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Hematopoietic Stem Cell Transplant (HCT) for Nonmalignant Disorders

Evan Shereck, M.D.September 13, 2013

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• Overview of nonmalignant disorders- Immunodeficiencies- Genetic/metabolic disorders- Inherited blood disorders- Bone marrow failure syndromes

• Review outcome of HCT for selected nonmalignant diseases • Discuss donor issues specific to nonmalignant diseases

Objectives

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Indications for Pediatric BMT

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Num

ber o

f Tra

nspl

ants 600

800

400

300

100

0

200

500

700

Num

ber o

f Tra

nspl

ants

OtherCancer

ALL AML HD MDS/MPDAplasticAnemia

NHL OtherLeuk

Non-MaligDisease

Allogeneic (Total N=1,496)Autologous (Total N=880)

CML

36%

Indications for HCT for Patients < 20 years

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The Cells Produced in Bone Marrow

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Immune System 101

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• Genetically heterogeneous group of diseases affecting distinct components of innate and adaptive immunity

- Lymphocytes (T, B cells) - Natural killer cells - Neutrophils - Dendritic cells - Complement proteins

• More than 120 gene defects have been described

Primary Immunodeficiencies

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Lymphocyte immunodeficiencies Severe combined immunodeficiencyOmenn syndromeDiGeorge syndrome CHARGE syndrome: Coloboma, heart anomalies, choanal atresia, retardation of growth and development, and genital and ear anomalies Wiskott-Aldrich syndromeX-linked lymphoproliferative disease, XLP1, XLP2

Phagocytic deficiencies Chronic granulomatous diseaseSevere congenital neutropeniasLeukocyte adhesion deficiency Schwachman-Diamond syndromeChediak-Higashi syndromeGriscelli syndrome, type 2Familial hemophagocytic lymphocytosis (perforin, MUNC13-4 or syntaxin deficiency) Interferon-ɣ receptor (IFN- ɣR) deficiencies

Other immunodeficiencies Cartilage hair hypoplasia Hyper IgD syndrome Autoimmune lymphoproliferative syndrome (ALPS) Hyper-IgE syndrome IPEX syndrome (Immunodysregulation,

polyendocrinopathy, enteropathy, X-linked syndrome CD25 deficiency Nuclear factor-κB (NF-κB) essential modulator

(NEMO) deficiency NF-κB inhibitor, alpha (IκBɑ) deficiency Immunodeficiency, centromeric instability, facial

dysmorphism (ICF) syndromeNijmegen breakage syndrome

Primary Immunodeficiencies Treated with HCT

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• Spectrum of disease depends on genetic defect

Early Onset – “Classic”Usually early infancy (birth – 12 months)Presentation:-Recurrent infections-Opportunistic infections-Poor growth-+/- congenital anomalies100% fatal within first 2 years of life

Late onset Late childhood to adulthoodPresentation:-Recurrent infections-Malignancies-Autoimmune disordersUsually fatal in first decades of life

Natural History of Inherited Immunodeficiencies

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Name Defect Phenotype Special

X-linked Common chain T-B+NK- J AK3 deficiency J anus kinase 3 T-B+NK- Rag 1 or 2 Recombinase-activating proteins 1 or 2 T-B-NK+ ‘Autoreactive’ GVHD

Artemis deficiency Artemis (also known as DCLRE1C) T-B-NK+ Native Americans, radiosensitive

Ligase 4 deficiency Ligase 4 T-B-NK+ Radiosensitive IL-7R deficiency IL-7 receptor T-B+NK+ CD45 deficiency CD45 T-B+NK+ CD3 deficiency CD3 subunit T-B+NK+ CD3 deficiency CD3 subunit T-B+NK+ CD3 deficiency CD3 subunit T-B+NK+

Cartilage hair hypoplasia Endoribonuclease T-B+NK+ Dwarfism, hypoplastic hair Finnish, Amish descent

p56lck deficiency p56lck Protein tyrosine kinase T-B+NK+ ADA deficiency Adenosine deaminase T-B-NK- PNP deficiency Purine nucleoside phosphorylase T-B-NK- Neurologic dysfunction, ataxia

Reticular dysgenesis Unknown T-B-NK- Bone marrow failure, sensorineural deafness

ZAP70 deficiency -chain-associated protein kinase CD4+, CD8- B+, NK+ Bare lymphocyte Syndrome type I I HLA class I I CD4-(mild), CD8+ B+,

NK+ North African

SCID with bowel atresia Unknown CD4+, CD8+, B+NK+ Abbreviations: ADA=adenosine deaminase; DCLREIC=DNA cross-link repair enzyme 1C; HLA=human leukocyte antigen

Known Severe Combined Immunodeficiencies

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Year MRD Haplo Haplo MUD MUD Unrelated Cord

