Cyclophosphamide for Prevention of Graft-Versus-Host Disease After Allogeneic Peripheral Blood Stem Cell Transplantation in Patients With Hematological Malignancies

May 17, 2017 updated by: Marco Mielcarek, Fred Hutchinson Cancer Center

A Phase II Study to Evaluate the Efficacy of Posttransplant Cyclophosphamide for Prevention of Chronic Graft-versus-Host Disease After Allogeneic Peripheral Blood Stem Cell Transplantation

This phase II trial studies how well cyclophosphamide works in preventing chronic graft-versus-host disease after allogeneic peripheral blood stem cell transplant in patients with hematological malignancies. Giving chemotherapy and total-body irradiation before transplantation helps stop the growth of cancer cells and prevents the patient's immune system from rejecting the donor's stem cells. Healthy stem cells from a donor that are infused into the patient help the patient's bone marrow make blood cells; red blood cells, white blood cells, and platelets. Sometimes, however, the transplanted donor cells can cause an immune response against the body's normal cells, which is called graft-versus-host disease (GVHD). Giving cyclophosphamide after transplant may prevent this from happening or may make chronic GVHD less severe.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

PRIMARY OBJECTIVES:

I. The primary objective of this study is to assess outcomes when high-dose cyclophosphamide (CY) is administered on days 3 and 4 followed by cyclosporine (CSP) after human leukocyte antigen (HLA)-matched related or unrelated mobilized blood cell transplantation with total-body irradiation (TBI) or busulfan (BU)-based conditioning.

SECONDARY OBJECTIVES:

I. The secondary objective of this study is to assess hematopoietic cell transplantation (HCT) outcomes when withdrawal of CSP is accelerated in patients without acute graft-versus-host disease (GVHD).

OUTLINE: Patients' conditioning regimens are determined by the Clinical Coordinator after consultation with the attending physician. Based on disease, patients receive either TBI or fludarabine and busulfan.

PREPARATIVE REGIMEN: Patients receive TBI twice daily (BID) on days -4 or -3 to -1. Some patients also receive fludarabine intravenously (IV) daily on days -5 to -2 and busulfan IV over 3 hours once daily (QD) or over 2 hours every 6 hours on days -5 to -2. Patients may also undergo central nervous system (CNS) prophylaxis, testicular irradiation, and/or involved field irradiation as per standard practice.

TRANSPLANTATION: Patients undergo allogeneic peripheral blood stem cell transplantation (PBSCT) on day 0 per standard practice.

GVHD PROPHYLAXIS: Patients receive cyclophosphamide IV over 1-2 hours on days 3-4. Patients also receive cyclosporine IV every 12 hours or every 8 hours beginning on day 5 with taper on days 56-126.

Treatment continues in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at day 180 and then annually for 5 years.

Study Type

Interventional

Enrollment (Actual)

43

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Washington
      • Seattle, Washington, United States, 98109
        • Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

No older than 65 years (Child, Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • Acute lymphocytic leukemia (ALL) in morphologic first complete remission (CR1) with high risk features defined as, but not limited to: evidence of adverse cytogenetics such as t(9;22), t(1;19), t(4;11), or mixed-lineage leukemia (MLL) rearrangements; presence of minimal residual disease; progenitor B-cell immunophenotype; high white blood cells (WBC) at diagnosis (> 30,000/ul in B-ALL; > 100,000/ul in T-ALL); or delayed attainment of CR (> 4 weeks) after induction therapy; additional clinical characteristics deemed to confer a high relapse risk may be discussed with and approved by the Principal Investigator (PI)

  • Acute myeloid leukemia (AML) in CR1 EXCEPT patients with low-risk features defined as:

    • Inv 16 or t(8;21) in the absence of c-kit mutations
    • Normal karyotype who are FLT3-ITD-negative and NPM1-positive in the absence of c-kit mutations
    • Patients with respective "low-risk" features are eligible, however, if (i) more than 1 cycle of induction therapy was required to achieve CR1 (ii) the patient had a preceding myelodysplastic syndrome (MDS) other than myelofibrosis, or (iii) secondary AML
  • Acute leukemia in 2nd or greater CR (CR >= 2)
  • Refractory or relapsed AML with =< 10% bone marrow blasts and no circulating blasts or proven extramedullary disease
  • AML transformed from myelodysplastic syndrome (MDS) with < 10% bone marrow blasts

