新药时代造血干细胞移植在外周t细胞 中山大学肿瘤防治中心内科 … · ptcl...

中山大学肿瘤防治中心内科

李志铭

新药时代造血干细胞移植在外周T细胞淋巴瘤治疗中的地位和发展趋势

国内外现状

• 初治TCL: ORR 39% - 84%, CRs low, 3-y, 5-y PFS 36% - 44% • BCCA研究显示复发TCL患者OS无差别: AITL 7.7 m, PTCL-NOS 6.5 m, ALCL 3.0 m

Incidence and 5-year OS across PTCL subtypes

Cancer Treat Rev, 2014

Heterogeneous subtypes of PTCLs Nodal Extranodal

AITL, 18% ENKL

ALK+ ALCL, 7% ENTL

ALK- ALCL, 5% HSL

ATCL, 10%

NOS, 26%

Histology strongly influences survival

• 5-year survival rates: ALK+ ALCL 70% (3-y EFS 75%) ALK- ALCL 49% PTCL-NOS 32% AITL 14%

JCO 2013

The 2016 revision of the World Health Organization (WHO) classification of lymphoid neoplasms

The 2016 revision of the World Health Organization (WHO) classification of lymphoid neoplasms

In contrast to BCL, PTCLs exhibit:

• More aggressive clinical features • B-symptoms • Extranodal disease • Increased serum lactate dehydrogenase • Bulky disease • Elevated Ki-67 • Over-expression of p53 • Inferior the prognosis [except for the low/low

intermediate risk group ALCL ALK (+)], with a 5-y DFS<30%, 10-y OS ~10%

Blood 2014

PTCL的分子亚型

ALCL的分子亚型

PTCLs treatment

• Historically, the treatment of PTCL has been largely derived from that applied for B-NHL.

• To date, the regimens that are used in the PTCL treatment may induce high remissions rates; however, durable remissions are rare

• It is essential to treat the aggressive PTCLs quite differently than aggressive B-cell

New agents in R/R PTCL Agents Pts ORR (%) CRR (%) PFS (m) DOR (m) OS (m) Romidepsin 130 25 15 4 17 11.3 Belinostat 129 26 10 - 8.3 - Chidamide 79 28 14 2.1 9.9 21.4 Pralatrexate 111 29 13 3.5 10.5 14.5 Bendamustine 60 50 28 3.6 3.5 6.2 BV* 58 86 57 13.3 12.6 - BV** 34 41 24 2.6 7.6 - Gemcitabine 20 55 30 - - - Alemtuzumab 14 36 14 - - -

*:ALCL only; **:non-ALCL

New agents in R/R PTCL subtypes

• ORR (%)

Pralatrexate Romidepsin Belinostat Chidamide BV PTCL-NOS 31 29 23 22 33 AITL 8 30 46 50 54 ALCL 29 24 15 41 86 ENKL - - - 19 -

New agents trials in PTCLs

Blood 2014

PTCL的临床转归

Blood Rev 2015

Upfront AutoSCT in PTCLs JCO 2009

Upfront AutoSCT in PTCLs JCO 2009

3-y OS 48% 3-y PFS 36%

3-y DFS 53%

CR

Upfront AutoSCT in PTCLs JCO 2009

NLG-T-01

JCO 2012

NLG-T-01 JCO 2012

5-y OS 51% 5-y PFS 43%

Prospective studies on HDT+ASCT in PTCL as first-line treatment

Author N High-dose egimen Response pro ASCT FU (m) DFS/PFS OS

Gisselbrecht 189(84 PTCL)

ACVBP/CEOP-ECVBP

63% CR PR1 No data 60 39% (5y) 46% (5y)

Mounier 28 BEAM/CBV 100% CR 78 44% (5y) 54% (5y)

Corradini 62 Mito/Mel or BEAM

56% CR 16% PR 76 30% (12y) 34% (12y)

Rodriguez 26 BEAM 65% CR 8% PR 35 53% (3y) 73% (3y)

Mercadal 41 BEAM/BEAC 49% CR 10% PR 38 30% (4y) 39% (4y)

Reimer 83 TBI-C 47% CR 24% PR 33 36% (3y) 48% (3y)

Nickelsen 33 Mega-CHOEP 49% CR 6% PR 53 26% (3y) 45% (3y)

D’Amore 166(115 underwent ASCT)

BEAM/BEAC (at Finnish

centers

83% CR/CRu 31% PR(130 pts.

