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

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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!!!