Oliva esther aml eurasian st. petersburg 2016

Treatment strategies and quality of
life in elderly AML patients
Esther N Oliva
Azienda Ospedaliera B-M-M
Reggio Calabria, Italy

Long term overall survival in AML patients aged ≥ 60 years
1. Alan K. Burnett ASH 2012 Ham-Wasserman lecture; Hematology 2012:1–6

Intensive chemotherapy
Kantarjian et al. Blood 2010
Duration of Complete Remission (CR) = 11 months

Whatever the age, CR is an essential prerequisite
for achieving long-term survival or cure
Ferrara et al, Clinical Geriatrics, 2000
Patients aged 75
yrs or older

Optimal active treatment strategies differ
depending on patient factors
Chemotherapy
Autologous HSCT
Allogeneic HSCT
Standard-dose
chemotherapy (7+3)
High-dose cytarabine
Low-dose cytarabine
Hypomethylating agents*
Clinical trial
Clinical trial
RIC HSCT
Hypomethylating agents*
Consolidation therapy
With the aim to maintain remission
Induction therapy
With the aim to eradicate the leukaemic clone
NCCN guidelines Acute Myeloid Leukaemia v2.2014
Available at NCCN.org. Accessed April 2014
*Azacitidine or decitabine
RIC = reduced intensity conditioning

Active treatment options for patients
with AML: induction therapy

Some older patients receive low-dose
cytarabine, but outcomes are generally poor
Survival
Prospective randomised trial to evaluate treatment outcomes with LDAC versus hydroxyurea in 202 patients
(≥60 years old: 98%) with AML (86%) or MDS (14%) ineligible for standard chemotherapy
LDAC (n=103)
HU (n=99)
Time, years
Patients,%
Burnett AK, et al. Cancer 2007;109:1114–24
LDAC = low-dose cytarabine
HU = hydroxyurea
Median OS with LDAC: ~4 months

7+3 – the mainstay of IC for patients with AML1
0 3 Days of the cycle
Cytarabine
100mg/m2
Anthracycline
IDA 12mg/m2 OR
mitoxantrone 12mg/m2 OR
DNR 40–50mg/m2
7 21 28
Response assessment
day +21–282
7+3 induction chemotherapy for AML is recommended for patients who are
considered able to tolerate it
1. Roboz GJ, et al. Curr Opin Oncol 2012;24:711–9
2. Dohner H, et al. Blood 2010;115:453–74IC = Intensive Chemotherapy; DNR = daunorubicin; IDA = idarubicin

Survival according to age in AML patients
eligible for IC
1. Appelbaum FR, et al. Blood 2006;107:3481–5
Survival
18,8
9,0
6,9
3,5
0,0
2,0
4,0
6,0
8,0
10,0
12,0
14,0
16,0
18,0
20,0
SurvivalTime,months
≤56
(n=368)
56–65
(n=246)
66–75
(n=274)
Age, years
≥75
(n=80)
Retrospective analysis of treatment outcomes in 968 patients with AML1
IC = Intensive Chemotherapy

Active treatment options for patients
with AML: consolidation therapy

Elderly
Intensive Postremission Chemotherapy
Impact of Cytarabine Dosage According to Age
Mayer et al. N Engl J Med, 1994

EBMT risk scoring can help identify patients who
may benefit from allogeneic HSCT
Investigation of the EBMT risk score* for predicting outcomes after allogeneic HSCT in a cohort of
56,505 patients with haematological disorders1
1. Gratwohl A, et al. Cancer 2009;115:1087–92
*Based on five pre-transplant factors: AGE of the patient, disease stage, time from diagnosis to
transplant, donor type, and donor-recipient sex combination.
EBMT = European Group for Blood and Marrow Transplantation
TRM = transplant-related mortality
OS
Years after transplantation
0
0.2
0.4
0.6
0.8
1.0
Probabilityofsurvival
0 1 2 3 4 5
TRM
Years after transplantation
0
0.2
0.4
0.6
0.8
1.0
ProbabilityofTRM
0 1 2 3 4 5
Score 0
Score 1
Score 2
Score 3
Score 4
Score 5
Score 6–7

