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Acute leukemia

By: Kamran Alimoghaddam

Acute Myeloid Leukemia (AML)

Morphologic aspects of acute lymphoblastic leukemia (ALL)

Definition:

Malignant clonal disorder of immature hematopoietic cells.

Characterized by aberrant an uncontrolled hematopoietic cell proliferation and arrest of maturation

Presented by impaction of BM by immature cells and prevention from normal hematopoiesis and release of abnormal blasts into peripheral blood.

Maturation of myeloid series

Stem cell progenitors myeloblast promyelocyte

myelocyte metamyelocyte neutrophil

release to peripheral blood

Maturation of monocytes

Stem cell monoblast promonocyte monocyte

Maturation of lymphocytes

Stem cell early pre B cells pre B cells B cells lymphoblast

pathophysiology

Leukemia is a maturation arrest of immature precurssors

The retained capacity of some differentiation is the basis for the phenotypic classification.

Acute non-lymphocytic leukemia ( Acute myelogenous leukemia)

Acute lymphocytic leukemia

proliferation of immature hematopoietic cells that have lost their capacity to differentiate normally

multistep process

level of differentiation at which malignancy becomes evident is variable

As the malignant clone expands, it does so at the expense of normal hematopoiesis

mechanism of normal marrow suppression in leukemia is complex

in many patients with hypercellular marrow, the pancytopenia is probably the result, at least in part, of physical replacement of normal marrow precursors by leukemic cells

In some patients with acute leukemia, however, a pancytopenia with hypocellular marrow develops, thus suggesting that marrow failure is not simply due to physical replacement of the marrow space but may also be due to substances released by the malignant cells

Molecular changes in acute leukemia

Genetic changes have a central role in pathogenesis of acute leukemia

Leukemia is a multistep process

Cytogentic changes are:

1- numerical (gain or loss of chromosomes)

2- structural ( translocations, inversions, isochromosoms, etc)

Southwest Oncology Group and Medical

Research Council cytogenetic risk category

definitions

Frequencies of cytogenetic risk categories and

specific clonal abnormalities, by cooperative group

Complete remission and overall

survival, by cytogenetic risk status

Common cytogenetic changes in AML

Trisomy 8 and loss of part or all of 5 and 7 chromosome

t(8,21): AML1/ETO

t(15,17):PML/RARA

inv(16):CBFb/MYH11

11q23 abn:MLL

Common cytogenetic changes in ALL

Hyperdiploidy or hypodiloidy

t(9,22):bcr/abl 190 kd tyrosin kinase

t(4,11)

t(1,19)

T(12,21): TEL/AML1

t(8,14): over expression of c-myc oncogene

Molecular events implicated in the pathogenesis of AML include activating mutations in genes encoding tyrosine kinases, such as fms-like tyrosinekinase 3 (FLT3), c-KIT, and N-RAS, and mutations genes encoding transcription factors involved in normal hematopoiesis, such as AML1, GATA1, and CCAAT/enhancer binding protein alpha (CEBPA).

incidence

The annual new case incidence of all leukemias is 8 to 10 per 100,000

This rate has remained static over the past three decades

The leukemias account for about 3% of all cancers in the United States

ALL is the most common cancer and the second leading cause of death in children younger than 15 years

ALL has a maximal incidence between 2 and 10 years of age, with a second, more gradual rise in frequency later in life

The incidence of AML gradually increases with age, without an early peak. Approximately half of AML cases occur in patients younger than 50 years.

Acute Myeloid LeukemiaMedian 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

Distribution of different leukemia by age

age

% of patients

ALL AML

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+

Ave

rag

e A

nn

ua

l R

ate

pe

r 1

00

,00

0

Male

Female

All persons

NCI SEER Program, 1995-1999.

