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

Phase 2

Completed

• Conditions: Adult Acute Myeloid Leukemia With Del(5q); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Childhood Chronic Myelogenous Leukemia; Accelerated Phase Chronic Myelogenous Leukemia; Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Lymphoblastic Leukemia in Remission; Adult Acute Myeloid Leukemia in Remission; Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Childhood Acute Lymphoblastic Leukemia in Remission; Childhood Myelodysplastic Syndromes
• Interventions: Drug: treosulfan; Drug: fludarabine phosphate; Radiation: total-body irradiation; Procedure: peripheral blood stem cell transplantation; Drug: tacrolimus; Procedure: allogeneic bone marrow transplantation; Procedure: allogeneic hematopoietic stem cell transplantation; Drug: methotrexate

• Registration Number: NCT00860574
• Lead Sponsor: Fred Hutchinson Cancer Center

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.

Study Timeline

• Study Start: 2009-02
• Study First Submitted: 2009-03-11
• Study First Submitted QC: 2009-03-11
• Study First Posted: 2009-03-12
• Primary Completion: 2013-02
• Disposition First Submitted: 2017-04-05
• Disposition First Submitted QC: 2017-04-05
• Disposition First Posted: 2017-04-07
• Status Verified: 2021-02
• Results First Submitted: 2021-02-09
• Results First Submitted QC: 2021-02-09
• Results First Posted: 2021-02-26
• Last Update Submitted: 2021-06-17
• Last Update Posted: 2021-06-22

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 96

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

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Treatment (allogeneic transplantation)	total-body irradiation	CONDITIONING REGIMEN: Patients receive fludarabine phosphate 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 PO 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.
Treatment (allogeneic transplantation)	peripheral blood stem cell transplantation	CONDITIONING REGIMEN: Patients receive fludarabine phosphate 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 PO 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.
Treatment (allogeneic transplantation)	allogeneic bone marrow transplantation	CONDITIONING REGIMEN: Patients receive fludarabine phosphate 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 PO 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.
Treatment (allogeneic transplantation)	allogeneic hematopoietic stem cell transplantation	CONDITIONING REGIMEN: Patients receive fludarabine phosphate 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 PO 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.
Treatment (allogeneic transplantation)	treosulfan	CONDITIONING REGIMEN: Patients receive fludarabine phosphate 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 PO 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.
Treatment (allogeneic transplantation)	fludarabine phosphate	CONDITIONING REGIMEN: Patients receive fludarabine phosphate 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 PO 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.
Treatment (allogeneic transplantation)	tacrolimus	CONDITIONING REGIMEN: Patients receive fludarabine phosphate 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 PO 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.
Treatment (allogeneic transplantation)	methotrexate	CONDITIONING REGIMEN: Patients receive fludarabine phosphate 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 PO 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.

Primary Outcome Measures

Name	Time	Method
Non Relapse Mortality (NRM) Incidence	At 6 months	Cumulative incidence of NRM at 6 months. NRM includes all deaths without relapse or disease progression.
Relapse Incidence	At 6 months

Secondary Outcome Measures

Name	Time	Method
Non Relapse Mortality Incidence	1 year after HCT
Overall Survival (OS)	at 2 years
Incidence of Chronic GVHD	at 6 months
Median Donor CD3 + T Lymphocyte Chimerism in Peripheral Blood	Day 28 after HCT	Donor chimerism was evaluated in peripheral blood T cells
Relapse-free Survival	at 2 years
Incidence of Grades II-IV Acute GVHD	at 6 months

Trial Locations

Locations (3)

University of Colorado; 🇺🇸 Denver, Colorado, United States

Oregon Health and Science University; 🇺🇸 Portland, Oregon, United States

Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium; 🇺🇸 Seattle, Washington, United States