Farhad Ravandi MD Professor of Medicine University of Texas MD Anderson Cancer Center Disclosure of Conflicts of Interest Dr Ravandi discloses that he is a consultantadvisor for Pfizer ID: 575557
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Slide1
Understanding Evolving Treatment Paradigms for Older Adults With Acute Myeloid Leukemia
Farhad
Ravandi
,
MD
Professor of Medicine
University of Texas MD Anderson Cancer CenterSlide2
Disclosure of Conflicts of Interest
Dr.
Ravandi
discloses that he is a consultant/advisor for Pfizer,
Sunesis
, Amgen, and Seattle Genetics. He has also received grants from
Sunesis
, Merck, Celgene, and
Bristol-Myers Squibb.Slide3
Annual US diagnoses: 7,820
Annual US deaths: 5,930
Annual US diagnoses: 6,770
Annual US deaths: 4,440
AML = acute myeloid leukemia.
Siegel et al, 2013.
AML
is a clonal malignant proliferation of myeloid blast cells in the marrow with impaired normal hematopoiesis.
AML: Scope of the ProblemSlide4
Age-Specific AML Incidence Rates
Juliusson
et al, 2009.Slide5
Overall Survival Declines With Age
Juliusson
, 2011.Slide6
Survival in Younger
Patients (<60
Yrs) in Different Treatment Eras
Kantarjian et al, 2010.Slide7
Survival in
Older Patients (≥60
Yrs) in Different Treatment Eras
Kantarjian et al, 2010.Slide8
Little Improvement in Survival Seen in Patients ≥70 Years
Kantarjian et al, 2010.Slide9
Survival in
AML Patients:
<60 vs ≥60 Years
Kantarjian et al, 2010.Slide10
How Are Older Patients With AML Being Treated?Slide11
SNF = skilled nursing facility.
Menzin
et al, 2002.
AML Therapy in the Elderly
, US
Age group,
yrs
65-74
75-84
85
Total
N
1,132
1,082
443
2,657
Received chemotherapy, %
44
24
630Hospitalized, %89
91
83
89
Hospital/SNF days, %
33
30
27
31
Median survival,
mos
3
2
1
2
Hospice, %
15
19
20
17Slide12
Juliusson
et al, 2006.
Intention to Induce by Age and
Region (Swedish Registry)Slide13
Menzin
et al, 2006.
Survival in Elderly AML by
Therapy
3,317
elderly patients aged
≥65
years
with
AML
1,193
(36%) received
chemotherapy (younger
, fewer comorbidities)
888 patients matched in both
cohorts
Survival
Median, mos
1 Year, %Overall4.4-Chemotherapy6.1 30
No therapy
1.7
1
0Slide14
Intensive vs Less Intensive
vs
Non
i
ntensive
Treatment of Older Patients With AMLSlide15
BID = twice daily.
NCCN, 2013.
Common
Induction Regimens Used
in O
lder Patients With
AML
Agents
Doses
“3 + 7
”
induction
Cytarabine (100-200 mg/m² infusion x 7 d) and anthracycline (daunorubicin, idarubicin, or
mitoxanrone
x 3 d)
3 + 7
regimen with intensified-dose
daunorubicin
Daunorubicin 90 mg/m² dailyLow-dose Ara
-C20 mg BID for 10 d, at 4-6 wk intervalsAzacitidine75 mg/m2/dDecitabine20 mg/m2 daily for 5 d, repeated monthlySlide16
NCCN, 2013; Rogers, 2010;
Higa
et al, 1991;
Jabbour
, et al; 2006; Harris et al, 2008.
Supportive Care Is Effective but Insufficient as a Primary Treatment
Symptom
Treatment
Fungal infections
Azole antifungals (
posaconazole
,
voriconazole
,
echinacandins
, amphotericin-B)
Bacterial infections
Broad-spectrum antibiotics
Viral infectionsAcyclovir, valacyclovir
LeukocytosisHydroxyureaNeutropeniaG-CSF (filgrastim), GM-CSF (sargramostim) during post-remission therapyAnemia/thrombocytopeniaUse leukocyte-depleted products for transfusion and irradiated blood products for patients receiving immunosuppressive therapy; screen for cytomegalovirusTumor lysis syndromeProphylaxis with intravenous hydration with diuresis, urinary alkalinization, allopurinol; treatment with rasburicaseCognitive decline
Patients should be monitored for nystagmus
,
dysmetria
, slurred speech, and ataxia before each dose of cytarabine
Nausea
/vomiting
Serotonin receptor antagonists (
ondansetron
)
Ocular toxicity
Saline or steroid drops in both eyes during cytarabine therapy
Oral
mucositis
Mouthwash with viscous
lidocaine
, Maalox, and injectable
diphenhydramineSlide17
CR = complete remission; SQ = subcutaneously.
Lowenberg
et al, 1989; Tilly et al, 1990.
“Standard” Chemotherapy
vs
Non
intensive
DNR +
A
ra
-C vs “watch and wait” (
hydroxyurea
)
CR in 58% vs 0%
Median survival: 21 vs 11 weeks
Survival at 2.5 years: 13% vs 0%
Ara
-C SQ 20 mg/m2 for 21 days vs 3 + 7 CR with 3 + 7: 52% vs 32% induction death with 3 + 7: 31% vs 10% Similar survival and CR durationSlide18
MDS = myelodysplastic syndromes.
Burnett et al, 2007.
Low-Dose
Ara
-C
vs
Hydroxyurea ± ATRA in Elderly AML or High-Risk MDS
217 elderly
patients:155
aged
≥65 years,
58
secondary AML,
30 high-risk
MDS
Ara
-C 20 mg BID x 10 every 4-6 weeks
vs hydroxyureaAra-CHydroxyurea
PN10299CR, % 1810.000061-Yr OS, %
27
3
0.0009Slide19
WHO PS = World Health Organization performance status.
Lowenberg
et al, 2009.
Conventional
vs
Escalated
-Dose
Daunorubicin
Daunorubicin
45 mg/m
2
N=411 (%)
Daunorubicin
90 mg/m
2
N=402 (%)
Age, median
yrs
[range]67 [60-79]
67 [60-83]WHO PS 0, 1 2363 (88)43 (10)354 (88)42 (10)Unfavorable cytogenetics98 (24)82 (21)CR221 (54)
259 (64)
Early death
49 (12)
44 (11)Slide20
Lowenberg
et al, 2009.
Conventional
vs
Escalated-dose
Daunorubicin,
Survival by AgeSlide21
IL = interleukin-2; Q = every.
Pautas
et al, 2010.
Idarubicin vs DNR in Induction ±
IL-2
in Maintenance of AML
Outcome
DNR
IDAx3
IDAx4
P
CR (%)
70
83
78
.04
3-Yr EFS (%)
16
23
22.10No difference in outcome by anthracycline armNo difference in outcome by IL-2 treatmentInduction with Ara-C with: 1) DNR 80 mg/m2/d x 3;
2) IDA 12 mg/m2
/d x 3
;
and 3
) IDA 12
mg/m
2
/d x 4
Maintenance with
IL-2 5 x 106/IU/m
2
/d x 5
Q
month
for 1
yearSlide22
Predictors of Treatment OutcomeSlide23
Appelbaum
et al, 2006.
Outcomes of 968 Patients Treated on SWOG Protocols
Patient age,
yrs
N
<56
(368)
56-65
(246)
66-75
(274)
>75
(80)
CR (%)
235
(64)
113 (46)
108 (39)
26 (33)Resistant (%)99 (27)91 (37)101 (37)29 (36)Median overall survival, mos
18.8
9.0
6.9
3.5
Median disease-free survival,
mos
21.6
7.4
8.3
8.9Slide24
Juliusson
et al, 2009.
Proportion of AML (non-APL) Patients, PS 0 to IV at
DiagnosisSlide25
Appelbaum
et al, 2006.
30
-Day
Mortality of
AML
Induction Therapy: Effect of PS
Age (
yrs
)
<56
56-65
66-75
>75
PS
Early Death (%)
0
2
11
121413
5
16
18
2
2
18
31
50
3
0
29
47
82Slide26
OS = overall survival.
Grimwade
et al, 2001.
Karyotype Significantly Impacts
CR and OS in Elderly
AMLSlide27
Appelbaum
et al, 2006.
Unfavorable Risk
Cytogenetics
Increase
With
AgeSlide28
Leith
et al, 1997.
CR
Rate Declines With Additional Cytogenetic Risk Factors
234
elderly AML patients treated with 3 + 7 induction
(SWOG
9031)
Unfavorable cytogenetics/CD34
phenotype
MDR-1 expression
Antecedent hematologic
disease/MDSSlide29
Kantarjian et al, 2006.
Prognostic
Model: MD Anderson
Prognostic Factor
CR Rate
8-Wk Mortality
1-Yr Survival
Age
≥75
yrs
■
■
■
Poor performance status
■
■
■
Unfavorable karyotype
■
■■Anemia■
Leukocytosis
■
Antecedent hematologic disease
■
■
■
Creatinine
>1.3
■
■
■
Elevated lactate dehydrogenase
■
Treated in laminar flow room
■
■
■Slide30
Kantarjian et al, 2006.
Prognostic Model Predicts Survival
Risk Factor
0
1-2
≥3
N
121
568
301
Survival, median
mos
1-yr (%)
2-yr (%)
18
63
35
7
33
19193CR (%)72
51
24
8-Wk mortality (%)
10
26
57Slide31
Kantarjian et al, 2006.
Disease
and
Patient Factors
Predict PrognosisSlide32
DFS = disease-free survival.
Dombret
et al, 2009; NCCN, 2013.
Molecular Risk Factors
Mutation
Impact
Normal
Cytogenetics
NPM1
survival
CEBPA
remission duration, OS, and DFS
FLT3-ITD
remission duration & OS
FLT3-TKD high-level mutations
survival
BAALC
resistance to induction chemotherapy ↓ OSMLL-PTD↓ remission durationGood-Risk CytogeneticsC-KIT
relapse risk & overall survival in patients with t(8;21)Slide33
Becker et al, 2010.
DFS and OS of Patients Age ≥60 Years (A and B) and
Age
≥70
Years (C and D)
With
Diploid AML by NPM1 StatusSlide34
Sekeres
et al, 2009.
Delaying Treatment Safe for Older PatientsSlide35
Decision Making
Based
on
Expected
Outcomes
8-Wk Mortality
CR Rate
3-Yr Survival
Conventional Chemotherapy
15%
40%
15%
Yes
30%
20%
10%
No
a
15-30%
20-40%10%?????aClinical trials of new investigational agents recommended.Nazha & Ravandi, 2013.Slide36
Novel Agents in Clinical DevelopmentSlide37
Selected Novel Agents in Clinical Trials for Older Patients With AML
Class
Examples
Anti-CD33 antibody conjugate
Gemtuzumab
ozogamicin
a,b
DNA methylation inhibitor
Azacitidine,
decitabine
a
HDAC
inhibitor
Valproic
acid,
pracinostat
Immunomodulatory agentLenalidomideaFLT3 kinase inhibitorQuizartinibb, sorafenib
Polo-like kinase (PLK1) inhibitorVolasertibbAminopeptidase inhibitorTosedostatTopoisomerase II inhibitorVosaroxinbProteasome inhibitorBortezomibNovel cytotoxicsClofarabinea, laromustine, amonafide, sapacitabine, CPX-351baOff label; binvestigational.Slide38
Montgomery et al
, 1992.
