A Prospective and Retrospective Data Collection Study to Evaluate Outcomes in males <= 17 years of age undergoing Allogeneic Hematopoietic Stem Cell Transplantation for the Treatment of Cerebral Adrenoleukodystrophy.

X-Linked adrenoleukodystrophy (ALD) is a rare genetic disease caused by a
defect in the breakdown of very long chain fatty acids (VLCFAs) in the
peroxisome, and their resulting accumulation is associated with a cerebral
inflammatory response that can lead to widespread demyelination. The incidence
of ALD is approximately 1:20,000 males; cerebral ALD (CALD) develops in boys
typically between 3 to 15 years of age, and represents approximately 30% to 35%
of patients with ALD.
Transplantation of allogeneic hematopoietic stem cells (allo-HSCT) is the only
effective therapy to date, and is capable of arresting disease progression in a
substantial proportion of patients if performed at an early stage of brain
demyelination. Although allo-HSCT can improve outcomes, it is associated with
significant morbidity and mortality, particularly for patients who undergo
unrelated or human leukocyte antigen (HLA)-mismatched allo-HSCT; a matched
sibling donor is available for <= 30% of patients.
From 2009 through 2012, there were 20 to 24 allo-HSCTs performed on patients
with CALD per year reported in the US, and the percentage of transplanted
patients who had unrelated allo-HSCT donors consistently increased from 75% to
92% from 2008 to 2012.

bluebird bio is evaluating Lenti-D Drug Product to treat male subjects with
CALD (<= 17 years of age at the time of parental/guardian consent and, where
appropriate, subject assent) in Study ALD-102. Retrospective data collected on
both untreated and allo-HSCT-treated CALD subjects in Study ALD-101 informed
the design of ALD-102 along with results from a clinical study using a similar
lentiviral vector (Study TG04.06.01), and feedback from key opinion leaders and
regulatory agencies. The clinical trial success criterion for Study ALD-102 is
based on a comparison of its primary efficacy endpoint with data obtained on
untreated subjects in Study ALD-101. Clinical data from allo-HSCT-treated
subjects from Study ALD-101 will provide additional context, in particular for
the evaluation of safety of Lenti-D Drug Product but also for efficacy as a
supportive analysis.

Study ALD-103 was designed to collect data both prospectively (subjects who
will undergo allo-HSCT during the study) and partially prospectively and
retrospectively (subjects who have undergone allo-HSCT up to 24 months before
study site activation) on all CALD patients eligible for allo-HSCT, using a
study design consistent with that described in Study ALD-102 with respect to
safety and efficacy assessments and their timing. It is anticipated that a
subset of the ALD-103 subjects will have similar baseline characteristics as
those treated in ALD-102.

-Evaluate the safety and efficacy of allogeneic hematopoietic stem cell
transplantation (allo-HSCT) in male subjects <= 17 years of age with cerebral
adrenoleukodystrophy (CALD)

Study ALD-103 will be a multi-site, global pro-spective and partially
retrospective study that is designed to evaluate outcomes of allo-HSCT in male
subjects with CALD <= 17of age. Retro-spective subjects will be <= 17 years of
age at the time of treatment, prospective subjects will be <= 17 years of age at
the time of con-sent).

This is a prospective and retrospective study and does not involve the use of
an investiga-tional drug or medicinal product, and allows the collection of a
defined subset of the data from these procedures.

Suitability for allo-HSCT and the choice of the treatment protocol utilized for
these subjects will be determined by the subjects* treating physicians as per
their institutional poli-cies/protocols and other local treatment guidelines.
Procedures to be performed will be those according to institutional protocols
and the accepted management of CALD, including supportive care, choice of graft
source, allo-HSCT protocol, prophylaxis and management of GVHD.

