Azacitidine as Maintenance Therapy

Following Hematopoietic Stem Cell

Transplantation for AML/MDS

A Single Center Experience

André Dias Américo

Médico Residente Transplante de Medula Óssea

Hospital Israelita Albert Einstein

Introduction

Azacitidine

Blast

Immunogenic

Antigens

de Lima, M et al. Maintenance Therapy With Low-Dose Azacitidine After Allogeneic HSCT for Recurrent AML or

MDS, Cancer 2010;116:5420-31

CD4+ Treg T CD8+

CD25+

CD127lo

FoxP3+

CD137+

CCR7+

Goodyear, OC et al. Azacitidine augments expansion of regulatory T cells after allogeneic stem cell transplantation

in patients with AML , Blood 2012;119(14):3361-3369

MAGE WT1 RAGE

Introduction

Azacitidine

• Safely administered after HSCT ª º

• Phase I/II Clinical Trials OS-2yr PFS-2 yr approximately

50% after RIC conditioningª º

• Better OS and PFS related with specific CD8 response

and earlier administration (< 90 days) º

• Retrospective study with neutral results after MAC

conditioningªª

ªde Lima, M et al. Maintenance Therapy With Low-Dose Azacitidine After Allogeneic HSCT for Recurrent AML or MDS,

Cancer 2010;116:5420-31

ºCraddock, C et al. Tolerability and Clinical Activity of Post-Transplantation Azacitidine in Patients Allografted for Acute

Myeloide Leukemia Treated on RICAZA Trial, Biol Blood Marrow Transplant 2016; 22: 378-393

ªªMaples, KT et al. Maintenance Azacitidine after myeloablative hematopoietic cell transplantation for myeloid

malignancies, Leuk & Lymph 2018; DOI: 10.1080/10428194.2018.1443334

Study Design:

Retrospective Cohort

Inclusion:

Age > 18 yo

AML or MDS diagnosis

HSCT followed by Azacitidine maintenance (in complete

morphological remission)

Outcomes:

Overall Survival

Relapse Free Survival

Statistical analysis: RR Core Team (2017). R: A language and environment for statistical computing.

R Foundation for Statistical Computing, Vienna, Austria.

URL https://www.R-project.org/

Methods

HSCT

Remission

Induction Morphological

Complete

Remission

D0 ~ D30

Aza

C1

Aza

C2

Aza

C24…

GVHD prophylaxis:

ATG (MUD)

either CsA or FK506

MiniMTX

Methods

Results 76 HSCT

for AML/MDS

2011-2018

17

Azacitidine Cohort

8 Early Deaths

42 did not received

azacitidine

9 azacitidine

as relapse treatment

+/- DLI

4

Completed/Ongoing

Treatment

13

Suspended Treatment

Death = 2

Personal = 1

Relapse = 2

Toxicity = 2

Missing = 6

Variable n = 17

Male (%) 9 (52,9%)

AML / MDS 14 / 3

Age (median) 53 [21-62] yrs

Active Disease (%) 6 (35%)

DRI Intermediate (%) 8 (47,1%)

MAC (%) 11 (64,7%)

PBSC Graft Source (%) 7 (41,2%)

Time to Aza (median) 46 [42-75] days

Aza Cycles (median) 3 [2-16]

DRI High/V. High (%) 9 (52,9%)

Table 1

8 Relapses/Death (47%)

Results - Progression Free Survival

Event

Control Aza

Median PFS ~ 3 years

6 Deaths (47%)

Results - Overall Survival

2 GVHD

2 Relapse

2 Infection

Control Aza

Survival

In this setting of high risk patients we

encountered somewhat lower relapse and death

rates than previously reported

Strenghts

• CIBMTR data center/data manager

• FACT accreditated center

Limitations

• Retrospective nature

• Small sample size

• Not the ideal setting to establish the role of

azacitidine in the post HSCT setting

Conclusions

Azacitidine as Maintenance Therapy

Following Hematopoietic Stem Cell

Transplantation for AML/MDS

A Single Center Experience

André Dias Américo, Larissa Lanes Teixeira, Luis Jorge

Santos Matos Filho, Cinthya Corrêa da Silva, Mariana Nassif

Kerbauy, Andreza Alice Ribeiro, Nelson Hamerschlak

Disease Status at the Time of Azacitidine Initiation

Morphological Remission: 17 (100%)

MDR positive by Flow Citometry: 4 (23,5%)

Chimerism > 90%: 16 (94%)

Preemptive Donor Lymphocyte Infusions: 0

Predictors of Relapse

High Risk Karyotype: 7 (42%)

Disease status prior to HSCT

2 RC: 4 (23,5%)

Active Disease: 6 (35%)

Motive n = 13

Death (%) 2 (15,3)

Personal (%) 1 (7,6)

Relapse (%) 2 (15,3)

Toxicity (%) 2 (15,3)

Missing (%) 6 (46,1)

Median Azacitidine Cycles: 3

Time to Aza (median) 46 [42-75] days

Azacitidine Treatment

VariableAza

(n=17)

AML / MDS 14 / 3

Age (mean) 51 yrs

DRI Intermediate (%) 8 (47,1%)

MAC (%) 11 (64,7%)

PBSC Graft Source (%) 7 (41,2%)

DRI High/V. High (%) 9 (52,9%)

Control

(n=51)

31/20

56 yrs

29 (56%)

22 (43,1%)

18 (35,2%)

21 (41,2%)

Second Complete

Remission (%)7 (13,2%)

Secondary AML (%)

4 (23,5%)

3 (17,6%) 5 (9,8%)

Progression Free Survival Overall Survival

Results - PFS and OS

Median PFS ~ 3 yrs Median OS Not Reached

Cumulative Incidence of Relapse

Relapse 7 (41%)

Univariate

Model

HR (IC 95%)

Multivariate

Model

HR (IC 95%)p p

Azacitidine

DRI Intermediate

0,50 (0,2-1,21) 0,1

0,44 (0,22-0,89) 0,02

0,41 (0,17-1,0) 0,009

0,39 (0,19-0,78)

Overall Survival

Progression Free Survival

0,005Azacitidine

DRI Intermediate

0,28-1,34 0,2

0,41(0,21-0,79) 0,008

0,49 (0,22-1,09)

0,36 (0,18-0,71)

events = 35

events = 38

Results - Cox Regression

All Grade < 3

Mostly Skin

1 Severe GVHD

Graft Versus Host Disease