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Understanding Evolving Treatment Paradigms for Older Adults With Acute
Myeloid Leukemia
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 consultant/advisor for Pfizer, Sunesis, Amgen, and Seattle Genetics. He has also received grants from Sunesis, Merck, Celgene, and Bristol-Myers Squibb.
• 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 Problem
Age-Specific AML Incidence Rates
Juliusson et al, 2009.
16-24 25-29 30-34 35-39 40-44 45-49 50-54 55-59 60-64 65-69 70-74 75-79 80-84 85-89 90+ 0
20
40
60
80
100
120
140
160
180
200
Males Females All
Patient Age (yrs)
Inc
ide
nc
e
Overall Survival Declines With Age
Juliusson, 2011.
Survival in Younger Patients (<60 Yrs) in Different Treatment Eras
Kantarjian et al, 2010.
Survival in Older Patients (≥60 Yrs) in Different Treatment Eras
Kantarjian et al, 2010.
Little Improvement in Survival Seen in Patients ≥70 Years
Kantarjian et al, 2010.
Survival in AML Patients:<60 vs ≥60 Years
Kantarjian et al, 2010.
How Are Older Patients With AML Being Treated?
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 6 30
Hospitalized, % 89 91 83 89
Hospital/SNF days, % 33 30 27 31
Median survival, mos 3 2 1 2
Hospice, % 15 19 20 17
Juliusson et al, 2006.
Intention to Induce by Age and Region (Swedish Registry)
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, %
Overall 4.4 -
Chemotherapy 6.1 30
No therapy 1.7 10
Intensive vs Less Intensive vs Nonintensive Treatment of Older Patients With
AML
BID = twice daily.NCCN, 2013.
Common Induction Regimens Used in Older Patients With AML
Agents Doses
“3 + 7” inductionCytarabine (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 daily
Low-dose Ara-C 20 mg BID for 10 d, at 4-6 wk intervals
Azacitidine 75 mg/m2/d
Decitabine 20 mg/m2 daily for 5 d, repeated monthly
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 infectionsAzole antifungals (posaconazole, voriconazole, echinacandins, amphotericin-B)
Bacterial infections Broad-spectrum antibiotics
Viral infections Acyclovir, valacyclovir
Leukocytosis Hydroxyurea
Neutropenia G-CSF (filgrastim), GM-CSF (sargramostim) during post-remission therapy
Anemia/thrombocytopeniaUse leukocyte-depleted products for transfusion and irradiated blood products for patients receiving immunosuppressive therapy; screen for cytomegalovirus
Tumor lysis syndromeProphylaxis with intravenous hydration with diuresis, urinary alkalinization, allopurinol; treatment with rasburicase
Cognitive declinePatients 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 diphenhydramine
CR = complete remission; SQ = subcutaneously.Lowenberg et al, 1989; Tilly et al, 1990.
“Standard” Chemotherapy vs Nonintensive
DNR + Ara-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 duration
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 hydroxyurea
Ara-C Hydroxyurea P
N 102 99
CR, % 18 1 0.00006
1-Yr OS, % 27 3 0.0009
WHO PS = World Health Organization performance status.Lowenberg et al, 2009.
Conventional vs Escalated-Dose Daunorubicin
Daunorubicin
45 mg/m2
N=411 (%)
Daunorubicin
90 mg/m2
N=402 (%)
Age, median yrs [range] 67 [60-79] 67 [60-83]
WHO PS 0, 1
2
363 (88)
43 (10)
354 (88)
42 (10)
Unfavorable cytogenetics 98 (24) 82 (21)
CR 221 (54) 259 (64)
Early death 49 (12) 44 (11)
Lowenberg et al, 2009.
Conventional vs Escalated-dose Daunorubicin, Survival by Age
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 .10
• No difference in outcome by anthracycline arm
• No difference in outcome by IL-2 treatment
• Induction 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/m2/d x 4
• Maintenance with IL-2 5 x 106/IU/m2/d x 5 Q month for 1 year
Predictors of Treatment Outcome
Appelbaum et al, 2006.
Outcomes of 968 Patients Treated on SWOG Protocols
Patient age, yrsN
<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 8.9
Juliusson et al, 2009.
Proportion of AML (non-APL) Patients, PS 0 to IV at Diagnosis
16-24 25-29 30-34 35-39 40-44 45-49 50-54 55-59 60-64 65-69 70-74 75-79 80-84 85-89 90+ All0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
WHO 0
WHO I
WHO II
WHO III
WHO IV
Missing
Age (yrs)
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 12 14
1 3 5 16 18
2 2 18 31 50
3 0 29 47 82
OS = overall survival.Grimwade et al, 2001.
Karyotype Significantly Impacts CR and OS in Elderly AML
CR OS (5-year)0
10
20
30
40
50
60
70
80
90
100
72
34
53
15
26
2
Favorable (7%): t(15;17), t(8;21), inv(16)
Intermediate (79%): normal, all others
Unfavorable (14%): complex (>5 abnormal)
Appelbaum et al, 2006.
Unfavorable Risk Cytogenetics Increase With Age
<55 56-65 66-75 >750%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
17
6 5 4
4855 56
45
35 39 39 51
Unfavorable
Intermediate
Favorable
Age (yrs)
Leith et al, 1997.
CR Rate Declines With Additional Cytogenetic Risk Factors
0 risk factors 1 risk factor 2 risk factors 3 risk factors0
10
20
30
40
50
60
70
80
90
100
81
44
24
12
• 234 elderly AML patients treated with 3 + 7 induction (SWOG 9031)
• Unfavorable cytogenetics/CD34 phenotype
• MDR-1 expression
• Antecedent hematologic disease/MDS
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 ■ ■ ■
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 (%)
186335
73319
193
CR (%) 72 51 24
8-Wk mortality (%) 10 26 57
Kantarjian et al, 2006.
