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Allogeneic Hematopoietic Cell Transplantation for Patients With Nonmalignant Inherited Disorders Using a Treosulfan Based Preparative Regimen.

Phase 2
54 Years
Open (Enrolling)
Nonmalignant Neoplasm

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Trial Information

Allogeneic Hematopoietic Cell Transplantation for Patients With Nonmalignant Inherited Disorders Using a Treosulfan Based Preparative Regimen.


I. To evaluate within the limits of a phase II study, the preliminary efficacy, as defined
by engraftment, of a regimen consisting of treosulfan and fludarabine followed by allogeneic
hematopoietic cell transplantation (HCT) in patients with nonmalignant inherited disorders.


I. To evaluate the incidence of non-relapse mortality 200 days and 1 year post-HCT.

II. To evaluate the incidence of grade II-IV acute graft-versus-host disease (GVHD).

III. To evaluate the incidence of chronic GVHD as defined as those patients requiring
systemic immunosuppression.

IV. To evaluate donor chimerism on days +28 and +100.

V. To assess disease response following HCT.

VI. To evaluate immune reconstitution following HCT.

VII. To evaluate the incidence of infections.

VIII. To evaluate overall survival.


CONDITIONING REGIMEN: Patients receive treosulfan intravenously (IV) over 2 hours on days -6
to -4 and fludarabine IV over 1 hour on days -6 to -2. Patients receive anti-thymocyte
globulin IV over 4-6 hours on days -4 to -2. Patients undergoing umbilical cord blood
transplantation will also receive low dose total-body irradiation on day -1.

TRANSPLANTATION: Patients will receive either bone marrow, peripheral blood stem cells
(PBSC), or umbilical cord blood from the donor on day 0. The use of either bone marrow,
PBSC, or umbilical cord blood will depend on the donor status.

IMMUNOSUPPRESSION: Patients will receive a combination of immunosuppressive medications to
try and prevent graft-versus-host disease. If patients undergo bone marrow or PBSC
transplantation, tacrolimus and methotrexate will be used. If patients undergo cord blood
transplantation, cyclosporine and mycophenolate mofetil will be used. In general, patients
will receive immunosuppression until at least 180 days after transplantation; however they
could be on immunosuppression longer if they develop graft versus host disease.

After completion of study treatment, patients are followed up periodically for 5 years.

Inclusion Criteria:

- Patients with a nonmalignant disease treatable by allogeneic HCT

- Patients with a known nonmalignant disease that is not clearly defined will need to
be discussed with the protocol principal investigator (PI) (Dr. Lauri Burroughs) and
potentially the nonmalignant board to determine if they are eligible for HCT on this

- DONOR: Human leukocyte antigens (HLA)-identical related donors or unrelated donors
matched for HLA-A, B, C, DRB1, and DQB1 or mismatched for a single allele at HLA-A,
B, C, DRB1 or a single DQB1 antigen or allele mismatch by high resolution
deoxyribonucleic acid (DNA) typing

- DONOR: Bone marrow is the preferred cell source; PBSC are allowed if donor refuses or
is unable to give marrow

- DONOR, Umbilical Cord Blood: Unit selection is based on the cryopreserved total
nucleated cell (TNC) dose and matching at HLA-A, B antigen level and DRB1 allele
level typing. While HLA-C antigen/allele level typing is not considered in the
matching criteria, if available, may be used to optimize unit selection.

- DONOR, Umbilical Cord Blood: The patient and the cord blood unit(s) must be matched
for at least 4 of 6 loci as defined above.

- DONOR, Umbilical Cord Blood: Selection of two UCB units is allowed to provide
sufficient cell dose

Exclusion Criteria:

- Patients with idiopathic aplastic anemia and Fanconi anemia; (patients with aplastic
anemia associated with paroxysmal nocturnal hemoglobinuria [PNH] or inherited marrow
failure syndromes, except Fanconi anemia, will be allowed)

- Patients with impaired cardiac function as evidenced by ejection fraction < 35% (or,
if unable to obtain ejection fraction, shortening fraction of < 26%) or cardiac
insufficiency requiring treatment or symptomatic coronary artery disease; patients
with a shortening fraction < 26% may be enrolled if approved by a cardiologist

- Patients with impaired pulmonary function as evidenced by diffusion capacity of the
lung for carbon monoxide (DLCO) < 50% of predicted (or, if unable to perform
pulmonary function tests, then oxygen [O2] saturation < 92% on room air)

- Patients with impaired renal function as evidenced by creatinine-clearance < 50% for
age, weight, height or serum creatinine > 2X upper normal limit or dialysis-dependent

- Patients with evidence of synthetic dysfunction or severe cirrhosis requiring
deferral of conditioning as recommended by a gastroenterology specialist

- Patients with an active infectious disease requiring deferral of conditioning; as
recommended by an infectious disease specialist

- Patients who are seropositive for human immunodeficiency virus (HIV)

- Females who are pregnant or breast-feeding

- Patients with a known hypersensitivity to treosulfan and/or fludarabine

- Receiving another experimental drug within 4 weeks of initiation of conditioning (day

- DONOR: Deemed unable to undergo marrow harvesting or PBSC mobilization and

- DONOR: HIV-positive

- DONOR: With active infectious hepatitis

- DONOR: Females with a positive pregnancy test

Type of Study:


Study Design:

Allocation: Non-Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Preliminary efficacy as defined by engraftment of a regimen consisting of treosulfan and fludarabine followed by allogeneic HCT in patients with nonmalignant inherited disorders

Outcome Time Frame:

1 year following transplant

Safety Issue:


Principal Investigator

Lauri Burroughs

Investigator Role:

Principal Investigator

Investigator Affiliation:

Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium


United States: Food and Drug Administration

Study ID:




Start Date:

July 2009

Completion Date:

Related Keywords:

  • Nonmalignant Neoplasm
  • nonmalignant diseases nonmalignant inherited disorders primary immunodeficiency diseases primary immune deficiency disorders chronic granulomatous disease IPEX
  • syndrome hemophagocytic lymphohistiocytosis Wiskott Aldrich Syndrome bone marrow failure syndromes Shwachman Diamond Syndrome Dyskeratosis Congenita Diamond
  • Blackfan Anemia inborn errors of metabolism metabolic diseases hemoglobinopathies sickle cell disease thalassemia reduced intensity transplantation
  • hematopoietic cell transplantation bone marrow transplantation umbilical cord blood transplanta
  • Neoplasms



Fred Hutchinson Cancer Research Center/University of Washington Cancer ConsortiumSeattle, Washington  98109
Children's Hospital of WisconsinMilwaukee, Wisconsin  53201
Oregon Health and Science UniversityPortland, Oregon  97201
Monroe Carell Jr. Children's Hospital at VanderbiltNashville, Tennessee  37232