PBSC revisited in present practice

Didier Blaise, MDBangkok

August, 28th, 2015

Members of Stem Cell Trialists’ Collaborative Group9 trials included (N=1,111 patients)

Ben DjulbegovicBill BensingerCorey CutlerIztok HozoClaudio AnnasettiHeloisa SoaresAmbuj Kumar

Nobert Schmitz

Alois Gratwohl

Jane Apperley

Roy Baynes

James Matcham

Didier Blaise

Mohamad Mothy

Mathieu Kuentz

Ray PowlesBhawna SirohiMike ClarkeSue RichardsRobert HillsKeith Wheatley

Dag Heldal

Jan Cornelissen

B Van der Holt

Stephen Couban

Tony Panzarella

David Simpson

Jeff Lipton

Carmino A de Souza

Afonso Vigorito

Eliana CM Miranda

James Morton

Entezam Sahovic Ed ColcolMahmoud Al-Jurf

Stem Cell Trialists , JCO, 2006

Stem Cell Trialists , JCO, 2006

PREVALENCE OF CGVHD

Months post-transplantation

Prev

alen

ce o

f cG

VHD

(%)

0 18 36 540

25

50

75

100BMTBCT

D Blaise et al , Blood, 2002

M Mohty et al , Leukemia 2003

BM versus PBSC

• Myeloablative CDT

• Mainly Familial HLA-Identical Donor

• GVHD prophylaxis: CSA/FK506 and MTX

M Mohty et al , Blood 2003

The increase from 2.5 to 5 mg/kg of r-ATG dose in RIC is beneficial

R Devillier et al , BMT 2012 9

CD34 dose after RIC: High dose or not?

11

Outcomes in RIC regimen

Mohty, Leukemia 2003

Extensive chronic GVHD

MACNo ATG

MRDCsA/MTX

RIC ATG

MRD/MUDCsA

12

Heterogeneity of the studies

Blood (2009) BBMT (2014) BBMT (2015)Pulsipher Törlén Remberger

Patients number 932 1054 544High doses CD34 OS OS OSDiseases Myeloid AML or DMS All Donor MUD MRD or MUD MRD or MUDConditionning R MAC/RIC/NMA RIC or NMA MAC or RICGVHD prophylaxis Heterogeneous Heterogeneous Heterogeneouscut off cd34 4.5x10.6/kg MRD 4x10.6/kg /MUD 6x10.6/kg 8.1x10.6/kg

Heterogenous population

13

Impact of CD34/CD3 cell dose

Homogenous population

CsA

RICPBSC

14

1) Peripheral blood stem cells

2) HLA identical : - Matched related - Matched unrelated donor;

3) Reduced intensity conditioning (RIC) regimen;

4) Ciclosporine A alone;

Selection criteria

FLU 30 mg/m²

FLU 30 mg/m²

FLU 30 mg/m²

FLU 30 mg/m²

FLU 30 mg/m²

BU 130mg/m2

BU 130mg/m2

ATG 2.5mg/kg

ATG 2.5mg/kg

Day-2 Day 0Day-1

HSCT

Day-5 Day-4 Day-3Day-6

15

Patient characteristics

N = 246 %

Age, years, median (range)

CD3 (106/kg), median (range)

Matched related donor

Lymphoid malignancies

Disease Risk Index Low

HCT-Comorbidity Index ≥ 3

All patients

CD34 (106/kg), median (range) 6.5 (2-14.2)

46%

59 (19-71)

279 (61-1919)

142 58%

132 54%

44 18%

110

16

Variables adjusted by Age, donor, HCT-CI, DRI, CD3

CD34≤6.5x106/kg CD34>6.5106/kgN=124 (%) N=122 (%)

3-4 AGVHD 10 8 0.674 1.2 0.581Ext CGVHD 24 21 0.539 0.7 0.243NRM 19 23 0.638 0.9 0.841RI 30 22 0.179 0.8 0.244PFS 62 68 0.179 0.8 0.322OS 52 55 0.405 0.8 0.200

pp HR

Univariate model Multivariate model

CD34 median

CD34 : median cut off

Extensive chronic GVHD

Initial Study, Leukemia 2003 Present Study, 2015

MAC RIC

18

CD3 : multivariate model

Variables adjusted by Age, donor, HCT-CI, DRI, CD34

HR 95CI p

PFS 0.8 [0.56-1.17] 0.272

OS 0.8 [0.54-1.24] 0.346

NRM 0.8 [0.46-1.47] 0.512

0.8CIR [0.50-1.30] 0.352

AGVHD III-IV 0.8 [0.36-1.68] 0.526

CGVHD Extensive 1.1 [0.65-1.93] 0.668

CD3 ≥ median

19

CONCLUSION

Impact of in vivo T cell depletion?

Myeloablative conditionning Reduced intensity conditionning No rational for limiting the maximal amount of CD3 or CD34 cell dose in the setting of RIC with ATG.

CD34 : No impact

CD3 : No impact

BM or PBSC for haplo HSCT

PBSC for HaploMarseille Experience on 102 patients

Characteristics

• Age: 59 (22 – 73)• Follow-up: 15 months (1 – 31)• CD 34+ (mediane) 5.1 x 106/Kg • CD3+ (mediane) 262 x 106/Kg • DRI: Intermediate 59%; High 30%; V.High 7%• HCT-CI ≥ 3: 63%• CDT: 68% Baltimore; 32% RTC

Hematologic RecoveryANC > 0,5x109/Lmediane 21 (14 – 47) jours

PLT > 20x109/Lmediane 35 (10- 134) jours

Chimerism J+90(séquençage CD3+) 98%

Graft Failure 2%

GVHD

2-y RI and 2-y NRM

0.0 0.5 1.0 1.5 2.0

0.0

0.2

0.4

0.6

0.8

1.0

2-y RI = 24%

Years from transplant

Cum

ulati

ve in

cide

nce

Time to Relapse (median, range): 3.3 months (0.5 – 14)

0.0 0.5 1.0 1.5 2.0

0.0

0.2

0.4

0.6

0.8

1.0

2-y NRM = 23 %

Cum

ulati

ve in

cide

nce

Years from transplant

100-day NRM 12%

2-y OS and PFS

BM PBSC P value

N° pts 46 23Age 44 (19-68) 54 (25-65) .06Follow-up (jours) 721 (365-728) 332 (135-498) <.0001PNN > 0,5 x 109/L (jours) 20 21 .18PLT >20 x 109/L (jours) 29 29 .13GVH aigue 2-4 25% 33% .43GVH chronique 13% 13% .21NRM 22% 12% .96

Probabilité de OS et PFS à 2 ans = 68 et 62%non statistiquement différente

L. Castagna et al. BBMT 2015

BMT CTN(BM)

IPC/UK/AUS/FHCRC(PBSC)

p value

Patients (N°) 43 43Follow-up (mos) 36 16

100 d aGVHD grade 3-4 0% 5% 0.410

2 y cGVHD 28% 18% 0.2142 y OS 58% 56% 0.735

Conclusions

• No increase for acute or chronic GVHD

• NRM, OS or PFS similar

• No benefit for hematologic recovery

• Ease for large program