  • MDS with following high risk features:

    • High risk cytogenetics (including, but not limited to: 7q--, inv[3], t[3q], del[3q] or complex karyotype)
    • International Prognostic Scoring System (IPSS) intermediate (INT)-2 or greater
    • Treatment-related MDS
    • Any phase of MDS if patient is < 21 years of age
  • Chronic myelogenous leukemia (CML) beyond 1st chronic phase or resistant or intolerant to tyrosine kinase inhibitors (adults) or any phase (pediatric < 21 years)
  • Chronic myelomonocytic leukemia
  • Philadelphia-negative myeloproliferative disorder
  • Lymphoma: relapsed chemotherapy-sensitive (complete or partial response) Hodgkin or non-Hodgkin lymphoma
  • Multiple myeloma-stage III
  • The patient or legal representative must be able to understand and give written informed consent
  • DONORS: The donor must be a genotypically HLA-identical sibling, a phenotypically HLA-matched first-degree relative, or an unrelated donor who is molecularly matched with the patient at HLA-A, B, C, DRB1
  • DONORS: Donors must meet the selection criteria for administration of G-CSF (filgrastim) and apheresis defined by the Foundation for the Accreditation of Cell Therapy (FACT) and will be screened per the American Association of Blood Banks (AABB)
  • DONORS: Donors must be capable of giving informed consent

Exclusion Criteria:

  • Prior autologous or allogeneic stem cell transplant
  • Performance status > 2 (Eastern Cooperative Oncology Group [ECOG]) or < 50 (Lansky; for patients < 16 years old)
  • Uncontrolled infection; the protocol principal investigator (PI) will be final arbiter if there is uncertainty regarding whether a previous infection is under adequate control to allow enrollment in the study
  • Positive serology for human immunodeficiency virus (HIV)-1, 2 or human T cell lymphotropic virus (HTLV)-1, 2
  • Left ventricular ejection fraction < 45% or shortening fraction < 25%; no uncontrolled arrhythmias or symptomatic cardiac disease
  • Symptomatic pulmonary disease; forced expiratory volume in one second (FEV1), forced vital capacity (FVC), diffusion capacity of the lung for carbon monoxide (DLCO) =< 50% of predicted (corrected for hemoglobin); if pulmonary function tests cannot be performed, an oxygen saturation < 92% on room air
  • Calculated (Cockcroft-Gault or appropriate calculation for pediatric patients) serum creatinine clearance =< 60 mL/min; if the calculated CrCl is 50-60 mL/min, but a measured CrCl by 24 hour urine collection is > 60 mL/min, this measurement is acceptable
  • Total serum bilirubin more than twice upper normal limit
  • Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) more than 3-fold higher than laboratory upper normal limits
  • Female patient must have negative serum pregnancy test (all women of child bearing-potential must have test performed)
  • DONORS: Potential donors who for psychological, physiological, or medical reasons cannot tolerate administration of G-CSF or apheresis
  • DONORS: Donors who are allergic to filgrastim or Escherichia (E.) coli-derived proteins
  • DONORS: Donor-related risks to recipients
  • DONORS: Positive anti-donor lymphocytotoxic crossmatch
  • DONORS: Donors who are positive for HIV

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Treatment (TBI, PBSCT, and cyclophosphamide GVHD prophylaxis)

PREPARATIVE REGIMEN: Patients receive TBI BID on days -4 or -3 to -1. Some patients also receive fludarabine IV daily on days -5 to -2 and busulfan IV over 3 hours QD or over 2 hours every 6 hours on days -5 to -2. Patients may also undergo CNS prophylaxis, testicular irradiation, and/or involved field irradiation as per standard practice.

TRANSPLANTATION: Patients undergo allogeneic PBSCT on day 0 per standard practice.