Clofarabine
N
N
N
N
N
H
2
O
H
O
H
O
C
l
F
Rationally designed purine analog
Resistant to deamination and phosphorolysis
Inhibition of DNA synthesis and repair
Inhibitor of RNR and DNA polymerase
Induction of apoptosisSlide39
CG = cytogenetics.
Kantarjian et al, 2010.
Clofarabine Frontline
Monotherapy
in Elderly
AML Patients
Parameter
N
% CR
% OR
DOR
OS
Age
70
69
33
39
15
7.2AHD4139518.6+12Intermediate CG4648
54
15
12
Unfavorable CG
62
32
42
9.5
7.2Slide40
Faderl
et al, 2008.
Clofarabine + Low Dose
Ara
-C in AML Frontline Patients
≥60 YearsSlide41
Epigenetic Therapy
M
M
M
M
DNA Methylation
Histone Modification
Phosphorylation
Methylation
Acetylation
Azacitidine
Decitabine
SAHA
Valproic acid
DepsipeptideSlide42
AZA = azacitidine; CCR = conventional care regimen; IC = intensive chemotherapy;
LDAC = low-dose cytarabine; BSC = best supportive care.
Fenaux
et al, 2010.
Azacitidine Prolongs Survival
in WHO-Defined
AML
113 older patients with
20-29% blasts (WHO AML)
Median age 70 years; poor cytogenetics 24%
55 randomly assigned to AZA, 58 to conventional care regimens (IC 10, LDAC 18, BSC, 25)
Median follow-up 20 months; median cycles 8 (1-39)
Parameter
AZA
CCR
P
value
CR (%)
18
16NSMedian OS24.516.00.005Hospitalization (pt/yr)3.44.30.03Infection (pt/yr)0.58
1.14
0.003Slide43
HI = hematologic improvement.
Thépot
et al, 2009.
Frontline Azacitidine
165
patients treated
with
azacitidine
75 mg/m
2
/D
5-7
± VPA and ATRA; 32% had 20-29
% marrow
blasts
Median
age 74
years
(31-91); 83% 65 years; median cycles 4; median follow-up 16 monthsResponseNo (%)CR + CRi19 + 3 (13)
PR10 (6)HI28 (17)Median response duration 6.9 months Median survival 9.4 months; 1-year OS 37%19%Slide44
Cashen
et al, 2010.
Frontline Decitabine
in Older
Patients With AML
N
CR
All Patients
55
24%
Presenting Bone Marrow Blast %
<30%
18
28%
30 to <50%
9
20%
≥50%
28
25% Presenting Peripheral Blood Absolute Blast Count
<1000
41
29%
1,000-10,000
11
9%
>10,000
3
0%Slide45
Blum et al, 2010.
10-Day Schedule of Decitabine
for
Older Patients W
ith
Untreated AMLSlide46
TC = treatment choice (best supportive care or low-dose cytarabine)
Kantarjian et al, 2012.
Decitabine
vs TCSlide47
Quintás-
Cardama
et al, 2012.
Epigenetic Therapy
vs
Ara
-C–Containing Regimens Slide48
Faderl
et al, 2012.
Clofarabine +
Low-dose
Ara
-
C Alternating
With Decitabine 60 patients with newly diagnosed AML
Median age 70 years (60-81) Secondary AML 23% Median follow-up 19.6 months 59 evaluable patients:
CR 58%, OR 66% OR 77% with diploid
cytogenetics
OR 45%
with
complex cytogeneticsSlide49
Gemtuzumab
Ozogamicin
Castaigne
et al, 2012.Slide50
Lenalidomide
ELN = European
LeukemiaNet
; ORR
= overall response
rate; RD = resistant disease;
ED = early death.
Pollyea et al, 2013.
Risk Group (ELN)
CR (%)
CRi
(%)
PR (%)
RD (%)
ED (%)
Favorable
14
14
14
570Intermediate-125017508Intermediate-217884225
Adverse
18
18
9
27
27
First-line azacitidine then
lenalidomide
ORR 40
%, including 28%
CR/
CRi
Common adverse events
were gastrointestinal,
fatigue,
and
myelosuppressionSlide51
CPX-351: Liposomal
Daunorubicin
and
Cytarabine
Lancet et al, 2012.
