treatment options in aml: a practical cased-based approach

TREATMENT OPTIONS IN AML: A PRACTICAL

CASED-BASED APPROACH

Current Status and Controversies in Acute Myeloid Leukemia

Induction Therapy

Edward A. Stadtmauer, MD University of Pennsylvania Health System

Acute Myeloid Leukemia (AML)

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

Acute Myeloid Leukemia

•Median age at diagnosis: 62 to 64 years

• Incidence

– <65 years of age: 1.8 cases per 100,000

– >65 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

Age-Specific Incidence Rates for AML

0

5

10

15

20

25

30

35

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+

Av

era

ge

An

nu

al

Ra

te p

er

10

0,0

00 Male

Female

All persons

NCI SEER Program, 1995-1999.

Age (yrs)

1995-1998

Initial Therapy of AML Diagnosis • 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

RemissionInduction

Post-remission Therapy

ConsolidationChemotherapy

SCT

Remission Induction

Cure

Clinically Detectable Disease

Induction Relapse Relapse

Time

To t

al L

e uke

mic

Cel

l Num

b er

Post-remission Therapy

Clinically Detectable DiseaseClinically Detectable Disease

InductionInduction ConsolidationConsolidation ConsolidationConsolidation

TimeTime

To t

al L

e uke

mic

Cel

l Num

b er

CureCure

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 <60 years

One of the major cancer therapy success stories of the 20th century

But … not all AML has a good prognosis

Prognostic Factors in AML

• Age– 60 years unfavorable

• Cytogenetics– Favorable: t(8;21), inv16, t(15;17)– Intermediate: normal, -Y, +6, +8; others not

considered favorable or unfavorable– Poor: Translocations or inversion of chromosome 3,

monosomy 5 or 7, t(6;9), t(9;22), abn 11q23, or complex

• Presenting white blood cell count– Hyperleukocytosis >100,000/μL unfavorable

• Treatment-induced AML or history of myelodysplastic syndrome

• Other unfavorable indicators– CD34 expression, MDR phenotype, FLT3-activating

mutations, and Bcl-2 expression

SWOG/ECOG Adult AML; Age <56: Cytogenetics and Survival

Slovak et al. Blood. 2000.

100

80

60

40

20

00 2 4 6 8

Years After Entering Study

Heterogeneity of 3 groups: P<.0001

At Risk Deaths Estimated (CI)at 5 Years

Favorable 121 53 55% (45%-64%)Intermediate 278 168 38% (32%-44%)Unfavorable 184 162 11% (7%-16%)

Sur

viva

l (%

)

Comparison of Prognostic Factors: Older and Younger Adults With AML

Characteristic <60 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 AML8% 20%-50%

Sekeres. Hematology. 2004.

ECOG AML Survival Data <60 years >60 years

Sur

viva

l

1.0

0.8

0.6

0.2

0.4

0.0

0 10 15 20 255

Years

Study Year. 1989-1997, n=553Median Survival= 3.2 months5-Year Survival =12%


Study Year. 1983-1986, n=142Median Survival= 6.3, months5-Year Survival =13%

Sur

viva

l

1.0

0.8

0.6

0.2

0.4

0.0

0 10 15 20 255

Years


Study Year. 1973-1979, n=454 Median Survival= 11.3 months5-Year Survival =11%


Appelbaum. Hematology. 2001.

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?

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

Randomized Trials of Induction Therapy >60 Years

• Only 2 studies have been reported

• Lowenberg B, et al. J Clin Oncol. 1989;7:1268.

–Survival advantage for induction chemotherapy but…

–21 weeks vs. 11 weeks

–Median survival 16 days longer than the time spent in the hospital

Induction Therapy Decision-Making and Expectations of AML >60 years

• Sekeres MA, et al. Leukemia. 2004;18:809.

– 43 patients >60 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 >50%

90% patients rate 1-year survival >50%

89% physicians rate chance of cure <10%

Most patients do not recall alternatives to therapy received;

all were presented options

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!

Is There a Best Antracycline?(Age <60)

•Comparisons

– Idarubicin 12 mg/m2 vs. daunorubicin Blood 1991, 1992; JCO 1992; EJC 1991

–Amsacrine vs daunorubicinLeukemia 1999; JCO 1987

–Mitoxantrone vs. daunorubicinLeukemia 1990; Ann Hematol 1994

•Summary: Similar outcomes

•Current trials: – Daunorubicin 45 mg/m2 vs. daunorubicin 90 mg/m2

Is There a Best Antracycline? (Age >60)

• No standard• Rowe JM, et al. Blood. 2004;103:479.

