diamond-blackfan anemia 101 · 2019-09-08 · diamond-blackfan anemia 101 blanche p alter, md, mph...
TRANSCRIPT
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Diamond-Blackfan Anemia 101
Blanche P Alter, MD, MPH
Clinical Genetics Branch
Division of Cancer Epidemiology and Genetics
Rockville, MD
DBA Camp, July 13, 2015
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Diamond-Blackfan Anemia
DBA, not BDA
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Questions
1. How many are new to DBA Camp?
2. How many have been here before?
3. How many have DBA and are 18 years of age
or older?
4. How many are from Canada?
5. How many are from outside the USA/Canada?
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My Tasks
1. DBA101 (advanced DBA) for those who
have not heard it.
2. Update on what is new in DBA research.
3. Address specific concerns of those who are
new to DBA.
All in 45 minutes…..(including questions)
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Diamond and Blackfan
Louis K Diamond, 1902-1999 Kenneth D Blackfan 1883-1941
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First DBA Scientific Meeting,
Bellagio, Italy
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Benign Hematology Oncology
Syndrome Hematology Leukemia
Solid
Tumors
Fanconi Anemia (FA) Aplastic AML SCC
Dyskeratosis Congenita (DC) Aplastic AML SCC
Diamond-Blackfan Anemia (DBA) Pure anemia AML Sarcomas
Shwachman-Diamond Syndrome (SDS) Neutropenia AML -
Severe Congenital Neutropenia (SCN) Neutropenia AML -
Amegakaryocytic Thrombocytopenia Thrombocytopenia AML -
Thrombocytopenia Absent Radii (TAR) Thrombocytopenia AML -
These disorders are the “Inherited Bone Marrow Failure Syndromes” (IBMFS).
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IBMFS Pathways
DNA Repair: FA
Telomere biology: DC
Ribosomes: DBA, SDS, DC
Platelet production: Amega
Apoptosis: SCN, others
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Background Diamond-Blackfan anemia (DBA), an Inherited
Bone Marrow Failure Syndrome (IBMFS) with
varying degrees of pure red cell aplasia
Heterogeneous disorder
Patients with an IBMFS have an increased risk of
cancer (leukemia and solid tumors)
Correlation between physical and/or laboratory
features and outcomes?
Birth rate 5-10 per million live births
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First Publications
Josephs HW: Anaemia of infancy and early
childhood. Medicine, 1936
Diamond LK, Blackfan KD: Hypoplastic
anemia. Am J Dis Child, 1938
Why not “Josephs, Diamond, Blackfan
anemia”?
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Diamond-Blackfan Anemia
Normochromic, usually macrocytic anemia, developing in infancy
Reticulocytopenia
Marrow erythroblastopenia
Normal or slightly decreased leukocytes
Normal or increased platelets
Increased fetal hemoglobin (Hb F)
Increased red cell adenosine deaminase (ADA)
~25% with physical findings: short, abnormal thumbs, etc
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Supportive Criteria for DBA
Major
• Mutation in a DBA gene (ribosomal?)
• Family history of DBA
Minor
• Increased red cell ADA
• Typical physical abnormalities
• Increased fetal hemoglobin (% Hb F)
• Other IBMFS ruled out
Vlachos et al, Br J Haematol 2008
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Sources of Data
Literature review
Prospective cohort at the NCI
DBAR
Biases:
• Volunteerism
• Selection (publication, enrollment)
• Information (incomplete records, self-report)
• Survival
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NCI’s Inherited Bone Marrow Failure
Syndromes Study 02-C-0052, www.marrowfailure.cancer.gov
Family Study
• Fanconi Anemia
• Dyskeratosis Congenita (DC)
• Diamond-Blackfan Anemia
• Shwachman-Diamond Syndrome
Questionnaires
Medical Record Review
Consultation
Evaluation at the NIH
Clinical Center • IBMFS Team
• Genetic Counseling
• Subspecialists
• Biospecimens
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DBA Literature 1936-2015
Case Reports: ~1430; (+ Case Series ~1400)
Male:Female: 1.08:1
Died: 149 (10% crude rate)
Alive: median age 8 yrs (0-60)
Died: median age 9 yrs (0-65)
Abnormal physical findings reported 30%
Remissions reported 10%
Biased by under-reporting, over-reporting,
and missing data.
