https://www.youtube.com/watch?v=hh0J8Se6Pq8 by sphperu

Tratamiento de los SMD de riesgo alto Pierre FENAUX, Hopital St Louis, Universidad Paris 7 y Grupo Francofono de las Myelodysplasias (GFM) Octubre de 2016 Lima

Objetivos del tratamiento en SMD •  Retrasar la progresion •  aumentar la supervivencia •  Mejorar las citopenias •  Mejorar la calidad de vida

Objetivos del tratamiento( SMD de riesgo alto)

•  Retrasar la progresion •  aumentar la supervivencia •  Mejorar las citopenias •  Mejorar la calidad de vida

Tratamiento de los SMD de riesgo alto •  •  •  •

Alo TPH Quimoterapia clasica (intensiva o no) Agentes hipometilantes Otros (en combinacion con hipometilantes, o como secunda linea)

Tratamiento de los SMD de riesgo alto •  •  •  •

Alo TPH Quimoterapia clasica (intensiva o no) Agentes hipometilantes Otros (en combinacion con hipometilantes, o como secunda linea)

Figure 1

0 standard Standard

1.00

RIC

1 reduced

0.75

REL

0.50

REL

0.25

NRM 0.00

Months post-transplant

NRM 36 0

Months post-transplant

Alo TPH sigue siendo el unico tratamiento con potencial curativo (Platzbecker, BBMT, 2012)

Median follow-up of 20 months 3-year OS was 39% for HCT and 7% for 5-aza

Superviviencia de los SMD de riesgo alto segun la presencia de un donante HLA identico : M Robin, Leukemia , 2015 •  •

163 patients : 21%no donor; 71% HLA-matched donor (34% sibling and 37% unrelated) and 9% patients HLA mismatched donor 117 patients treated by AZA and 40 by CT. marrow blasts < 10% achieved in 68% and 57% for patients without and with donor

Decision model

The discounted life expectancies for the strategies of immediate Table 3. Discounted life expectancy, in years, for alternative transplantation strategies

transplantation, transplantation at the time of AML progression,

Transplantation at a fixed time point Transplantation and transplantation at a fixed interval after diagnosis for each of the of 2, at diagnosis 4 IPSS risk groups 2 y are shown in Table 4 y 3. Fixed time6intervals y

Patients, by IPSS risk group

4, 6, and 8 years after diagnosis were chosen for analysis.

All patients

For low-risk and int-1–risk IPSS groups, transplantation at the Figure 2. Overall survival of patients included in the analysis. (A) Overall survival Low MDS Risk Assessment Workshop patients who did not 6.51 6.86 progression was 7.47associated with7.46 of the International undergo time of leukemic a higher life stem cell transplantation, stratified by IPSS score atBlood the time of diagnosis (P ! .001 (print ISSN 0006-4971, online ISSN 1528-0020), is published weekly 5.02 Int-1 4.61 4.74 4.72 expectancy than was the strategy of transplantation at the time of for differences in risk groups). (B) Overall survival IBMTR/FHCRC bone of Hematology, 2021 L St, NW, Suite 900, by of thetheAmerican Society diagnosis. For3.21 both of these risk groups, at Int-2 2.94 however, transplantation 2.85 marrow transplantation cohort of patients, stratifiedWashington by IPSS risk score the time of DCat4.93* 20036. transplantation (P ! .001 for differences in risk groups). a fixedSociety intervalofafter diagnosisall(but prior to the development of Copyright 2011 by The American Hematology; rights reserved. High

3.20*

Patients younger than 40 y

for the entire months). Low cohort was 35.4 months (range, 1.4-206.7 5.62 There were Int-1260 individuals included in the MDS transplantation 2.48 cohort. Median (range, Int-2 follow-up of this cohort was 11.4 months 1.65* 0.1-131.6 months). In comparison to the nontransplantation cohort, High — the transplantation cohort was younger, and had a higher proportion of cases with more advanced MDSdata by FAB and IPSS criteria. The — indicates insufficient to perform analysis. IBMTR MDS transplantation cohort was younger and had less*Dominant strategies. advanced IPSS scores than the FHCRC cohort. The AML cohort was composed of 230 patients whose median follow-up was 7.9 months (range, 0-115.2 months). There were no significant differences in age or sex distribution between the MDS and the AML transplantation cohorts. Median survival of the nontransplantation cohort was 62.9 months. When stratified by IPSS score, median survivals were 141.1, 62.9, 22.5, and 4.9 months for the low-, intermediate-1 (int-1)–, intermediate-2 (int-2)–, and high-risk groups, respectively (Figure 2A, P ! .0001 for differences by log rank test). The 25% leukemic transformation time was 31.2 months for the entire cohort and 84.6, 19.2, and 2.7 months for the int-1–, int-2–, and high-risk groups, respectively. The 25% transformation rate was not reached in the low-risk group (P ! .0001 for differences by log rank test). Median survival for the MDS transplantation cohort was 14.0 months. When stratified by IPSS score, median survivals were 40.2, 20.5, 14.8, and 6.1 months for the 4 IPSS groups (Figure 2B; P " .04 by log rank test). There were no differences in survival outcomes between the IBMTR and FHCRC subgroups (P " .09).

2.75

AML) was the strategy that maximized overall discounted life years. The gains in discounted life expectancy for delayed transplan6.63 7.53 8.32 tation compared with transplantation at the time of diagnosis are 4.04 5.37 6.53 seen in Figure 3. For the more-advanced IPSS risk groups (int-2 1.51 discounted life 1.52expectancy and high), the1.48 strategy that maximized — at the time of— — was transplantation diagnosis. The decrement in life expectancy associated with delayed transplantation in these groups is shown in Figure 3. Quality-adjusted discounted life expectancy was approximated using the utility values shown in Table 1; results are shown in Table 4. Adjustment for QoL did not change the preferred treatment strategy for any of the 4 IPSS risk groups; however, some strategies were influenced by the estimated QoL parameters (such as the strategy for low-risk disease). No decisions were sensitive to varying (between 25% and 75%) the estimate of the proportion of patients who would not undergo transplantation once MDS had progressed to AML. When all above analyses were limited to patients younger than 40 years, the preferred treatment strategy for the low-risk and int-1risk IPSS groups was transplantation at progression to AML. All discounted life expectancy values were improved when compared with the data analyzed in its entirety. These analyses were insensitive to QoL parameters. For the int-2–risk group, transplantation at the time of diagnosis remained the preferred strategy. Analyses of the younger age cohort were limited by the small numbers of patients and clinical events in the nontransplantation group. There were too few high-risk

Table 3. Discounted life expectancy, in years, for alternative transplantation strategies Transplantation at a fixed time point

Transplantation at diagnosis

Transplantation at AML progression

Low

6.51

6.86

7.47

7.46

7.49*

7.21

Int-1

4.61

4.74

4.72

5.02

5.20*

5.16

Int-2

4.93*

3.21

2.94

2.85

2.84

High

3.20*

2.75

Low

5.62

6.63

7.53

8.32

9.00

10.21*

Int-1

2.48

4.04

5.37

6.53

7.49

10.21*

Int-2

1.65*

1.48

1.51

1.52

1.53

High

—

Patients, by IPSS risk group All patients

Patients younger than 40 y

— indicates insufficient data to perform analysis. *Dominant strategies.

in favor of transplantation early after the diagnosis of MD regardless of IPSS risk group. In fact, one study demonstrated th transplantation earlyat after the diagnosis of MDS was associate Transplantation 8 y with the most AML progression favorable outcome.16 Despite these results, it remai unclear whether early transplantation for all patients with MD 7.49* 7.21 of survival for the group as a whole. T 5.20* leads to maximization 5.16 2.84 address this question, 2.84 we performed a decision analysis usin 2.75 2.75 clinical data from IMRAW, IBMTR and FHCRC. 9.00 7.49 1.53

10.21* 10.21* Table 4. Quality-adjusted discounted life expectancy, in years, for 1.53

—

Transplantation at diagnosis

2 years

Low

5.99

6.37

Int-1

4.23

4.41

Int-2

4.53*

2.99

High

2.94*

2.53

Low

5.17

6.16

Int-1

2.29

3.78

Int-2

1.52*

1.39

High

—

Patients, by IPSS risk group All patients

Patients younger than 40 y

— indicates insufficient data to perform analysis. *Dominant strategies.

1.0

Nontransplantation therapy RIC transplantation

Cuando hacer un alotraplante RIC en pacientes de 60-70 anos de edad ? Overall Survival (probability)

0.8

0.6

0.4

0.2

J. Koreth et al. ,JCO, 2013

P < .001

Early Allo SCT

No early allo SCT

IPSS low / int-1 Overall life expectancy (months)

IPSS int-2 / high Overall life expectancy (months)

100

120

140

Time (months)

Fig 2. (A) Monte Carlo analysis for low/intermediate-1 International Prognostic Scoring Sy Kaplan-Meier survival plots (n ! 10,000; with log-rank P value) are indicated for the modeled 10-ye conditioning (RIC) transplantation (blue line) versus no early RIC transplantation (gold line nontransplantation strategy in low/intermediate-1 IPSS MDS quality-adjusted life expectancy (QA plot for the utilities of the Markov states “alive after RIC transplantation” and “alive with MDS w the range in which nontransplantation therapy produces superior QALE. The blue area indicates th The red square indicates the plausible range of quality of life (QoL) for “alive with low/intermedi does not cross the threshold line. This result is interpreted as insensitive, that is, the conclusion range. (C) Monte Carlo analysis for intermediate-2/high IPSS MDS. Simulated Kaplan-Meier survi the modeled 10-year time period, comparing a strategy of early RIC transplantation (blue line graphically indicate survival benefit of the early RIC transplantation strategy in intermediate-2/high sensitivity analysis. Two-way sensitivity plot for the utilities of the Markov states “alive after transplantation” is shown. The gold area indicates the range in which nontransplantation therapy which RIC transplantation produces superior QALE. The red square indicates the plausible range “alive after RIC transplantation” and does not cross the threshold line. This result is interpreted as change within the plausible QoL range. HCT, hematopoietic cell transplantation.

IPSS.21 In low/intermediate-1 IPSS MDS, therapeutic recommendations for the majority include BSC or ESA therapy. In intermediate-2/high IPSS MDS, the standard of care is hypomethylating agent therapy. MAC or RIC transplantation may be considered for patients with intermediate-2/high IPSS MDS who have an available donor. Data are limited on RIC transplantation in MDS, a potentially curative—albeit potentially toxic—therapy in patients ! 60 years of age. Reports have documented the feasibility and lack of adverse impact of age of RIC transplantation for various hematologic malignancies including, but not specifically focusing on, MDS.41,52,53 There is an even greater paucity of data comparing RIC transplantation

versus nontra domized com Decision available infor ranges of outc to 70 years w transplantatio in multiple ad only change i 2B). Converse tion offers LE long-term pla

www.jco.org

Alo TPH: como tratamiento de primera linea o precedido por QT o hipometilantes ? Depiende del % de blastos medulares, cariotipo y tipo de trasplante : –  blastos <10% : trasplante inmediato –  blastos medulares > 10% •  Cariotipo normal : QT intensiva antes del trasplante •  Cariotipo desfavorable : hipometilantes antes del trasplante

Impacto de azacitidina antes de un alotrasplante en los SMD G. Damaj et al. Damaj, JCO, 2013JC0,

2013

■  retrospective study SFGM-TC and GFM : è  417 MDS allografted between 1999-2009

■  Sibling / unrelated excluding cord blood ,classical or RIC

Supportive ttt

AZA alone

171

180

Impact of azacitidine before allo SCT in MDS 3y OS based on prior TTT

1.0

5-Aza Chimiothérapie 5-Aza + Chimiothérapie

Survie Globale

0.8

0.6

p=0,027

0.4

0.2

p=0,10

0 0

200

400

600

800

1000

1200

Jours 1.0

Mortalité non liée à la rechute à 3 ans

3y NRM based on prior TTT

p=0,136

0.8

0.6

0.4

p=0,036

0.2

0 0

200

400

600 Jours

G. Damaj et al.; ASH 2011; abs. 160

800

1000

1200

1.0

Tasa muy alta de recaida post alo en caso de cariotipo muy desfavorable ( IPSS-R) y/o mutacion TP53 Survival by 5-group cytogenetic classification.

Deeg H J et al. Blood 2012;120:1398-1408

Bejar et al. JCO 2014

DOI: 10.1200/JCO.2016.67.3616

120

Time (months)

120

144

168

Time (months) TET2 KRAS/NRAS

Cumulative Survival (proportion) Cumulative Survival (proportion)

1.0 1.0 0.9 0.9 0.8 0.8 0.7 0.7 0.6 0.6 0.5 0.5 0.4 0.4 0.3

192 INTRODUCTION 216

168

192 216 P = .04

Time (months) 0.4

48 clinical 72 heterogeneity 96 120reﬂects 144different 168 somatic 192 216

mutations that cause clonal proliferation and 0.3 Time (months) evolution of myelodysplastic cells.2-4 The fact that MDS have highly variable 0.2 ASXL1 clinical courses makes risk stratiﬁcation of cruTP53 1,5 Not mutated cial importance in0.1clinical decision making. Mutated Not mutated Several prognostic scoring systems based on

Myelodysplastic syndromes (MDS) 1.0 are myeloid neoplasms that range from conditions with 1.0 Not mutated a near-normal life expectancy to0.9 forms that are Mutated mutated close toNot acute myeloid leukemia 0.9 (AML).1 Their

0.2 0.1 0.1 0

120

144

96 (months) 120 144 Time Time (months)

168

0.3 0.2 0.2 0.1

P = NS P = NS 192 216

192

0.1 0

216

Cumulative Survival (proportion)

0.8 Mutated 0.8 0 24 48 72 0.7 1 © 2016 by American Society of Clinical Oncology 0.7 0.6by at INSERM on September 28, 2016 from 193.54.110.33 Information downloaded from jco.ascopubs.org and provided Copyright © 2016 American Society 0.6of Clinical Oncology. All rights reserved. Copyright 2016 by American0.5 Society of Clinical Oncology 0.5 0.4 1.0 0.4 0.3 Mutated

0.3 0.2

144

Mutated

P = .008 96

120

144

192

144

192

Mutated

Cumulative Survival (proportion)

Cumulative Survival (proportion) 6

Not mutated

0.9 0.8 0.7

0.2 0.1

Not mutated

216

Not mutated Mutated

0.5 0.4 0.3 0.2 0.1

P = NS 0

120

144

168

192

0.5 0.4

0.2 0.1

120

Time (months)

P = NS 0

Time (months)

Cumula

0.5 0.4 0.3

120

144

168

192

216

0.2 0.1 24

High-Risk IPSS-R

1.0 0.9

Not mutated Mutated

0.8 0.7

P = NS

0.6

120

144

168

192

216

144

168

192

216

0.9 0.8

0.4 0.3 ASXL1 0.2

Not mutated

0.1

0.7

Mutated

P = .001 0

0.6

120

144

168

192

216

Time (months)

0.5 0.4 0.3 0.2 0.1 0

Very High–Risk IPSS-R

1.0 0.9

Not mutated Mutated

0.8 P = .003

0.7 96 0.6

120

144

168

192

216

Time (months) 0.5

0.2 0.1

2016 by 144 American Society of Clinical 6 © 120 96 168 192 216 Oncology

We then focused on patients with MDS/AML. Mutations in ASXL1, RUNX1, and TP53 genes conﬁrmed an independent effect on probability of relapse and OS after transplantation (ASXL1: HR, 2.41 [95% CI, 1.59 to 4.41], P = .029 and HR, 2.09 [95% CI, 1.64 to 3.89], P = .021; RUNX1: HR, 2.46 [95% CI, © 2016 by American Society of Clinical Oncology

P = .063

JOURNAL OF CLINICAL ONCOLOGY

193.54.110.33 Time (months) Information downloaded from jco.ascopubs.org and provided by at INSERM on September 28, 20160 from 24 48 72

not including ASXL1, RUNX1, and TP53 mutations, respectively, and compared them using the likelihood ratios test. The model comparison resulted in a signiﬁcant P value (P , .001), thus conﬁrming the importance of accounting for gene mutations in the prognostic model.

