may be CD4- /CD8+,rarely double negative or double positive Most derived from αβ (TCR) rarely γδ (TCR) CD21-ve, CD30 maybe positive on rare cells TCR gene rearrangements positive EBER maybe positive in neoplastic cells T(6,14) rare VAV1 rearrangements -10% CD28 fusions PLCG mutations -15% Epigenetic (MML2, TET2, KDM6A, ARID1B, DNMT3,CREBBP,MLL,ARID2) Signaling pathways (TNFAIP3,APC,CHD8,ZAP70,NF1,TNFRSF14,TRAF3 Tumor suppressor TP53, FOXO1,BCORL1,ATM

12 GEP CAN DISTINGUISH 2 SUBTYPES OF PTCL- NOS GATA3 high expression skews to Th2, eosinophilia, infers worse prognosis TBX21/T-bet skews to Th1- further subgroups with expression of cytotxic markers Good correlation between molecular signatures and protein expression hence GATA3 and TBX21 can be reliable surrogates for molecular signature Javeed Iqbal et al. Blood 2014;123:

13 ANAPLASTIC LARGE CELL LYMPHOMAS ALCL- alk+ shows expression of alk by IHC- excellent prognosis ALCL-alk- GEP signature closer to ALK+ALCL and can be distinguished from CD30+ PTCL- Primary cutaneous ALCL Lymphomatoid papulosis Breast implant associated ALCL

14 GENETIC HETERGENICITY OF ALK-ve ALCL N=73 DUSP22 (n=21) and TP63 (n=6) rearrangements were mutually exclusive 45 cases lacked both rearrangements and ALK expression ( triple negative) 5 yr OS for DUSP % 5 yr OS for TP63+ 17% 5 yr OS Triple negative patients 42% Feldman et al Blood 2014 Feldman et al 2015

15 HEPATOSPLENIC T CELL LYMPHOMA Arises from ɣȣ T cells of the liver sinuses and splenic red pulp hepatosplenomegaly without significant adenopathy and pancytopenia Median age is 35,M>F Association with iatrogenic immunosuppression - Infliximab, purine analogues, Crohn s disease and recipients of solid organ transplantation 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 Most common chromosomal abnormality is isochromosome 7q and trisomy 8 WGS -13 recurrent mutated driver genes, SED2,INO80,ARID1B,STAT5B,STAT3,PIK3C STAT5B STAT3 D,--Dave et al 2016 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.

16 INTESTINAL T- CELL LYMPHOMA EATL MEITL INDOLENT T-CELL LPD OF THE GIT 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), HLA-DQ homozygosity ch 1q gains Invasion of intestinal mucosa Villous atrophy of surrounding tissue Epitheliotropism,surrounding mucosa intact. ɣȣ origin,cd8 and CD56 positive Monomorphic Postive for MATK Gains in ch 8q24 involvling MYC are seen Some cases express αβ subtype small mature lymphoid cells that are mostly CD8+ with no evidence of STAT3 SH2 domain mutation Pathologic features consistent with diagnosis RCD type 2 is a risk factor for EATL Activation of epithelial stress response by continuous exposure to antigliadin ab sustains cellular growth via IL-15, JAK/STAT STAT5mutations 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% 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 Indolent clinical course Do not require aggressvie therapy Treat as per primary diagnosis High incidence of GIT bleed and other complications

17 FUNCTIONAL MUTATIONS ACROSS SUBTYPES OF PTCL GENETIC CHANGE PATHWAY HISTOLOGIC SUBTYPE Rho A mutations Encode small GTPase AITL,TFH PTCL ( 60 70%), ATLL TET2, DNMT3A inactivating mutations Epigenetic modifiers 50 70% TFH PTCL 20 30% T FH PTCL IDH2 gain of function mutation Epigenetic modifier 25% of AITL SETD2 MEITL,HSTCL FYN,CD28, PLCG1,PI3K, CARD11 Mutation induced activation of AITL,TFH PTCL,PTCL NOS,ALK TCR and costimulatory molecules ALCL,CTCL,ATLL ITK SYK,CTLA4 CD28, CTLA4 ICOS gene fusions DUSP22 and VAV1 rearrangements JAK/STAT pathway JAK1,JAK3,STAT3,STAT5B Activating mutations T cell leukemia and extra nodal PTCL

