Co-infusion of haematopoietic stem cells from a haplo-identical donor and single unit unrelated cord blood in patients with a high risk of relapse:
A Phase l/ll study to assess safety and to investigate the biological mechanism of the anti-tumor response

Although haematopoietic stem cells transplantation (HSCT) has become much safer
over the last decade the major limitation remain *transplantation related
mortality (TRM; e.g. due to viral reactivations/disease)* and relapse (in
malignancies). Within the group of malignancies there is a subgroup of
patients with a *very high risk (of relapse) profile* (e.g. relapse AML,
refractory lymphoma, relapse after first allo-HSCT). Although this *very high
risk group* may potentially benefit from allo-HSCT with the currently
available *standard* transplant protocols the expected survival rates are very
low <20%. Cord blood (CB) is emerging as stem cell source for HSCT because it
has many advantages above the conventional bone marrow grafts. Disadvantages
are however low stem cell count/kg for adults associated with prolonged
neutropenia and a slower T cell recovery. T cell depleted haplo-grafts have the
advantage of early neutrophil engraftment but are associated with higher rates
of secondary graft-failure and poor T-cell reconstitution associated with viral
infections. KIR-mismatching in Haplo-grafting is suggested to have
anti-leukemic potential.

To study the safety of co-infusion of a alphabetaT-/CD19 B-cell depleted
haematopoietic stem cells from haplo-identical donor and a single unit cord
blood unit and to investigate the anti-tumor responses from both grafts.

It is a single center study within the UMC Utrecht, including adult patients
with and indication for allo-
SCT. Patients will be included during a period of 4 years. According to Simon
et al. (Optimal two-stage designs for phase
II clinical trials) it was estimated that a minimum of 13 and a maximum of 37
have to be included. To our opinion in 4years
time a number of 37 should be feasible.
For all patients with an indication for allogenic HSCT, the best treatment
option is discussed in a multidisciplinary meeting.
This treatment protocol will be considered as one of the options for eligible
patients. When considered the best option, the
treatment proposal is discussed with the patient/ parents. Informed consent has
to be obtained both for HSCT itself, for
immune reconstitution studies, and for the Cord+ Haplo HSCT protocol.
If informed consent is obtained, the best CB unit is ordered. After apheresis
or bone-marrow harvest of the haplo-donor
graft, the cells are purified by the SCT lab using negative selection with
anti-TCR**- and CD19-microbeads.
Just prior to transplant the Cord blood unit is thawed and infused immediately
thereafter, followed by infusion of the
selected haplo-cells. All other treatment, both in- and outpatient care is the
same as it is for other allogenic HSCT patients.
CRFs are filled out by the responsible doctors of the SCT ward and outpatient
clinic on day 0; +1; +3; +10 days; +2 wks,
+4 wks, +6 wks, + 8 wks, + 10 wks, +12 wks: +100 dys; +4 months; +5 months; +6
months, +9 months, +1 year.
Main outcome parameters of this safety trial are aGVHD and TRM. Stopping rules
on the two outcome parameters have
been defined , implying an interim analysis of TRM after the first 100 days of
the first 13 patients and of the cumulative
incidence of TRM after the first 100 days of the first 13 patients. In line
with Simon the trial will be discontinued early if
>4 out of 13 patients died of TRM

For a group of patients with a very high risk malignancy: Instead of using a
single donor, or no transplantation at all, a combination of a cord blood unit
and selected cells from a haplo-identical family-donor are infused at the day
of transplant. The selection procedure of the haplodonor allows mismatch
NK-cells and gammadeltaT-cells in the graft for extra anti-tumor effect.

In more detail: The intervention applies to the selection of the donor source
and preparation of the grafts.
1) combining a cord blood unit with a minimum of > 1,5 x 10E7 NC/kg with
coinfused cells form a haplo-identical
familydonor
2) preference of a KIR mismatch between haplodonor and recipient for recipients
with a malignant indication for HSCT
(see protocol)
3) selection of the haplograft purified by TCR**- and CD19-negative selection
leaving in the graft:
-5 x 10 E6/kg CD34+ /kg (in case of difficult apheresis minimum of 2.5 x
10E6/kg).
-Maximum number of T cells < 5x 10 E4/kg.
-NK cells and gamma delta T cells for extra antiviral and anti-tumor activity
4) Using conditioning regimens without ATG. This is explained on page 20 of the
protocol under "Safety of infusion of
innate immune cells".

Potential Burden:
The protocol only comprehends the use of a different donor source (a
combination of 2 donor sources). All other acts, measurements, follow-up and
level of care are similar to off-study patients undergoing allogenic HSCT.

Potential Risks:
1) Potentially increased risk of aGVHD because of cumulative alloreactivity
from 2 different donors: (1)CB + (2) the co-infusion of haplo-donor derived NK
cells and gammadelta T-cells (together with CD34+ hematopoietic stem cells
from the haplodonor).
2) Possible increased risk of cGVHD (associated with 1)
3) Possible increased risk of engraftment syndrome, due to speed of
engraftment, and expected enhanced graft vs graft reaction (because of presence
of NK and gammadeltaT-cells in the Haplo-graft).
4) Possible risk of rejection of the cord blood graft (or both the CB and the
haplo-graft) due to increased graft-versus-graft reaction and augmented
NK/gamma deltaT cell power of the haplo-graft.

Potential Benefits:
1) lower TRM due to swift and secure early engraftment, and lower
virus-associated toxicity
2) Less relapse due to NK-(CB and Haplo), gamma delta T-cell (Haplo) and alpha
betaT-cellular (CB) activity.
3) Potentially lower risk of aGVHD and cGVHD because it is expected that the
CB will be the sustained engrafting donor (CB is associated with lower levels
of GvHD) and NK and gammadelta T-cells from the Haplo-donor are suggested not
to be associated with GvHD. In addition, due to the decreased risk of
infections (early engraftement, anti-viral potential of NK and gammadelta
T-cells), the combination of these to donors may result in reduced associated
tissue damage. Reduced tissue damage may prevent the occurrence of
allo-reactivity.