Transcript Vlachos – Introduction to DBA and Its Treatment

Introduction to
Diamond Blackfan Anemia
and Its Treatment
Adrianna Vlachos, MD
The Feinstein Institute for Medical Research
Hofstra North Shore-LIJ School of Medicine
Cohen Children’s Medical Center of New York
DBA Camp July 2015
Diamond Blackfan Anemia
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Definitions
Diagnosis
Genetics
DBA Registry
 Demographics
 Congenital Anomalies
 Outcomes
 Remission
 Proven Treatments
 Corticosteroids
 Transfusion Therapy and Iron Chelation
 Stem Cell Transplantation
 Experimental Treatments
 Leucine
 Sotatercept
 Cancer
Future Directions
DBAR Team
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Diamond Blackfan Anemia Registry
Adrianna Vlachos, MD
 Jeffrey M. Lipton, MD, PhD
 Eva Atsidaftos, MA
 Jessica Kang, BS
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1-888-884-DBAR
DBA SAP Team
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DBA Surveillance and Awareness
Program
Adrianna Vlachos, MD
 Jeffrey M. Lipton, MD, PhD
 Johnson Liu, MD - Medical Hematology
 Sandeep Jauhar, MD – Cardiology
 Yael Toby Harris, MD – Endocrinology
 Phyllis Speiser, MD – Pediatric Endocrinology
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Acknowledgements
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DBA patients, their families, and their physicians
Diamond Blackfan Anemia Foundation
Daniella Maria Arturi Foundation
Pediatric Cancer Foundation
NHLBI (R01 and Resequencing Project)
CDC
DOD
Our numerous collaborators
Collaborators
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National Human Genome
Research Institute/NIH
 David Bodine, PhD
 Kelly O’Brien
University of Arkansas
 Jason Farrar, MD
University of Louisville
 Steven R Ellis, PhD
Phoenix Children’s
Hospital
 Robert Arceci, MD,
PhD+
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National Cancer Institute/NIH
 Blanche Alter, MD, MPH
 Philip Rosenberg, PhD
Children’s Hospital Boston
 Hanna Gazda, MD
 Alan Beggs, PhD
Children’s Hospital of
Philadelphia
 Monica Bessler, MD, PhD
St Mary’s Hospital, UK
 Josu De La Fuente, MD
 Sarah Ball, MD
DBA is an Inherited Bone Marrow
Failure Syndrome (IBMFS)
IBMFS have Key Shared Characteristics:
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Pathophysiology
Mutant cells have a low threshold for apoptosis
Apoptosis = programmed cell death
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Clinical
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Bone Marrow Failure
Congenital Anomalies
Cancer Predisposition
May present in adulthood
Differential Diagnosis of Childhood Pure
Red Cell Aplasia
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Congenital ( or inherited)
• Diamond Blackfan anemia
• Pearson Syndrome
Acquired
• Immune
 Transient erythroblastopenia of childhood
(TEC)
• Infection associated
 Parvovirus
• Severe renal failure, nutritional
• Drugs or Toxins
Expanded Definition of DBA
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Results of International Registries
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More Robust Epidemiology = the science that studies the
patterns, causes, and effects of health and disease
conditions in defined populations.
Gene Discovery
Discoveries
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Ten of 14 published “DBA genes” discovered through
the DBAR:
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Demonstrate extremely variable expression within and
between families
Demonstrate that DBA is not rarely inherited - but is familial
with autosomal dominant transmission in almost 50% of cases
(RPS19, Sarah Ball)
Diamond Blackfan Anemia
“Classic” Diagnostic Criteria
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Described by Josephs in 1936 and Diamond
and Blackfan in 1938 as a ‘pure’ red cell
aplasia
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“Classic” Definition in 1976 by Alter and
colleagues:
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Moderate to severe macrocytic anemia
Reticulocytopenia
Normal bone marrow cellularity with a scarcity of red
cell precursors
Age less than 1 year
“Modern” Diagnostic Criteria
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Definitive but not essential
 RP mutation, GATA1 mutation or other mutation yet to be
described
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Major
 Positive family history
 Anemia, reticulocytopenia, reduced red cell precursors in BM
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Minor
 Elevated erythrocyte adenosine deaminase (eADA) activity
 Congenital anomalies (including short stature)
 Elevated fetal hemoglobin
 Macrocytosis (large red cell volume for age)
 Age less than 1 year
 No evidence of another IBMFS (FA, SDS, etc)
 No evidence of parvovirus infection
Criteria for an Expanded Diagnosis
“non-classic DBA”
A patient meeting some of the classic criteria and having a known
DBA-associated mutation
A patient with a positive family history and no features of DBA and
having a known DBA-associated mutation
“probable DBA”
Some major and some minor criteria
DBA Genes
Gene
% of cases
Locus
Inheritance
Gene Product
RPS19
25%
19q13.2
AD
RPS19
RPS17
1
15q25.2
AD
RPS17
RPS24
2
10q22-23
AD
RPS24
RPL35A
2-4
3q29
AD
RPL35A
RPL5
7
1p22.1
AD
RPL5
RPL11
5-10
1p36.11
AD
RPL11
RPS7
1
2p25.3
AD
RPS7
RPS10
2-6
6p21.31
AD
RPS10
RPS26
2-6
12q13.2
AD
RPS26
RPS29
<1
14q21.3
AD
RPS29
RPL26
<1
17p13.1
AD
RPL26
RPL15
<1
3p24.2
AD
RPL15
RPL31
<1
2q11.2
AD
RPL31
GATA1
<1
Xp11.23
X-linked Rec
GATA1
DBA Genes
Autosomal Dominant: Haploinsufficiency for genes
encoding structural ribosomal proteins
Farrar JE, Vlachos A, et al. Blood. 2011;118(26):6943-51.
Diamond Blackfan Anemia
Registry (DBAR)
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The DBAR of North America was formally
established in 1991
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Today the DBAR is a robust tool for
studying DBA
Objective of the DBAR
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To develop a demographic, clinical
and laboratory database in order to
facilitate the study of
 the
epidemiology of DBA
 the biology of DBA
Demographics
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Enrollment – 726 patients
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M:F ~1:1
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Median age of presentation of anemia
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2 months (range, birth to 12 yrs)
Median age of diagnosis of DBA
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4.5 months (range, birth to 28yr10mo)
Year
2013
2010
2007
2004
2001
1998
1995
1992
1989
1986
1983
1980
1977
1974
1971
1968
1965
1962
1959
1956
1953
1950
1947
1944
1941
Number of Patients
Patient Distribution By Birth Year
30
Red = patients enrolled since 2010
25
20
15
10
5
0
DBA is characterized by
Congenital Anomalies
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47% of all patients
 50%
cranio-orofacial
 38% upper extremity
 39% genitourinary
 30% cardiac
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21% with more than one anomaly
Cleft Palates in DBA
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Confounding diagnoses
• Treacher Collins syndrome
• Pierre Robin sequence
DBA Patient Reported with
Treacher Collins Syndrome
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Absent lower
eyelashes
Deformed ears
Small cheek bones
Short, recessed chin
Cleft Palate Study
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Congenital anomalies
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5.7% of all registered patients had
orofacial clefts
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Cleft palate
 Submucous
 Soft palate only
Cleft lip and palate
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17
3
3
4
TCOF1 mutation analysis
• 3 done – all normal
Cleft Palate – Genotype Correlation
RPS19 + RPS19 –
CP +
0
11
CP -
26
74
Trend: Patients with cleft palate appear not to be
mutated at RPS19.