18 POPULATION SUBSETS OF THE CELLS AND CORRESPONDING T-CELL LYMPHOMAS Laurence de Leval, and Philippe Gaulard Blood 2014;123:

19

20 DIAGNOSTIC PITFALLS 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: y 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 GEP- research only

21 PROGNOSTIC SCORE FOR PTCL PROGNOSTIC SCORE FOR NK/T CELL LYMPHOMA Korean prognostic score for NK/T cell lymphomas B symptoms, stage, LDH, regional adenopathy PINK- age>60, stage III/IV, distant nodal involvement, non-nasal type PINK E >60 t III/IV di t t d l PINK- E- age>60, stage III/IV, distant nodal involvement, non-nasal type, EBV virus DNA

22 WHY SHOULD PTCL BE TREATED DIFFERENTLY INTERNATIONAL PERIPHERAL T-CELL STUDY NORTH AMERICAN PTCL STUDY GROUP Vose et al Hsi, et al: Am J Surg path -2014

23 GOAL OF UPFRONT THERAPY IS TO ACHIEVE A DEEP REMISSION Anthracyclin based regimens are still considered the standard of care CHOP most common Anthracyclin based regimens achieve a CR in 17-70% of cases but high risk of relapse with 5 yr OS of 38-58%- meta-analysis Abouyabis et al 2011 No survival advantage seen with anthracycline induction based on 2 retrospective studies (International T cell lymphoma project) and BCCA Contrary results by Mayo Clinic and University of Michigan- 326 pts treated with anthracyclins had a median PFS and OS of 10 and 18 months compared to < 2 months in non- anthracycline treated patients best for PTCL-nos and AITL Briski et al 2014

24 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 NA NA Some had transplant Addition of etoposde improved EFS but not OS in younger patients with normal LDH 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 %, 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-fractionated cyclophosphamide, vincristine,,pegylated liposomal doxorubicin and dexamethasone alternating with methotrexate/cytarab ine (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

25 HOW TO IMPROVE OUTCOME CONSOLIDATION / MAINTAINENCE THERAPY Improve the remission rate with upfront therapies Consolidate remission with 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

26 AUTOLOGOUS STEM CELL TRANSPLANT AS CONSOLIDATION THERAPY - INTENT TO TREAT n % ASCT CR/PR % OS % PFS % d Amore et al /166 51% at 5 years (ALCLalk- best) 44% at 5 years Corradini et al / (12 yrs) (12yrs) Reimer et al /26 50 ( 3 yrs ) N/A D Amore et al /35 67 ( 3 yrs ) N/A Rodriguez et al / ( 3 yrs ) 53 ( 3 yrs ) Mercadal et al /10 39 ( 4 yrs ) 30 (4 yrs )

27 EFFECT OF UPFRONT TRANSPLANT IN PTCL ALCL ALK+ ALCL ALK- PTCL-NOS AITL NK/T 5 yr OS rate%- Int T cell Project 5 year OS rate % Abouyabis et al 3 year OS Schmitz et al 5 year OS % D Amore et al ( all subtypes Not included

28 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 Very aggressive histologies like HSCTL, gamma/delta lymphomas not likely to achieve chemosensitive remission Adverse factors by multivariate analysis, BM involvement, PS>2 D Amore et al JCO 2012

29 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% 4 year estimated OS is 80%, median PFS not reached, No SCT Horowitz et al : abstract 2993 ASH 2016

