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Patients 18 years old or younger with marrow aplasia or single lineage cytopenias will be receive intravenous busulfan (4 doses x 2 days), cyclophosphamide (4 doses x 4 days) and fludarabine (4 doses x 4 days), as used in our most current study that led to \> 90% survival rates . Busulfan pharmacokinetics will not be used. All patients will receive rabbit ATG (4 doses x 4 days) prior to and granulocyte-colony stimulating factor (G-CSF) after transplant to promote engraftment. Cyclosporine will not be used for GVHD prophylaxis. The source of the stem cells for all patients will be peripheral blood stem cells mobilized by treatment of the donor with G-CSF. T-cell depletion will be performed by positive CD34 selection with the use of the Miltenyi system (CliniMACS device). Enrollment on this arm will include up to 50 patients.

Patients 18 years old or younger with MDS or AML will receive intravenous busulfan (4 doses x 2 days), cyclophosphamide (4 doses x 4 days) and fludarabine (4 doses x 4 days). Busulfan pharmacokinetics will be used in this arm, as the dose of busulfan is higher. All patients will receive rabbit ATG (thymoglobulin) (4 doses x 4 days) prior to and G-CSF post transplant to promote engraftment. Cyclosporine will not be used for prophylaxis against GVHD. The source of the stem cells for all patients will be peripheral blood stem cells induced and mobilized by treatment of the donor. T-cell will be performed by positive CD34 selection with the use of the Miltenyi system (CliniMACS device).

The maximum number of patients enrolled in this arm will be 10.

Patients 19 years old or older with marrow aplasia or MDS or AML will receive intravenous busulfan (4 doses x 2 days), cyclophosphamide (4 doses x 4 days) and fludarabine (4 doses x 4 days). In this study, we will test whether outcomes can be improved, yet engraftment maintained, with a slightly reduced dose of busulfan. Patients will receive rabbit ATG (4 doses x 4 days) prior to and G-CSF post transplant to promote engraftment. Cyclosporine will not be used for GVHD prophylaxis. The source of the stem cells will be peripheral blood stem cells collected from donors treated with G-CSF. T-cell depletion will be performed by positive CD34 selection with the use of the Miltenyi system (CliniMACS device). The maximum number of patients enrolled will be 10.

A standard dose of busulfan, associated with excellent outcomes in our previous trial will be used for young patients with marrow aplasia (arm A).

A higher dose of busulfan will be used in younger patients with MDS and AML (arm B) to maximize disease control.

A lower dose of busulfan will be used in older patients (arm C) to minimize toxicity.

Arms A, B and C - Cytoxan will be given as a 1-2 hour infusion for 4 days. The dose will be adjusted according to patients ideal body weight for obese patients.

Arms A, B and C - Fludarabine will be given IV over 30 minutes daily for 4 days. The dose will be adjusted according to renal function according to Institutional guidelines.

Arms A, B and C - 4 doses will be given prior to transplant to promote engraftment.

rabbit ATG

All patients will also receive G-CSF post-transplant to foster engraftment.

G-CSF

The source of stem cells for all patients will be peripheral blood stem cells (PBSC) induced and mobilized by treatment of the donor with G-CSF for 4-6 days. T-cell depletion will be uniformly performed by positive CD34 selection with the use of the Miltenyi system (CliniMACS device).

Peripheral blood stem cell

Jamie Wilhelm

Sara Loveless, RN

Parinda Mehta, MD

Sheri Ballard

K. Scott Baker, MD

The purpose of this study is to determine whether the use of lower doses of busulfan and the elimination of cyclosporine will further reduce transplant-related side effects for patients with Fanconi Anemia (FA). Patients will undergo a transplant utilizing mis-matched related or matched unrelated donors following a preparative regimen of busulfan, fludarabine, anti-thymocyte globulin and cyclophosphamide.

The trial proposed is a three arm phase II treatment protocol designed to investigate the safety and efficacy of risk-adjusted chemotherapy-based cytoreductive regimen plus a CD34+ selected T-cell depleted peripheral blood stem cell (PBSC) stem cell transplant for the treatment of patients with Fanconi anemia and severe hematologic disease. Candidates for this trial will include patients with Fanconi anemia presenting with severe marrow failure (transfusion dependent) or myelodysplastic syndrome, or acute myelogenous leukemia for whom an allogeneic stem cell transplant is indicated.

HSCT for Patients With Fanconi Anemia Using Risk-Adjusted Chemotherapy

A Phase II Trial of HSCT for the Treatment of Patients With Fanconi Anemia Lacking a Genotypically Identical Donor, Using a Risk-Adjusted Chemotherapy Only Cytoreduction With Busulfan, Cyclophosphamide and Fludarabine

Patients will be observed for acute and/or chronic graft versus host disease (GvHD). Standard clinical criteria for the grading of acute and chronic GvHD will be done according to IBMTR guidelines.

For patients with MDS or AML, relapse will be analyzed as to type and genetic origin of the MDS/leukemic cells.

Patients will be followed for 5 years through annual contact with their treatment center in order to track the risk of developing a secondary malignancy.

Primary non-engraftment is diagnosed when the patient fails to achieve an ANC \>=500/mm3 at any time in the first 28 days post-transplant. If (1) after achievement of an absolute neutrophil count (ANC) \>=500/mm3, the ANC declines to \<500/mm3 for more than 3 consecutive days in the absence of relapse, or, (2) there is absence of donor cells in the marrow and/or blood as demonstrated by chimerism assay in the absence of relapse, a diagnosis of secondary graft failure is made. The patient is not evaluable for graft failure or rejection if recurrence of host MDS is detected concurrently.

