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Chemotherapy, Total Body Irradiation, Donor Bone Marrow Transplant, and Immunosuppressive Therapy in Treating Patients with Severe Aplastic Anemia

Trial Status: Closed to Accrual

This phase II trial studies how well chemotherapy, total body irradiation, donor bone marrow transplant, and immunosuppressive therapy work in treating patients with severe aplastic anemia. Drugs used in chemotherapy, such as fludarabine phosphate and cyclophosphamide, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving chemotherapy and total-body irradiation before a donor bone marrow transplant helps stop the growth of cells in the bone marrow, including normal blood-forming cells (stem cells) and cancer cells. It may also stop 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 called graft-versus-host disease. Giving immunosuppressive therapy, such as tacrolimus and mycophenolate mofetil, after the transplant may stop this from happening. Giving chemotherapy, total body irradiation, donor bone marrow transplant, and immunosuppressive therapy may work better in treating patients with severe aplastic anemia.

Inclusion Criteria

  • Confirmed diagnosis of SAA (acquired or inherited), either from initial diagnosis or follow-up assessments, defined as: * Bone marrow hypocellularity is required and relative to patient’s age (normocellularity is 100- patient age in years) ** Often marrow cellularity < 50% but with < 30% residual hematopoietic cells may be applied where appropriate at the discretion of the principal investigator (PI) * Two out of three of the following (in peripheral blood): neutrophils < 0.5 x 10^9/L, platelets < 20 x 10^9/L (without transfusions), reticulocyte count < 60 x 10^9/L
  • No suitable fully matched related (6/6 match for human leukocyte antigen [HLA]-A and B at intermediate or high resolution and DRB1 at high resolution using deoxyribonucleic acid [DNA] based typing) donor if under age 25 years
  • DONOR: * HLA haploidentical relative of the patient; a unidirectional mismatch in either the graft versus host or host versus graft direction is considered a mismatch; the donor and recipient must be identical at least one allele (high resolution DNA-based typing) at the following genetic loci: HLA-A, -B, -C, and DRB1 * If patient over age 25 years, may use HLA identical sibling donor * If patient has inherited bone marrow failure syndrome (IBMFS) and clear evidence of same disorder in potential related donors, unrelated donor may be used; unrelated donor must be a 10/10 match using HLA-A, -B, -C, DRB1, and DPB1; unrelated donor may also be used in case of donor specific antibodies to related donors or other clinical causes of unsuitable related donors
  • Patient and/or legal guardian must sign informed consent for BMT
  • The potential donor must be willing to donate bone marrow
  • Left ventricular ejection fraction (LVEF) at rest >= 40%; for patients aged < 13 years, shortening fraction (SF) >= 26% by echocardiogram or LVEF by multigated acquisition scan (MUGA) may be used
  • Total bilirubin < 3.0 x the upper limit of normal (ULN) for age (patients who have been diagnosed with Gilbert’s disease are allowed to exceed this limit)
  • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 5.0 x ULN for age
  • For patients >= 13.0 years of age at the time of enrollment: estimated creatinine clearance > 50 mL/minute (using the Cockcroft-Gault formula and actual body weight)
  • For patients >= 1.0 year of age but < 13.0 years of age at the time of enrollment: glomerular filtration rate (GFR) estimated by the updated Schwartz formula >= 90 mL/min/1.73 m^2; if the estimated GFR is < 90 mL/min/1.73 m^2, then renal function must be measured by 24-hour creatinine clearance or nuclear GFR, and must be > 50 mL/min/1.73 m^2
  • For patients >= 8 years of age (or otherwise able to complete pulmonary function testing per established American Thoracic Society standards), diffusing capacity of the lungs for carbon monoxide (DLCO) (corrected/adjusted for hemoglobin) > 40% and forced expiratory volume in one second (FEV1) > 50% predicted (without administration of bronchodilator) and forced volume vital capacity (FVC) > 50% predicted
  • For patients < 8 years of age unable to perform pulmonary function tests (PFTs) due to age or developmental ability: (1) no evidence of dyspnea at rest and (2) no need for supplemental oxygen and (3) oxygen (O2) saturation > 92% on room air
  • Karnofsky or Lansky performance status >= 70%
  • Females and males of childbearing potential must agree to practice 2 effective methods of contraception at the same time, or agree to abstinence

