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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

Number of Participants Who Developed Chronic GVHD

Number of Participants Who Developed Acute GVHD

Number of Participants Who Engrafted by Day 42

Number of Participants Who Experienced Treatment Related Mortality (TRM) Day 100

Number of Participants Who Experienced Treatment Related Mortality (TRM) Day 200

Number of Participants Who Had ANC Recovery at Day 22

Number of Participants Who Had Relapse of Disease

Number of Participants Who Developed Grade II Acute GVHD

Number of Participants Who Developed Grade III Acute GVHD

Number of Participants Who Developed Mild Chronic GVHD

Number of Participants Who Developed Moderate Chronic GVHD

Number of Participants Who Developed Severe Chronic GVHD

Number of Participants Who Developed Steroid Refractory Acute GVHD

Overall Study

Urinary Tract, Sexual Organs, and Pregnancy Conditions

Hemoglobinuria

Hemoglobinuria, Paroxysmal

Proteinuria

Urination Disorders

Urologic Diseases

Urogenital Diseases

Female Urogenital Diseases

Pregnancy Complications

Female Urogenital Diseases and Pregnancy Complications

Male Urogenital Diseases

Urological Manifestations

Hemolysis

Anemia, Hemolytic

Paroxysmal Nocturnal Hemoglobinuria

Antineoplastic Agents

Antirheumatic Agents

Cyclophosphamide

Immunologic Factors

Antineoplastic Agents, Alkylating

Alkylating Agents

G-CSF mobilized peripheral stem cells and post haplo-identical transplantation cyclophosphamide

This research protocol is therefore designed to evaluate the safety and effectiveness of using an unmanipulated G-CSF mobilized peripheral stem cell allograft from a haploidentical donor and post-transplant cyclophosphamide for patients with SAA, or SAA evolving to MDS, or PNH that has proven to be refractory to conventional immunosuppressive therapy (IST) in patients who lack an HLA-matched donor (sibling/ or matched unrelated donor.

Peripheral Blood Stem Cells

Jennifer A Farren

For more information at the NIH Clinical Center contact Office of Patient Recruitment (OPR)

Background:

Severe aplastic anemia (SAA), and myelodysplastic syndrome (MDS), and paroxysmal nocturnal hemoglobinuria

(PNH) cause serious blood problems. Stem cell transplants using bone marrow or blood plus chemotherapy can help. Researchers want to see if using peripheral blood stem cells (PBSCs) rather than bone marrow cells works too. PBSCs are easier to collect and have more cells that help transplants.

Objectives:

To see how safely and effectively SAA, MDS and PNH are treated using peripheral blood hematopoietic stem cells from a family member plus chemotherapy.

Eligibility:

Recipients ages 4-60 with SAA, MDS or PNH and their relative donors ages 4-75

Design:

Recipients will have:

* Blood, urine, heart, and lung tests
* Scans
* Bone marrow sample

Recipients will need a caregiver for several months. They may make fertility plans and a power of attorney.

Donors will have blood and tissue tests, then injections to boost stem cells for 5-7 days.

Donors will have blood collected from a tube in an arm or leg vein. A machine will separate stem cells and maybe white blood cells. The rest of the blood will be returned into the other arm or leg.

In the hospital for about 1 month, recipients will have:

* Central line inserted in the neck or chest
* Medicines for side effects
* Chemotherapy over 8 days and radiation 1 time
* Stem cell transplant over 4 hours

Up to 6 months after transplant, recipients will stay near NIH for weekly physical exams and blood tests.

At day 180, recipients will go home. They will have tests at their doctor s office and NIH several times over 5 years.

Severe aplastic anemia (SAA),myelodysplastic syndrome (MDS), and paroxysmal nocturnal hemoglobinuria (PNH) 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% of responders will relapse.

Although allogeneic stem cell transplantation (allo-SCT) offers the opportunity of cure, HLA-matched donors are available for only half the patients needing a transplant. Combined haplo-cord transplantation has recently been shown to be a viable transplant option for those patients lacking an HLA matched donor. In our ongoing protocol 08-H-0046, we have utilized this approach in 29 patients with SAA, and SAA evolving to MDS with 27/29 patients having sustained engraftment and achieving transfusion independence. However, engraftment patterns have varied substantially and, in some patients,, cord engraftment was profoundly delayed or never occurred.

Haploidentical peripheral blood stem cell transplantation (haplo-SCT) has the advantage over cord transplantation of immediate allograft availability, higher stem cell doses, and the feasibility of repeating cell collections if necessary for collecting CD34+ cells for stem cells boosts or lymphocytes to treat or prevent disease relapse or infection. Recently, the use of post-transplant cyclophosphamide (Cy) has been shown to be an effective strategy to prevent GVHD in recipients of haploidentical HSCT, but most reports have focused on patients with hematological malignancies. At present, few data exist on the use of haploidentical transplantation using post-transplant cyclophosphamide for patients with aplastic anemia that have ATG-refractory disease and are heavily-transfused and HLA-alloimmunized. These patients are at an exceedingly high-risk for graft rejection compared to other patient populations.

This research protocol is therefore designed to evaluate the safety and effectiveness of using an unmanipulated GCSF mobilized peripheral stem cell allograft from a haploidentical donor and post-transplant cyclophosphamide for patients with SAA,SAA evolving to MDS, or PNH that has proven to be refractory to conventional therapy in patients who lack an HLA-matched donor (sibling/ or matched unrelated donor).

The primary endpoint of the study is chronic GVHD-free survival (defined as the percentage of patients who are alive with no evidence of moderate or severe chronic GVHD at 1-year post-transplant). Secondary endpoints will include engraftment, 100 day and 200-day treatment related mortality (TRM), and standard transplant outcome variables such as non-hematologic toxicity, incidence and severity of acute and chronic GVHD, and relapse of disease. Health related quality of life will also be assessed as secondary outcome measure.

Haplo-identical Transplantation for Severe Aplastic Anemia, Hypo-plastic MDS and PNH Using Peripheral Blood Stem Cells and Post-transplant Cyclophosphamide for GVHD Prophylaxis

evaluate 1 year chronic GVHD-free survival rate (defined by the percentage of patients who are alive with no evidence of moderate or severe chronic GVHD at 1 year) of using G-CSF mobilized peripheral stem cells and post haplo-identical transplantation cyclophosphamide in subjects with severe aplastic anemia or refractory anemia (RA) or SAA subjects

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)
Haplo-identical Transplantation for Severe Aplastic Anemia, Hypo-plastic MDS and PNH Using Peripheral Blood Stem Cells and Post-transplant Cyclophosphamide for GVHD Prophylaxis	NCT03520647	Severe Aplastic... Hypo-Plastic My... Paroxysmal Noct...	Cyclophosphamid... Peripheral Bloo...	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)

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