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Stem cell recipients received co-infusion of unrelated umbilical cord blood (UCB) and haploidentical CD34+ cells from a related donor following non-myeloablative conditioning for neutropenic patients with severe aplastic anemia (SAA) or myelodysplastic syndrome (MDS) with refractory anemia (RA)

unrelated umbilical cord blood will be co-infused with haploidentical CD34-selected cells from a related donor for treatment of severe aplastic anemia and myelodysplastic syndrome.

Umbilical Cord Blood

Richard W Childs, M.D.

This study will evaluate the safety and effectiveness of treating patients with severe aplastic anemia (SAA) or myelodysplastic syndrome (MDS) with both peripheral blood stem cells from a family member and umbilical cord blood stem cells from an unrelated donor.

Patients with SAA or MDS for whom other treatments have failed or are not available may be eligible for this study. Candidates may not have a tissue-matched sibling or matched unrelated donor and must have a family member who is a partial tissue type match.

Participants undergo the following tests and procedures:

* Insertion of a central intravenous (IV) line (plastic tube) into a large vein. The tube is used for giving the donated stem cells and antibiotics and other medicines, for transfusions of red blood cells and platelets, and for collecting blood samples.
* Preparatory chemotherapy (fludarabine, cyclophosphamide and anti-thymocyte globulin) and total body irradiation to suppress immunity and prevent rejection of the donated cells.
* Infusion of the donated stem cells and umbilical cord cells.
* Immune suppression with the drugs tacrolimus, mycophenolate mofetil and prednisone to prevent rejection of the donated cells and to prevent graft-versus-host disease (GVHD), a complication of stem cell transplants in which the donors immune cells destroy the patients healthy tissues.

The average hospital stay after stem cell transplantation is 3 to 4 weeks. Patients return for frequent follow-up visits for the first 2 to 4 months after transplantation. Once the patient returns home, his or her referring physician is asked to send results of any laboratory testing to the NIH researchers at least every 3 months for the first 3 years and annually thereafter. Patient follow-up visits are scheduled at NIH at 1, 2, 3, 4 and 5 years after transplantation to monitor for signs of disease or post-transplantation complications, such as infection or GVHD. After 5 years, participants are offered the opportunity to enroll in NHLBIs long-term evaluation and follow-up care protocol.

Severe aplastic anemia (SAA) and myelodysplastic syndrome (MDS) are life-threatening bone marrow disorders. For SAA patients, long term survival can be achieved with immunosuppressive treatment. However, of those patients treated with immunosuppressive therapy, one quarter to one third will not respond, and about 50 percent of responders will relapse.

Allogeneic bone marrow transplantation from either HLA-matched sibling or matched unrelated donor cures about 70 percent of patients with SAA and 30-60 percent of patients with MDS. Unfortunately, most patients with these disorders are not suitable candidates for hematopoietic stem cell transplantation (HSCT) due to advanced age or lack of a histocompatible donor. For such patients, transplantation using unrelated cord blood (UCB) has been shown to be a reasonable alternative transplant strategy. The advantage to UCB transplant is the ease and rapidity of availability, requirement of less than perfect HLA match, and lower rates of graft versus host disease compared to mismatched bone marrow or peripheral blood stem cell transplants. The major disadvantage of UCB transplantation in adults is the limited number of nucleated cells contained within the cord unit resulting in prolonged neutropenia and failure of engraftment which contributes to infection and transplant related mortality (TRM). In order to harness the advantage of UCB availability and to overcome the disadvantage of delayed neutrophil recovery, we propose to test whether co-administration of unrelated umbilical cord blood and a relatively low number of highly purified haploidentical peripheral blood CD34+ cells from a related donor might promote rapid engraftment and reduce TRM secondary to prolonged neutropenia associated with conventional umbilical cord blood transplant (UCBT).

This research protocol is therefore designed to evaluate the safety and effectiveness of co-infusion of unrelated umbilical cord blood and haploidentical CD34 plus cells from a related donor following nonmyeloablative conditioning for neutropenic patients with SAA or MDS with refractory anemia (RA) that has proven to be refractory to medical therapy. Subjects will receive a novel non-myeloablative immunosuppressive conditioning regimen of cyclophosphamide, fludarabine, horse ATG (antithymocyte globulin) and one dose of total body irradiation (200cGy) followed by an infusion of the allografts. The haploidentical stem cell product will be T-cell depleted and enriched for CD34 plus cells using the Miltenyi CliniMacs system. To reduce TRM secondary to prolonged neutropenia associated with conventional UCB transplantation, haploidentical CD34+ stem cells will be co-infused with a single UCB unit (serologically matched at greater than or equal to 4/6 HLA loci).

