DC Management and Treatment

Part 2

Camp SunshineSeptember 16, 2016

Alison A. Bertuch, MD, PhDAssociate Professor

Baylor College of MedicineBone Marrow Failure Program Director

Texas Children’s HospitalEmail: abertuch@txch.org

What needs to be screened?

1. Head, neck and dental

2. Skin

3. Peripheral blood, bone marrow, immune system

4. Eyes

5. Gastrointestinal, liver

6. Bones

7. Lungs (not pulmonary fibrosis)

8. Growth/development

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3b. Myelodysplastic syndrome (MDS)

3

NORMAL

Normal cell numbers

Normal cell appearance

APLASTIC ANEMIA

Decreased cell numbers

Normal cell appearance

Few cells mature

MYELODYSPLASIA

Cell numbers normal or

abnormal

Abnormal cell appearance

Cells do not mature normally

How is MDS different from aplastic

anemia?

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MYELODYSPLASIA

Cell numbers normal or abnormal

Cells do not mature normally

Cells entering the

bloodstream have

a shortened

survival

Immature cells

accumulate in the

bone marrow

May progress to

leukemia

Risk of MDS is increased in DC

5Alter et al., Br J Haematol 2010

Observed/expected

cases= 2,663

When and How to Treat MDS in DC

• Dysplasia affecting more than one bone marrow lineage

• Progressive dysplasia

• Increasing blasts

• Associated chromosomal abnormalities

– Loss of chr 5 (5q-) – Deletion or loss of chr 7

– Extra chr (trisomy) 8 – 20q abnormalities

– 11q23 translocation – 3q abnormalities

• Hematopoietic stem cell transplantation

– Need approach tailored to DC Drs. Tolar and Agarwal

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When and How to Treat MDS in DC

• Dysplasia affecting more than one bone marrow lineage

• Progressive dysplasia

• Increasing blasts

• Associated chromosomal abnormalities– Loss of chr 5 (5q-) – Deletion or loss of chr

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– Extra chr (trisomy) 8 – 20q abnormalities

– 11q23 translocation – 3q abnormalities

• Role of agents such as azacitidine (Vidaza) and decitabine (Dacogen) has not been determined

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What can you do?

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Screening for MDS

• Monitor or be aware of signs and symptoms

– Paleness, fatigue

– Easy bruisability, bleeding, petechiae

– Infections (bacterial, fungal, severe viral)

• Complete blood counts (CBC)

– If normal counts, every 4-6 months; spread out to once a year if

stable in select patients (e.g., mid adulthood onset pulmonary

fibrosis)

– If counts ABnormal, get CBCs more often based on your doctor’s

advice

• Bone marrow exams including aspirate, biopsy,

cytogenetics and MDS FISH studies

– Every year (or sooner if declining counts)

– Flow cytometry for leukemic cells if dysplastic cells are observed

on initial review 9

3c. Immunologic Abnormalities in DC

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Stems from bone marrow failure and deficiencies

in lymphocyte development

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Immunologic Abnormalities in DC

• May be prominent in patients, especially with HHS

• Reduction in antibody producing (B) cells most commonly observed

– Decrease in circulating antibodies

– Decreased antibody responses to specific antigens, including vaccines

– Increased risk of sinopulmonary infections

• May also have a reduction T cells, increasing risk to opportunistic infections, e.g.,

– Pneumocystis jirovecii infection (pneumonia)

• If PJP prophylaxis is recommended, do not use trimethoprim/sulfamethoxazole (Bactrim) due to risk of bone marrow suppression

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Immunologic Abnormalities in DC

• Spectrum of presentations

– Severe combined immunodeficiency (SCID) in infancy

with noninfectious, severe enteropathy with

intractable diarrhea (HHS, some with RTEL1

mutations)

– Common variable immunodeficiency (CVID) in

adolescence

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What can you do?

