Evolving Treatments for Acute Leukemia and Myelodysplastic

Syndromes

Mark B Juckett MD

University of Wisconsin

Leukemia Mortality by State

Incidence of Leukemia in Older Adults

Rate/100,000 Proportion

ALL 0.9 5%

CLL 7.2 44%

AML 5.8 35%

CML 2.7 16%

Incidence of 55-64 age group, data from 1994-98, SEER database

AML/MDS - definition

• Clonal neoplastic disorder of a myeloid stem cell– Problems with blood production

• Anemia, thrombocytopenia, neutropenia

– Problems with neoplastic cell growth• Constitutional symptoms, leukostasis, organ

dysfunction, bone pain

AML 1994-1998 Incidence by ageIn United States

BMT Candidates

Pathogenesis - “the usual”

• Complex interaction between agents, environment, genetics.

• Accumulation of genetic events (mutations, deletions, etc), multistep process

• Faulty genetic program impedes differentiation, favors growth

• Process continues until organ dysfunction, cell growth causes symptoms

Genetic Events alter Differentiation

Environmental Factors Associated with AML/MDS

• Environment– Arsenic

– Benzene

• Smoking• Ionizing radiation

– Medical radiation

– Nuclear accidents

– Radon ?

• Chemotherapy– Alkylating agents

• Cyclophosphamide

– Topoisomerase II• etoposide

• Other drugs– Immunosuppressives

– Chloramphenicol

Genetic Factors

• Down Syndrome• Fanconi Syndrome• Bloom Syndrome• Klinefelter Syndrome• Ataxia-telangiectasia• Dyskeratosis

Congentia

• Congenital aneuploidy• Identical Sib with

AML• Combined

Immunodeficiency• Li-Fraumeni

syndrome

Environmental Risk Factors for MDS

Nisse BJH 112;927, 2001• 204 MDS patients and controls

• Interviewed at home – demographic data, lifetime residence, medical

history, proximity to nuclear, chemical, industrial plants, carcinogen exposure.

• Occupational history with exposure to list of compounds.

• Reviewed validity with occupational experts (reviewers blinded)

OR P

Farmers 3.66 0.0001

Textile operators 3.66 0.001

Health professionals 10.0 0.004

Near industrial plant 2.45 0.007

Technical sales rep 4.45 0.013

Smoking 1.74 0.015

Machine operators 2.69 0.015

Oil use 1.10 0.029

Environmental Risk Factors Results

Nisse BJH 112;927, 2001

AML Classification

• WHO Classification 1997

• Rely on morphology, immunophenotype, genetic & clinical features

• Most important - Cytogenetics

• Most morphological distinctions difficult

• Increasingly merge with myelodysplastic syndromes

JCO 17:3835, 1999

WHO Classification - AML

• AML with recurrent cytogenetics– t(8;21), t(15;17), t(16;16), 11q23

• AML with multilineage dysplasia

• AML with MDS, therapy related

• AML – subtype by morphology (M0, M1, etc.)

JCO 17:3835, 1999

WHO Classification - MDS• Refractory anemia

– with ringed sideroblasts– without ringed sideroblasts

• Refractory cytopenia with multilineage dysplasia

• Refractory anemia with excess blasts

• 5q- syndrome

• Myelodysplastic syndrome, NOS

JCO 17:3835, 1999

Cytogenetic abnormalities AML

• Best Prognosis

• Intermediate Prognosis

• Worst Prognosis

t(8;21)

t(16;16)

t(15;17)

Normal cytogenetics

Trisomy 8

Chromosome 5, 7

11q23 abnl

3q21,26 abnl

Complex

Myelodysplasia - International Prognostic Index

• Blasts• Cytogenetics

– Y-, 5q-, 20q- • good

– chr 7 or multiple• bad

• Cytopenia– 0 or 1 good

– 2 or 3 bad

• Median Survival– Low Risk

• 5.7 years

– Low Intermediate• 3.5

– High Intermediate• 1.2

– High• 6 months

Initial Treatment Strategy for AML

• Rapidly control metabolic imbalances

• Transfuse (Hgb > 8, Plt > 10 - 20k)

• Control WBC if needed– Hydroxyurea– Leukapheresis

• Evaluate cardiorespiratory function

• Given chemotherapy when “tuned”

Presentation - Emergencies

• Coagulopathy - Acute promyelocytic

• Tumor lysis syndromes

• Hypercalcemia

• Neutropenic sepsis

• Leukostasis

• Pulmonary Failure

• Severe cytopenia

Initial Diagnosis

• Usually made by CBC and manual differential

• Bone Marrow Biopsy– Biopsy and Aspiration– Marrow samples sent for:

• Flow cytometry

• Cytogenetics

• FISH (as indicated)

Proposed treatment schema for AMLInduction

Favorable UnfavorableIntermediate

Standard anthracycline + cytarabine (3 + 7)

Favorable 84 – 90%

Intermediate 76 – 84%

Unfavorable 55 – 57%

CR Rates

*Not APL

Next step - “Consolidation”

• No further therapy – 100% relapse, median 4.1 mo (Cassileth, JCO 6:583)

• Chemotherapy alone– Standard high dose cytarabine 2 or 3 times

• Autologous Bone Marrow Transplantation

• Allogeneic Bone Marrow Transplantation

Consolidation Favorable Cytogenetics

• Standard– 3 or 4 cycles of high dose cytarabine

• Possible Benefit– Myeloablative chemo/radiotherapy with

autologous peripheral blood stem cell rescue

• Unclear Benefit– Allogeneic BMT (studies inconclusive)

• Results - long-term survival 50-60%

• Standard (under 65)

– Matched sibling donor available• Allogeneic BMT in first CR

– No donor• High dose cytarabine followed by autologous BMT

• Results– Allogeneic BMT - 55-65% 3-year survival– Autologous BMT - 40-50% 3-year survival

Consolidation Intermediate Cytogenetics

• Standard– Matched sibling donor

• Allogeneic BMT in first CR (under 65)

– No donor• Alternative donor (under 55)• maybe Autologous BMT ?

• Results– Allogeneic BMT - 30-50% 3-year survival– Other - less than 15%

Consolidation Unfavorable Cytogenetics

Bone Marrow Transplantation

• Best - Matched Sibling (1/4 change/sib)

• Matched Unrelated, Partial matched family an option - even more risky

• Best case - Non-relapse Mortality 20-30%

• Autologous - Less risk, more relapse

• Prolonged recovery - disability 1 year

• Long term problems ?

Survival after AML (< 55 years)

AML Pts on ECOG protocols since 1973

Survival after AML (> 55 years)

AML Pts on ECOG protocols since 1973

Novel Approaches

• Immunoconjugates

• Signal Transduction modifiers

• Non-myeloablative transplantation

• Multidrug resistance modulation

AML/MDS Activation PathwaysTyrosine Kinases Ras Signaling

Gemtuzumab Ozogamicin (Mylotarg®)

• FDA Approved Indication– “Mylotarg is indicated for the treatment of patients

with CD33 positive acute myeloid leukemia in first relapse who are 60 years of age or older and who are not considered candidates for cytotoxic chemotherapy.”

• IgG4 chimeric murine/human monoclonal antibody against CD33 conjugated with calicheamicin

Gemtuzumab Ozogamicin Structure

MurineVariableRegion

Human Constant Region IgG4

Linker

Calicheamicin

Mylotarg in relapsed AML

NR

CR

CRp

Cooperative Group Trial - ECOG E4999

A rm AC yta rab in e 1 g m /m 2 /d x4 d

M ylo ta rg 6 m g /m 2

A rm BC yta rab in e 1 g m /m 2 x4 d

L ip o D au n oru b ic in 1 3 5 m g /m 2 x3 d

A rm CC yc lo 3 0 0 m g /m 2 q 1 2 x3 dC yta rab in e 1 g m /m 2 x4 d

Top otecan 1 .5 m g /m 2 x4 d

R an d om ize

•Patients with relapsed/refractory AML•AML CD33 positive

Myeloablative SCT

High dose radiationHigh dose chemo

Stem cells

Supportive CareWatch and Wait

Non-myeloablative SCT

Immunosuppression

Stem cells

Manipulate the Immune response to maximize Graft vs. Disease

Multidrug Resistance

ChemotherapyIN

MDR

ChemotherapyOUT

Multidrug Resistance

ChemotherapyIN

MDR

MDR Block

MDR modulation in poor-risk AML

List, Blood, 98:3212, 2001

Treatment of MDS

• “Standard Care” - supportive

• BMT - only curative option

• Under investigation– Immunomodulation - ATG, thalidomide, Ontak– Differentiation - Doxercalciferol, arsenic,

amifostine, decitabine– Signaling Pathway inhibitors – Novel BMT regimens

Conclusions

• AML/MDS are diseases of older people

• Prognosis is best predicted by cytogenetics

• Outcome has improved for patients under 55

• Outcome has not improved for older people

• HSC transplantation is indicated for most younger patients

• New agents really do look promising