Clinical trial NCT00860574: Treosulfan, Fludarabine Phosphate, and Total-Body Irradiation Before Donor Stem Cell Transplant in Treating Patients With High-Risk Acute Myeloid Leukemia, Myelodysplastic Syndrome, Acute Lymphoblastic Leukemia
Official title: A Multi-Center Study of Conditioning With Treosulfan, Fludarabine and Escalating Doses of TBI for Allogeneic Hematopoietic Cell Transplantation in Patients With Acute Myeloid Leukemia (AML) Myelodysplastic Syndrome (MDS), and Acute Lymphoblastic Leukemia (ALL)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Accelerated Phase Chronic Myelogenous Leukemia
Adult Acute Lymphoblastic Leukemia in Remission
Adult Acute Myeloid Leukemia in Remission
Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities
Adult Acute Myeloid Leukemia With Del(5q)
Adult Acute Myeloid Leukemia With Inv(16)(p13;q22)
Adult Acute Myeloid Leukemia With t(15;17)(q22;q12)
Adult Acute Myeloid Leukemia With t(16;16)(p13;q22)
Adult Acute Myeloid Leukemia With t(8;21)(q22;q22)
Blastic Phase Chronic Myelogenous Leukemia
Childhood Acute Lymphoblastic Leukemia in Remission
Childhood Acute Myeloid Leukemia in Remission
Childhood Chronic Myelogenous Leukemia
Childhood Myelodysplastic Syndromes
Chronic Myelomonocytic Leukemia
de Novo Myelodysplastic Syndromes
Previously Treated Myelodysplastic Syndromes
Recurrent Adult Acute Lymphoblastic Leukemia
Recurrent Adult Acute Myeloid Leukemia
Recurrent Childhood Acute Lymphoblastic Leukemia
Recurrent Childhood Acute Myeloid Leukemia
Secondary Myelodysplastic Syndromes
Untreated Adult Acute Lymphoblastic Leukemia
Untreated Childhood Acute Lymphoblastic Leukemia
Lead sponsor: Fred Hutchinson Cancer Center
Sponsor class: OTHER
Collaborators: name: National Heart, Lung, and Blood Institute (NHLBI)
name: National Cancer Institute (NCI)
First posted: 2009-03-12
Enrollment: 96
Sex: ALL
Maximum age (years): 60
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: This phase II trial is studying how well giving treosulfan together with fludarabine phosphate and total-body irradiation followed by donor stem cell transplant works in treating patients with high-risk acute myeloid leukemia, myelodysplastic syndrome, acute lymphoblastic leukemia. Giving chemotherapy, such as treosulfan and fludarabine phosphate, and total-body irradiation before a donor bone marrow or peripheral blood stem cell transplant helps stop the growth of cancer cells. It may also stop the patient's immune system from rejecting the donor's stem cells. The donated stem cells may replace the patient's immune cells and help destroy any remaining cancer cells (graft-versus-tumor effect). Sometimes the transplanted cells from a donor can also make an immune response against the body's normal cells. Giving tacrolimus and methotrexate before and after transplant may stop this from happening

Detailed description: PRIMARY OBJECTIVES:

I. Decrease the incidence of relapse to \< 15% at 6 month post transplant in patients with high risk acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) transplanted from related or unrelated donors, without unacceptably increasing toxicity (10% non-relapse mortality \[NRM\] at 6 months).

SECONDARY OBJECTIVES:

I. Evaluate the incidence of NRM at 180 days and 1 year after hematopoietic cell transplantation (HCT).

II. Evaluate overall survival (OS) and relapse-free survival (RFS). III. Incidence of grades II-IV acute graft-versus-host disease (GVHD). IV. Incidence of chronic GVHD. V. Donor chimerism on days +28 and +100.

OUTLINE:

CONDITIONING REGIMEN: Patients receive fludarabine phosphate intravenously (IV) over 30 minutes on days -6 to day -2 and treosulfan IV over 2 hours on days -6 to day -4. Patients also undergo total-body irradiation on day 0.

TRANSPLANTATION: Patients undergo allogeneic peripheral blood stem cell transplantation or bone marrow transplantation on day 0.

GVHD PROPHYLAXIS: Patients receive tacrolimus IV continuously or orally (PO) twice daily (BID) on days -1 to 56, followed by a taper until day 180 in the absence of GVHD. Patients also receive methotrexate IV on days 1, 3, 6, and 11.

