Bone Marrow Failure and Acute Leukemia: More mutations, more problems 6/18/13. Rebecca Olin, MD, MSCE
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1 Bone Marrow Failure and Acute Leukemia: More mutations, more problems 6/18/13 Rebecca Olin, MD, MSCE BIOGRAPHY: Rebecca Olin MD MSCE is an Assistant Professor of Clinical Medicine at UCSF. After undergraduate work at Amherst College, she received her MD degree from University of Pennsylvania School of Medicine. She subsequently completed residency training in Internal Medicine and fellowship in Hematology/Oncology, both also at University of Pennsylvania. During fellowship she also received a Masters degree in Clinical Epidemiology, with a focus both on clinical trial development and outcomes research. She has been at UCSF as an Assistant Professor since 2009, and has a clinical practice which focuses on acute leukemia, myelodysplastic syndromes and other hematologic disorders, as well as stem cell transplantation. Her research area of interest is in evaluating quality of life and functional status in older stem cell transplant recipients, with a goal of learning more about how to make stem cell transplant safer. BIBLIOGRAPHY: 1. National Marrow Donor Program. Available from: BeTheMatch.org. 2. A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington's disease chromosomes. The Huntington's Disease Collaborative Research Group. Cell Mar 26;72(6): Byrd JC, Mrozek K, Dodge RK, Carroll AJ, Edwards CG, Arthur DC, et al. Pretreatment cytogenetic abnormalities are predictive of induction success, cumulative incidence of relapse, and overall survival in adult patients with de novo acute myeloid leukemia: results from Cancer and Leukemia Group B (CALGB 8461). Blood Dec 15;100(13): Calado RT, Young NS. Telomere diseases. N Engl J Med Dec 10;361(24): Dohner H, Estey EH, Amadori S, Appelbaum FR, Buchner T, Burnett AK, et al. Diagnosis and management of acute myeloid leukemia in adults: recommendations from an international expert panel, on behalf of the European LeukemiaNet. Blood Jan 21;115(3): Sanz MA, Lo Coco F, Martin G, Avvisati G, Rayon C, Barbui T, et al. Definition of relapse risk and role of nonanthracycline drugs for consolidation in patients with acute promyelocytic leukemia: a joint study of the PETHEMA and GIMEMA cooperative groups. Blood Aug 15;96(4): Shimamura A, Alter BP. Pathophysiology and management of inherited bone marrow failure syndromes. Blood Rev May;24(3):
2 Bone Marrow Failure Syndromes and Acute Leukemia: More mutations, more problems Rebecca Olin MD MSCE UCSF Mini Medical School June Huntington Disease A Progressive neurological disorder Typical onset in 30 s, progresses over years until death Genetically inherited 50% chance No treatment, no cure MacDonald
3 Laboratory Values (Review) We order a CBC = Complete Blood Count RBC = red blood cells (erythrocytes) Platelets WBC = white blood cells Neutrophils Lymphocytes Monocytes Basophils Eosinophils Acquired BMFS Inherited BMFS Acquired Aplastic Anemia Aplastic = failure to develop Aplastic anemia is a misnomer because it is not just about anemia Failure of the bone marrow to make enough cells of all three lineages Failure to make blood Aka The Empty Marrow Disorder of the bone marrow stem cell Clinical Presentation Diagnosis Rare disease: <5 cases per million people per year Clinical presentation is based on the deficiency of each of the cell lines Low white blood cells: fever, susceptibility to infection Low red blood cells: fatigue, pallor, shortness of breath Low platelets: bleeding, bruising Aplastic Anemia Normal Bone Marrow 2
4 Causes of Aplastic Anemia Chemicals eg pesticides Medications wide variety Viruses hepatitis, HIV, parvovirus Radiation Inherited predisposition MAJORITY ARE UNKNOWN idiopathic Aplastic Anemia is an Autoimmune Disease Patient s own T-cells (T lymphocytes) are attacking the bone marrow stem cell Treatment is based on suppressing the T-cells Treatment of Aplastic Anemia Anti-thymocyte Globulin (ATG) T Cyclosporine T More later Acquired BMFS Inherited BMFS Fanconi Anemia Fanconi Anemia Genes Inherited genetic disease Aplastic anemia, leukemia Susceptibility to cancers Other physical abnormalities: short stature, skin findings, abnormality of thumbs, small head 60% have some physical abnormality (40% do not) Mean age of diagnosis is 6 years, but some in 20 s, 30 s Shimamura 2010 Shimamura
5 DNA Damage DNA Repair Up to one million events per cell per day! Fanconi Anemia: Diagnosis Blood lymphocytes are cultured with a DNA crosslinking chemical (MMC, DEB) Normal cells can repair the damage, FA cells cannot Shimamura 2010 Acquired BMFS Inherited BMFS Dyskeratosis Congenita Inherited syndrome Aplastic anemia Cancers Lung fibrosis and liver cirrhosis Other physical abnormalities: abnormal nails, lacy rash, white patches in mouth, premature grey hair 75% have some physical abnormality (25% do not) Mean age of diagnosis is 14 years, but some up to 50s, 60s Shimamura