– 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. 2002;100:3869.– Mitoxantrone and etoposide vs. daunorubicin and cytarabine– No benefit of ME over DA

• MRC. Blood. 2001;98:1302.– DAT best but not direct comparison at same

cytarabine doses

• Summary: Similar outcomes

Survival by Anthracycline Type

100

80

60

40

20

0 1 2 3 4 5 0

DA n=116MA n=114IA n=118

Rowe JM, et al. Blood 2004;103:479.

Years

Sur

viva

l (%

)

Is There a Best Dose of Cytarabine in Induction?

• No evidence for a dose escalation above 100 mg/m2

• 100–200 mg/m2 standard

• Addition of high-dose cytarabine to the induction regimen has not yet been shown to increase efficacy, but does increase toxicity

Consolidation Therapy for AML• Age <60 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 >60 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

Summary: AML Remission Induction Therapy

• Combination therapy

– Cytarabine plus an anthracycline (daunorubicin, idarubicin, or mitoxantrone)

– “7+3” 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 >60 years of age

• Standard consolidation includes cycles of HiDAC

– 30% to 45% long-term relapse-free survival <60 years

– No clear benefit for age >60 years

Stone RM. CA Cancer J Clin. 2002;52:363.

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)

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 >60 years

OH

CH3 CH2

OCH3O

IgG4 anti-CD33Linker

DNA minor groovebinding

Me

O

O

NH

NHN

O

S

H

HO O

OCH3

NH O

O

OCH3

N

O

OCH3HOCH3

OCH3

HNHO

OO

OH

CH3S

CH3

OCH3

I

O

O

O

S

Me Me

OCH3

Calicheamicin derivative

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. 2003;102:4277.

Age <60 years (n=53) 60 years (n=21)

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

Phase II Studies of GO + Chemotherapy for De Novo AML

DeAngelo. ASH 2003. Oral presentation.

GO + Chemotherapy: Efficacy

<60 years 60 years Response Rates (n=53) (n=21)

OR 81% 48%CR 79% 43%CRp 2% 5%*

Median OS >15 months 13.4 months

Median RFS 12.8 months 11.1 months


*Platelet count 97,000/μL; patient lost to follow-up.

GO + Chemotherapy: Toxicity <60 years 60 years (n=53) (n=21)

Elevated bilirubin 17% 14%Elevated AST 19% 24%Elevated ALT 17% 14%

VOD Induction induced 0% 0% HSCT associated >115 days after GO* 0% <115 days after GO† 56%

*Includes 8 allogeneic, 2 mini-allogeneic, and 2 autologous HSCT†9 allogeneic HSCT


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

• n=12 (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. 2005;29:53.

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

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 >65 years

– Age >18 years with poor cytogenetics

– Secondary AML

• Dosage: 600 mg p.o. BID for 21 days every2 to 4 weeks

Lancet JE et al. Blood. 2003;102:176a. Abstract 613.

Tipifarnib: Clinical Activity in De Novo AML

(n=92)

• 21% CR– 33% OR (CR + PR)

– 36% OR in patients >75 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. 2003;102:176a. Abstract 613.

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. 2002;100:1224-1232.2. Kolitz JE, et al. Blood. 2001;98:461a.

Current Comparative Clinical Trials Investigating Induction Chemotherapy

•Age <60

•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

Current Comparative Clinical Trials Investigating Induction Chemotherapy

•Age >60

•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

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

>60 10-35



Corporate Friday SymposiumManchester Grand Hyatt

Randle Ballroom C-EFriday, December 3, 2004

7:00am-11:00am

The Role of Transplantation in Acute Myelogenous Leukemia (AML)

Michael W. Schuster, M.D.

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 “7&3” induction chemotherapy. A younger brother with a “wild lifestyle” is a perfect HLA match.

“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

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

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.Zittoun RA, et al. N Engl J Med. 1995; 332:217.

Zittoun R. A. et al. N Engl J Med. 1995;332:217.

Disease-free Survival After Autologous or Allogeneic BMT or a Second Course of Intensive Consolidation Therapy

Intensive therapy 126 74 37 24 17 7 1Autologous BMT 128 76 49 38 26 10 4Allogeneic BMT 168 87 63 48 29 15 0

55%±4%

48%±5%

30%±4%

Intensive therapy (n=126; 81 events)Autologous BMT (n=128; 64 events)Allogeneic BMT (n=168; 70 events)

100

80

70

60

50

40

30

20

10

90

0 4 5 6 71 2 3Years

Dis

ease

-fre

e S

urvi

val (

%)

Zittoun R. A. et al. N Engl J Med. 1995;332:217.

Overall Survival After a First Complete Remission With Autologous or Allogeneic BMT or a Second

Course of Intensive Consolidation Therapy

100

Patients at RiskIntensive Therapy 126 95 67 40 25 9 2Autologous BMT 128 94 60 45 29 12 4Allogeneic BMT 168 100 67 50 31 16 0

90

80

70

60

50

40

30

20

10

0 1 2 3 4 5 6 7

Ove

rall

Su

rviv

al (

%)

Year

Intensive Therapy (n = 126; 57; events)Autologous BMT (n = 128; 50 events)Allogeneic BMT (n = 168; 61 events)

59%±4%56%±5%46%±5%

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

DFS From CR According to Donor Availability

Suciu S, et al, Blood. 2003;102:1232.

100

90

80

70

60

50

40

30

20

10

0

0 4 6 82

Events/Patients Number of patients at risk:229 /441 171 91 28 No Donor

126/293 336 80 33 Donor

52.2% (±3.2%) 38.4% 17.41%

42.2% (±2.6%) 52.2% 5.3%

P=.044

Relapse Death in CR

Per

cent

Pat

ient

s A

live

in C

R

Years

Relapse Death in CR

71/94 21 32 6 No Donor

32/61 28 39 8 Donor

51/104 45 25 8 No Donor

32/61 25 11 3 Donor

DFS From CR According to Donor Availability in Four Cytogenetic

Groups100

80

60

40

20

00 4 6 82

23/73 45 25 9 No Donor 68/5 27 18 4 Donor

65.7% (±5.9% 28.3% 6.0%

62.1% (±7.2% 21.9% 26.9%

P=.54

100

80

60

40

20

0 4 62

48.5% (±5.3%) 46.6% 5.0%

45.2% (±6.7%) 35.1% 19.7%

Relapse Death in CR

P=.510

100

80

60

40

20

00 4 6 82

Ev/Pt Number of patients at risk:

43.4% (±6.5%) 38.2% 38.4%

18.4% (±4.3%) 78.9% 3.2%

Relapse Death in CR

P=.0078

100

80

60

40

20

00 4 6 82

57.8% (±5.2%) 26.5% 15.7%

41.2% (±4.3%) 53.8% 5.0%

Relapse Death in CR

P=.0078

84/170 60 29 5 No Donor 41/148 56 32 18 Donor

8Years

Pe

rce

nt

Pa

tien

ts A

live

in C

R

Years


Pe

rce

nt

Pa

tien

ts A

live

in C

R



Good Risk

Unknown RiskBad/Very Bad Risk

Intermediate Risk

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. 1998;351:687.

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. 1998;339:1649.

Cassileth PA, et al. N Engl J Med. 1998;339:1649.

Probability of Disease-free Survival According to Post-remission Therapy

1.0

0.8

0.6

0.4

0.2

1.51.00.50.00.0

3.53.02.52.0 4.54.0 5.0

Time Since Remission (yr)

Pro

po

rtio

n S

urv

ivin

gW

ith

ou

t D

ise

ase

Group No. of Event/No. at Risk

Autologous transplantation 48/116 18/66 4/45 2/34 0/22Allogeneic transplantation 41/113 14/71 5/55 1/32 0/22 Cytarabine 48/117 21/69 5/47 1/29 0/18

Autologous bone marrow transplantationAllogeneic bone marrow transplantationHigh-dose cytarabine

• 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. 1997;90:2978.

Comparison of Autologous BMT and Intensive Chemotherapy as Post-remission Therapy in

Adult AML

Allogeneic BMT (n = 88)First Course of ICC (n=134)Log-ranked test: P=.62

No Benefit With Either Auto- or Allo-Transplant

Harousseau JL, et al, Blood. 1997;90:2978.

1.0

0.5

0.00 48 60 10812 24 36 72 84 96

Time in months

1.0

0.5

0 48 6012 24 36 72 84 96

Autologous BMT (n = 86)First Course of ICC (n=78)Log-ranked test: P=.41

Time in months

0.0

Dis

ease

-fre

e S

urvi

val

Dis

ease

-fre

e S

urvi

val

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”

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. 2004;104: 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. 2004;104;Abstract 101

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

Causes of Treatment Failure



Corporate Friday SymposiumManchester Grand Hyatt

Randle Ballroom C-EFriday, December 3, 2004

7:00am-11:00am

Chemotherapy for Relapsed AML: Making the

Best out of a Bad Situation

Gary Schiller, MD

University of California, Los Angeles

Resistant Acute Myeloid Leukemia

Definition

• Refractory leukemia

– Disease unresponsive to initial induction chemotherapy

• Relapsed leukemia

– Disease that recurs following an initial

complete remission


• 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


• 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

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.

