Introduction to Diamond Blackfan Anemia
and Its TreatmentAdrianna Vlachos, MD
The Feinstein Institute for Medical ResearchHofstra North Shore-LIJ School of Medicine
Cohen Children’s Medical Center of New York
DBA Camp July 2015
Diamond Blackfan Anemia
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
Diamond Blackfan Anemia Registry Adrianna Vlachos, MD Jeffrey M. Lipton, MD, PhD Eva Atsidaftos, MA Jessica Kang, BS
1-888-884-DBAR
DBA SAP Team
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
Acknowledgements
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 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+
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: Pathophysiology
Mutant cells have a low threshold for apoptosisApoptosis = programmed cell death
Clinical Bone Marrow Failure Congenital Anomalies Cancer Predisposition May present in adulthood
Differential Diagnosis of Childhood Pure Red Cell Aplasia
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
Results of International Registries More Robust Epidemiology = the science that studies the
patterns, causes, and effects of health and disease conditions in defined populations.
Gene Discovery
Discoveries Ten of 14 published “DBA genes” discovered through
the DBAR: 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
Described by Josephs in 1936 and Diamond and Blackfan in 1938 as a ‘pure’ red cell aplasia
“Classic” Definition in 1976 by Alter and colleagues:
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
Definitive but not essential RP mutation, GATA1 mutation or other mutation yet to be
described
Major Positive family history Anemia, reticulocytopenia, reduced red cell precursors in BM
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 mutationA 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 GenesGene % 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 GenesAutosomal 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)
The DBAR of North America was formally established in 1991
Today the DBAR is a robust tool for studying DBA
Objective of the DBAR
To develop a demographic, clinical and laboratory database in order to facilitate the study of the epidemiology of DBA the biology of DBA
Demographics Enrollment – 726 patients
M:F ~1:1
Median age of presentation of anemia 2 months (range, birth to 12 yrs)
Median age of diagnosis of DBA 4.5 months (range, birth to 28yr10mo)
Nu
mb
er o
f P
atie
nts
Year
Patient Distribution By Birth Year
1941
1944
1947
1950
1953
1956
1959
1962
1965
1968
1971
1974
1977
1980
1983
1986
1989
1992
1995
1998
2001
2004
2007
2010
2013
0
5
10
15
20
25
30
Red = patients enrolled since 2010
DBA is characterized by Congenital Anomalies
47% of all patients 50% cranio-orofacial38% upper extremity39% genitourinary30% cardiac
21% with more than one anomaly
Cleft Palates in DBA
Confounding diagnoses• Treacher Collins syndrome• Pierre Robin sequence
DBA Patient Reported with Treacher Collins Syndrome
Absent lower eyelashes
Deformed ears Small cheek bones Short, recessed chin
Cleft Palate Study
Congenital anomalies • 5.7% of all registered patients had
orofacial clefts• Cleft palate 17
Submucous 3Soft palate only 3
• Cleft lip and palate 4
TCOF1 mutation analysis• 3 done – all normal
Cleft Palate – Genotype Correlation
0 11
26 74CP -
CP +
RPS19 + RPS19 –
Trend: Patients with cleft palate appear not to be mutated at RPS19.
RPL5 4* 3
RPS26 1 10
CP+ CP-
Cleft Palate – Genotype Correlation
Literature: CP described with RPL11 mutation***Gazda et al. Blood , 2009**Quarello et al. Haematologica, 2009
Conclusions from this study
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
Deaths Treatment Related
stem cell transplant-related complications iron overload infections
PCP varicella pneumonia Pseudomonas pneumonia/sepsis
vascular access device complication
DBA Outcomes
Deaths DBA related
malignancy severe aplastic anemia
Unknown pulmonary embolism
Treatment and Status of DBAPatients Enrolled in the DBAR
Corticosteroids 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
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
Remission Results
73% entered remission while on steroids 16% in remission while receiving both
steroids and transfusions 8% in remission from chronic transfusions
Remission Results
Median age of remission for all pts:
5.7 years (range, 0.3 to 46.6 years) males 5.8 years (range, 0.3 to
46.6) females 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
Median duration of remission:
11.5 years (range, 6 months to 48.1 years)
The actuarial likelihood of entering remission is approximately 20% by 25 years of age
Remission Conclusions
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.
Remission patients may be the key to understanding DBA!!
Treatments for DBA
Transfusion therapy 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
Treatments for DBA
Corticosteroid trial 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
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
Treatments for DBA
Corticosteroid therapy Watch growth!!!! If falling off growth curve, or having pathologic
fractures, need to consider a steroid hiatus 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 Deferoxamine (Desferal) – SC or IV Deferasirox (Exjade) - PO Deferasirox (Jadenu) - PO Deferiprone (Ferriprox) - PO
Treatments for DBA Chelation therapy
After age 2, begin 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 Chelation therapy
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
• Myeloablative Regimens• 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
Causes of death Infection Veno-occlusive disease (VOD) Graft vs Host Disease (GvHD) Graft failure/rejection Secondary cancers
Characteristics of Cancer in DBA
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.
By age 30: 16% had a BMT11% had died 0% had AML 3% had a solid tumor
By mid-40’s: 18% had a BMT19% had died – iron overload, transplant related comp 5% had AML16% had a solid tumor
Published DBA Cancer Data
Summary of Published Results
By mid 40’s: 5% had AML 16% had developed a solid tumor
22% Cumulative incidence of cancer Not including MDS
Neoplasms in DBA Patients from the DBAR
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 transfusion dependent at time of cancer
steroid dependent
never received treatment
were in remission
was 4 years status post BMT
was 15 years status post BMT
Cancer Outcomes
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
EARLY diagnosis Screening for cancer More solid tumors than leukemia, but may
be more MDS
INDIVIDUALIZED treatments Use of Neupogen for low neutrophil counts Possible dose reduction of chemotherapy
when warranted
Future Directions
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!!!