6 Dyskeratosis Congenita Genes Telomeres Calado 2009 Telomere Function Every time a cell divides, a very small amount of DNA at the ends of chromosomes is not replicated and therefore lost Telomeres are martyrs to protect coding genetic material from being lost telomeres get shorter instead Telomere Maintenance Enzyme complex called telomerase, containing both proteins and RNA 11 Kb cord blood 6 Kb age 90 TERC Calado 2009 (Go UCSF!) Elizabeth Blackburn Calado 2009 Cellular Consequences of Telomere Erosion Calado 2009 Shimamura
7 Spectrum of Telomere Diseases Dyskeratosis Congenita: Diagnosis Telomere length (kb) Age (years) Calado 2009 Treatment of BMF Syndromes Aplastic anemia stem cell transplant Only fixes the bone marrow problem, not the problem in other body tissues Cancers chemotherapy per cancer type Problem: very sensitive to side effects of chemotherapy (FA in particular) Require intensive screening programs to detect cancers, and unique stem cell transplant approaches Normally <5% blasts 6
8 Acute Myeloid Leukemia (AML) Most common acute leukemia in adults Chronic lymphocytic leukemia (CLL) is most common 3-5 cases of AML per 100,000 people per year Clinical presentations: low blood counts leukostasis sludging B B BB BB B B BB BB B B BB BB infiltration AML: Definition and Causes AML: Sub-classification and Prognosis Definition of AML: >20% blasts in bone marrow <5% = normal 5-20% = myelodysplastic syndrome (MDS), a precursor to AML Causes: largely unknown Prior chemotherapy Prior radiation Certain chemicals eg benzene Genetic disorders eg Fanconi Risk Category Chromosomal Abnormality in Leukemia Cells Favorable inv16 t(8;21) t(15;17) - APL Intermediate Normal Other abnormalities Unfavorable Loss of 5 Loss of 7 Chemotherapy-related Complex (>=3) Byrd 2002 AML: Sub-classification and Prognosis Molecular Diversity of AML with Normal Chromosomes Risk Category Favorable Chromosomal Abnormality in Leukemia Cells inv16 t(8;21) t(15;17) - APL Intermediate Normal Other abnormalities Unfavorable Loss of 5 Loss of 7 Chemotherapy-related Complex (>=3) Molecular Abnormality in Leukemia Cells Normal with NPM1 t(8;21) with C-kit Normal with FLT3 Dohner
9 Phase 1: Induction Process of Treating AML reduce the number of leukemia cells in the body by orders of magnitude goal: remission = chemo Phase 2: Consolidation get ride of every single last leukemia cell in the body goal: cure = more chemo or stem cell transplant Normally <5% blasts Acute Promyelocytic Leukemia (APL) Defined by existence of t(15;17) translocation 15 PML PML RARα 17 RARα Function of PML not well understood Function of RAR proteins is to bind certain genes, promote normal differentiation of cells Abnormal RARα has abnormal function 8
10 APL: Prognosis Used to be worst prognosis acute leukemia survival <1 month without treatment Since the development of targeted therapies against PML-RAR, is now the best form All-trans retinoic acid (ATRA) Arsenic Relapse-free survival (Chemo + ATRA) Sanz 2000 Evolution of APL Treatment APL and Bleeding Chemotherapy 1990 s, 2000 s Chemotherapy plus ATRA 2000 s Chemotherapy, ATRA plus arsenic 2010 s ATRA plus arsenic (no chemo?) APL commonly presents with bleeding problems DIC, or disseminated intravascular coagulation Due to release of granules from promyelocytes, which affect blood s clotting proteins DIC can worsen during initial treatment, as promyelocytes die and dump granules Early death rate from bleeding complications is 10-30% What is a Stem Cell Transplant? It s not a surgery Consists of chemotherapy (+/- radiation) followed by infusion of hematopoietic (blood) stem cells into a vein 9
11 First, Some Terminology How is a stem cell transplant different from a bone marrow transplant? Basically, it s two terms for the same thing It has to do with how we get them out More Terminology: Autologous vs Allogeneic There are two kinds of stem cell transplant: Autologous Derived or transferred from the same individual's body Allogeneic Being genetically different although belonging to or obtained from the same species DIFFERENT: Philosophy / rationale Diseases and disease scenarios Level of risk Autologous SCT Autologous SCT Goal is to administer very high doses of chemotherapy If some is good, more is better Problem is, healthy bone marrow cells are destroyed CHEMO Stem cells Remove stem cells (and freeze) Administer high doses of chemotherapy = KILL CANCER! Infuse stem cells to rescue / regenerate bone marrow Low blood counts Allogeneic SCT Allogeneic SCT Works in two ways 1) Replace bad bone marrow (and/or cancer) with good bone marrow 2) Use the new immune system to recognize any remaining cancer cells as foreign and attack them CHEMO Stem cells Graft versus Host Disease (? ) Administer high doses of chemotherapy to KILL CANCER Infuse donor stem cells to regenerate bone marrow Donor stem cells recognize and KILL CANCER Low blood counts Donor stem cells recognize patient host and attack = Graft Versus Host Disease Immune Suppressive Medications Infections 10
12 Stem Cell Source SCT Cures Disease and Saves Lives 1 Sibling donor 25% 2 Matched unrelated donor Umbilical cord blood 3 Half-matched donor: 50% if sibling 100% if parent or child Thank you for your attention! 11
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