Should peripheral T-cell lymphoma be treated by autologous or allogeneic SCT?

Transcription

1 Francesco d Amore, MD, PhD Dept. Of Hematology Aarhus University Hospital, Aarhus, Denmark Should peripheral T-cell lymphoma be treated by autologous or allogeneic SCT? Disclosure of Interest: Nothing to Disclose

2 Upfront ASCT in PTCL: Scenario with conventional CHOP/CHOP-like approach Meta-analysis of CHOP/CHOP-like outcome in PTCL 31 clinical trials: tot 2815 pts ( period: ) Overall (all subtypes): 5 yr OS 38.5% ALCL (overall) 56.5% Abouyabi s et al, ISNR Hematology 2011

3 Autotransplantation in PTCL (retrospective) Salvage Treatment Author n CR OS Comment Vose (1990) 17 59% 35% (2y) Fanin (1999) 64 n.d. 70% (5y) ALCL Rodriguez (2001) 29 79% 39% (3y) subgroup Blystad (2001) 40 80% 58% (3y) Song (2003) 36 42% 48% (3y) Rodriguez (2003) 78 68% 56% (5y) subgroup Schetelig (2003) 15 67% 44% (5y) AIL, subgroup Jagasia (2004) 28 50% 69% (3y) incl. CTCL Jantunen (2004) 37 76% 54% (5y) subgroup Kewalramani (2006) 24 n.d. 33% (5y) Nademanee (2006) 57 n.d. 45% (2y) subgroup Kim (2007) 40 n.d. 11.5m subgroup Smith (2007) 32 n.d. 43% (3y) subgroup Chen (2008) 53 79% 40% (5y) subgroup Khouri (2008) 59 80% 43.5m subgroup

4 Autotransplantation in PTCL (retrospective) - 1. Line Treatment Author n Regimen CR OS Comment Rodriguez (2007) 19 Rodriguez (2007) 74 BEAM, BEAC, CVB, Cy+TBI BEAM, BEAC, CVB, Cy+TBI 79% 60% (5y) only AILT, subgroup n.d. 68% (5y) incl. ALCL Feyler (2007) 64 misc n.d. 53% (3y) incl. ALK+ALCL Kyriakou (2008) 146 misc 70% 59% (4y) only AILT, subgroup Khouri (2008) 79 mainly BEAM n.d. 60% (5y) incl. ALCL, subgroup Lee (2008) 47 misc n.d. 86% (5y DFS) only extranodal PTCL Yang (2009) 64 misc n.d. 53% (3y) only PTCLu Nademanee A (2011) 67 misc n.d. 54% (5y) 66 mo med follow-up Prochazcha V (2011) 29 misc 66% 65% (2y) PTCL-NOS, alk-neg ALCL, AILT, EATL Iriyama N (2013) 28 Double CHOP> Cy+Eto+Ranimustine 68% 63% (5y) Alk+ ALCL excluded

5 Proportion HDT in PTCL-NOS Retrospective data from the International T-cell Project Proportion possibly an advantage and, if so, rather upfront 1.0 Overall survival 1.0 Failure-free survival p= p< Time Time HD Therapy yes no CENSOR FAIL TOTAL MEDIAN Transplantation CENSOR FAIL TOTAL MEDIAN 1. line line Armitage, Vose, et al. J Clin Oncol (2008)

6 Largest prospective PTCL trials with HDT in 1st line Study Histology Type Design N of pts (ITTP) Med follow-up Accrual status Efficacy (Ref) Treatment naive PTCL ACT sptcl IIS phase mo Ongoing ASH 2012 NLG-T-01 sptcl IIS phase mo Closed JCO 2012 Reimer et al sptcl IIS phase mo Closed JCO 2009 IIS = Investigator-initiated study