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Immunologic Abnormalities in DC

Testing to evaluate for the immune systems

• Quantitative levels for immunoglobulins

(antibodies) IgG; IgM and IgA

• Lymphocyte T, B, and NK cell subsets

• Lymphocyte proliferative responses to mitogens

and antigens

• Antibody titers to specific antigens (e.g., tetanus,

diphtheria, poliomyelitis and pneumococcal)

• IgM isohemagglutinin titers

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Treatment of Immunologic Abnormalities

Type is dependent on the specific deficiency

• Low IgG level – routine intravenous or subcutaneous immunoglobulin

• Recurrent infection with specific antibody deficiency – routine intravenous or subcutaneous immunoglobulin

• Poor T (CD4) cell numbers – antibiotic prophylaxis for Pneunocystis jirovecii pneumonia

• Flu vaccine for all

• HCST

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4. Eye Complications

• Up to 40% of patients with DC

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Eye Complications

Tsilou et al,

Ophthalmology. 2010

Tear duct present Tear duct absent

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Obliteration of the lacrimal draining system,

most common problem >

• Constant tearing

• Conjunctivitis

• Inflammation of the eyelids (blepharitis)

• Corneal ulcers

Eye Complications

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Obliteration of the lacrimal draining system:

treatment >

• Surgical creation of a channel from the

lacrimal sac to the nasal cavity

• Placement of glass implants to allow draining

from corner of the eye into the nose

Eye Complications

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Eyelashes growing in

and irritating the eye

Misdirected eye lashes (trichiasis) and in turning

(entropion) or out turning (ectropion) of the eyelid or

eye lashes >

• Conjunctivitis, blepharitis

• Corneal inflammation and scarring

• May eventually lead to impairment of vision

Tsilou et al,

Ophthalmology. 2010

Eye Complications

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Treatments:

• Early recognition is key > be seen by an

ophthalmologist

• Surgical repair of lids; removal of misdirected

eyelashes

Tsilou et al,

Ophthalmology. 2010

Eyelashes growing in

and irritating the eye

Eye Complications

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Eye Complications

Exudative retinopathy:

Revesz syndrome (TINF2)

Coats’ plus (CTC1/STN1)

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Eye Complications

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Other retinal changes:

• Atherosclerosis of the retinal vessels

• Areas lacking blood perfusion

• Areas of abnormal blood vessel growth

• Exudative retinopathy > retinal hemorrhage,

detachment

➢May lead to vision loss and blindness

Early detection is key!

➢Natural history studies needed

5. Gastrointestinal Manifestations

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• Observed in 15-20% of

children and adults with

telomere disorders

• Cells lining of the gastro-

intestinal tract turnover at

a high rate

Moore, KA and Lemischka, IR. Science 2006

Esophageal Stenosis

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• Observed in DC, more often males

• May be under-diagnosed

• Symptoms– Difficulty swallowing or feeling that

food is not passing to the stomach

– Unintended weight loss or failure to thrive

– Regurgitation of food or liquids

– Painful swallowing

– Heartburn

• Adaptive behaviors, e.g., prolonged chewing, avoidance of certain goods

http://digestive.niddk.nih.gov/

Esophageal Stenosis

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• Diagnosis

– Video swallow study

– Upper GI endoscopy

• Treatment

– Dilatation of the esophagus,

possibly multiple times

– Acid blocking medicines http://digestive.niddk.nih.gov/

Enteropathy

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• Disease of the small intestine

• Nonspecific symptoms that may be chronic and intermittent– Nausea

– Nonlocalizing abdominal pain

– Early satiety (feeling full after a small portion of food)

– Food intolerance or allergies

– Loose stools or diarrhea

– Failure to thrive in infants

– Failure to gain weight or weight loss in older children and adults

Enteropathy

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• Diagnostic evaluation– Upper GI tract endoscopy and colonoscopy with

biopsies

– Findings may be subtle and nonspecific

– In patients after HCST, may mimic or be due to graft-vs-host disease

• Treatment– Diet adjustment

– Avoidance of gluten, anecdotally helpful

➢Natural history and treatment studies needed!

Enterocolitis

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• Inflammation of the GI tract

• Mostly seen in infants with HHS

• Symptoms

– Severe abdominal pain

– Bloody diarrhea

– Failure to thrive

• Secondary processes

– Bowel perforation

– Bacterial sepsis

Enterocolitis

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• Likely due to defects in the lining of the intestine AND immune defects

• Diagnosis – clinical findings

• Colonoscopy may be helpful

Treatment:

• Supportive care

• Bowel rest

• Antibiotic and nutritional support

• May improve following HSCT

Unexplained GI bleeding

• May be mild to severe with significant blood loss

• Patients may experience blood stools and/or blood emesis (vomiting)

• Source of bleeding frequently unclear

• May occur in cases of non-cirrhotic portal hypertension (impaired blood flow through the liver)

• Prevalence in DC population not known

• Empiric treatments utilized

➢Natural history and treatment studies needed!