The primary endpoint is donor engraftment by day 42 (defined as an ANC of greater than 500 from either the haplo donor, the cord, or both combined). Secondary endpoints will include standard transplant outcome variables such as non-hematological toxicities, incidence and severity of acute and chronic GVHD, and relapse of disease. We will also evaluate ANC recovery (ANC greater than 500 cells/microl) at day 22, and 100 day and 200 day treatment related mortality (TRM) of this novel transplant approach. Health related quality of life will also be assessed pre-transplant 30 and 100 days post-transplant, and every 6 months until 5 years post transplant.

Stem Cell Transplant Using Peripheral and Cord Blood Stem Cells to Treat Severe Aplastic Anemia and Myelodysplastic Syndrome

Co-Infusion of Umbilical Cord Blood and Haploidentical CD34+ Cells Following Nonmyeloablative Conditioning as Treatment for Severe Aplastic Anemia and MDS Associated With Severe Neutropenia Refractory to Immunosuppressive Therapy

Participants who reached engraftment by day 42 (±3 days) defined as an absolute neutrophil count (ANC) of U\> U500 cells/µl

Participants who developed chronic graft-versus-host disease (GVHD)

Participants who had acute graft-versus-host disease (GVHD)

Number of participants who experienced treatment related mortality (TRM) by day 100

Number of participants who experienced treatment related mortality (TRM) by day 200

Number of participants who reached engraftment by day 22 (±3 days) defined as an ANC of U\> U500 cells/µl

Participants who had experienced relapse of disease

Participants who developed Grade II Acute GVHD as defined by CIMBTR criteria for Organ Stages of Acute GVHD.

Stage II Acute GVHD: Skin - rash on 25-50 percent body surface area; Liver - Total Bilirubin 3.1-6.0 mg/dL; Lower GI - Diarrhea 1001-1500 mL/day.

Grade I GVHD is characterized as mild disease, grade II GVHD as moderate, grade III as severe, and grade IV life-threatening.

Participants who developed Grade III Acute GVHD as defined by CIMBTR criteria for Organ Stages of Acute GVHD.

Stage III Acute GVHD: Skin - Rash on \>50% of body surface; Liver - Total Bilirubin 6.1 - 15.0 mg/dL; Lower GI - Diarrhea \> 1500 mL/day

Grade I GVHD is characterized as mild disease, grade II GVHD as moderate, grade III as severe, and grade IV life-threatening.

Participants who developed mild chronic graft vs host disease (GVHD).

Mild chronic GVHD is 2 or fewer organs with no more than score 1 and no lung involvement. Mild disease is associated with a good prognosis whereas severe disease is associated with higher treatment-related mortality and lower survival.

Organs are scored on a 0 to 3 scale from no involvement/no symptoms to severe functional compromise.

Participants who experienced moderate chronic GVHD.

Moderate GVHD is 3 or more organs with score 1, any organ with score 2, or lung with score 1, and usually requires systemic immune-suppressive treatment. Mild disease is associated with a good prognosis whereas severe disease is associated with higher treatment-related mortality and lower survival.

Organs are scored on a 0 to 3 scale from no involvement/no symptoms to severe functional compromise.

Participants who developed severe chronic GVHD.

Severe chronic GVHD is any organ with a score of 3 or lung with a score of 2, and means that substantial organ damage already exists. Mild disease is associated with a good prognosis whereas severe disease is associated with higher treatment-related mortality and lower survival

Organs are scored on a 0 to 3 scale from no involvement/no symptoms to severe functional compromise.

Participants who had developed steroid refractory (not responding to standard steroid therapy) acute GVHD.

National Heart, Lung, and Blood Institute (NHLBI)

Co-infusion of UCB and Haploidentical CD34+ Cells

Age, Categorical

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

Childs, William

All recipients that received unrelated umbilical cord blood (UCB) and haploidentical CD34+ cells

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Stem Cell Transplant Using Peripheral and Cord Blood Stem Cells to Treat Severe Aplastic Anemia and Myelodysplastic Syndrome	NCT00604201	Myelodysplastic... Severe Aplastic...	Umbilical Cord ...	4 Years - 75 Years	National Institutes of Health Clinical Center (CC)
Stem Cell Transplant Using Peripheral and Cord Blood Stem Cells to Treat Severe Aplastic Anemia and Myelodysplastic Syndrome	NCT00604201	Myelodysplastic... Severe Aplastic...	Umbilical Cord ...	4 Years - 75 Years	National Institutes of Health Clinical Center (CC)
Stem Cell Transplant Using Peripheral and Cord Blood Stem Cells to Treat Severe Aplastic Anemia and Myelodysplastic Syndrome	NCT00604201	Myelodysplastic... Severe Aplastic...	Umbilical Cord ...	4 Years - 75 Years	National Institutes of Health Clinical Center (CC)

Spots Global Cancer Trial Database for myelodysplastic syndrome (mds) with refractory anemia (ra)