7 Overall survival 1 0,8 0,6 Parameter N pts 83 Schedule - CHOP-21 x Mobilizing DexaBEAM - TBI+CY Median follow-up 33 mo 0,4 0, Time (months) (n=83) 1 0,8 Progression-free survival 5 yr OS 3 yr PFS 40% 36% 0,6 0,4 0, Time (months) (n=83)

8 Excluded: Precursor TCL alk+ ALCL CTCL Primary leukemic PTCL CHO(E)P : yrs: CHOEP-14 (n=118) yrs: (n=42) 60 mo median follow-up CHO(E)P-14d x 3 CR, PR CHO(E)P-14d x 3 (stem cell collection) CR, PR HDT (BEAM) NC,PD NC,PD JCO 2012;30(25): Follow-up

9 NLG-T-01: OS and PFS Median follow-up: 5 yrs (range 2-8 yrs) OS, whole cohort 5-yr OS 51% N of evaluable patients: 160 Median age: 57 yrs months Number at risk % CI Survivor function Dose-dense induction followed by HDT/ASCT: is well tolerated PFS, whole cohort 5-yr PFS 44% leads to long-term PFS in 44% of pts best in alk-neg ALCL (5y PFS:61%; OS:70%) useful reference for future studies months Number at risk % CI Survivor function

10 ASCT 1st line in PTCL OS +PFS in the Nordic and German trial Comparison of treatment schedules Induction Conditioning regimen Nordic trial CHOEP-14 x6 BEAM German trial CHOP-21 x4-6 + DexaBEAM/ESHAP (mobilizing) HdCy+TBI OS Nordic trial German trial PFS Nordic trial German trial 3-yrs 57% 48% 5-yrs 51% 40% 3-yrs 49% 36% 5-yrs 44% n.d.

11 NLG-T-01: OS and PFS - largest subtypes Median follow-up: 5 years 1.0 OS, largest subtypes 1.0 PFS, largest subtypes p=0.21 (logrank test) 0.2 p=0.26 (logrank test) months months PTCL-NOS Alk-negative ALCL AILT EATL PTCL-NOS Alk-negative ALCL AILT EATL Histology 5-yr OS 95% CI ALCL 70% 50%-83% AILT 52% 33%-69% EATL 48% 26%-67% PTCL-NOS 47% 34%-59% Meta-analysis CHOP 5y OS (Abouyaby, 2011) 56.5 % 36.5 % 21 % 34% Histology 5-yr PFS 95% CI ALCL 61% 42%-76% AILT 49 % 30%-65% EATL 38 % 18%-57% PTCL-NOS 38 % 25%-50%

12 Intensified induction + upfront ASCT in EATL Retrospective analysis of prospectively collected data Parameter Comment Values N pts Data period Outcome (historical comparison) CHOP-like IfosfVepEpi + MTX+ASCT CHOP-like IfosfVepEpi + MTX+ASCT N tot = 54 N tot = yr OS 22 vs 52%

13 Guidelines ESMO + NCCN

14 1st line treatment of PTCL Patterns of treatment failure 26% 18% 7% Diagnosis 2 yr 3 yr est 5 yrs PFS = 44% End of induction, consolidation Improve induction Improve consolidation/ consider maintenance New trials

15 18 yrs The ACT trial 65 yrs 80 yrs R R A 30 - A 30 - A 30 - A 30 - A 30 - A 30 - A 30 - A 30 - HDT HDT N=133 N=250 N=117

16 Proportion Proportion ACT-1 Response rates and time-related end-points 15 mo median follow-up Response rates Response rates N (%) ORR 42 (67) CR/CRu 38 (61) PR 4 (6) SD 3 (5) PD 16 (25) Not evaluable 2 (3) Total 63 (100) Time-related end-points (not arm-specific) Primary EFS Months End-point 1-yr (95% CI) EFS 55% (42-67) PFS 54% (42-67) OS 78% (67-88) Secondary PFS Months d Amore et al, ASH 2012 abs #57

