A clinical study to investigate Interferon gamma (IFN*) signature in patients post HSCT and in patients with impaired HSC proliferation pre-transplant

IFNγ has been reported to play a deleterious effect on hematopoietic stem cell
(HSC) proliferation. This negative activity is suspected to play a central role
in conditions where hematopoietic stem cell proliferation is impaired like when
engraftment failure occurs after HSC transplant (1) (2) (3). Initial
observational investigations in children who received allogeneic hematopoietic
stem cell transplant (HSCT) in patients with various conditions such as
hemophagocytic lymphohistiocytosis (HLH), severe aplastic anemia (SAA),
erythroid and metabolic disorders, primary immune deficiencies and leukemia
have demonstrated a strong association between IFNγ activity measured by
elevated biomarker levels (e.g. CXCL9) few days post-transplant and the risk of
primary graft failure (GF) (Sponsor*s data on file and (4)). The same CXCL9
elevation was observed in patients developing secondary graft failure
(Sponsor*s data on file). In this condition, IFN* is thought to be produced by
activated residual T cells from the recipient against the donor cells. On the
contrary, IFNγ activity may also be elevated in patients developing Graft
Versus Host Disease (GVHD), where donor T cells act against the recipient
organs. Finally, it is also considered that IFNγ may play a role in other
diseases where HSC proliferation is impaired like in aplastic anemia (AA)
patients (5). Emapalumab, an anti-IFNγ antibody has been recently approved by
the FDA for HLH treatment (6), a disease where activated T cells produce
abnormal amounts of IFNγ.

HSCT cohort:
* -To investigate the relationship between IFNγ levels and IFNγ activity by
measuring CXCL9 levels and the risk of graft failure
* -To investigate the relationship between IFNγ levels and IFNγ activity by
measuring CXCL9 levels and the occurrence of GVHD
* -To measure exploratory biomarkers associated with GF and GVHD
IHSCP cohort:
* -To investigate the IFNγ levels and IFNγ activity by measuring CXCL9 levels
in patients with impaired HSC proliferation pre-transplant
* -To measure exploratory biomarkers associated with impaired HSC proliferation

This is a multinational interventional non drug study designed to assess IFNγ
activity by measuring IFNγ and CXCL9 in serum.
IFNγ activity will be investigated in two cohorts of patients:
-First group will include patients post HSCT at risk of graft failure defined
based on their underlying diseases and on the transplant procedure. HLH
patients are not part of this cohort since specific protocols are ongoing for
the treatment for HLH with emapalumab and data is collected post HSCT.
-Second group will contain patients with conditions where HSC proliferation is
impaired (e.g. aplastic anemia) and with respective controls (healthy
volunteers (HV)).
These two groups of patients will be called HSCT and Impaired HSC proliferation
cohorts respectively. Clinical data and sample collection for both groups might
be performed prospectively or retrospectively in case required samples are
available at the collaborating center.

Participation in this study is not intended to change the routine treatment
that patients receive as determined by their prescribing
clinicians* all treatment decisions and type and timing of disease monitoring
are at the discretion of the treating physician. No additional visits to the
clinic will be required for the purposes of the study.

For HSCT cohort, the following sampling time points are required: on day -7,
pre HSCT on day 0, 1, 3, 5, 9, 13, 17, 21, 28, 31, 38 and one additional sample
at the time when primary or secondary GF is suspected if not on the planned
schedule. In addition, the following time points are recommended: day 7, 11,
15, 19, 24, 35, 42. It is also suggested to collect a sample when GVHD is
diagnosed during any visit that the patients will attend as part of his/her
standard treatment during the first 100 days post-transplant. The patient will
be followed up until around day 100 post-transplant. This follow up will
consist of capturing HSCT outcome information from patient hospital records
around day 100.

For IHSCP cohort pre-transplant, it is recommended that, one sample (2 mL of
blood) per patient at the time of diagnosis (if possible not more than 1 week
from the date of diagnosis) is collected. Age/sex matched control samples
should be collected from healthy volunteers or malignant patients outside of
this protocol after appropriate consent. The matching will be performed per age
categories in three groups: < 18, >= 18 - 60 <, >= 60. Control samples for IHSCP
will be obtained from existing commercial biobanks of HV or malignant patients
matching age and sex of patients participating in the study.

Blood samples will be taken several times during the study from a vein (or
finger) with a disposable needle. The risks associated with taking blood
samples include local irritation, bruising, bleeding and inflammation of the
area of needle insertion. Whenever possible the blood will be drawn from an
existing venous access to avoid multiple needle insertions through the skin. In
addition, numbing creams may be used to decrease the pain level.

Participants will not receive any direct benefits from this study. However,
participation in the study will help to learn about the relationship between
the measured proteins in the blood (INF* and CXCL9) and GF or conditions where
HSC proliferation is impaired. Information gathered blood samples may help to
predict the risk of GF and may guide the administration of treatment helping
the successful engraftment in the future. In addition, it can also help to
develop new treatments for conditions where proliferation of HSC is impaired