Age (yrs)

1995-1998

Etiology:

Genetic disorders:

1-21+ 6-ataxia telangectasia

2-klien-felter 7-CVID

3-Bloom syn 8-SCID

4-Fanconi’s anemia

5-+13

Etiology: environmental factors

Irradiation

Chemical agents: benzene, oil products, smoking, insecticides

Drugs: chemotherapeutic agents

Immune suppression

Viral oncogenes: HIV,EBV, HTLV1,2

BM failures

Clinical presentation

BM failure

Infiltration of organs and tissues

Leukostasis

Couagulopathy and DIC

Organomegaly

Metabolic changes

Bone pain

Constitutional symptoms

Pulmonary leukostasis with diffuse involvement of small and large vessels.

Lab findings

Aneima

Thrombocytopenia

DIC: abn pt, ptt, FDP, fibrinogene level

Leukocytes

mean: 15000/mm3

5% aleukemic

25-40% leukocyte less than 5000

20% leukocyte more than 100000

Couagulation abnormalities

Diagnosis

BMA/B

Immuno-phenotyping

Cytogenetic and molecular studies

http://www.conference-cast.com/asco/grandrounds2/enlarge.asp?Slide=04&max=69&dir=bloomfield2


Normal blood film

Normal plattlets

Normal blood smear

AML blood smear

AML-M5

AML-M5

AML-M7

AML-M7

AML-M7 immunostain

AML

Acute leukemia classification(FAB)

subtype MPO PAS NSE Mab

reaction

cytogenetic

M0AUL

- - - CD13,14

33,34

various

M1Acute leukemia with minimal differentiation

+/- - +/- CD13,14

33,34

various

M2Aml with differentiation

+++ + +/- CD13,14

33,34

Various

T(8,21)

Acute leukemia classification

M3Apl

+++ + + CD13,33

HLA-DR-

T(15,17)

M4Acute myelomonocytic leukemia

++ ++ +++ CD13,33,

14,11c,15b

various

M4EEosinophilic variant

++ ++ +++ CD13,33,

14,11c,15b

Inv(16)

M5aMonoblastic leukemia

+/- ++ +++ CD11c,

15b

11q23

Acute leukemia classification

M5bAcute monoblastic leukemia

- ++ +++ CD11c,15bvarious

M6erythroleukemia

- ++ -Antiglycophorin

CD71various

M7Megakaryocytic leukemia

- + +/- Cd41,42,61various

New classification of AML(WHO)

Recurrent cytogenetic abnormality AML

APL with t(15,17)

AML-M4E inv(16)

AML-M2 t(8,21)

T(9,11) ,INV3, T(6,9),T(1,22)

AML with NPM1 or CEBPA mutation

Therapy related AML Post chemotherapy, sometimes 11q23

MDS related AML Post myelodyspalasia, bad prognosis

Other types Including other types of AML

Myeloid sarcoma, Dawn sydrom



































Survival of patients by intention to treat analysis

Survival Function

SURVIVAL

120010008006004002000

Cum

Sur

viva

l

1.0

.9

.8

.7

.6

.5

.4

.3

.2

.1

.0

Survival Function

Censored

Survival of patients by intention to treat analysisfor APL and Arsenic Troxide

Survival Function

SURVIVAL

120010008006004002000

Cum

Sur

viva

l

1.0

.9

.8

.7

.6

.5

.4

.3

.2

.1

.0

Survival Function

Censored




















Acute lymphocytic leukemia classification

subtype MPO PAS NSE Mab reaction

cytogenetic

ALL-L1 - +++ - CD19,20,

22,10

2,3,5

t(4,11)

t(1,19)

t(4,11)

ALL-L2 - ++ -

ALL-L3 - - - SIg

Tdt-

t(8,14)

DNA microarray technology

A microarray works by exploiting the ability of a given mRNA molecule to bind specifically to, or hybridize to, the DNA template from which it originated

By using an array containing many DNA samples, scientists can determine--in a single experiment--the expression levels of hundreds or thousands of genes within a cell by measuring the amount of mRNA bound to each site on the array

http://www.jco.org/content/vol20/issue7/images/large/34ff1.jpeg

http://www.jco.org/content/vol20/issue7/images/large/34ff1.jpeg

Some microarray experiments can contain up to

30,000 target spots

Types of Microarrays

There are three basic types of samples

that can be used to construct DNA

microarrays--two are genomic and the

other is "transcriptomic," that is, it

measures mRNA levels

Applications of microarray:

I. Changes in Gene Expression

Levels(microarray expression

analysis) expression chips

II. Genomic Gains And Losses

III. Mutations in DNA

Cluster analysis of leukemic marrow samples



Sixteen distinct groups of patients with AML

were identified on the basis of strong

similarities in gene-expression profiles.


