Transcript Department of Pediatrics Strategic Planning Retreat DRAFT – as of

Hematopoietic Stem Cell Transplant
(HCT) for Nonmalignant Disorders
Evan Shereck, M.D.
September 13, 2013
1
Objectives
• 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
2
Indications for Pediatric BMT
3
Indications for HCT for Patients < 20 years
800
Allogeneic (Total N=1,496)
Number of Transplants
700
Autologous (Total N=880)
600
500
400
36%
300
200
100
0
Other
Cancer
ALL
AML
Aplastic
Anemia
HD
NHL
MDS/MPD
CML
Other
Leuk
NonMalig
Disease
4
The Cells Produced in Bone Marrow
5
Immune System 101
6
Primary Immunodeficiencies
• 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
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Primary Immunodeficiencies Treated with HCT
Lymphocyte immunodeficiencies
Severe combined immunodeficiency
Omenn syndrome
DiGeorge syndrome
CHARGE syndrome: Coloboma, heart anomalies, choanal
atresia, retardation of growth and development, and genital
and ear anomalies
Wiskott-Aldrich syndrome
X-linked lymphoproliferative disease, XLP1, XLP2
Phagocytic deficiencies
Chronic granulomatous disease
Severe congenital neutropenias
Leukocyte adhesion deficiency
Schwachman-Diamond syndrome
Chediak-Higashi syndrome
Griscelli syndrome, type 2
Familial 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) syndrome
Nijmegen breakage syndrome
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Natural History of Inherited Immunodeficiencies
• Spectrum of disease depends on genetic defect
Early Onset – “Classic”
Usually early infancy (birth – 12
months)
Presentation:
-Recurrent infections
-Opportunistic infections
-Poor growth
-+/- congenital anomalies
100% fatal within first 2 years of life
Late onset
Late childhood to adulthood
Presentation:
-Recurrent infections
-Malignancies
-Autoimmune disorders
Usually fatal in first decades of life
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Known Severe Combined Immunodeficiencies
Name
Defect
Special
X-linked
Common
JAK3 deficiency
Janus 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
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+
deficiency
chain
Phenotype
T-B+NK-
Dwarfism, hypoplastic hair
Finnish, Amish descent
Cartilage hair hypoplasia
Endoribonuclease
T-B+NK+
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
Bare lymphocyte
Syndrome type II
-chain-associated protein kinase
HLA class II
CD4+, CD8- B+, NK+
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
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Outcomes of HCT for SCID
Year
Conditioning
MRD
Haplo
Haplo
MUD
MUD
Unrelated
Cord
None
None
Myeloablative
Myeloablative
Reduced
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
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Percent Surviving
Effect of Age on Transplant
Day of Life at Transplant
Rebecca H. Buckley, J. All & Clin Immunol, 2012
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SCID Newborn Screen
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Unique Features for HCT for SCID
• 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
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Inherited Metabolic Diseases
• Genetic defects in enzymes  accumulation of metabolic
products in body organs  progressive dysfunction  death
• Multiple diseases, some amenable to HCT some not
Rule of thumb: If replacing leukocytes can generate the missing
enzyme, then HCT may be effective
• Time is of essence
Ultimate outcome and QOL not improved if end-organ symptoms
are present
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Lysosomes
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Metabolic Disorders & Transplantation
Standard of care
 MPS IH (Hurler)
 Metachromatic
leukodystrophy (MLD)
 Globoid Cell
leukodystrophy (Krabbe)
 -mannosidosis
 acid lipase deficiency
(Wolman disease)
 Cerebral ALD
Under Investigation
 Hunter
 I-cell
 Recessive Osteopetrosis
 Niemann-Pick
 Gaucher
 Farber
 Tay-Sachs
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Strategies to Replace Enzymes
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?
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19
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The Challenge of Fixing the CNS: Microglia
 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
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Hurler Syndrome (MPS IH)
Signs and symptoms
Macrosomia
Developmental delay
Chronic rhinitis/otitis
Obstructive airway disease
Umbilical/inguinal hernia
Skeletal deformities
Carpal tunnel syndrome
Corneal clouding
Hearing loss
Enlarged tongue
Cardiovascular disease
Hepatosplenomegaly
Joint stiffness
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.
22
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
23
Event-Free Survival Post HCT for Hurler’s
Boelens JJ et al, Pediatr Clin of N. Am, 2010
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Neuro Outcomes for Hurler’s
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
Peters: Blood 1998: 91 (7) 2601-08
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Unique Features for HCT for Metabolic Disorders
•
•
•
•
•
•
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
26
Limitations of HCT for Rare Metabolic Disorders
• 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
27
HCT for Hemoglobinopathies
• Sickle cell disease
• Thalassemia major
28
Sickle cell disease
World’s most common serious disease due to a single gene mutation
Normal
Sickle (6glu
val)
…..G A G G A G…..
…..G T G G A G…..
29
Inheritance of Sickle Cell Disease
• 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
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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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Therapeutic Approaches for Sickle Cell Disease
•
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
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Thalassemia Major
• 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
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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
34
35
Matched Sibling HCT for Sickle Cell
93%
85%
9%
Time (years) after BMT
36
Unrelated Donor HCT for Thalassemia
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
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Survival for Unrelated Cord Blood Transplantation
for Hemoglobinopathies
Sickle cell
Thalassemia
Ruggeri A, Eurocord, 2011
38
Unique Features of HCT for Hemoglobinopathies
•
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
39
Severe Aplastic Anemia (SAA)
•
Two of the following:
• Neutrophils < 500/L (15005000)
• 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
40
Symptoms
41
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
42
Aplastic Anemia- Treatment
 Supportive care
 Immunosuppressive therapy
 HCT
43
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Probability of Overall Survival
Kennedy-Nasser et al, Biol Blood Mar Transpl, 2006
45
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
46
Conclusions
• Increasing use of HCT for non-malignant disorders
• Donor/conditioning different depending on dz
• Early consultation to HCT team for non-malignant dz
47
Thank You!
The Doernbecher Pediatric BMT Team
•
•
•
•
•
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
All the patients and families whose care we
have been privileged to provide
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