Case 1

Case 1

• 82 y/o WF. MDS for one year ( ? cytogenetics). On EPO and Transfusion PRN. transfusion dependence and WBC PTA. WBC 115K, Hb 6.7, PLT 72K. Bone marrow revealed AML (M1). She refused chemotherapy. Hydoxyurea + supportive care. Last WBC 50K. She developed A.fib., CHF and pulmonary edema. She expired on day 10.

Case 2

• 73 y/o WM. MDS(RAEB) for 11 months and transformed into AML. WBC 0.9K, Hb 7, PLT 15K, ANC 0.1. He received full dose of Cytarabine + Idarubicine(7+3) +G-CSF. Day 14, marrow was hypocellular. He had profound pancytopenia, and developed pneumonia and sepsis. He was intubated and went into multi-organ failure. He died on day 21 post-induction.

Case 3• 63 y/o health Asian female. Dx AML on 8/02 in Jakarta,

Indonesia. She was treated with chlorambucil and hydroxyurea. She visited daughter in U.S. and developed fever. WBC 15.2K and blasts 11%. Hb 8.9, PLT 44K. Peripheral blood flowcytometry confirmed AML (M2). She received standard induction chemotherapy with Ara-C and idarubicin (7+3). The course was complicated by persistent fever, bacteremia, GI bleeding, ileus, CHF, pulmonary edema, pneumonia, A.Fib, V-tach. She received granulocyte transfusion for 3 weeks and TPN for one week. The 14 day marrow showed no leukemia. Her WBC started to recover on day 25 post-induction. She stayed in hospital for a total 35 days.

Management of AML in Elderly

Minxiang Gu, MD

November 1,2002

Acute Myeloid Leukemia

• Incidence: increases with age

- All age: 2.3/100,000

- Age60: 13.7/100,000

- Median age: 65-70 years old

Standard treatment of AML in young age patients

AML Induction chemotherapy( Daunarubicin + Cytarabin Etoposide)

20 %resistant

70-80%CR1

Consolidation(HDAC)

Allo BMT

35-40%cure

50-60 %relapsed

33-69% CR2

15% 3-5Y S

50% cure

15-20% relapsed

BMT 25-35% cure

MitoxantronIdarubicinDoxarubicine

HDT +ABMT

Favorable/Intermediate

Unfavorable

Allo feasible

Yes No

HDAC

Mitoxantrone +Eto Ara C

Allo BMT

Salvage chemo(same CR1 regimen,HDAC+Mitoxantrone+Eto)

Donor lymphocyteinfusion (20% CR2)

Nonmyeloablative SCT

2nd Allo hight mortality

Allo

2nd Auto

27-35% 2 Ysurvival

40-50%cure

?%relapse

Outcome of the treatment in elderly AML

Age < 60 60

CR 70 % 45-55 %

MS 11 months 6-9 months

5 year survival 35-40 % 5-8 %

Response Rate and Mortality of Induction Chemotherapy

Hiddemann, W et al, JCO 17(11) 1999

49% 34% 64% 15%

Why are Elderly AML doing poorly?

Major Prognostic Factors in AML

• For response:– Cytogenetics

/molecular genetics

– WBC count

– MDR phenotype

– Secondary AML

– Age

• For relapse:– Cytogenetics /molecular

genetics– Time towards completed

response– WBC count– flt-3 mutations– Autonomous proliferation– Secondary AML– Age

Karyotype and the Prognosis

Elderly AML have higher incidences of unfavorable chromosomal abnormalities and lower incidences of favorable chromosomal abnormalities

< 60 years >60 years

No. of Patients % No. of Patients %

Favorable 108 17 10 4

Intermediate 427 65 175 63

Unfavorable 123 18 94 33

Frequency of Karyotypes and Age :


Elderly AML has high prevalence of MDR expression

• MDR (multidrug resistance gene)

• MDR1:• P-glycoprotein, 170 kDa, chromosome 7• ATP-dependent transport protein• Binds to a variety of substrates (anthracycline,

epipodophylotixin)• Reversal agents: calcium channel blocker (verapamile),

Cyclosporine A, Quinidine, PSC 833. • Expressed in 70% of AML patients > 60 and only 37% in patients

<60. • Correlated to lower CR, short remission duration and poor

survival.

Elderly AML and Secondary AML

• Higher incidence of secondary AML in elderly.

• The de novo AML in elderly is cytogeneticly similar to secondary AML.