Response assessable) 60.5 51% (5y) 44% (5y)

Retrospective studies on HDT+ASCT in PTCL as first-line treatment Author N High-dose regimen Response pro ASCT FU (m) DFS/PFS OS

Rodriguez 19 BEAM/BEAC 42% CR1 26% PR1 25 55% (3y) 25% (5y) Rodriguez 74 BEAM/BEAC No data 67 63% (5y) 67% (5y) Feyler 64 TBI

BEAM BEC/Flu/Mel

48% CR1 23% PR1

48 50% (3y) 53% (3y)

Kyriakou 146 BEAM (74%) 33% CR1 36% PR1

31 49% (4y) 59% (4y)

Prochazka 18 BEAM No data 26 52% (2y) 71% (2y)

Numata 39 MCEC TBI-based

69% CR1 78 61% (5y) 62% (5y)

Beitinjaneh 126 BEAM BEAM-like conditioning

33% CR1 51% chemo sensitive relapse 16% RD

39 30% (4y) 39% (4y)

Prochazka 29 (19 ASCT)

ProMACE-CytBOM BEAM

66% CR 10% PR

55.1 52% (2y) 65% (2y)

Hwang 35(25 ASCT)

BEAM/BEC Flu-RIC TBI-C based

84% CR/PR (median prior treatment 1-4)

39 No data 70% (3y)

Ahn 31 BEC 74% CR 26% PR

32 64.5% (3y) 64.5% (3y)

Smith 115 TBI BEAM/BEAM-like conditioning CBMel/BC Other

35% CR1 21% CR2 14% PIF sensitive

71 47% (3y) 59% (3y)

ASCT in CR1 May not Extend PFS in Pts with PTCLs AJH 2016

ASCT in CR1 May not Extend PFS in Pts with PTCLs

AJH 2016

Author N High-dose regimen Response pro ASCT

FU (m) DFS/PFS OS

Vose 17

TBI-Mel CytTBI-C CytEC TBI-C Local RT CyBCNU-E

42% CR 26% PR 28 28% (2y) 35% (2y)

Fanin 64 Diverse 47% CR 43 56% (5y) 70% (5y)

Rodriguez 29 BEAM/BEAC/BCE-thio/TBI -C/TBI-CE/CE/CEP

38% CR 48% PR 43 32% (3y) 39% (3y)

Blystad 40 BEAM/BEAC/TBI-BEAC w/o E/TBI-C/Mel-Mito

70% CR 30% PR 25 56% (3y) 58% (3y)

Song 36 Mel/E 42% CR 50% PR 42 37% (3y) 48% (3y)

Rodriguez 115 BEAM/BEAC/TBI-C/CVB/others

56% CR 38% PR 37 60% (5y)

49% (5y) at 2 line 56% (5y) 45% (5y) at 2 line

Schetelig 29 BEAM BEAM-like/ICE ICE-like/TBI-C/BC/others

No data 60 37% (5y) 39% (5y) at 2 line

60% (5y) 44% (5y) at 2 line

Studies on HDT+ASCT for PTCLs as salvage treatment

Author N High-dose regimen Response pro ASCT FU (m) DFS/PFS OS

Zamkoff 16 TBI-C/Thio-CE/CE-Carm/BC/TBI-CE

60% CR 40% PR No data 12 weeks 72 weeks

Jantunen 37 BEAC/BEAM 87% CR/PR 24

44% (5y) 28% (5y) at 2 line

54% (5y) 45% (5y) at 2 line

Jagasia 28 TBI-CE/CVB 39% CR 46% PR 44 50% (3y) 69% (3y)

Kewalramani 24 TBI/chemo alone (no data)

63% CR 37% PR 72 24% (5y) 33% (5y)

Kim 40 BEAM/BEAC/BEC/CE

28% CR 52% PR 16 No data 11.5 months

Smith 32 BEC No data 30 18% (5y) 34% (5y)

Feyer 64(ASCT) 18(Allo-SCT)

TBI BEAM BC Flu/Mel

48% CR1 6% CR2 23% PR 22% PD

37

50% (3y) 49% (2y) CR2/PR/SD 37% (2y) PD

53% (3y) 49% (2y) CR2/PR/SD 34% (2y) PD

Chen 53 BCNU-CE/TBI-CE

89% CR/PR 60

25% (5y) 9% (5y) at 2 line

48% (5y) 37% (5y) at 2 line

Studies on HDT+ASCT for PTCLs as salvage treatment

Author N High-dose regimen

Response pro ASCT FU (m) DFS/PFS OS

Lee 47 CVB/MCEC/BEAM 58% CR 117 No data No data

Yang 64 BEAM/CVB 33% CR 58% PR 30

44% (3y) 33% (3y) at 2 line

53% (3y) 46% (3y) at 2 line

Mak 38 (21 ASCT/17 allo-SCT)

No data No data ～48 48% (3y) 55% (3y)

Nademanee 67

Pts<60 TBI+E/C Pts≥60 BCNU or BEAM

21% CR1/PR1 65.8 75% (5y) 54%

Czyz 65

BEAM CBV TBI-C Others

55% CR 45% PR 53 59.4% 61.5%

Studies on HDT+ASCT for PTCLs as salvage treatment

CR at transplant predicts survival

Ann Hematol, 2007

CR at transplant predicts survival

Ann Hematol, 2007

CR at transplant predicts survival

Ann Hematol, 2007

CR at transplant predicts survival

Ann Hematol, 2007

mOS 11.5 m

mEFS 3.6 m

CR at transplant predicts survival

Ann Hematol, 2007

， 自体外周血造血干细胞移植: NKT淋巴瘤，1st

获益患者 1. CR、 2. III-IV期 3. 预后不良

（kim HJ,et al. Bone Marrow Transplant. 2006)

