Fludarabine Phosphate and Total Body Irradiation Followed by a Donor Peripheral Stem Cell Transplant in Treating Patients With Myelodysplastic Syndromes or Myeloproliferative Disorders

Low-Dose TBI Dose Escalation to Decrease Risks of Progression and Graft Rejection After Hematopoietic Cell Transplantation With Nonmyeloablative Conditioning as Treatment for Untreated Myelodysplastic Syndrome or Myeloproliferative Disorders - A Multi-Center Trial

Status

Completed

Phases

Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT00397813

Enrollment

Registered

2006-11-10

Start date

2006-01-31

Completion date

2018-03-31

Last updated

2020-01-31

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Atypical Chronic Myeloid Leukemia, BCR-ABL1 Negative, Chronic Myelomonocytic Leukemia, de Novo Myelodysplastic Syndrome, Essential Thrombocythemia, Myeloproliferative Neoplasm, Paroxysmal Nocturnal Hemoglobinuria, Polycythemia Vera, Polycythemia Vera, Post-Polycythemic Myelofibrosis Phase, Primary Myelofibrosis, Refractory Anemia, Refractory Anemia With Excess Blasts, Refractory Anemia With Ring Sideroblasts, Refractory Cytopenia With Multilineage Dysplasia, Refractory Cytopenia With Multilineage Dysplasia and Ring Sideroblasts

Brief summary

This phase II trial studies the side effects and best dose of total-body irradiation when given together with fludarabine phosphate followed by a donor peripheral stem cell transplant in treating patients with myelodysplastic syndromes (MDS) or myeloproliferative disorders (MPD). Giving low doses of chemotherapy, such as fludarabine phosphate, and total-body irradiation before a donor peripheral blood stem cell transplant helps stop the growth of cancer cells. Giving chemotherapy or radiation therapy before or after transplant also stops 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 cyclosporine and mycophenolate mofetil after the transplant may stop this from happening.

Detailed description

PRIMARY OBJECTIVES: I. Decrease the incidence of day-200 hematopoietic cell transplantation (HCT) failure to \< 20% in patients with MDS-Refractory anemia (RA)-(ringed sideroblasts \[RS\])/MPD and in patients with chronic myelomonocytic leukemia (CMML)/refractory anemia with excess blasts (RAEB). SECONDARY OBJECTIVES: I. The rate of relapse/progression in patients with MPD or MDS-RA and those with CMML or MDS-RAEB. II. The probability of progression free survival (PFS) in patients with MPD or MDS-RA and those with CMML or MDS-RAEB. III. The kinetics of donor engraftment. IV. The incidence of infections. OUTLINE: This is a dose-escalation study of total body irradiation (TBI). NONMYELOABLATIVE CONDITIONING REGIMEN: Patients receive fludarabine phosphate intravenously (IV) on days -4 to -2 and undergo TBI on day 0. PERIPHERAL BLOOD STEM CELL (PBSC) TRANSPLANTATION: Patients undergo filgrastim (G-CSF)-mobilized PBSC infusion after TBI on day 0. IMMUNOSUPPRESSION: Matched Related Donor: Patients receive cyclosporine orally (PO) twice daily (BID) on days -3 to 56, followed by a taper until day 180. Patients also receive mycophenolate mofetil (MMF) PO BID beginning 4-6 hours after transplantation on day 0 and continue until day 27. Unrelated Donor: Patients receive cyclosporine PO BID on days -3 to 100, followed by a taper until day 180. Patients also receive MMF PO three times daily beginning 4-6 hours after transplantation on day 0 and continue until day 40, followed by a taper until day 96. After completion of study treatment, patients are followed periodically.