On the basis of SAM-selected genes, the leukemias

were partitioned into two groups with the use of a

different clustering approach (k-means cluster

analysis). Standard Kaplan–Meier survival analysis

confirmed the prognostic significance of these two

clusters: one is associated with a good outcome,

and the other with a poor outcome.

Bullinger et al. first established, using unsupervisedclustering, that the 6283 genes whose expressionvaried the most among the leukemic samplescould be used to identify specific subgroups of AML.

a gene-expression profile based

133 genes predicted the clinical outcome

across cytogenetic risk groups.

conclusion

AML samples with a normal karyotype

separated into two subgroups based on

distinct

samples with t(8;21) and inv(16) each

separate into

different subgroups.

Treatment

Supportive care

Metaboilic support

Chemotherapy

BMT/HSCT

prognosis

Without treatment almost always are fatal

Remission rate with chemotherapy between 70-90%

Relapse rate is usually high

Long term survival less than 40% with chemotherapy alone

With BMT chance of cure increase to 50-60%

Prognostic factors:

Age

Performance

History of chemotherpay or hematologic disorders

Extramedulary disease

CNS or testis involvement

Serum LDH

Response to chemotherapy

cytogenetic

Acute lymphocytic leukemia

Hematology, oncology and BMT research center, Shariati hospital

Hematology, oncology and BMT research center, Imam hospital


Flow data from a typical case of precursor-B acute lymphoblastic leukemia (ALL).

0

10

20

30

40

50

60

70

male

female

Total patient numbers:149

Shariati hospital :94

Imam hospital: 55

Induction

VCR

DAN

CY

Pred

CNSProphylaxis:

HDMTX

IT

ARA-C

VP16

IT X 2

CY

VCR

ADR

Pred

IT

Maintenacne

VCR,Pred,MTX,6MP

30

mo

Selection for

HSCT

ALL treatment plan (HORCBMT)

CR rate:77.7%

Characteristic of patients in Shariati hospital

Median age: 19.6+/-10.01

Median WBC count at presentation: 14800+/- 76779.29( 200-369000)

Median Hb level at presenation: 8.3+/-2.5

Median Plt level at presentation: 38000+/-65748

Organ involvement

Splenomegaly: 70%

Lymphadenopathy:60%

Immunophenotypic and morphologic charactristic of patients

Early pre-B:37.5%

Pre-B: 29.7%

T cell:32.8%

L1:12.1%

L2:87.9%


Flow data from a typical case of precursor-B acute lymphoblastic leukemia (ALL).

Remission induction

Early death( TRM): 6%

Complete remission on day 28: 87.8% of alive patients

Median follow up:10.5 mo (1-42mo)

Median RFS:23.61year RFS:64% and 2 year RFS:47%

Survival Function

for RF survival analysis

1400120010008006004002000

1.1

1.0

.9

.8

.7

.6

.5

.4

.3

.2

.1

.0

Survival Function

Censored

Median Overal survival for patients in CR 27.9 mo1 year OS:69% and 2 year OS:51% 3 yearOS:16%

Survival Function

1400120010008006004002000

Cum

Surv

ival

1.0

.8

.6

.4

.2

0.0

Survival Function

Censored

Allogeneic hematopietic cell transplantation for acute myeloid leukemia

Conventional treatment of AML:

Kinetic of AML: 1012 leukemia cells at presentation and 3 log reduction of the cells after a successful remission induction, usually we can’t to eradicate all of the leukemic cells despite the best chemotherapy regimen. Remaining cells are resistant to chemotherapy agents.