The occurrence of severe post-transplant regimen-related severe morbidity (grade IV toxicity) and/or mortality will be the second endpoint of this study. In the context of the agents or agent-combination used for cytoreduction used, particular attention will be given to toxicity involving (1) the liver, (2) the lungs, (3) the oral mucosa and gastrointestinal tract, and (4) the central nervous system.

Memorial Sloan Kettering Cancer Center

Fred Hutchinson Cancer Center

Children's Hospital Medical Center, Cincinnati

Immune System Diseases

Precursor Cell Lymphoblastic Leukemia-Lymphoma

Lymphoma

Hemoglobinuria

Leukemia, Lymphoid

Hemoglobinuria, Paroxysmal

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Urological Manifestations

Hemolysis

Anemia, Hemolytic

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Lymphoblastic Lymphoma

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Paroxysmal Nocturnal Hemoglobinuria

Thiotepa

Myeloablative and will consist of hyperfractionated TBI - 1375 cGy administered in 11 doses of 125 cGy each over a total of four days, with three doses on three days and two doses on the last day, fludarabine 25 mg/m2 IV x 5 days, and thiotepa 5mg/kg IV x 2 days. Recipients of HLA identical related transplants will not receive ATG to promote engraftment. Recipients of HLA mismatched related or unrelated stem cells will receive ATG for two days prior to the transplant. G-CSF mobilized CD34+E- PBSCs obtained from the HLA compatible donor will be infused on day 0. Post transplantation G-CSF will be administered only if clinically indicated and should begin on or after d+7.

Patients will be clinically evaluated at each clinic visit for incidence and severity of acute and chronic GVHD and transplant associated morbidity. Sequential evaluation of functional reconstitution of hematopoiesis and immunity will be made as per the BMT Service guidelines.

cytoreductive regimen followed by a CD34+E- selected allogeneic stem cell transplant

Ann Jakubowski, MD

This is a phase II, single-center study to evaluate the efficacy of a novel cytoreductive regimen followed by CD34+E- selected T cell depleted allogeneic stem cell (or soybean agglutinated and E-rosetted BM) transplant as treatment for patients with acute and chronic leukemias, lymphoma and myelodysplstic syndrome/PNH. The impact of the change in conditioning regimen and use of CD34-selected T cell depleted PBSCs on transplanted related morbidity and mortality and disease free survival will be assessed.

The purpose of this study is: (1) to try to kill any cancer or precancer cells that are in your body, and to reduce the side effects of a transplant, which we have seen in our previous studies, (2) to see if this treatment with a new recipe of radiation and chemotherapy can suppress your immune system enough for the stem cells to 'take' and grow, (3) to see if the specially prepared stem cells can grow in you without a problem called graft-versus-host disease (GvHD) occurring.

One of the major side effects of any stem cell transplant is a condition known as graft vs. host disease or GVHD. GVHD is an immune reaction caused by certain cells from the transplanted stem cells called T-lymphocytes (or T-cells). The T-cells from your donor may see your organs as foreign and attack them. New ways to remove the T-cells from the stem cells before the transplant are being used to try and prevent GVHD. In some studies, the removal of T-cells from the stem cells has been successful for many patients in preventing both short-term (acute) and long-term (chronic) forms of GVHD. However, the removal of T-cells may increase the chance that the new bone marrow developing from the stem cells will be rejected or will not function well. Rejection of the transplant means that some of your own cells have survived the chemo and radiation therapy, and are attacking the new bone marrow cells. This condition can be lifethreatening because of an increased risk of infections and bleeding and would require your getting more treatment and additional stem cells. Studies like this one are designed to find better ways to avoid GVHD without increasing the risk of other problems such as graft rejection.

Trial of Allogeneic Stem Cell Transplants From HLA Compatible, Related and Unrelated Donors After a Myeloablative Preparative Regimen With Hyperfractionated TBI, Thiotepa and Fludarabine For Adult Patients With Lymphohematopoietic Disorders

Phase II Trial of Allogeneic T-Cell Depleted Hematopoietic Stem Cell Transplants From HLA Compatible, Related and Unrelated Donors After a Myeloablative Preparative Regimen With Hyperfractionated TBI, Thiotepa and Fludarabine For Treatment of Adult Patients (>18 Years) With Lymphohematopoietic Disorders

Calculate the median overall survival of transplant patients

National Cancer Institute (NCI)

Adult Patients (\>18 years) with Lymphohematopoietic Disorders will receive Allogeneic T-Cell Depleted Hematopoietic Stem Cell Transplants After a Myeloablative Preparative Regimen With Hyperfractionated TBI, Thiotepa and Fludarabine

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
HSCT for Patients With Fanconi Anemia Using Risk-Adjusted Chemotherapy	NCT02143830	Fanconi Anemia Severe Marrow F... Myelodysplastic... Acute Myelogeno...	Busulfan Cyclophosphamid... Fludarabine rabbit ATG G-CSF Peripheral bloo...	3 Months -	Children's Hospital Medical Center, Cincinnati
Trial of Allogeneic Stem Cell Transplants From HLA Compatible, Related and Unrelated Donors After a Myeloablative Preparative Regimen With Hyperfractionated TBI, Thiotepa and Fludarabine For Adult Patients With Lymphohematopoietic Disorders	NCT00587054	Allogeneic Stem... Leukemia Non-Hodgkins Lymphoblastic L... Myelodysplastic... Paroxysmal Noct...	cytoreductive r...	18 Years - 55 Years	Memorial Sloan Kettering Cancer Center
HSCT for Patients With Fanconi Anemia Using Risk-Adjusted Chemotherapy	NCT02143830	Fanconi Anemia Severe Marrow F... Myelodysplastic... Acute Myelogeno...	Busulfan Cyclophosphamid... Fludarabine rabbit ATG G-CSF Peripheral bloo...	3 Months -	Children's Hospital Medical Center, Cincinnati

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