Interventions

DRUGCyclosporine

Given PO

DRUGFludarabine Phosphate

Given IV

OTHERLaboratory Biomarker Analysis

Correlative studies

DRUGMycophenolate Mofetil

Given PO

PROCEDURENonmyeloablative Allogeneic Hematopoietic Stem Cell Transplantation

Undergo transplantation

PROCEDUREPeripheral Blood Stem Cell Transplantation

Undergo PBSC transplant

RADIATIONTotal-Body Irradiation

Undergo TBI

Study design

Allocation

NON_RANDOMIZED

Intervention model

SINGLE_GROUP

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

50 Years to 75 Years

Healthy volunteers

Inclusion criteria

* Patients aged \>= 50 and \< 75 years (yrs) with CMML, or previously untreated MDS or MPD * Patients aged \< 50 yrs at high risk for regimen related toxicity using standard high dose regimens; factors considered high risk include pre-existing conditions such as a chronic disease affecting kidneys, liver, lungs, or heart or previous failed HCT * An human leukocyte antigen (HLA)-identical related or an HLA-matched unrelated donor (Fred Hutchinson Cancer Research Center \[FHCRC\] matching allowed will be Grade 1.0 to 2.1) is available * Recovery from the effects of previous chemotherapy, with a minimum of 21 days from initiation of last therapy; hydroxyurea or anagrelide may be used to manage elevated cell counts in patients up to the time they begin therapy under this protocol * Patients \< 12 yrs of age must be discussed on a case by case basis with the primary investigator (PI) of the protocol prior to registration * A signed informed consent form or minor assent form * MDS: MDS classifiable by the World Health Organization (WHO) system as RA, RARS, refractory cytopenia with multilineage dysplasia (RCMD), RCMD and ringed sideroblasts (RCMD-RS) or RAEB * MDS: No previous myelosuppressive therapy; for the purpose of this protocol myelosuppressive chemotherapy will be defined as chemotherapy given with the intent of inducing a complete remission (e.g., standard 7+3, high dose intermittent ARA-C \[HIDAC\], or Mylotarg) * MDS: Patients must have \< 10% marrow blasts; fewer than 10% marrow blasts must be documented by marrow examination within 3 weeks of initiation of conditioning * CMML: Patients with CMML1 who have not received myelosuppressive therapy must have \< 10% marrow blasts; fewer than 10% marrow blasts must be documented by marrow examination within 3 weeks of initiation of conditioning; OR patients with CMML who have progressed beyond CMML1 and have received myelosuppressive chemotherapy must have \< 5% marrow blasts; fewer than 5% marrow blasts must be documented by marrow examination within 3 weeks of initiation of conditioning * MPD: Patients with polycythemia vera with persistent thrombotic or hemorrhagic complications despite conventional therapy, or who have progressed to postpolycythemic marrow fibrosis * MPD: Patients with essential thrombocythemia with persistent thrombotic or hemorrhagic complications despite conventional therapy, or who have progressed to myelofibrosis * MPD: Chronic idiopathic myelofibrosis with peripheral blood cytopenias * MPD: Patients must have \< 10% marrow blasts; fewer than 10% marrow blasts must be documented by marrow examination within 3 weeks of initiation of conditioning * MPD: No previous myelosuppressive therapy; for the purpose of this protocol myelosuppressive chemotherapy will be defined as chemotherapy given with the intent of inducing a complete remission (e.g., standard 7+3, HIDAC, or Mylotarg) * Atypical chronic myeloid leukemia (CML): Philadelphia chromosome-negative patients with a diagnosis of atypical CML * Atypical CML: Patients must have \< 10% marrow blasts; fewer than 10% marrow blasts must be documented by marrow examination within 3 weeks of initiation of conditioning * Atypical CML: No previous myelosuppressive therapy; for the purpose of this protocol myelosuppressive chemotherapy will be defined as chemotherapy given with the intent of inducing a complete remission (e.g., standard 7+3, HIDAC, or Mylotarg) * Paroxysmal nocturnal hemoglobinuria (PNH): Patients with the non-aplastic form of PNH (cellular bone marrow) who have had a history of life-threatening complications of their disease including thrombotic events, severe hemolysis or Budd Chiari syndrome are eligible; other patients may be considered following approval at PCC and approval by the Principal investigator * Matched Related Donor: Related to the patient and is genotypically or phenotypically HLA-identical * Matched Related Donor: Donor age \< 75 yrs unless cleared by institutional PI * Matched Related Donor: Capable of giving written, informed consent * Matched Related Donor: Donor must consent to PBSC mobilization with G-CSF and apheresis * Unrelated Donor: FHCRC matching allowed will be grades 1.0 to 2.1: Unrelated donors who are prospectively: 1. Matched for HLA-A, B, C, DRB1 and DQB1 by high resolution typing; 2. Only a single allele disparity will be allowed for HLA-A, B, or C as defined by high resolution typing * Unrelated Donor: Patient and donor pairs homozygous at a mismatched allele in the graft rejection vector are considered a two-allele mismatch, i.e., the patient is A\*0101 and the donor is A\*0102, and this type of mismatch is not allowed * HLA Matched Related Donor: G-CSF mobilized peripheral blood mononuclear cell (PBMC) only will be permitted as a hematopoietic stem cell (HSC) source on this protocol * HLA Matched Unrelated Donor: Donor must consent to PBSC mobilization with G-CSF and apheresis; bone marrow unrelated donors are not eligible for this protocol

Exclusion criteria

* Organ dysfunction as defined by the following: * Symptomatic coronary artery disease or cardiac ejection fraction \< 35% (or, if unable to obtain ejection fraction, shortening fraction of \< 26%); if shortening fraction is \< 26% a cardiology consult is required with the principal investigator (PI) having final approval of eligibility; ejection fraction is required if age \> 50 years or there is a history of anthracycline exposure or history of cardiac disease * Diffusing capacity of the lung for carbon monoxide (DLCO) \< 35%, TLC \< 35%, forced expiratory volume (FEV)1 \< 35% and/or receiving supplementary continuous oxygen; the FHCRC PI of the study must approve of enrollment of all patients with pulmonary nodules * Liver function abnormalities: Patient with clinical or laboratory evidence of liver disease will be evaluated for the cause of liver disease, its clinical severity in terms of liver function, bridging fibrosis, and the degree of portal hypertension; the patient will be excluded if he/she is found to have fulminant liver failure, cirrhosis of the liver with evidence of portal hypertension, alcoholic hepatitis, esophageal varices, a history of bleeding esophageal varices, hepatic encephalopathy, uncorrectable hepatic synthetic dysfunction evinced by prolongation of the prothrombin time, ascites related to portal hypertension, bacterial or fungal liver abscess, biliary obstruction, chronic viral hepatitis with total serum bilirubin \> 3mg/dL, or symptomatic biliary disease * Bone marrow documenting blast count \>= 10% or \>= 5% in CMML patients who have progressed beyond CMML1 and received myelosuppressive chemotherapy * Patients with active non-hematologic malignancies (except non-melanoma skin cancers); this exclusion does not apply to patients with non-hematologic malignancies that do not require therapy * Patients with a history of non-hematologic malignancies (except non-melanoma skin cancers) currently in a complete remission, who are less than 5 years from the time of complete remission, and have a \> 20% risk of disease recurrence * Presence of \>= 5% circulating leukemic blasts (in the peripheral blood) detected by standard pathology * Active central nervous system (CNS) involvement of disease * Karnofsky performance score \< 70% or Lansky-Play Performance score \< 70 for pediatric patients * Life expectancy severely limited by diseases other than malignancy * Fungal infections with radiological progression after receipt of amphotericin product or active triazole for \> 1 month * Active bacterial infection * Patients of fertile age who refuse contraception for a twelve month period post-transplant * Females who are pregnant or breastfeeding * Human immunodeficiency virus (HIV) seropositivity * Severe psychological illness such as major psychosis (e.g. schizophrenia), major bipolar depression, or suicidal situational depression * Matched Related Donor: Identical twin * Matched Related Donor: Any contra-indication to the administration of subcutaneous G-CSF at a dose of 16mg/kg/d for five consecutive days * Matched Related Donor: Serious medical or psychological illness * Matched Related Donor: Pregnant or lactating females * Matched Related Donor: Prior malignancy within the preceding five yrs, with the exception of non-melanoma skin cancers * Matched Related Donor: HIV seropositivity * Unrelated Donor: A positive anti-donor cytotoxic crossmatch is an absolute donor exclusion; donors are excluded when preexisting immunoreactivity is identified that would jeopardize donor hematopoietic cell engraftment; this determination is based on the standard practice of the individual institution; the recommended procedure for patients with 10 of 10 HLA allele level (phenotypic) match is to obtain a panel reactive antibody (PRA) screens to class I and class II antigens for all patients before HCT; if the PRA shows \> 10% activity, then flow cytometric or B and T cell cytotoxic cross matches should be obtained; the donor should be excluded if any of the cytotoxic cross match assays are positive; for those patients with an HLA class I allele mismatch, flow cytometric or B and T cell cytotoxic cross matches should be obtained regardless of the PRA results * Unrelated Donor: Marrow donors * Unrelated Donor: Donors who are HIV-positive and/or medical conditions that would result in increased risk to the donor G-CSF mobilization and G-PBMC collections * Unrelated Donor: Serious medical or psychological illness * Unrelated Donor: Pregnant or lactating females * Unrelated Donor: Prior malignancy within the preceding five yrs, with the exception of non-melanoma skin cancers * Unrelated Donor: HIV seropositivity

Design outcomes

Primary

Measure	Time frame	Description
Number of Patients With HCT Failure.	200 days	HCT failure will be defined as graft rejection (defined as \< 5% donor T-cell chimerism) or disease progression within 200 days of transplant.

Secondary

Measure	Time frame	Description
Number of Patients Who Had Infections	1 year	Number of patients who experienced bacterial, fungal, or viral infections.
Number of Patients Who Engrafted	1 year	Continued engraftment will be defined as the detection of donor T-cells (CD3+) as a proportion of the total T-cell of greater than 5%.
Number of Patients With Progression-free Survival	1 year	Evidence of disease progression will be an indication for therapeutic intervention. Defined as any evidence by morphologic or flow cytometric evaluation of the bone marrow aspirate of an incremental increase in 5% blasts in MDS/CMML; defined as any evidence of blastic transformation in agnogenic myeloid metaplasia/atypical CML; and defined as progressive erythrocytosis, thrombocytosis, or evidence of leukemic transformation in polycythemia vera and essential thrombocythemia.
Number of Patients With Relapse/Progression	1 year	Evidence of disease progression will be an indication for therapeutic intervention. Defined as any evidence by morphologic or flow cytometric evaluation of the bone marrow aspirate of an incremental increase in 5% blasts in MDS/CMML; defined as any evidence of blastic transformation in agnogenic myeloid metaplasia/atypical CML; and defined as progressive erythrocytosis, thrombocytosis, or evidence of leukemic transformation in polycythemia vera and essential thrombocythemia.

Countries

United States

Participant flow

Participants by arm

Arm	Count
Arm A - Dose Level 1 Arm A - patients with MPD or MDS-RA/RARS Dose Level 1 - 300 cGy TBI NONMYELOABLATIVE CONDITIONING REGIMEN: Patients receive fludarabine phosphate IV on days -4 to -2 and undergo TBI on day 0. PBSC TRANSPLANTATION: Patients undergo filgrastim-mobilized PBSC infusion after TBI on day 0. IMMUNOSUPPRESSION: Matched Related Donor: Patients receive cyclosporine PO BID on days -3 to 56, followed by a taper until day 180. Patients also receive MMF PO BID beginning 4-6 hours after transplantation on day 0 and continue until day 27. Unrelated Donor: Patients receive cyclosporine PO BID on days -3 to 100, followed by a taper until day 180. Patients also receive MMF PO three times daily beginning 4-6 hours after transplantation on day 0 and continue until day 40, followed by a taper until day 96.	36
Arm A - Dose Level 2 Arm A - patients with MPD or MDS-RA/RARS Dose Level 2 - 400 cGy TBI NONMYELOABLATIVE CONDITIONING REGIMEN: Patients receive fludarabine phosphate IV on days -4 to -2 and undergo TBI on day 0. PBSC TRANSPLANTATION: Patients undergo filgrastim-mobilized PBSC infusion after TBI on day 0. IMMUNOSUPPRESSION: Matched Related Donor: Patients receive cyclosporine PO BID on days -3 to 56, followed by a taper until day 180. Patients also receive MMF PO BID beginning 4-6 hours after transplantation on day 0 and continue until day 27. Unrelated Donor: Patients receive cyclosporine PO BID on days -3 to 100, followed by a taper until day 180. Patients also receive MMF PO three times daily beginning 4-6 hours after transplantation on day 0 and continue until day 40, followed by a taper until day 96.	0
Arm A - Dose Level 3 Arm A - patients with MPD or MDS-RA/RARS Dose Level 3 - 450 cGy TBI NONMYELOABLATIVE CONDITIONING REGIMEN: Patients receive fludarabine phosphate IV on days -4 to -2 and undergo TBI on day 0. PBSC TRANSPLANTATION: Patients undergo filgrastim-mobilized PBSC infusion after TBI on day 0. IMMUNOSUPPRESSION: Matched Related Donor: Patients receive cyclosporine PO BID on days -3 to 56, followed by a taper until day 180. Patients also receive MMF PO BID beginning 4-6 hours after transplantation on day 0 and continue until day 27. Unrelated Donor: Patients receive cyclosporine PO BID on days -3 to 100, followed by a taper until day 180. Patients also receive MMF PO three times daily beginning 4-6 hours after transplantation on day 0 and continue until day 40, followed by a taper until day 96.	0
Arm B - Dose Level 1 Arm B - patients with MDS-RAEB or CMML Dose Level 1 - 300 cGy TBI NONMYELOABLATIVE CONDITIONING REGIMEN: Patients receive fludarabine phosphate IV on days -4 to -2 and undergo TBI on day 0. PBSC TRANSPLANTATION: Patients undergo filgrastim-mobilized PBSC infusion after TBI on day 0. IMMUNOSUPPRESSION: Matched Related Donor: Patients receive cyclosporine PO BID on days -3 to 56, followed by a taper until day 180. Patients also receive MMF PO BID beginning 4-6 hours after transplantation on day 0 and continue until day 27. Unrelated Donor: Patients receive cyclosporine PO BID on days -3 to 100, followed by a taper until day 180. Patients also receive MMF PO three times daily beginning 4-6 hours after transplantation on day 0 and continue until day 40, followed by a taper until day 96.	12
Arm B - Dose Level 2 Arm B - patients with MDS-RAEB or CMML Dose Level 2 - 400 cGy TBI NONMYELOABLATIVE CONDITIONING REGIMEN: Patients receive fludarabine phosphate IV on days -4 to -2 and undergo TBI on day 0. PBSC TRANSPLANTATION: Patients undergo filgrastim-mobilized PBSC infusion after TBI on day 0. IMMUNOSUPPRESSION: Matched Related Donor: Patients receive cyclosporine PO BID on days -3 to 56, followed by a taper until day 180. Patients also receive MMF PO BID beginning 4-6 hours after transplantation on day 0 and continue until day 27. Unrelated Donor: Patients receive cyclosporine PO BID on days -3 to 100, followed by a taper until day 180. Patients also receive MMF PO three times daily beginning 4-6 hours after transplantation on day 0 and continue until day 40, followed by a taper until day 96.	5
Arm B - Dose Level 3 Arm B - patients with MDS-RAEB or CMML Dose Level 3 - 450 cGy TBI NONMYELOABLATIVE CONDITIONING REGIMEN: Patients receive fludarabine phosphate IV on days -4 to -2 and undergo TBI on day 0. PBSC TRANSPLANTATION: Patients undergo filgrastim-mobilized PBSC infusion after TBI on day 0. IMMUNOSUPPRESSION: Matched Related Donor: Patients receive cyclosporine PO BID on days -3 to 56, followed by a taper until day 180. Patients also receive MMF PO BID beginning 4-6 hours after transplantation on day 0 and continue until day 27. Unrelated Donor: Patients receive cyclosporine PO BID on days -3 to 100, followed by a taper until day 180. Patients also receive MMF PO three times daily beginning 4-6 hours after transplantation on day 0 and continue until day 40, followed by a taper until day 96.	24
Total	77