Parameter
CPX-351
(n=26)
7+3 Regimen
(n=15)
Pts with 2 risk factors (%)
23 (88.5)
12 (80.0)
Pts with 3 risk factors (%)
3 (11.5)
3 (20.0)
CR (%)
11 (42.3)
4 (26.7)CRi (%)7 (26.9)0CR + CRi (%)18 (69.2)4 (26.7)60-day mortality (%)1 (3.8)6 (40.0)
Median EFS (mos)
9.1
1.1
Median OS (
mos
)
23 (88.5)
12 (80.0)Slide52
Quizartinib
in Relapsed/Refractory AML
DOR = duration of response.
Cortes et al, 2013
Parameter
FLT3-ITD positive
(n=17)
FLT3-ITD negative
(n=37)
Total
(n=76)
ORR
53.0
14.0
30.3
CR, %
5.9
0
2.6
CRp, %5.95.43.9CRi, %11.806.6PR, %
29.4
8.1
17.1
Median DOR, weeks
NR
NR
13.3
Median OS, weeks
NR
NR
14.0Slide53
Frontline Volasertib
+ LDAC
vs
LDAC in
Elderly Patients
Maertens
et al, 2012.
Event-free SurvivalSlide54
Vosaroxin
: Quinolone Derivative Selective for Topoisomerase II
Stuart et al, 2010;
Roboz
et al, 2010.
Parameter
Frontline
Relapsed/
Refractory
N (treated)
29
69
Median age
71
60 (18 – 73)
ORR (CR +
CRp
)
38%
29%30-day all-cause mortality7%3%Median OS (mos)7.77.1Slide55
Case Study 1
A 62-year-old woman presents with low-grade fever, anemia, thrombocytopenia, and
leucopenia
H
as
no comorbid conditions, no antecedent hematologic disorder, and normal organ
function
Bone
marrow exam reveals M1 AML and diploid cytogenetics
What is the recommended induction therapy for this patient?Slide56
Case Study 2
A 72-year-old woman presents
with low grade fever, anemia (
Hgb
9.4 g/
dL
),
neutropenia (1.6 x 109/L) and thrombocytopenia (42 x
109/L)
Has a history of congestive heart failure and renal insufficiency, as well as antecedent MDS
Serum
creatinine
is 2.1 mg/
dL
. Bone
marrow
exam is consistent with AML with 46% blasts and with complex cytogenetics.
What treatment would you recommend?Slide57
Case Study 3
A 71-year-old man with a history of AML presented with
inv
(16)
.
Treated
with
3 + 7 induction therapy and achieved CR
Post-induction biopsy revealed no residual blasts (<5%) and no hypoplasia
What is the optimal post-remission therapy for this patient?Slide58
Case Study 4
A 75-year-old woman presents with bruising and
petechiae
R
eports some bleeding when brushing her teeth
WBC is 1.2 with 76%
promyelocytes
, Plt 12, and Hgb 8.4Bone marrow exam is consistent with APL. You send a specimen for cytogenetic and molecular studies.
What treatment would you recommend?Slide59
Key Takeaways
Older patients can benefit from treatment in addition to supportive care
CR rates of 50-60% can be achieved using conventional regimens
Treatment does not translate to prolonged survival for most
Patients should be treated in clinical trials
High risk of induction death: low-intensity strategies
Lower risk of induction death: compare conventional to less-intensive strategiesSlide60
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, et al (2006).
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of a phase II pharmacokinetic/ pharmacodynamic (PK/PD)
study
of
combination
voreloxin
and cytarabine in patients
with
relapsed
or
refractory
acute
myeloid
leukemia
.
J
Clin
Oncol
,
28
(15s
).
A
bstract
6526
.Slide63
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