Exclusion Criteria

  • Patient with previous administration of immunosuppressive therapy for SAA
  • Patients with Fanconi anemia; at a minimum, the diagnosis of Fanconi anemia must be excluded by diepoxybutane (DEB) or equivalent testing on peripheral blood or marrow in patients younger than 30 years of age; (additional mutational testing may have been performed in a clinical or research capacity on a per patient basis but is not considered an exclusion criteria)
  • Clonal cytogenetic abnormalities consistent with pre-myelodysplastic syndrome (pre-MDS) or MDS on marrow examination (e.g. monosomy 7)
  • Presence of anti-donor HLA antibodies (positive anti-donor HLA antibody is defined as a positive cross-match test of any titer by complement-dependent cytotoxicity or flow cytometric testing or the presence of anti-donor HLA antibody to the high expression loci HLA-A, B, C, or DRB1 with mean fluorescence intensity [MFI] > 1000 by solid phase immunoassay)
  • Prior allogeneic stem cell transplant
  • Prior solid organ transplant
  • Uncontrolled bacterial, viral, or fungal infection at the time of enrollment; uncontrolled is defined as currently taking medication and with progression or no clinical improvement on adequate medical treatment
  • Seropositivity for the human immunodeficiency virus (HIV)
  • Active hepatitis B or C determined by serology and/or nucleic acid testing (NAT)
  • Female patients who are diagnosed as pregnant by beta human chorionic gonadotropin (hCG) testing (per institutional practice) or breast-feeding
  • Prior malignancies except resected basal cell carcinoma or treated cervical carcinoma in situ; cancer treated with curative intent > 5 years previously will be allowed; cancer treated with curative intent =< 5 years previously will not be allowed unless approved by the PI


Johns Hopkins University / Sidney Kimmel Cancer Center
Contact: Amy Elizabeth DeZern
Phone: 410-502-7208


I. To determine if it is feasible for previously untreated severe aplastic anemia (SAA) patients to be transplanted using non-myeloablative conditioning and post transplantation cyclophosphamide.


I. To estimate overall survival at one year.

II. To estimate full donor chimerism by day 60.

III. To estimate the cumulative incidence of non–relapse-related mortality following transplant.

IV. To estimate the incidences of primary and secondary graft failure following transplant.

V. To estimate the cumulative incidences of grade II-IV and grade III-IV acute graft versus-host disease (GVHD).

VI. To estimate the cumulative incidence of chronic graft versus-host disease (GVHD).

VII. To estimate the cumulative incidence of absolute neutrophil count (ANC) and platelet recovery.

VIII. To estimate GVHD free relapse free survival (GRFS).

IX. To summarize major transplant related toxicities and to estimate transplant related mortality (TRM).


Patients receive anti-thymocyte globulin intravenously (IV) over 6 hours on days -9 and over 4 hours on days -8 and -7, fludarabine phosphate IV on days -6 to -2, and cyclophosphamide IV over 1-2 hours on days -6, -5, 3, and 4. Patients undergo total body irradiation (TBI) on day -1 and bone marrow transplantation (BMT) on day 0. Patients also receive tacrolimus IV or orally (PO) on days 5-365 and mycophenolate mofetil PO thrice daily (TID) or IV on days 5-35.

Patients are followed up at 1, 2, 3, 4, 8, and 12 weeks, at 6 months, and 1 year after BMT.

Trial Phase Phase II

Trial Type Treatment

Lead Organization
Johns Hopkins University / Sidney Kimmel Cancer Center

Principal Investigator
Amy Elizabeth DeZern

  • Primary ID J1688
  • Secondary IDs NCI-2016-01351, IRB00107139, CRMS-64588
  • ID NCT02833805