Donor Bone Marrow Transplant Followed by Chemotherapy in Treating Patients with Relapsed or Refractory Severe Aplastic Anemia or Other Bone Marrow Failure Syndromes

Status: Active


This phase II trial studies donor bone marrow transplant followed by chemotherapy in treating patients with severe aplastic anemia that has come back (relapsed) or does not respond to treatment (refractory), or other bone marrow failure syndromes. Infusing stem cells from a donor into a patient may help the patient’s bone marrow make stem cells, red 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). Currently, treatment to suppress the immune system is given before transplant to stop graft-versus-host disease from happening. Giving treatment to suppress the immune system after the transplant may work better in stopping graft-versus-host disease, and may help increase the number of donors for a patient by allowing people with stem cells that do not exactly match the patient to be donors. Giving treatment to suppress the immune system after the transplant may work better in stopping graft-versus-host disease, and may increase the amount of possible donors for a patient by better preventing graft-versus-host disease.

Eligibility Criteria

Inclusion Criteria

  • Patients with relapsed or refractory SAA or very SAA defined: * Bone marrow (< 25% cellular) * Peripheral cytopenias (at least 2 of 3) ** ANC < 500 per ml ** Platelets < 20,000 per ml ** Absolute reticulocytes (retic) < 60,000 or corrected retic < 1% * Very severe: as above, but ANC < 200 * Disease may be designated as acquired or inherited if previous counts known (these other bone marrow failure disorders that are characterized by aplastic anemia may go by additional names such as dyskeratosis congenita or paroxysmal nocturnal hemoglobinuria [PNH]) * Failed at least one course of immunosuppressive therapy (if presumed acquired disease); patients with inherited disease will be characterized as refractory and do not require immunosuppressive first
  • Good performance status (Eastern Cooperative Oncology Group [ECOG] 0 or 1; Karnofsky and Lansky 70-100)
  • Patients and donors must be able to sign consent forms (or if a minor the parent will sign); donors should be willing to donate
  • Patients must be geographically accessible and willing to participate in all stages of treatment
  • Left ventricular ejection fraction >= 35%, or shortening fraction > 25% (for pediatric patients, a normal ejection fraction is required)
  • Bilirubin =< 3.0 mg/dL (unless due to Gilbert’s syndrome or hemolysis)
  • Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 5 x upper limit of normal (ULN)
  • Forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC) >= 40% of predicted; or in pediatric patients, if unable to perform pulmonary function tests due to young age, oxygen saturation > 92% on room air
  • DONOR: Donors must meet the selection criteria as defined by the Foundation for the Accreditation of Hematopoietic Cell Therapy (FAHCT) and will be screened per the American Association of Blood Banks (AABB) (AABB guidelines and the recipients will be informed of any deviations)
  • DONOR: Weight >= 20 kg and patient or guardian able to provide consent
  • DONOR: HLA mismatched or haploidentical related donors (including 1st degree relatives and half siblings) * The donor and recipient must be identical at least one allele of each of the following genetic loci: HLA-A, HLA-B, HLA-Cw, HLA-DRB1, and HLA-DQB1; a minimum match of 5/10 is therefore required, and will be considered sufficient evidence that the donor and recipient share one HLA haplotype
  • DONOR: Matched unrelated donors * Unrelated volunteer donor matched for HLA-A, -B, -C and -DRB1 defined by high resolution molecular typing ** Mismatched unrelated volunteer donors may be considered if no other suitable donor is available
  • DONOR: When more than one donor is available, the donor with the lowest number of HLA allele mismatches will be chosen, unless there is HLA cross-match incompatibility or a medical reason to select otherwise, in which case donor selection is the responsibility of the principal investigator (PI), in consultation with the immunogenetics laboratory; in cases where there is more than one donor with the least degree of mismatch, donors will be selected based on the most favorable combination of (i) HLA compatibility in cross-match testing and (ii) ABO compatibility; will prioritize the lowest number of mismatches in the host-versus-graft (HVG) direction (to potentially minimize graft rejection risk)
  • DONOR: Donor must be medically, socially, and psychologically fit to donate
  • DONOR: HLA-identical sibling
  • DONOR: For a partially HLA-mismatched transplant, the patient must lack antibodies against donor HLA molecules; specifically, complement dependent cytotoxicity and flow cytometric crossmatch assays must be negative, and the mean fluorescence intensity (MFI) of any anti-donor HLA antibody by solid phase immunoassay should be < 3000; consult with Immunogenetics for the clinical significance of any anti-donor antibody; desensitization to remove anti-donor antibody should only be performed for patients who have no other donor options
  • DONOR: If there is more than one donor with the least amount of HVG allele mismatches, the following prioritization will be used: (will always minimize HVG mismatch as highest priority) * ABO compatibility (in order of priority) ** Compatible or minor ABO incompatibility ** Major ABO incompatibility * Cytomegalovirus (CMV) status ** The CMV status of the pair donor-recipient is frequently employed to select a potential donor; this is a controversial issue and the data available is somewhat limited; the following guidelines are recommended: *** For a CMV seronegative recipient, use a CMV seronegative donor *** For a CMV seropositive recipient, use a CMV seropositive donor * In CMV- patients with CMV+ stem-cell donors, primary CMV infection/reactivation develops in about 30%; data from the European Registry shows the following: seropositive patients receiving grafts from CMV+ HLA-identical sibling donors had the same survival as patients grafted from CMV- donors; however, matched unrelated donor (MUD) recipients receiving grafts from CMV+ donors had an improved 5-year survival, an improved event-free survival, and a reduced transplant-related mortality; there was no influence on the relapse incidence; the effects of donor CMV status remained in multivariate analyses; the effect of donor status was different among different disease categories; in patients with chronic myelogenous leukemia, T-cell depletion abrogated the beneficial effect of donor status, suggesting that the effect is mediated through transfer of donor immunity; these data suggest that donor CMV status influences outcome of unrelated stem cell transplant (SCT)
  • DONOR: ABO compatibility (in order of priority) * Compatible or minor ABO incompatibility * Major ABO incompatibility
  • DONOR: The cytomegalovirus (CMV) status of the pair donor-recipient is frequently employed to select a potential donor; the following guidelines are recommended: * For a CMV seronegative recipient, use a CMV seronegative donor * For a CMV seropositive recipient, use a CMV seropositive donor
  • DONOR: Donor parity and sex mismatch, have also been associated with an increased risk of acute GVHD (aGVHD) and decreased survival in some but not all studies; donor age and weight should be also taken into consideration * Suggestions (in no order of priority): ** Younger (18 years of age or older) and lighter donors should be preferred * If all else is equal, male donors may be preferred over nulliparous female donors who may be preferred over multiparous female donors * Other factors such as donor age and health history will be integrated into the donor selection process per standard practice and may be prioritized over HLA, ABO and CMV status; children donors may be used if appropriate