P = .028 96

Time (months)

0.6

Fig 2. (Continued).

www.jco.org

Fig 2. Relationship between (A) number of mutations and (B) type of oncogenic mutations and overall survival of patients 0.4 with myelodysplastic syndromes (MDS) receiving allogeneic hematopoietic stem-cell transplantation. (C) Posttransplantation overall survival among patients with acute myeloid leukemia (AML) evolving from MDS according to genetic ontogeny group. NS = not signiﬁcant. 0.3

0.3

216

P = NS

JOURNAL OF CLINICAL ONCOLOGY

0.6

1.0

Fig 2. Relationship between (A) number of mutations and (B) type of oncogenic mutations and overall survival of patients with 0.4 myelodysplastic syndromes (MDS) receiving allogeneic hematopoietic stem-cell transplantation. (C) Posttransplantation overall survival among patients with acute myeloid leukemia (AML) evolving from 0.3 MDS NS = not signiﬁcant. SRSF2 1.0according to genetic ontogeny group. 1.0 EZH2

0.9

Not mutated Mutated

TET2

P = .003 P = .001 168 192 216

168

0.1

0.7

216

Mutated

96 (months) 120 144 Time 0.5 Time (months)

0.2 DNMT3A

0.5 (months) Time

0.8 0.7

0.3

0.8

Time (months)

0.9

96 0.6120

168

0.9

Cumulative Survival (proportion)

0732-183X/16/3499-1/$20.00

Not mutated

Cumulative Survival (proportion)

Oncology

1.0

Cumulative Survival (proportion)

RUNX1

Cumulative Survival (proportion)

Oncology, Fondazione IRCCS Policlinico San Matteo, P.le Golgi 19, 27100 Pavia, Italy; e-mail: matteogiovanni.dellaporta@ unipv.it

Cumulative Survival (proportion)

Cumulative Survival (p Cumulative Surviv

0.1

0.7and IPSS-R risk improved the ability Combining somatic mutations B to stratify patients by cap0.5 at an individual level. Accounting for various combinations of turing more prognostic information 0.6 1.0 IPSS-R risk and somatic mutations, the 5-year probability of survival after HSCT ranged from 0% 0.4 to 73%. 0.5 0.9 0.3 Conclusion 0.8 Somatic mutation in ASXL1, 0.4 RUNX1, or TP53 is independently associated with unfavorable out0.2 comes and shorter survival after and MDS/AML. Accounting 0.3allogeneic HSCT for patients with MDS 0.7in clinical practice and in for these genetic lesions may 0.1 improve the prognostication precision P = .008 P = NS 0.2 designing clinical trials. 0.6

Corresponding author: Matteo G. Della Porta, MD, Department of Hematology

Cumulative Survival (proportion) Cumulative Survival (proportion)

Cumulative Survival (p Cumulative Surviv

0.7 0.5 0.6 0.4 0.5 0.3 0.4 0.2 0.3 0.1 0.2

120

144

168

192

216

Time (months)

Fig 3. Posttransplantation overall survival of patients with myelodysplastic syndromes classiﬁed by the revised International Prognostic Scoring System (IPSS-R) and stratiﬁed according to the presence of mutations in the ASXL1, RUNX1, and TP53 genes.

mutation recurred at the time of relapse, whereas in patients 7 and 9, mutations of RUNX1 and ASXL1 (both with low VAF before transplant) expanded at the time of disease recurrence, respectively. www.jco.org

Tratamiento de los SMD de riesgo alto •  •  •  •

Alo TPH quimoterapia clasica (intensiva o no) Agentes hipometilantes Otros (en combinacion con hipometilantes, o como secunda linea)

Survival with Anthracycline-AraC Chemotherapy 1. 0

0.8

Survival (%)

100

Survival Probability

N = 99

0.6

0.4

0.2

0 0

100 120 140

Wattel E. et al. Br J Haematology. 1997;98:983-991.

0.0 0

100

200 310 Weeks

410

With Permission of E Estey, MD

520

0.8

Idarubicin-AraC 0.6

Fludarabin-AraC

0.2

0.4

Topotecan-AraC

0.0

Probability of Relapse or Death After CR

1.0

Intensive Chemotherapy (MDAnderson Experience)

100

200 Time (weeks)

300

400

AZA-001: OS â&#x20AC;&#x201C; azacitidine versus LDAC (Brit J Haematol, 2010) 1.0 Azacitidine

Probability of survival

0.9

LDAC

0.8 0.7 0.6 0.5 0.4 0.3 0.2 0

10 20 Time from randomisation (months)

AZA 001 trial: azacytidine vs LD AraC (Brit J Haematol, 2010) AZA

LD araC

Median nÂ° cycles

4.5

Median OS

24.5

15.3

P<0.001

OS fav karyotype

HR=0.46

OS unfav karyo

24.5

2.9

HR=0.07

CR+PR

31%

12%

P=0.046

53%

25%

P=0.006

Transf indep

45%

13%

P=0.01

Severe infections/pt year

0.44

P=0.017

Median days in hospital/pt year

P<10-4

Tratamiento de los SMD de riesgo alto •  •  •  •

Alo TPH quimoterapia (intensiva o no) Agentes hipometilantes Otros (en combinacion con hipometilantes, o como secunda linea)

Indicaciones de hipometilantes en los SMD •  •  •  •  •  •  •  •

Azacitidina o Decitabina ? En que enfermedades y cuando empezar ? Hasta que edad ? Factores pronosticos de respuesta y supervivencia ? Qué regimen? Durante cuanto tiempo? Como valorar la respuesta ? Qué prevention y tratamiento de efectos secundarios ? Solos o en combinacion ?

Indicaciones de hipometilantes en los SMD •  •  •  •  •  •  •  •

EORTC Decitabine Phase III study (Wijermans et al,JCO, 2011) Low-dose intravenous decitabine vs best supportive care in MDS with 11â&#x20AC;&#x201C;30% blasts

Improvement in progression free survival, but not survival

100

Overall survival

90 80

Médian (mnthss) : 10,1 vs 8,5 HR = 0,88, 95% CI (0,66; 1,17) p=0,38

70 60 50 40

Decitabine

Supportive care

20 10 0 0

Mois Abs 226 – CO – P WIJERMANS et al.

Azacitidine Survival Study (AZA 001) (Lancet Oncol, 2009) AZA 75 mg/m2/d x 7 d q28 d Screening/Central Pathology Review Investigator CCR Tx Selection Randomization

CCR •  Best Supportive Care (BSC) only •  Low Dose Ara-C (LDAC, 20 mg/m2/d x 14 d q28-42 d) •  Std Chemo (7 + 3)

BSC was included with each arm Tx continued until unacceptable toxicity or AML transformation or disease 26progression

AZA 001:Overall Survival: Azacitidine vs CCR ITT Population

Log-Rank p=0.0001 HR = 0.58 [95% CI: 0.43, 0.77] Deaths: AZA = 82, CCR = 113 Difference: 9.4 months

Proportion Surviving

1.0 0.9 0.8 0.7

50.8% 24.4 months

0.6 0.5 0.4

15 months

26.2%

0.3

AZA CCR

0.2 0.1 0.0 0

Time (months) from Randomization

AZA 001:Criterios secundarios •  Time to AML –  26.1 mos with AZA vs 12.4 with CCR, p=0.004

•  RBC transfusion independence –  45% with AZA vs 11% with CCR, p<0.0001

•  Infections requiring IV antimicrobials –  Reduced by 33% with AZA vs CCR

having an IPSS risk score of 1.5 or more—intermediate-2 and high-risk groups) with sufﬁcient follow-up data reported to the registry of the GESMD between 2000 and 2013. Reporting criteria did not change with time. Patients with therapy-related MDS were included in the analysis whereas patients receiving an allogeneic hematopoietic cell

IPSS<2.5, az

IPSS≥2.5, co

0.75 Survival probability

daily clinical practice is scarce. Further, the survival advantage of azacitidine over other treatment alternatives for higher-risk MDS patients outside the scope of clinical trials remains unknown.

1 Servicio de Hematología, Hospital Universitario Central de Asturias, Departamento de Medicina, Universidad de Oviedo, Oviedo, Spain; 2Universidad Autónoma de Chile, Santiago de Chile, Chile; 3IMIBIC, Hospital Universitario Reina Sofía, Universidad de Córdoba, Córdoba, Spain; 4Hospital Universitario La Paz, Madrid, Spain; 5Hospital Clinic, Barcelona, Spain; 6Hospital de Txagorritxu, Victoria-Gasteiz, Spain; 7Hospital del Mar, Barcelona, Spain; 8Hospital Universitario Morales Messeguer, Murcia, Spain; 9Instituto catalán de Oncología, Instituto de Investigación Josep Carreras, Instituto Catalán de Oncología, Hospital Germans Trias i Pujol, Badalona, Spain; 10Hospital Universitario de Salamanca, Salamanca, Spain; 11Hospital Clínico Universitario, Instituto de Investigación INCLIVA, Valencia, Spain; 12Hospital Son Llatzer, Palma de Mallorca, Spain; 13Hospital Vall D´Hebrón, Barcelona, Spain; 14Hospital Sant Pau, Universidad Autónoma de Barcelona, Barcelona, Spain; 15Grupo Español de Síndromes Mielodisplásicos, Valencia, Spain and 16Hospital Universitario y Politécnico La Fe, Valencia, Spain. Correspondence: Dr T Bernal, Servicio de Hematología, Hospital Universitario Central de Asturias, Departamento de Medicina, Universidad de Oviedo, Avda de Roma s/n, Oviedo 33011, Spain. E-mail: Teresa.bernal@sespa.princast.es Received 3 March 2015; revised 21 April 2015; accepted 24 April 2015; accepted article preview online 6 May 2015; advance online publication, 22 May 2015

IPSS≥2.5, az

0.50

0.25

0.00 0

12 24 36 48 60 72 84 96 Time (months)

Figure 3. Impact of azacitidine on survival. (a) Survival c (b) Estimated survival curves according to the Cox regr and leukocyte count at diagnosis. There were no signi according to the treatment and the IPSS. (d) Impact of

•  Median survival 13.4 months for azacitidine- treated patients and 12.2 for patients under CCT (P = 0.41) •  in patients with chromosome 7 abnormalities, trend toward a better survival was observed in azacitidine-treated patients (median survival 13.3 compared with 8.6 for CCT (P = 0.08) •

AML compared with 26% of the azacitidine-trea (P = 0.42). In the multivariable model with competitiv transformation was not signiﬁcantly associated with treatment received (hazard ratio, 1.14; 95% CI, 0.85–1 The low number of events precluded to analyze th treatment on AML progression in speciﬁc subsets of

DISCUSSION In this work we studied the changes in the th outcomes over a 14-year period in a series of 821 p higher-risk MDS included in the registry of the expected, our data show that the use of azacitidine therapy in higher-risk MDS has experienced a fourfol recent years, largely due to the publication of the re large randomized clinical trials5,6 showing azacitidine effective than conventional treatment and demonstr of them a clear survival beneﬁt in patients with hig (AZA-MDS-001 trial).5 However, in sharp contrast wit of these randomized multicenter trials comparing a conventional CCT in patients with higher-risk MD unable to show in an unselected population of signiﬁcant advantage for azacitidine-treated patients both OS and AML-free survival. Noteworthy, OS in patients (median OS, 12.3 months) was similar © 2015 Macmillan Publishers Limited

Figure 1. Overall survival of patients with HR-MDS treated with azacitidine compared with patients with HR-MDS receiving (a) BSC only or (b) intensive chemotherapy. (c) OS of patients with HR-MDS treated with azacitidine according to the type of response (d) compared with patients with HR-MDS receiving BSC only. In d, patients who responded to azacitidine were grouped as those who achieved a CR, PR, marrow CR or HI with or without SD. In that same Figure, as well as in c, non-responders were deﬁned as patients without a bone marrow evaluation and lacking a HI, SD without HI or progressive disease. Hematological remission and improvement were based on International Working Group 2006 criteria for MDS. OS was measured with the Kaplan–Meier method as the time from treatment to death or last follow-up, and compared with the log-rank test. AZA, azacitidine; BSC, best supportive care; CI, conﬁdence interval; CR, complete remission; HI, hematologic improvement; HR-MDS, higher-risk myelodysplastic syndromes; IC, intensive chemotherapy; OS, overall survival; PR, partial remission; SD, stable disease.

Figure 1. Overall survival of patients with HR-MDS treated with azacitidine compared with patients with HR-MDS rec intensive chemotherapy. (c) OS of patients with HR-MDS treated with azacitidine according to the type of resp patients with HR-MDS receiving BSC only. In d, patients who responded to azacitidine were grouped as those who ac CR or HI with or without SD. In that same Figure, as well as in c, non-responders were deﬁned as patients without a and lacking a HI, SD without HI or progressive disease. Hematological remission and improvement were based o Group 2006 criteria for MDS. OS was measured with the Kaplan–Meier method as the time from treatment to dea compared with the log-rank test. AZA, azacitidine; BSC, best supportive care; CI, conﬁdence interval; CR, complete re improvement; HR-MDS, higher-risk myelodysplastic syndromes; IC, intensive chemotherapy; OS, overall surviva SD, stable disease.

Email: kim_dajung@hanmail.net Y-G.L. and H-J.K. contributed equally to this work.

ª 2013 Blackwell Publishing Ltd, British Journal of Haematology

doi:10.1111/bjh.12256

•  300 patients, 203 azacitidine and 97 decitabine. •  Propensity-score matching yielded 97 patient pairs. •  no significant differences between the azacitidine and decitabine groups regarding ORR (44% vs. 52%), OS (26 vs. 229 months), EFS (7.7 vs. 7 months), and AML transformation (16% vs. 22% at 1 year) •  In patients > 65 years of age, survival was significantly better in the azacitidine group (P = 0.017) •  Patients who received decitabine experienced more frequent episodes of grade 3 or 4 cytopenia and infectious episodes.

Email: kim_dajung@hanmail.net

Table IV. Deaths and safety profile in the overall and the propensity-matched cohort Y-G.L. and H-J.K. contributed equally to this work.

Propensity-matched cohort (n = 194)

Overall cohort (n = 300)

ª 2013 Blackwell Publishing Ltd, British Journal of Haematology

•

Deaths Deaths during first 3 months of treatment Grade 3 or 4 haematological toxicity* Neutropenia Thrombocytopenia Anaemia Infectious episodes requiring antimicrobial per 100 cycles (episodes/cycles)

Azacitidine (n = 203)

Decitabine (n = 97)

112 (55%) 10 (5%)

44 (45%) 8 (8%)

136 132 96 11!8

doi:10.1111/bjh.12256

(67%) (65%) (47%) (147/1251)

84 64 56 15!7

(87%) (66%) (58%) (85/547)

Azacitidine (n = 97) 49 (51%) 6 (6%) 68 63 46 8!6

(70%) (65%) (47%) (52/604)

Decitabine (n = 97) 44 (45%) 8 (8%) 84 64 56 15!7

(87%) (66%) (58%) (86/547)

Data are number (%). *National Cancer Institute’s Common Toxicity Criteria based on laboratory data.

In the absence of a randomized comparison study, a recent meta-analysis attempted to compare the efficacy of the 2 HMAs (Gurion et al, 2010); survival benefits were shown for azacitidine but not for decitabine. The authors noted that reduced efficacy from a shorter administration period may ª 2013 Blackwell Publishing Ltd, British Journal of Haematology

account for the lack of survival improvement seen with decitabine. Another meta-analysis included the same randomized trials and performed similar analyses using a different method (Kumar et al, 2010), obtaining practically the same results. They also presented an indirect comparison of azacitidine 7

Address for correspondence: Yanhui Xie, MD, Department of Hematology, Huadong Hospital Afﬁliated to Fudan University, West Yan’an Rd 221, Shanghai 200030, China E-mail contact: xyh@medmail.com.cn

and conclude that the 2 drugs are effective and show a significant overall survival (OS) benefit in patients with MDS.8-10 However, which of the 2 drugs has better efficacy is not clear. In 2013,

Clinical Lymphoma, Myeloma & Leukemia Month 2014

-1

Clinical Lymphoma, Myeloma & Leukemia, 2014

•  768 DAC, 624 AZA •  no differences for CR, RBC-TI, hematologic toxicity •  When compared with BSC, AZA significantly improved OS and time to AML but not decitabine. •  In IPSS high or age> 75 years, treatment with azacitidine was a favorable factor, but decitabine showed no advantage.

Indicaciones de hipometilantes en los SMD •  •  •  •  •  •  •  •

AZA en SMD/LMA despues de SMP (S Thépot, Blood, 2010)

•  54 patients with MDS or AML post myeloproliferative disorder (in the French ATU program) •  52% responses, with reversal to features of MPD (polycythemia, thrombocythemia ) in one half of responders

Azacytidine en pacientes con 20 to 30% blastos (JCO, 2010) 1.0

p=0,0038 HR = 0.47 (95% CI : 0,28 ; 0,79) Décès : AZA = 24, CCR = 41

Proportion Survivants

0.9 0.8 0.7

50,2% 24,46 mois

0.6 0.5

AZA

0.4

15,97 mois

0.3 0.2 0.1

CCR

15,9%

0 0

Temps (mois) après randomisation # at risk AZA

CCR

Abs 3636 – Po III-718 – P FENAUX et al. (2)

after a Paris median number of 6France cycles of AZA (range 2–17). Three, 4 and Hopital Avicenne et université 13, APHP, Bobigny, 10.1 and 19.9 months in t-MDS/AML that failed AZA, tc Hôpital Claude Huriez 2 - Service des maladies sang,and Lille, no France had achieved CR,dumCR response to AZA prior to transplant, 1. Introduction cytogenetic abnormalities, International that combined respondedintoanAZA, de novo Prognostic MDS/AML that failed d Institut Paoli Calmettes, Marseille, France respectively. Four (44%) of the transplanted patients wereSystem still alive, Scoring (IPSS) de that distinguishes subgroups withto signifie novo MDS/AML4that responded AZA, respectivel Hopital Cochin et université paris 5, APHP, Paris, France 5+, 17+, 32+ and 42+ transplant, respectively. −4 f Myelodysplastic syndromes (MDS) aremonths clonalafter hematopoicantly different risk ofpprogression to AML and survival [2]. Other Hopital Universitaire de Limoges, France < 10 ). g One, France 2 and 3 year overallby survival (OS) from onset of treatment Institut Gustave Rousy,disorders Villejuif, etic stem cell (HSC) characterized ineffective prognostic factors have been identified, including having therapy h Hopital Universitaire de Tours, France was 36%, 14% and 8% respectively. Female genderrelated (median OS 11.1 hematopoiesis leading to blood cytopenias and by a high incidisease, myelofibrosis, LDH, and somatic mutations [3–5]. i 4. Discussion Hopital Universitaire de Clermontvs Ferrand, Francein males, p = 0.01) and ECOG performance sta7 months dence of progression tomonths acute myeloid leukemia (AML) [1]. MDS The poor prognosis of t-MDS/AML is due in particular to the high tusor(median OS 9.1tomonths in patient with 0–1 versus 5.8 and AML can arise de novo be secondary the administration of ECOG prevalence of complex karyotype in this with sub-group [6].MDS treated in the sam By comparison de novo monthsrelated in patients with ECOG 2–4, p = 0.04) had a significant MDS/AML or t-MDS/AML). azacitidine (AZA) was[8], approved in Europehad fora higher the frequenc antineoplastic agents (therapy In 2008, effect ATU program the 54 t-MDS/AML a r t i c lfactors e i on nofOS fMDS owhile amarrow b s and t rblast a cpercentage t karyotype had no signifMain prognostic include the and number depth treatment of high risk MDS and AML with 20–30% marrow plex karyotype (71 vs 43%), received fewer cycles of AZA However, was amarrow trend for lower OS in patients the results of a phase III randomized trial icant impact. the percentage of marrow blaststhere and bone following of cytopenias, blasts, 6 cycles) due to more frequent discontinuation of AZ vs Article history: The effect of azacitidine (AZA) in therapy related MDS and AML (t-MDS/AML) is not well established. with chromosome 7 abnormality (median OS 6.3 vs 10.6 months in showing a survival advantage over conventional treatments includReceived 2 November 2012 4 cycles (41.7% vs 25% in received de novoAZA MDS/AML) mainly re 54 patients (42 t-MDS and 12 t-AML), 71% of whom had complex karyotype, for at least patients without chromosome 7 abnormality, p = 0.06). Received in revised form 17 February 2013 ing chemotherapy [7].higher Nevertheless, therapy related cases were incidence ofinearly deaths. Despite those one cycle (median 4 cycles). The overall response rate (ORR) was 39% the whole cohort and 62% in poor fe Accepted 18 February 2013 from that phase III 36%, trial, and the impact of azacitidine patients who received ≥4excluded cycles. One, 2 and 3 year OS was 14% and 8% respectively. Female gender had a similar ORR (38% vs 45% in de novo M MDS/AML ∗ Corresponding Available online xxx author at: Hôpital Avicenne – Service d’hématologie clinique, in has not beensignificantly well studied. (p = 0.01) and ECOG 0–1 (pthose = 0.04)patients were associated better OS, whileOS karyotype andof 14% vs 3.3. Comparison with de novo p =with 0.53), but significantly shorter (2 year OS MDS treated with AZA Paris 13 University, Assistance Publique-Hopitaux de Paris (AP-HP), 125 rue de marrow blast percentage had no significant comparison de of novo treated in we impact. published overall a MDS/AML compassionate Recently, de By novo MDS, p results =with 0.0005). 93009 Bobigny, France. Tel.: +33 148957055; fax: +33 148957058. Stalingrad, Keywords: program, t-MDS/AML had a similar response rategroup (38% vs 45% in dewith novohigher MDS/AML, p =of0.53), patient named program ofOur AZA in 282 patients MDS previously reported anrisk ORR 52% includin A comparison betweenthe thesame current t-MDS/AML cohort and 204 E-mail address: lionel.ades@avc.aphp.fr (L. Adès). syndromes Myelodysplastic but significantly shorter OS (2 year OS of 14% vs 33.9%, p = 0.0005). However, in a multivariate analysis Therapy-related MDS/AML with AZA in 54 MDS/AML arising after MPN [10], with de novo MDS/AML (with marrow blasts < 30%) also included in our performed in all patients (de novo and therapy related cases), only complex karyotype and high IPSS, Azacitidine 0145-2126/$ – see front matter © 2013 Elsevier Ltd. All rights reserved. response duration of 9 months. published cohort [8] is shown in Table 1. t-MDS/AML previously and not etiology (i.e. de novo versus therapy related), had a significant impact on OS. Nine (15%) patients http://dx.doi.org/10.1016/j.leukres.2013.02.014 Ourwere ORRstill of 39% patients were significantly younger (median 68.5 vs 72.5 years, received allogeneic stem cell transplantation, 4 of whom alive.(including 15% CR) in t-MDS/AML is rate (including CR) reported in t-M the 38% response p = 0.02), were more often females (61% vs 34%, p = 0.001), had © 2013 Elsevier Ltd. All14% rights reserved. Please cite this article lower in press as: Bally C, et treatment of therapy related syndrome Cancer and acute by the myelodysplastic Memorial Sloan-Kettering Center in 42 pati platelet count (39al.G/lAzacitidine vs 61 G/l, in p =the 0.0003), a higher fremyeloid leukemia (tMDS/AML): report on 54 patients Francophone Myelodysplasies (GFM). Res or decitabine [12]Leuk and to the(2013), 42% reported in t-M quency ofAcomplex karyotype (71%by vs the 43%,Groupe p < 0.001), a higher Desazacitine http://dx.doi.org/10.1016/j.leukres.2013.02.014 by Fianchi et al. with AZA [13]. In our experience, this proportion of high IPSS (61% vs 40%, p = 0.03), and had received similar to that observed in de novo MDS/AML treated wit fewer cycles of AZA (median 4 vs 6 cycles, p = 0.001) while other spite of the fact that de novo cases had more favorable p pretreatment characteristics (WHO diagnosis, marrow blast per1. Introduction cytogenetic abnormalities, combined in an International Prognostic factors (especially fewer complex cytogenetic findings a centage, WBC count, hemoglobin level) did not significantly differ. Scoring System (IPSS) that distinguishes 4 subgroups with signifiIPSS). The smaller number of cycles in t-MDS/AML was mainly due to Myelodysplastic syndromes (MDS) are clonal hematopoicantly different risk of progression to AML and survival [2]. Other Neither of the 2 previously published studies of hyp more frequent discontinuation of AZA before 4 cycles (41.7% vs etic stem cell (HSC) disorders characterized by ineffective prognostic factors have been identified, including having therapy lating agents in t-MDS/AML[12,13], however, compared 25% in de novo MDS/AML, p = 0.027). Early discontinuation in thematopoiesis leading to blood cytopenias and by a high incirelated disease, myelofibrosis, LDH, and somatic mutations [3–5]. and t-MDS/AML for OS. In the present study, OS was MDS/AML was largely related to a higher incidence of early deaths dence of progression to acute myeloid leukemia (AML) [1]. MDS The poor prognosis of t-MDS/AML is due in particular to the high t-MDS/AML compared to de novo MDS/AML treated w (19% vs 9% in de novo MDS/AML, p = 0.01). Early deaths in patients and AML can arise de novo or be secondary to the administration of prevalence of complex karyotype in this sub-group [6]. in the same compassionate patient named program. with t-MDS/AML were due to sepsis (n = 6), bleeding (n = 2) or proantineoplastic agents (therapy related MDS/AML or t-MDS/AML). In 2008, azacitidine (AZA) was approved in Europe for the in multivariate analysis, only high IPSS and complex k gression (n = 2). Main prognostic factors of MDS include the number and depth treatment of high risk MDS and AML with 20–30% marrow retained prognostic significance on OS, while the fact t-MDS/AML had a similar response rate as de novo MDS/AML of cytopenias, the percentage of marrow blasts and bone marrow blasts, following the results of a phase III randomized trial therapy related lost its poor prognostic significance. In (38% vs 45% in de novo MDS/AML, p = 0.53), but significantly shorter showing a survival advantage over conventional treatments includexperiences with treatments other than hypomethylatin OS (2 year OS of 14% vs 33.9% in de novo MDS, p = 0.0005, Fig. 1). ing chemotherapy [7]. Nevertheless, therapy related cases were excluded from that phase III trial, and the impact of azacitidine ∗ Corresponding author at: Hôpital Avicenne – Service d’hématologie Please cite this article in press as: Ballyclinique, C, et al. Azacitidine in the treatment of therapy related myelodysplastic syndrome an in those patients has not been well studied. Publique-Hopitaux de Paris (AP-HP), 125 rue Paris 13 University, Assistance myeloid leukemia (tMDS/AML): A report on de54 patients by the Groupe Francophone Des Myelodysplasies (GFM). Leuk Res of a compassionate Recently, we published overall results Stalingrad, 93009 Bobigny, France. Tel.: +33 148957055; fax: +33 148957058. http://dx.doi.org/10.1016/j.leukres.2013.02.014 patient named program of AZA in 282 patients with higher risk MDS E-mail address: lionel.ades@avc.aphp.fr (L. Adès). 0145-2126/$ – see front matter © 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.leukres.2013.02.014

Please cite this article in press as: Bally C, et al. Azacitidine in the treatment of therapy related myelodysplastic syndrome and acute myeloid leukemia (tMDS/AML): A report on 54 patients by the Groupe Francophone Des Myelodysplasies (GFM). Leuk Res (2013), http://dx.doi.org/10.1016/j.leukres.2013.02.014

AZA 001:Overall Survival: Azacitidine vs CCR ITT Population

Log-Rank p=0.0001 HR = 0.58 [95% CI: 0.43, 0.77] Deaths: AZA = 82, CCR = 113 Difference: 9.4 months

Proportion Surviving

1.0 0.9 0.8 0.7

50.8% 24.4 months

0.6 0.5 0.4

15 months

26.2%

0.3

AZA CCR

0.2 0.1 0.0 0

Time (months) from Randomization

Indicaciones de hipometilantes en los SMD •  •  •  •  •  •  •  •

AZA en pacientes mayores de 80 anos (Itzykson, Blood, 2011) 1

,6 Age <80

Age â&#x2030;¥80 OS

Survie Cum.

,2 0 0

20 25 Temps

30 months

AZA 001 trial: results in patients > 75 years (Seymour J, 2011)

Indicaciones de hipometilantes en los SMD •  •  •  •  •  •  •  •

methyltransferase 3A (DNMT3A) (4) and ten-eleven translocation 2 (TET2) (5, 6), respectively — as well as those involved in histone-modifying complexes — additional sex combs-like 1

Authorship note: Kristen Meldi, Tingting Qin, Valeria Santini, and Maria E. Figueroa contributed equally to this work. Conflict of interest: The authors have declared that no conflict of interest exists. Submitted: August 27, 2014; Accepted: February 9, 2015. Reference information: J Clin Invest. 2015;125(5):1857–1872. doi:10.1172/JCI78752.

radation (16, 17). DMTis can also cause DNA damage (18), because AZA is mostly incorporated into RNA, it may have ad tional effects on RNA processing and translation (19). Despite utility of DAC and AZA, only a subset of MDS and CMML patie respond to them. Only approximately 50% of patients treated w DMTis show a hematological improvement (HI) or better tha associated with a survival benefit (20). Furthermore, as man 6 months of treatment may be required for the therapeutic be fit of DMTis to become apparent, thus forcing half of the patie jci.org

Volume 125

Number 5

May 2015

•  167 differentially methylated regions (DMRs) of DNA at baseline distinguished responders from nonresponders using NGS . These DMRs were primarily localized to nonpromoter regions and overlapped with distal regulatory enhancers Metodo: ERBBS

1857

https://ash.confex.com/ash/2013/cop/papers/confirmation.cgi

Reference

M SĂŠbert, submttted

* : p<0.05 compared to Normal

Impact of Cytogenetics on OS (compared to NK) cytogenetic

Cytogenetic

patients

isolated del(20q)

isolated del(5q)

Isolated trisomy 8

Normal

297

Trisomy 8

127

del20q

isolated del(7q)

3q26

Complex

272

non isolated -7/del(7)

195

monosomal

218

non isolated del(5q)/-5

212

del(17p)

Hazard Ratio (95% CI)

Reference

Worse

Better -1 -1

1 1

Factores pronosticos del tratamiento con AZA ? ATU francesa 282 pacientes l  validacion con los pacientes del estudio AZA-001 161 pacientes l

Cohorte d’ATU (développement)

bajo Intermedio alto

1,0

Analisis multivariada

HR [95% CI]

puntuacion

Performance status

2,0 [1,4-2,9]

<10-4

≥ 4 unidades de GR/8 semanas

1,9 [1,4-2,6]

<10-4

Presencia de blastos circulantes

2,0 [1,5-2,7]

<10-4

Citogenetica (IPSS)

Probabilité cumulée de survie

0,8

p<0,0001

<10-4

Riesgo intermedio

1,4 [0,8-2,3]

Desfavorable

3,0 [2,0-4,3]

0,6

ATU (n=269) (N,%)

Survie médiane globale (mois)

(N,%)

Survie médiane globale (mois)

30 (11%)

23 (15%)

Intermedio

1-3

191 (71%)

15,0

114 (75%)

21,4

Elevado

4-5

48 (18%)

6,1

15 (10%)

9,3

Grupo, de riesgo

Score

0,4

0,2

bajo

0,0 0

30 Mois

AZA-001 (n=152)

R. Itzykson et al.,Blood , 2011

determine the characteristics of long-term survivors. In the updated analysis, with a median follow-up of 41.3 months, 54 of the 282 patients were still alive and the median number of AZA cycles received was 6 (range 1-53). Median OS was 13.5 months, and the 3-year estimate of OS was 17.5% (95% confidence interval [CI]: 12.6%-22.4%). Sixteen of the 30 patients in the favorable risk group were still alive and median OS of this group was reached at 32.1 months. Our proposed prognostic score remained highly valid (Figure 1; "4). Censoring at the time of allogeneic stem cell log-rank test:ISSN P ! 101528-0020), Blood (print ISSN 0006-4971, online is published weekly did2021 not affect those results. by the American Society of transplantation Hematology, L St, NW, Suite 900, Thirty-four patients (M/F: 20/14), with a median age of 69 years Washington DC 20036. Copyright 2011 by The American Society rightsafter reserved. (range 42-86) hadofanHematology; OS of at least all 3 years AZA onset. At AZA onset, their World Health Organization diagnosis was refractory cytopenia with multilinage dysplasia, refractory anemia with excess blasts (RAEB)–1, RAEB-2, and AML with 20%-30% blasts in 1, 6, 21, and 6 cases, respectively. Four of them had therapyrelated MDS. PS was ! 2 in 30 cases (88%). Cytogenetic risk was low, intermediate, high, and not available in 18 cases (53%; all with normal karyotype), 8 cases (24%), 7 cases (21%: 3 with isolated monosomy 7 and 4 with complex abnormalities), and 1 case (2%). Only 22 of the 34 patients (64%) had responded to AZA according to International Working Group 2006 criteria,5 including 7 (21%) complete responses (CR), 1 (3%) partial response (PR), 4 (12%) marrow CR, and 10 (29%) stable disease with hematologic improvement. Three years after AZA onset, 6 (18%) of the 34 patients were still receiving AZA, 8 (24%) had been allografted, and 15 (44%) had received other treatments including intensive chemotherapy (n # 2), low-dose chemotherapy (n # 2), investigational drugs (n # 6), or decitabine (n # 5). Altogether this updated report indicates that long-term survival with AZA in higher-risk MDS can be predicted using our dailypractice scoring system. Long-term survival can be achieved even in some of the patients with poor risk features including therapyrelated cases, cases with 20%-30% blasts or with high-risk karyotype, and some patients who do not achieve CR or PR. However, for the majority of patients, long-term outcome remains poor, prompting the investigation of second-line therapies.

