diamond-blackfan anemia 101€¦ · • other ibmfs ruled out vlachos et al, br j haematol 2008 :...
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Diamond-Blackfan Anemia 101 Blanche P Alter, MD, MPH Clinical Genetics Branch
Division of Cancer Epidemiology and Genetics Bethesda, MD
DBA Camp, July 9, 2012
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Diamond-Blackfan Anemia DBA, not BDA
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Diamond and Blackfan
Louis K Diamond, 1902-1999 Kenneth D Blackfan 1883-1941
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1974
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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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DBA in Australia
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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
4 yo, steroids 32 yo, Txs 33 yo, p-BMT4 yo, steroids 32 yo, Txs 33 yo, p-BMT 38 yo 41 yo
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Suspected Diagnosis of DBA Pure anemia below 1 year of age Macrocytic (large red cells) Decreased reticulocytes Marrow normal cellularity, decreased
erythroid precursors Rare neutropenia Very rare thrombocytopenia
Vlachos et al, Br J Haematol 2008
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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 Hb • Other IBMFS ruled out
Vlachos et al, Br J Haematol 2008
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Method Literature review Prospective cohort at the NCI
Biases:
• Volunteerism • Selection (publication, enrollment) • Information (incomplete records, self-report) • Survival
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DBA Literature 1936-2012 Case Reports: ~1250; (+ Case Series >1100) Male:Female: 1.05:1 Died: 141 (11% crude rate) Alive: median age 7 yrs (0-60) Died: median age 9 yrs (0-65) Abnormal physical findings 30% Remissions reported 10%
Biased by under-reporting, over-reporting, and missing data.
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DBA Literature: Age at Diagnosis 0
5010
015
020
025
0Fr
eque
ncy
0 1 2 3 4 5Age, Years
0-5 YEARS
12
34
56
7Fr
eque
ncy
0 10 20 30 40 50 60 70Age, Years
6-70 YEARS
Median age at diagnosis 2.5 mo; 85% by 1 and 97% by 5 years
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Survival Before and After 2000
0.00
0.25
0.50
0.75
1.00
Pro
babi
lity
0 10 20 30 40 50 60 70Years of Age
DBA
39 45
p = 0.02
1936-99 2000-12
More than 83% were over age 18
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Aase Syndrome and other Thumbs
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Neck
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DBA Patient and ?
Google Images
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DBA Literature Physical Abnormalities 1936-2012
0% 5% 10% 15% 20% 25% 30% 35%
CNSEarsDevtNeck
GonadsGU
SkeletalEyes
CardiacLow BW
OtherHead, face, palate
Thumbs + HandsShort
Any PE
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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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Major Complications in DBA Anemia Rarely pancytopenia Iron overload MDS/AML Sarcoma
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Treatment of DBA Current:
• Steroids • Transfusions • Iron chelation • Stem cell transplant
Future clinical trials: • Leucine • Lenalidomide
Spontaneous remission, ~25%
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Steroids 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 At diagnosis For first year of life – or not? Hb drops by ~1 gm/week Transfuse every 4 weeks, with 15 cc/kg Pre-tx, Hb <8 g/dL Post-tx, Hb >12 g/dL
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Iron Chelation 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 Who?
• Steroid-refractory, transfusion-dependent • Age <10?
What? • Bone marrow • Cord blood • Peripheral blood (stimulated with G-CSF)
Donors? • Matched sibling • Unrelated • Haploidentical
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Stem Cell Transplants Total 1972-
1999 2000-2005
2006-2012*
Number 113 49 40 24 Donor Sib 55 35 17 3
Other 34 5 22 7 Source BM 71 35 29 7
Cord 17 5 10 2 PBSC 2 0 1 1
Died 24/84 11/40 12/38 1/6 Recent trend: more alternative donors, and cord blood *Missing data
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Stem Cell Transplant by Dates 0.
000.
250.
500.
751.
