Can the steady-state hematopoiesis be improved post-ASCT by infusion of the autologous stem cell transplant directly in the bone marrow compartment?

Introduction and rationale
Autologous stem cell transplantation is a frequently applied treatment modality
for patients with multiple myeloma (MM) and relapsing lymphoma. The autologous
stem cell transplant is re-infused intravenously following high-dose
chemotherapy. Post-ASCT a gradual normalization of peripheral blood cell counts
occurs but normal peripheral blood cell counts of all three lineages is noticed
in only 40% of the patients one year post-transplantation3. The consequences
are that future chemotherapy application is limited in the case of relapsing
disease. In this situation the hematopoietic stem cell compartment demonstrates
an increased susceptibility for the cytotoxic effects of chemotherapy resulting
in prolonged periods of peripheral pancytopenia.
The observed impaired regenerative capacity of the stem cell compartment
post-ASCT and the impaired cell function under conditions of stress
(chemotherapy) might be attributed to: (1) an impaired hematopoietic stem cell
(HSC) function and engraftment due to accumulated DNA damage of stem cells and
micro-environment as result of chemotherapy exposure; (2) a limited number of
hematopoietic stem cells lodge in the bone marrow compartment due to the lack
of relevant homing receptors and trapping of the infused cells in lung, liver
and spleen; (3) an impaired homing of cells that are part of the
micro-environment which limits the regenerative capacity of the stem cell
compartment.
These findings result in a *relative* shortage of HSC*s in the bone marrow
compartment and as consequence a higher productive rate of remaining bone
marrow cells for producing adequate peripheral blood cells counts. These
findings are in line with preliminary results demonstrating that bone marrow
progenitors 6-9 months post-ASCT have the phenotypic profile of
granulocyte-macrophage progenitors (GMP) instead of common myeloid progenitors
(CMP). Moreover post-ASCT patients demonstrate a higher proliferative activity
of the bone marrow compartment at normal peripheral blood cell counts as tested
in-vivo with FLT-PET scanning.

Recent findings in mice and human have demonstrated that engraftment and
recovery of hematopoietic cells following ASCT can be improved by infusing the
autologous stem cell transplant directly in the bone marrow compartment4-8.
This approach has the advantage that the lodging of the HSC*s in the bone
marrow is less dependent on the migratory/adhesion capacity of the cells. In
addition the cells are directly located in their own micro-environment, and an
concomitant regeneration of microenvironment and hematopoietic compartments
take place.
(protocol page 6)

To improve the steady hematopoiesis post-ASCT by infusing the autologous
transplant directly in the bone marrow compartment.
(protocol page 6)

The study design is a pilot study. The feasibility of the autologous stem cell
re-infusion will be explored in 15 patients diagnosed with lymphoma and MM.

The admittance of the stem cell transplant immediately in the bone marrow
compartment.

- Tingle the spina iliaca; a subcutaneous anaesthesia will be given in advance.
- If the transplant does not catch. If day-21 after transplant there is no
granulocyte (<0.1 x 109/l) or thrombocyte (10x < 109/l) recovery if there is no
other cause then a complete stem cell transplant (>5 x 106 CD34+ cells/kg) will
be infused through the blood stream.
- Perform an FLT-PET.