Current Status and Controversies of Acute Myeloid Leukemia Induction Therapy

1
TREATMENT OPTIONS IN AML A PRACTICAL CASED-BASE
D APPROACH
2
Current Status and Controversies in Acute Myeloid
Leukemia Induction Therapy

• Edward A. Stadtmauer, MD
• University of Pennsylvania Health System

3
Acute Myeloid Leukemia (AML)
4
Acute Myeloid Leukemia

• Uncontrolled proliferation of immature bone
  marrow cells
• Transformed cells incapable of normal
  differentiation into mature myeloid cells
• Leukemic cells prevent the maturation and
  differentiation of other bone marrow cells
• Results in anemia, low platelets, and
  neutropenia
• Mortality results primarily from infection,
  bleeding, or tumor lysis

5
Acute Myeloid Leukemia

• Median age at diagnosis 62 to 64 years
• Incidence
• lt65 years of age 1.8 cases per 100,000
• gt65 years of age 16.3 cases per 100,000
• Approximately 12,000 cases in 2004
• 1.2 of all cancer deaths
• Most common cause of cancer death in young men
  and women
• Public health problem in older adults

6
Age-Specific Incidence Rates for AML
1995-1998
35
Male
Female
30
All persons
25
20
Average Annual Rate per 100,000
15
10
5
0
00-04
05-09
10-14
15-19
20-24
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
Age (yrs)
NCI SEER Program, 1995-1999.
7
Initial Therapy of AML

• Complete remission (CR) must be attained to cure
  patient
• CR defined as
• Clearance of peripheral blood bone marrow of
  leukemic blasts
• Reconstitution of normal hematopoiesis
• Resolution of leukemic infiltrates

• Diagnosis

Remission Induction
Post-remission Therapy
Consolidation Chemotherapy
SCT
8
Remission Induction
Induction
Relapse
Relapse
Cure
Clinically Detectable Disease

• Total Leukemic Cell Number

Time
9
Post-remission Therapy
Induction
Consolidation
Consolidation

Clinically Detectable Disease

• Total Leukemic Cell Number

Cure
Time
10
Acute Myeloid Leukemia Remission Induction

• Cytarabine 100mg/m2/day x 7 days continuous
  infusion anthracycline bolus x 3 days
• Add ATRA if APL (may delete cytarabine)
• Expect 60 to 80 complete remission rateif lt60
  years
• One of the major cancer therapy success stories
  of the 20th century
• But not all AML has a good prognosis

11
Prognostic Factors in AML

• Age
• ?60 years unfavorable
• Cytogenetics
• Favorable t(821), inv16, t(1517)
• Intermediate normal, -Y, 6, 8 others not
  considered favorable or unfavorable
• Poor Translocations or inversion of chromosome
  3, monosomy 5 or 7, t(69), t(922), abn 11q23,
  or complex
• Presenting white blood cell count
• Hyperleukocytosis gt100,000/µL unfavorable
• Treatment-induced AML or history of
  myelodysplastic syndrome
• Other unfavorable indicators
• CD34 expression, MDR phenotype, FLT3-activating
  mutations, and Bcl-2 expression

12
SWOG/ECOG Adult AML Age lt56 Cytogenetics and
Survival
100
At Risk Deaths Estimated (CI) at 5
Years Favorable 121 53 55 (45-64) Intermedia
te 278 168 38 (32-44) Unfavorable 184 162 11
(7-16)
80
60
Survival ()
40
20
Heterogeneity of 3 groups Plt.0001
0
4
6
0
2
8
Years After Entering Study
Slovak et al. Blood. 2000.
13
Comparison of Prognostic Factors Older and
Younger Adults With AML

• Characteristic lt60 years ?60 years
• /100,000 in US 1.8 17.6
• Cytogenetics
• Favorable 6-12 1-4
• Unfavorable 3-7 6-18
• MDR1 expression 35 71
• Secondary AML 8 20-50

Sekeres. Hematology. 2004.
14
ECOG AML Survival Data
lt60 years gt60 years
Study Year. 1989-1997, n553 Median Survival 3.2
months 5-Year Survival 12
Study Year. 1989-1997, n1044 Median Survival
20.6 months 5-Year Survival 37
1.0
1.0
Study Year. 1983-1986, n142 Median Survival
6.3, months 5-Year Survival 13
Study Year. 1983-1986, n499 Median Survival
13.4 months 5-Year Survival 24
0.8
0.8
0.6
0.6
Study Year. 1973-1979, n293 Median Survival 3.5
months 5-Year Survival 6
Study Year. 1973-1979, n454 Median Survival
11.3 months 5-Year Survival 11
Survival
Survival
0.4
0.4
0.2
0.2
0.0
0.0
0
20
25
5
10
15
0
5
25
10
15
20
Years
Years
Appelbaum. Hematology. 2001.
15
Current Common Clinical Questions

• Should every patient with AML receive induction
  therapy?
• How old is old?
• What is the best anthracycline?
• What is the best dose of cytarabine?
• What is the best consolidation?

