Optimizing Cord Blood and Haploidentical Aplastic Anemia Transplantation (CHAMP) (BMT CTN #1502)

Purpose

Acquired SAA is a rare bone marrow failure disorder with an estimated annual incidence of 2 cases per million and with over 600 new cases in the United States each year. A major challenge in treating acquired SAA is the management of patients who are refractory to immunosuppressant therapy (IST) or have relapsed after IST. HSCT is the only curative option for these patients but many are ineligible because they lack a suitable donor.

The Blood and Marrow Transplant Clinical Trials Network (BMT CTN) seeks to increase options for these patients by using novel therapeutic strategies (optimized preparative regimens and targeted antithymocyte globulin (ATG) pharmacokinetics (PK)) to expand the donor pool utilizing UCB for transplantation. The goal of this protocol is to test whether optimized approaches using two alternative donor sources will achieve acceptable outcomes in SAA patients. Ideally, a direct comparison of the two approaches would allow us to determine a best approach.

However, given 1) the rarity of the disease, 2) the fact that different centers often prefer different stem cell sources, and 3) the fact that most comparisons of alternative donor stem cell sources have shown very similar outcomes, this protocol allows both approaches to be performed, but there are no planned comparisons of outcomes between the two cohorts.

Treatment

Unrelated Cord Blood HSCT:
The unrelated cord blood arm will be treated with a preparative regimen of an individualized dose of Antithymocyte Globulin (ATG) (dose calculated based on actual weight and absolute lymphocyte count), fludarabine (150 mg/m^2), cyclophosphamide (100 mg/kg), and low dose total body irradiation (TBI) (200 cGy) before undergoing the UCB HSCT. GVHD prophylaxis will be tacrolimus combined with mycophenolate mofetil (MMF). G-CSF will be administered post-transplant.

Haplo Bone Marrow HSCT
The haplo bone marrow arm will be treated with a preparative regimen of Antithymocyte Globulin (ATG) (4.5 mg/kg), fludarabine (150 mg/m^2), cyclophosphamide (29 mg/kg), and low dose total body irradiation (TBI) (200 cGy) before undergoing the haplo HSCT. GVHD prophylaxis will be with post-HSCT cyclophosphamide (100 mg/kg), tacrolimus, and mycophenolate mofetil (MMF). G-CSF will be administered post-transplant.

Eligibility

  • Patient is < 75 years of age at time of enrollment.
  • Confirmed diagnosis of SAA, either from initial diagnosis or follow-up assessments, defined as:

- Bone marrow cellularity < 25% or marrow cellularity < 50% but with < 30% residual hematopoietic cells.
- Two out of three of the following (in peripheral blood): Neutrophils < 0.5 x10^9/L, Platelets < 20 x10^9/L, or Reticulocyte count < 20 x10^9/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 DNA-based typing) or unrelated donor (8/8 match for HLA-A, B, C, and DRB1 at high resolution using DNA-based typing) available. Search for an unrelated donor and enrollment on this protocol may be abandoned if the clinical situation dictates an urgent transplant in the best medical judgment of the treating provider. The definition of clinical urgency may include a low likelihood of identifying a suitable matched unrelated donor within 6-8 weeks from referral and the medical need to choose a donor without further delay beyond that time.
  • Failed at least one trial of immunosuppressive therapy (IST) by being refractory or having relapsed. IST could have included ATG based regimens, calcineurin inhibitors and/or other higher dose therapy directed at the treatment of primary SAA.
  • Available alternative donor:

- Cord blood unit(s) must be matched at a minimum of 4/6 to the recipient at HLA-A and B at low resolution using DNA-based typing and HLA-DRB1 at high resolution using DNA-based typing. Based on a published report from Eurocord, for single unit transplantation, the single unit pre-cryopreserved total nucleated cell (TNC) dose must be a minimum of 4.0 x10^7/kg recipient weight. For double cord transplants, each unit must have a minimum of 1.5 x10^7/kg pre-cryopreserved TNC and a minimum total of 4.0 x10^7/kg (sum of unit 1 and unit 2). For non-red blood cell depleted units, the minimum pre-cryopreserved TNC dose is 2.0 x10^7/kg recipient weight.
or
- HLA haplo first degree relatives of the patient including biological parents, siblings or half siblings, or children with 2, 3, or 4 mismatches using DNA-based typing. 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 a minimum of one allele (at high resolution DNA-based typing) at the following genetic loci: HLA-A, -B, -C, and DRB1.

  • Patient and/or legal guardian must sign informed consent for HSCT.
  • In the haplo cohort, the donor and/or legal guardian must be able to sign informed consent documents.
  • In the haplo cohort, the potential donor must be willing to donate bone marrow.
  • In the haplo cohort, the weight of the haplo donor must be ≥ 20 kg.
  • Adequate organ function
  • Karnofsky or Lansky performance status ≥ 60%.
  • Females and males of childbearing potential must agree to practice 2 effective methods of contraception at the same time or agree to abstinence.

Contact

For additional study information, please reach out to Emma Rosenau:

Age

18 and under
18 to 65
65 and over

Gender

Male
Female

Keywords

Hematopoietic Stem Cell Transplantation

Principal Investigator

John R Wingard, M.D.

Sponsoring Group

Department of Medicine

Department

Department of Medicine

Contact Information

roseeg@ufl.edu

352-294-8938


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