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

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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.

Burnett AK, Milligan D, Prentice AG, et al (2007). A comparison of low-dose cytarabine and hydroxyurea with or without all-trans retinoic acid for acute myeloid leukemia and high-risk myelodysplastic syndrome in patients not considered fit for intensive treatment. Cancer, 109(6):1114-1124.

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Castaigne S, Pautas C, Terré C, et al (2012). Effect of gemtuzumab ozogamicin on survival of adult patients with de-novo acute myeloid leukaemia (ALFA-0701): a randomised, open-label, phase 3 study. Lancet, 379(9825):1508-1516.

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