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5b. Liver Disease

• May be mild to severe, end-stage disease

• Signs of liver disease

– Increased levels of enzymes released into the blood when the liver is damaged (e.g., ALT/AST)

– Decreased levels of proteins produced by the liver (e.g., albumin, clotting factors)

– Abnormal liver architecture on ultrasound, nodular, heterogeneous appearance

– Portal hypertension

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Liver Disease Screening

• Annual liver function tests– ALT, AST, GGT, bilirubin

– Prothrombin time (measure of clotting factors)

– Albumin

• Ultrasound of liver and spleen to look for any abnormalities in architecture, tumors, or portal hypertension

• LFTs and ultrasound more frequently if on androgens

• If abnormal, consider liver biopsy

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Liver Disease Treatment

• No known specific treatments

• ? Liver transplantation if eligible

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“Prevention” of liver disease

• Minimize or avoid alcohol consumption

• Avoid drugs associated with liver toxicity to the

extent possible

– http://www.hepcnet.net/drugsandliverdamage.html

• Hepatitis A and B immunization

• Weight management to minimize fatty liver

• Assessment and treatment of iron overload in

patients on red cell transfusions

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7. Pulmonary Arteriovenous

Malformations

• Other names

– Pulmonary arteriovenous fistulae

– Pulmonary arteriovenous aneurysms

– Cavernous angiomas of the lungs

– Pulmonary telangiectasias

• Several case reports and recent case series on

diffuse pulmonary AVM in DC

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Pulmonary Arteriovenous Malformations

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Pulmonary Arteriovenous Malformations

Signs and symptoms

– Shortness of breath• Worsens when lying down

• Worsens when upright

– Poor oxygenation

– Unexplained decrease in DLCO

– Clubbing of fingernails• ? Modified in patients with DC and nail dystrophy

Diagnosis

– Bubble study: Transthoracic echocardiogram with intravenous injection of agitated saline bubble contrast

Differential diagnosis– Hepatopulmonary syndrome with or without cirrhosis or

portal hypertension

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Pulmonary Arteriovenous Malformations

• General treatment

– Endovascular (coiling) interventions for

simple/single AVMs

– Lung transplantation for diffuse disease

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Pulmonary Arteriovenous Malformations

Research Letter

Pulmonary AVM: an uncharacterized phenotype of dyskeratosis congenita. Khincha, P.P., Bertuch, A.A., Agarwal, S., Keel, S., Shimamura, A., Townsley, D.M.,

Young, N.S., Boulad, F., Simoneau, T., Justino, H., Kuo, C., Artandi, S., McCaslin,

C., Cox, D.W., Chaffee, S., Giri, N., Alter, B.P., and Savage, S.A.

Eur Respir J. 2016, Accepted.

13 patients

Median age at of DC/TBD dx - 13 years (range 1-27 years)

Median age of PAVM dx was 15 years (range 3-32 years)

6 patients w/TINF2 mutation

10 s/p HSCT

9 did not have evidence of liver disease at the time of their

PAVM diagnosis

2 were asymptomatic

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Pulmonary Arteriovenous Malformations

Research Letter

Pulmonary AVM: an uncharacterized phenotype of dyskeratosis congenita. Khincha, P.P., Bertuch, A.A., Agarwal, S., Keel, S., Shimamura, A., Townsley, D.M.,

Young, N.S., Boulad, F., Simoneau, T., Justino, H., Kuo, C., Artandi, S., McCaslin,

C., Cox, D.W., Chaffee, S., Giri, N., Alter, B.P., and Savage, S.A.

Eur Respir J. 2016, Accepted.

No clear effective treatment modality

➢ Natural history and treatment studies needed!

Closing Thoughts

• Not everyone gets all of these complications!

– This advice needs to be tailored to your specific case

• Stringent avoidance of all potentially hepatic,

pulmonary or hematopoietic drugs may delay

treatment or result in suboptimal treatment

– Weigh risks and benefits!

• You may need to educate your doctors

– Share our names as resources

– Refer them to the DCO website, including the guide!

• You know yourself / your child best

– Voice your concerns

– Be your strongest advocate 43

Closing Thoughts

Remember that the treatments of the future may be

different from the treatments of today

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THANK YOU!!!

Feel free to ask questions!

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