30 CHOP BASED COMBINATION THERAPIES TREATMENT N MEDIANFU ORR CR MEDIANPFS 2 YR PFS MEDIAN OS 2 YEAR OS CHOP14+ALEMTUZUMAB MONTHS 90% 65% 10 MONTHS 27% 27MONTHS 55% CHOP21+BORTEZOMIB MONTHS 76% 65% 9 MONTHS 37% 22MONTHS 52% CHOP21+BEVACIZUMAB MONTHS 90% 49% 8 MONTHS 25% 22MONTHS 42% CHOP21+DENILEUKIN DIFTIOX 49 22MONTHS 65% 55% 12 MONTHS 43% NOT REACHED 65% CHOP21+EVEROLIMUS MONTHS 90% 57% 11 MONTHS 33% NOT REACHED 70% CHOP21+BELINOSTAT 23 89% 72% CHOP+ PRALATREXATE ONGO ING CHOP+ ROMIDEPSIN ONGO ING

31 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 (1-12) 29%/11% PTCL- nos 32%, 10.1 Numbers are small to PTCL-nos -59 salcl 17. AITL--- 13, tmf 12 other salcl- 35%, AITL- 8%, tmf- 25% other 38% months (,1-22.1) make individual deductions about histological subtypes Romidepsin 130 PTCL- nos 69, AITL- 27, ALK-ve ALCL -21, Other (1-8) 25%/15% PTCL- nos 29/14, 28 Median OS 11.3 AITL- 30/19, Alk-ve months ( months ALCL -24/19, Other 1-48) Median duration of 0/0 response not reached for CR patients Belinostat 129 PTCL-nos 77, AITL 22,ALCL- 15,EATL 2,NK/T- 2, HSTCL- 2 Brentuximab Vedotin 2(1-8) 26%/11% PTCL-nos- 23%,AITL,46%/18%, ALCL- 15%,EATL ) 0,ENKTCL-50%, HSTCL-0 58 salcl 2 (1-6) 86%/59% 13.2 ( ) Mogamulizumab 27 ATLL /31 Median PFS 5.2 months Time to CR is 3.7 months Seems to have a higher response rate in AITL Medain OS not reached 1 year:70%, 3 year:63%, 4year: 64%) Median OS 13.7

32 ORR % FOR FDA APPROVED AGENTS FOR PTCL Pralatrexate romidepsin Belinostat Brentuximab vedotin All PTCL nos AITL ALCL

33 R/R PTCL AGENT N HISTOLOGIC AL subtypes n MEIDAN PRIOR THERAPIES ORR/CR Response by histology ORR/CR DOR/PFS COMMENTS Brentuximab 35 PTCL-nos 2(19) 1-9) 41%/24% PTCL-nos PTCL-nos vedotin 22,AITL n /14 AITL54/38 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, ) 50/28 Median DOR Median OS 6.3 PTCL- nos 23, ALCL- 2, EATL ( 1-21) months Alemtuzumab 14 PTCL-nos 10, 2(1-4) 36/21 AITL 4 Crizotinib 9 Alk+ ALCL 89/78 NR Lenalidomide 50 AITL- 26, PTCL-nos- 20, ALCL- 3, 3 (1-11) 22/11 AITL-31/15 PTCL-nos 20 ENKTCL- 1 Gem/Dex/Cispl atin 51 PTCL 69/19 Median PFS 4 months 72% went to auto or allo transplant

34 PROSPECTIVE STUDIES EVALUATING PTCL OUTCOMES COMPLETE REGISTRY 72 sites worldwide 5 years of follow up designed to evaluate whether the results of clinical studies are being incorporated into daily practice and compare treatment practices among various practice settings T- CELL PROJECT International 75 centers Consecutive patients followed for 5 years Tissue bank 1510 cases from

35 PTCL HISTOLOGY COMPLETE REGISTRY

36 SYSTEMIC THERAPY FOR RELAPSED/REF PTCL PATIENTS 285 patients in COMPLETE 50 rel, 69/ ref Real world outcomes REFRACTORY no response to initial therapy OR progression within 1month RELAPSED progression at least 1 month from a CR or PR Novel agents used more as second line therapy in Relapsed patients vs multi-agent therapy in ref patients Lansigan et al ASH

37 COMPLETE REGISTRY OUTCOME DATA Overall Survival from Initial PTCL Diagnosis Overall Survival from Rel/Ref Diagnosis Outcomes worse for refractory patients Lansigan et al-ash

38 OUTCOME OF PRIMARY REF/REL PTCL T CELL PROJECT 1020 cases of rel/ref 937 received active therapy 47% rel, 21% ref Median time to rel 8 months RELAPSE - progression at least one month after completion of front line therapy in CR or PR REFRACTORY- no response to initial therapy or requiring salvage therapy immediately after completing frontline therapy SAR ( survival after relapsed/ref dz) 5.8 months At 3 yrs SAR was 28% for rel and 21% for ref dz. Patients responding to salvage therapy and ASCT had a SAR of 48% compared to no HDT p,0.001 Relapse > 12 months and ASCT associated with better outcome BELLEI ET AL ASH

39 EVENT FREE SURVIVIAL AT 24 MONTHS EFS24 UI/Mayo clinic, Swedish lymphoma registry, BCCA 775 patients Median survival after progression within 24 months as 4.9 months Median survival after EFS24 was not reached 5 yr OS 78% inferior to expected survival of 92% In EFS 24- favorable outcome with younger age < 60 ( OS 91% vs 98% at 5 ys) and in patients achieving ASCT in CR1-- patients in EFS24 who were not transplanted in CR1 had a 5 year survival of 74% vs 90% expected EFS 24 helps stratify patients Establish the role of ASCT as consolidation MAURER ET AL ASH

40 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

41 RISK OF CNS RELPASE N=616- Exclude patients with CNS involvement at dx- median fu 5.7 yrs 1 year and 5 yr CI was 1.8% and 2.4% Median OS after CNS involvement was 1.6 months >1 Extranodal site, and high IPI by univariate analysis Alk + ALCL > 1 EN had a higher incidence of CNS relapses - 15% at one year All occur within 6 months of dx Chiara et al - ASH ABSTRACT 4153

42 STEM CELL TRANSPLANTATION FOR RELAPSED PTCL

43 STUDIES OF ASCT IN PTCL Number Clinical setting Results Rodriguez et al 29 Salvage 3 yr OS 36% Blystad et al 40 First line CR/ Salvage 3 yr PFS 28% 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%

44 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 5 yr OS is 54.4%, myeloablative PFS = 46.5% Le Gouill et al 2008 PTCL Multiply relapsed 77 Corridiani et al Rodrigues et al 2006 PTCL Relapsed/ refractory 17 T cell NHL Multiply relapsed 11 2/3 ablative 1/3 RIC RIC/ Thiotepa/Flu/Cy 7 RIC 4 CMR 5 yr OS 57% 5 yr DFS 53% TRM 33% 3 yr OS 81%,DFS 62%, 5 yr survival for CR is 75% 2 yr F/u OS 57%

45 ALLOGENEIC STEM CELL TRANSPLANT IN T-CELL NHL 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? Le Gouill et al 2008

46 ALLOGENEIC TRASNPLANTS FOR PTCL AT CITY OF HOPE - FINAL OUTCOME 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 Zain et al Leuk Lymphoma Aug;52(8):

47 Allo vs ASCT for PTCL 59 patients / 10 years SCT for aggressive dz 5 year outcomes better with allo SCT Remission status at transplant (CR1 vs CR2 vs remission beyond vs not in remission) predicted OS and PFS Kamarajah et al ASH 2016 abstract 680

48 ALLOGENEIC OR AUTOLOGOUS TRANSPLANTATION AS FIRST LINE THERAPY FOR YOUNGER PATIENTS WITH PERIPHERAL T CELL LYMPHOMA: CHOEP x 4 CR/PR/SD randomized DHAP and ASCT MAC and allo transplant ( sibs) 58/104 eligible patients Pre- planned interim analysis did not show survival benefit of allo transplant vs ASCT 38% of patients did not proceed to transplant Trial was stopped prematurely Schmitz et al ASCO abstract 2015

