MDS – Selecting transplant candidates:

regimens and outcomes

Fábio Kerbauy

NCCN- 2017 – Low Risk

NCCN- 2017 – High/Int Risk

•Age impact in HCT

•Who and when

•Pre HCT therapy

•Conditioning regimen intensity

•Post HCT maintenance

Points for discussion

MDS – Age at diagnosis3,4 pts/100.000/ano

R-IPSS and age

Greenber PL et al. Blood, 2012; 120(12): 2454-2465

MA (BuTCy) in MDS – Median 46yo

Deeg et al, Blood 2002; 100:1201-1207

TRM 100d e 1 y

MRD=12% / 28%

MUD = 13% / 30%

Conditioning regimens for HCT

Blood 2014 124:344-353Boglarka Gyurkocza and Brenda M. Sandmaier

Efeito GVL – EBMT megafile (n=48.000)

HCT for SMD – CIBMTR

Allo HCT in 70+ yo patients – USAMedian age: 72 (70-84)

NMA/RIC in MDS >40ª - CIBMTR

McClune BL, et al. JCO; 2010

– Acute GVHD II-IV: 54%

– Chornic GVHD Extensive: 33%

– Day-100 TRM 10%

– NO SOS

Kerbauy FR et al. Leuk Lymphoma. 2011;52:321-4

CONCLUSIONS

▪“Low” TRM▪Feasable in older patients (3 patients 75+)▪Advanced stage disease: poor disease control▪Not reliable for SCUP (data not shown)

IV BuFlu – Brazilian experience

Atrash G et al, BBMT 2011

Sobrevida em 2 anos: 46%

IV BuFlu age 55 to 80+

MA x RIC x NMA ???Martino R, Iacobelli S, Brand R, et al. Retrospective comparison of reduced-intensity conditioning and conventional high-dose conditioning for allogeneic hematopoietic stem cell transplantation using HLA-identical sibling donors in myelodysplastic syndromes. Blood. 2006;108(3):836-846.

Deeg HJ, Scott BL, Fang M, et al. Five-group cytogenetic risk classification, monosomal karyotype, and outcome after hematopoietic cell transplantation for MDS or acute leukemia evolving from MDS. Blood. 2012;120(7):1398-1408.

Deeg HJ, Shulman HM, Anderson JE, et al. Allogeneic and syngeneic marrow transplantation for myelodysplastic syndrome in patients 55 to 66 years of age. Blood. 2000;95(4):1188-1194.

Lim Z, Brand R, Martino R, et al. Allogeneic hematopoietic stem-cell transplantation for patients 50 years or older with myelodysplastic syndromes or secondary acute myeloid leukemia. J Clin Oncol. 2010;28(3):405-411

RIC: > relapse, < TRM = less fit, comorbidities

MA: < relapse, > TRM = High risk, good performance status, no comorbidities

Luger SM, Ringdén O, Zhang MJ, et al. Similar outcomes using myeloablative vs reduced-intensity allogeneic transplant preparative regimens for AML or MDS. Bone Marrow Transplant. 2012;47(2):203-211.

MAC x RIC – Prospective trial (AML/MDS)

18 to 65 yo

Scott BL et al, JCO, 2017:35; 1154-61

MAC x RIC – Prospective trial (AML/MDS)

Scott BL et al, JCO, 2017:35; 1154-61

MAC x RIC – Prospective trial (AML/MDS)

Scott BL et al, JCO, 2017:35; 1154-61

Multicenter biologic assignment trial comparing reduced-intensity allogeneic

hematopoietic cell transplant to hypomethylating therapy or best supportive care

in patients aged 50 to 75 with intermediate-2 and high-risk myelodysplastic

syndrome

ClinicalTrials.gov NCT01339910 NCT02016781.

•MA conditioning regimens should be used whenever It is

possible. Better PFS.

•Choose the one you feel more confortable with

•NMA/RIC: less fit, comorbidities

•“Prospective trials” for older patients (75+)

•GVHD still a big issue in older patients

•Use tools to help!!

Conditioning regimes

NMA (Flu/TBI) n= 1092 - Is GVHD good?