Disease and Patient Factors Predict Prognosis
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 ↓ OS
MLL-PTD ↓ remission duration
Good-Risk Cytogenetics
C-KIT relapse risk & overall survival in patients with t(8;21)
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 Status
Sekeres et al, 2009.
Delaying Treatment Safe for Older Patients
Decision Making Based on Expected Outcomes
8-Wk Mortality CR Rate 3-Yr
SurvivalConventional Chemotherapy
15% 40% 15% Yes
30% 20% 10% Noa
15-30% 20-40% 10% ?????
aClinical trials of new investigational agents recommended.
Nazha & Ravandi, 2013.
Novel Agents in Clinical Development
Selected Novel Agents in Clinical Trials for Older Patients With AML
Class Examples
Anti-CD33 antibody conjugate Gemtuzumab ozogamicina,b
DNA methylation inhibitor Azacitidine, decitabinea
HDAC inhibitor Valproic acid, pracinostat
Immunomodulatory agent Lenalidomidea
FLT3 kinase inhibitor Quizartinibb, sorafenib
Polo-like kinase (PLK1) inhibitor Volasertibb
Aminopeptidase inhibitor Tosedostat
Topoisomerase II inhibitor Vosaroxinb
Proteasome inhibitor Bortezomib
Novel cytotoxics Clofarabinea, laromustine, amonafide, sapacitabine, CPX-351b
aOff label; binvestigational.
Montgomery et al, 1992.
Clofarabine
N
N N
NNH2
OHO
HO
Cl
F
Rationally designed purine analog
Resistant to deamination and phosphorolysis
Inhibition of DNA synthesis and repair
Inhibitor of RNR and DNA polymerase
Induction of apoptosis
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 7.2
AHD 41 39 51 8.6+ 12
Intermediate CG 46 48 54 15 12
Unfavorable CG 62 32 42 9.5 7.2
Faderl et al, 2008.
Clofarabine + Low Dose Ara-C in AML Frontline Patients ≥60 Years
Clo Clo + Ara-C Total0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
31
6759
38
2023
31
19 21
Induction deaths
Resistance
CR + CRp
Epigenetic Therapy
M M M M
DNA Methylation Histone Modification
Phosphorylation
Methylation
Acetylation
AzacitidineDecitabine
SAHAValproic acidDepsipeptide
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 16 NS
Median OS 24.5 16.0 0.005
Hospitalization (pt/yr) 3.4 4.3 0.03
Infection (pt/yr) 0.58 1.14 0.003
HI = hematologic improvement.Thépot et al, 2009.
Frontline Azacitidine
• 165 patients treated with azacitidine 75 mg/m2/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 months
Response No (%)
CR + CRi 19 + 3 (13)
PR 10 (6)
HI 28 (17)
• Median response duration 6.9 months
• Median survival 9.4 months; 1-year OS 37%
19%
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%
Blum et al, 2010.
10-Day Schedule of Decitabine for Older Patients With Untreated AML
All Patients (N =
53)
Age <74 (N =
25)
Age 74+ (N =
28)
Normal Karyotype
(N = 21)
Complex Karyotype
(N = 16)
Monosomy 7 / del(7q) (N = 11)
0
20
40
60
80
100
CR Incomplete CR
Perc
ent R
espo
nse
TC = treatment choice (best supportive care or low-dose cytarabine)Kantarjian et al, 2012.
Decitabine vs TC
Quintás-Cardama et al, 2012.
Epigenetic Therapy vs Ara-C–Containing Regimens
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 cytogenetics
Gemtuzumab Ozogamicin
Castaigne et al, 2012.
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 57 0
Intermediate-1 25 0 17 50 8
Intermediate-2 17 8 8 42 25
Adverse 18 18 9 27 27
• First-line azacitidine then lenalidomide• ORR 40%, including 28% CR/CRi• Common adverse events were gastrointestinal,
fatigue, and myelosuppression
CPX-351: Liposomal Daunorubicin and Cytarabine
Lancet et al, 2012.
ParameterCPX-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) 0
CR + 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)
Quizartinib in Relapsed/Refractory AML
DOR = duration of response.Cortes et al, 2013
ParameterFLT3-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, % 5.9 5.4 3.9
CRi, % 11.8 0 6.6
PR, % 29.4 8.1 17.1
Median DOR, weeks NR NR 13.3
Median OS, weeks NR NR 14.0
Frontline Volasertib + LDAC vs LDAC in Elderly Patients
Maertens et al, 2012.
Event-free Survival
Vosaroxin: Quinolone Derivative Selective for Topoisomerase II
Stuart et al, 2010; Roboz et al, 2010.
Parameter FrontlineRelapsed/Refractory
N (treated) 29 69
Median age 71 60 (18 – 73)
ORR (CR + CRp) 38% 29%
30-day all-cause mortality 7% 3%
Median OS (mos) 7.7 7.1
Case Study 1
A 62-year-old woman presents with low-grade fever, anemia, thrombocytopenia, and leucopenia
Has 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?
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?
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?
Case Study 4
A 75-year-old woman presents with bruising and
petechiae Reports some bleeding when brushing her teeth WBC is 1.2 with 76% promyelocytes, Plt 12, and Hgb
8.4 Bone marrow exam is consistent with APL. You send
a specimen for cytogenetic and molecular studies.
What treatment would you recommend?
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 strategies
References
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Blum W, Garzon R, Klisovic RB, et al (2010). Clinical response and miR-29b predictive significance in older AML patients treated with a 10-day schedule of decitabine. Proc Natl Acad Sci USA, 107(16):7473-7478.
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