Conditioning   None None Myeloablative MyeloablativeReduced intensity

Myeloablative

 Dror et al. 1993 — 67% (12) 50% (12) — — —

 Buckley et al. 1999 100% (12) 78% (77) — — — 66% (3)

 Bertrand et al. 1999 — 46% (50) 54% (129) — — —

 Dalal et al. 2000 — — — 67% (9) — —

 Knutsen/Wall 2000 — — — — — 88% (8)

 Antoine et al. 2003 81% (104) — — 63% (28) — —

 Rao et al. 2005 — — — 71% (7) 83% (6) —

 Bhattacharya et al. 2005 — — — — — 80% (10)a

 Grunebaum et al. 2006 92% (13) — 53% (40) 81% (41) — —

MRD (matched related donor), Haplo (haplocompatible family donor), MUD (matched unrelated donor) Percentage indicates overall survival , Number in parentesis = number of patients

Outcomes of HCT for SCID

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Rebecca H. Buckley, J. All & Clin Immunol, 2012

Effect of Age on Transplant

Day of Life at Transplant

Perc

ent S

urvi

ving

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SCID Newborn Screen

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• Bad disease need HCT ASAP, any suitable donor

• Conditioning not needed for “complete” SCID

• Most patients needs some form of conditioning- Maternal T-cell engraftment at birth

- Dysfunctional/over-reactive T-cells

• High rates of toxicity, TRM and GVHD observed

• Goal is to condition with minimal amount of conditioning necessary to achieve engraftment

• Full donor chimerism usually not necessary

• Newborn screening in some states

Unique Features for HCT for SCID

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• Genetic defects in enzymes accumulation of metabolic products in body organs progressive dysfunction death

• Multiple diseases, some amenable to HCT some notRule of thumb: If replacing leukocytes can generate the missing

enzyme, then HCT may be effective

• Time is of essenceUltimate outcome and QOL not improved if end-organ symptoms

are present

Inherited Metabolic Diseases

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Lysosomes

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Metabolic Disorders & Transplantation

MPS IH (Hurler) Metachromatic

leukodystrophy (MLD) Globoid Cell

leukodystrophy (Krabbe) -mannosidosis acid lipase deficiency

(Wolman disease) Cerebral ALD

Hunter I-cell Recessive Osteopetrosis Niemann-Pick Gaucher Farber Tay-Sachs

Standard of care Under Investigation

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Enzyme replacement therapy (“ERT”)• Required for the life of the patient• Does not penetrate into the brain

Gene Therapy• Correction of patient’s own cells• Over-produce missing enzyme in other cells

Cellular therapy with “normal” cells• HCT: how does this help the brain?

Strategies to Replace Enzymes

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Cells of the immune system within the brain

About 15% of cells in the brain are microglia

Derived from hematopoietic precursors

Likely takes months for these cells to make their way into the brain

Timing is of essence

The Challenge of Fixing the CNS: Microglia

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Umbilical/inguinal hernia

Cardiovascular disease

Obstructive airway disease

Corneal clouding

Hepatosplenomegaly

Chronic rhinitis/otitis

Joint stiffness

Developmental delay

Hearing loss

Enlarged tongue

Signs and symptoms

Carpal tunnel syndrome

Skeletal deformities

Macrosomia

Neufeld EF, Muenzer J. In: Scriver C, Beaudet A, Sly W, Valle D, eds. The Metabolic and Molecular Bases of Inherited Disease. New York, NY: McGraw-Hill; 2001:3421-3452.

Hurler Syndrome (MPS IH)

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HCT for Hurler syndrome

• Since early 1980s, > 500 transplants done

• Considered the standard of care for Hurler

• Donor-derived microglia engraft over 4-6 months, providing enzyme to the CNS

• Enzyme infusions used for less severely effected patients (Scheie), as those without severe neurologic deterioration

• Opportunity exists for combination therapy

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Boelens JJ et al, Pediatr Clin of N. Am, 2010

Event-Free Survival Post HCT for Hurler’s

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Peters: Blood 1998: 91 (7) 2601-08

The sooner the better!

Mental = chronological age in 64% transplanted before age 2

Vs.

Mental = chronological age in < 25% transplanted after age 2

P=0.01

Neuro Outcomes for Hurler’s

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• High risk for toxicity and mortality• High risk for rejection/ graft failure• Must balance these risks to achieve best outcomes• Full chimerism not needed to achieve clinical effect• Reduced-intensity regimens preferred in most patients• Related donors carriers of enzyme defect are not good

donors. Unrelated cord blood preferred • Hard to measure effect of transplant on CNS manifestations• Many of the somatic symptoms do not improve after BMT,

some may ‘worsen’ • Lack of data a big problem for insurance companies

Unique Features for HCT for Metabolic Disorders

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• Magic in numbers…• Rare nature of diseases and variation in severity limits the

power of studies, ability to randomize, etc.• Well designed cooperative trials important, but limited

resources, experience complicates assessments and outcome analysis

• Growing interest in newborn screening may provide a chance to treat very early in the course of disease; cooperative trials may be important

Limitations of HCT for Rare Metabolic Disorders

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• Sickle cell disease• Thalassemia major

HCT for Hemoglobinopathies

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Sickle cell disease

World’s most common serious disease due to a single gene mutation

Normal …..G A G G A G…..Sickle (6glu val) …..G T G G A G…..