Subjects will be monitored from Screening before allo-HSC infusion, through
their Month 48 Visit after allo-HSC infusion. Follow-up will include monitoring
of outcome measures at months 1, 2, 3, 6, 9, 12, 18, 24, 36 and 48 after
allo-HSC infusion (prospective analysis).

In addition to the subjects in the prospective analysis, subjects who received
an allo-HSCT on or after January 1, 2013 and died before study data collection
retrospective), or subjects who will be available prospectively on-study for at
least the Month 24 visit (24 ± 1 month after allo-HSC infusion) (partial
prospective/retrospective) may also be en-rolled and followed for up through
their Month 48 Visit after their most recent allo-HSC infusion.

In summary, subjects will be enrolled in the following three cohorts:
• allo-HSCT (prospective): subjects who will be consented before they received
an allo-HSC infusion. They will be consented and enrolled on the study during
the Screening Period.
• allo-HSCT (partial prospective/retrospective): subjects who will be consented
after they received an allo-HSC infusion but before they reach 24 months
post-infusion. Subjects in this cohort will prospectively participate in at
least the Month 24 Visit in order to obtain on-study data for this and all
visits after M24.
• allo-HSCT retrospective: subjects who received an allo-HSC infusion on or
after January 1, 2013 and have died before study data collection.

This research collects a sub-set of the data generated under institutional
standard of care protocols for patients with CALD undergoing treatment with
allogenic-HSCT. The following study burdens and risks or not part of the
standard of care:
- Completion of two surveys by the parents/legal guardian about the quality of
life of their child pre-transplantation and at month 1, 3, 6, 12 and 24
post-transplantation.
- Blood samples collection for VLFCAs measurement
- Blood samples collection for biomarker analyses
- Optional blood sample collection
- Neuropsychological assessment at month 12, 36, 48
- MRI at month 12
- Collection of health economic data

MRI
MRI is a painless procedure that requires that the patient lies quietly on a
padded table that gently glides him into the magnetic field. While the scanner
is performing the scan, the patient will hear some humming and thumping sounds.
These are normal and should not worry the patient. A contrast agent called
gadolinium will be injected into the patient*s vein in order to give a clearer
image of the area being examined. Anytime an injection is given, there is the
potential for bruising or swelling at the injection site. Occasionally, minor
allergic reactions occur in the form of itching, sneezing, hives, swelling of
the eyes, wheezing or nausea. These symptoms may require treatment with
medication. Rarely, a more serious reaction will occur.
If the patient cannot lie still, he will likely need sedation or general
anesthesia so that the investigator can perform the MRI.

Sedation
Conscious sedation is a term used when medication is given that causes the
patient to relax and not feel pain but the patient is aware of what is going on
around him. Conscious sedation is generally well tolerated; however, if too
much of the medicine is given, problems with the patient*s breathing may occur.
A doctor or nurse will be watching the patient during the entire procedure.

General Anesthesia
General anesthesia will be given if the patient cannot lie still for the brain
MRI. The common risks from general anesthesia are nausea and vomiting when
waking up, a sore throat or croaky voice caused by introduction of a tube in
the trachea or throat to maintain respiration.
Rare events can include tooth damage, painful redness of the vein in which the
products were injected, dullness or paralysis of an arm or a leg due to the
prolonged position on the operating table, temporary memory difficulties or
impaired concentration.

Intravenous Line Placement / Blood Collection
There may be pain, swelling, or bruising around the vein where IV line will be
inserted or blood is collected. The patient may feel dizzy or may faint. The
patient may get an infection at the place on his body where IV line will be
inserted or his blood is collected.
The blood samples that are collected as part of the study will be collected at
the same time as the blood collected for the standard of care assessments, so
that blood only has to be collected once.

Quality of life questionnaires
The parents/legal guardian will be asked to complete two different Quality of
Life questionnaires about their child during the study. Some of the questions
asked may make them feel uncomfortable or embarrassed.

The research will lead to a better understanding of the outcomes of standard
procedures related to allogenic-HSCT for CALD.