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

Eligibility criteria: Inclusion Criteria:

* Acute myeloid leukemia (AML):

  * All AML patients beyond 1st remission;
  * Intermediate or high risk AML patients (based on South West Oncology Group \[SWOG\] cytogenetic criteria) in 1st complete remission
* Myelodysplastic syndrome (MDS)
* Other myeloid malignancies as chronic myelogenous leukemia (CML), CML accelerated phase, CML blast crisis, chronic myelomonocytic leukemia (CMML) (to be approved by patient care conference \[PCC\])
* With Karnofsky Index or Lansky Play-Performance Scale \> 70% on pre-transplant evaluation
* Able to give informed consent (if \> 18 years), or with a legal guardian capable of giving informed consent (if \< 18 years)
* Previous autologous or allogeneic HCT is allowed
* Donors must be:

  * Human leukocyte antigen (HLA)-identical related donors or
  * Unrelated donors matched for HLA-A, B, C, DRB1, and DQB1 defined by high resolution deoxyribonucleic acid (DNA) typing or mismatched for one HLA allele, except for HLA-C where no mismatch is allowed
  * Able to undergo peripheral blood stem cell collection or bone marrow harvest
  * In good general health, with a Karnofsky or Lansky Play Performance score \> 90%
  * Able to give informed consent (if \> 18 years), or with a legal guardian capable of giving informed consent (if \< 18 years)
* Acute lymphoblastic leukemia (ALL): all ALL patients not eligible for other protocols

Exclusion Criteria:

* Receiving umbilical cord blood
* With impaired cardiac function as evidenced by ejection fraction \< 35% or cardiac insufficiency requiring treatment or symptomatic coronary artery disease
* With impaired pulmonary function as evidenced by partial pressure of oxygen (pO2) \< 70 mm Hg and diffusing capacity of the lung for carbon monoxide (DLCO) \< 70% of predicted or pO2 \< 80 mm Hg and DLCO \< 60% of predicted; or receiving supplementary continuous oxygen
* With impaired renal function as evidenced by creatinine-clearance \< 50% for age, weight, height or serum creatinine \> 2x upper normal limit or dialysis-dependent
* With hepatic dysfunction as evidenced by total bilirubin or aspartate aminotransferase (AST) or alanine aminotransferase (ALT) \> 2.0 x upper normal limit or evidence of synthetic dysfunction or severe cirrhosis
* With active infectious disease requiring deferral of conditioning, as recommended by an Infectious Disease specialist
* With human immunodeficiency virus (HIV)-positivity or active infectious hepatitis because of possible risk of lethal infection when treated with immunosuppressive therapy
* With central nervous system (CNS) leukemic involvement not clearing with intrathecal chemotherapy and/or cranial radiation prior to initiating conditioning (day -6)
* With life expectancy severely limited by diseases other than malignancy
* Women who are pregnant or lactating because of possible risk to the fetus or infant
* With known hypersensitivity to treosulfan and/or fludarabine
* Receiving another experimental drug within 4 weeks before initiation of conditioning (day -6)
* Unable to give informed consent (if \> 18 years) or with a legal guardian (if \< 18 years) unable to give informed consent
* Ineligible donors will be those:

  * Deemed unable to undergo marrow harvesting or PBSC mobilization and leukapheresis
  * Who are HIV-positive
  * With active infectious hepatitis
  * Females with a positive pregnancy test
  * Unable to give informed consent (if \> 18 years) or with a legal guardian (if \< 18 years) unable to give informed consent

Primary outcomes:
measure: Relapse Incidence
timeFrame: At 6 months
measure: Non Relapse Mortality (NRM) Incidence
timeFrame: At 6 months
Secondary outcomes:
measure: Non Relapse Mortality Incidence
timeFrame: 1 year after HCT
measure: Overall Survival (OS)
timeFrame: at 2 years
measure: Relapse-free Survival
timeFrame: at 2 years
measure: Incidence of Grades II-IV Acute GVHD
timeFrame: at 6 months
measure: Incidence of Chronic GVHD
timeFrame: at 6 months
measure: Median Donor CD3 + T Lymphocyte Chimerism in Peripheral Blood
timeFrame: Day 28 after HCT
Other outcomes:
Locations:
city: Denver
country: United States
facility: University of Colorado
state: Colorado
city: Portland
country: United States
facility: Oregon Health and Science University
state: Oregon
city: Seattle
country: United States
facility: Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium
state: Washington
Study officials:
affiliation: Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium
name: Boglarka Gyurkocza
role: PRINCIPAL_INVESTIGATOR
References: