ESISTE UN RUOLO PER IL TRAPIANTO ALLOGENICO?

Alida Dominietto

ALLOGENEIC HSCT IN MM PTS

# WHEN AND WHO?

# PATIENT AGE

# COMORBIDITIES

# DONOR TYPE

# CONDITIONIG REGIMEN

# TRANSPLANT MORTALITY

# RELAPSE

EBMT database >70000 pts

Sureda A et al. BMT 2018

n= 3405

Sobh et al. Leukemia 2016

n= 1924n=2004

n= 3405

ALLO-UPFRONT

TANDEM AUTO-ALLO

OUTCOME ACCORDING TO TIME OF TX:

LATER ALLO HSCT

Sobh et al. Leukemia 2016

cGVHD correlates with clinical response, suggesting

the existence of a graft-versus-myeloma effect

Crawley et al. Blood 2005

Persistent molecolar remission after allo-HSCT is a strong

predictive factor for long term relapse-free survival

Corradini, Blood 2003

Long-term clinical outcomes by molecular remission statusFollow up: 12.1 years

Ladetto et al, Leukemia 2016

Comparison Studies of Tandem Auto-Allo vs Auto-Auto

Study

Moreau et al 2008* (Blood)

Garban et al 2006 (Blood)

Giaccone et al. 2011* (Blood)

Bruno et al. 2007 (N Engl J Med)

Gharton et al 2013* (Blood)

Bjorkstrand et al 2011 (JCO)

Pts

219

65

80

82

251

107

Regimen

Mel200-Mel220

Mel200-Bu Flu ATG

Mel200-Mel200

Mel200-TBI200

Mel200-Mel200

Mel200-Flu TBI200

TRM(%)

5

11

4

16

3 at 2 yrs

12 at 2 yrs

CR(%)

33

33

26

55

41

51

OS(%)

44 at 5 yrs

33 at 5 yrs

35 at 7 yrs

59 at 7 yrs

58 at 5 yrs

65 at 5 yrsBjorkstrand et al 2011 (JCO)

Krishnan et al. 2011

(Lancet Oncol)

Knop et al 2009

Rosinol et al 2009 (Blood)

107

185

397

73

126

85

25

Mel200-Flu TBI200

Mel200-Mel200

Mel200-Flu TBI200

Mel200-Mel200

Mel200-Flu Mel140 (ATG)

Mel200-Mel200 or CVB

Mel200-Flu Mel140

12 at 2 yrs

-

-

NR

16

5

16

51

45

58

32

59

42

45

65 at 5 yrs

80 at 3 yrs

77 at 3 yrs

70 at 3 yrs

60 at 3 yrs

60 at 5 yrs

62 at 5 yrs

* Follow up studies

Haematologica 2018

244 pts1998-2016Conditioning FLU + 2Gy TBI

Median follow-up of surviving patients 8.3 years ( range 1-18)

72% 67%

POSTRELAPSE SURVIVAL

44% vs

35%

p=0.05

Htut et al. BBMT 2018

Patriarca et al. BBMT 2018 UPDATE

LONG TERM PFS IN DONOR GROUP 0.

500.

751.

00P

roba

bilit

y

PFS

p<0.0001

p<0.0001

Donor 7 y PFS : 18%

0.00

0.25

0.50

Pro

babi

lity

0 20 40 60 80months

donor no_donor

Median follow-up of surviving patients 110 months ( range 38-180)

Donor 2 y PFS : 42%

No donor 2 y PFS 18%

No donor 7 y PFS 0

Patriarca et al. BBMT 2018 UPDATE

RIC , n=33

50%

DFS for 51 MM pts 2001-2018: Genova data

27%

MAC , n=18

CONCLUSION 1

# Most of the available data on allogeneic HSCT upfront inMM pts are before the era of the novel agents, are notstratified for risk and the results are discordant.

# Even thouth the evidence of a graft versus myeloma effectis associated with a long term disease control, a consistentsurvival benefit is not clearly demonstrated.survival benefit is not clearly demonstrated.

# Allo-HSCT should be considered AT DIAGNOSIS foryoung ultra high/high-risk patients only in clinical trilas andin EARLY RELAPSE (18 mm) from first-line treatmentwith/wo high-risk features according to IMWG/EMN/NCCNrecommendations.

ALLOGENEIC HSCT IN MM PTS

# WHEN AND WHO?

# PATIENT AGE

# COMORBIDITIES

# DONOR TYPE

# CONDITIONIG REGIMEN

# TRANSPLANT MORTALITY

# RELAPSE

L’indicazioneL’indicazione al trapianto per TUTTI al trapianto per TUTTI I PAZIENTI è I PAZIENTI è necessariamentenecessariamenteaccompagnataaccompagnata dalladalla valutazionevalutazione del del Comorbidity Index (HCTComorbidity Index (HCT --CI)CI)

Sorror, Blood 2005

http://www.hctci.org/Home/Calculator Sorror, Blood 2013

CI-INDEX AND OUTCOME

Barba et al. BBMT 2014442 pts BMT 1998-2008 only RIC

ALLOGENEIC HSCT IN MM PTS

# WHEN AND WHO?

# PATIENT AGE

# COMORBIDITIES

# DONOR TYPE

# CONDITIONIG REGIMEN

# TRANSPLANT MORTALITY

# RELAPSE

High dose post-transplant cyclophosphamide + unmanipulated BM haplo tx

1 anti-host and anti-

donor T cells

are destroyed in the

periphery

1

2

3

L Lutznik, BBMT 2008; AM Raiola, BBMT 2013

2 development of

peripheral tolerance

3 Intrathymic clonal

deletion of donor-

derived anti host T

cells

COMPARABLE OUTCOME but LOWER ACUTE and CHRONIC GvHD FOR HAPLO TX compared to HLAID-SIB/UD/CB