The similarity between advanced MDS and elderly AML

Cytogenetics MDS Elderly AML

Normal karyotypes 31% 27%

Single abnormality 14% 13%

Double abnormality 17% 14%

Complex karyotypes 37% 46%

Abnormal 5 20% 31%

Abnormal 7 27% 27%

Rossi G, et al.; Leukemia 14, 2000

Biological characteristics distinguishing secondary AML (t-AML and AML in the elderly) from true de novo AML

t-AML/t-MDS Elderly ‘de novo’ AML True ‘de novo’ AML

Age

Typical cytogenetic abnormality

Multilineage dysplasia/dyspoiesis

Multi drug resistant phenotype (MDR1)

Common in elderly Elderly common in younger

-5/del(5q), inv(3) t(3:21), -7/del(7q), 17/I 17q, complex, -20q, t(11q23), +8, +13.

+8, -5/del(5q), -7, del(7q), Complex

t(15:17), t(8:21), inv(16). Complex

>55 years 79% >55 years, 64% Uncommon

High frequency; > 70% High frequency; >70% Low frequency; MDR1 usually absent in t(15:17), inv(16) and t(8:21)

Dann.E J, et al Best Practice & Research Clinical Haematology, 14(1) 2001

Why are Elderly AML doing poorly? (summary)

• Higher incidence of unfavorable cytogenetics.• Higher incidence of MDR expression.• Increased prevalence of antecedent

hematological disease.• Limited proliferative capacity of hemapoietic

stem cell.• Comorbility and different metabolism cause

high treatment related mortality.

Complete Remission Rate by Disease Status, Cytogenetic Status, and MDR1 Expression in Elderly AML (SWOG9031)

Secondary AML De Novo AML

Unfavorable intermed/favorable Unfavorable intermed/favorable

Pts CRs %CR Pts CRs %CR Pts CRs %CR Pts CRs %CR

MDR1 expression

Bright/moderate positive (>0.15)

Dim positive (0.10-0.14)

Negative (<0.10)

15 2 13 9 1 11 17 4 24 40 19 48

2 0 0 3 1 33 6 3 50 16 10 63

2 0 0 7 4 57 2 0 0 27 22 81

Leith,C P. et al, JCO 89(9) 1997

- 211patients > 55, median age 68 years- Induction: 7+3

- MDR1 expression 71% in elderly- A important prognostic factor for likelihood of CR in induction chemotherapy

Should we treat elderly AML with intensive

chemotherapy?

- Supportive Care verses Anti-leukemia Chemotherapy

60 AML Pts (age 65-82, median age 72, PS 0-4)

ARM A (31) ARM B (29)

Management 1-2 cycles of daunorubicin, vincristine and cytarabine. + one more cycle if achieve CR

“wait and see” + cytoreductive agent (hydroxyurea +cytarabine) for leukocytosis related complication

CR 58 % 0 %

2 Y survival 17% 0 %

Mean survival 21 weeks 11 weeks

Median % of days in H 55% 50%

Löwenberg, B , et al. JCO 7(9) 1989

On the Value of Intensive Remission-Induction Chemotherapy in Elderly Patients of 65+ Years With Acute Myeloid Leukemia: A Randomized Phase

III Study of the European Organization for Research and Treatment of

Cancer Leukemia Group

What modification should be made

to increase the response rate and reduce the treatment-related

mortality

Remission induction Chemotherapy

Therapy Age No. of CR ED Disease-free Overall First (mg/m2) group patients (%) (%) Survival(months) Survival(months) Author

DNR 3 X 50 55-70 90 43 NA 9 5 BishopAraC 7 X100Eto 75 X7DNR 3 X 50 54 NA 14 8AraC 7 X100RBZ 4 X 100 > 65 87 52 10 13.8 12.8 TillyAraC 7 X200 (P,.01) (P<.01)LD-AraC21 X 20 32 31 8.3 8.8DNR 3 X 45 >60 100 38 46 NA 2.5 DillmanAraC7 X 200DNR 3 X 45 44 40 NA 3AraC 7 X 100DNR 1 X 60 > 65 51 23 23 2.7 3.7 RuutuAraC 5 X 2006-GT 5 X 200Eto 75 X 160 60 4 7.2 9.96-GT 5 X 200 (P=.007) (P+.042)Ida 3 X 15

Add New Agents and Change the Dose of Cytarabine


RBZ, rubidazone; 6-GT, thioguanine

Daunorubicin Dose and Treatment Response to the Induction Therapy(1)

Therapy Age No. of CR (%) ED(%) Disease-Free Overall First(mg/m2) Group Patients Survival (months)survival(months) Author