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DBA Literature: Age at Diagnosis
Median age at diagnosis 2.5 mo; 90% by 2 and 99% by 10 years
0
100
200
300
Fre
quency
0 1 2 3 4 5Age Years
0-5 YEARS
24
68
10
12
Fre
quency
0 10 20 30 40 50 60 70Age Years
6-70 YEARS
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0.0
00.2
50.5
00.7
51.0
0
Pro
babili
ty
0 10 20 30 40 50 60 70Years of Age
DBA
Survival Before and After 2005
More than 95%
were reported to
be over age 18 in
the last decade,
compared with
20% in the earlier
reports p <0.0001
1936-2004
2005-15
Cases according to year of publication
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DBA Literature Physical Abnormalities
0 10 20 30 40
Ears
Devt
Head
Gonads
Neck
Hands
GU
Skeletal
Cleft palate
Face
Eyes
Cardiac
Thumbs
Short
Any PE
% of Cases
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Comparison of Physical Findings
Note that NCI has higher frequencies – more thorough exams?
0 20 40 60 80
Devt
Neck
Gonads
GU
Skeletal
Eyes
Cardiac
Other
Head, face, palate
Thumbs + Hands
Short
Any PE
DBAR
N&O
NCI
Lit
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Aase Syndrome and other Thumbs
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Neck 1
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Major Complications in DBA
Anemia
Rarely pancytopenia
Iron overload
MDS/AML
Tumors
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Treatment of Anemia in DBA Current:
• Steroids
• Transfusions
• Iron chelation
• Stem cell transplant
Future clinical trials:
• Leucine
• Lenalidomide
• Sotatercept
Spontaneous remission, ~10-20%
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Steroids for Anemia
Prednisone, 2mg/kg/day, divided 3 times per
day, for 1-4 mo
If response, taper slowly
• 2 doses per day x 1 month
• 1 dose per day x 1 month
• Double this dose, every other day in am
If no response, transfuse
Consider stem cell transplant (SCT)
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Transfusions for Anemia
At diagnosis
For first year of life – or not?
Hb drops by ~1 gm/week
Transfuse every 4 weeks, with 15 mL/kg
Pre-tx, Hb <8 g/dL
Post-tx, Hb >12 g/dL
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Chelation for Iron Overload
Generally after 15-20 transfusions
Age >2 years
Ferritin >1000
Cardiac and liver iron measured by MRI
Desferal: subQ or IV, 40-50 mg/kg/day, over
8-12 hrs (overnight)
Exjade (oral)
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Stem Cell Transplant for Anemia Who?
• Steroid-refractory, transfusion-dependent
• Age <10?
What?
• Bone marrow
• Cord blood
• Peripheral blood (stimulated with G-CSF)
Donors?
• Matched sibling
• Unrelated
• Haploidentical
• Cord
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0.0
00.2
50.5
00.7
51.0
0
Pro
babili
ty
0 2000 4000 6000 8000Days
Stem Cell Transplant Survival
Apparent survival better in recent decade, but
small numbers (15 vs 76)
1936-2004
2005-15
p =0.4
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Genetics
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ASCO modified 2/02
Disease-Associated Mutations
A mutation is a change in the normal base pair sequence
Commonly used to define DNA sequence
changes that alter protein function
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Autosomal Dominant Inheritance
Normal Affected Normal
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Ribosome Genes
rRNA
18S 5.8S 28S
RPL26
RPL35A
RPL11 RPL5
RPS10
RPS7RPS17
RPS24
RPS19
RPS26
40S
60S
mRNA
40S60S
SBDS40S 60S
RPS29
RPL15
Courtesy of S Savage
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DBA Genes, Autosomal Dominant
25
6
23
1117
53.511
40
1RPS19
RPS26
RPS24
RPS10
RPS7
RPS17
RPS29
RPL5
RPL11
RPL35A
RPL26
RPL15
Unknown
GATA-1
DBA
X-linked
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Exome Sequencing and Filtering
http://www.nature.com/ng/journal/v42/n1/images/ng0110-13-F1.jpg
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NCI IBMFS, 2002 - 2015
Syndrome Families Patients
Fanconi Anemia 122 141