Long-term outcome of reduced-intensity
allogeneic HSCT in AML patients in CR
Popat U, et al. BMT 2012

RIC HSCT may be preferred over IC for selected
patients with AML
RIC HSCT can be an option for some older AML patients or those unfit for standard transplant
Retrospective analysis of allogeneic HSCT (61% using a RIC regimen, usually including fludarabine) versus IC
990 eligible patients with AML (median age 60 [range 50–70])
Relapse
IC only (n=838)
HSCT (n=152)
p=0.001
Kurosawa S, et al. Biol Blood Marrow Transplant 2011;17:401–11IC= intensive chemotherapy; RIC = reduced intensity conditioning
Years from CR1
0
0.2
0.4
0.6
0.8
1.0
Cumulativerisk
0 1 2 3 4 5
OS
p=0.012
Years from CR1
0
0.2
0.4
0.6
0.8
1.0
Cumulativesurvival
0 1 2 3 4 5

Non relapse mortality is higher in patients
receiving a RIC HSCT
Kurosawa S, et al. Biol Blood Marrow Transplant 2011;17:401–11NRM = non-relapse mortality
NRM
IC alone (n=838)
HSCT (n=152)
p<0.001
Years from CR1
0
0.2
0.4
0.6
0.8
1.0
CumulativeNRM
0 1 2 3 4 5

Quality of Life in Elderly Patients with
Acute Myeloid Leukemia undergoing
Induction Chemotherapy

<60 yrs (n=142) ≥60 yrs(n=97)
QoL Domain mean (SD) mean (SD) P-value
Global Health / QOL 45.7 (26.9) 45.7 (26.5) 0.99
Physical Functioning 74.2 (25.8) 75.4 (27.9) 0.75
Role Functioning 44.9 (33.2) 48.7 (37.4) 0.41
Emotional Functioning 64.9 (25.1) 72.6 (23.8) 0.02
Cognitive Functioning 74.9 (24.7) 76.7 (24.8) 0.59
Social Functioning 42.2 (33.1) 55.2 (34.3) 0.004
FACT-F (0-52) 29.0 (12.9) 30.3 (13.9) 0.48
ESAS Global Fatigue (0-10) 5.2 (2.5) 5.2 (2.6) 0.82
Impact of age on Quality of Life (QoL) in
patients with AML
N= 239(median age 57.5 yrs)
Instruments: EORTC QLQ-C30 e FACT-F
Timilshina N et al. Annals of Oncology 2014 ; 25: 883–888

QoL in elderly patients with AML at diagnosis
 113 cases > 60 yrs
 Mean age 72 yrs (± 6)
 48 (42%) IC
 65 (58%) palliative care
Oliva EN et al. Haematologica 2011; 96(5): 696-702IT= IC; PT= palliative care
Items addressed by QOL-E Disease-specific:
•Dyspnea (shortness of breath)
•Dependence on hospital and staff
•Dependence on transfusions

 61 elderly patients with AML undergoing IC
 EORTC QLQ-C30 QoL instrument
 28 evaluable for QOL changes (only responders)
 Improvements in QoL after induction+consolidation:
 Physical Functioning (p<0.001)
 Role Functioning (p=0.001)
 Emotional Functioning (p< 0.001)
 Social Functioning (p=0.007)
Schumacher et al. Leukemia 1998 Apr; 12(4):586-92
Improvement in QoL in elderly AML patients
in CR after IC
QoL= Quality of life
IC= intensive chemotherapy

Conclusions: Patient reported outcome benefits overcome
adverse events in elderly patients obtaining a CR with IC.
*Significant improvements in
 Fatigue
 Nausea
 Vomiting
 Loss of appetite
 Insomnia
*p< 0.001
IC= intensive chemotherapy
Improvement of symptoms in elderly patients in
CR after IC
Schumacher et al. Leukemia 1998 Apr; 12(4):586-92