16
Older Adults Are Not as Responsive to or
Tolerant of Treatment

• Comorbid diseases
• Slow metabolism of induction-regimen drugs
• Particularly cytarabine
• High drug levels
• Hesitancy to give full doses
• Biologically poor prognosis

17
Randomized Trials of Induction Therapy gt60 Years

• Only 2 studies have been reported
• Lowenberg B, et al. J Clin Oncol. 198971268.
• Survival advantage for induction chemotherapy
  but
• 21 weeks vs. 11 weeks
• Median survival 16 days longer than the time
  spent in the hospital

18
Induction Therapy Decision-Making and
Expectations of AML gt60 years

• Sekeres MA, et al. Leukemia. 200418809.
• 43 patients gt60 years
• Approx. 50 chose induction chemotherapy
• 1-year mortality 63, no difference in treatment
  groups
• Induction chemotherapy 79 of first 6 weeks in
  hospital
• Supportive care 14 of first 6 weeks in hospital
• Older patients overestimate potential benefit
  from induction therapy
• 74 patients rate chance of cure gt50
• 90 patients rate 1-year survival gt50
• 89 physicians rate chance of cure lt10
• Most patients do not recall alternatives to
  therapy received
• all were presented options

19
Treatment Options for Older Patient

• Be realistic
• Supportive care/Palliation
• Blood and platelet transfusions
• Antibiotics
• Growth factors
• Standard-dose induction chemotherapy
• Low-dose chemotherapy
• Hydrea?
• Low-dose cytarabine
• Clinical trials!

20
Is There a Best Antracycline?(Age lt60)

• Comparisons
• Idarubicin 12 mg/m2 vs. daunorubicin
• Blood 1991, 1992 JCO 1992 EJC 1991
• Amsacrine vs daunorubicin
• Leukemia 1999 JCO 1987
• Mitoxantrone vs. daunorubicin
• Leukemia 1990 Ann Hematol 1994
• Summary Similar outcomes
• Current trials
• Daunorubicin 45 mg/m2 vs. daunorubicin 90 mg/m2

21
Is There a Best Antracycline? (Age gt60)

• No standard
• Rowe JM, et al. Blood. 2004103479.
• Cytarabine 100 mg/m2 intravenously continuous
  infusion
• for 7 days
• Daunorubicin 45 mg/m2 or mitoxantrone 12 mg/m2 or
  idarubicin 12 mg/m2 bolus intravenously for 3
  days
• No difference in efficacy or toxicity (35-50
  CR)
• SWOG. Blood. 20021003869.
• Mitoxantrone and etoposide vs. daunorubicin and
  cytarabine
• No benefit of ME over DA
• MRC. Blood. 2001981302.
• DAT best but not direct comparison at same
  cytarabine doses
• Summary Similar outcomes

22
Survival by Anthracycline Type
100
DA n116
MA n114
80
IA n118
60
Survival ()
40
20
0
1
2
3
4
5
0
Years
Rowe JM, et al. Blood 2004103479.
23
Is There a Best Dose of Cytarabine in Induction?

• No evidence for a dose escalation above
• 100 mg/m2
• 100200 mg/m2 standard
• Addition of high-dose cytarabine to the induction
  regimen has not yet been shown to increase
  efficacy, but does increase toxicity

24
Consolidation Therapy for AML

• Age lt60 years
• At least 3 cycles of HiDAC (3g/m2 bid D1,3,5)
• Superior to 1 cycle of HiDAC
• Superior to low-dose cytarabine maintenance
• Superior to no post-remission therapy
• Role of stem cell transplant
• Age gt60 years
• No randomized trial shows any post-remission
  therapy better than no therapy
• But . . . all studies showing long term survival
  include consolidation
• Single cycle of HiDAC
• Repeated cycles of induction therapy
• Low-dose cytarabine maintenance
• IL-2 and histamine maintenance

25
Summary AML Remission Induction Therapy

• Combination therapy
• Cytarabine plus an anthracycline (daunorubicin,
  idarubicin, or mitoxantrone)
• 73 schedule
• Remission induction rates
• 70 to 80 in patients 18 to 40 years of age
• 60 to 70 in patients 40 to 60 years of age
• 40 to 50 in patients gt60 years of age
• Standard consolidation includes cycles of HiDAC
• 30 to 45 long-term relapse-free survival lt60
  years
• No clear benefit for age gt60 years