Cleft Palate – Genotype
Correlation
CP+
CP-
RPL5
4*
3
RPS26
1
10
Literature: CP described with RPL11 mutation**
*Gazda et al. Blood , 2009
**Quarello et al. Haematologica, 2009
Conclusions from this study
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DBA patients with orofacial clefting
represent a “family” of distinct DBA
genotypes
Mutations in RPL5 and RPS26 (and
RPL11) are associated with cleft palate/lip
Helps in genetic screening as well
DBA Outcomes
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Deaths
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Treatment Related
stem cell transplant-related complications
 iron overload
 infections
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PCP
varicella pneumonia
Pseudomonas pneumonia/sepsis
vascular access device complication
DBA Outcomes
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Deaths
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DBA related
malignancy
 severe aplastic anemia
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Unknown
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pulmonary embolism
Treatment and Status of DBA
Patients Enrolled in the DBAR
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Corticosteroids
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79% respond initially but only 32% can be sustained
on tolerable doses
33% are on Red Cell Transfusions
12% had a Stem Cell Transplant
12% are in Remission
11% are Deceased
All 3 treatment modalities are sub-optimal and are
associated with significant toxicity
Need to develop new and more effective therapies
Remission
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568 patients enrolled in the DBAR
79 patients experienced a remission
71 patients were available for analysis
Same 1:1 Male: female ratio as DBAR
 Median age at diagnosis: 3 mo
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Remission Results
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73% entered remission while on steroids
16% in remission while receiving both
steroids and transfusions
8% in remission from chronic transfusions
Remission Results
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Median age of remission for all pts:
5.7 years (range, 0.3 to 46.6 years)
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males
females
5.8 years (range, 0.3 to 46.6)
4.8 years (range, 0.9 to 26)
Median duration of treatment to remission:
38 months (range, 1 month to 37.6 years)
Remission Results
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Median duration of remission:
11.5 years (range, 6 months to 48.1 years)
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The actuarial likelihood of entering
remission is approximately 20% by 25
years of age
Remission Conclusions
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Remission is not restricted to a particular
phenotype or genotype and that the
likelihood of remission is influenced by
unknown modifier genes and/or epigenetic
factors.
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Remission patients may be the key to
understanding DBA!!
Treatments for DBA
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Transfusion therapy
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Chronic red cell transfusion regimen
Starts when Hb is less than 8 gm/dL
 Transfuse 10-15 ml/kg every 3-4 weeks
 Goal: maintain adequate quality of life while
maintaining growth
 Ideally transfuse until vaccinations given (age 1)
 May need to end earlier if venous access difficulty
 If needs Port, please ask for a plastic one
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Treatments for DBA
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Corticosteroid trial
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Start after vaccinations complete or sooner if venous
access difficult
Prednisone equivalent at 2 mg/kg/day, usually given
twice daily
Give Pred with Zantac or Prevacid as may affect
stomach
Begin ~2 weeks after a transfusion and continue for
no more than 4 weeks if no response
Start Bactrim or Septra to prevent Pneumocystis
pneumonia once response obtained
Treatments for DBA
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Corticosteroid therapy
If response noted than wean to 1 mg/kg/day
over 2 months and then 0.5 mg/kg/day or
1 mg/kg/every other day
Goal: Best response at the lowest dose
possible
 May need 3x/week or 2x/week
 Must be brave enough to wean, as patient
might be in remission
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Treatments for DBA
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Corticosteroid therapy
Watch growth!!!!