Primary
 Difference in 2- and 5-year DFS between 5-Aza and BSC arms.
Secondary
 Difference in 2- and 5-year OS between 5-Aza and BSC arms.
 Difference in changes in QoL from diagnosis in both arms
 Difference in number and duration of hospitalizations in both
arms in the 2 years post-remission
QOL-ESS AZA AMLE TRIAL:
Design – Prospective randomized trial
Elderly AML patients undergoing IC reaching a CR are randomized to receive post-remission
azacitidine or best supportive care
QoLESS AZA-AMLE
Objectives

Ist 3+7 induction cycle
2nd 3+7 induction
cycle
Consolidation
Randomization
Off-protocol
CR or PR
CR
CR
NR
PR/Resistance/
Relapse
Relapse
A
M
L
D
I
A
G
N
O
S
I
S
BSC vs 5-Azacitidine
1:1
QOLESS-AZA-AMLE: Study design
3+7= daunorubicin 40mg/m2 daily on days 1–3
+ cytarabine 100mg/m2 daily as a continuous IV infusion on days 1–7
Consolidation = 3-hour infusion of cytarabine 800mg/m2 BID on days 1–3
BSC = best supportive care; NR= no remission; PR = partial remission
Oliva et al. ASH 2015 poster presentation
Q
O
L
A
S
S
E
S
S
M
E
N
T
QOL ASSESSMENT
QOL ASSESSMENT

Characteristics of patients at diagnosis

QoL at diagnosis and correlations with hemoglobin
Factors not associated with QoL:
PLT, leukocytes, blasts, ECOG PS, de novo/secondary, Charlson comorbidity index

Changes in QoL after induction chemotherapy

Changes in QoL after consolidation in patients in CR

Changes in QoL according to QoL at diagnosis
improvement deterioration

Changes in symptoms according to intensity of
symptoms at diagnosis

Baseline role function according to response

QOL-ESS AZA AMLE TRIAL:
Impact of post-remission on AML free survival (1st interim analysis)
QoLESS AZA-AMLE

Decitabine
Azacitidine
Hypomethylating Agents in AML

Kaplen-Meier curve for overall survival (intent-to-treat population).
Cashen A F et al. JCO 2010;28:556-561©2010 by American Society of Clinical Oncology
Response to Decitabine for the First-Line Treatment of Elderly AML
•CR rate of 25%
•30-day mortality 7%
•Median overall survival 7.7 mo.s
•Acceptable extramedullary toxicity
Multicenter, Phase II Study of Decitabine for the First-Line Treatment of Elderly AML
Decitabine 20 mg daily for 5 days q28

Response
TC
Decitabine
(n = 242)
Supportive
Care (n = 28)
Cytarabine
(n = 215)
Total TC
(n = 243)
No. % No. % No. % No. %
CR 1 3.6 17 7.9 18 7.4 38 15.7
CRi 1 3.6 6 2.8 7 2.9 24 9.9
CRp 0 0 1 0.5 1 0.4 5 2.1
CR + CRp 1 3.6 18 8.4 19 7.8* 43 17.8*
Partial remission 1 3.6 8 3.7 9 3.7 6 2.5
Stable disease 3 10.7 52 24.2 55 22.6 67 27.7
Progressive disease 10 35.7 69 32.1 79 32.5 50 20.7
Not evaluable 12 42.9 63 29.3 75 30.9 57 23.6
Kantarjian H M et al. JCO 2012;30:2670-2677
CR, complete remission; CRi, CR with incomplete blood count recovery;
CRp, CR with incomplete platelet recovery; TC, treatment choice.
Multicenter, Randomized, Open-Label, Phase III Trial of Decitabine Versus Patient Choice,
With Physician Advice, of Either Supportive Care or Low-Dose Cytarabine for the
Treatment of Older Patients With Newly Diagnosed Acute Myeloid Leukemia

Overall survival in a protocol-specified 2009 clinical cut-off analysis of decitabine and
treatment choice (TC) in the intent-to-treat population.
No difference in median OS with decitabine (7.7 months;
95% CI, 6.2 to 9.2 months) versus TC (5.0 months; 95% CI,
4.3 to 6.3 months).
The estimated HR for death (decitabine:TC) was 0.85 (95%
CI, 0.69 to 1.04).
At the mature analysis (2010 cutoff), 446 deaths
(92.0%) were reported (decitabine, n = 219; TC, n =
227).
Median OS values were the same, but differences
reached significance.