Conventional chemotherapy includes: standard dose of Cytarabin Arabinoside and Daunorubicine

RR=65-80%

long term survival less than 30%

Remission Induction

Cure

Clinically Detectable Disease

Induction Relapse Relapse

Time

Post-remission Therapy


Induction Consolidation Consolidation

Time

Cure

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

Consolidation : High dose Cytarabine (3gr/m2 x 6 times and at least 4

times) is effective in good risk AML and long term survival is about 60%)

High dose cytarabine isn’t effective in other AMLs

long term survival in AMLs other than good risk patients isn’t usual after first complete remission.

Allogeneic BMT recommended in these patients

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

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


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)

Prognostic factors:

Cytogenetic: the most important risk factor ( t(15,17), t(8,21), inv(16) are good risk AML)

Age

leukocytosis

therapy related or post MDS, AML

Allogeneic HSCT after CR of AML

Long term survival is around 46-62% after allogeneic HLA matched sibling HSCT.

GVL effect is the reason of lower relapse rate

T cells are effector cells in GVHD and GVL phenomenon

Best time for HSCT in AML patients( except for good risk AMLs) is at first remission

conditioning regimens including TBI/CY or BU/CY

minitransplant in high risk patients who can’t tolerate aggressive conditioning

Allogeneic v.s. Autologous v.s. Standard chemotherapy for AML in first remission

More than16 studies performed to compare the survival after allogeneic HSCT to autologous BMT or chemotherapy

Most of these studies showed better survival for allogeneic transplantation

no study reported a significant survival advantage or lower relapse rate for chemotherapy or autologous HSCT.

Shariati hospital experience in allogeneic HSCT for AML

40 allogeneic HSCT in AML and 31 are alive ( 77.1%) v.s. 17-20% survival of conventional chemotherapy

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 hadbad/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

Perc

en

t P

atien

ts 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 Groups

100

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 P

atie

nts

Aliv

e in

CR

Years


Pe

rcen

t P

atie

nts

Aliv

e in

CR



Good Risk

Unknown RiskBad/Very Bad Risk

Intermediate Risk

ECOG AML Survival Data<60 years >60 years

Su

rviv

al

1.0

0.8

0.6

0.2

0.4

0.0

0 10 15 20 255

Years

Study Year. 1989-1997, n=553

Median Survival= 3.2 months

5-Year Survival =12%

Study Year. 1973-1979, n=293


5-Year Survival =6%

Study Year. 1983-1986, n=142

Median Survival= 6.3, months


Su

rviv

al

1.0

0.8

0.6

0.2

0.4

0.0

0 10 15 20 255

Years

Study Year. 1983-1986, n=499



Study Year. 1973-1979, n=454



Study Year. 1989-1997, n=1044



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 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

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


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

Surv

ival (%

)

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

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 groove

binding

Me

O

O

NH

NHN

O

S

H

HOO

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 abnormalitiesNabhan C, et al. Leuk Res. 2005;29:53.

Farnesyltransferase inhibitorsin 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 neutropeniaLancet 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


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

TREATMENT OPTIONS IN AML:

A PRACTICAL

CASED-BASED APPROACH

The Role of Transplantation in Acute

Myelogenous Leukemia (AML)

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. 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 BMTor a Second Course of Intensive Consolidation Therapy

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

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 3

Years

Dis

ea

se-f

ree S

urv

ival (%

)


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

Course of Intensive Consolidation Therapy

100

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

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%

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.


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

1.0

0.8

0.6

0.4

0.2

1.51.00.50.0

0.0

3.53.02.52.0 4.54.0 5.0

Time Since Remission (yr)

Pro

po

rtio

n S

urv

ivin

g

Wit

ho

ut

Dis

ea

se

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

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)


Time in months

0.0

Dis

ea

se-f

ree S

urv

ival

Dis

ea

se-f

ree S

urv

ival

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 –

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 FailureNon-myeloablative

51%

22%

22%

5% 0%

Relapse

GVHD

Infection

Other

Pulmonary

Myeloablative

30%

12%

9%9%

40%Relapse

GVHD

Infection

Other

Pulmonary


A PRACTICAL


Chemotherapy for Relapsed AML: Making the Best out of a Bad Situation

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 Chemotherapy

Cytarabine-based 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 26 Refractory (5) 50% CR

