• CD34+ cell dose and CD3+ cell dose [ Designated as safety issue: No ]
• Degrees of UCB, haploidentical related donor CD34+ cell, and recipient chimerism in T-lymphocyte, NK cell, and myeloid lineages assessed by PCR of short tandem repeats (STRs) [ Designated as safety issue: No ]
• ANC recovery rate (ANC ≥ 500 cells/µL) on day 22 [ Designated as safety issue: Yes ]
• Days to an UCB-derived ANC of 500 cells/µL and 1,000 cells/µL [ Designated as safety issue: Yes ]
• Platelet recovery (days to a platelet count of 20,000/mm³ and 50,000/mm³ and days to transfusion independence) [ Designated as safety issue: Yes ]
• Red blood cell recovery (days to transfusion independence) [ Designated as safety issue: Yes ]
• Incidence and severity of acute graft-vs-host disease (GVHD) [ Designated as safety issue: Yes ]
• Incidence and severity of chronic GVHD [ Designated as safety issue: Yes ]
• Graft failure (loss of the graft ) as measured by chimerism [ Designated as safety issue: No ]
• Non-hematological effects attributable to the preparative regimen [ Designated as safety issue: No ]
• Disease progression or relapse [ Designated as safety issue: No ]
• Transplant-related mortality before and after day 100 and day 200 [ Designated as safety issue: Yes ]
• Disease free-survival and overall survival [ Designated as safety issue: No ]

• CD34+ cell dose and CD3+ cell dose [ Designated as safety issue: No ]
• Degrees of UCB, haploidentical related donor CD34+ cell, and recipient chimerism in T-lymphocyte, NK cell, and myeloid lineages assessed by PCR of short tandem repeats (STRs) [ Designated as safety issue: No ]
• ANC recovery rate (ANC ≥ 500 cells/µL) on day 22 [ Designated as safety issue: Yes ]
• Days to an UCB-derived ANC of 500 cells/µL and 1,000 cells/µL [ Designated as safety issue: Yes ]
• Platelet recovery (days to a platelet count of 20,000/mm³ and 50,000/mm³ and days to transfusion independence) [ Designated as safety issue: Yes ]
• Red blood cell recovery (days to transfusion independence) [ Designated as safety issue: Yes ]
• Incidence and severity of acute graft-vs-host disease (GVHD) [ Designated as safety issue: No ]
• Incidence and severity of chronic GVHD [ Designated as safety issue: No ]
• Graft failure (loss of the graft ) as measured by chimerism [ Designated as safety issue: No ]
• Non-hematological effects attributable to the preparative regimen [ Designated as safety issue: No ]
• Disease progression or relapse [ Designated as safety issue: No ]
• Transplant-related mortality before and after day 100 and day 200 [ Designated as safety issue: Yes ]
• Disease free-survival and overall survival [ Designated as safety issue: No ]

RATIONALE: Giving chemotherapy, antithymocyte globulin, and total-body irradiation before a donor umbilical cord blood transplant and a donor peripheral stem cell transplant helps stop the growth of abnormal cells. It also stops the patient's immune system from rejecting the donor's stem cells. When the healthy stem cells from a donor are infused into the patient they may help the patient's bone marrow make stem cells, red blood cells, white blood cells, and platelets. Sometimes the transplanted cells from a donor can make an immune response against the body's normal cells. Giving tacrolimus, mycophenolate mofetil, and prednisone or methylprednisolone before and after transplant may stop this from happening.

PURPOSE: This phase II trial is studying how well giving cyclophosphamide together with fludarabine, antithymocyte globulin, and total-body irradiation followed by donor umbilical cord blood transplant and donor peripheral stem cell transplant works in treating patients with severe aplastic anemia or myelodysplastic syndromes associated with severe neutropenia that has not responded to immunosuppressive therapy.

OBJECTIVES:

Primary

• To evaluate the potential of > 80% of patients with severe aplastic anemia or myelodysplastic syndromes associated with severe neutropenia refractory to immunosuppressive therapy to achieve engraftment of the umbilical cord blood (UCB) unit (defined as UCB-derived absolute neutrophil count [ANC] ≥ 500 cells/μL) by day 42 when treated with a nonmyeloablative conditioning regimen comprising cyclophosphamide, fludarabine phosphate, anti-thymocyte globulin, and total-body irradiation followed by donor umbilical cord blood transplantation and haploidentical related donor CD34+ peripheral blood stem cell transplantation.

