Rethinking the Treatment of Older Adults With Acute Myeloid Leukemia

Mark J. Levis, MD, PhD

Associate Professor of Oncology

The Sidney Kimmel Comprehensive Cancer Center

Johns Hopkins University

Disclosure of Conflicts of Interest

Mark J. Levis, MD, PhD, discloses that he has served as an advisor/consultant for Teva Pharmaceuticals and Ambit Biosciences Corp.

Unapproved Use Disclosure

The University of Cincinnati College of Medicine and i3

Health require CME faculty (speakers) to disclose to

attendees when products or procedures being discussed

are off-label, unlabeled, experimental, and/or

investigational (not FDA approved), and any limitations on

the information that is presented, such as data that are

preliminary or that represent ongoing research, interim

analyses, and/or unsupported opinion.

Dr. Levis discloses that he will discuss off-label uses of

decitabine and sorafenib.

Learning Objectives

Assess methods to classify and determine the prognosis of older adults with acute myeloid leukemia (AML)

Explain how patient characteristics and risk stratification affect treatment selection

Evaluate efficacy and safety data on existing and novel therapies for older adults with AML

• Annual US diagnoses: 7,820• Annual US deaths: 5,930

• Annual US diagnoses: 6,770• Annual US deaths: 4,440

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

MRC Trials: Younger Adults 15 to 59 Years (n=7,704)

MRC = United Kingdom Medical Research Council.Burnett, 2012.

MRC Trials: Older Adults 60+ Years (n=3,541)

Burnett, 2012.

Traditional Paradigm for the Treatment of AML

Induction therapy

Complete response

Primary refractory

Salvage therapy

Consolidation chemotherapy

Relapse?

Complete response?

Allogeneic transplant

Modern Paradigm for the Treatment of AML

Complete response?

Induction therapy

Risk Stratify

Complete response

Relapse?

Primary refractory

Salvage therapy

Consolidation chemotherapy

Allogeneic transplantRisk

Stratify

Ara-C = cytarabine; ICE = idarubicin/cytarabine/etoposide; ADE = daunorubicin/cytarabine/etoposide; IA = idarubicin/cytarabine.National Comprehensive Cancer Network (NCCN), 2013.

Common Induction Regimens Used in Adult Patients With AML

Agents Doses

“7 + 3” inductionCytarabine (100–200 mg/m² infusion x 7 d) and anthracycline (daunorubicin, idarubicin, or mitoxanrone x 3 d)

Intensified induction Various combinations of Ara-C, etoposide, anthracycline (ICE, ADE, IA, etc.)

Low-dose Ara-C 20 mg bid for 10 d

Azacitidine 75 mg/m2 daily for 5–10 d

Decitabine 20 mg/m2 daily for 5 d

Hi-DAC = high-dose cytarabine; HLA = human leukocyte antigen.NCCN, 2013.

Common Consolidation Regimens Used in Adult Patients With AML

Agents Doses

“HiDAC” (4 cycles) Cytarabine (3,000 mg/m²) infused over 3 hrs bid on Days 1, 3, and 5

Allogeneic transplant Either myeloablative or nonmyeloablative, with an HLA-matched or alternative donor

Low-dose Ara-C 20 mg bid for 10 d at 4–6 wk intervals

Azacitidine 75 mg/m2/d for 5–10 d, repeated monthly

Decitabine 20 mg/m2/d for 5 d, repeated monthly

How do older patients with AML fit into this modern paradigm?

SNF = skilled nursing facility.Menzin et al, 2002.

AML Therapy in Elderly Americans

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

Age group (yrs)

NA = not applicable.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-Yr (%)

Overall 4.4 NA

Chemotherapy 6.1 30

No therapy 1.7 10

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/thrombocytopeniaLeukocyte-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 declinePatient monitoring 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

DNR = daunorubicin; CR = complete response; 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. “7 + 3”

– CR with “7 + 3”: 52% vs. 32%

– induction death with “7 + 3”: 31% vs. 10%

– Similar survival and CR duration

Pts = patients.Juliusson et al, 2006.