Results of Standard-dose

Chemotherapy “Salvage”

•Complete remission rate 25%-60%

•Median remission duration 90-250 days

•Prolonged myelosuppression and toxicity

Other Chemotherapeutic Approaches

OutcomesPatient Characteristics

#AgentsYear

Author

36% CR

Duration 9 mos

Refractory (9)

Relapsed (50)

59

Fludarabine

Ara-C

1992

Estey

28% CR

Duration 7 mos

Refractory (3)

Relapsed (22)

25

Carboplatin1989

Meyers

3% CRRefractory (6)

Relapsed (25)

31

Homoharringtonine

1989

Kantarjian

47% CR

Duration 7 mos

Refractory (0)

Relapsed (17)

17

2 CDA1992

Santana

42% CR

Duration 4-7 mos

Refractory (21)

Relapsed (31)

Other (9)

61

Mitoxantrone

VP-16

1988

Ho

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%


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 199 TBI/Cy MUD 10 Refractory (14) 12%-27% DFS

Allogeneic Bone Marrow

Transplantation

Matched related donors

• Refractory disease

– Leukemia-free survival: 18% 5%

– Actuarial relapse rate: 63% 7%

• Relapsed disease



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


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 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. 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


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


A PRACTICAL



A PRACTICAL


Acute Myeloid LeukemiaMedian age at diagnosis: 62 to 64 years

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







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+

Ave

rag

e A

nn

ua

l R

ate

pe

r 1

00

,00

0

Male

Female

All persons


Age (yrs)

1995-1998

Remission Induction

Cure



Time




Time

Cure










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



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

0

0 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%)

Surv

ival (%

)

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 expression35% 71%

Secondary AML 8% 20%-50%

Sekeres. Hematology. 2004.


Su

rviv

al

1.0

0.8

0.6

0.2

0.4

0.0

0 10 15 20 255

Years

Study Year. 1989-1997, n=553



Study Year. 1973-1979, n=293


5-Year Survival =6%

Study Year. 1983-1986, n=142



Su

rviv

al

1.0

0.8

0.6

0.2

0.4

0.0

0 10 15 20 255

Years

Study Year. 1983-1986, n=499



Study Year. 1973-1979, n=454



Study Year. 1989-1997, n=1044






How old is old?




Older Adults Are Not as Responsive to or Tolerant of Treatment

Comorbid diseases

Slow metabolism of induction-regimen drugs

Particularly cytarabine

High drug levels























Be realistic


Antibiotics

Growth factors



Low-dose cytarabine

Clinical trials!


Comparisons






mg/m2









cytarabine doses



100

80

60

40

20

0

1 2 3 4 5 0

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


Years

Surv

ival (%

)



100 mg/m2










Combination therapy


“7+3” schedule







No clear benefit for age >60 yearsStone RM. CA Cancer J Clin. 2002;52:363.









OH

CH3 CH2

OCH3O


DNA minor groove

binding

Me

O

O

NH

NHN

O

S

H

HOO

OCH3

NH O

O

OCH3

N

O

OCH3HOCH3

OCH3

HNHO

OO

OH

CH3S

CH3

OCH3

I

O

O

O

S

Me Me

OCH3



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





FLAG-Ida are in continuous CR at median of 8 months

Combination with thioguanine increased hepatotoxicityKell WJ, et al. Blood. 2003;102:4277.



Days 1,2,3 Days 1-7


Days 1-7

GO 6 mg/m2 Day 4

Cyto-


Intermed 60% 72%

Poor 32% 28%

Unknown 6 3





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






<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%













ras mutations







4 patients with MDS




Secondary AML




(n=92)

21% CR 33% OR (CR + PR)












CALGB trial of ADE +/– PSC-833 in patients aged

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


Age <60





CSF



Age >60






MRC: dauno/ara-C vs. Hydrea/low-dose ara-C +/– ATRA





18-40 70-80

40-60 60-80

>60 10-35


A PRACTICAL


Corporate Friday Symposium

Manchester Grand Hyatt

Randle Ballroom C-E

Friday, December 3, 2004

7:00am-11:00am



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.




