Acute Myeloid Leukemia Marcelo C. Pasquini, MD, MS Associate Professor of Medicine Adult BMT Program Heme-Malignancies Division of Hematology/Oncology

Acute Myeloid Leukemia Outline Bone marrow as a blood forming organ Biology of Acute Myeloid Leukemia Treatment Bone marrow Transplant

Bone Marrow: the source of blood production and the immune system All blood cells arise from hematopoietic stem cells Self renewing Pluripotent Blood production is highly regulated Messages from the body (e.g. erythropoietin from kidney) Microenvironments produce specific cells Cytokines (SCF, IL3) Growth factors (G-CSF) Normal bone marrow

Hematopoiesis Scheme Lymphoid Compartment Stem Cell Compartment Myeloid Compartment

AML and Morphologic Differences

WHO AML Classification

Prognostic factors in AML Disease markers Chromosomes Genetic markers Performance status Age

Yearly incidence of AML per 100 000 inhabitants Epidemiology   Median age is 72 y Peak incidence at 80-84 y        At least 70% of patients up to age 80 have a PS of 0-II      Yearly incidence of AML per 100 000 inhabitants according to age and sex in Sweden 1997 to 2006, in the SEER registry (whites, 2004-2008),24 and in the United Kingdom.25 United Kingdom data were given for 20-year age intervals (20-39, 40-59, 60-79, and 80+ years). Yearly incidence of AML per 100 000 inhabitants Juliusson G et al. Blood 2009;113:4179-4187 Juliusson G et al. Blood 2012;119:3890-3899

Prognosis in AML-Age Juliusson G et al. Blood 2009;113:4179-4187

Life Expectancy Average life expectancy for: Newborn ~ 76 years 50 year old ~ 30 years (80) 55 year old ~ 25 years (80) 60 year old ~ 22 years (82) 65 year old ~ 18 years (83) 70 year old ~ 14 years (84) 75 year old ~ 10 years (85) 80 year old ~ 8 years (88) http://www.ssa.gov/OACT/STATS/table4c6.html

Southwest Oncology Group Leukemia Committee percentage of patients in cytogenetic risk groups by age category. Southwest Oncology Group Leukemia Committee percentage of patients in cytogenetic risk groups by age category. The percentage includes only patients with a known cytogenetic risk group. Appelbaum F R et al. Blood 2006;107:3481-3485

4 3 Region 2 2 1 Short arm 'p' 3 Region 1 2 1 Centromere 1 2 Region 1 3 Long arm 'q' 1 Region 2 2 1 2 3 Region 3 4

Normal Male Karyotype: 46, XY Prior to cell division, all the genetic material within the nucleus is packaged in chromosomes. We can collect blood, stimulate the nucleated cells to divide in culture and use agents to block cell division at this particular stages.

47, XY, +8

Report Sample

Florescence In Situ Hybridization How about FISH? Florescence In Situ Hybridization

Cytogenetic Evaluation Std Cytog. FISH Cells analyzed 20 200-500 Cell cycle Metaphase Metaphase and Interphase Abnormality specific No Yes Cell culture

Overall Survival by SWOG Cytogenetic Risk Status Slovak et al, Blood 2000; 96: 4075-4083

Genetic markers in AML

Dohner H, Hematology 2007, p412-419

Molecular Markers and Prognosis New Good Guys NPM1 mutation without FLT3 ITD CEBPA mutation New Bad Guys FLT3 ITD MLL PTD KIT mutation (Associated with t(8;21) or inv(16)) Overexpression of BAALC WT1 mutations IDH1/2

Frequencies and Distribution of the NPM1, CEBPA, MLL, FLT3, and NRAS Mutations, According to Mutation Class Figure 1. Frequencies and Distribution of the NPM1, CEBPA, MLL, FLT3, and NRAS Mutations, According to Mutation Class. Frequencies are given for the 438 patients in whom data on all genes were available. ITD denotes internal tandem duplication, PTD partial tandem duplication, and TKD mutation of the tyrosine kinase domain. Schlenk R et al. N Engl J Med 2008;358:1909-1918

Favorable Intermediate Unfavorable NPM1pos+FLT3ITDneg CEEBPA mut t(8;21) + c-kit mutation Intermediate FLT3 ITD Unfavorable

AML and Genetic Variation

AML Up-Front Treatment Induction “7+3” Post-Remission Therapy CR Allogeneic BMT Consolidation Chemotherapy Autologous BMT Diagnosis CR: Complete Remission

First report of “7 + 3” Cancer Chemotherapy reports Part 1 Vol. 57, No. 4, Nov/Dec 1973

Induction therapy 7 + 3 Azacitidine Decitabine Clofarabine

Hematopoietic Cell Transplant Preparative or Conditioning Regimen: Radiation and or Chemotherapy HSCT D D R R D R D RL D RL D Recipient Donor Complete Chimera

Indications for Hematopoietic Stem Cell Transplants in the US, 2012 Number of Transplants

Trends in Allogeneic Transplants by Recipient Age* * Transplants for AML, ALL, NHL, Hodgkin Disease, Multiple Myeloma

100 20 40 60 80 Probability, % Years p < 0.0001 Early (n=7,607) Intermediate (n=2,124) Advanced (n=2,578) 1 2 6 4 5 3 s25 Survival after HLA-identical Sibling Donor Transplants for AML, 2002-2012 By Disease Status

Survival after Unrelated Donor Transplants for AML, 2002-2012 100 20 40 60 80 Probability, % Years 1 2 6 4 5 3 Early (n=7,365) Intermediate (n=4,172) Advanced (n=4,095) p < 0.0001 By Disease Status

Conclusions AML is a heterogeneous disease Understanding prognosis helps in planning therapy Understanding better the biology is helping the development of new treatments. Transplants for AML are less toxic and able to help a greater number of patients.