Intention to Induce by Age and Region (Swedish Registry)

Region

Pts

con

side

red

for

rem

issi

on in

duct

ion

ther

apy

(%)

APL = acute promyelocytic leukemia; RI = resistive index. Juliusson et al, 2006.

Survival Among Patients Ages 70–79

(region, sample size)

aData not available for all patients.ATRA = all-trans retinoic acid; MDS = myelodysplastic syndromes.Burnett et al, 2007.

Low-Dose Ara-C vs. Hydroxyurea ± ATRA in Elderly AML or High-Risk MDS

217 elderly patients aged ≥60: 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

na 102 99 NA

CR (%) 18 1 0.00006

1-Year OS (%) 27 3 0.0009

WHO = World Health Organization; PS = performance status.Lowenberg et al, 2009.

Conventional vs. Escalated-Dose Daunorubicin

Daunorubicin

45 mg/m2

No. (%)

Daunorubicin

90 mg/m2

No. (%)

Total patients (n) 411 402

Age, median [range] (yrs) 67 [60–79] 67 [60–83]

WHO PS 0 or 1

PS 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

Lowenberg et al, 2009.

Conventional vs. Escalated-Dose Daunorubicin, Survival by Age (cont.)

VPA = valproic acid; ATRA = all trans retinoic acid; CRi = complete response with incomplete hematologic recovery; PR = partial response; HI = hematologic improvement.Thépot et al, 2009.

Frontline Azacitidine

• Sample of 165 patients treated with azacitidine 75 mg/m2 ± VPA and ATRA ; 32% had 20%–29% marrow blasts

• Median age, 74 yrs (31–91); 83% 65 years; median cycles, 4; median follow-up, 16 mos

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%

AZA = azacitidine; IC = intensive chemotherapy; LDAC = low-dose cytarabine; BSC = best supportive care; CCR = conventional care regimen; NS = not significant. 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 11, LDAC 20, BSC 27) 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

Initial Conclusions

Modern AML treatment requires risk stratification at multiple time points

Treatment confers a survival benefit over supportive care, even in older AML patients

Risk Stratification(Questions to Consider for Each Patient)

Will the patient survive treatment?How likely is it that a patient will achieve

remission?– What type of induction therapy should be used?

If a remission is achieved, will the patient benefit from consolidation?– What type of consolidation therapy should be

used?

Appelbaum et al, 2006.

Thirty-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

Juliusson et al, 2009.

Proportion of AML (Non-APL) Patients, PS 0 to 4 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)

Pts

per

WH

O p

erfo

rman

ce s

tatu

s (%

)

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 mg/dL ■ ■ ■

Elevated lactate dehydrogenase ■

Treated in laminar flow room ■ ■ ■

Kantarjian et al, 2006.

Prognostic Model Predicts Survival

Survival 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

1. Complex karyotype2. Monosomy karyotype3. Deletion of 5 or 74. t(6;9)5. inv(3)6. 11q23 (MLL gene)

Unfavorable1. inv(16)2. t(8;21)3. t(15;17)

Favorable

IntermediateEverything else

Cytogenetic Risk Categories

MLL = mixed lineage leukemia; inv = inversion; t = translocation. Grimwade et al, 2001; Slovak et al, 2000.

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)

Inci

denc

e of

pts

with

ris

k cy

toge

netic

s

Molecular Risk CategoriesFLT3/ITD mutations = unfavorable riskNPM1 mutations = favorable risk

– In the absence of a FLT3/ITD mutation

CEBPA mutations = favorable risk– In the presence of double mutations

C-KIT mutations = unfavorable risk– In the context of core binding factor AML

FLT3 = fms-related tyrosine kinase 3; ITD = internal tandem duplication; NPM1 = nucleophosmin;CEBPA = CCAAT/enhancer binding protein, alpha; C-KIT = type III tyrosine kinase growth factor receptor.Kottaridis et al, 2001; Dohner et al, 2005; Taskesen et al, 2011; Paschka et al, 2006.