Storb R et al. J Clin Oncol; 2013: 31: 1530-37

In vivo T-cell depletion - ATG

Kekre N & Antin JH Blood. 2017; 1(9); 573-575

Bacigalupo A. Blood. 2017; 1(9); 569-572

Problems:

•3 formulations – horse, rabbit and Jurkat T-cell

•Dosage variations

•Can increase rate of infections (EBV, CMV)

In vivo T-cell depletion - ATG

Arai y et al. Leukemia & Lymphoma 2017, 58, 1840-1848

In vivo T-cell depletion - ATGAnti-thymocyte globulin as graft-versus-host disease prevention in the setting of allogeneic peripheral blood stem cell transplantation: a review from the Acute Leukemia Working Party

of the European Society for Blood and Marrow Transplantation

Frédéric Baron et al. Haematologica 2017;102:224-234

Brazilian algoritm – Vigoritto A. et al - 2017

MieloablativoNão Mieloablativo ou

Intensidade reduzida

Aparentado

Mieloablativo Não Mieloablativo ou

Intensidade reduzida

NÃO aparentado Haploidêntico

Inibidor de calcineurina (preferencial:

Ciclosporina)

associado ao Metotrexato

Pacientes pediátricos: se medula óssea,

apenas ciclosporina ou tacrolimo e

mini-metotrexato

Inibidor de calcineurina

(preferencial: Ciclosporina)

associado ao MTX ou Ácido

micofenólico.

Se sangue periférico:

ciclosporina e ATG

Inibidor de calcineurina

(preferencial:

Ciclosporina)

associado ao Metotrexato

e ATG

Inibidor de calcineurina

(preferencial: Ciclosporina)

associado ao MTX ou Ácido

micofenólico e ATG

Sangue do cordão Umbilical

TCTH alogênico

Profilaxia da DECH

Pacientes pediátricos e adultos até 70 anos;

Doador aparentado ou não aparentado;

Condicionamento mieloablativo ou não mieloablativo;

Com MO, sangue periférico ou cordão umbilical.

Ciclofosfamida

50mg/kg/dia, D+3 e D+4

associada à inibidor de

calcineurina (preferencial:

ciclosporina) e ácido

micofenólico

Ácido micofenólico

associado a inibidor de

calcineurina.

preferencial:

ciclosporina

Choose Wisely! #ASBMT

Arai y et al. Leukemia & Lymphoma 2017, 58, 1840-1848

Through the efforts of the Choosing Wisely Task Force, led by Sita Bhella, MD, MEd, FRCPC, and Matthew Seftel, MD MBChB , MPH , MRCP, the ASBMT and CBMTG have jointly released the following recommendations:

1.Don't routinely use peripheral blood stem cells for patients with aplastic anemia when a suitable bone marrow donor is available due to a higher risk of graft-versus-host disease.

2.Don't use greater than 2 mg/kg/day of methylprednisolone (or equivalent) for the initial treatment of graft-versus-host disease.

3.Don't routinely use two cord blood units for standard umbilical cord blood transplantation when a single unit of adequate size is available, recognizing that higher cell doses are preferred when using units with greater HLA mismatch.

4.Don't routinely use peripheral blood stem cells for matched unrelated donor transplantation using myeloablative conditioning and standard graft-versus-host disease prevention regimens when a suitable bone marrow donor is available.

5.Don't routinely give immunoglobulin replacement to adult hematopoietic cell transplantation recipients in the absence of recurrent infections regardless of the IgG level.

TCTH em MDS: Karnosfsky status

Heindenreicht S, et al. BBMT; 2016

Tools!! – HCT-CI & GA

Muffly LS et al. Haematologica 2014

Sorror MS et al. J Clin Oncol 2007

R-IPSS in HCT patients

Della Porta M et al, Blood, 2014

MDS transplantation risk index (TRI)

Della Porta M et al, Blood, 2014

Scoring system prognostic of outcome –MDS/TCTH - CIBMTR

Shaffer BC et al, JCO, 2016

•Age

•Kafnofsky

•Citog

•Peripheral Blasts(</> 3%)

•Plt (</> 50.000/mm3)

Is It worth waiting? – Marcov decision Model

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

Is It worth waiting? – Marcov decision Model

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

Vale a pena esperar? – Marcov decision Model

Koreth J et al. J Clin Oncol; 2013, 31: 2662-2671

SEM TCTH COM TCTH

MDS and mutations

Bejar R et al. NEJM, 2011

EBMT activity survey. Passweg et al. BMT, 2017; 52: 191-196

Impact of drug development on SCT - MDS

•ATG in MA/RIC when peripheral blood stem cells are used

•BM instead of PBSC in MUD – Choose wisely

•USE TOOLS!!

• GA

• HCT-CI

• R-IPSS

• HCT-IPSS

• Marcov Decision Model

Conditioning regimens

brigado!fkerbauy@gmail.com@fkerbauy@fkerbauy