Stone RM. CA Cancer J Clin. 200252363.
26
New Approaches in AML Induction

• Immunotherapeutic approaches
• Gemtuzumab ozogamicin
• IL-2 and histamine dihydrochloride
• Cell-signaling modulation
• FLT3 inhibitors (tyrosine kinase target)
• Farnesyltransferase inhibitors
• Drug-resistance modulation
• PSC-833
• Bcl-2 antisense (oblimersen)
• Zosquidar (LY335979)
• Anti-angiogenic therapy
• Proteosome inhibition (bortezomib)

27
Gemtuzumab Ozogamicin (GO)

• Recombinant, humanized murine monoclonal
  anti-CD33 antibody
• CD33 expressed on 90 of blasts from patients
  with AML
• Absent from normal hematopoietic stem cells
• Calicheamicin derivative is a cytotoxic
  antibiotic
• Linked by hydrolyzable linker
• Shown to be active in AML in first relapse gt60
  years

28
GO Chemotherapy in De Novo AML

• Pilot study for MRC AML-15 trial
• 64 patients aged 17 to 59 years treated with
  induction
• GO chemotherapy
• GO (3 or 6 mg/m2) with chemotherapy
• DAT daunorubicin, ara-C, thioguanine
• DA daunorubicin, ara-C
• FLAG-Ida fludarabine, ara-C, G-CSF, idarubicin
• 86 achieved CR with course 1 of GO
  chemotherapy
• 78 of patients treated with GO DA or
• FLAG-Ida are in continuous CR at median of 8
  months
• Combination with thioguanine increased
  hepatotoxicity

Kell WJ, et al. Blood. 20031024277.
29
Phase II Studies of GO Chemotherapy for De Novo
AML
Age lt60 years (n53) ?60 years
(n21) Dosing Daunomycin 45 mg/m2
Cytarabine 100 mg/m2 Days 1,2,3 Days
1-7 Cytarabine 100 mg/m2 GO 6 mg/m2 Days
1 8 Days 1-7 GO 6 mg/m2 Day
4 Cyto- genetics Favorable 8 0
Intermed 60 72 Poor 32 28
Unknown 6 3
DeAngelo. ASH 2003. Oral presentation.
30
GO Chemotherapy Efficacy

• lt60 years ?60 years Response Rates
  (n53) (n21)
• OR 81 48
• CR 79 43
• CRp 2 5
• Median OS gt15 months 13.4 months
• Median RFS 12.8 months 11.1 months

Platelet count 97,000/µL patient lost to
follow-up.
DeAngelo. ASH 2003. Oral presentation.
31
GO Chemotherapy Toxicity

• lt60 years ?60 years
• (n53) (n21)
• Elevated bilirubin 17 14
• Elevated AST 19 24
• Elevated ALT 17 14
• VOD
• Induction induced 0 0
• HSCT associated
• gt115 days after GO 0 ?
• lt115 days after GO 56 ?

Includes 8 allogeneic, 2 mini-allogeneic, and 2
autologous HSCT 9 allogeneic HSCT
DeAngelo. ASH 2003. Oral presentation.
32
GO for De Novo AML in Patients Age 65 Years or
Older

• Interim report on a Phase II trial of GO as
  induction, consolidation, and maintenance therapy
  in previously untreated patients with AML who
  were 65 years of age
• n12 (29 patients planned)
• CR in 27 (3/11) evaluable patients
• 7.6 months median duration of response
• Generally well tolerated
• No patient experienced grade 3 or 4 hepatic
  toxicity
• No documented VOD or SOS
• 5 patients developed transient LFT abnormalities

Nabhan C, et al. Leuk Res. 20052953.
33
Farnesyltransferase inhibitors in AML

• ras mutations
• Activating mutations of ras in 10 to 30 of AML
  patients
• May lead to enhanced proliferation and survival
• Inhibition of farnesyltransferase inhibits
  activation of ras protein
• Inhibitors of farnesyltransferase in clinical
  development

34
Tipifarnib (R115777) Phase II Trial in De Novo
AML

• 104 patients with previously untreated high-risk
  AML and MDS
• 94 patients with AML
• 4 patients with MDS
• 6 patients with CMML
• High risk defined as
• Age gt65 years
• Age gt18 years with poor cytogenetics
• Secondary AML
• Dosage 600 mg p.o. BID for 21 days every2 to 4
  weeks

Lancet JE et al. Blood. 2003102176a. Abstract
613.
35
Tipifarnib Clinical Activity in De Novo AML