APL

CBF(inv[16], t[8;21])

CEBPA

NPM1c

Poor-risk cytogenetics

(5q-; 7q-; inv[3], complex, etc.)

FLT3/ITD

Otherint. risk

AML Categories Defined by Cytogenetic and Molecular Abnormalities in All Adults

NPM1c = mutated nucleophosmin; CBF = core-binding factor; int. = intermediate.Kottaridis et al, 2001; Dohner et al, 2005; Taskesen et al, 2011; Paschka et al, 2006.

APL

CBF(inv16, t8;21)

CEBPA

NPM1c

Poor-risk cytogenetics

(5q-; 7q-; inv[3], complex, etc)

FLT3/ITD

Otherint. risk

AML Categories Defined by Cytogenetic and Molecular Abnormalities in Older Adults

Kottaridis et al, 2001; Dohner et al, 2005; Taskesen et al, 2011; Paschka et al, 2006.

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)

Kar

yoty

pe In

fluen

ce o

n P

atie

nt S

urvi

val

(%)

Wt = wild type; mut = mutation.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

Overall Survival of Older AML Patients With or Without a FLT3/ITD Mutation

Patients enrolled on UK MRC AML16 trial Treated with intensive induction

Lazenby et al, 2014.

Median follow-up, 2.1 years

Nonmyeloablative Allogeneic Transplantin Patients by Decade

PFS = progression-free survival; OS = overall survival. Kasamon et al, 2013.

Sekeres et al, 2009.

Delaying Treatment Safe for Older Patients

More Conclusions

Performance status and karyotype have a major impact on the likelihood of surviving induction therapy in older AML patients

Adverse karyotypes are more common in older AML patients

Molecular and cytogenetic features influence outcomes in older AML patients the same way they do in younger AML patients

If possible, treatment of an older AML patient should be delayed until an initial risk stratification can be performed

Novel Agents in Clinical Development

Selected Novel Agents in Clinical Trials for Older Patients With AML

Class Examples

Purine analog Clofarabinea

DNA methylation inhibitor Azacitidine, decitabinea

Histone deacetylase (HDAC) inhibitor

Vorinostatb, pracinostatb

Anti-CD33 antibody conjugate Gemtuzumab ozogamicina,b

Immunomodulatory agent Lenalidomidea

FLT3 kinase inhibitor Quizartinibb, PLX3397b, ASP2215b

Polo-like kinase (PLK1) inhibitor

Volasertibb

Novel cytotoxics CPX-351b

aOff-label.bInvestigational.Slide adapted from Ravandi F, 2012.

RNR = ribonucleotide reductase.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

OR = overall response; DOR = duration of response; AHD = antecedent hematologic disorder; 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

Clofarabine for Newly-Diagnosed Older AML Patients Median age: 74 years Clofarabine 20 mg/ m2 for 5 days vs. low-dose Ara-C CR rate:

– Clofarabine: 22%– Low-dose Ara-C: 12%

Burnett et al, 2013.

Epigenetic Therapy

M M M M

DNA Methylation Histone Modification

Phosphorylation

Methylation

Acetylation

AzacitidineDecitabine

PracinostatVorinostat

PBC = absolute peripheral blood count.Cashen et al, 2010.

Frontline Decitabine in Older Patients With AML

NCR(%)

All Patients 55 24

Presenting Bone Marrow Blast (%)

<30 18 28

30 to <50 9 20

≥50 28 25

Presenting PBC

<1000 41 29

1,000 to 10,000 11 9

>10,000 3 0

Blum et al, 2010.

Ten-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. Treatment Choice

Newly-diagnosed

AMLRandomize

Complete response?

“7 + 3”/HiDAC

ClofarabineDecitabine

maintenance

Allogeneic transplant

HLA-matched sibling?

FollowRandomize

E2906 Trial on Clofarabine Newly-diagnosed AML, age >60 Multicenter, cooperative group study

Eastern Cooperative Oncology Group (ECOG), 2012.

Gemtuzumab Ozogamicin

Castaigne et al, 2012.