17 The ACT and NLG-T-01 trials Outcome meta-analysis with regard to ASCT R R NLG-T-01 (>60y) A 30 - A 30 - CHO(E)P-14 A 30 - A 30 - CHO(E)P-14 A 30 - A 30 - CHO(E)P-14 A 30 - A 30 - CHO(E)P-14 CHO(E)P-14 CHO(E)P-14 Auto Auto Auto Meta-analysis Cohort Est. N NLG-T-01 Std ACT yrs (CHOP + HDT) yrs (CHOP + HDT) Std ACT yrs (CHOP) 60-70

18 NLG-T-01: long-term follow-up (8 yr median) Induction Consolidation Follow-up 1st yr Follow-up 2nd yr Follow-up 3rd yr Follow-up 4th yr Follow-up 5th yr Follow-up 6th yr Follow-up 7th yr Follow-up Median 98 ( ) months Histology Early (<2yrs) post-therapeutic relapses Late ( 2yrs) post-therapeutic relapses N Time points for relapse (yrs) N Time points for relapse (yrs) PTCL-NOS 8 0.2; 0.2; 0.3; 0.3; 0.5; 0.9; 1.3; ; 3.6; 3.8; 3.9; 5.3 AILT 6 0.2; 0.3; 0.3; 0.5; 1.0; ; 4.2; 6.1 ALCL (alk-) 6 0.2; 0.3; 0.3; 0.3; 0.3; ; 5.0; 6.4 EATL 5 0.3; 0.4; 0.8; 0.8; ; 7.1 SCPL HSTCL d Amore et al. 12th ICML Lugano 2013; abs #

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20 #155: Intensified chemo-immunotherapy for patients affected by nodal peripheral T-cell lymphomas (PTCLs) at diagnosis: Final results of a phase II multicentre prospective trial P. Corradini et al. Italian phase II study performed (NCT ) A: yrs: 2 x CHOP-21 + Campath (30 mg) 2 x Hyper-C-Hidam (Cy-AraC-Mtx) Responding pts received auto-sct or allo-sct based on genetic stratification B: yrs: 6 x CHOP-21 + Campath (10 mg) Cohort of 86 pts (A: n=61; B: n=25) PTCL-NOS: 49% AILT: 24% ALCL Alk-neg: 22% EATL: 5%

21 P. Corradini et al. FINDINGS: A: yrs B: yrs Median follow-up 40 mo 48 mo Estimated 4yrs OS PFS DFS 48.8% (95% CI, %) 44.0% (95% CI, %) 79.0% (95% CI, %) 31.5% (95% CI, %) 26.7% (95% CI, %) 44.4% (95% CI, %) NRM 13% (majority of pts belonged to the allo-sct cohort) 12% ORR at the end of induction 67% (CR 56%; PR 11%) - Consolidation Multivariate analysis (PFS, OS) Auto-SCT: 14 pts (OS vs non-transpl:hr 0.04; p=0.004) Allo-SCT: 23 pts (OS vs non-transpl:hr 0.22; p=0.008) No consolidation: 23 (PD: 18 pts; toxic deaths: 5 pts) 1 pt maintained remission without consolidation ccr for at least 6 mo: significant for both PFS and OS Undergo transplantation: significant for OS - CONCLUSION: Upfront transplantation was associated with a prolonged DFS in younger patients. No outcome improvement for the chemoimmunotherapy treated elderly cohort

22 Modality N pts Med age Histologies (N) Auto yrs ALCL: 53 PTCL-NOS: 34 AITL: 13 Allo yrs ALCL: 51 PTCL-NOS: 63 AITL: 12 Total 241

