Il trapianto allogenico: quando e per chi? Daniela Cilloni (Torino) - - PowerPoint PPT Presentation

Il trapianto allogenico: quando e per chi?

Daniela Cilloni (Torino)

Number of allogeneic HCTs for MDS paAents 65 years of age in the United States, 2005-2012.

Biology of blood and marrow transplanta3on 2017

HSCT in MDS : for whom, when and how?

• SelecAon of paAents
• Type of transplant (HSC source)
• Treatment before transplant
• InducAon regimens/intensity
• Timing of transplant

For whom?

• Intermediate 2 and high IPSS risk
• Intermediate, high and very high R-IPSS
• Therapy related MDS
• High transfusion requirement

2015

HematopoieAc cell transplantaAon (HCT)- specific comorbidity index

Blood 2005;106:2912-9

Comorbidity and Disease Status–Based Risk StraAficaAon of Outcomes Among PaAents With AML or MDS Receiving Allogeneic HematopoieAc Cell TransplantaAon

J Clin Oncol 2007;25:4246-54

Effect of comorbidity on survival

• f MDS paAents

Overall Survival Risk of Non-Leukemic Death

Blood 2007;110:#2453

AML HSCT: URD, Sibling Donor, and UCB Survival Minnesota, Paris, and Nantes

Peffault de la Tour, 2013

What about low/intermediate-1 IPSS?

• Life expectancy of paAents with

Intermediate-1 or low IPSS risk at diagnosis was higher when transplanaAon was delayed but performed before progression to AML.

Cutler et al., Blood 2004; 104:579-585

No SCT SCT

Adapted from Koreth et al. JCO 2013 Low and Intermediate-1 risk IPSS pa5ents survival benefit of the nontransplantaAon strategy in low/intermediate-1 IPSS MDS

Adapted from Koreth et al. JCO 2013 Intermediate-2 and high risk IPSS pa5ents survival benefit of the early RIC transplantaAon strategy in intermediate-2 and high risk IPSS MDS

When? Timing of transplantation

immediate transplantation for Int-2/high-risk pts delayed transplantation for Int1/low risk pts until progression ( but before transformation to AML)

100 75 50 25 60 48 36 24 12

Months <4 months (n = 36) >12 months (n = 39) 4–12 months (n = 53) P = 0.03 Survival

Bone marrow transplantation from HLA-identical siblings as first-line treatment in patients with myelodysplastic syndromes: early transplantation is associated with improved outcome

V Runde1, T de Witte2, R Arnold3, A Gratwohl4, J Hermans5, A van Biezen5, D Niederwieser6, M Labopin7, MP Walter-Noel8, A Bacigalupo9, N Jacobsen10, P Ljungman11, E Carreras12, HJ Kolb13, C Aul14 and J Apperley15 on behalf of the Chronic Leukemia Working Party of the European Group for Blood and Marrow Transplantation (EBMT)

University Hospital of Essen, Germany; University Hospital St Radboud, Nijmegen, The Netherlands; University Hospital Charite ´,

Bone Marrow Transplanta3on 1998

Early HSCT is associated with improved outcome

HSCT in MDS : for whom, when and how?

• SelecAon of paAents
• Type of transplant (HSC source)
• Treatment before transplant
• InducAon regimens/intensity
• Timing of transplant

PBSC compared to BM as SC source :

• faster engraftment
• more cGVHD
• lower NRM
• better 2-yrs EFS

Guardiola et al., Blood 2002 Maris et al. Blood 2003 Deeg et al., Blood 2002

Stem cell source (PBSC or BM?)

Stem cell donor

• match related donor (MRD)
• match unrelated donor (MUD) 8/8
• match unrelated donor (MUD) 7/8
• Alterna5ve donors?
• Cord blood
• HaploidenAcal donor

Adjusted probability of transplant-related mortality in adult MDS paAents by donor source.

MUD= match unrelated donor MRD= match related donor

Blood 2013;122:1974

Blood 2013;122:1974 Adjusted probability of relapse in adult MDS paAents by donor source

MUD= match unrelated donor MRD= match related donor

Blood 2013;122:1974

MUD= match unrelated donor MRD= match related donor

Adjusted probability of DFS in 694 adult MDS paAents by donor source.

Blood 2013;122:1974

MUD= match unrelated donor MRD= match related donor

Adjusted probability of overall survival in 701 adult MDS paAents by donor source.

Bone Marrow TransplantaAon (2013), 1–6

American Journal of Hematology 2017

• Chemotherapy for those with high blast count ?(>10%)
• Hypomethylating agents before transplant ?

Pre transplant induc5on therapy: really needed?