Upfront ASCT in PTCLs: Meta-Analysis

Acta Haematol 2014

Upfront ASCT in PTCLs: Meta-Analysis

Acta Haematol 2014

Upfront ASCT in PTCLs: Meta-Analysis

Acta Haematol 2014

Upfront ASCT in PTCLs: Meta-Analysis

Acta Haematol 2014

New agents in R/R TCL after ASCT

Semin in Hemat 2014

ASCT in untreated or R/R PTCLs: Meta-Analysis

Biol Blood Marrow Transplant 2015

ASCT in untreated or R/R PTCLs: Meta-Analysis

Biol Blood Marrow Transplant 2015

ASCT in untreated or R/R PTCLs: Meta-Analysis

Biol Blood Marrow Transplant 2015

ASCT in untreated or R/R PTCLs: Meta-Analysis

Biol Blood Marrow Transplant 2015

Role of HDT and ASCT in PTCLs

• Remains undefined • Reports with inconsistent results • Small size in clinical trials • Heterogeneity of PTCLs [ALK (+) included] • Debatable timing of ASCT

Allo-SCT in PTCLs

• Limited data • Reserved for young and fit, relapsed, heavily

pre-treated, and chemo-refractory pts • Compared to autologous SCT: a similar or

higher probability of disease control, higher risk of NRM, and similar OS in R/R NHL

Author N High-dose regimen

Response pro SCT FU (m) TRM DFS/PFS

OS Per conditioning regime

Corradini 17 100% RIC 12% CR 70% PR 28 RIC(2y):6% 64% (3y) 81% (3y)

Murashige 28 82% MAC 18% RIC 57% CR 34 RIC(1y):20%

MAC(1y):30% 34% (2y) 40% (2y) No data

Feyler 18 100% MAC No data 57 MAC(3y):39% 33% (3y) 39% (3y)

Hamadani 14 57% MAC 43% RIC

21% CR 35% PR 34 (Overall) 57% (3y)

No data 56% (3y) 58% (3y)

Le Gouill 77 74% MAC 26% RIC

40% CR 30% PR 43

(Overall) 34% (5y) Non-significance MIC vs RIC

53% (5y)

57% (5y) Non-significance MIC vs RIC

Kyriakou 45 56% MAC 44% RIC

27% CR 22% PR 29 MAC(3y):29%

RIC(3y):24% 53% (3y) 64% (3y) MAC(3y):58% RIC(3y):71%

Studies on HDT-allo-SCT in PTCL

Studies on HDT-allo-SCT in PTCL

Author N High-dose regimen

Response pro SCT FU (m) TRM DFS/PFS

OS Per conditioning regime

Dodero 52 100% Thio-RIC

75% CR/PR 67 RIC(5y):12% 40% (5y) 50% (5y)

Kanakry 44 55% RIC 45% MA

32% PR/CR PIF 25% acti disease

46 MAC(1y):10% RIC(1y):8% 40% (2y)

43% (2y) MAC(2y):42% RIC(2y):44%

Smith 126 MAC 59% RIC 36% Unknown 5%

14% CR1 16% CR2 18% PIF sensitive

49 MAC(3y):32% RIC(3y):27% 37%

46% MAC(3y):39% RIC(3y):52%

ASCT vs Allo-SCT JCO 2013

ASCT vs Allo-SCT JCO 2013

ASCT vs Allo-SCT JCO 2013

ASCT vs Allo-SCT JCO 2013

ASCT vs Allo-SCT

JCO 2013

Crizotinib as a bridge to allo-SCT in refractory ALK-positive ALCL and provided maintenance

post-alloSCT with promising effect • Progressed through 8 lines of chemotherapy in 11

months (CHOP, gemcitabine-based therapy, pralatrexate, HD-MTX with CNS involvement, and brentuximab)

JNCCN 2014

Allo-ASCT in ENKL

Clin Lymphoma Myeloma Leuk 2015

Allo-SCT in PTCLs: Meta-Analysis

Acta Haematol 2015

Allo-SCT in PTCLs: Meta-Analysis

Acta Haematol 2015

Allo-SCT in PTCLs: Meta-Analysis

Acta Haematol 2015

Allo-SCT in PTCLs: Meta-Analysis

Acta Haematol 2015

New agents in R/R TCL after Allo-SCT

Semin in Hemat 2014

Problems and Strategies of Allo-SCT

• Major problems: relapse and late effects • Strategies to reduce the risk of relapse: Optimization of SCT techniques (e.g.,

improved GVHD prophylaxis) Posttransplant MRD Post-transplant maintenance Pre-emptive therapy (e.g., with novel

therapies)

Summary

• Prospective studies investigating the role of ASCT and allo-SCT in PTCL patients should be conducted

• Investigation of novel agents and development of more effective therapeutic strategies are warranted urgently

• PTCL patients should be encouraged to participate in clinical trials