23 Auto vs Allo PFS and OS (all pts) Auto vs Allo NRM Auto vs Allo PFS and OS (CR1 excl) RIC vs Myabl NRM

24 Should SCT in 1st remission be the standard of care for patients with PTCL? Treatment setting Ptt. Description No. of ptt. in the cohort (%) young & fit 241/470 (51) 1st-line* ( 65 y & PS 2) elderly & fit 164/470 (35) (> 65 y & PS 2) Frail (PS>2) 65/470 (14) Bjerregaard-Pedersen M 12th ICML, abs #234, Ann Oncol Suppl 2013 age >65-67yrs (45-50%) alk+alcl (no pediatric cases) (3%) stage I low-risk non-bulk disease (2%) severe co-morbidity (4%) (only for allosct): no donor availability For approximately 50-60% of them => no

25 Should high-dose therapy with autologous stem cell support be recommended in 1st remission for the 40-50% transplant eligible patients with PTCL? yes, as it probably provides the possibility to improve the quality of remission and thereby the duration of respons Although no randomized clinical trials are presently available to answer the question in a definitive way And limited to 1 transplant- and risk-eligible 2 chemosensitive (CR, CRu, PR) 3 risk-eligible (i.e. stage I non-bulk, IPI 0-1 excluded)

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27 Should peripheral T-cell lymphoma be treated by auto or allogeneic SCT? F. d Amore Aarhus University Hospital, Aarhus, Denmark Berlin, October 2013

28 NLG-T-01: Flow chart 166 pts enrolled 6 pts inclusion criteria not fulfilled Flow chart of the NLG-T-01 study cohort showing the number and types of treatment failures and the responding patients throughout the different stages of the treatment algorithm. 160 pts confirmed diagnosis 156 pts Evaluable response Intention-to-treat population 4 pts not evaluable response ORR pre-tx 131 (82%) CR/CRu 82 (51%) PR 49 (31%) % Tx 115 (72%) 131 pts CR/PR after 6xCHOEP 115 pts transplanted 25 pts primary refractory 16 pts PD/tox/mobilisation failure/other before Tx CR/CRu 100d post-tx 90 (56%) 90 pts CR/CRu 3 mo post Tx 25 pts PR/PD/tox

29 NLG-T-01: CHOP vs elderly CHOEP Median follow-up: 5 years Subcohort 5yr OS 5yr PFS yrs CHOEP (n=50) 40% 39% yrs CHOP (n=42) 45% 34% NLG-T01: OS for CHOP vs 'elderly' CHOEP, p= analysis time CHOEP CHOP

30 NLG-T-01: OS and PFS ALCL vs non-alcl histology Median follow-up: 5 years NLG-T01: OS - ALCL vs non-alcl, p=0.026 NLG-T01: PFS - ALCL vs non-alcl, p= analysis time analysis time alcl = Not ALCL alcl = ALCL alcl = Not ALCL alcl = ALCL

31 NLG-T-01: ALCL vs non-alcl No difference in age, CS, IPI and BM involvement Age Clinical stage Histology median (yrs) Rank-sum (obs/exp) p-value* Histology CS I-II N (%) CS III-IV N (%) p-value (Fisher s exact) ALCL 53.8 yrs 10632/10385 non-alcl 50.2 yrs 2248/ ALCL 8 (26%) 23 (74%) non-alcl 23 (18%) 106 (82%) * Two-sample Wilcoxon rank-sum (Mann-Whitney) test IPI BM involvement Histology IPI low N (%) IPI int-high N (%) p-value (Fisher s exact) Histology No N (%) Yes N (%) p-value (Fisher s exact) ALCL 12 (39%) 19 (61%) non-alcl 33 (26%) 96 (74%) ALCL 23 (74%) 8 (26%) non-alcl 96 (74%) 33(26%) 1.000

32 NLG-T-01: Prognostic factors Parameter OS PFS HR CI 95% p-value HR CI 95% p-value Univariate analysis Female gender Age (per year) PS BM involvement ALCL histology Elevated s-ldh CS III-IV Multivariate analysis ALCL histology Age (per year) PS Female gender BM involvement