6172

Figure 1. Updated Kaplan-Meier estimates of overall survival (OS) of our previously reported cohort of 282 higher-risk myelodysplastic syndromes (MDS) patients treated with azacitidine, with a median follow-up of 41.3 months. (A) Global cohort (n # 282).1 (B) Cohort according to our risk stratification: low (n # 30, median OS: 32.1 month); intermediate (int; n # 191, median OS: 15.0 months); high (n # 48; median OS: 6.1 month; log-rank test: P ! 10"4).

Raphael Itzykson Service d’He´matologie Clinique Hoˆpital Avicenne, Assistance Publique–Hoˆpitaux de Paris (AP-HP), and Universite´ Paris 13, Bobigny, France Sylvain The´pot Service d’He´matologie Clinique Hoˆpital Avicenne, AP-HP, and Universite´ Paris 13, Bobigny, France Bruno Quesnel Service des Maladies du Sang, Centre Hospitalier Universitaire (CHU), Lille, France Francois Dreyfus Service d’He´matologie Clinique, Hoˆpital Cochin, AP-HP, and Universite´ Paris 5, Paris, France

BLOOD, 21 JUNE 2012 ! VOLUME 119, NUMBER 25

count, !10⁹/L 45%

45%

" 0.8

54%

40%

43%

40%

.465

15.3

12.2

Platelet count, !10⁹/L

5084

20.3

42%

15.1

50%

9.7

60%

.287

16.1

70%

8.1

44%

15.9

41%

14.1 .646

.0001

1.00

32% weekly Blood (print ISSN 0006-4971, online ISSN50-100 1528-0020), is published by the American Society of Hematology, 2021 L St, NW, Suite 900, " 100 25% Washington DC 20036. BM % Copyright 2011 by The American Society ofblasts, Hematology; all rights reserved. !2 2% 3-5 3% 5-10 18% " 10 77% Cytogenetic group Very good 1% Good 37% Intermediate 18% Poor 12% Very poor 32% IPSS-R classification Low ! 1% Intermediate 11% High 34% Very high 55%

.10

.12

.0001

46%

21.8

39%

12.3

45%

15.1

38%

7.1

0.00

! 50

scoring syst high-risk p (median no conclude th

Overall Survival 0.25 0.50 0.75

! 0.8

0 .463

.0001

46%

30.7

47%

17.6

39%

Figure 1. OS a median follow

Correspondence: Professor M Fontenay, Service d’He´matologie Biologique, GH Broca-Cochin-Hoˆtel-Dieu, AP-HP, Department of Immunology and Hematology, Institut Cochin, INSERM U1016, CNRS UMR 8104, Faculty of Medicine, University Paris Descartes, 27 rue du Faubourg Saint-Jacques, 75679 Paris, Cedex 14, France. E-mail: michaela.fontenay@inserm.fr 12 These two authors contributed equally as first authors. Received 20 November 2010; revised 9 February 2011; accepted 3 March 2011; published online 15 April 2011

responses (P ¼ 0.014). Neither baseline hemoglobin leve (P ¼ 0.8) nor previous MDS duration (P ¼ 0.6) affected respon rate, andAZA in bivariate the favorable impact of TET Patients were to receive at theanalyses, Food and Drug Adminismutations on response was independent of baseline hemoglob tration (FDA)/European Medicines Agency (EMEA) approved and 2 of previous disease duration (both P ¼ 0.02).

Treatment

schedule (75 mg/m per day, 7 days every 4 weeks). Patients having received X1 cycle of AZA and with bone marrow Impact of duration AZA or exposure on response evaluation after X4 cycles, or whoofdied progressed before TET2 mutated patients received a median of 13 cycles (rang completion of four cycles were considered evaluable (those two 4–26), compared with 7 (1–39) in WT patients (P ¼ 0.004). Thu groups were considered treatment failures). we analyzed whether longer exposure to AZA could ha

confounded the impact of TET2 status on response achievemen First, patients achieving any type of response (including SD wi HI) had received a similar number of AZA cycles in both group median 13 cycles (range 4–20) in TET2 MUT patients an 9 cycles (3–36; P ¼ 0.23) in TET2 WT patients. In addition, in bivariate logistic regression, presence of a TET2 mutation tend to predict an improved ORR (OR ¼ 4.95 (0.99–25.0), P ¼ 0.05 independently of the number of AZA cycles (OR ¼ 1.0 (1.01–1.14), P ¼ 0.049). When SD with HI was excluded fro responses, the independent favorable impact of TET2 mut tions reached statistical significance (TET2 MUT: OR ¼ 4.2 (1.17–15.63), P ¼ 0.028; number of AZA cycles: OR ¼ 1.0 (0.98–1.10), P ¼ 0.23). As all cases of early AZA discontinuatio occurred in WT patients, the influence of TET2 status on OR was analyzed in the 79 patients having received four or mo cycles. In those 79 patients, the ORR (including HI) was 11/1 (85%) in TET2 mutated patients and 33/66 (50%) in TET2 W patients (P ¼ 0.031). Finally, only 4 of the 45 IWG respons observed in the study occurred after more than six AZA cycle all of them in the TET2 WT patients. Thus, it is unlikely that t higher response rate of TET2 mutated patients reflects la responses caused by prolonged AZA exposure.

•  Mutated TET2 (p=0.04) and favorable cytogenetic risk predicted higher response rate •

Response duration and overall survival however, comparable in the MUT and WT groups.

Impact of TET2 mutation type on AZA response

Responses rates were 7/9 (78%, CR: n ¼ 5, mCR/CRi: n ¼ 2) patients with frameshift mutations, 4/5 (80%, CR: n ¼ mCR/CRi: n ¼ 2, SD with HI: n ¼ 1) with nonsense mutatio and 3/3 (100%, CR: n ¼ 1, SD with HI: n ¼ 2) with missen mutations (Table 2). We analyzed the impact of TET2 status o Leukemia

TP53 mutations are associated with poorer survival with azacitidine in high risk MDS (Bally, Leuk Res , 2013)

help stratify patients according to their response rates, but these models pathways targeted by these drugs may be better candidates. are not sufﬁciently conclusive to deny eligible patients a trial of AZA or DEC and AZA (which is metabolized into DEC intracellularly) DEC based on their predictions alone.5,6 Better biomarkers of response inhibit DNA methyltransferases and decrease the methylation of cytosine residues. Several the most genes in to HMAs needed. are the only class of drugs apSince the FDA approval ofofAZA andfrequently DEC, ourmutated understanding hypomethylating agentsare(HMAs)

Introduction

of DNA proved for the treatment of patients with higher-risk myelodysplastic the molecular genetic basis for MDS has expanded dramatically. somatic mutations have been identified in more than 40 syndromes (MDS). Azacitidine (AZA) was approved by the Food and Recurrent Submitted June 17, 2014; accepted August 29, 2014. Prepublished online as The publication costs of this article were defrayed in part by page charge Firstfor Edition paper, 15,was 2014;later DOI 10.1182/blood-2014-06payment. Therefore, andmutated solely to indicate fact,been this article is herebywith many of these genesthis have associated Drug AdministrationBlood (FDA) MDS inSeptember 2004 and shown to genes, and marked “advertisement” in accordance with 18 USC section 1734. 7-9 582809. important clinical measures including overall survival. confer an overall survival benefit compared with supportive care in Because 2014 by The Americanthe Society of Hematology online 1version of this article contains data supplement. a randomized phase The 3 study. mutated© genes underlie pathogenic mechanisms driving the Decitabine (DEC), thea deoxynucleotide initiation and progression of MDS, they may represent molecular analog of AZA, was approved for the treatment of MDS in 2006 based biomarkers of drug sensitivity or resistance. This is exemplified on its ability to improve blood counts and decrease bone marrow blasts BLOOD, 23 OCTOBER 2014 x VOLUME 124, NUMBER 17 2705 by the observation that MDS with deletions of the long arm of proportions.2 However, only 40% to 50% of patients treated with either chromosome 5 (del[5q]) have a striking sensitivity to lenalidomide, AZA or DEC experience hematologic improvement (HI) with these whereas MDS patients without this lesion are less likely to have agents, and complete responses (CRs) occur in as few as 10% to 15% of a hematologic response and are much less likely to have a cytogenetic treated patients.3,4 Effective methods for identifying patients who are or prolonged response.10 No such cytogenetic correlate has been most likely to respond to treatment with an HMA would be of immediate clinical utility. Clinical features and patient characteristics may found for the HMAs, but single-gene mutations involving the help stratify patients according to their response rates, but these models pathways targeted by these drugs may be better candidates. are not sufficiently conclusive to deny eligible patients a trial of AZA or DEC and AZA (which is metabolized into DEC intracellularly) 5,6 DEC based on their predictions alone. Better biomarkers of response inhibit DNA methyltransferases and decrease the methylation of cytosine residues. Several of the most frequently mutated genes in to HMAs are needed.

•  N=213, 40 genes

Figure 4. Kaplan-Meier curves for overall survival in the 146 out of 213 study patients with survival data. (A) Survival of patients with and without TET2 mutations. (B) Survival of patients with and without TP53 mutations. (C) Survival of patients with and without PTPN11 mutations. (D) Survival of complex karyotype patients with and without TP53 mutations vs patients without complex karyotypes.

techniques, we were able to identify mutations in .90% of patients

mutations in comutated patients (Figure 2C). The acquisition of

Submitted June 17, 2014; accepted August 29, 2014. Prepublished onlinesimilar as to The publication costs studies of this article secondary were defrayed page mutations in (of part whichby ASXL1 wascharge the most frequent) in patterns those seen in prior multigene of MDS. Blood First Edition paper, September 15, 2014; DOI 10.1182/blood-2014-06Therefore, and etsolely indicate thismore fact, this progressive article isdisease hereby indicate clonally that might be Our ﬁndings are payment. consistent with those of Itzykson al, whoto could more resistant to treatment. previously reported that 11 of 13 (85%) MDS patients TET2 inherently marked “advertisement” inwith accordance with 18 USC section 1734. 582809. The online version of this article contains a data supplement.

BLOOD, 23 OCTOBER 2014 x VOLUME 124, NUMBER 17

The mechanism by which TET2 mutations might influence mutations detected by Sanger sequencing responded to treatment to HMAs is not clear. Altered methylation has been obwith AZA compared©with a 52% rate for their overall of response 2014 by response The American Society Hematology cohort of 86 patients. In that study, mutations in other genes were served in patients with TET2 mutations and in animal models of Tet2 loss. However, measurement of pretreatment DNA methylation not examined, and small subclonal TET2 mutations likely went undetected. Our broader and more sensitive multigene analysis by itself has not been found to be predictive of response to HMAs.22 similarly identified TET2 mutations as predictive of response to In our murine bone marrow transplant experiment, exposure to AZA HMAs in a larger cohort of patients. Surprisingly, consideration of preferentially decreased the clonal advantage associated with loss 2705 mutations in other genes did not reveal additional predictors of of Tet2 function. This effect may be associated with a greater AZA favorable response, and inclusion of low VAF mutations weakened sensitivity in more actively cycling cells because AZA results in the association between TET2 mutation status and response rate. cell division–dependent passive demethylation of DNA. Mice with However, our approach identified the 10% of patients with mu- hematopoietic Tet2 loss are known to have increased myeloid tated TET2 and WT ASXL1 as the group most likely to respond to progenitor proliferation.19,23-25 treatment. Potential explanations for this finding include partial An important finding of our study was that no pattern of mutation resistance to HMAs caused by ASXL1 mutations. In this model, the was strongly associated with a lack of response to treatment. ASXL1-mutated subclone would be expected to grow in size during Responses to HMAs were observed even in patients with mutations disease progression, or relapse, and might confer primary rethat confer a very poor prognosis. Therefore, our data indicate that sistance. ASXL1-mutated patients with WT TET2 did have a lower mutation information alone should not be used as a basis for denying likelihood of response, but this was not statistically significant therapy with an HMA if treatment is indicated. Studies examining (OR 0.63 [0.35-1.15], P 5 .13). Alternatively, we observed that samples collected at multiple time points are needed to identify muASXL1 mutations were often subclonal or at a lower VAF than TET2 tations predictive of acquired resistance or relapsed disease.26-28

Indicaciones de hipometilantes en los SMD •  •  •  •  •  •  •  •

Study of three alternative dosing schedules of azacitidine in MDS (Lyons, JCO, 2009) Phase II, prospective, multicenter, randomized, open-label, 3-arm trial

Screening

Cycle 1-6 AZA 5-2-2 75 mg/m2 SC

Day -21 to -1

AZA 5-2-5 50 mg/m2 SC

AZA 5 75 mg/m2 SC q 28 or 42 days

AZA 5 75 mg/m2 SC Initial randomization

Repeat cycle every 28 days

Maintenance randomization

Lyons, ASH 2007

azacitidine has been shown to delay disease progression, increase red blood cell (RBC) transfusion independence and enhance quality of life compared with supportive care in patients with MDS [2,3]. Azacitidine has been approved by the European Medicines Agency and the Food and Drug Administration for the treatment of MDS (for int-2-/high-risk MDS and belonging to all five French–American–British subgroups of MDS, respectively). As azacitidine becomes integrated into standard clinical practice for the treatment of MDS, the focus of research will shift towards further optimisation of clinical outcomes and effective management of adverse events (AEs). To this end, a few studies have assessed the efficacy and safety of alternative dosing schedules of azacitidine which could potentially eliminate the requirement for weekend dosing [4,5]. To date, however, the only regimen proven to extend survival compared with CCR is the approved schedule of 75 mg/m2 /day for seven continuous days every 28 days. Here we report the case of a 75-year-old man with MDS, who was initially treated with a 5-day schedule of azacitidine (100 mg/day for five days every 28 days) and was subsequently switched to the approved 7-day dosing schedule following disease progression.

Azacitidine in a patient with myelodysplastic syndrome: Impact of switching from a 5-day to the approved 7day dosing schedule .

Voso MT, Fianchi L, Criscuolo M, Greco M, D'Alo F, Hohaus S, Pagano L, Leone G. Leuk Res. 2012 2. Case report

A 75-year old male Caucasian patient was referred to our hospital in June 2007 with anemia and asthenia. Comorbidities included hypertension and hypercholesterolemia. At presentation, hemoglobin (Hb) level was 9.8 g/dL, mean corpuscular volume (MCV) was 103 fL, platelet count was 219 × 109 /L, white blood cell (WBC) count was 2.7 × 109 /L and the absolute neutrophil count (ANC) was 1.4 × 109 /L (Fig. 1). The percentage of BM blasts was 2%. Standard metaphase cytogenetics analysis revealed an intermediate-risk karyotype (Table 1). Based on these observations, the patient was diagnosed with International Prognostic Scoring System (IPSS) int-1-risk MDS. 0145-2126/$ – see front matter © 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.leukres.2011.08.010

Fig. 1. Blood and bone marrow blast counts of a 75-year-old male with referral in June 2007–March 2010.

