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

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


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

3-y DFS 53%

CR

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


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%


CR at transplant predicts survival

Ann Hematol, 2007


Ann Hematol, 2007

mOS 11.5 m

mEFS 3.6 m


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

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

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


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


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

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

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

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...

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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...