DNR 3 x45 >60 226 31 54 NA NA YatesAraC 7 x 100DNR 3 X30 47 41 NA NAAraC 7 x 100 P<.05DNR 3 x 60 35 57 NA NAAraC 7 x 100DNR 3 x 60 >70 40 25 60 NA 1 KahnAraC 7 x 2006-TGDNR 1X 50 30 25 NA 5AraC 5 x 200 (P< .05) (P=.02)6-TGDNR 3 X 50 >60 335 47 33 NA 12% at 10 years ReesAraC 5 x 200DNR 1X 50 45 28 NA 5% at 10 yearsAraC 1 X 100DNR 3 X 60 >60 340 55 20 8 8 Buchner AraC 7 X 200 (P=.026) (P=.031) 20% at 5 years 14% at 5 years updated 19986-TG 7 X 200DNR 3 X 30 43 31 7 2AraC 7 X 200 10% at 5 years 5% at 5 years6-TG 7 X 200


Daunorubicin Dose and Treatment Response to Induction Therapy(2)

DNR Dose No. of CR(%) ED(%) DFS at (mg/m2/course) Patient 5Y(%)

< 90 1456 45 26 14

> 90 877 54 25 26


Remission Induction Chemotherapy (summary)

• Agents and Intensity:

• Add etoposide or 6-TG - not beneficial

• Increase or decrease the dose of cytarabine - not beneficial

• Reduce DNR dose: impact on CR rate and long-tern outcome

• Conclusion:

• As a population, favor intensive therapy (standard dose) to improve initial CR and long-tern survival.

Postremission Therapy

Intensive Postremission Chemotherapy in Adults with Acute Myeloid leukemia

Likelihood of 4 Y survival:

Age %

<40 38

40-60 27

>60 9

Mayer et al, N Engl J Med 6:896, 1994

-1088 Pts 7+3 induction 693 in CR 596 Pts consolidation-Dose of Ara-C 100mg/m2, 400mg/m2 or 3000mg/m2 Q12 day 1, 3, 5.

Only 29% patients >60 finished 4 courses versus 62% of younger patients.

Cytarabine dose and patients age versus CR in 4 years

AraC dose(mg/m2) CR in 4 years (%)

<60 >60

100 24 16

400 29 16

3000 44 16

• Conclusion: Consolidation chemotherapy with HDAC (3g/m2) improves disease free and overall survival only in patient < 60 years of age.

Mitoxantrone Versus Daunorubicin in Induction-Consolidation Chemotherapy --- The Value of Low Dose Cytarabine for Maintenance

of Remission , and an Assessment of Prognostic Factors in Acute Myeloid Leukemia Cooperative Group of the European Organization for the Research and Treatment of Cancer and the Dutch-Belgian Hemato-

Oncology Cooperative Hovon Group Randomized Phase III Study AML

Lowenberg et al, JCO 16(3), 1998

489 Pts (median age 68)

Induction Chemotherapy (DNR + AraC or MTZ + AraC)

147 CR Pts

AraC 10 mg/m2 SC Q12 Hr day 1-12, Q42 days interval x 8 cycles or disease relapse.

No further treatment

5Y DFS 13% 7 % P = 0.006

OAS 18% 15% P = 0.29

Postremission therapy in older patients with de novo acute myeloid leukemia: a randomized trial comparing mitoxantrone and

intermediate-dose cytarabine with standard-dose cytarabine

205 Pts in CR(60)

169 medically well

AraC alone (100mg/m2/day, 5 days/month) X 4

ID AraC (500 mg/m2/12 hr) +

mitoxantrone(5mg/m2/12hr) X 6

7.7 Y follow up

AraC AraC + mitoxantrone

Relapse 77% 82%

Median DFS 11 M 10 M

Median Survival 20 M 16 M

Richard et al, Blood 98(3),2001

Conclusion

• No standard consolidation regimen for elderly AML.

• May benefit from standard dose or lower dose Ara-C therapy.

Salvage Therapy for Relapsed or Persistent AML in Elderly

Aggressive Salvage Treatment is not Appropriate for the Majority of Elderly Patients with Acute Myeloid

Leukemia Relapsing from First Complete Remission

• 150 patients with relapsed AML after CR1, median age 66 (61-79).

• Treatment group (99): HDAC or FLAG (fludarabine+AraC+G-CSF) or IDAC +idarubicin/or mitoxantrone.

• Control group(51): No treatment. Best supportive care + Hydrea for leukocytosis.

• Outcome:

Ferrara F et al, Blood 2000, 96: 324a

ASC BSC ASC(CR1>12M) ASC(CR1<11M)CR2 36% 0%Resistent disease 41%Induction death 22%Median SFR 5M 3M 10M 4MMedian CR2 duration 8M 11M 5M

• WBC, cytogenetics and age > or < 70 had no inference on SFR.