33 Population-based clinicopathological features Danish Lymphoma Registry LYFO ( ) PTCL-NOS (n=218) AITL (n=91) ALK+ ALCL (n=49) ALK- ALCL (n=89) EATL (n=15) All (n=462) Med age (yrs) M/F ratio Stage III/IV (%) PS (ECOG) (%) 0 I II III IV >1 Exnod site (%) BM involvement, % Approximately 49% of the pts were not eligible (e.g. high age, poor PS) for trials involving upfront SCT. Approximately 80% of pts were considered eligible for any interventional clinical trial (age, PS, comorbidity, unable to give informed consent etc). Of the potential 80% candidates (any trial), only 11% were actually included in a clinical trial emphasizing the need of optimizing recruitment strategies and trial designs, particularly for the frailest subset of pts. Pedersen et al. 12th ICML Lugano 2013; abs # 234

34 HDT in PTCL Summary and perspectives Did NLG-T-01 improve upon a comparable historical cohort? Possibly 1.0 OS, whole cohort % months Number at risk % CI Survivor function A characterization of long-term responders vs refractory and relapsing patients should be attempted Trial-specific TMA and nucleic acid analysis from FFPE samples Work in progress NGS acgh GEP mirna Protein analysis on frozen tissue samples and validation with WB and IH

35 NLG-T-01: Demographics Characteristic No. of patients (%) Age, yrs - Median - Range Sex - Male - Female (67) 53 (33) B-symptoms 94 (59) Pre-therapeutic clinicopathological patient characteristics (N=160) Elevated s-ldh 99 (62) PS 2 46 (29) Bulk 26 (17) CS III-IV 129 (81) BM involvement 41 (26) IPI ( 2) 115 (72) Histological subtype - PTCL-NOS - ALK-neg ALCL - AILT - EATL - Panniculitis-like - T/NK nasal type - Hepatosplenic 62 (39) 31 (19) 30 (19) 21 (13) 6 (4) 5 (3) 5 (3) ALCL PL HSL T/NK EATL AILT NOS

36 NLG-T-01: Toxicity and causes of death Toxicity Gr.3-4 % of total Hematological 65% Non-hematological 45% - Infection 37% - Gastrointestinal 4% - Mucositis 4% Cause of death N pts % of deceased % of total Lymphoma 54 75% 34% Toxicity 7 10% 4% 2nd cancer 2 3% 1% Other causes 6 8% 3% Unknown 3 4% 2% Total % 45%

37 NLG-T-01: OS - rare subtypes Median follow-up: 5 years OS, rare subtypes Histology 3-yr OS 95% CI PL 50% 11%-80% HS 40% 5%-75% T/NK 40% 5%-75% analysis time panniculitis-like (PL) Hepatosplenic (HS) Extranodal T/NK (T/NK)

38 NLG-T-01: PFS - rare subtypes Median follow-up: 5 years PFS, rare subtypess Histology 3-yr OS 95% CI PL 50% 11%-80% HS 40% 5%-75% T/NK analysis time panniculitis-like (PL) Hepatosplenic (HS) extranodal T/NK (T/NK)

39 ACT-1 SAEs before and after the ALZ dose amendment Treatment group Before amendment (n=8) SAE per patient After amendment (n=35) 6x (n=21) 2/ 3 (0.67) 8/ 18 (0.44) 6x + A (n=22) 13/ 5 (2.60) 13/ 17 (0.76) Total (n=43) 15/8 (1.89) 21/ 35(0.60) Blood 2011; 118:1755

40 Proportion of patients ACT-1 Feasibility (Blood 2011; 118:1755) Schedule adherence 6 x median: 73 6 x + A median: Days Infections Haematological toxicity CTC Leukocytopenia WHO= 4 Thrombocytopenia WHO= 3, 4 Anemia WHO= 3, 4 6 x CHOP SC harvest and recovery % pts 6 x CHOP - A all Type of infection 6x 6x + A Bacterial 54.8% 45.9% Fungal 6.5% 5.4% Viral 29.0% 35.1% Unknown 71.0% 75.7% Parameter N reinfused CD34+ cells (10 6 )/ kg b.w. Days to ANC >0.5x10 9 /l Days to Platelets >50x10 9 /l 6x Median 6x + A Median p- value

