Leukemia, Myelodysplastic Syndromes
Conditions
Keywords
adult acute lymphoblastic leukemia in remission, adult acute myeloid leukemia in remission, childhood acute lymphoblastic leukemia in remission, recurrent adult acute lymphoblastic leukemia, recurrent adult acute myeloid leukemia, recurrent childhood acute lymphoblastic leukemia, recurrent childhood acute myeloid leukemia, secondary acute myeloid leukemia, myelodysplastic syndromes, childhood myelodysplastic syndromes
Brief summary
RATIONALE: Drugs used in chemotherapy, such as treosulfan and fludarabine, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Giving treosulfan and fludarabine together with a donor bone marrow transplant or a peripheral stem cell transplant may be an effective treatment for acute myeloid leukemia, acute lymphoblastic leukemia, or myelodysplastic syndrome. PURPOSE: This phase II trial is studying giving treosulfan together with fludarabine to see how well it works in treating patients who are undergoing a donor stem cell transplant for acute myeloid leukemia, acute lymphoblastic leukemia, or myelodysplastic syndrome.
Detailed description
OBJECTIVES: Primary Phase * Determine the best dose of treosulfan when administered with fludarabine as a reduced-intensity conditioning regimen followed by allogeneic hematopoietic stem cell transplantation, in terms of incidence of severe to fatal toxicity to major organ systems and incidence of graft failure, in patients with acute myeloid leukemia, lymphoblastic leukemia, or myelodysplastic syndrome. Secondary Phase * Determine the safety of this regimen, in terms of incidence of grade II-IV acute and chronic graft-versus-host disease, in these patients. * Determine, preliminarily, the efficacy of this regimen, in terms of incidence of relapse, overall and disease-free survival, donor chimerism on days 28 and 100, and incidence of 200-day and 1-year nonrelapse mortality, in these patients. * Determine the pharmacokinetic and pharmacodynamic profile of treosulfan in patients treated with this regimen. OUTLINE: This is a multicenter, dose-finding study of treosulfan. * Reduced-intensity conditioning: Patients receive treosulfan IV over 2 hours on days -6 to -4 and fludarabine IV over 30 minutes on days -6 to -2. Cohorts of 5-10 patients receive escalating/de-escalating doses of treosulfan until the best dose is determined among the 3 pre-selected doses. The best dose is defined as the dose preceding that at which 4 of 10 patients experience dose-limiting toxicity. * Allogeneic hematopoietic cell transplantation (AHCT): Patients undergo allogeneic bone marrow or peripheral blood stem cell transplantation on day 0. All male patients with acute lymphoblastic leukemia OR male patients with acute myeloid leukemia who have prior or current testicular involvement receive external-beam radiotherapy to the testicles before AHCT. After completion of study treatment, patents are followed periodically. PROJECTED ACCRUAL: A total of 60 patients will be accrued for this study.