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• Autosomal recessive inheritance 2 parents with HgB S trait: 25% risk of child with SCD

Not just in African Americans• African ancestry

• Caribbean, Central/South America

• Mediterranean (Greece, Italy)

• Middle East

• India

Inheritance of Sickle Cell Disease

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Sickling of Red Blood Cells

•VASO-OCCLUSION•ANEMIA•HEMOLYSIS

CLINICAL MANIFESTATIONS:

Acute: - Painful crisis - Acute chest syndrome - Stroke - Splenic sequestration - Aplastic crisis - Priapism

Chronic organ dysfunctions: - Spleen - Kidneys - Lungs: Pulmonary hypertension - Osteonecrosis - Eyes - Skin ulcers - Liver

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• Hydroxyurea (increase % fetal Hgb, decrease sickling)

• Symptomatic management

• Exchange transfusions and iron chelation therapy

• Some patients may benefit from HCT

- Recurrent pain crisis

- Recurrent acute chest syndrome

- CNS disease

• Benefit of HCT decreases as age increases

Therapeutic Approaches for Sickle Cell Disease

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• Inability to produce adequate amount of hemoglobin

• Autosomal recessive inheritance

• > African, Mediterranean, Asian descent

• Chronic hemolytic anemia, poor growth, infections, bone

deformities

• Death, if untreated

Thalassemia Major

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Management of Thalassemia Major

• Symptomatic management

• Chronic transfusions and iron chelation therapy

+ splenectomy

• Only known cure is HCT

• Goal is to offer HCT early before chronic iron deposition

causes end-organ damage

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Time (years) after BMTTime (years) after BMT

93%93%

85%85%

9%9%

Matched Sibling HCT for Sickle Cell

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Kaplan-Meier probabilities of survival, thalassemia-free survival, nonrejection mortality, and rejections for 32 thalassemia patients who received transplants from HLA-matched unrelated donors

(parenthesis: 95% confidence limits at 2 years).

La Nasa G et al. Blood 2002;99:4350-4356

Unrelated Donor HCT for Thalassemia

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Sickle cell

Thalassemia

Ruggeri A, Eurocord, 2011

Survival for Unrelated Cord Blood Transplantation for Hemoglobinopathies

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• High risk of rejection

- Myeloablative conditioning is preferred

• Many patients with end-organ damage cannot tolerate

full conditioning reduced intensity

• Carrier relatives (HgB S trait) can be donors

• Very small matched unrelated donor pool available

Unrelated cord blood attractive, but risk of rejection high

• Benefit of HCT decreases as age increases

Unique Features of HCT for Hemoglobinopathies

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• Two of the following:

• Neutrophils < 500/L (1500-5000)• Platelet count < 20 x 109/L (180-

440)• Abs. reticulocyte count < 40 x

109/L (20-80)

AND

• Bone marrow biopsy < 25% cellularity

Carmitta et al, Blood, 1976

Severe Aplastic Anemia (SAA)

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Symptoms

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Causes of Aplastic Anemia

Inherited

Fanconi anemia Dyskeratosis congenita Diamond Blackfan anemia Shwachman-Diamond

syndrome

Acquired

Pregnancy Drugs Infections Immune disorders Benzene Ionizing radiation Idiopathic

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Aplastic Anemia- Treatment

Supportive care Immunosuppressive therapy HCT

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Probability of Overall Survival

Kennedy-Nasser et al, Biol Blood Mar Transpl, 2006

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Unique Features of Aplastic Anemia

May be able to use reduced conditioning Related and Unrelated have similar outcomes Try to transplant early May need prolonged immunosuppression taper

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• Increasing use of HCT for non-malignant disorders• Donor/conditioning different depending on dz• Early consultation to HCT team for non-malignant dz

Conclusions

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• Eneida Nemecek, MD, MS• Bill Chang, MD, PhD• Peter Kurre, MD• Allison Franco, RN, BSN, CPHON• Erica Soler, RN, PNP

• Nycole Ferguson• Shirley Mason• Christina Burgin• Julian Kern• Meena Mishra• Amanda Tuggle

The Doernbecher Pediatric BMT Team

All the patients and families whose care we have been privileged to provide

Thank You!