Evolving Treatments for Acute Leukemia and Myelodysplastic Syndromes Mark B Juckett MD University of Wisconsin
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