From diagnosis, the patient was observed for five mo November 2007 he complained of persistent asthenia. A fu count showed Hb level of 9.6 g/dL, MCV of 107 fL, platele of 296 × 109 /L, WBC of 3.0 × 109 /L and ANC of 1.4 × 109 /L Treatment with erythropoietin (EPO) and folic acid was i In July 2008, the patient became RBC transfusion depen RBC units/month). There was a deterioration in Hb level (7 WBC count (2.5 × 109 /L), and ANC (0.9 × 109 /L; Fig. 1). T was 106 fL. The BM aspirate revealed an increased blast co and trilineage dysplasia. The patient was reassessed as hav int-2-risk MDS and classified as refractory cytopenia with m eage dysplasia according to WHO classification. EPO treatm halted and a 5-day schedule of azacitidine was initiated wit dose of 100 mg/day s.c. from days 1 to 5 of a 28-day cycle cycles disease activity was stable with persistent bilinear cy and BM blast count of 4%; therefore, treatment was contin In September 2009, following 11 cycles of the 5-day sch azacitidine, there was further deterioration in Hb level (7 WBC count (2.0 × 109 /L) and ANC (0.6 × 109 /L; Fig. 1). The B count was 5%, and karyotype was normal (Table 1). In ber 2009, the patient consented to a switch to the approv and schedule of 75 mg/m2 /day from days 1 to 7 of a 28-da In March 2010, following three cycles of the 7-day sch azacitidine, the patient presented a considerable improve anemia. Transfusion independence was achieved after two standard-dose azacitidine [Hb, 9.7 g/dL; MCV, 96 fL; WBC, 3 cells/L; and ANC, 2.0 × 109 cells/L (Fig. 1)]. The platelet co 229 × 109 /L. The BM aspirate was hypocellular, with dyspla tures in the granulocytic and megakaryocytic lineages, and

ure, dysplasia, and increased risk of developing acute myeloid leukemia (AML). Patients with untreated higher-risk disease (International Prognostic Scoring System [IPSS] intermediate (Int)-2-/high risk) have a poor prognosis with a median survival of approximately 1 yr or less. The hypomethylating agent therapy (HMT), azacitidine (Vidaza!, Celgene Corporation, Summit, NJ), improves survival vs. conventional care regimens in higher-risk MDS. Azacitidine treatment is also associated with delayed disease progression, reduced transfusion requirements, and enhanced quality of life (1). Azacitidine is usually well tolerated in very elderly patients (2) and patients with signiﬁcant comor-

cell transplantation (SCT). Azacitidine is also indica patients with World Health Organization (WHO)AML (20–30% blasts) and chronic myelomonocytic mia (CMML) (4). Several treatment cycles may be required before p respond to azacitidine. In the phase III AZA-001 tria of responders achieved their ﬁrst response within six Of these patients, 48% achieved improved response continued dosing after the ﬁrst response (5). Moreov minating treatment in responding patients may quick to the return of aberrant promoter methylation an silencing, resulting in accelerated relapse (5). It is imp

median 10 treatment cycles (range, 5–31) Reasons for treatment discontinuation included comorbidities, infections, and patient choice… » Following cessation of HMT, 77% patients progressed after a median 5.4 months (range, 1.2–27.1), a median 13.2 months (range, 2.6–38.3 months) after achievement of best response.

Manuscript

azacitidine, are first-line treatment in higher-risk myelodysplastic syndromes (MDS) and are also commonly used in elderly acute myeloid leukemia (AML) patients [1–6]. In contrast to conventional induction-consolidation chemotherapy in AML, for which the role of maintenance therapy is not yet accepted [7], HMA therapy in MDS and AML is currently

Corresponding Author: Guillermo Garcia-Manero, Department of Leukemia, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77025, ggarciam@mdanderson.org. Conflict of Interest: The authors report no conflict of interest.

•  16 higher-risk MDS (n=5) or AML (n=11) who achieved PR (n=1) or CR (n=15) and stopped HMA therapy while in response •  They received a median of 12 courses (range 1–24) •  Loss of response after discontinuation of therapy was rapid, with a median progression-free survival of 4 months

Indicaciones de hipometilantes en los SMD •  •  •  •  •  •  •  •

AZA 001:Azacitidina actua de manera lenta •

response after 2 to more than 6 cycles

•  Continuing treatment improves responses in 48% of the cases

1.0

Probabilité cumulée

0.9 0.8

87% (6 cycles)

0.7 0.6 0.5 0.4

50% (2 cycles)

0.3

Extrêmes : 1-22 cycles

0.2 0.1 0 0

Nombre de cas : 91

Temps (cycles) :

Abs 227 – CO – L R SILVERMAN et al.

1. Introduction Patients with higher-risk myelodysplastic syndromes (MDS) have a high likelihood of transforming to acute myeloid leukemia (AML) and an overall survival (OS) measured in months. The primary goal of therapy in these patients is to alter the natural course of the disease [1–3]. The DNA methyltransferase inhibitors azacitidine (AZA) and decitabine (DAC) are considered first-line therapies, with AZA having demonstrated an improvement in overall sur-

∗ Corresponding author at: Department of Hematologic Malignancies, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Dr, Tampa, FL 33612, United States. E-mail address: Rami.komrokji@moffitt.org (R.S. Komrokji).

vival compared to conventional care regimens, at a median of 24.5 months vs. 15.0 months, respectively, in the AZA-001 study [4,5]. This impact on survival was observed in AZA-treated patients despite relatively low response rates (complete remission (CR) 17% and partial remission (PR) 12%) [6]. A subsequent analysis of the AZA-001 trial showed that treatment with AZA can prolong OS even in patients who did not achieve a CR or PR [7], raising the question of whether achieving a CR should be a therapeutic goal [8]. Furthermore, AZA-treated patients achieving a hematologic improvement (HI) or better had a 95% reduction in the risk of death compared to patients treated with conventional care (hazard ratio.05 [95% CI: .01–.43], P = .006) [9]. The decision of when to continue higher-risk MDS patients on AZA or DAC to maximize their chance of response, or of concluding that a response is unlikely to occur and switching to another agent,

Please cite this article in press as: A. Nazha, et al., Outcomes of patients with myelodysplastic syndromes who achieve stable disease after treatment with hypomethylating agents, Leuk Res (2015), http://dx.doi.org/10.1016/j.leukres.2015.12.007

•  291 patients treated with AZA or DAC •  Among patients with SD at 4–6 months, 29 (20%) achieved a better response at a later treatment time point •  Patients with SD who subsequently achieved CR had superior OS compared to patients who remained with SD (28.1 vs. 14.4 months)

AZA 001 trial:Secondary Endpoints: IWG (2000) CR,PR and HI

Response Overall (CR+PR)

CR PR IWG HI Major+Minor

AZA N=179 (%)

29 17 12 49

Proportion of patients surviving

AZA-001: 2-year OS with azacitidine by best response (IWG 2000) (Gore, 2012) 1.0 78.4% 71.7%

0.8 0.6

HI CR

0.4 CCR

0.2 0

Time from randomisation (months) IWG = International Working Group; HI = haematological improvement PR = partial response; CR = complete response

Adapted from List AF, et al. Oral presentation at ASCO 2008, Chicago, IL [abstract 7006]

Received 16 June 2011; accepted for publication

0·2

6 September 2011 Correspondence: G. Huls, Department of Haematology, University Medical Centre Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands. E-mail: g.huls@int.umcg.nl

ª 2011 Blackwell Publishing Ltd, British Journal of Haematology

Fig 4. Absolute platelet increase in patients who had at least a doubling of platelet count after the first azacitidine cycle. Fourteen patients had at least a doubling of their platelet count at start of the second cycle of azacitidine treatment compared to the start of the first cycle. Twelve patients started with platelet counts below 100 · 109/l and after one azacitidine cycle 7 of 14 patients had platelet counts above 100 · 109/l.

In conclusion, treatment with azacitidine is effective in routine daily clinical practice in patients with variable risk groups of MDS, CMML and AML. An at least two-fold increase in platelet counts after the first cycle of ª 2011 Blackwell Publishing Ltd, British Journal of Haematology

0·0

distribution, and reproduction in any medium, provided the original author and source are credited.

ABSTRACT 0 4 8

P = 0·003

Time since start azacitidine treatment (months)

the– efficacy of decitabine to myelodysplastic syndrome (MDS), there is a N group 1: 13 11 9 Despite 5 – N group 2: 54 41 29 17 3 2 wide and no definite predictive marker has been identified. This N group 3: 7 6 4 range 1 of responses, 1 – 9 5 5 1 – – N group 4: study aimed to describe the efficacy of decitabine and to identify potential predictors doi:10.1111/j.1365-2141.2011.08893.x Fig. 5. Validation of Itzykson’s prognostic scoreand (Itzykson et al 2011a) in patients with MDS. We retrospectively analyzed clinical of response survival for Overall Survival. (A) The score was computed for each patient, data of MDS patients at Samsung Medical Center between August 2008 and August assigning one point to: performance score ‡2, presence of circulating 2011. The response assessment was conducted using the International Working Group blasts, RBC transfusion dependency of ‡4 u/8 weeks and intermediate risk cytogenetics; assigning two points to poor riskcriteria cytogenetics.for MDS. We analyzed 101 MDS patients (total 613 cycles) (IWG) response Patients were segregated into three risk groups: low (score 0), interreceived decitabine for a median of four cycles. The overall response was 52.5% mediate (score 1–3), andwho high (score 4–5) risk groups. According to Van der Helm, this risk score, 13 patients had= low53/101). risk, 61 patients The had intermediate (n median time to any response was two cycles with the median risk and nine patients BJH, had high risk2011 scores. (B) The intermediate risk overall survival 16.7 months. Patients who showed hematologic improvement had group was divided into patients with and without anof at least two-fold increase in platelet (PLT)significantly count after the first cycle of azacitidine. longer survival than those who did not (9.8 vs. 22.9 months, p = 0.004). The difference in OS was evident in the Intermediate-2/High risk group (p = 0.002) azacitidine treatment predicted longer OS and may be a useful not inoutcome the Intermediate-1 risk group (p = 0.145). Multivariate analysis confirmed early indicator for but a favourable of azacitidine that platelet response (no platelet transfusions for at least 3 days) during the second treatment. cycle of treatment was an independent predictor for response, OS and Leukemia free survival. Based on the results of this study, for patients with hematological Authorship and disclosure improvement, recovery of platelet count by the second cycle of therapy can be used LvdH collected the data, analysed and interpreted the data, as anand early of improved survival and an increased response rate. performed statistical analysis wrotepredictive the manuscript,marker CA collected data, PWW, MvMK, RS, BJB, AB, MH, BvR, OdW, JW, EJL, SALdB, MM, REB, FCdB, ME, AJ and AAvdL INTRODUCTION enrolled patients and collected the data, JK provided the medicine for study, NV performed statistical analysis, EV

International Prognostic Scoring System (IPSS) remains the most widely used prognostic system for therapeutic decisions. The IPSS advises the use of supportive care with transfusion and growth factor supplementation as treatment in lower risk groups of patients. Allogeneic stem cell transplantation is the only curative treatment for the high risk group; however, in the post-epigenetic therapy era, treatment approaches for patients with MDS have improved significantly. Specifically, hypomethylating agents improve the transfusion requirement and quality of life while decreasing leukemic transformation and survival. Azacitidine [1-3] and decitabine [4-6] are currently the two available agents with the capacity to

Myelodysplastic syndromes (MDS) are a group of clonal hematopoietic disorders marked 7 by ineffective hematopoiesis, peripheral cytopenias, and an increased risk of transformation to acute myeloid leukemia. MDS is associated with a wide array of clinical manifestations and treatment outcomes. MDS treatment is based on prognostic factors that predict survival and likelihood of progression to AML. Currently, development of prognostic systems that allow for risk stratification and that can guide the timing and choice of MDS therapy is needed. The www.impactjournals.com/oncotarget

16653

Oncotarget

Cytogene?c Response and OS M Sébert, submitted •  Landmark analysis at 3 months •  Comparing achievement of Cytogenetic responses or not - in pts with IWG 2006 response - in pts without IWG 2006 response

0.75

1.00

Kaplan-Meier survival estimates

0.00

0.25

0.50

P= ns

40 60 analysis time CyR = yes

80 CyR = No

100

leukaemia. We describe a comprehensive analysis of the mutational landscape of these tumours, combining whole-exome and whole-genome sequencing. We identify an average of 14±5 somatic mutations in coding sequences of sorted monocyte DNA and the signatures of three mutational processes. Serial sequencing demonstrates that the response to hypomethylating agents is associated with changes in DNA methylation and gene expression, without any decrease in the mutation allele burden, nor prevention of new genetic alteration occurence. Our findings indicate that cytosine analogues restore a balanced haematopoiesis without decreasing the size of the mutated clone, arguing for a predominantly epigenetic effect.

1 INSERM U1170, Gustave Roussy, 114, rue Edouard Vaillant, 94805 Villejuif, France. 2 Department of Hematology, Gustave Roussy Cancer Center, 114, rue Edouard Vaillant, 94805 Villejuif, France. 3 INSERM US23, CNRS UMS3655, Gustave Roussy, 114, rue Edouard Vaillant, 94805 Villejuif, France. 4 Department of Pathology, University of Michigan Medical School, 1500 E Medical Center Dr, Ann Arbor, Michigan 48109, USA. 5 Department of Pathology and Tumour Biology, Kyoto University, Yoshida-Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan. 6 Universite´ Lyon 1, UMR CNRS 5558, Universite´ Claude Bernard, 16 rue Raphael Dubois, Lyon 69100, France. 7 Centre León Be´rard, INSERM U1052, CNRS UMR5286, 8 Prom. Leá et Napoleón Bullukian, 69008 Lyon, France. 8 Department of Hematology, Assistance Publique–Ho ˆpitaux de Paris, Hoˆpital Saint-Louis, 1 Avenue Claude Vellefaux, 75010 Paris, France. 9 Department of Hematology, Assistance Publique–Hoˆpitaux de Paris, Hoˆpital Avicenne, 125 Rue de Stalingrad, 93000 Bobigny, France. 10 Cancer Research Institute de Lille, INSERM U837, 1 Place de Verdun, 59000 Lille, France. 11 Institut de me´decine re´geńe´ratrice, Biothe´rapie et Institut de biologie computationnelle, INSERM U1040, Universite´ de Montpellier, 80 avenue Augustin Fliche. 34295 Montpellier, France. 12 Department of Hematology, Centre Hospitalier Universitaire de Nıˆmes, Universite´ Montpellier-Nıˆmes, 4 Rue du Professeur Robert Debre´, 30029 Nıˆmes, France. 13 Laboratory of Genome Informatics, Kinghor Center for Clinical Genomics, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst New South Wales 2010, Australia. 14 Centre National de Geńotypage, 2 rue Gaston Cre´mieux CP 5721, 91 057 Evry, France. 15 Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire CB10 1SA, UK. 16 Theoretical Biology and Biophysics, Los Alamos National Laboratory, P.O. Box 1663, Los Alamos, New Mexico 87545, USA. 17 Center for Nonlinear Studies, Los Alamos National Laboratory, P.O. Box 1663, Los Alamos, New Mexico 87545, USA. 18 Department of Hematology, Malignant hematology, H. Lee Moffitt Cancer Center, 12902 USF Magnolia Drive, Tampa, Florida 33612, USA. 19 Department of Biostatistics, Gustave Roussy Cancer Center, 114 rue Edouard Vaillant, 94805 Villejuif, France. 20 Department of Hematology, Faculty of Medicine, University Paris-Sud, 63 Rue Gabriel Pe´ri, 94270 Le Kremlin-Biceˆtre, France. * These authors contributed equally to this work. Correspondence and requests for materials should be addressed to E.S. (email: eric.solary@gustaveroussy.fr).

NATURE COMMUNICATIONS | 7:x | DOI: 10.1038/ncomms10767 | www.nature.com/naturecommunications

•

response to HMAs is associated with changes in DNA methylation and gene expression, without any decrease in the mutation allele burden, nor prevention of new genetic alteration occurence. HMAs restore a balanced haematopoiesis without decreasing the size of the mutated clone, arguing for a predominantly epigenetic effect.

Indicaciones de hipometilantes en los SMD •  •  •  •  •  •  •  •

Manejo de los efectos secundarios con hipometilantes •  Efectos secundarios locales con AZA •  citopenias (especialmente during los primeros 1 a 3 ciclos): –  Anemia y trombopenia : transfusiones •  Nivel de Hb y plaquetas para empezar trasfusiones? •  Trombopenia: agonistos del receptor de TPO ?

–  Neutropenia con fiebre •  G-CSF profilactico ? •  profilaxis con antibioticos o antifungales?

Predicting infections in high-risk patients with MDS/AML treated with azacitidine: A retrospective multicenter study D Merkel

Am J Hemat, 2013

•

153 infectious events during 928 treatment cycles (16.5%) administered to 100 patients •  114/153 (75%) events required hospitalization and 30 (19.6%) were fatal •  In multivariate analysis, only low Hb level, low PLT count, and unfavorable cytogenetics remained significant. « …Patients with poor cytogenetics in whom AZA is prescribed despite low PLT count are particularly at high risk for infections and infection prophylaxis may be considered… »

4%, p= 0.251) were similar in PRO+ and PRO- pts. Moreover, among pts with baseline ANC<1G/L, there was a trend for a lower incidence of deaths due to infection in PRO+ than in PRO- (11% v 30%, p=0.076). PRO+ pts had a higher probability of receiving >= 6 cycles of AZA (76 vs 61% in PRO-pts, p=0.04). Median OS was 22.6 months in PRO+ and 15.7 months in PRO- pts (p=0.17). Conclusion :Baseline ANC was the only factor significantly influencing the incidence of hospitalization in ICU for infection and the risk of fatal infection in MDS treated with AZA. In this comparison, primary anti infectious prophylaxis (PRO+) was not associated with a clear reduction in the incidence of infections requiring https://ash.confex.com/ash/2012/cop/papers/viewpaper.cgi?Re…8865&Hash=d7f3eed922ff7eaeafd96e622775fcc9&password=818205

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•  Prophylactic treatment with levofloxacine- posaconazole •  During the 6 first cycles •  Prospective studies needed

Blood (print ISSN 0006-4971, online ISSN 1528-0020), is published weekly by the American Society of Hematology, 2021 L St, NW, Suite 900, Washington DC 20036. Copyright 2011 by The American Society of Hematology; all rights reserved.