Lenalidomide

ELN = European Leukemia Net; 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

16 of 110 (15%) patients remained alive for >12 months after taking quizartinib and were classified as long-term survivors

CRc 58%

7%

51%

21%

100

80

60

40

20

FLT3/ITD N=110

CR/CRp

CRi

PR

CRc = CR + CRi + CRp.Cortes et al, 2012.

Quizartinib Induces a High Response Rate in Older Patients With

Relapsed/Refractory FLT3/ITD AML

Pat

ient

s ac

hiev

ing

posi

tive

outc

omes

(%

)

Frontline Volasertib + LDAC vs. LDAC in Elderly Patients

Maertens et al, 2012.

Event-Free Survival

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) 0

CR + CRi (%) 18 (69.2) 4 (26.7)

60-d mortality (%) 1 (3.8) 6 (40.0)

Median EFS (mos) 9.1 1.1

Median OS (mos) 23 (88.5) 12 (80.0)

Case Study 1: Transplantation

Case Study 1 A 67-year-old woman presents with low-grade

fever, anemia, thrombocytopenia, and leucopenia Has no comorbid conditions or antecedent

hematologic disorder; organ functions are normal Bone marrow exam reveals AML and cytogenetic

analysis reveals loss of a translocation between chromosome 9 and 11 at band q23 in 17 out of 20 metaphases

What is the recommended therapy for this patient?

Case Study 1 (cont.)

She receives induction with cytarabine, daunorubicin, and etoposide

Achieves a CR• Remission marrow shows normal karyotype• Reduced performance status, ineligible for further

therapy until Day 70 Undergoes a nonmyeloablative allogeneic

transplant with her HLA-matched sister as donor She is in ongoing remission 1 year after her

diagnosis• Normal performance status

Case Study 2: Favorable Risk

Case Study 2

A 72-year-old man presents in December 2010 with dyspnea and a white count of 149,000

No comorbid conditions or history of an antecedent hematologic disorder

Diagnosis: AML Normal karyotype; NPM1c

What treatment would you recommend?

Case Study 2 (cont.)

Receives induction therapy with cytarabine and idarubicin (“7 + 3”)

Achieves a CR Started on HiDAC consolidation therapy Relapses after 22 months Re-induced with HiDAC and achieves a second

remission Enrolled in a clinical trial for maintenance anti-

interleukin-3 receptor (CD123) antibody Remission is ongoing

Case Study 3: Progression of AML

Case Study 3 A 71-year-old man presents with fever, profound

fatigue, anemia, and circulating blasts• ECOG PS of 3• Bone marrow biopsy, 30% blasts• Complex cytogenetics, including loss of

chromosomes 5 and 7 Other past medical history:

• Chronic myelomonocytic leukemia for 1 year• Emphysema• Chronic atrial fibrillation/flutter; on anticoagulation

therapy• Stage III rectal colorectal adenocarcinoma, neo-

adjuvant radiation therapy, post-operation chemo 3 years prior

What treatment would you recommend?

Case Study 3 (cont.)

5-azacitidine 75 mg/m2 for 5 days per cycle; gets monthly treatment as outpatient

Peripheral blood cleared of blasts PS improves Bone marrow shows persistent blasts after 6 cycles Disease progression nearly a year later

• ECOG PS still 1 Referred for a clinical trial

Case Study 4: Other AML subtypes

Case Study 4

A 75-year-old woman presents in February 2010 with

bruising and petechiae Reports some bleeding when brushing her teeth WBC is 9.3 with 71% 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?

WBC = white blood cell count; Plt = platelet count; Hgb = hemoglobin count.

Case Study 4 (cont.)

Receives ATRA/daunorubicin and achieves CR Consolidation with arsenic and ATRA Currently in ongoing remission

Key Takeaways Older patients can benefit from treatment in addition to

supportive care Risk stratification prior to induction is particularly

important for older AML patients Older AML patients are more likely to have unfavorable

karyotypes Cytogenetic and molecular abnormalities influence the

outcome in older AML patients the same way they do in younger AML patients

Patients should be treated in clinical trials whenever possible- Novel agents, as well as novel combinations of

established agents, are currently under investigation

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