Treatment-Emergent Serious Adverse Events
©2012 by American Society of Clinical Oncology
Adverse Event
TC
Decitabine
(n = 238)
Supportive Care
(n = 29)
Cytarabine
(n = 208)
Total TC
(n = 237)
No. % No. % No. % No. %
Total Serious AE 12 41 150 72 162 68 190 80
Febrile neutropenia 0 0 33 16 33 14 57 24
Thrombocytopenia 0 0 11 5 11 5 21 9
Anemia 0 0 12 6 12 5 15 6
Neutropenia 0 0 7 3 7 3 15 6
Pneumonia 6 20 42 20 48 20 57 24
Sepsis 1 3 17 8 18 7 30 12
Disease progression 2 7 29 14 31 13 27 11
Pyrexia 2 7 18 9 20 8 23 10
General physical health
deterioration
1 3 13 6 14 6 15 6
Treatment-emergent adverse events were defined as new or worsening AEs between the time of first
dose (or randomisation for patients given BSC only) to the end of the safety follow-up period

36
488 Patients Enrolled
Investigator Preselection
LDAC
n=312 (64%)
IC
n=87 (18%)
BSC Only
n=89 (18%)
AZA
n=44
Randomisation
BSC
n=45
AZA
n=154
LDAC
n=158
AZA
n=43
IC
n=44
AZA-AML-001 trial – elderly AML patients > 30% blasts
Dombret H, et al. Blood 2015, Vol 126, 3.
Multicenter, randomized trial – azacitidine (AZA) versus other physician preselected
conventional treatment (CCR)
BSC = best supportive care
LDAC = low dose cytarabine
IC = intensive chemoherapy

*Stratified by ECOG PS and cytogenetic risk; ITT = intention to treat
AZA = azacitidine; CCR = preselected conventional chemotherapy regimen
Median follow-up: 24.4 months
40
AZA (n=241)
CCR (n=247)
0
0.2
0.4
0.6
0.8
1.0
0 4 8 12 16 20 24 28 32 36
Time from randomisation, months
10.4 months
6.5 months Stratified:* p=0.101
Overall survival - AZA versus CCR
Probabilityofsurvival
1-year OS: AZA 46.5%; CCR 34.2% (95% CI: 3.5%, 21.0%)

OS in patients treated with AZA vs the individual
components of the CCR arm*
*not powered to detect statistical differences between AZA and the individual components of the CCR arm
30.3 18.61-yr OS (%) 48.5 34.0 55.8 50.9
Patients (n) 44 45 154 158 43 44
Azacitidine
CCR
0
2
4
6
8
10
12
BSC
(n=89)
LDAC
(n=312)
IC
(n=87)
MedianOS,
months
5.8
3.7
11.2
6.4
13.3
12.2
14
“Median OS was higher with AZA versus BSC, and was similar to that with LDAC and IC“
p=0.0288
p=0.4270
p=0.5032

Responses in patients treated with AZA versus
CCR
CCyR = complete cytogenetic remission in ≥20 metaphases
CR = complete response; CRi = CR with incomplete blood count recovery; NE = not evaluable
PD = progressive disease; PR = partial response; SD = stable disease
AZA = azacitidine; CCR = preselected conventional chemotherapy regimen
27,8
19,5
8,3
2,1
1,2
29,5
8,3
18,3
25,1
21,9
3,2
5,7
1,2
23,9
8,1
25,1
0
5
10
15
20
25
30
35
CR + CRi CR CRi CCyR PR SD PD NE
Patients,%
Azacitidine CCR
p=0.5766
p=0.0191
p=0.1833
p=1.0
p=1.0
p=0.5384
p=0.0589

Rates of RBC-TI and PLT-TI in patients who were
TD at baseline
38,5
40,6
27,6
29,3
0
5
10
15
20
25
30
35
40
45
RBC-TI Platelet-TI
Patients,%
Azacitidine
CCR
PLT = platelet; RBC = red blood cell
TD = transfusion dependent; TI = transfusion independent
“Higher proportions of patients who were TD at baseline attained RBC-TI or platelet-TI with AZA vs CCR.
Furthermore, the proportions of patients who remained or became RBC-TI or platelet-TI were higher with AZA.”