MRC 10


GOELAM







EORTC GIMEMA study







Autologous BMT 128 76 49 38 26 10 4

Allogeneic BMT 168 87 63 48 29 15 0

55%±4%

48%±5%

30%±4%




100

80

70

60

50

40

30

20

10

90

0 4 5 6 71 2 3

Years

Dis

ea

se-f

ree S

urv

ival (%

)




100

Patients at Risk


Autologous BMT 128 94 60 45 29 12 4

Allogeneic 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




59%±4%

56%±5%

46%±5%

AML in First Complete Remission (CR1)

EORTC/GIMEMAAML-10 trial

Of 1198 patients younger than 46 years of age, 822 achieved CR




The DFS rates were 43.4% and 18.4%, respectively, in patients whose leukemia had bad/very bad risk cytogenetics



100

90

80

70

60

50

40

30

20

10

0

0 4 6 82


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

Perc

en

t P

atien

ts 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


100

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


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

rcen

t P

atie

nts

Aliv

e in

CR

Years


Pe

rcen

t P

atie

nts

Aliv

e in

CR



Good Risk


Intermediate Risk



(53% vs. 40%; P=.04)





no difference






1.0

0.8

0.6

0.4

0.2

1.51.00.50.0

0.0

3.53.02.52.0 4.54.0 5.0


Pro

po

rtio

n S

urv

ivin

g

Wit

ho

ut

Dis

ea

se




Cytarabine 48/117 21/69 5/47 1/29 0/18








Adult AML





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



Time in months

0.0

Dis

ease

-fre

e S

urv

ival

Dis

ease

-fre

e S

urv

ival
















non-myeloablative?




51%

22%

22%

5% 0%

Relapse

GVHD

Infection

Other

Pulmonary

Myeloablative

30%

12%

9%9%

40%Relapse

GVHD

Infection

Other

Pulmonary


A PRACTICAL




Randle Ballroom C-E


7:00am-11:00am


Gary Schiller, MD

University of California, Los Angeles


Definition

Refractory leukemia


Relapsed leukemia


complete remission


A case history










Refractory leukemia


Relapsed leukemia






Etoposide

Carboplatin

Fludarabine

Radiation



Salvage Therapy



<1 year

1-2 years

>2 years


Co-morbid disease


Salvage Therapies

Patient selection

Small sample size




Study design

Patient Selection








Resistant Leukemia






Chemo-modulation


Immunomodulation






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


Ara-C

33 Refractory (3)

Relapsed (10)

MDS (12)

Others (8)

10% CR

Duration 14W


Ara-C

47 Relapsed (14)

Others (33)

45% CR


Duration 16W

Gore 1989 Ara-C

VP-16

41 Refractory (16)

Relapsed (25)

63% CR

Duration ?









#AgentsYear

Author

36% CR

Duration 9 mos

Refractory (9)

Relapsed (50)

59

Fludarabine

Ara-C

1992

Estey

28% CR

Duration 7 mos

Refractory (3)

Relapsed (22)

25

Carboplatin1989

Meyers

3% CRRefractory (6)

Relapsed (25)

31

Homoharringtonine

1989

Kantarjian

47% CR

Duration 7 mos

Refractory (0)

Relapsed (17)

17

2 CDA1992

Santana

42% CR

Duration 4-7 mos

Refractory (21)

Relapsed (31)

Other (9)

61

Mitoxantrone

VP-16

1988

Ho


Author Year


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


Author Year

Agents

Tx Type


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


Yeager 1986

Bu/Cy Purged-auto


Gorin 1986

TBI/Cy

Purged-auto

11 Refractory (4)

Relapsed (5)

Other (2)

27% survival @ 1 yr


Transplantation


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%






10% to 43%


Author Year

Agents Tx Type


Schnitz 1988

TBI/VP 16


Relapsed (9)

54% DFS

Santos 1983


Relapsed (17)

0 +

29% DFS

Forman 1991

TBI/Cy/Ara-C

TBI/VP 16


Clift 1992

TBI/Cy MRD 126

First Relapse (126)