Kantarjian H M et al. Blood 2010;116:3163-3170

ÂŠ2010 by American Society of Hematology

Effect of romiplostim on median platelet counts on day 1 of each treatment cycle (left panel) and on median platelet counts at nadir during each treatment cycle (right panel).

Kantarjian H M et al. Blood 2010;116:3163-3170

ÂŠ2010 by American Society of Hematology

ASH 2016 â&#x20AC;&#x201C; SUPPORT Thrombopoietin (TPO) receptor agonist eltrombopag in combination with azacitidine for primary treatment of MDS patients with thrombocytopenia: outcomes from the randomized, placebo-controlled, phase III SUPPORT study Michael Dickinson,1 Honar Cherif,2 Pierre Fenaux,3 Moshe Mittleman,4 Amit Verma,5 Maria Socorro O. Portella,6 Paul Burgess,7 Uwe Platzbecker8

Indicaciones de hipometilantes en los SMD •  •  •  •  •  •  •  •

Histone deacetylase (HDAC) inhibitors Short-chain fatty acids (SCFA)

Butyrate derivatives, Valproic acid

Hydroxamic acids

Trichostatin A, SAHA (Vorinostat) LHB 589 Pyroxamide

Epoxyketone-containing cyclic tetrapeptides

Trapoxins

Non-epoxyketone-containing cyclic tetrapeptides

FK228, Apicidin

Benzamides

MGCD-0103, MS-275

Decitabine With or Without Valproic Acid in Patients With MDS and AML

Eligibility criteria: • MDS by FAB of any age • AML age > 60 • No good-risk AML • No prior high-dose chemotherapy • No prior decitabine > 1 cycle or azacitidine > 2 cycles

R A N D O M I Z E

Decitabine 20 mg/m2 IV/1 h daily days 1-5 q 4 weeks

Decitabine 20 mg/m2 IV/1 h daily days 1-5 q 4 weeks Valproic acid 50 mg/kg/day p.o. days 1-7 q 4 weeks

Issa et al Cancer, 2013

article. Clinical Trials repository link available on JCO.org. Corresponding author: Steven Gore, MD, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, 1650 Orleans St, Baltimore, MD 21231; e-mail: gorest@jhmi.edu. © 2014 by American Society of Clinical Oncology 0732-183X/14/3299-1/$20.00 DOI: 10.1200/JCO.2013.50.3102

INTRODUCTION

by DNA methyltransferase inhibitors (DNMTis), combination arm (in particular thromb

such as Total azacitidine decitabine. PostTreatment Fail (AZA) CNSRand Median influenced these results because the ob translational Until recently, no treatment has demonstrated a surAzacitidine 26modification 24 2 of histone 7.1 tails, such as logical normalization. The use of IWG deacetylation vival benefit for patients with myelodysplastic synAzacitidine + 26 or methylation, 24 2 are also 5.3 implicated in 7 1 Histone deacetylase the silencing of transcription. drome (MDS). A major breakthrough in our entinostat 0.8 today, more appropriate to evaluate c

1.0

Overall Survival (probability)

tions are found at the end of this

understanding of the physiopathology of these diseases has been the demonstration of the role of an impaired epigenetic 0.6 regulation in the progression of MDS to acute myeloid leukemia (AML)2-4 and resistance to conventional treatment.5 DNA promoter methylation downregulates expression of key genes 0.4 affecting cell fate through their impact on cell cycle or apoptosis.6 Such epigenetic marks can be reversed

inhibitors (HDACis, valproic acid, sodium phenylbutyrate, vorinostat, entinostat, and others) syner- profile by refining blood counts thresho gistically induce re-expression of genes whose or hematological improvement and in expression is silenced through promoter methylclearance (marrow CR) as a significan ation when administered in vitro after a DNMTi.8 AZA has become the treatment standard for the choice of HDACi by itself could be high-risk MDS since randomized trials demon- suggest a higher response rate with a c strated improved survival compared with standard

nostat in a phase I dose escalation trial tion data serves as one arm of the cur Information downloaded from jco.ascopubs.org and provided by at INSERM on April 10, 2014 from 193.54.110.33 Copyright © 2014 American Society of Clinical Oncology. All rights reserved. randomized phase II study in high risk M Copyright 2014 by American Society of Clinical Oncology differences between entinostat and vor 10 20 30 40 50 60 0 targets: entinostat specifically targets th Time (months) whereas vorinostat is a nonclass-selectiv deacetylases, as well as other protein d Fig 2. Kaplan-Meier representation of the azacitidine alone (arm A) and the azacitimg/m2/d given for 10 days entinostat 4with mg/m2/d day 3 These andother deacetylases a dine ! entinostat (arm B) regimens+/for overall population (A), patients myelodysthe nucleus. plastic syndrome and chronic myelomonocytic leukemia (B), and patients with acute this drug on P53 or Beta-catenin pathw myeloid leukemia (C). Survival is represented from the day of first administration of The possible correlation of SOCS treatment to the date of death or last follow-up. Arm A is in blue and arm B is in gold. CNSR, censored. 27% CR+PR in the AZA and AZA+ entinostat grouprate will need to be confirmed in addit larger series of patients but is in line wi impact of SOCS1 on myeloid neoplasm 2 of improved response after prolonged to AZA monotherapy, 50 mg/m /d for 10 days, was twice that obdoses of AZA will require direct compar served in the reference C9221 study, therefore fulfilling the efficacy dose regimen. The design of such a st criteria defined as the trial objective. A previous study had evaluated criteria as trial objectives considering different schedules of AZA aiming to demonstrate that shorter (5 strated in the AZA001 study. Regarding days) or more convenient schedules of AZA (5 days treated, weekend our cohort seemed shorter than the off, 2 days treatment: 5-2-2) can give hematologic response rates 25 notable differences in the compositio similar to those obtained with the conventional 7-day schedule. In 0.2

•  AZA 50 day 10. •  32% vs

www.jco.org

«Escoger el ganador » con AZA 5 AZACYTIDINE 75 mg/m2 x 7 jours VALPROIC ACID

5 AZACYTIDINE 75 mg/m2 x 7 jours

IDARUBICIN 5 AZACYTIDINE 75 mg/m2 x 7 jours REVLIMID 5 AZACYTIDINE 75 mg/m2 x 7 jours

6 cycles

North American Intergroup Randomized Phase 2 MDS Study S1117: Study Design

Higher-risk MDS or CMML

(IPSS >1.5 and/or blasts >5%)

AZA (IV/SC) 75 mg/m2/d (d1-7) N=92

Groups: SWOG, ECOG, Alliance, NCIC Total Sample Size: 276

AZA (IV/SC) + LEN (PO) 75 mg/m2/d (d1-7) + 10mg/d x 21d N=93

AZA (IV/SC) + Vorin (PO) 75 mg/m2/d (d1-7) + 300mg BID (d3-9) N=91

Primary Objective: 20% improvement of ORR (CR/PR/HI) based on 2006 IWG Criteria Secondary Objectives: OS, RFS, LFS Power 81%, alpha 0.05 for each combo arm vs. AZA 03/2012 â&#x20AC;&#x201C; 06/2014

Sekeres et al. ASH 2014: LBA - 5

Sekeres, M. et. al., 2014, American Society of Hematology Annual Meeting, Abstract LBA-5

Tratamiento de los SMD de riesgo alto •  •  •  •

Alo TPH Quimoterapia clasica (intensiva o no) Agentes hipometilantes Otros (en combinacion con hipometilantes, o como secunda linea)

3322

4,5 the gene expression ; and the histone tails modifitherapies had notthe demonstrated a this group was13conventional months, which was better than OS of patients after failure of decitabine, in which a median OS and 1-year probcations, which change the accessibility the reading clear survival benefit, (P and!standard of carechemused who received low-dose chemotherapy .05), intensive ability of survival were reported. Theof M.D. Anderson MDS scoring 13RNA polymerases.6 In addition to the funframe supportive transfusion and"growth factors, such otherapy (P ! .05), or palliative care (P .001). Interestingly, systemto predicted survival in that cohort. This score includes age, 2 damental role of epigenetic in physiologas erythropoietin. progresses to among the 17 patients re-treated withWhen DNMTdisease inhibitors (including bone marrow blast count,regulation and cytogenetics, which also had progical settings chromosome X inactivation), leukemia, prognosis clearly unfavorable, with 16 of 17 received decitabine), noneis of 10 evaluable patients nostic value (eg, in our series. The initial response toit AZA also had an appears these mechanisms are This involved in canimpact that on survival after failure. raises interesting issues reachieved complete or partial response, and the median was chemotherapy-resistant disease and an OS overall garding possibleand effects of AZA, including, suggested by others, a 11.8 months. survival (OS) of less than 1 year. cer pathogenesis progression in multipleasmod7 possible modification thethe MDS natural history.11,24 Finally, 37 patients were treated withadvances allogeneichave SCTbeen after els. In the hematology of field, DNMT inhibitors In(14%) past years, significant A variety of salvage regimens were administered a median of 5 months (range, 1 to 26 months) afterimplication AZA failure. azacitidine (AZA) and 2-deoxy-5-azacytidine (de- to patients in the made with the demonstration of the of current cohort, although information salvage treatment was Twenty-eight patients underwent transplantation up front (including citabine) have demonstrated clinicalregarding activity with epigenetic regulation in disease pathogenesis, espe3 missing for many of them. Outcome after any 14 with progressive disease), and nine underwent transplantation after cytologic and cytogenetic responses in patients withtype of treatment cially during disease progression. Epigenetic reguappeared better than supportive care, though, which possibly reflected one or more salvage treatments (including AML-like chemotherapy in patient selection. Allogeneic transplantation remained the option with seven patients and/or investigational agents in four patients). Their © 2011 by American Society of Clinical Oncology Information jco.ascopubs.org and provided by at INSERM 26, 2013with fromlong-term 193.54.110.33 the best outcome, survival in a substantial proportion mediandownloaded survival wasfrom 19 months and was significantly superior to that on November Copyright © 2011 American Society of Clinical Oncology. All rights reserved. of patients even if some patients underwent transplantation with proof other treatments. Five patients were alive greater than 3 years after gressive disease. Of note, we were not able to analyze the choice of transplantation. The median OS of the 14 patients who underwent conditioning regimen, which plays an important role for patients with transplantation with progressive disease after AZA was 17 months and MDS and AML.25 Likewise, the improved outcome with investigawas not reached in the 14 patients who underwent transplantation tional treatments (ITs) may in part reflect patient selection and closer with stable disease after AZA (P ! .08). monitoring associated with enrollment on clinical trials. These findings are also in line with the results from the M.D. Anderson experience after decitabine failure12,26 that showed response rates of 20% to 30% with IT, DISCUSSION which was comparable with results of intensive chemotherapy. Dedicated This report is the first to present the outcome of a large series of studies for each type of treatment will be necessary to refine the response patients with MDS patients who were treated with AZA and whose rates and prognosis factors associated with each group of patient. This will disease failed to respond or progressed after an initial clinical also include studies for patients with low-risk MDS and de novo AML, response. This work is based on the compilation of four data sets, two indications for which AZA is currently increasingly used.27-30 including three clinical trials and the French AZA compassionate Finally, this study is also important in the perspective of designuse program. The median OS of 5.6 months for high-risk MDS ing future clinical trials in this population. We suggest that the survival confirmed the poor outcome of these patients. The results of our of patients treated with palliative care (median OS, 4.1 months; 1-year multivariate model showed that simple clinical and biologic charprobability of OS, 17%; 95% CI, 14.3% to 26.1%) should be considacteristics, including age, sex, cytogenetics, initial bone marrow ered as the most relevant reference, because no standard treatment is blast count before AZA, and initial response to AZA, can predict currently available.

3326

JOURNAL

CLINICAL ONCOLOGY

Corresponding author: Elias Jabbour, MD, Department of Leukemia, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd., Box 428, Houston, TX 77030; Fax: (713) 794-4297; ejabbour@mdanderson.org Department of Leukemia, The University of Texas M. D. Anderson Cancer Center, Houston, Texas DOI: 10.1002/cncr.25247, Received: October 1, 2009; Revised: November 13, 2009; Accepted: December 21, 2009, Published online May 17, 2010 in Wiley InterScience (www.interscience.wiley.com)

3830

Cancer

August 15, 2010

Cancer 2010

median survival 4.3 months, 12-month survival rate 28%.

have completed a regular peer review and have been accepted for publication. E-publishing of this PDF file has been approved by the authors. After having E-published Ahead of Print, manuscripts will then undergo technical and English editing, typesetting, proof correction and be presented for the authors' final approval; the final version of the manuscript will then appear in print on a regular issue of the journal. All legal disclaimers that apply to the journal also pertain to this production process.

Table 2: Prognostic factors at the time of hypomethylating agent failure Parameter at HMA failure

Score

Beta

P-Value

ECOG Performance status > 1

1.0

.56

.01

Very poor Cytogenetic Category

1.0

.57

< .001

> 75 - < 84

1.0

.52

< .001

> 84

Age at diagnosis, years

•

2.0

.90

< .001

Bone Marrow Blast > 20 %

.75

.36

.01

Transfusion dependent (yes vs no)

.75

.39

< .001

1.0

.54

< .001

455 higher-risk disease with HMA failure; 314 (69.0%) were treated with AZA and 141 (31.0%) with DAC •  6 factors predictive of OS at the time of HMA failure •  The new model (the post HMA model) identified two risk groups: Low: score < 2.25, median OS 11.0 months high: score > 2.25 and median OS 4.5 months Platelets

< 30

Higher risk MDS:second (or greater) line treatment: single agents •  Low dose Clofarabine (T Braun, C Gardin) 26% responses (ASCO 212)

•  Erlotinib (S Thépot) 15% responses, Berlin MDS-F meeting 2013

•  SGI 110 (Decitabine prodrug) (M Sébert) •  Phase III Rigosertib versus BSC or LD araC(Onconova)

Patients with myelodysplastic syndromes are categorised into risk groups according to the International Prognostic Scoring System (IPSS)5 or the Revised IPSS (IPSS-R) criteria.6 The IPSS-R combines five prognostic variables (cytogenetics, bone marrow blasts, haemoglobin, platelets, and neutrophils) for the overall categorisation of mortality risk. Over the past decade, hypomethylating drugs have become the standard of care for patients with high-risk myelodysplastic syndromes (defined as 5–30%

who have treatment failure with hypomethylating drugs, Dana Farber Cancer Institute, including primary failure (no response or progression Boston, MA, USA during treaatment) and secondary failure (relapse after (D P Steensma MD); University of Kansas Medical Center, response), is 4–6 months.7,10,12 National Comprehensive assessment from the KS, analysis. Westwood, USA We analysed transformation 1 13 time to acute myeloid leukaemia by the Kaplan-Meier Cancer Network guidelines and clinical trials suggest (S Kambhampati MD); with data censoredzuatKöln, the last bone marrow that, in the absence of progression, patients treated method, with Universitätsklinikum assessment for any patient with no bone marrow blast Klinik I für Innere Medizin, a hypomethylating drug, such as azacitidine, should count of more than 30%, and at randomisation for any Köln, Nordhein-Westfalen, had no follow-up bone marrow assessment. receive up to nine cycles of treatment to maximisepatient the who Germany (Prof K-A Kreuzer MD); We summarised the incidence of treatment-emergent likelihood of response. No drug has been shown to bleeding and infections by severity.

www.thelancet.com/oncology Published online March 8, 2016 http://dx.doi.org/10.1016/S1470-2045(16)00009-7

A 100

Rigosertib Best supportive care Hazard ratio 0·87 (95% CI 0·67–1·14); p=0·33

Overall survival (%)

80 60 40 20 0

Number at risk Rigosertib 199 Best supportive 100 care

157 71

114 47

86 35

52 19

29 14

11 8

7 3

4 2

3 1

1 0

B Hazard ratio 0·72 (99% CI 0·46–1·13); p=0·060

100

Median OS 8.2 months in the rigosertib group vs 5.9 months (p=0·33).