Hypomethylating agents and transplant

Patients who discontinue 5AC for various reasons have a median survival of only 5.6 months When 5AC is discontinued because of progressive disease the median survival is 17 months even after HSCT In the study by Prébet et al the median survival was not reached in patients transplanted with stable disease at the time when 5AC was stopped CONCLUSION: for patients who are transplant candidates HCT should be considered while still responding to hypomethylating therapy

Pretransplantation Induction Chemotherapy and Posttransplantation Relapse in Patients with Advanced Myelodysplastic Syndrome

Bart L. Scott,1,2 Barry Storer,1,2 Michael R. Loken,3 Rainer Storb,1,2 Frederick R. Appelbaum,1,2

• H. Joachim Deeg1,2

1Fred Hutchinson Cancer Research Center; 2University of Washington School of Medicine; and 3Hematologics

Inc., Seattle, Washington

125 MDS pa5ents 33 chemotherapy 92 no chemotherapy

32 S-AML 24 CHT 8 no CHT

93 RAEB/RAEB-T 9 CHT 62 no CHT

. Biology of Blood and Marrow TransplantaAon 11:65-73 (2005)

Pretransplantation Induction Chemotherapy and Posttransplantation Relapse in Patients with Advanced Myelodysplastic Syndrome

Bart L. Scott,1,2 Barry Storer,1,2 Michael R. Loken,3 Rainer Storb,1,2 Frederick R. Appelbaum,1,2

• H. Joachim Deeg1,2

1Fred Hutchinson Cancer Research Center; 2University of Washington School of Medicine; and 3Hematologics

Inc., Seattle, Washington

125 MDS pa5ents 33 chemtorapy 92 no chemotherapy

32 S-AML 24 CHT 8 no CHT

93 RAEB/RAEB-T 9 CHT 62 no CHT

. Biology of Blood and Marrow TransplantaAon 11:65-73 (2005)

Damaj et al. Biol Blood and Marrow Transpl 2014

5-Azacitidine for myelodysplasia before allogeneic hematopoietic cell transplantation

T Field1, J Perkins1, Y Huang2, MA Kharfan-Dabaja1, M Alsina1, E Ayala1, HF Fernandez1, W Janssen1, J Lancet3, L Perez1, D Sullivan1, A List3 and C Anasetti1

Bone Marrow Transplanta3on (2010) 45, 255–260

200 400 600 800 1000 1200 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1 Days Overall Survival

Vidaza = N Vidaza = Y p-value = 0.25

200 400 600 800 1000 1200 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1 Days Relapse-free Survival

Vidaza = N Vidaza = Y p-value = 0.30

200 400 600 800 1000 1200 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1 Days Cumulative Incidence

• f Relapse

Vidaza = N Vidaza = Y p-value = 0.66

200 400 600 800 1000 1200 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1 Days Cumulative Incidence of non-relapse Mortality

Vidaza = N Vidaza = Y p-value = 0.16

54 paAents 30 AZA 24 no AZA

Multicenter study evaluating the impact of hypomethylating agents as bridging therapy to hematopoietic stem cell transplantation in myelodysplastic syndromes

Kim et al . Int J Hemtol 2014 109 paAents 81 HMA 28 no HMA

A B

A B

C D E F

Kim et al . Int J Hemtol 2014

OS and RFS according to HMA treatment group

Azaci5dine vs induc5on chemotherapy before HSCT: SeaSle retrospec5ve data in 68 pa5ents

Gerds A.T.et al. Biol Blood Marrow Transpl. 2012

(35 pts AZA, 33 IC)

Biol Blood Marrow Transplant 22 (2016)

256 MDS paAents at the MD Anderson Cancer Centres 40 (15.6%) chemotherapy 122 ( 47.7%) HMA 16 (6.2%) Chemo+HMA

Cytogenetics, Donor Type, and Use of Hypomethylating Agents in Myelodysplastic Syndrome with Allogeneic Stem Cell Transplantation

Betul Oran 1,*, Piyanuch Kongtim 1, Uday Popat 1, Marcos de Lima 1, Elias Jabbour 2, Xinyan Lu 3, Julien Chen 1, Gabriella Rondon 1, Partow Kebriaei 1, Sairah Ahmed 1, Borje Andersson 1, Amin Alousi 1, Stefan Ciurea 1, Elizabeth Shpall 1, Richard E. Champlin 1