 If falling off growth curve, or having pathologic
fractures, need to consider a steroid hiatus
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Consult endocrinology for all patients,
sooner if having growth issues
Treatments for DBA
If no response to steroids then discontinue!! –
do NOT increase dose
 Resume transfusion therapy
 Maintain growth and keep Hb>8 or higher
 At 10-15 transfusions, need to begin chelation
therapy
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Deferoxamine (Desferal) – SC or IV
 Deferasirox (Exjade) - PO
 Deferasirox (Jadenu) - PO
 Deferiprone (Ferriprox) - PO
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Treatments for DBA
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Chelation therapy
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After age 2, begin
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Exjade at 20-40 mg/kg/day
Jadenu at 14-28 mg/kg/day
If ferritin not decreasing, may need to consider
Desferal therapy
Once able, obtain T2* to check heart and liver iron
load
Consider liver biopsy if high
If iron overload high, start Desferal at 50-60
mg/kg/day over 10-12 hours/day subcutaneously
Treatments for DBA
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Chelation therapy
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If too high or cardiac issues, need to give Desferal
24 hrs/day intravenously
Can combine Exjade/Jadenu and Desferal
Ferriprox may cause low white cell counts
(neutropenia) and has caused severe infection and
death
But, is a very good drug for unloading iron stored in
the heart
So, is used in patients in cardiac failure with very
strict follow-up
Stem Cell Transplantation
DBA Patients have had SCT reported to the DBAR
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Myeloablative Regimens
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Chemotherapy without total body irradiation
Chemotherapy with total body irradiation
Reduced intensity Regimens
Non-myeloablative Regimens
76.9+8.4%
35.9+13.5%
p=0.026
93.8+6.1%
54.8+15.4%
p=0.038
85.7+13.2%
32.1+11.7%
p=0.047
Outcomes
Stem Cell Transplantation
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Causes of death
Infection
 Veno-occlusive disease (VOD)
 Graft vs Host Disease (GvHD)
 Graft failure/rejection
 Secondary cancers
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Characteristics of Cancer
in DBA
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Hematologic malignancies
Young age at diagnosis
Poor prognosis
DBA is a cancer predisposition syndrome
Relative Risk of Cancer in DBA vs. the
General Population
Cancer Type
No. of observed
cancers
O/E ratio
95% CI
All cancers
18
5.42
3.21-8.57
Colon and
rectum
3
23.42
4.83 – 68.44
Sarcoma
2
32.58
3.95 – 117.77
Female genital
3
11.99
2.47 – 35.05
AML
2*
27.93
3.38 – 100.88
MDS
4*
286.97
77.21 – 734.71
N=608 patients; *One patient had MDS that evolved to
AML – counted in each.
Published DBA Cancer Data
By age 30:
16% had a BMT
11% had died
0% had AML
3% had a solid tumor
By mid-40’s:
18% had a BMT
19% had died –
iron overload,
transplant related comp
5% had AML
16% had a solid tumor
Summary of Published Results
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By mid 40’s:
5% had AML
 16% had developed a solid tumor
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22% Cumulative incidence of cancer
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Not including MDS
Neoplasms in DBA Patients from
the DBAR
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Gastrointestinal Cancers
Osteogenic Sarcoma/Other Sarcoma
Gynecological Cancer
Skin Cancer
Hematologic malignancies
MDS
Median age at presentation of 1st cancer:
41 years (2-69)
Cancer and DBA
Patient Characteristics:
No at-risk genotype -- the most
common genotypes are represented
No at-risk phenotype -- transfusion
versus steroid dependent versus
remission
Cancer and DBA
Initial Patient Characteristics
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transfusion dependent at time of cancer
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steroid dependent
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never received treatment
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were in remission
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was 4 years status post BMT
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was 15 years status post BMT
Cancer Outcomes
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Some patients with cures
Deaths due to neutropenia with chemotherapy,
leading to sepsis
Deaths leading to progressive disease due to
not getting treatments as per schedule
(because of low counts)
IMPROVING – with EARLY diagnosis and
individualized treatments
Cancer Outcomes
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EARLY diagnosis
Screening for cancer
 More solid tumors than leukemia, but may
be more MDS
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INDIVIDUALIZED treatments
Use of Neupogen for low neutrophil counts
 Possible dose reduction of chemotherapy
when warranted
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Future Directions
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Continue gene discovery – still with 25% of patients
to be diagnosed – with Dr. Bodine
Report stem cell transplant results
Redo cancer analysis – with Dr. Alter and Dr.
Rosenberg
Continue clinical trials
Continue to inform medical hematologists about
DBA!!!