0,250

0,500

0,750

1,000

UCB; 34%

SIBS ; 45%HAPLO; 52%

mmUD;40% MUD; 43%

Overall survival

0,0000,0 266,7 533,3 800,0 1066,7 1333,3 1600,0

days from transplant

p=0.11

Acute GvHD (grade II-IV)

UCB; 19%

SIBS ; 31%

HAPLO; 14%

mmUD;42%

P<0.001

MUD; 21%

Chronic GvHD (moderate-severe)

MUD; 22%

UCB; 23%HAPLO; 15%

SIBS ; 29%

P = 0.053

mmUD;19%

Raiola et al. BBMT 2014

CONCLUSION 2

# Patient age at transplant is increased during thelast decade, due to better control of transplantrelated complications.

# It is mandatory the evaluation of the comorbiditiesin order to assess the risk of mortality at transplant.in order to assess the risk of mortality at transplant.

# The Sorror HCT-CI is simple and it is a veryuseful prognostic indicator.

# Haplo transplant is a valid alternative option, witha comparable outcome to the other donors and witha lower a/c GvHD.

ALLOGENEIC HSCT IN MM PTS

# WHEN AND WHO?

# PATIENT AGE

# COMORBIDITIES

# DONOR TYPE

# CONDITIONIG REGIMEN

# TRANSPLANT MORTALITY

# RELAPSE

Beginning in 1991

Classic Myeloablative conditioning

Median FU=26 months

40% at 76 months

Progress over years

BUT !!!BUT !!!

TRM is still high

Gahrton et al. 2001

After 2000

Reduced Intensity Conditioning

NMA = fludarabine + TBI 2Gy

50% 50%20%40%

MA with reduced toxixity (RIC)=Fludarabine + melphalan 140 mg/m 2

(as alternative FLU+CY/BU+FLU)

N=196

N=320

BM

Conditioning regimen for allo-HSCT in MM pts in Genoa

CY CY

FOR HAPLO TX

-9 -8 -7 -6 -5 -4 -3 -2 -1 0 +3 +4 +5

Thiotepa 10 mg/Kg day -6Fludarabine 50 mg/m^2 day -5-4-3Melphalan 140 mg/mq day -2

TMI 4 Gy day -9-8-7+boost tomotherapy on PET + bone lesions

ALLOGENEIC HSCT IN MM PTS

# WHEN AND WHO?

# PATIENT AGE

# COMORBIDITIES

# DONOR TYPE

# CONDITIONIG REGIMEN

# TRANSPLANT MORTALITY

# RELAPSE

TRM for all patients allografted GE SAN MARTINO N=2574

34%

27%

15%

10%Year 2015-2018, n=187

Year 2010-2014, n=449

Year 2000-2010, n=786

Year <2000, n=1134

ALLOGENEIC HSCT IN MM PTS

# WHEN AND WHO?

# PATIENT AGE

# COMORBIDITIES

# DONOR TYPE

# CONDITIONIG REGIMEN

# TRANSPLANT MORTALITY

# RELAPSE

‘New drugs’ as salvage therapy after allo-HSCT

5y OS 60%5y OS 50%

Montefusco et al. BBMT 2017 Giaccone et al. BBMT 2018

Synergy between donor T cells and ‘new drugs’

Mobilization of PBSC

NDMM risk-analysis(Tp53 bi-allelic mutation, 1q amp and GEP70 signature)

ALLOGENIC TRANSPLANTATION (HCT)

INDUCTION TREATMENT

UP-FRONT THERAPYASCT

New proposal for high risk MM pts

ALLOGENIC TRANSPLANTATION (HCT)

ARM A

Maintenance with ixazomib

ARM B

Observation

Ultra-high RISK

MRD assessment at CR

SINGLE-AGENT IXAZOMIB MAINTENANCE AFTER ALLO-HSCT FOR

DOUBLE-HIT MM PATIENTS to reduce the risk of relapse

CONCLUSION 3

# Myeloablative reduced toxicity conditioning regimen (melphalanbased) is preferred to NMA for allo-HSCT in MM pts.

# Adding TMI to the standard conditioning regimen can be an option toreduce the risk of relapse w/o toxicity

# New drugs are synergic to donor T lymphocytes in relapsed patients# New drugs are synergic to donor T lymphocytes in relapsed patientsafter allo-HSCT with long term survival

# The incorporation of the proteasoma inhibitors (ixazomib) after allo-HSCT in high risk patients can be a new strategy in upfront setting.

R-ISSHAEMATOLO

BMT

U

HARVESTHARVEST

CONDITIONING CONDITIONING

CSE

OGY

DEPT

UNIT

CSE

Haematology Dept

A Ghiso

C Ghiggi

S. Nati

S Aquino

AM Congiu

A Ibatici

G Beltrami

E Angelucci

BMT Unit

C di Grazia

R Varaldo

M T Van Lint

S Bregante

AM Raiola

T Lamparelli

F Gualandi

Stem Cell Lab

S Geroldi

S Lucchetti

A Bo

Data Managers

M Daneri

G.Conti

B Bruno (GITMO)

Immunology

C Mingari

D Pende

R Meazza

Nursing team

Infect Dis Unit

C Viscoli

M Mikulska

alida.dominietto@hsanmartino.it

Radiotherapy Unit

S Vagge

R Corvò