Interventions
DRUGfludarabine
30 mg/m2, IV for 5 days
DRUGtreosulfan
12 or 14 g/m2, IV for 5 days
PROCEDUREallogeneic blood or bone marrow transplantation
bone marrow or peripheral blood stem cells
Sponsors
medac GmbH
National Cancer Institute (NCI)
OHSU Knight Cancer Institute
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
No minimum to 60 Years
Healthy volunteers
No
Inclusion criteria
DISEASE CHARACTERISTICS: * Diagnosis of acute myeloid leukemia, lymphoblastic leukemia, or myelodysplastic syndrome * Any phase allowed, including any of the following: * Disease in remission * Relapsed or primary refractory disease * No CNS leukemic involvement not clearing with prior intrathecal chemotherapy and/or cranial radiotherapy * Planning to undergo unmanipulated allogeneic bone marrow or peripheral blood stem cell transplantation * Filgrastim (G-CSF) mobilization of bone marrow or stem cells allowed * Donor available, meeting 1 of the following criteria: * HLA-identical related donor * HLA-A, -B, -C, -DRB1, and -DQB1 matched unrelated donor by high-resolution DNA typing * A single allele mismatch allowed PATIENT CHARACTERISTICS: Performance status * Karnofsky 70-100% OR * Lansky 70-100% Life expectancy * Not specified Hematopoietic * Not specified Hepatic * Bilirubin ≤ 2 times upper limit of normal (ULN) * AST ≤ 2 times ULN * No evidence of synthetic dysfunction * No severe cirrhosis * No active infectious hepatitis Renal * Creatinine clearance ≥ 50% * Creatinine ≤ 2 times ULN * Dialysis independent Cardiovascular * No cardiac insufficiency requiring treatment * No symptomatic coronary artery disease * Ejection fraction ≥ 35% (for patients with history of cardiac disease or anthracycline exposure) Pulmonary * PO\_2 ≥ 70 mm Hg AND DLCO ≥ 70% of predicted OR * PO\_2 ≥ 80 mm Hg AND DLCO ≥ 60% of predicted * Not requiring supplementary continuous oxygen Other * Not pregnant or nursing * Negative pregnancy test * Fertile patients must use effective contraception * No other disease that would severely limit life expectancy * No HIV positivity * No active infection requiring deferral of conditioning * No known hypersensitivity to the study drugs PRIOR CONCURRENT THERAPY: Biologic therapy * See Disease Characteristics * No prior allogeneic bone marrow or stem cell transplantation * No concurrent umbilical cord blood or autologous transplantation Chemotherapy * See Disease Characteristics Radiotherapy * See Disease Characteristics Other * More than 4 weeks since prior experimental drugs * Concurrent enrollment on another protocol for graft-versus-host disease prophylaxis allowed
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients Experiencing Regimen-related Toxicity Events in Study Population | 34 days and 2 years | Proportion of patients experiencing regimen-related toxicity to major organ systems from day minus 6 to day 28. Major organ systems: cardiac, bladder/renal, pulmonary, hepatic, neurologic and gastrointestinal |
| Number of Patients Experiencing Graft Failure | 42 days | Graft versus Host Disease (GVHD) is a frequent complication of allogeneic bone marrow transplant in which the engrafted donor cells attacks the patient's organs and tissue. Acute GVHD (aGVHD) usually occurs during the first three months following an allogeneic BMT. Chronic GVHD (cGVHD) usually develops after the third month post-transplant. Patients may experience one, both or neither. |
| Incidence (Percent of Participants) With Nonrelapse Mortality (NRM) by Day 200 (Secondary Phase Only) | 200 days | NRM (Non relapse mortality) - death not attributed to the primary cancer. |
Secondary
| Measure | Time frame |
|---|---|
| Number of Subjects Who Are Without Disease at One Year as Indicator of Disease Free Survival. | One year |
Countries
United States
Participant flow
Recruitment details
Patients recruited at OHSU Knight Cancer Institute clinics in Portland, Oregon and Fred Hutchinson Cancer Research Center or University of Washington Medical Center clinics, Seattle, Washington.
Participants by arm
| Arm | Count |
|---|---|
| Treosulfan and Fludarabine Conditioning Conditioning with Treosulfan (12 or 14 g/m2, IV for 5 days) and Fludarabine (30 mg/m2, IV for 5 days) followed by Allogeneic Hematopoietic Cell Transplantation for High-Risk Hematologic Malignancies | 60 |
| Total | 60 |
Baseline characteristics
| Characteristic | Treosulfan and Fludarabine Conditioning |
|---|---|
| Age, Customized < 21 years | 10 Participants |
| Age, Customized Between 21 - 50 years | 31 Participants |
| Age, Customized Between 50 - 60 years | 19 Participants |
| Cytogenetic risk group Good | 16 Participants |
| Cytogenetic risk group Intermediate | 8 Participants |
| Cytogenetic risk group Poor | 36 Participants |
| Disease risk group High -relapsed/refract. ALL/AML/MDS w/ IPSS>=2.5 | 12 Participants |
| Disease risk group Low - AML/ALL in 1st rem., MDS with IPSS=0 | 26 Participants |
| Disease risk group Standard (ALL or AML in 2nd or greater rem.) | 22 Participants |
| Disease status at transplantation Acute Lymphoblastic Leukemia(ALL)2nd/3rd remission | 3 Participants |
| Disease status at transplantation Acute Myelogenous Leukemia(AML)1st remission | 26 Participants |
| Disease status at transplantation AML, 2nd or greater remission. | 10 Participants |
| Disease status at transplantation AML, relapsed or primary refractory | 8 Participants |
| Disease status at transplantation MDS: RA with excess blasts in transformation | 7 Participants |
| Disease status at transplantation Myelodysplastic Syndrome(MDS): Refract. Anemia(RA) | 6 Participants |
| Donor type HLA (human leukocyte antigen) -identical sibling | 30 participants |
| Donor type HLA-matched unrelated donor | 30 participants |
| Hematopoietic Cell Transplantation Comorbidity Index (HCT CI) 0 | 13 Participants |
| Hematopoietic Cell Transplantation Comorbidity Index (HCT CI) 1-2 | 19 Participants |
| Hematopoietic Cell Transplantation Comorbidity Index (HCT CI) >=3 | 28 Participants |
| Region of Enrollment United States | 60 participants |
| Sex: Female, Male Female | 36 Participants |
| Sex: Female, Male Male | 24 Participants |
| Stem cell source Bone marrow | 7 participants |
| Stem cell source Filgrastim-mobilized PBPC | 53 participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 0 / 60 |
| serious Total, serious adverse events | 5 / 60 |
Outcome results
Primary
Incidence (Percent of Participants) With Nonrelapse Mortality (NRM) by Day 200 (Secondary Phase Only)
NRM (Non relapse mortality) - death not attributed to the primary cancer.
Time frame: 200 days
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Treosulfan and Fludarabine Conditioning | Incidence (Percent of Participants) With Nonrelapse Mortality (NRM) by Day 200 (Secondary Phase Only) | 5 percent of participants |
Primary
Number of Patients Experiencing Graft Failure
Graft versus Host Disease (GVHD) is a frequent complication of allogeneic bone marrow transplant in which the engrafted donor cells attacks the patient's organs and tissue. Acute GVHD (aGVHD) usually occurs during the first three months following an allogeneic BMT. Chronic GVHD (cGVHD) usually develops after the third month post-transplant. Patients may experience one, both or neither.
Time frame: 42 days
Population: For graft failure 2 of the 60 patients were not evaluable because they exeperienced another event (relapsed) before they could be evaluable for graft failure.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Treosulfan and Fludarabine Conditioning | Number of Patients Experiencing Graft Failure | acute graft vs. host disease (aGVHD) | 36 participants |
| Treosulfan and Fludarabine Conditioning | Number of Patients Experiencing Graft Failure | chronic graft vs. host disease (cGVHD) | 31 participants |
Primary
Number of Patients Experiencing Regimen-related Toxicity Events in Study Population
Proportion of patients experiencing regimen-related toxicity to major organ systems from day minus 6 to day 28. Major organ systems: cardiac, bladder/renal, pulmonary, hepatic, neurologic and gastrointestinal
Time frame: 34 days and 2 years
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Treosulfan and Fludarabine Conditioning | Number of Patients Experiencing Regimen-related Toxicity Events in Study Population | Severe Regimen Related Toxicity (RRT) | 2 participants |
| Treosulfan and Fludarabine Conditioning | Number of Patients Experiencing Regimen-related Toxicity Events in Study Population | Nonrelapse mortality at 2 years | 5 participants |
Secondary
Number of Subjects Who Are Without Disease at One Year as Indicator of Disease Free Survival.
Time frame: One year
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Treosulfan and Fludarabine Conditioning | Number of Subjects Who Are Without Disease at One Year as Indicator of Disease Free Survival. | 58 participants |