Baseline characteristics

Characteristic	Arm A - Dose Level 2	Arm A - Dose Level 3	Arm A - Dose Level 1	Arm B - Dose Level 1	Arm B - Dose Level 2	Arm B - Dose Level 3	Total
Age, Categorical <=18 years	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Age, Categorical >=65 years	0 Participants	0 Participants	18 Participants	7 Participants	3 Participants	19 Participants	47 Participants
Age, Categorical Between 18 and 65 years	0 Participants	0 Participants	18 Participants	5 Participants	2 Participants	5 Participants	30 Participants
Age, Continuous	—	—	64.5 years	66.5 years	68 years	68.5 years	67 years
Ethnicity (NIH/OMB) Hispanic or Latino	—	—	1 Participants	0 Participants	0 Participants	0 Participants	1 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	—	—	35 Participants	12 Participants	4 Participants	23 Participants	74 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	—	—	0 Participants	0 Participants	1 Participants	1 Participants	2 Participants
Race (NIH/OMB) American Indian or Alaska Native	—	—	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Asian	—	—	0 Participants	0 Participants	0 Participants	4 Participants	4 Participants
Race (NIH/OMB) Black or African American	—	—	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) More than one race	—	—	0 Participants	0 Participants	0 Participants	1 Participants	1 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	—	—	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Unknown or Not Reported	—	—	1 Participants	0 Participants	1 Participants	0 Participants	2 Participants
Race (NIH/OMB) White	—	—	35 Participants	12 Participants	4 Participants	19 Participants	70 Participants
Region of Enrollment United States	—	—	36 participants	12 participants	5 participants	24 participants	77 participants
Sex: Female, Male Female	—	—	10 Participants	7 Participants	2 Participants	5 Participants	24 Participants
Sex: Female, Male Male	—	—	26 Participants	5 Participants	3 Participants	19 Participants	53 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk	EG003 affected / at risk	EG004 affected / at risk	EG005 affected / at risk
deaths Total, all-cause mortality	10 / 36	0 / 0	0 / 0	10 / 12	3 / 5	9 / 24
other Total, other adverse events	16 / 36	0 / 0	0 / 0	9 / 12	2 / 5	13 / 24
serious Total, serious adverse events	3 / 36	0 / 0	0 / 0	7 / 12	2 / 5	4 / 24

Outcome results

Primary

Number of Patients With HCT Failure.

HCT failure will be defined as graft rejection (defined as \< 5% donor T-cell chimerism) or disease progression within 200 days of transplant.

Time frame: 200 days