Secondary

• To evaluate ANC recovery rate (ANC ≥ 500 cells/μL) on day 22.
• To evaluate the safety of this novel transplant regimen (non-hematologic toxicities).
• To evaluate treatment-related mortality on day 100 and day 200.
• To determine the incidence and severity of acute and chronic graft-versus-host disease (GVHD) following treatment with this transplant regimen.

OUTLINE:

• Nonmyeloablative preparative conditioning regimen: Patients receive cyclophosphamide IV over 60 minutes once daily on days -7 and -6, fludarabine phosphate IV over 30 minutes once daily on days -5 to -1, and anti-thymocyte globulin IV over 4 hours once daily on days -5 to -2. Patients also receive a single dose of total-body irradiation over 30 minutes on day -1.
• Donor stem cell transplantation: Patients undergo donor umbilical cord blood transplantation and haploidentical related donor CD34+ peripheral blood stem cell transplantation on day 0.
• Graft-versus-host-disease (GVHD) prophylaxis: Patients receive tacrolimus IV continuously over 24 hours or orally twice daily beginning on day -4 and continuing for at least 6 months and mycophenolate mofetil IV or orally twice daily beginning on day 0 and continuing for 100 days. Patients also receive oral prednisone or methylprednisolone IV beginning on day -5 (prior to the first dose of ATG) and continuing until day 19.

After completion of study treatment, patients are followed every 3 months for 3 years, every 6 months for 2 years, and then annually thereafter.

• Leukemia
• Myelodysplastic Syndromes
• Precancerous/Nonmalignant Condition

• Biological: anti-thymocyte globulin
• Drug: cyclophosphamide
• Drug: fludarabine phosphate
• Drug: methylprednisolone
• Drug: mycophenolate mofetil
• Drug: prednisone
• Drug: tacrolimus
• Procedure: in vitro-treated peripheral blood stem cell transplantation
• Procedure: nonmyeloablative allogeneic hematopoietic stem cell transplantation
• Procedure: umbilical cord blood transplantation
• Radiation: total-body irradiation

DISEASE CHARACTERISTICS:

• Diagnosed of 1 of the following:

  • Severe aplastic anemia characterized by all of the following:

    • Bone marrow cellularity < 30% (excluding lymphocytes)
    • Transfusion dependence for platelets and/or RBCs
    • Neutropenia (absolute neutrophil count [ANC] < 500 cells/μL)
    • Failed at least two forms of immunosuppressive therapy

  • Myelodysplastic syndromes characterized by all of the following:

    • Refractory anemia (RA) OR RA with ringed sideroblasts (RARS)
    • Neutropenia (ANC < 500 cells/μL)
    • Refractory to one or more lines of therapy
    • History of 1 or more opportunistic infections related to neutropenia

• At least one HLA-haploidentical (≥ 3/6 HLA matched) related donor (2-75 years old) available

  • No HLA identical or 5/6 HLA-matched related stem cell donor available
  • At least 2 x 10^6 CD34+ cells/kg required from haploidentical related donor
  • No haploidentical related donor with sickling hemoglobinopathies, including HbSS, HbAS, or HbSC

• At least one 4/6 HLA-matched (HLA-A, B, and DR loci) umbilical cord blood (UCB) unit from the National Marrow Donor Program available

  • UCB unit must contain a minimum total nucleated cells (TNC) (prior to thawing) of ≥ 1.5 x 10^7 cells/kg of recipient body weight

    • UCB unit must contain ≥ 1.7 x 10^5 CD34+ cells/kg (prior to thawing) if the minimum criterion of TNC is not met
• Not deemed to be a candidate for a 6/6 HLA-matched related or unrelated stem cell transplantation

PATIENT CHARACTERISTICS:

• ECOG performance status 0-1
• Transaminases ≤ 5 times upper limit of normal
• Serum bilirubin ≤ 4 mg/dL
• Creatinine clearance ≥ 50 mL/min
• DLCO ≥ 40% predicted
• Left ventricular ejection fraction ≥ 40% by ECHO OR ≥ 30% by MUGA
• HIV-negative
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception
• No major anticipated illness or organ failure incompatible with survival from transplant
• No severe psychiatric illness or mental deficiency sufficiently severe as to make compliance with the transplant regimen unlikely and make informed consent impossible
• No active infection not adequately responding to appropriate therapy
• No history of a malignant disease that is liable to relapse or progress within 5 years

PRIOR CONCURRENT THERAPY:

• At least 45 days since prior immunosuppressive therapy with horse anti-thymocyte globulin (ATG) or rat-ATG