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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!