• (n92)
• 21 CR
• 33 OR (CR PR)
• 36 OR in patients gt75 years
• Median OS 5.8 months
• Median OR in responding patients has not been
  reached, with 60 alive at 15 months
• Toxicity
• Grade 4 toxicity occurred in 13 of patients,
  mainly infection during neutropenia

Lancet JE et al. Blood. 2003102176a. Abstract
613.
36
Trials of Drug Resistance Reversal in AML

• Cyclosporine A is a potent inhibitor of
  p-glycoprotein (MDR1)
• PSC-833 is a non-immunosuppressive cyclosporine
  analog
• Randomized trials of PSC-833 in combination with
  chemotherapy in patients with relapsed/refractory
  disease did not show benefit
• CALGB trial in older adults stopped early because
  of therapy-related deaths in PSC-833 group
• A SWOG trial in relapsed/refractory AML with
  continuous infusion DnR/HiDAC / CyA showed no
  difference in CR rate but lower relapse rate
  resulting in survival advantage
• CALGB trial of ADE / PSC-833 in patients aged
  18-59 years recently closed

Baer MR, et al. Blood. 20021001224-1232.2.
Kolitz JE, et al. Blood. 200198461a.
37
Current Comparative Clinical Trials Investigating
Induction Chemotherapy

• Age lt60
• ECOG dauno (45mg/m2)/ara-C vs. dauno (90mg/m2)
• SWOG dauno/ara-C / GO
• EORTC ida/ara-C vs. ida/HiDAC
• HOVON ida/ara-C vs. ida/HiDAC / G-CSF
• MRC dauno/HiDAC vs. FLAG-ida / GO

38
Current Comparative Clinical Trials Investigating
Induction Chemotherapy

• Age gt60
• CALGB dauno/ara-C / oblimersen (Bcl-2
  antisense)
• ECOG dauno/ara-C / zosquidar (MDR modulator)
• SWOG dauno/ara-C / cyclosporine A
• EORTC ida/ara-C / GO
• HOVON dauno (45mg/m2)/ara-C vs. dauno (90mg/m2)
• MRC dauno/ara-C vs. Hydrea/low-dose ara-C
  / ATRA

39
AML Induction Therapy Conclusions

• AML remains a challenging disease to induce into
  complete remission, particularly for older
  patients
• Many targeted approaches in combination with
  anthracycline and cytarabine hold promise for
  improved patient outcomes

Age (years) Remission ()
18-40 70-80
40-60 60-80
gt60 10-35
40
TREATMENT OPTIONS IN AML A PRACTICAL CASED-BASE
D APPROACH Corporate Friday Symposium Manchester
Grand Hyatt Randle Ballroom C-E Friday, December
3, 2004 700am-1100am
41
The Role of Transplantation in Acute Myelogenous
Leukemia (AML)

Michael W. Schuster, M.D.
42
Case Presentation

• 45-year-old Wall Street investment banker
  presents to the ER with fevers and epistaxis. He
  is found to have a WBC count of 18,000 with 80
  blasts and a platelet count of 4,000. A bone
  marrow aspirate and biopsy confirm the dx of M0
  AML. Cytogenetics reveal monosomy 7, and he
  goes into prompt remission following 73
  induction chemotherapy. A younger brother with a
  wild lifestyle is a perfect HLA match.

43

• We show that patients assigned to allo-SCT
  have a significantly better outcome
• EORTC-LG/GIMEMA AML-10
• The number of relapses were substantially
  lower in the autologous BMT group
• MRC 10
• We conclude that intensive consolidation
  chemotherapy should be considered the standard
  post-remission therapy in adults with AML in CR1
• GOELAM

44
Mixed Results With Transplantation as
Consolidation

• EORTC/GIMEMA study showed benefit to both auto
  and allo transplant arms
• MRC 10 trial showed benefit to auto transplant
  arm
• American Cooperative Group study showed no
  benefit to either auto or allo arm
• GOELAM study showed no benefit to auto transplant
  arm

45
Autologous or Allogeneic Bone Marrow
Transplantation (BMT) Compared With Intensive
Chemotherapy in AML

• EORTC GIMEMA study
• Randomized 623 patients in complete remission
• Autologous as well as allogeneic bone marrow
  transplantation results in better disease-free
  survival than intensive consolidation
  chemotherapy with high-dose cytarabine
• and daunorubicin