Overall survival (%)

80 60 40 20 0

Number at risk Rigosertib 127 Best supportive 57 care

102 39

78 26

56 18

37 9

19 6

9 3

6 2

3 2

2 1

1 0

C 100

Hazard ratio 0·61 (99% CI 0·36–1·03); p=0·015

Overall survival (%)

Role of th

60 40 20 0

Number at risk Rigosertib Best supportive care

2 0

1 0

Time from randomisation (months) 93 41

71 21

52 9

38 5

19 3

8 3

2 2

2 0

Figure 2: Overall survival curves for the rigosertib group and best supportive care group (A) For the intention-to-treat population, (B) patients with primary hypomethylating drug failure, and (C) patients with IPSS-R very high risk. IPSS-R=Revised International Prognostic Scoring System.

We tes survival a treatment We reject interactio in interpr because a and poss regression determine of treatme We gen treatment the model diagnosis bone ma concentra number o 8 weeks o We test response Haenszel We did overall su hypometh during or drug tre failure ( previous h previous abnormal classificat published spectively prognosti best supp was outsi We used for the s SAS (vers The pro study is re

Onconova and the c data, and Lymphom writing of access to submit fo

Results

Between 299 patien 100 were a population

www.thelancet.com/oncology Published online March

Higher risk MDS:second (or greater) line treatment: « add on approach » •  AZA+ Vorinostat (T Prébet, N Vey) •  AZA+ LDE 225 (Anti SMO) (T Prébet, N Vey)

«Escoger el ganador » despues del fracaso de HMA: cooperacion internacional Continuar AZACiTIDINA 75 mg/m2 x 7 d

Tratamiento de soporte

Droga B

AZACITIDINA

+ Droga A

Grupo Francofono de las Mielodisplasias •  Activa ensayos clinicos en los SMD (35 centros en Francia y Belgica Suiza, Tunisia) •  Website: www. gfmgroup.org •  Registro Online de los SMD franceses •  Estrecha cooperacion con: - una asociacion de pacientes con SMD - la International MDS Foundation - el European Leukemia Net

Poor prognosis of TP53/p53 mutations with all available treatments TP53 mutations and results of AZA in MDS (Bally,Leuk Res, 2013)

VOLUME 32 ! NUMBER 25 ! SEPTEMBER 1 2014

JOURNAL OF CLINICAL ONCOLOGY Blood (print ISSN 0006-4971, online ISSN 1528-0020), is published weekly by the American Society of Hematology, 2021 L St, NW, Suite 900, Washington DC 20036. Copyright 2011 by The American Society of Hematology; all rights reserved. R E P O R T

0.75

Rafael Bejar, Kristen E. Stevenson, Bennett Caughey, R. Coleman Lindsley, Brenton G. Mar, Petar Stojanov, Gad Getz, David P. Steensma, Jerome Ritz, Robert Soiffer, Joseph H. Antin, Edwin Alyea, Philippe Armand, Vincent Ho, John Koreth, Donna Neuberg, Corey S. Cutler, and Benjamin L. Ebert

Published online ahead of print at www.jco.org on August 4, 2014. Processed as a Rapid Communication manuscript Supported by National Institute of Diabetes and Digestive and Kidney Diseases Grant No. 5K08DK091360 and an American Society of Hematology scholar award (R.B.) and by National Heart, Lung, and Blood Institute Grant No. R01HL082945, a Leukemia and Lymphoma Society scholar award, and the Yellow Diamond Foundation Fund (B.L.E.). Terms in blue are defined in the glossary, found at the end of this article and online at www.jco.org. Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article. Corresponding author: Benjamin L. Ebert, MD, PhD, Brigham and Women’s Hospital, 1 Blackfan Circle, Karp CHRB 5.211, Boston, MA 02115; e-mail: benjamin_ebert@dfci.harvard.edu. © 2014 by American Society of Clinical Oncology 0732-183X/14/3225w-2691w/$20.00 DOI: 10.1200/JCO.2013.52.3381

Somatic Mutations Predict Survival After Transplantation for MDS

Patients and Methods We used massively parallel sequencing to examine tumor samples collected from 87 patients with MDS before HSCT for coding mutations in 40 recurrently mutated MDS genes. Results Mutations were identified in 92% of patients, most frequently in the ASXL1 (29%), TP53 (21%), DNMT3A (18%), and RUNX1 (16%) genes. In univariable analyses, only TP53 mutations were associated with shorter overall (OS; hazard ratio [HR], 3.74; P ! .001) and progression-free survival (HR, 3.97; P ! .001). After adjustment for clinical variables associated with these end points, mutations in TP53 (HR, 2.30; P " .027), TET2 (HR, 2.40; P " .033), and DNMT3A (HR, 2.08; P " .049) were associated with decreased OS. In multivariable analysis including clinical variables, complex karyotype status, and candidate genes, mutations in TP53 (HR, 4.22; P ! .001) and TET2 (HR, 1.68; P " .037) were each independently associated with shorter OS. Nearly one half of patients (46%) carried a mutation in TP53, DNMT3A, or TET2 and accounted for 64% of deaths. Three-year OS in patients without these mutations was 59% (95% CI, 43% to 72%), versus 19% (95% CI, 9% to 33%) in patients with these mutations. Conclusion Mutations in TP53, TET2, or DNMT3A identify patients with MDS with shorter OS after HSCT. J Clin Oncol 32:2691-2698. © 2014 by American Society of Clinical Oncology INTRODUCTION

Diagnosis and predicted prognosis of patients with myelodysplastic syndrome (MDS) are largely determined by morphologic and clinical measures.1,2 Recurrent somatic mutations, which are drivers of MDS pathogenesis and can be powerfully associated with clinical phenotype, are not currently incorporated into the routine clinical care of patients with this disorder.3,4 Somatic mutations are common in MDS, with # 75% of patients carrying " one abnormality in the 30 most frequently mutated genes.5-7 Abnormalities in specific genes, such as NRAS, RUNX1, and TP53, have been associated with prognostically important variables, including elevated bone marrow blast proportion and severe thrombo-

cytopenia.3 Therefore, it is likely that acquired mutations could also predict response to specific interventions, such as treatment with hypomethylating agents or survival after hematopoietic stemcell transplantation (HSCT).8 Calculation of risks, benefits, and timing of HSCT is often difficult in MDS.9-11 Older age and comorbidities typical of patients with MDS are frequently associated with unacceptable risk of early death after transplantation. Even in younger and generally healthier patients, deciding when HSCT is appropriate can be challenging. In particular, patients with poor prognostic features may be directed to transplantation because they have few treatment options available or because standard therapeutics are not expected to provide durable responses.

A Not complex (n = 59) Complex karyotype (n = 28)

Variable

Entire cohort (N ! 87) Genetic mutation (present v absent) TP53 TET2 Day-100 landmark analysis (n ! 72) 0 Karyotype (complex v other) Genetic mutation (present v absent) TP53 DNMT3A

P = .005

0.8 0.6 0.4 0.2

95% CI

" .001 .037

4.22 2.29

2.30 to 7.76 1.05 to 5.00

2.85

1.35 to 6.47

.013

3.78 2.62

1.81 to 7.89 1.15 to 5.96

" .001 .022

Abbreviations: HR, hazard ratio; OS, overall survival. ! Final model obtained from backward-elimination selection algorithm candidates included variables with univariable P " .20.

Time (months)

B 1.0

Not complex (n = 59) Complex and TP53 unmutated (n = 12) Complex and TP53 mutated (n = 16)

0.8 0.6 0.4 0.2

Time (months)

C 1.0

TP53 mutated (n = 18) TET2 mutated, no TP53 (n = 10) DNMT3A mutated, no TP53 or TET2 (n = 12) No TP53, TET2, or DNMT3A mutations (n = 47)

0.8 0.6 0.4 0.2

Table 3. Multivariable! Models Identifying Independent Significant Risk Factors for OS

1.0

0.00

Overall Survival (probability)

Benjamin L. Ebert, Brigham and Women’s Hospital, Harvard Medical School, Boston; Petar Stojanov, Gad Getz, and Benjamin L. Ebert, Broad Institute, Cambridge, MA.

Overall Survival (probability)

Alyea, Philippe Armand, Vincent Ho, John Koreth, Donna Neuberg, and Corey S. Cutler, Dana-Farber Cancer Institute; R. Coleman Lindsley and

Purpose Recurrently mutated genes in myelodysplastic syndrome (MDS) are pathogenic drivers and powerfully associated with clinical phenotype and prognosis. Whether these types of mutations predict outcome after allogeneic hematopoietic stem-cell transplantation (HSCT) in patients with MDS is not known.

Overall Survival (probability)

University of California at San Diego, La Jolla, CA; Kristen E. Stevenson, R. Coleman Lindsley, Brenton G. Mar, David P. Steensma, Jerome Ritz, Robert Soiffer, Joseph H. Antin, Edwin

0.50

Listen to the podcast by Dr Estey at www.jco.org/podcasts Rafael Bejar and Bennett Caughey,

OS selon les mutations de p53 (p =0.0054)

1.00

Somatic Mutations Predict Poor Outcome in Patients With Myelodysplastic Syndrome After Hematopoietic Stem-Cell Transplantation

0.25

O R I G I N A L

2691

Time (months)

TP53

TET2

DNMT3A

Fig 2. Overall survival (OS) by TP53 and DNMT3A mutation status. OS of patients (A) with and without complex karyotype and (B) with complex karyotype stratified by TP53 mutation status and compared with survival of patients with noncomplex karyotype; (C) OS and mutation distribution showing overlap between patients with TP53, TET2, and DNMT3A mutations. Each column indicates individual patient; colored bars represent mutations of genes in that row.

www.jco.org

these genes were found in nearly one half of patients in this cohort. Mutations of other genes associated with poor prognosis in prior studies, such as RUNX1, ASXL1, SRSF2, and U2AF1, were not associated with differences in OS in our cohort of patients who underwent HSCT (Data Supplement).3,22-24 This may have been the result of disease-modifying effects of conditioning and transplantation or because of the fact that the prognostic significance of these gene mutations is more pronounced in lower-risk patients, of whom there were few in this study. In contrast, TP53 mutations have independent prognostic value, even in higher-risk patients with MDS, in whom they are most commonly found.3,21 The DNMT3A and TET2 genes encode epigenetic modifiers that regulate DNA methylation, and both are recurrently mutated in MDS, acute myeloid leukemia, and other hematologic malignancies. In acute myeloid leukemia, mutations of both genes are enriched in patients with intermediate-risk karyotypes and are associated with poor prognosis.25,26 In MDS, the clinical significance of DNMT3A mutations is less clear but also seems to be unfavorable, whereas TET2 mutations are not associated with survival.5,7,18,19,27,28 Both TET2 and DNMT3A mutations are relatively promiscuous and often co-occur with other mutated genes that can predict outcomes. For example, in a study of lower-risk patients with MDS, DNMT3A mutations were not associated with OS in univariable analysis. However, the DNMT3A-mutant/SF3B1-wild-type subgroup did have shorter OS.19 In our transplantation cohort of largely higher-risk patients, SF3B1 mutations were rare, and most DNMT3A-mutant samples were SF3B1 wild type (88%). DNMT3A and TET2 mutations identified in pretransplantation samples were largely from patients without adverse clinical features known to predict poor outcome. Most of these patients did not have a complex karyotype and were not more likely to have an elevated bone marrow blast percentage before transplantation. Nevertheless, we found that patients with a TET2 or DNMT3A mutation were at increased risk of relapse and death after transplantation, particularly when other predictive variables were considered. We conclude that consideration of TET2 and DNMT3A mutation status can help predict the risk of mortality in patients with MDS. In MDS, TP53 mutations have long been known to be associated with karyotype, elevated bone marrow blast percentage, and severe thrombocytopenia.3,29-31 Despite these links with prognostically adverse clinical features, TP53 mutations have strong and independent © 2014 by American Society of Clinical Oncology

2695

500

1000 analysis time MUT

1500

Histone deacetylase (HDAC) inhibitors Short-chain fatty acids (SCFA)

Butyrate derivatives, Valproic acid

Hydroxamic acids

Trichostatin A, SAHA (Vorinostat) LHB 589 Pyroxamide

Epoxyketone-containing cyclic tetrapeptides

Trapoxins

Non-epoxyketone-containing cyclic tetrapeptides

FK228, Apicidin

Benzamides

MGCD-0103, MS-275

Combinations of hypomethylating agents and other drugs

•  AZA+ Lenalidomide (Sekeres, Blood, 2012): 71% responses, 41% CR

•  AZA+ gentuzumab (Nand, Blood , 2013): 40% CR

Combinations of hypomethylating agents and other drugs

•  AZA+ Idarubicin (L Adès) (ASH 2105) 50% responses (41% CR+PR+ marrow CR)

•  Intensive AZA (5 d /2 weeks) (L Adès, ASH 2015) •  AZA+ deferasirox (O Hermine)

Intensive AZA trial: Response Rate (n=27)

ORR 70%

Combinations of hypomethylating agents and other drugs

•  AZA+ Volasertib •  AZA+ anti PD-1 or PD-L1

anuscript

been shown that T cell expression of the immunoinhibitory receptor PD-1 is regulated by DNA methylation. In 12 of 27 patients (44%) PD-1 promoter demethylation was observed in sorted peripheral blood T cells isolated over consecutive cycles of treatment with 5-azacytidine (5-aza). The PD-1 promoter demethylation correlated with an increase in PD-1 expression. Moreover, demethylation of the PD-1 promoter Users may view, print, copy, download text and data- minerate the content in such documents, for the purposes of academic res correlated with a significantly worseand overall response (8% vs. 60%, p = 0.014), subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms and a trend towards a shorter overall survival (p = 0.11) was observed. A significantly Corresponding author: Guillermo Garcia-Manero MD,promoter Department was of Leukemia, University of Texas higher baseline methylation level of the PD-1 observed in T cells of MD Anderson Cancer Ce 1515 Holcombe Blvd., Houston, TX 77030, Phone 713 745 3428, FAX: 713 563 0289, ggarciam@mdanderson.org. non-responding patients compared to healthy controls (p = 0.023).

Conflicts of interest: The authors have nothing to disclose.

Accordingly, in addition to their beneficial function, HMAs induce PD-1 expression is available at Leukemia’s website. on TSupplementary cells in theinformation MDS microenvironment, thereby likely hampering the immune response against the MDS blasts. Thus, we suggest that activation of the PD-1 checkpoint during HMA treatment can be a possible resistance mechanism, which may be overcome by combination therapy with a PD-1 pathway inhibitor.

in patients with higher-risk MDS [2]. 5-azacytidine (5-aza) treatment has also prolonged overall survival (OS) in patients with AML with 20–30% bone marrow blasts [5], and decitabine (5-aza-2’deoxycytidine) has improved the response rates in older patients (> 65 yrs) with newly diagnosed AML [6]. In addition, HMAs are also approved by the U.S Food and Drug Administration and the European Medicines Agency for treatment of chronic myelomonocytic leukemia (CMML). Still, only about 50% of the HMA treated patients achieve a clinical response, the majority will lose response over time [2], and the outcome after HMA failure is poor with a median survival of only

INTRODUCTION Myelodysplastic syndromes (MDS) are clonal hematopoietic stem cell disorders, characterized by increased proliferation and aberrant differentiation combined with a high rate of apoptosis [1]. This results in ineffective hematopoiesis and peripheral blood cytopenias as well as an increased risk of developing acute myeloid leukemia (AML). Compared to conventional care regimens, hypomethylating agents (HMAs) have resulted in improved outcomes in MDS [2–4], including delayed leukemic transformation [4] and prolonged survival www.impactjournals.com/oncotarget

9612

Oncotarget

« Pick a winner approach » with AZA 5 AZACYTIDINE 75 mg/m2 x 7 jours

Raffoux et al. ‘08

VALPROIC ACID

5 AZACYTIDINE 75 mg/m2 x 7 jours

IDARUBICIN 5 AZACYTIDINE 75 mg/m2 x 7 jours REVLIMID 5 AZACYTIDINE 75 mg/m2 x 7 jours

6 cycles Sekeres et al. ‘07

INTRODUCTION

Although allogeneic blood or marrow transplantation (BMT) is the only potentially curative approach for many patients with hematologic malignancies, the inability to identify a matched donor and the sometimes prohibitive delays with matched unrelated donor BMT1 have historically been major barriers. In contrast, partially HLA-mismatched related, or HLA-haploidentical, donors can be promptly identified for most patients. HLA3152

mismatched allografting used to be associated with excess risks of graft-versus-host disease (GVHD), graft failure, and nonrelapse mortality (NRM).2-7 However, modern approaches to GVHD prophylaxis, such as high-dose post-transplantation cyclophosphamide (PTCy), have greatly reduced the morbidity of HLA-haploidentical BMT (haploBMT), making it a viable alternative for patients lacking HLA-matched donors.8,9 As a pharmacologic form of tolerance induction,10 high-dose PTCy moderates GVHD and graft