• BSC group required less hospitalization(p=.003), less transfusion (p=.004 and .006) and less antibiotics(p=.001).

• Conclusion:

– Aggressive salvage chemotherapy results in a true survival benefit only for a minority of elderly AML( CR1>12M). The remaining ones should be managed with BSC or allocated into experimental trial.

Ferrara F et al, Blood 2000, 96: 324a

Efficacy and Safety of Gemtuzumab Ozogamicia (Mylotarg) in

Patients With CD33-Positive Acute Myeloid Leukemia in First Relapse

• Humanized Anti-CD 33 antibody conjugated with calicheamicin.

• 142 patients median age 61.

• Dose: 9 mg/m2 IV over 2 hours, Q 14 days for 2 doses.

• Outcome:– CR= 23% ; CRp = 19%; OR = 42%

– RFS of CR+CRp = 6.8 months

– Median survival:

CR=12.6 M; CRp=11.1M;

NR=2.9M; Average = 5.9M.

Sievers,EL et al, JCO 19(13) 2001

Treatment-Emergent Adverse Events (Grade 3 and 4)

• Infusion related: – Chill 11%

– Fever 7%

– Hypotension 4%

– 1st dose 34%; 2nd dose 12 %

• Treatment related:– Sepsis 16%

– fever 15%

– Chill 13%

– N/V 11%

– Dyspnea9%

– Hypertension 9%

– Hypotension 7%

– Pneumonia 7%

– Hyperbilirubinemia 33%

– Elevated ALT and ALT 17%

– Mucositis 4%

– Myelosuppression• Neutropenia 93 %

• Thrombocytopenia 99%

• Bleeding 15% – Epistaxis: 3%

– ICH: 4%

The Role of Hematopoietic Growth Factors

A Controlled Study of Recombinant Human Granulocyte Colony-stimulating Factor in Elderly Patients after

Treatment for Acute Myelogenous Leukemia

Dombret. H et al, N Eng J Med 332(25) 1995

1 8 28

7+3 inductionLenograstin(5ug/kg/day) or Placebo

Neutrophil recoverTreatment failureMax 28 days

Days

- 173 AML Pts, age 65

- Main end point: 8 weeks

• G-CSF given after the induction chemotherapy for AML patients 65 year old:

• Did not decrease the mortality rate at 8 weeks.

• Did not improve the overall survival.

• Did not cause persistent or early relapse of disease

• Did shorten the duration of neutropenia.

• Did improve CR.

G-CSF Placebo8 wks Mortality Rate 23% 27% P=0.06Median duration of Neutropenia 21 days 27 days P<0.01CR 70% 47% P=0.002OAS in 8 weeks P=0.76

Granulocyte-Macrophage Colony-stimulating Factor after Initial Chemotherapy for Elderly Patients with Primary Acute Myelogenous Leukemia

• GM-CSF given after the induction chemotherapy for AML patients 60 year old:

• Did not decrease the severe myelosuppression

• Did not stimulate re-growth of leukemia

• Did not improve CR

Stone, RM et al N Eng J Med 332(25), 1995

-388 Pts, 60, median age 69GM-CSF Placebo

No.of patients 193 195CR 51% 54% P=0.61Treatment failure 2% 2%Median duration of Neutropenia15 days 17 days P=0.02

Summary

• Elderly AML represent a discrete population in terms of the biology of the disease, prognosis and treatment-related complications. It should be managed differently from the younger age population.

• The cytogenetics, MDR expression, secondary AML, performance status and comorbility play important roles in the clinical decision making.

• If there is no contraindication, the standard induction chemotherapy is favored to achieve better CR rate and long-term survival.

• Hematopoietic growth factors can be used safely to shorten the duration of critical neutropenia, but not improve CR rate and overall survival.

• The standard regimen for postremission therapy has not been established. Standard or low dose of Ara-C can be considered.

• Aggressive chemotherapy in relapsed AML only show survival benefit in small group of patients. Mylotarg shows benefit in this setting.

Diagnosis

Unfavarable biology

(Cytogenetics, MDR, 2nd AML)

Yes No Contraindication against intensive(standard) therapy

Yes NoSupportive care onlyNew approaches

Intensive

(standard) therapy


Decision making in Elder AML

Future

• Reversal of drug resistance: PSC833(a cyclosporine analogue).

• Non-myeloablation SCT

• Post-translational protein modulator:– Farnesyl transferase inhibitor– Histone deacetylase inhibitor

Documents

Case 1