Post hoc analysis of survival in patients who did
not achieve CR
33,8
20,4
0
5
10
15
20
25
30
35
40
AZA CCR
1-yearOS,%
∆13.4% (95% CI: 4.5%, 22.4%)
6,9
4,2
0
1
2
3
4
5
6
7
8
AZA CCR
MedianOS,months
Stratified log-rank p=0.0170
Median OS 1-year OS

TEAE, % AZA (n=236) LDAC (n=153) IC (n=42)
Nausea 27.1 22.2 42.9
Neutropenia 19.9 22.9 31.0
Thrombocytopenia 17.4 22.2 21.4
Febrile neutropenia 14.8 20.3 31.0
Vomiting 14.4 10.5 7.1
Decreased appetite 13.6 9.2 11.9
Constipation 13.1 6.5 11.9
Injection site reaction 12.7 0 0
Pyrexia 13.2 15.7 23.8
Diarrhoea 12.3 5.2 21.4
Injection site erythema 11.9 0 0
Anaemia 7.6 13.7 14.3
Leukopenia 7.2 8.5 14.3
Hypokalaemia 1.7 3.9 11.9
Oral herpes 0.8 2.0 11.9
Most frequent drug-related TEAEs† in patients
treated with AZA versus LDAC or IC‡
†Coded using MedDRA and graded according to CTCAE v4.0 criteria
‡These data are not adjusted for duration of drug exposure

0
5
10
15
20
25
Cycles 1–2 Cycles 3–4 Cycles 5–6
Patients,%
Febrile neutropenia Neutropenia Thrombocytopenia Anaemia
Incidence of haematological TEAEs* (any grade)
by cycle in patients treated with AZA†
*Coded using MedDRA and graded according to CTCAE v4.0 criteria
†These data are not adjusted for duration of drug exposure

Rates of hospitalisation and time spent in hospital
due to TEAEs per patient-year of drug exposure
1,96
2,39
0
1
2
3
Hospitalisation
due to TEAEs
Perpatient-yearof
treatmentexposure
28,5
38,3
0
10
20
30
40
50
Time spent in hospital due
to TEAEsDaysperpatient-yearof
treatmentexposure
Azacitidine CCR
p=0.0083 p<0.0001
Rates of hospitalisation due to TEAEs Time spent in hospital due to TEAEs

• No meaningful deterioration from baseline
was observed with AZA or CCR in the 4
domains through cycle 9
• Few changes were statistically significant
(p<0.05) and fewer met the MID threshold
– Patients receiving CCR achieved meaningful
improvement in Fatigue at cycles 7 and 9 and in
Global Health Status/QoL at cycle 9
• Multivariate MMRM analysis showed no
significant differences between AZA and
CCR in the 4 preselected domains, except
for Fatigue in favor of CCR (p=0.04);
however, the difference was no longer
significant after controlling for receipt RBC
transfusions within 5 days of HRQL
assessment (p=0.09)
Decreasing scores indicate improvement in the Fatigue and Dyspnea domains and increasing
scores indicate improvement in the Physical Function and Global Health Status/QoL domains
*Met the threshold for minimally important difference (MID)
-15
-10
-5
0
5
10
15
Cycle 3 Cycle 5 Cycle 7 Cycle 9
Mean Change v. Baseline AZA vs. CCR
Fatigue & Dyspnea
Fatigue- AZA Dsypnea- AZA
Fatigue- CCR Dyspnea- CCR
-15
-10
-5
0
5
10
15
Mean Change v. Baseline AZA vs. CCR
Physical Functioning & Global Health/QoL
Physical Functioning- AZA Global Health/ QoL- AZA
Physical Functioning- CCR Global Health/ QoL- CCR
ImprovementImprovement
* *
*
Results – Quality of life Outcomes: AZA vs CCR
Minden et al. Poster P184 EHA 2015