•  271 patients with hematologic malignancies, •  NMA, T-cell–replete haplo-BMT with high-dose post- transplant CY •  median age 61 , 27 (10%) age 70 to 75 years •  For age 50s, 60s, and 70s : –  6-month NRM probabilities of 8%, 9%, and 7%, respectively (P ︎ .20) –  3-year PFS 39%, 35%, and 33% –  3-year OS 48%, 45%, and 44%

Allogeneic HSCT in lower risk MDS: A prospective multicenter phase II study based on donor availability on behalf of the GFM & SFGM-TC (M Robin)

Information aboutwithin ordering may be transplantation. found online at:1 recurrences occurring thereprints first year after a selection bias, as we included only patients in this immune http://bloodjournal.hematologylibrary.org/site/misc/rights.xhtml#reprints Donor lymphocyte infusions (DLI) are a well-established salvage monitoring study who had received at least four cycles of Aza in therapy in this situation. In contrast to the success seen in chronic order to assure a serial measurement in individual patients. myeloid leukemia,about theirsubscriptions efficacy in AML MDS is restrictedmay to be found During theat:course of treatment, Tregs (CD3 þ CD4 þ CD25 þ Information andor ASH membership online þ somehttp://bloodjournal.hematologylibrary.org/site/subscriptions/index.xhtml patients. In addition, this benefit is also hampered by the FoxP3 ) and lymphocyte subpopulations including T cells substantial risk to induce severe graft-versus-host disease (GVHD), (CD3 þ ), T helper cells (CD3 þ /CD4 þ ), cytotoxic T cells (CD3 þ / 2 especially when DLI are administered early after transplantation. CD8 þ ), NK cells (CD3-/CD56 þ ) and B cells (CD20 þ ) were Recently, the combination of azacitidine (Aza) and DLI has proven measured by flow cytometry using a FACSCalibur (BD Biosciences, to induce sustained remissions in about one-third of the patients Heidelberg, Germany). Data were analyzed with FCS Express V3 with AML or MDS relapsing after allo-SCT.3–5 The incidence and software (De Novo Software, LA, CA, USA). Peripheral blood severity of GVHD following this combined approach has been samples were routinely obtained prior to treatment, after the first reported to be lower in comparison with historical data using DLI (day 6), second (day 34), fourth (day 90) and sixth Aza cycle (day alone.3–7 As a potential mechanism, murine models have sugge146). For staining of Tregs and lymphocyte subsets the FoxP3 sted that Aza upregulates the transcription factor FoxP3, thereby Staining Kit and the Multitest IMK Kit (both from BD Biosciences, þ expanding CD4 regulatory T cells (Tregs), which play an Heidelberg, Germany) were used according to the manufacturer’s important role in the control of GVHD.8–10 This has also been recommendations. The gating strategy to measure Tregs (CD3 þ recently shown in 17 patients with AML receiving Aza maintenance CD4 þ CD25 þ FoxP3 þ ) is shown in Figure 1a. therapy following allo-SCT.11 Data on Tregs in patients who receive Looking at all the patients, we observed a 1.5-fold increase in Aza and DLI to treat relapse are lacking so far. the absolute number of Tregs in the PB after four Aza cycles (day We serially monitored CD3 þ CD4 þ CD25 þ FoxP3 þ Tregs and 0: 8.23/ml vs day 90: 13.26/ml, P ¼ 0.0479), but this increase varied lymphocyte subsets in the peripheral blood (PB) of 13 patients between the individual patients. By grouping the patients on the with AML (n ¼ 8) or MDS (n ¼ 5) who received Aza and DLI as first basis of the median time to relapse (day 446), we found a 3.2-fold salvage therapy for relapse after allo-hematopoeitic SCT. increase in the absolute number (day 0: 4.7/ml vs day 90: 14.8/ml, Detailed demographics as well as relapse characteristics are P ¼ 0.031) as well as a 1.9-fold increase in the frequency of Tregs summarized in Table 1. Seven of these patients were treated (day 0: 6.7% vs day 90: 12.9% of CD3 þ CD4 þ cells, P ¼ 0.06) during within a prospective multicenter phase II study (AZARELA, http:// treatment with Aza in the group of patients who relapsed early clinicaltrials.gov NCT-00795548) and their clinical results have (Figures 1b and c). On the other hand, in those patients who recently been published,5 while the other six patients were treated relapsed late the absolute number (day 0: 12.2/ml vs day 90: 11.9/ accordingly at our institution. All patients gave written informed ml, NS) and frequency (day 0: 4.7% vs day 90: 3.9%, NS) of Tregs in consent and the study was approved by the Institutional Review PB was already higher and remained unchanged during treatment BoardBlood of The Heinrich University Dusseldorf. The treatment (print ISSNHeine 0006-4971, online ISSN 1528-0020), is published weekly by the American Society (Figure 1c). With regard to other lymphocyte subpopulations no of Hematology, 2021 St, NW, Suite Washington DC 20036. schedule contained up to Leight cycles of 900, Aza (Vidaza, Celgene significant changes were observed (Supplementary Figure S1). 2 CopyrightSummit, 2011 by The Society Hematology; all rightsThe reserved. Corporation, NJ, American USA) either 100ofmg/m /day on finding that Aza-induced expansion of Tregs is apparently 2 days 1–5 or 75 mg/m /day subcutaneously on days 1–7 repeated restricted to patients relapsing early after allo-SCT is in line with every 28 days and DLI envisaged after every second Aza data recently published by Goodyear et al.11 They reported a þ cycle (day 34/90/146) with increasing numbers of CD3 cells. significant increase of the Treg numbers (43-fold) in patients Additional DLI were permitted according to the individual treated with Aza as maintenance therapy in comparison to timephysician’s decision.5 matched controls. These patients commenced Aza therapy at 1–7 Hematological relapse occurred after a median of 446 days months following allo-SCT. Similar to the time dependency in our (range: 19–1688 days) following allo-SCT. The median number of study, Goodyear et al.11 observed the greatest effect on Treg Aza cycles was 6 (range: 4–8). DLI were administered in all expansion after three cycles of Aza, reflecting an early period patients, with a median number of 2 DLI per patient (range: 1–4 following allo-SCT, while no difference was observed after six or DLI). Five patients received one DLI, three patients two DLI, four nine cycles.11 patients three DLI and one patient four DLI, resulting in a The expansion of Tregs during Aza treatment might also median total T-cell dose of 5.0 # 106 CD3 þ cells/kg per patient explain the relatively low rate and mild presentation of þ (range: 1–119 CD3 cells/kg) (Table 1). GVHD in our patients despite a dose-escalating DLI schedule.

Can AZA induce an immune response, especially after allo SCT ? Induction of a CD8+ T-cell response to the MAGE cancer testis antigen by combined treatment with azacitidine and VPA in AML and MDS. Goodyear O, Blood. 2010 :1908-18. 8

Accepted article preview online 1 March 2013; advance online publication, 22 March 2013

an enhanced graft-versus-leukemia effect without provoking graft-versus-host disease (GvHD).

of AML or MDS after allo-HSCT (AZARELA) trial was a prospective, EBMT (European Group for Blood and Marrow Transplantation)-labeled,

Medical Faculty, Department of Hematology, Oncology and Clinical Immunology, University of Duesseldorf, Medical Faculty, Duesseldorf, Germany; 2University Hospital Carl Gustav Carus, Medizinische Klinik I, Dresden, Germany; 3Goethe University, Medizinische Klinik II, Frankfurt, Germany; 4Charite´ Campus Virchow Klinikum, Department of Haematology, Oncology and Tumor Immunology, Berlin, Germany; 5University of Heidelberg, Medizinische Klinik V, Heidelberg, Germany; 6St. Johannes Hospital, Department of Hematology and Oncology, Duisburg, Germany and 7University Hospital Hamburg-Eppendorf, Clinic for Stem Cell Transplantation, Hamburg, Germany. Correspondence: Dr T Schroeder, Department of Hematology, Oncology and Clinical Immunology, University of Duesseldorf, Medical Faculty, Moorenstr. 5, Duesseldorf, Nord Rhine Westphalia, 40225, Germany. E-mail: thomas.schroeder@med.uni-duesseldorf.de Parts of this study have been presented at the 52nd American Society of Hematology (ASH) Annual Meeting, Orlando, FL, 4–7 December 2010, the BMT Tandem Meeting 2011, Honolulu, HI, 17–21 February 2011, the 37th Annual Meeting of the European Group for Bone and Marrow Transplantation (EBMT), Paris, France, 3–7 April 2011 and at the 53rd American Society of Hematology (ASH) Annual Meeting, San Diego, CA, 10–13 December 2011. 8 These authors contributed equally to this work. Received 16 October 2012; revised 16 December 2012; accepted 3 January 2013; accepted article preview online 14 January 2013

•  N= 30 •  up to 8 cycles azacitidine (100 mg/m2/day, days 1–5, every 28 days) followed by DLI after every second azacitidine cycle. •  A median of three courses azacitidine (range 1–8) were administered, and 22 patients (73%) received DLI. •  Overall response rate 30%, including 7 CR ( 23%) and 2 PR (7%). •  5 patients remained in CR for a median of 777 days

•  181 relapses after an allograft for MDS (n=116) or MDS (n=65). 69 received additional DLI •  25% responses to Azacitidine : 15% CR, 10% PR •  Response higher in patients transplanted in CR (p= 0.04) and those transplanted for MDS (p= 0.023). •  2 year OS 48% if CR versus 12% overall. •  OS determined by time to relapse post-transplant > 6 months (p= 0.001) and marrow blast % at time of relapse (p= 0.01). •  DLI did not improve response rates or OS .

“Preventive” Post-transplant azacytidine in very high risk MDS patients: a phase II prospective study (M Robin) Inclusion criteria Patients aged from 18 to 70 years MDS according to WHO with a very complex cytogenetic (according to IPSS-R) or TP 53 gene mutation?

•  Aza (reduced dose) started on day 40 •  Immunosuppression stopped on day 70 •  DLI started on day 100

Treatment of higher risk MDS (and AML)with complex karyotypes including del 5q by DNR+AraC + Lenalidomide

Induction Course

monthly consolidations x6

monthly Maintenance

1st Cohort

DNR 45 mg/m2 x3 ARAC 200 mg/m2x7 Lenalidomide 10 mg x 21

DNR 45 mg/m2 x1 ARAC 60 mg/m2x 10 Lenalidomide 10 mg x 14

Lenalidomide 10 mg x 14

2nd Cohort

DNR 60 mg/m2 x3 ARAC 200 mg/m2x7 Lenalidomide 10 mg x 21

DNR 60 mg/m2 x1 ARAC 60 mg/m2x 10 Lenalidomide 10 mg x 14

Lenalidomide 10 mg x 14

3rd Cohort

(L AdĂ¨s, ASH 2014)

DNR 60 mg/m2 x3 ARAC 200 mg/m2x7 Lenalidomide 25 mg x 21

DNR 60 mg/m2 x1 ARAC 60 mg/m2x 10 Lenalidomide 25 mg x 14

Lenalidomide 25 mg x 14

Response (82 patients) N° pts

46%

CRi

10%

Early Death

•  Overall Response rate 61% •  68% of CR patients achieved complete or partial cytogenetic response

•  aza(75 mg/m2/d x 5 ) and len (10 mg/d x21 ) •  N=36 ( IPSS: 5 int1, 20 int 2, 11 high) •  Median CR duration 17 months •  ; median OS 37 m for CR patients, 13.6 m for the entire cohort 3-55

)

ORR = 71%

Intensive AZA trial: Response Rate (n=27)

ORR 70%

106

Phase I study of oral azacitidine in MDS, CMML, AML Garcia-Manero G, J Clin Oncol. 2011 •  MTD was 480 mg/dx7. Most common grade 3/4 adverse events were diarrhea (12.2%), nausea (7.3%), vomiting (7.3%), febrile neutropenia (19.5%), and fatigue (9.8%). •  Mean relative oral bioavailability ranged from 6.3% to 20%. •  Oral and SC azacitidine decreased DNA methylation in blood, with maximum effect at day 15 of each cycle. •  Overall response was 35% in previously treated patients and 73% in previously untreated patients.

Terms in blue are defined in the glossary, found at the end of this article and online at www.jco.org. Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article. Corresponding author: Benjamin L. Ebert, MD, PhD, Brigham and Women’s Hospital, 1 Blackfan Circle, Karp CHRB 5.211, Boston, MA 02115; e-mail: benjamin_ebert@dfci.harvard.edu. © 2014 by American Society of Clinical Oncology 0732-183X/14/3225w-2691w/$20.00 DOI: 10.1200/JCO.2013.52.3381

0.6

INTRODUCTION

cytopenia. Therefore, it is likely that acquired mutations could also predict response to specific interventions, such as treatment with hypomethylating agents or survival after hematopoietic stemcell transplantation (HSCT).8 Calculation of risks, benefits, and timing of HSCT is often difficult in MDS.9-11 Older age and comorbidities typical of patients with MDS are frequently associated with unacceptable risk of early death after transplantation. Even in younger and generally healthier patients, deciding when HSCT is appropriate can be challenging. In particular, patients with poor prognostic features may be directed to transplantation because they have few treatment options available or because standard therapeutics are not expected to provide durable responses. © 2014 by American Society of Clinical Oncology

2691

Overall Survival

the Yellow Diamond Foundation Fund (B.L.E.).

(95% CI, 9% to 33%) in patients with these mutations.

TET2 Day-100 landmark analysis (n ! 72) Karyotype (complex v other) Genetic mutation (present v absent) TP53 DNMT3A

0.4 0.2

2.29

2.85

3.78 2.62

Abbreviations: HR, hazard ratio; OS, overall surv ! Final model obtained from backward-eliminatio dates included variables with univariable P " .20

Time (months)

B Overall Survival (probability)

No. R01HL082945, a Leukemia and Lymphoma Society scholar award, and

1.0

Not complex (n = 59) Complex and TP53 unmutated (n = 12) Complex and TP53 mutated (n = 16)

0.8 0.6 0.4 0.2

Time (months)

C Overall Survival (probability)

Heart, Lung, and Blood Institute Grant

1.0

TP53 mutated (n = 18) TET2 mutated, no TP53 (n = 10) DNMT3A mutated, no TP53 or TET2 (n = 12) No TP53, TET2, or DNMT3A mutations (n = 47)

0.8 0.6 0.4 0.2

Time (months) TP53

TET2

DNMT3A

www.jco.org

these genes were found in nearly one half Mutations of other genes associated with studies, such as RUNX1, ASXL1, SRSF2, and ated with differences in OS in our cohort o HSCT (Data Supplement).3,22-24 This may disease-modifying effects of conditioning a cause of the fact that the prognostic signific tions is more pronounced in lower-risk pat few in this study. In contrast, TP53 mut prognostic value, even in higher-risk patie they are most commonly found.3,21 The DNMT3A and TET2 genes encode regulate DNA methylation, and both are rec acute myeloid leukemia, and other hema acute myeloid leukemia, mutations of bo patients with intermediate-risk karyotypes poor prognosis.25,26 In MDS, the clinical mutations is less clear but also seems to be u mutations are not associated with survival.5 DNMT3A mutations are relatively promisc with other mutated genes that can predict o a study of lower-risk patients with MDS, D not associated with OS in univariable DNMT3A-mutant/SF3B1-wild-type subgro In our transplantation cohort of largely hi mutations were rare, and most DNMT3 SF3B1 wild type (88%). DNMT3A and TET2 mutations identi samples were largely from patients withou known to predict poor outcome. Most of th complex karyotype and were not more likel marrow blast percentage before transplan found that patients with a TET2 or DNMT creased risk of relapse and death after tra when other predictive variables were cons consideration of TET2 and DNMT3A mut dict the risk of mortality in patients with M In MDS, TP53 mutations have long be with karyotype, elevated bone marrow bla thrombocytopenia.3,29-31 Despite these link verse clinical features, TP53 mutations hav

Alternative protocols of decitabine? Decitabine 20mg/m2/jx5 IV Dose ( 4 w cycles )

Nb CR(IWG 2006) /Total (%)

20 mg/m2/j x 5 d IV

33 (39)*

10 mg/m2 x2/j x 5 dSC

3 (21)

10 mg/m2/j x 10 d IV

4 (24)

* Statistically significant

Kantarjian et al. Cancer 2007;109:1133, 207