Zittoun RA, et al. N Engl J Med. 1995 332217.
46
Disease-free Survival After Autologous or
Allogeneic BMT or a Second Course of Intensive
Consolidation Therapy
100
90
Intensive therapy (n126 81 events)
Autologous BMT (n128 64 events)
80
Allogeneic BMT (n168 70 events)
70
60
554
50
Disease-free Survival ()
40
485
30
304
20
10
4
6
7
5
3
0
1
2
Years
Intensive therapy 126 74
37 24 17 7
1 Autologous BMT 128 76
49 38 26 10
4 Allogeneic BMT 168 87
63 48 29
15 0
Zittoun R. A. et al. N Engl J Med. 1995332217.
47
Overall Survival After a First Complete Remission
With Autologous or Allogeneic BMT or a Second
Course of Intensive Consolidation Therapy
100
Intensive Therapy (n 126 57
events) Autologous BMT (n 128 50
events) Allogeneic BMT (n 168 61 events)
90
80
70
60
594 565 465
50
Overall Survival ()
40
30
20
10
4
5
6
7
0
1
2
3
Year
Patients at Risk Intensive Therapy 126
95 67 40 25 9
2 Autologous BMT 128 94 60
45 29 12 4 Allogeneic
BMT 168 100 67 50
31 16 0
Zittoun R. A. et al. N Engl J Med. 1995332217.
48
Patients Younger than 46 Years with AML in First
Complete Remission (CR1)EORTC/GIMEMAAML-10 trial

• Of 1198 patients younger than 46 years of age,
  822 achieved CR
• 734 patients received a single intensive
  consolidation (IC) course
• 293 had a sibling donor and 441 did not
• Allo-SCT and auto-SCT were performed in 68.9 and
  55.8
• The DFS rates were 43.4 and 18.4, respectively,
  in patients whose leukemia had bad/very bad risk
  cytogenetics

49
DFS From CR According to Donor Availability
100
90
80
70
Relapse Death in CR
60
52.2 (3.2) 38.4 17.41
50
Percent Patients Alive in CR
42.2 (2.6) 52.2 5.3
40
30
20
P.044
10
0
6
8
4
0
2
Years
Events/Patients
Number of patients at risk

• /441 171 91
  28 No Donor
• 126/293 336 80
  33 Donor

Suciu S, et al, Blood. 20031021232.
50
DFS From CR According to Donor Availability in
Four Cytogenetic Groups
100
100
Good Risk
Intermediate Risk
Relapse Death in CR
Relapse Death in CR
80
65.7 (5.9 28.3 6.0
80
60
48.5 (5.3) 46.6 5.0
60
Percent Patients Alive in CR
62.1 (7.2 21.9 26.9
40
40
45.2 (6.7) 35.1 19.7
20
20
P.51
P.54
0
0
Years
0
4
6
8
2
0
4
6
2
8
Ev/Pt Number of patients at risk
Ev/Pt Number of patients at risk
51/104 45 25 8
No Donor 32/61 25 11
3 Donor
23/73 45 25 9
No Donor 68/5 27 18
4 Donor
100
100
Unknown Risk
Bad/Very Bad Risk
Relapse Death in CR
Relapse Death in CR
80
80
57.8 (5.2) 26.5 15.7
60
60
43.4 (6.5) 38.2 38.4
Percent Patients Alive in CR
40
40
41.2 (4.3) 53.8 5.0
18.4 (4.3) 78.9 3.2
20
20
P.0078
P.0078
0
Years
0
0
4
6
8
2
0
4
6
2
8
Ev/Pt Number of patients at risk
Ev/Pt Number of patients at risk
71/94 21 32 6
No Donor 32/61 28 39
8 Donor
84/170 60 29 5
No Donor 41/148 56 32
18 Donor
51
MRC AML-10 Trial

• 381 patients were randomized
• Superior disease-free survival at 7 years
• (53 vs. 40 P.04)
• The addition of autologous BMT to 4 courses of
  intensive chemotherapy substantially reduces the
  risk of relapse in all risk groups, leading to
  improvement in long-term survival

Burnett et al. Lancet. 1998351687.
52
Chemotherapy Compared With Autologous or
Allogeneic BMT in the Management of AML in First
Remission

• American Cooperative Group study shows
• no difference
• 740 patients eligible
• Survival after complete remission was somewhat
  better after chemotherapy than after autologous
  marrow transplantation (P.05) or after
  allogeneic marrow transplantation (P.04)

Cassileth PA, et al. N Engl J Med. 19983391649.
53
Probability of Disease-free Survival According to
Post-remission Therapy
1.0
Autologous bone marrow transplantation
Allogeneic bone marrow transplantation
High-dose cytarabine
0.8
0.6
Proportion Surviving Without Disease
0.4
0.2
0.0
0.0
0.5
1.5
1.0
3.0
2.5
2.0
4.0
5.0
3.5
4.5
Time Since Remission (yr)
Group
No. of Event/No. at Risk Autologous
transplantation 48/116
18/66 4/45
2/34 0/22 Allogeneic
transplantation 41/113
14/71 5/55
1/32 0/22 Cytarabine
48/117
21/69 5/47
1/29 0/18
Cassileth PA, et al. N Engl J Med. 19983391649.
54
Comparison of Autologous BMT and Intensive
Chemotherapy as Post-remission Therapy in Adult
AML