Dyskeratosis congenita 95 146
Diamond-Blackfan
Anemia
85 104
Shwachman-Diamond
Syndrome
29 26
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Red Cell Adenosine Deaminase (ADA)
N % Elevated
Glader, 1983 12/12 100
Whitehouse, 1986 9/19 47
Glader, 1986 23/26 88
Glader, 1988 26/29 90
Orfali, 2004 48/50 96
Willig, 1998 28/34 82
Fargo, 2012 31/37 84
Fargo et al, Br J Haematol 2013
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ADA in DBA, non-DBA, and Relatives
0.0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
4.0
4.5
5.0e
AD
A,
IU/g
of
Hb
DC FA SDS Other DBA
Relatives
Non-DBA
Relatives
Figure 1
DBA All non-
DBA
84%
5% 5% 5% 10% 0% 7% 0%
ADA is ~85 sensitive, and >90% specific Fargo et al, BJH 2013
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ADA and DBA Gene Mutation
Gene negative
eADA: 1.23
Gene negative
eADA: 1.04
Gene negative
eADA: 1.49
Gene negative
eADA: 0.36
Gene negative
eADA: 0.74
RPL 11
eADA: 4.62Gene negative
eADA: 0.6
RPS 7
eADA: 1.03
Gene negative
eADA: 0.56
RPS 7
eADA: 2.45
RPS 7
eADA: 2.0
Associated Not associated
ADA is not always elevated (arrow) in DBA, and elevated
ADA does not always track with mutated DBA gene
Fargo et al, BJH 2013
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Telomere Length
Lymphocytes
0.0
2.0
4.0
6.0
8.0
10.0
12.0
14.0
0 20 40 60 80 100
Age, years
Te
lom
ere
Le
ng
th,
kb
FA
FA BMT
FA Mosaic
DBA
SDS
Other
Rels
Telomeres <1% of
normal are diagnostic
of dyskeratosis
congenita, and are
very RARE in DBA.
Alter et al, Blood 2007
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DBA do not have Very Short TL A
Alter et al, Haematologica 2015
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Ovarian Reserve in DBA
DBA patients (n=12) DBA relatives (n=13) Healthy Volunteers (n=16)0
1
2
3
4
5
6
7
8
9
10
11NS, p=0.211
NS, p=0.110
AM
H (
ng
/ml)
FA patients (n=22) DC patients (n=15) DBA patients (n=12)0
1
2
3
p=0.013
p=0.003
456789
1011
AM
H (
ng
/ml)
DBA have higher AMH than FA or DC DBA AMH are in normal range
Sklavos et al, J Clin Endo and Metab, 2015
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Cancer Reported in Literature
Type Number
Leukemia 11
Non-Hodgkin Lymphoma 1
Osteogenic sarcoma 6
Sarcoma soft tissue 1
Stomach 1
Thyroid 1
Melanoma 1
Myelodysplastic Syndrome (MDS) 6
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Cancer Reported in Literature
0.0
00.2
50.5
00.7
51.0
0
Pro
babili
ty
0 10 20 30 40 50 60 70Years of Age
Median age = 55 years
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Cancer in the DBAR, 17/608 Patients
1
10
100
1000
Total Colon Sarcoma Gyn AML MDS
Log
SIR
4
Vlachos et al: Blood 2012
Significant
types of
cancers
2
3
2 3
17
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NCI DBA Cancer, 2015
Cancer Observed Expected O/E
All (not MDS) 6 3 1.9
Lung 3 0.31 9.7
Cervix 1 0.04 24.7
Colon 2 0.16 12.7
MDS 3 0.02 142
Bold are significant
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A B C D
Cancer in the IBMFS
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NCI DBA Summary
Physical anomalies and/or short stature are
common.
More frequent than previously reported:
• Head and face, cardiac, skeletal (other than upper limb)
and developmental delay.
Transfusions and steroids are associated with long-
term morbidity.
Cancer in 6%.
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Transition from Pediatric to Adult Care
When?
• Age 18
• Age 21
• When leave home for work or college
Who decides?
• Those with DBA
• Parents
• Doctors
How?
X
X
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Medical Information Sources
NY Times Oct 20, 2013 Wendy MacNAUGHTON
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www.marrowfailure.cancer.gov
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Blanche Alter, MD, MPH
Sharon Savage, MD
Neelam Giri, MD
Ann Carr, Genetic Counselor
Lisa Leathwood, Research Nurse
Maureen Risch, Research Nurse
Brochure and Study Team
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Many thanks
To all the families