Exclusion Criteria

  • Patients will not be excluded on the basis of sex, racial or ethnic background
  • Prior transfusions from selected donor
  • Women of childbearing potential who currently are pregnant (human chorionic gonadotropin positive [HCG+]) or who are not practicing adequate contraception
  • Patients who have any debilitating medical or psychiatric illness that would preclude their giving informed consent or their receiving optimal treatment and follow up
  • Uncontrolled viral, bacterial, or fungal infections (human immunodeficiency virus [HIV] infection permitted if viral load undetectable)

Locations & Contacts


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


Children's Hospital of Wisconsin
Status: Active
Contact: Monica S. Thakar
Phone: 414-955-7546
Medical College of Wisconsin
Status: Active
Contact: David Arthur Margolis
Phone: 414-337-7066

Trial Objectives and Outline


I. To determine if it is feasible for severe aplastic anemia (SAA) patients to be transplanted using non-myeloablative conditioning and post transplantation cyclophosphamide with partially human leukocyte antigen (HLA)-mismatched donors.


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).


PREPARATIVE REGIMEN: Patients receive anti-thymocyte thymoglobulin intravenously (IV) over 6 hours on day -9 and over 4 hours on days -8 and -7, fludarabine phosphate IV over 30-60 minutes on days -6 to -2, and cyclophosphamide IV over 1 hour on days -6 and -5. Patients undergo total body irradiation (TBI) on day -1.

BONE MARROW TRANSPLANT: Patients undergo T cell replete partially HLA mismatched or matched unrelated allogeneic bone marrow transplant (BMT) on day 0.

POST-TRANSPLANT CYCLOPHOSPHAMIDE: Patients receive cyclophosphamide IV over 1-2 hours on days 3 and 4.

GVHD PROPHYLAXIS: Beginning at least 24 hours after completion of post-transplant cyclophosphamide, patients receive tacrolimus per institutional standards (patients >= 18 years) or IV every 12 hours (patients < 18 years) from day 5-365 without taper. Dosing may be changed to PO BID once a stable therapeutic level is achieved and the patient can tolerate PO medications. Patients also receive mycophenolate mofetil PO or IV thrice daily (TID) on days 5-35.

After completion of study treatment, patients are followed up yearly.

Trial Phase & Type

Trial Phase

Phase II

Trial Type


Lead Organization

Lead Organization
Johns Hopkins University / Sidney Kimmel Cancer Center

Principal Investigator
Amy Elizabeth DeZern

Trial IDs

Primary ID J1424
Secondary IDs NCI-2014-02148, CIR00006537, CIR00011746 ID NCT02224872