• GOELAM study also showed no benefit to transplant
  as consolidation therapy
• 517 eligible patients studied
• The type of post-remission therapy had no
  significant impact on the outcome

Harousseau JL, et al. Blood. 1997902978.
55
No Benefit With Either Auto- or Allo-Transplant
1.0
1.0
0.5
0.5
Disease-free Survival
Disease-free Survival
Allogeneic BMT (n 88)
Autologous BMT (n 86)
First Course of ICC (n134)
First Course of ICC (n78)
Log-ranked test P.62
Log-ranked test P.41
0.0
0.0
0
48
60
12
36
84
96
0
48
60
108
12
24
36
72
84
96
24
72
Time in months
Time in months
Harousseau JL, et al, Blood. 1997902978.
56
How Do We Reconcile the Four Studies?

• GOELAM may have had superior results because of
  greater dose intensity of consolidation
  chemotherapy (24 g vs. 6 g of ara-C)
• GOELAM had an unusually high relapse rate in the
  allo arm
• GOELAM introduced amsacrine and etoposide into
  consolidation treatment
• Two of the studies had a course of consolidation
  before transplant 2 did not apples and oranges

57
Reduced Intensity Transplants

• IV busulfan with fludarabine anti-leukemic
  efficacy at least equal to BuCy
• ? the new standard
• ? de Lima M, Courial D, Shehjahan M et al.
  Blood. 2004104 Abstract 97
• First-line therapy in CR1 also with fludarabine
  and busulfan low incidence of NRM
• LFS at 18 mos in high-risk pts, 75
• a valid option in AML
• ?Blaise D. Bouron JM, Faucher C, et al. Blood.
  2004104Abstract 101

58
NST vs. Myeloablative Transplant at Relapse

• How do you decide auto vs. allo vs.
• non-myeloablative?
• Results with NST vs. myeloablative may be
  comparable

Alyea EP, et al. Blood. 2004
59
Causes of Treatment Failure
60
TREATMENT OPTIONS IN AML A PRACTICAL CASED-BASE
D APPROACH Corporate Friday Symposium Manchester
Grand Hyatt Randle Ballroom C-E Friday, December
3, 2004 700am-1100am
61
Chemotherapy for Relapsed AML Making the Best
out of a Bad Situation

• Gary Schiller, MD
• University of California, Los Angeles

62
Resistant Acute Myeloid Leukemia

• Definition
• Refractory leukemia
• Disease unresponsive to initial induction
  chemotherapy
• Relapsed leukemia
• Disease that recurs following an initial
• complete remission

63
Resistant Acute Myeloid Leukemia

• A case history
• 67-year-old female presented with a history of
  acute leukemia of F.A.B. M1 phenotype with normal
  diploid cytogenetics diagnosed 8 years prior to
  presentation
• Initial treatment consisted of 2 cycles of
  induction chemotherapy and 1 cycle of high-dose
  cytarabine/mitoxantrone consolidation
• Initial remission lasted 5 months

64
Resistant Acute Myeloid Leukemia

• Therapy for AML in first relapse
• Investigational trial of timed-sequential
• therapy with rHu-G-CSF and 12 doses of
• high-dose cytarabine
• Second remission duration 7 years
• At second relapse, leukemia morphology
  unchanged, but 3/20 cells showed trisomy 8

65
Patient Characteristics

• Refractory leukemia
• High incidence of adverse cytogenetics,
  antecedent hematologic disturbance, adverse
  immunophenotypic features, expression of multiple
  drug resistance
• Relapsed leukemia
• A heterogeneous group, some secondarily
  resistant, some biologically favorable. Variable
  pretreatment features.

66
Salvage Chemotherapy Protocols

• Most are high-dose cytarabine-based
• Non-cytarabine regimens
• Monoclonal antibody
• Combination regimens
• Anthracycline
• Etoposide
• Carboplatin
• Fludarabine
• Radiation
• Hematopoietic growth factors

67
Factors Predictive of Response to Salvage Therapy

• Response to induction chemotherapy
• Duration of first complete remission
• lt1 year
• 1-2 years
• gt2 years
• Disease characteristics
• Co-morbid disease

68
Hazards in Evaluating Salvage Therapies

• Patient selection
• Small sample size
• Influence of pretreatment characteristics
• Influence of co-morbid disease
• Variability of initial post-remission treatment
• Study design

