bone marrow failure and acute leukemia: more...

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. 1993 Mar 26;72(6):971‐83. 3. 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. 2002 Dec 15;100(13):4325‐36. 4. Calado RT, Young NS. Telomere diseases. N Engl J Med. 2009 Dec 10;361(24):2353‐65. 5. 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. 2010 Jan 21;115(3):453‐74. 6. 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. 2000 Aug 15;96(4):1247‐53. 7. Shimamura A, Alter BP. Pathophysiology and management of inherited bone marrow failure syndromes. Blood Rev. 2010 May;24(3):101‐22.

6/14/2013

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Bone Marrow Failure Syndromes and Acute Leukemia:

“More mutations, more problems”

Rebecca Olin MD MSCE

UCSF Mini Medical School

June 18 2013

A

Huntington Disease

Progressive neurological disorder

Typical onset in 30’s, progresses over 10-20 years until death

Genetically inherited – 50% chance

No treatment, no cure

MacDonald 1993

Overview

Review of normal hematopoiesis (blood development)

Bone Marrow Failure Syndromes Aplastic Anemia

Fanconi Anemia

Dyskeratosis Congenita

Acute Leukemias Acute Myeloid Leukemia

Acute Promyelocytic Leukemia

Hematopoietic Stem Cell Transplantation

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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



Fanconi Anemia





Overview

Inherited BMFS

Acquired 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

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

DiagnosisNormal Bone MarrowAplastic Anemia

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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

More later…

Anti-thymocyte Globulin (ATG)

TT

Cyclosporine



Fanconi Anemia





Overview

Inherited BMFS

Acquired BMFS

Fanconi Anemia

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

Fanconi Anemia Genes

Shimamura 2010

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DNA Damage

Up to one million events per cell per day!

DNA Repair

Fanconi Anemia: Diagnosis

Blood lymphocytes are cultured with a DNA cross-linking chemical (MMC, DEB)

Normal cells can repair the damage, FA cells cannot

Shimamura 2010



Fanconi Anemia





Overview

Inherited BMFS

Acquired BMFS


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 2010

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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

11 Kb – cord blood

6 Kb –age 90

Calado 2009

Telomere Maintenance

Enzyme complex called telomerase, containing both proteins and RNA

(Go UCSF!)Elizabeth Blackburn

Calado 2009

TERC

Cellular Consequences of Telomere Erosion

Calado 2009 Shimamura 2010

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Spectrum of Telomere Diseases

Calado 2009

Dyskeratosis Congenita: Diagnosis

Telomere length (kb)

Age (years)

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



Fanconi Anemia





Overview

Normally <5% blasts

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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:

BB

BB

BB

BB

B

BB

BB

BB

BB

B

low blood counts leukostasis – “sludging”

infiltration

AML: Definition and Causes

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

AML: Sub-classification and Prognosis

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

Risk Category Chromosomal Abnormality in Leukemia Cells

Molecular Abnormality in Leukemia Cells

Favorable inv16

t(8;21)

t(15;17) - APL

Normal with NPM1

Intermediate Normal

Other abnormalities

Unfavorable Loss of 5

Loss of 7

Chemotherapy-related

Complex (>=3)

t(8;21) with C-kit

Normal with FLT3

Molecular Diversity of AML with Normal Chromosomes

Dohner 2010

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Process of Treating AML

Phase 1: Induction 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



Fanconi Anemia





Overview

Normally <5% blasts

Acute Promyelocytic Leukemia (APL)

Defined by existence of t(15;17) translocation

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

15

17

PML

RARα

PML RARα

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APL: Prognosis

Used to be worstprognosis acute leukemia survival <1 month without

treatment

Since the development of targeted therapies against PML-RAR, is now the bestform All-trans retinoic acid

(ATRA) Arsenic

Relapse-free survival (Chemo + ATRA)

Sanz 2000

Evolution of APL Treatment

Chemotherapy

Chemotherapy plus ATRA

Chemotherapy, ATRA plus arsenic

ATRA plus arsenic(no chemo?)

1990’s, 2000’s

2000’s

2010’s

APL and Bleeding

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%



Fanconi Anemia





Overview 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

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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

Goal is to administer very high doses of chemotherapy If some is good, more is better

Problem is, healthy bone marrow cells are destroyed

Remove stem cells(and freeze)

Administer high doses of chemotherapy

=KILL CANCER!

Infuse stem cells to “rescue” / regenerate

bone marrow

CHEMO

Stem cells

Low blood counts

Autologous SCT

Allogeneic SCT

Works in two ways1) 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

Administer high doses of chemotherapy toKILL CANCER

Infuse donor stem cells to regenerate bone

marrow

Donor stem cells recognize and

KILL CANCER

Donor stem cells recognize patient “host” and attack

= Graft Versus Host Disease

CHEMO

Stem cells

Low blood counts

Graft versus Host Disease ( ? )

Infections

Allogeneic SCT

Immune Suppressive Medications

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Stem Cell SourceSibling donor – 25%

Half-matched donor: 50% if sibling 100% if parent or child

Matched unrelated donor

Umbilical cord blood

3

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SCT Cures Disease and Saves Lives

http://BeTheMatch.org

Thank you for your attention!

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