Case 1

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.

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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(73) 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.

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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 (73). 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.

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Management of AML in Elderly

• Minxiang Gu, MD
• November 1,2002

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Acute Myeloid Leukemia

• Incidence increases with age

- All age 2.3/100,000 - Age?60
13.7/100,000 - Median age 65-70 years old
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(No Transcript)
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Outcome of the treatment in elderly AML
Age lt 60 ? 60
CR 70 45-55 MS 11 months 6-9
months 5 year survival 35-40 5-8
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Response Rate and Mortality of Induction
Chemotherapy
49 34 64 15
Hiddemann, W et al, JCO 17(11) 1999
9
Why are Elderly AML doing poorly?
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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

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Karyotype and the Prognosis
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Elderly AML have higher incidences of unfavorable
chromosomal abnormalities and lower incidences of
favorable chromosomal abnormalities
Frequency of Karyotypes and Age
lt 60 years gt60 years
No. of Patients No. of
Patients
Favorable 108 17 10 4 Intermediate 427 65 175
63 Unfavorable 123 18 94 33
Hiddemann, W et al, JCO 17(11) 1999
13
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 gt 60 and only
  37 in patients lt60.
• Correlated to lower CR, short remission duration
  and poor survival.

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Elderly AML and Secondary AML

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

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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
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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(321), -7/del(7q), 17/I 17q,
complex, -20q, t(11q23), 8, 13.
8, -5/del(5q), -7, del(7q), Complex
t(1517), t(821), inv(16). Complex
gt55 years 79 gt55 years, 64
Uncommon
Low frequency MDR1 usually absent in t(1517),
inv(16) and t(821)
High frequency gt 70 High frequency gt70
Dann.E J, et al Best Practice Research
Clinical Haematology, 14(1) 2001
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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.

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Complete Remission Rate by Disease Status,
Cytogenetic Status, and MDR1 Expression in
Elderly AML (SWOG9031)
- 211patients gt 55, median age 68 years -
Induction 73
Secondary AML De Novo AML
Unfavorable intermed/favorable
Unfavorable intermed/favorable
MDR1 expression
Pts CRs CR Pts CRs CR
Pts CRs CR Pts CRs
CR
Bright/moderate positive (gt0.15) Dim
positive (0.10-0.14) Negative (lt0.10)
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
- MDR1 expression 71 in elderly - A important
prognostic factor for likelihood of CR in
induction chemotherapy
Leith,C P. et al, JCO 89(9) 1997
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Should we treat elderly AML with intensive
chemotherapy?- Supportive Care verses
Anti-leukemia Chemotherapy
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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
Löwenberg, B , et al. JCO 7(9) 1989
60 AML Pts (age 65-82, median age 72, PS 0-4)
ARM A (31)
ARM B (29)
Management
wait and see cytoreductive agent (hydroxyurea
cytarabine) for leukocytosis related complication
1-2 cycles of daunorubicin, vincristine and
cytarabine. one more cycle if achieve CR
CR 58 0 2 Y survival
17 0 Mean survival 21
weeks 11 weeks Median of days in H 55 50
21
What modification should be made to increase
the response rate and reduce the
treatment-related mortality
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Remission induction Chemotherapy
23
Add New Agents and Change the Dose of Cytarabine
RBZ, rubidazone 6-GT, thioguanine
Hiddemann, W et al, JCO 17(11) 1999
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Daunorubicin Dose and Treatment Response to the
Induction Therapy(1)
Hiddemann, W et al, JCO 17(11) 1999
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Daunorubicin Dose and Treatment Response to
Induction Therapy(2)
DNR Dose No. of CR()
ED() DFS at (mg/m2/course)
Patient 5Y()
lt 90 1456 45 26
14 gt 90 877 54 25
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Hiddemann, W et al, JCO 17(11) 1999
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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.

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Postremission Therapy
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Intensive Postremission Chemotherapy in Adults
with Acute Myeloid leukemia
Mayer et al, N Engl J Med 6896, 1994
-1088 Pts 73 induction 693 in
CR 596 Pts consolidation -Dose of
Ara-C 100mg/m2, 400mg/m2 or 3000mg/m2 Q12 day 1,
3, 5.
Likelihood of 4 Y survival Age lt40 38
40-60 27 gt60 9

• ? Only 29 patients gt60 finished 4 courses
  versus 62 of younger patients.

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Cytarabine dose and patients age versus CR in 4
years
AraC dose(mg/m2) CR in 4 years () lt60
gt60 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 lt 60 years of age.

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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
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Postremission therapy in older patients with de
novo acute myeloid leukemia a randomized trial
comparing mitoxantrone and intermediate-dose
cytarabine with standard-dose cytarabine
Richard et al, Blood 98(3),2001
AraC alone (100mg/m2/day, 5 days/month) X 4
7.7 Y follow up
169 medically well
205 Pts in CR(?60)
ID AraC (500 mg/m2/12 hr) mitoxantrone(5mg/m2/12
hr) X 6
AraC AraC mitoxantrone
Relapse 77 82 Median DFS
11 M 10 M Median Survival 20
M 16 M
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Conclusion

• No standard consolidation regimen for elderly
  AML.
• May benefit from standard dose or lower dose
  Ara-C therapy.

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Salvage Therapy for Relapsed or Persistent AML in
Elderly
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Aggressive Salvage Treatment is not Appropriate
for the Majority of Elderly Patients with Acute
Myeloid Leukemia Relapsing from First Complete
Remission
Ferrara F et al, Blood 2000, 96 324a

• 150 patients with relapsed AML after CR1, median
  age 66 (61-79).
• Treatment group (99) HDAC or FLAG
  (fludarabineAraCG-CSF) or IDAC idarubicin/or
  mitoxantrone.
• Control group(51) No treatment. Best supportive
  care Hydrea for leukocytosis.
• Outcome

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• WBC, cytogenetics and age gt or lt 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( CR1gt12M). The remaining ones should be
  managed with BSC or allocated into experimental
  trial.

Ferrara F et al, Blood 2000, 96 324a
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Efficacy and Safety of Gemtuzumab Ozogamicia
(Mylotarg) in Patients With CD33-Positive Acute
Myeloid Leukemia in First Relapse
Sievers,EL et al, JCO 19(13) 2001

• 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 CRCRp 6.8 months
• Median survival
• CR12.6 M CRp11.1M
• NR2.9M Average 5.9M.

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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
• Dyspnea 9
• 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

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The Role of Hematopoietic Growth Factors
39
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
- 173 AML Pts, age ? 65 - Main end point 8 weeks
Neutrophil recover Treatment failure Max 28 days
Lenograstin(5ug/kg/day) or Placebo
73 induction
1 8
28
Days
40

• 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.

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Granulocyte-Macrophage Colony-stimulating Factor
after Initial Chemotherapy for Elderly Patients
with Primary Acute Myelogenous Leukemia
Stone, RM et al N Eng J Med 332(25), 1995
-388 Pts, ? 60, median age 69

• 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

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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.

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• 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.

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Decision making in Elder AML
Diagnosis
Unfavarable biology (Cytogenetics, MDR, 2nd AML)
Contraindication against intensive(standard)
therapy
Yes
No
Yes
No
Supportive care only New approaches
Intensive (standard) therapy
Hiddemann, W et al, JCO 17(11) 1999
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Future

• Reversal of drug resistance PSC833(a
  cyclosporine analogue).
• Non-myeloablation SCT
• Post-translational protein modulator
• Farnesyl transferase inhibitor
• Histone deacetylase inhibitor