00P
roba
bilit
y
0 5 10 15 20 25Years after BMT
1972-1999
0.00
0.25
0.50
0.75
1.00
Pro
babi
lity
0 5 10 15 20 25Years after BMT
2000-2005
0.00
0.25
0.50
0.75
1.00
Pro
babi
lity
0 5 10 15 20 25Years after BMT
2006-2012
Better survival in recent interval, but small numbers
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SCT Survival by Donor
Sib and Alternative donor similar in recent interval, but small numbers
0.00
0.25
0.50
0.75
1.00
Pro
babi
lity
0 5 10 15 20 25Years after BMT
1972-1999
0.00
0.25
0.50
0.75
1.00
Pro
babi
lity
0 5 10 15 20 25Years after BMT
2000-2005
0.00
0.25
0.50
0.75
1.00
Pro
babi
lity
0 5 10 15 20 25Years after BMT
2006-2012
Sib
Alt
Sib
Alt
Sib Alt
p=0.03 p=0.004 p=0.5
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SCT Survival by Age
Age at BMT may not be critical
0.00
0.25
0.50
0.75
1.00
Pro
babi
lity
0 5 10 15 20 25Years after BMT
1972-1999
<10 >10
p=0.8 0.
000.
250.
500.
751.
00P
roba
bilit
y
0 5 10 15 20 25Years after BMT
2000-2005
<10 >10
p=0.3
0.00
0.25
0.50
0.75
1.00
Pro
babi
lity
0 5 10 15 20 25Years after BMT
2006-2012
<10
>10
p=0.4
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0
25
50
75
100
FA DC DBA SDS SCN Amega TAR
Cum
lativ
e Pr
obab
ility
%
Literature Cases: Cumulative Probability of Cancer by Age 50 yrs
2000 No. of Cases in Reports, with or without Cancer
Shimamura and Alter: Blood Reviews 2010
550
970
560
374
100
300
We need better qualitative and quantitative data.
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NCI IBMFS
Syndrome Families Fanconi Anemia 91 Diamond-Blackfan Anemia 70 Dyskeratosis congenita 60 Shwachman-Diamond Syndrome 29
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Autosomal Dominant Inheritance
Normal Affected Normal
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DBA Inheritance Autosomal dominant 40s ribosome biogenesis
• 25% RPS19 • 6% RPS26 • 3% RPS10 • ~2% RPS24 • ~1% RPS17 • ~1% RPS7
Haploinsufficiency
60s ribosome biogenesis • 7% RPL5 • 5% RPL11 • 3% RPL35a
Doherty et al, Am J Hum Genet 2010
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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
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ADA in DBA, non-DBA, and Relatives
ADA is ~85-90% sensitive, and >90% specific
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ADA and Mutated Genes
22/23 with mutated gene, 9/14 without mutated gene had elevated ADA
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ADA and DBA Gene Mutation
ADA is not always elevated in DBA, and elevated ADA does not always track with mutated DBA gene
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Fetal Hemoglobin (Hb F)
Hb F is increased in all IBMFS; and is age-dependent.
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Telomere Length
Telomeres <1% of normal are diagnostic of dyskeratosis congenita, and are very RARE in DBA.
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NCI DBA Cancer
Colon 1 Lung 2 Skin basal cell 1 MDS/AML 0
Numbers too small to be significant
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1
10
100
1000
10000
Total Solid Tumor
Tongue AML MDS
Log
SIR
FA
DC
DBA
SDS
Risk for Cancer in FA, DC and DBA, NCI Cohort
* *
*Not significant in DBA
Alter et al, BJH 2010
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DBA compared with FA, DC, SDS Overall Survival
0
0.2
0.4
0.6
0.8
1
0 20 40 60
Years of Age
Prob
abili
ty
FA DC DBA SDS
Survival Free of Cancer
0
0.2
0.4
0.6
0.8
1
0 20 40 60
Years of Age
Prob
abili
ty
FA DC DBA SDS
Survival Free of BMF
0
0.2
0.4
0.6
0.8
1
0 20 40 60
Years of Age
Prob
abili
ty
FA DC DBA SDS
A B C
Alter et al, BJH, 2010
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NCI DBA Data 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 3%. Survival plateau 80% at 35 yrs.
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www.marrowfailure.cancer.gov
Clinical Genetics Branch: Neelam Giri, Mark Greene, Sharon Savage Westat: Lisa Leathwood, Maureen Risch, Ann Carr