Biology of Blood and Marrow Transplantation

journal homepage: www.bbmt.org

2014

Variable RI TRM EFS OS HR P Value HR P Value HR P Value HR P Value Age, per 10 yr 1.06 .50 1.4 .002 1.3 .002 1.3 .002 WHO histological subtype Low/intermediate Ref Ref Ref Ref High risk 2.0 .02 1.0 .90 1.6 .02 1.5 .05 CMML 1.5 .30 1.4 .40 1.6 .10 1.5 .20 MDS-U 1.0 .90 1.4 .20 1.3 .20 1.3 .20 T-MDS 1.4 .10 1.2 .40 1.5 .02 1.5 .01 Cytogenetics by 5-group risk Very good/good Ref Ref Ref Ref Intermediate 1.2 .70 1.4 .40 1.4 .20 1.3 .30 Poor 1.4 .40 1.2 .50 1.4 .20 1.6 .06 Very poor 3.9 <.0001 1.1 .60 3.4 <.0001 3.3 <.0001 MK CN Ref Ref Ref Ref MK 1.2 .50 1.4 .20 1.5 .06 1.6 .03 MKþ 4.1 <.0001 1.2 .50 3.7 <.0001 3.7 <.0001 Previous therapy for MDS Untreated Ref Ref Ref Ref Chemo only 1.1 .70 1.5 .30 1.4 .20 1.4 .20 HMA only 1.0 .90 1.5 .10 1.3 .20 1.4 .10 ChemoþHMA .8 .70 1.8 .20 1.2 .50 1.5 .30 Response by IWG at HSCT CR Ref Ref Ref Ref AD .8 .30 1.7 .10 1.1 .50 1.3 .20 Untreated .8 .50 1.0 .90 .8 .50 .9 .60 Cytogenetic remission Yes Ref Ref Ref Ref No 1.2 .60 1.0 .90 1.3 .20 1.5 .10 BM blast at HSCT <5% ref Ref Ref Ref 5% 2.0 .01 .9 .80 1.6 .006 1.6 .006 Ferritin level 1130 Ref Ref Ref Ref >1130 1.0 .80 2.0 .009 1.6 .01 2.0 .001 Missing 1.7 .06 1.2 .60 1.5 .05 1.7 .02 Stem cell source PB Ref Ref Ref Ref BM .9 .90 1.4 .20 1.2 .30 1.3 .10 Donor source MRD ref Ref ref Ref MUD .7 .20 1.7 .02 1.2 .30 1.4 .06 Conditioning regimen MAC Ref Ref ref RIC .6 .05 2.1 .001 1.2 .20 1.2 .40 Time to transplantation after diagnosis 8 months Ref Ref ref >8 months .6 .03 1.2 .50 .8 .10 .8 .10 Transplantation yr Before 2005 Ref Ref Ref Ref After 2005 .8 .30 .8 .40 .7 .10 .7 .10

Best condiAoning regimens

The ideal regimen would have no associated toxicity and prevent relapse in all patients, but….

the extent of toxicity correlates with conditioning intensity RIC regimens are associated with minimal toxicity, but they carry a higher risk of relapse than high-intensity regimens Major advantage of RIC: possibility of applying HCT to older patients, who are unlikely to tolerate high dose therapy.

patients more than 60-65 years of age or pts with significant comorbid conditions should receive RIC regimens.

Poor cytogenetyc risk should receive intensification of the conditioning regimen because of the high risk of relapse

JCO 2017

Kroger JCO 2017

Bone Marrow TransplantaAon (2017), 1–6

NRM Relapse

Bone Marrow TransplantaAon (2017), 1–6

Conv MC=ConvenAonal high-dose myeloablaAve condiAoning regimen HyperMC =hyperintensive myeloablaAve condiAoning regimen IntermRIC= intermediate-intensity condiAoning NMA= non-myeloablaAve or minimal-intensity condiAoning

Mar3no et al. Bone Marrow Transplanta3on (2013) 48, 761

Conv MC=ConvenAonal high-dose myeloablaAve condiAoning regimen HyperMC =hyperintensive myeloablaAve condiAoning regimen IntermRIC= intermediate-intensity condiAoning NMA= non-myeloablaAve or minimal-intensity condiAoning

Mar3no et al. Bone Marrow Transplanta3on (2013) 48, 761

De WiXe et al. Blood 2017

Impact of red blood cell transfusion requirement Ann Hematol (2016) 95:1971–1978

How intensive does a condiAoning regimen need to be in

• rder to allow for engraiment and prevent relapse?

What intensity will the paAent tolerate? Should the condiAoning intensity be adjusted to the disease stage (i.e. the risk of relapse)? Is it beneficial to give pre-HCT “debulking” therapy? Is there a place for post-HCT adjuvant or preempAve therapy?

Several quesAons remain to be answered