• Within the LDAC preselection group, HRQL
outcomes with AZA (n=102) and LDAC
(n=95) were largely consistent with the
primary HRQL analysis
• Patients randomized to AZA achieved
meaningful improvement in the Fatigue &
Global Health Status/QoL domains at cycle
9
Decreasing scores indicate improvement in the Fatigue and Dyspnea domains
of the QLQ-C30, and increasing scores indicate improvement in the Physical
Function and Global Health Status/QoL domains
*Met the threshold for minimally important difference (MID)
-15
-10
-5
0
5
10
15
Mean Change v. Baseline AZA vs. LDC
Post-Hoc Analysis of Patients Pre-Selected to LDC
Physical Functioning- AZA Global Health- AZA
Physical Functioning- LDC Global Health- LDC
ImprovementImprovement
*
*
-15
-10
-5
0
5
10
15
Mean Change v. Baseline AZA vs. LDC
Post-Hoc Analysis of Patients Pre-Selected to LDC
Fatigue- AZA Dyspnea- AZA
Fatigue- LDC Dyspnea- LDC
Minden et al. Poster P184 EHA 2015
Results – Quality of Life Outcomes in Patients
Preselected to Receive LDAC

Defining response to treatment:
ELN response criteria in AML
Category Definition (no minimum duration of response required)
CR BM blasts <5%; absence of blasts with Auer rods; absence of EMD; absolute
neutrophil count >1.0 x 109/L; platelet count >100 x 109/L; RBC-TI
CR with incomplete
recovery (CRi)
All CR criteria except for residual neutropenia (<1.0 x 109/L) or
thrombocytopenia (<100 x 109/L)
Morphological leukaemia-
free state
BM blasts <5%; absence of blasts with Auer rods; absence of EMD; no
haematological recovery required
PR Relevant in the setting of phase I and II clinical trials only; all haematological
criteria of CR required with decrease of at least 50% in the percentage of BM
blasts to a value between 5–25%
Cytogenetic CR (CRc) Reversion to a normal karyotype at the time of morphologic CR (or CRi) in cases
with an abnormal karyotype at the time of diagnosis; based on the evaluation of
20 metaphase cells from BM
Molecular CR (CRm) No standard definition; depends on molecular target
Dohner H, et al. Blood 2010;115:453–74
Definitions of response based primarily on IWG criteria
ELN = European LeukemiaNet

Defining treatment failure: ELN response criteria
in AML
Category Definition
Resistant disease (RD) Failure to achieve CR or CRi (general practice; phase II–III trials), or failure to
achieve CR, CRi, or PR (phase I trials)
Only includes patients surviving ≥7 days following completion of initial treatment,
with evidence of persistent leukaemia by blood and/or BM examination
Death in aplasia Deaths occurring ≥7 days following completion of initial treatment while patient
has cytopenias; with an aplastic or hypoplastic BM obtained within 7 days of
death, without evidence of persistent leukaemia
Death from indeterminate
cause
Deaths occurring before completion of therapy, or <7 days following its
completion
Deaths occurring ≥7 days following completion of initial therapy with no blasts in
the blood, but no BM examination available
Relapse BM blasts ≥5%; or reappearance of blasts in the blood; or development of EMD
Dohner H, et al. Blood 2010;115:453–74

Defining haematological improvement:
IWG response criteria in MDS
Category Definition (response must be maintained for ≥8 weeks)
Erythroid response (pre-
treatment Hb <11g/dL)
≥1.5g/dL increase in Hb; reduction in transfusion frequency of ≥4 transfusions/8
weeks compared with the 8 weeks prior to treatment (pre-treatment transfusions
are only counted if given for Hb of ≤9g/dL)
Platelet response
(pre-treatment platelet count
<100 Χ 109/L)
Absolute increase of ≥30 Χ 109/L for patients with a pre-treatment platelet count
of >20 x 109/L
Increase from <20 x 109/L to >20 x 109/L and by at least 100%
Neutrophil response
(pre-treatment ANC
<1.0 Χ 109/L)
At least 100% increase in ANC and an ANC of
>0.5 x 109/L
Cheson BD, et al. Blood 2006;108:419–25

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