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

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.

• treosulfan (Drug), also known as dihydroxybusulfan, Ovastat, tresulfon: Given IV
• fludarabine phosphate (Drug), also known as 2-F-ara-AMP, Beneflur, Fludara: Given IV
• total-body irradiation (Radiation), also known as TBI: Low dose starting at 2Gy
• peripheral blood stem cell transplantation (Procedure), also known as PBPC transplantation, PBSC transplantation, peripheral blood progenitor cell transplantation, transplantation, peripheral blood stem cell: Given IV per institutional standard practice
• tacrolimus (Drug), also known as FK 506, Prograf: Given IV or PO
• allogeneic bone marrow transplantation (Procedure), also known as bone marrow therapy, allogeneic, bone marrow therapy, allogenic, transplantation, allogeneic bone marrow, transplantation, allogenic bone marrow: Given IV per institutional standard practice
• allogeneic hematopoietic stem cell transplantation (Procedure): Given IV per institutional standard practice
• methotrexate (Drug), also known as amethopterin, Folex, methylaminopterin, Mexate, MTX: Given IV

Primary outcomes

• Relapse Incidence [At 6 months]
• Non Relapse Mortality (NRM) Incidence [At 6 months]: Cumulative incidence of NRM at 6 months. NRM includes all deaths without relapse or disease progression.

Secondary outcomes

• Non Relapse Mortality Incidence [1 year after HCT]
• Overall Survival (OS) [at 2 years]
• Relapse-free Survival [at 2 years]
• Incidence of Grades II-IV Acute GVHD [at 6 months]
• 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

Sex: All, ages: any to 60 Years

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

Participant flow

Outcome results

• Relapse Incidence (Primary), Count of participants, Participants: Treatment (Allogeneic Transplantation) 18
• Non Relapse Mortality (NRM) Incidence (Primary), Count of participants, Participants: Treatment (Allogeneic Transplantation) 6
• Non Relapse Mortality Incidence (Secondary), Count of participants, Participants: Treatment (Allogeneic Transplantation) 6
• Overall Survival (OS) (Secondary), Count of participants, Participants: Treatment (Allogeneic Transplantation) 71
• Relapse-free Survival (Secondary), Count of participants, Participants: Treatment (Allogeneic Transplantation) 62
• Incidence of Grades II-IV Acute GVHD (Secondary), Count of participants, Participants: Treatment (Allogeneic Transplantation) 57
• Incidence of Chronic GVHD (Secondary), Count of participants, Participants: Treatment (Allogeneic Transplantation) 20
• Median Donor CD3 + T Lymphocyte Chimerism in Peripheral Blood (Secondary), Median, percentage of T cells: Treatment (Allogeneic Transplantation) 100 (88 to 100)

Adverse events

Time frame: Toxicities Before Day 100

Serious adverse events by term

Other adverse events by term

• Boglarka Gyurkocza, Principal investigator, Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium

NIH grants: P01HL036444