Salvage Chemotherapy Protocols

• Most are high-dose cytarabine-based

• Non-cytarabine regimens– Monoclonal antibody

• Combination regimens– Anthracycline

– Etoposide

– Carboplatin

– Fludarabine

– Radiation

– Hematopoietic growth factors

Factors Predictive of Response to Salvage Therapy

• Response to induction chemotherapy

• Duration of first complete remission

– <1 year

– 1-2 years

– >2 years

• Disease characteristics

• Co-morbid disease

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

Patient Selection

• Four distinctive groups with progressively less favorable disease biology

– CR > 2 yr, no previous salvage therapy

– CR 1-2 yr, no previous salvage therapy

– CR <1 yr or without initial CR, no previous salvage therapy

– CR <1 yr or without initial CR, on subsequent salvage for unresponsive disease

Estey E, et al. Cancer Chemother Pharmocol. 1997;40:S9.

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

Studies of Standard-dose ChemotherapyCytarabine-based RegimensAuthor 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

Results of Standard-dose Chemotherapy “Salvage”

•Complete remission rate 25%-60%

•Median remission duration 90-250 days

•Prolonged myelosuppression and toxicity

Other Chemotherapeutic ApproachesOutcomesPatient Characteristics#AgentsYearAuthor

36% CR

Duration 9 mos

Refractory (9)

Relapsed (50)

59Fludarabine

Ara-C

1992Estey

28% CR

Duration 7 mos

Refractory (3)

Relapsed (22)

25Carboplatin1989Meyers

3% CRRefractory (6)

Relapsed (25)

31Homoharringtonine1989Kantarjian

47% CR

Duration 7 mos

Refractory (0)

Relapsed (17)

172 CDA1992Santana

42% CR

Duration 4-7 mos

Refractory (21)

Relapsed (31)

Other (9)

61Mitoxantrone

VP-16

1988Ho

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

High-dose Chemotherapy

Author Year Agents Tx Type #PatientCharacteristics 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 @ 2 yr

Yeager 1986 Bu/Cy Purged-auto

25 Relapsed (25) 40% survival @ 2 yr

Gorin 1986 TBI/Cy Purged-auto

11 Refractory (4)

Relapsed (5)

Other (2)

27% survival @ 1 yr

Autologous Bone Marrow Transplantation

Author Purging AgentActuarial Disease-free

Survival

Yeager, et al

NEJM. 1986;315:1471

4HC 43%

Lenarsky, et al

BMT. 1990;6:425-9

4HC 61%

Meloni, et al

Blood. 1990;75:2282

None 52%

Gorin, et al

Blood. 1986;67:1367

Asta Z-7557 25%

Ball, et al

Blood. 1986;68:1311

MoAb + C’ 31%

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%

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

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%

Investigational Agents/

New Therapies• Modifiers of multiple-drug resistance

– PSC-833

– Tamoxifen

• Immunomodulatory agents

– Interleukin-2

– Monoclonal antibodies

– Donor leukocytes

• Differentiation agents

Methods for Analyzing New Therapies

• Patient characteristics

– Refractory disease

– Relapsed disease <6 mos

6 to12 mos Duration of first remission

>12 mos

– Previous salvage therapy

– Molecular/cytogenetic disease features

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

New Approaches in AML

• New chemotherapeutic drugs

• Modulation of drug resistance

• Sensitization

• Anti-angiogenesis

• Modulation of cell signaling

• Immunotherapeutic

New Chemotherapeutic Drugs

• Clofarabine

– Phase II clinical trial in 62 patients with AML, MDS, CML in blast crisis, and ALL32% 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. 2003;102:2379.

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

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

FLT-3 inhibitors in AML

• Novartis PKC412

• Cor/Millenium drug

• Cephalon drug

Immunotherapy in AML

• Immune mediated graft-vs.-leukemia effect of allogeneic transplantation

• Immunomodulatory agents

• Tumor antigens

– CD33

Gemtuzumab Ozogamicin (GO)

• Recombinant humanized anti-CD33 monoclonal antibody

• Conjugated with calicheamicin

• Internalization of toxin liberated in acidic microenvironment

GO Trials in AML

• Phase II trial

• N=142, first relapse, age >60, 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. 2001;19:3244.

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 < 5% marrow blasts in 17

Harousseau JL, et al. Proc. Am Soc Clin Oncol. 2002; 21:265.

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

treatment options in aml: a practical cased-based approach

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