Haplo-identical SCT for HR Hematologic Malignancies w/Post-Transplant In-Vivo T-cell Depletion

For patients whose disease cannot be brought into remission the prognoses are worse
primarily due to high rates of post-HSCT relapse. For patients who have poor donor options
(i.e., lack an adequately matched allogeneic marrow donor), the prognoses are worse for a
successful outcome due to higher rates of treatment related mortality (TRM). Their options
are to seek investigational treatments without HSCT or alternative investigational HSCT
protocols for which they are eligible. Patients who have relapsed after an allogeneic HSCT
are at high risk for either relapse or TRM after a subsequent HSCT, even if an additional
state of complete remission can be achieved prior to the subsequent HSCT.

This current treatment protocol is designed to assess alternative HSCT treatments for
patients with refractory/very high risk disease features and/or inadequate single sources of
HLA- matched -donor stem cells. The goal is to cure their hematological malignancy with the
combination of chemotherapy and potentially destruction of cancerous cells by the new, donor
immune cells.

For patients whose only potential for cure is allogeneic HSCT but who are lacking a well
matched relative or unrelated donor source, haplo-identical donors (i.e., "half identical"
donors) are a remaining option. However, without some form of immune manipulation of the
donor marrow (e.g. pre-infusion in vitro or in the test tube/laboratory T-depletion, or
depletion of donor T-cells), outcomes after haplo-identical HSCT have very poor results with
unacceptable TRM, non-engraftment or severe graft-vs-host disease (GVHD)2 leading to fatal
complications. GVHD is a complication that can occur after a stem cell or bone marrow
transplant in which the newly transplanted donor cells attack the healthy tissues in the
transplant recipient's body.

Thus, to better treat resistant leukemia, there is a need for either improved cytoreduction
(pre-transplant reduction in the number of the cancer/leukemia cells) regimens for
refractory disease, and/or for improved methods of eliminating cancer cells after the
transplant has occurred.

Using well matched donors, investigators have studied the use of HSCT using mild
chemotherapy but exploiting the donor cell immune reaction post-stem cell infusion to
"allow" the reaction against leukemia and lymphoma cancer cells. This has generally proven
ineffective for patients with disease not in remission at the time of transplant.

Thus new approaches to combat residual refractory disease are still needed. Also, for
patients lacking well-matched donors, new methods to facilitate use of haplo-identical
donors are needed.

Investigators hypothesize that HSCT from a partially matched (haplo-identical) related
(usually sibling or parent or child) donor can be safe and effective for patients with very
high risk hematologic malignancies when combined with an intensive, myeloablative (marrow
destroying) cytoreduction treatment pre-HSCT followed by post-transplant cyclophosphamide
for prevention of Graft Versus Host Disease (GVHD) in the recipient. This approach has been
employed at other centers, primarily in adult recipients.2-4One center's experience in
pediatric patients demonstrated that non-relapse mortality was low and donor engraftment
occurred in 12 of 12 patients.5More experience with this approach is needed in pediatric
HSCT patients.

In this Pilot Study, investigators hope to determine the likelihood that a myeloablative
cytoreduction regimen followed by haplo-identical HSCT and high-dose post-transplant
cyclophosphamide leads to adequate engraftment for high-risk hematologic malignancy
patients. The patients that will be transplanted on this study are patients whose likelihood
of survival without a transplant would be very low (<10-15 %, whether due to relapse after
prior HSCT, poor disease control, or no matched donor available).

This treatment protocol does not involve an investigational drug but the combination of
chemotherapy drugs in a new sequence/scheduling along with the use of haplo-identical donor
stem cells. In this treatment protocol, patients will be treated in three different strata
according to what defines their high-risk for a poor outcome. Each stratum will be comprised
of a pre-transplant chemotherapy conditioning regimen followed by infusion of
haplo-identical related donor marrow stem cells, followed in turn by post-transplant
cyclophosphamide as immunosuppression to prophylaxe against GVHD.

The chemotherapeutic agents in this study, including cyclophosphamide, are routinely
administered in children and adolescents for treatment. Cyclophosphamide is most commonly
administered as a component of the pre-transplant cytoreduction therapy. However, for this
treatment protocol investigators plan to assess the ability of utilizing a combined approach
of the chemotherapeutic agents, with cyclophosphamide, as an effective prevention of GVHD
infused after receiving a transplant from a closely matched (but not identical) family
member.

The common elements of this research are high-dose cytoreduction therapy prior to HSCT,
high-dose cyclophosphamide following HSCT and partially matched, related donor bone marrow
cells as the source of stem cells infused for transplantation. The research question is the
outcome of the patients treated with this combination. The cytoreduction regimen is tailored
for the specific risk (prior HSCT, poor disease control vs no matched donor source of stem
cells).

Inclusion Criteria:

- Patients must have confirmed diagnosis of hematologic malignancy (leukemia, lymphoma
or MDS) with the following:

- Resistant/refractory hematologic malignancies (disease exceeding 5% of marrow cells
by morphology, which is a description of white blood cell types as assessed via light
microscopy; or with measurable extramedullary disease, which is detection of leukemia
at sites other than blood and marrow. This includes disease that infiltrates into
tissues other than the spleen and marrow. i.e. nodal disease, which is leukemia
and/or lymphoma involving a lymph node or chloroma, which is a collection of leukemic
cells forming a mass/tumor mass) (Stratum 1).

- Or have relapsed following an initial allogeneic HSCT (Stratum 1).

- And/or lack an adequately matched unrelated donor (URD) or unrelated cord blood (URB)
hematopoietic stem cell (HSC) source (see protocol section 2) (Strata 1, 2 & 3).

- Adequate cardiac, pulmonary, renal, and hepatic functions

- Central vascular access providing a combined 3 access ports for all patients.

- Females of childbearing potential must have a negative pregnancy test prior to
therapy. Pregnancy tests will only be done prior to therapy. Sexually active patients
will be informed of the risk of not using adequate contraception.

- Recipient or legal guardian must be informed of the study, and have signed a consent
form.

- Recipients must have a related haplo-identical donor.

Exclusion Criteria:

- High risk hematologic malignancies in remission (and no prior allogeneic HSCT), where
allogeneic HSCT is indicated but an appropriately matched HSC source (sibling,
unrelated adult or UCB) is available.

- Patients with systemic infections and/or organ dysfunction mandating a reduced
intensity conditioning regimen are also excluded.