23% DFS

Schiller 1994

TBI/Cy

Bu/Cy


Relapsed (47)

23% DFS



Transplantation









New Therapies


PSC-833

Tamoxifen


Interleukin-2


Donor leukocytes



New Therapies


Refractory disease

Relapsed disease

<6 mos


>12 mos






Dose-escalation



Remission rate




Sensitization

Anti-angiogenesis


Immunotherapeutic







Arsenic trioxide






younger patients





of cases


Cor/Millenium drug

Cephalon drug




Tumor antigens

CD33


monoclonal antibody





CR in 30%










Conclusions







A PRACTICAL



A PRACTICAL


Current Status and Controversies in Acute Myeloid Leukemia Induction Therapy

Edward A. Stadtmauer, MDUniversity 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







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+

Ave

rag

e A

nn

ua

l R

ate

pe

r 1

00

,00

0

Male

Female

All persons


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


ConsolidationChemotherapy

SCT

Remission Induction

Cure



Time




Time

Cure










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



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

0

0 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%)

Surv

ival (%

)

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 expression35% 71%

Secondary AML 8% 20%-50%

Sekeres. Hematology. 2004.


Su

rviv

al

1.0

0.8

0.6

0.2

0.4

0.0

0 10 15 20 255

Years

Study Year. 1989-1997, n=553



Study Year. 1973-1979, n=293


5-Year Survival =6%

Study Year. 1983-1986, n=142



Su

rviv

al

1.0

0.8

0.6

0.2

0.4

0.0

0 10 15 20 255

Years

Study Year. 1983-1986, n=499



Study Year. 1973-1979, n=454



Study Year. 1989-1997, n=1044






How old is old?




Older Adults Are Not as Responsive to or Tolerant of Treatment

Comorbid diseases

Slow metabolism of induction-regimen drugs

Particularly cytarabine

High drug levels























Be realistic


Antibiotics

Growth factors



Low-dose cytarabine

Clinical trials!


Comparisons






mg/m2









cytarabine doses



100

80

60

40

20

0

1 2 3 4 5 0

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


Years

Surv

ival (%

)



100 mg/m2










Combination therapy


“7+3” schedule







No clear benefit for age >60 yearsStone RM. CA Cancer J Clin. 2002;52:363.









OH

CH3 CH2

OCH3O


DNA minor groove

binding

Me

O

O

NH

NHN

O

S

H

HOO

OCH3

NH O

O

OCH3

N

O

OCH3HOCH3

OCH3

HNHO

OO

OH

CH3S

CH3

OCH3

I

O

O

O

S

Me Me

OCH3



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





FLAG-Ida are in continuous CR at median of 8 months

Combination with thioguanine increased hepatotoxicityKell WJ, et al. Blood. 2003;102:4277.



Days 1,2,3 Days 1-7


Days 1-7

GO 6 mg/m2 Day 4

Cyto-


Intermed 60% 72%

Poor 32% 28%

Unknown 6 3





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






<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%













ras mutations







4 patients with MDS




Secondary AML




(n=92)

21% CR 33% OR (CR + PR)












CALGB trial of ADE +/– PSC-833 in patients aged

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


Age <60





CSF



Age >60






MRC: dauno/ara-C vs. Hydrea/low-dose ara-C +/– ATRA





18-40 70-80

40-60 60-80

>60 10-35


A PRACTICAL




Randle Ballroom C-E


7:00am-11:00am



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.




