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Subjects will receive pretransplantation conditioning of total-body irradiation (1,200 cGy delivered in 8 fractions over 4 days \[Days -9 through -6\] and cyclophosphamide (60 mg/kg IV daily x 2 on Days -3 and -2). Donor lymphocyte infusion will occur on day -6; donor CD34+ cells will be infused on Day 0.

1,200 cGy, delivered in 8 fractions of 150 cGy bid x 4 days

Radiation

Cyclophosphamide 60 mg/kg IV daily x 2 consecutive days

Donor Lymphocyte Infusion (DLI)

2-10 x 10E6/kg donor CD34+ selected cells

Haploidentical Stem Cell Transplantation

Joel A Brochstein, MD

This clinical pilot trial is intended to evaluate the feasibility, efficacy and safety of hematopoietic stem cell transplantation (HSCT) from Human Leukocyte Antigen (HLA)-mismatched related donors for children and young adults with hematologic malignancies who lack a suitably matched related or unrelated donor. The methodology will be one that has been successfully utilized in adult patients at Thomas Jefferson University.

Allogeneic HSCT is a potentially curative therapy for a number of malignancies. A barrier to the institution of this potentially curative strategy in hematologic malignancies is the availability of donors. Only 30% of patients in North America or Europe who may benefit from allogeneic HSCT will have an available HLA matched sibling donor. The ability to find a matched sibling donor is proportional to the number of children in the family. Because of the decreasing size of nuclear families, it is becoming less likely for patients to have an HLA identical matched sibling. Registries can provide a matched unrelated allogeneic stem cell graft for an additional 30% of patients. However this is not an option for patients who do not have a match in the registry, or whose disease status precludes them from waiting to identify an appropriate unrelated donor. The ability of finding a well matched unrelated donor is even more limited for segments of the population with mixed race ancestry as well as for African Americans who, because of a higher degree of HLA diversity, will be unlikely to find an unrelated donor who matches their HLA type.

In these settings it is easier and faster to identify a partially HLA-matched (or haploidentical) family member as a stem cell donor. The use of haploidentical donors broadens the application of HSCT because it is not as limited by family size or racial/ethnic HLA diversity. Because parents and children, as well as siblings can be used as haploidentical donors, this type of transplant enfranchises almost every segment of the population.

Since, in this study, the donor lymphoid and stem cell portions of the graft are collected and administered at different time points during the conditioning regimen, this approach to haploidentical HSCT is referred to as a 2 Step regimen. The approach does not involve ex vivo T cell depletion, but uses cyclophosphamide to tolerize donor lymphocytes within the framework of a myeloablative conditioning regimen. Preliminary experience with this approach in adult patients at Thomas Jefferson University for myeloablative haploidentical HSCT dates back to 2005 with the first trial using myeloablative conditioning formally launched in 2006. That initial trial met its accrual goals and the current trial is one of the successor trials derived from that experience.

The conditioning regimen includes total body irradiation (TBI) (1.5 Gray x 8) and CY (60 mg/kg x 2). Tacrolimus and Mycophenolate Mofetil (MMF) are used as post-transplant immunosuppression in relatively standard fashion.

The novel aspect of the regimen is in the administration of the graft. If one considers that a standard allograft consists of two components, a lymphoid portion and a stem cell portion, what is unique here is the administration of these two portions separately, at different time points during the conditioning regimen rather than together. The lymphoid portion, including a fixed dose of CD3+ cells/kg is administered prior to cyclophosphamide while the hematopoietic stem cell (HSC) portion of the graft is administered after cyclophosphamide has been metabolized and eliminated. Thus, the transplant occurs in 2 steps.

Stem Cell Transplantation From HLA Partially-Matched Related Donors for Patients With Hematologic Malignancies

A Two Step Approach to Allogeneic Hematopoietic Stem Cell Transplantation From HLA Partially-Matched Related Donors for Patients With Hematologic Malignancies

Absolute neutrophil count \>500/microliter x 3 consecutive days

Alive and free of disease at 2 years post-transplantation

Proportion of subjects with Grade II-IV acute graft-versus-host disease

Proportion of subjects with Grade III-IV acute graft-versus-host disease

Proportion of subjects who have experienced disease relapse by 2 years post-transplantation

New York Blood Center

Northwell Health

Associate Chief for Cellular Therapy, CCMC

patients with high-risk hematologic malignancies will receive hematopoietic stem cell transplantation from haploidentical donors after treatment with cyclophosphamide

14.5 mg/kg, IV qd on day -6 and -5 and 50 mg/kg, IV on day +3 and +4

Hematopoietic Stem Cell Transplantation,

Rocco Pastano, MD

The purpose of this study is to determine if engraftment can be achieved safely in patients with high-risk hematologic malignancies who undergo non-myeloablative transplant with peripheral stem cells from Human Leukocyte Antigen (HLA) haploidentical donors with pre and post-transplant cyclophosphamide as immunosuppression.

It is important to extend the option of nonmyeloablative, hematopoietic stem cell transplantation (HSCT) for potential therapy of hematologic malignancies to patients who do not have an HLA-matched donor. Almost all patients would have a related donor identical for one HLA haplotype (haploidentical) and mismatched at HLA-A, B or DR of the unshared haplotype. Thus far, nonmyeloablative HSCT from HLA-mismatched donors has been associated with a high rate of graft failure and graft-versus-host disease (GVHD). In this protocol, we will use a combination of immunosuppressive agents including cyclophosphamide administered before and after HSCT to facilitate engraftment and to delete highly alloreactive T-cell clones presumably involved in GVHD.

Hematopoietic Cell Transplantation for Patients With Hematologic Malignancies Using Related, HLA-Haploidentical Donors

Nonmyeloablative Hematopoietic Stem Cell Transplantation (SCT) for High-Risk Hematologic Malignancies With Related, HLA-Haploidentical Donors: A Phase II Trial of Immunosuppression With Cyclophosphamide Administered Before and After SCT

percentage of donor engraftment after 84 from baseline

Incidence and severity of graft versus host disease after 200 days from the baseline

incidence of non-relapse-related mortality after 200 days from the baseline

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Stem Cell Transplantation From HLA Partially-Matched Related Donors for Patients With Hematologic Malignancies	NCT02566395	Acute Lymphobla... Acute Myelogeno... Myelodysplastic... Chronic Myeloge... Non-Hodgkin Lym... Hodgkin Lymphom...	Radiation Cyclophosphamid... Donor Lymphocyt... Haploidentical ...	2 Years - 21 Years	Northwell Health
Stem Cell Transplantation From HLA Partially-Matched Related Donors for Patients With Hematologic Malignancies	NCT02566395	Acute Lymphobla... Acute Myelogeno... Myelodysplastic... Chronic Myeloge... Non-Hodgkin Lym... Hodgkin Lymphom...	Radiation Cyclophosphamid... Donor Lymphocyt... Haploidentical ...	2 Years - 21 Years	Northwell Health
Hematopoietic Cell Transplantation for Patients With Hematologic Malignancies Using Related, HLA-Haploidentical Donors	NCT01374841	Hematologic Neo...	Cyclophosphamid... Hematopoietic S...	18 Years - 70 Years	European Institute of Oncology

Spots Global Cancer Trial Database for haploidentical donors