49 CITY OF HOPE ALGORITHIM FOR TREATING PTCL

50 NEW AND EMERGING THERAPIES FOR PTCL NOVEL COMBINATIONS NOVEL A GENTS AND STRATEGIES PATIENT SELECTION FOR APPRIATE TARGETED AGENTS IMMUNOTHERAPY

51 NOVEL THERAPEUTIC APPROACHES FOR PTCL AGENT MECH OF ACTION TRIAL DESIGN RESPOSNE RATE DUVELISIB PI3 kinase inhibitor Phase 1 N=33 ORR 42% Acceptabel safety Copanalisib Phase II N=17 RP6530 Phase 1 N=13 Decitabine Hypomethylating agents Case reports ORR 21% with 2 CRs Ongoing 5 AZa Phase II N=19 EZH2 /EZH1 inhibitors Epigenetic therapy Ongoing phase 1 a histone methyl transferase subunit of a Polycomb repressor complex Romidepsin + 5 Aza Combination therapies Phase I/II Ongoing Romidepsin + pralatrexate PhaseI/II Ongoing ORR 53% higher in AITL RR 77% Romidepsin + lenalidomide PhaseI/II RR 68% Forodosine Purine nucleoside inhibitor N= 48 ORR 22% Immunotherapy PD1 and PDL1 antibody Case reports positive Trials on going CAR T CAR T for CD4, CD5, CD30 Animal models and in vivio studies

52 CLINICAL TRIALS AT COH FOR PTCL Study Phase II Study of Romidepsin Plus Lenalidomide for Patients with Previously Untreated PTCL A Phase I/II Trial of CHOEP Chemotherapy plus Lenalidomide as Front Line Therapy for Patients with Stage II, III and IV Peripheral T Cell Non Hodgkin's Lymphoma A Phase 1/2a Open Label Study to Determine the Safety and Tolerability of ALRN 6924 in Patients with Advanced Solid Tumors or Lymphomas Expressing Wild Type p53 Protein A Phase II Study to Determine Feasibility and Safety of Single Agent MK 3475 in Relapsed or Refractory PeripheralT Cell Non Hodgkin Lymphoma A Phase I Trial of MEDI 570 in Patients with Relapsed/Refractory Peripheral T Cell Lymphoma (PTCL) Follicular Variant and Angioimmunoblastic T Cell Lymphoma (AITL) Phase II Trial of Intravenous Fenretinide (N (4 hydroxyphenyl) Retinamide, 4 HPR) Emulsion for Patients with Relapsed/Refractory Peripheral T cell Lymphomas (PTCL) A Phase I/Ib, Dose Escalation Study to Evaluate Safety and Efficacy of RP6530, a DualPI3K Delta/Gamma Inhibitor, inpatients With Relapsed or Refractory T cell Lymphoma Eligibility Untreated PTCL > 60 or ineligible for chemotherapy Untreated PTCL Relapsed PTCL, need to evaluate for wild type p53 in tumor sample Relapsed PTCL Relapsed TFH PTCL or AITL Relapsed PTCL Relapsed PTCL

53 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, 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 Suzuki et al: Curr Ocol rep :

54 CITY OF HOPE ALGORITHIM FOR NK/T CELL LYMPHOMA

55 CONCLUSIONS PTCL New WHO classification incorporates GEP data Prospective data now becoming available to study the diseases in more detail including epidemiology, clinical outcomes in real time Treatments are now being defined for specific subtypes Current upfront treatments are not curative Improved molecular pathology will define specific subtypes that can benefit from unique therapeutic approaches Single agents have limited efficacy and combination therapies will likely l improve outcome Continued need for collaboration and well designed clinical trials to make progress

56 T cell Project Patient characteristics N % 1248 Median age 56 Male gender PTCL nos AITL ALCL ALK ALCL ALK NKTCL Unclassified 37 3 Extranodal Curative intent HDT 1 st consolidation 75 7 HDT salvage No HDT

57