MRC 10


GOELAM







EORTC GIMEMA study







Autologous BMT 128 76 49 38 26 10 4

Allogeneic BMT 168 87 63 48 29 15 0

55%±4%

48%±5%

30%±4%




100

80

70

60

50

40

30

20

10

90

0 4 5 6 71 2 3

Years

Dis

ea

se-f

ree S

urv

ival (%

)




100

Patients at Risk


Autologous BMT 128 94 60 45 29 12 4

Allogeneic 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




59%±4%

56%±5%

46%±5%

AML in First Complete Remission (CR1)

EORTC/GIMEMAAML-10 trial

Of 1198 patients younger than 46 years of age, 822 achieved CR




The DFS rates were 43.4% and 18.4%, respectively, in patients whose leukemia had bad/very bad risk cytogenetics



100

90

80

70

60

50

40

30

20

10

0

0 4 6 82


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

Perc

en

t P

atien

ts 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


100

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


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

rcen

t P

atie

nts

Aliv

e in

CR

Years


Pe

rcen

t P

atie

nts

Aliv

e in

CR



Good Risk


Intermediate Risk



(53% vs. 40%; P=.04)





no difference






1.0

0.8

0.6

0.4

0.2

1.51.00.50.0

0.0

3.53.02.52.0 4.54.0 5.0


Pro

po

rtio

n S

urv

ivin

g

Wit

ho

ut

Dis

ea

se




Cytarabine 48/117 21/69 5/47 1/29 0/18








Adult AML





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



Time in months

0.0

Dis

ease

-fre

e S

urv

ival

Dis

ease

-fre

e S

urv

ival
















non-myeloablative?




51%

22%

22%

5% 0%

Relapse

GVHD

Infection

Other

Pulmonary

Myeloablative

30%

12%

9%9%

40%Relapse

GVHD

Infection

Other

Pulmonary


A PRACTICAL




Randle Ballroom C-E


7:00am-11:00am


Gary Schiller, MD

University of California, Los Angeles


Definition

Refractory leukemia


Relapsed leukemia


complete remission


A case history










Refractory leukemia


Relapsed leukemia






Etoposide

Carboplatin

Fludarabine

Radiation



Salvage Therapy



<1 year

1-2 years

>2 years


Co-morbid disease


Salvage Therapies

Patient selection

Small sample size




Study design

Patient Selection








Resistant Leukemia






Chemo-modulation


Immunomodulation






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


Ara-C

33 Refractory (3)

Relapsed (10)

MDS (12)

Others (8)

10% CR

Duration 14W


Ara-C

47 Relapsed (14)

Others (33)

45% CR


Duration 16W

Gore 1989 Ara-C

VP-16

41 Refractory (16)

Relapsed (25)

63% CR

Duration ?









#AgentsYear

Author

36% CR

Duration 9 mos

Refractory (9)

Relapsed (50)

59

Fludarabine

Ara-C

1992

Estey

28% CR

Duration 7 mos

Refractory (3)

Relapsed (22)

25

Carboplatin1989

Meyers

3% CRRefractory (6)

Relapsed (25)

31

Homoharringtonine

1989

Kantarjian

47% CR

Duration 7 mos

Refractory (0)

Relapsed (17)

17

2 CDA1992

Santana

42% CR

Duration 4-7 mos

Refractory (21)

Relapsed (31)

Other (9)

61

Mitoxantrone

VP-16

1988

Ho


Author Year


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


Author Year

Agents

Tx Type


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


Yeager 1986

Bu/Cy Purged-auto


Gorin 1986

TBI/Cy

Purged-auto

11 Refractory (4)

Relapsed (5)

Other (2)

27% survival @ 1 yr


Transplantation


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%






10% to 43%


Author Year

Agents Tx Type


Schnitz 1988

TBI/VP 16


Relapsed (9)

54% DFS

Santos 1983


Relapsed (17)

0 +

29% DFS

Forman 1991

TBI/Cy/Ara-C

TBI/VP 16


Clift 1992

TBI/Cy MRD 126

First Relapse (126)

23% DFS

Schiller 1994

TBI/Cy

Bu/Cy


Relapsed (47)

23% DFS



Transplantation









New Therapies


PSC-833

Tamoxifen


Interleukin-2


Donor leukocytes



New Therapies


Refractory disease

Relapsed disease

<6 mos


>12 mos






Dose-escalation



Remission rate




Sensitization

Anti-angiogenesis


Immunotherapeutic







Arsenic trioxide






younger patients





of cases


Cor/Millenium drug

Cephalon drug




Tumor antigens

CD33


monoclonal antibody





CR in 30%










Conclusions







A PRACTICAL


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