69
Patient Selection

• Four distinctive groups with progressively less
  favorable disease biology
• CR gt 2 yr, no previous salvage therapy
• CR 1-2 yr, no previous salvage therapy
• CR lt1 yr or without initial CR, no previous
  salvage therapy
• CR lt1 yr or without initial CR, on subsequent
  salvage for unresponsive disease

Estey E, et al. Cancer Chemother Pharmocol.
199740S9.
70
Options for Treatment of Resistant Leukemia

• Standard-dose chemotherapy
• High-dose (myeloablative) chemotherapy
• Autologous bone marrow transplantation
• Allogeneic bone marrow transplantation
• Combined-sequential therapy
• Chemo-modulation
• Inhibitors of drug resistance
• Immunomodulation
• Gemtuzumab ozogamicin

71
Studies of Standard-dose Chemotherapy Cytarabine-b
ased Regimens
Author Year Agents Patient Characteristics Outcomes
Amadori 1991 Mitoxantrone VP-16 Ara-C 32 Refractory (18) Relapsed (8) After BMT (6) 66 CR Duration 16W
Carella 1993 Ida Ara-C VP-16 92 Refractory (36) Relapsed (50) Other (11) 43 CR Duration 16W
Kusnierz-Glaz 1993 Ida Ara-C 33 Refractory (3) Relapsed (10) MDS (12) Others (8) 10 CR Duration 14W
Reese 1993 Mitoxantrone Ara-C 47 Relapsed (14) Others (33) 45 CR
Takaku 1985 Ara-C 30 Relapsed Ref (28) 40 CR Duration 16W
Gore 1989 Ara-C VP-16 41 Refractory (16) Relapsed (25) 63 CR Duration ?
Hiddemann 1986 Ara-C Mitoxantrone 26 Refractory (5) Relapsed (21) 50 CR
Capizzi 1985 Ara-C ? Asp 13 Refractory (3) Relapsed (10) 70 CR Duration 21W
72
Results of Standard-dose Chemotherapy Salvage

• Complete remission rate 25-60
• Median remission duration 90-250 days
• Prolonged myelosuppression and toxicity

73
Other Chemotherapeutic Approaches
Outcomes
Patient Characteristics

Agents
Year
Author
42 CR Duration 4-7 mos
Refractory (21) Relapsed (31) Other (9)
61
Mitoxantrone VP-16
1988
Ho
47 CR Duration 7 mos
Refractory (0) Relapsed (17)
17
2 CDA
1992
Santana
3 CR
Refractory (6) Relapsed (25)
31
Homoharringtonine
1989
Kantarjian
28 CR Duration 7 mos
Refractory (3) Relapsed (22)
25
Carboplatin
1989
Meyers
36 CR Duration 9 mos
Refractory (9) Relapsed (50)
59
Fludarabine Ara-C
1992
Estey
74
Timed-sequential Therapies
Author Year Agents Patient Characteristics Outcomes
Puntous 1993 GM-CSF Ara-C Amsacrine 10 Refractory (0) Relapsed (10) Early (1) 70 CR Duration 6 mos
Yamada 1995 G-CSF Ara-C Aclarubicin 18 Relapsed (18) Late (12) 83 CR Duration 6 mos
Schiller 1995 G-CSF Ara-C 15 Refractory (2) Relapsed (13) 64 CR Duration 6 mos





75
High-dose Chemotherapy
Author Year Agents Tx Type Patient Characteristics Outcomes
Brown 1990 Cy VP 16 None 40/65 Refractory (20) Relapsed (20) 42 CR Duration 3-5 mos
Körbling 1989 TBI/Cy Purged-auto 30/52 Relapsed (30) 34 DFS _at_ 2 yr
Yeager 1986 Bu/Cy Purged-auto 25 Relapsed (25) 40 survival _at_ 2 yr
Gorin 1986 TBI/Cy Purged-auto 11 Refractory (4) Relapsed (5) Other (2) 27 survival _at_ 1 yr




76
Autologous Bone Marrow Transplantation
Author Purging Agent Actuarial Disease-free Survival
Yeager, et al NEJM. 19863151471 4HC 43
Lenarsky, et al BMT. 19906425-9 4HC 61
Meloni, et al Blood. 1990752282 None 52
Gorin, et al Blood. 1986671367 Asta Z-7557 25
Ball, et al Blood. 1986681311 MoAb C 31
77
Results of Autologous Bone Marrow Transplantation
for Relapsed Leukemia

• Complete remission rate 50 to 100
• Median remission duration 3 to 11 months
• Actuarial leukemia-free survival at 1 year 10
  to 43

78
High-dose Chemotherapy
Author Year Agents Tx Type Patient Characteristics Outcomes
Schnitz 1988 TBI/VP 16 MRD 16 Refractory (3) Relapsed (9) 54 DFS
Santos 1983 Bu/Cy MRD 33 Refractory (16) Relapsed (17) 0 29 DFS
Forman 1991 TBI/Cy/Ara-C TBI/VP 16 MRD 21 Refractory (21) 43 DFS
Clift 1992 TBI/Cy MRD 126 First Relapse (126) 23 DFS
Schiller 1994 TBI/Cy Bu/Cy MUD 55 Refractory (8) Relapsed (47) 23 DFS
Sierra 1997 TBI/Cy MUD 108 Refractory (14) Relapsed (94) 12-27 DFS


79
Allogeneic Bone Marrow Transplantation

• Matched related donors
• Refractory disease
• Leukemia-free survival 18 ? 5
• Actuarial relapse rate 63 ? 7
• Relapsed disease
• Leukemia-free survival 27 ? 6
• Actuarial relapse rate 45 ? 10

80
Investigational Agents/ New Therapies

• Modifiers of multiple-drug resistance
• PSC-833
• Tamoxifen
• Immunomodulatory agents
• Interleukin-2
• Monoclonal antibodies
• Donor leukocytes
• Differentiation agents

81
Methods for Analyzing New Therapies

• Patient characteristics
• Refractory disease
• Relapsed disease
• lt6 mos
• 6 to12 mos Duration of first remission
• gt12 mos
• Previous salvage therapy
• Molecular/cytogenetic disease features

82
Methods for Analyzing New Therapies (cont.)

• Avoid the hazards of Phase I/II studies
• Dose-escalation
• Toxicity vs. response
• Develop criteria of response
• Remission rate
• Duration of response

83
New Approaches in AML

• New chemotherapeutic drugs
• Modulation of drug resistance
• Sensitization
• Anti-angiogenesis
• Modulation of cell signaling
• Immunotherapeutic

84
New Chemotherapeutic Drugs

• Clofarabine
• Phase II clinical trial in 62 patients with AML,
  MDS, CML in blast crisis, and ALL
• 32 achieved complete remission
• AML of short CR1 CR 2/11
• AML with long CR1 CR 7/8
• 2nd or subsequent relapse CR 8/12
• Arsenic trioxide

Kantarjian H, et al, Blood. 20031022379.
85
Modulation of Drug Resistance

• Randomized trials of PSC-833
• CALGB trial in older adults
• SWOG trial in relapsed/refractory AML
• CALGB trial of ADE and PSC-833 in
• younger patients

86
Tyrosine Kinase Inhibitors in AML

• C-kit and FLT-3 are overexpressed in myelobasts
• C-kit mutations in AML are rare
• Mutations in FLT-3 occur in 20 to 30
• of cases

87
FLT-3 inhibitors in AML

• Novartis PKC412
• Cor/Millenium drug
• Cephalon drug

88
Immunotherapy in AML

• Immune mediated graft-vs.-leukemia effect of
  allogeneic transplantation
• Immunomodulatory agents
• Tumor antigens
• CD33

89
Gemtuzumab Ozogamicin (GO)

• Recombinant humanized anti-CD33 monoclonal
  antibody
• Conjugated with calicheamicin
• Internalization of toxin liberated in acidic
  microenvironment

90
GO Trials in AML

• Phase II trial
• N142, first relapse, age gt60, no antecedent MDS,
  or auto-transplant
• CR in 30
• Grade III/IV liver toxicity in 25
• Few infusion-related events
• 13 deaths, usually disease progression

Sievers EL, et al, J Clin Oncol. 2001193244.
91
Farnesyl Transferase Inhibitors

• Tipifarnib
• Phase I trial showed responses in 8 of 25 AML
  patients
• 2 patients achieved CR
• Phase II trial in 50 evaluable patients showed
  response to lt 5 marrow blasts in 17

• Harousseau JL, et al. Proc. Am Soc Clin Oncol.
  2002 21265.

92
Conclusions

• Studies of salvage treatment are heavily
  influenced by patient disease characteristics
• Alternative, standard chemotherapeutics do not
  seem to have a significant advantage over
  single-agent cytarabine
• Allogeneic progenitor cell transplantation may be
  the only means of producing sustained
  leukemia-free survival
• Randomized trials of salvage treatment,
  including allogeneic progenitor cell
  transplantation, have not been performed
• Investigational therapies may best be subjected
  to analysis of a homogeneous well-characterized
  patient population and hold greater promise for
  managing resistant AML

93
TREATMENT OPTIONS IN AML A PRACTICAL CASED-BASE
D APPROACH