41 ACT-1 vs NLG-T-01 ORR and 1-year PFS/OS 15 mo median follow-up ACT-1 (not arm-specific, no ALCL) NLG-T-01 (without ALCL) 50% CHOP -14x6 50% A- x6 + ASCT CHOEP-14 x6 +ASCT ORR % CR-CRu (%) yr PFS (%) 1-yr OS (%) 54.4 (95% CI: 42;67) 77.6 (95% CI: 67;88) 57,5 (95% CI: 50; 65) 68,3 (95% CI: 61; 75) The non arm-specific outcome of the ACT-1 trial is similar to the one of the NLG-T-01 trial for ORR, CR,1-yr PFS and OS d Amore et al, ASH 2012 abs #57

42 Efficacy of Alemtuzumab in combination with doseadjusted EPOCH in untreated nodal PTCL Grant C et al ASCO 2012, Abstr.8051 Nodal PTCL Nodal PTCL ATLL ATLL P=0.06 P=0.08 Prior dose-finding Phase I study (Janik et al, ASH 2007) 30 mg pr course of daepoch Courtesy of dr. Cliona Grant (adapted) 45 mo median follow-up CD52 expression Jiang BJH 2009 Geissinger L& L 2009 PTCL-NOS 93% 90 % AILT 100% 90% ALCL --- 0% HS 100% T/NK 25%

43 HDT in PTCL some statements HDT with ASCR per se does probably not make a major difference in PTCL 25-35% 15-25% 5-10% Diagnosis SCT 1 yr 3 yr 5 yrs PFS Improve induction Consolidate response Maintain response Retrospective and prospective data favour the use of HDT as part of a dose-dense induction/consolidation strategy in chemosensitive patients in the upfront setting On the basis of the experience from the first large PTCL-restricted prospective trials a heterogeneity of responses should be acknowledged with regard to specific subtypes and to individual patients within the single subtypes

44 Autotransplantation in PTCL - 1. Line Treatment Prospective PTCL-restricted trials N pts Age Regimen Tx rate (%) CR/PR (%) TRM (%) OS FU Corradini (Leukemia 2006) 62 (inkl.alk+ ALCL) 43 1.APO>DHAP>HD Mito/Mel 2. MACOP-B> hdarac/ Mito> BEAM % (12 y) 76 mo Rodriguez (EJH2006) MegaCHOP/IFE % (3y) 35 mo Mercadal (Ann Oncol 2008) HighCHOP/ESHAP altern. > BEAM/BEAC n.d. 39% (4y) 3.2 y

45 Aims of NLG-T-01 To provide a PTCL-restricted prospective trial with a cohort of sufficient size to perform subtype analysis N=160 To provide a cohort with a risk-profile as close as possible to the spectrum of transplant-eligible patients seen in daily clinical practice Median age: 57yrs; IPI 2 : 72% To provide a follow-up of sufficient length to allow an appropriate estimate of both early and late failures Median follow-up: 5 years; Report of 9-yrs median follow-up analysis planned for 2014

46 HDT in PTCL some statements HDT with ASCR per se does probably not make a major difference in PTCL If at all, retrospective and prospective data seem to favour the use of HDT as part of a dose-dense induction + consolidation strategy in chemosensitive patients in the upfront setting On the basis of the experience from the first large PTCLrestricted prospective trials a heterogeneity of responses should be acknowledged with regard to specific subtypes and to individual patients within the single subtypes (trial-specific correlative biological studies are warranted to biologically differentiate responders form non-responders)