GVHD PROPHYLAXIS: Patients receive cyclophosphamide IV over 1-2 hours on days 3-4. Patients also receive cyclosporine IV every 12 hours or every 8 hours beginning on day 5 with taper on days 56-126.
Drug: fludarabine phosphate
Given IV
Other Names:
  • 2-F-ara-AMP
  • Beneflur
  • Fludara
Drug: cyclophosphamide
Given IV
Other Names:
  • Cytoxan
  • Endoxan
  • CPM
  • CTX
  • Endoxana
Radiation: total-body irradiation
Undergo TBI
Other Names:
  • TBI
Procedure: allogeneic hematopoietic stem cell transplantation
Undergo allogeneic PBSCT
Drug: busulfan
Given IV
Other Names:
  • BSF
  • BU
  • Misulfan
  • Mitosan
  • Myeloleukon
Drug: cyclosporine
Given IV
Other Names:
  • ciclosporin
  • cyclosporin
  • cyclosporin A
  • CYSP
  • Sandimmune
Procedure: peripheral blood stem cell transplantation
Undergo allogeneic PBSCT
Other Names:
  • PBPC transplantation
  • PBSC transplantation
  • peripheral blood progenitor cell transplantation
  • transplantation, peripheral blood stem cell

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Chronic GVHD Requiring Systemic Immunosuppressive Treatment
Time Frame: At 1 year after transplantation
Chronic GVHD will be defined by National Institutes of Health (NIH) criteria and requiring systemic treatment. A reduction in the cumulative incidence of GVHD from ~35% to ~15% at 1 year would represent a reasonable goal. A sample size of 42 patients provides 90% power to observe such a difference with one-side 5% type-1 error.
At 1 year after transplantation

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Donor Engraftment
Time Frame: At day 28
Donor engraftment is defined as the count (percent) of patients with full donor chimerism. Full donor chimerism is defined as at least 95% donor CD3 cells in peripheral blood.
At day 28
Grades II-IV and III-IV Acute GVHD
Time Frame: Through day +100 post-transplant
Grades II-IV and III-IV GVHD will be assessed with the use of cumulative incidence plots.
Through day +100 post-transplant
Duration of Systemic Immunosuppressive Treatment
Time Frame: Up to 5 years
The need for additional immunosuppressive treatment with agents other than those used for prophylaxis, the reasons for their administration (acute GVHD, chronic GVHD, or other reasons) and the duration of its administration will be determined. Patients will be monitored to determine the duration of systemic immunosuppressive treatment. Primary and secondary treatment of acute GVHD and withdrawal of systemic immunosuppressive treatment will be assessed with the use of cumulative incidence plots.
Up to 5 years
Persistent or Recurrent Malignancy After HCT
Time Frame: At 2 years
Recurrent or progressive malignancy will be assessed with the use of cumulative incidence plots. Recurrent malignancy will be defined by hematologic criteria. Recurrent malignancy will also be defined as any unplanned medical intervention designed to prevent progression of malignant disease in patients who have molecular, cytogenetic or flow-cytometric evidence of malignant cells after transplantation.
At 2 years
Non-relapse Mortality
Time Frame: At 2 years
Defined as death in the absence of recurrent or progressive malignancy after HCT. Non-relapse morality will be assessed with the use of cumulative incidence plots. This secondary endpoint will be characterized and presented as a cumulative incidence.
At 2 years
Overall Survival
Time Frame: At 1 year post-transplant
Overall survival will be evaluated as Kaplan-Meier estimates.
At 1 year post-transplant
Disease-free Survival
Time Frame: At 1 year post-transplant
Disease-free survival will be evaluated as Kaplan-Meier estimates.
At 1 year post-transplant
Hematologic Recovery
Time Frame: Up to day +100
Descriptive statistics will be used to assess the median days of neutrophil and platelet recovery. The day of neutrophil recovery is defined as the first day of three consecutive lab values on different days, after the conditioning regimen-induced nadir of blood counts, that the absolute neutrophil count is > 500/uL. The day of platelet recovery is defined as the first day of three consecutive lab values on different days, after the conditioning regimen-induced nadir of blood counts, that the platelet count is >= 20,000/uL without platelet transfusion support in the seven days prior.
Up to day +100
Graft Failure
Time Frame: By greater than or equal to 28 days post-transplant
Descriptive statistics will be used to assess the incidence of primary graft failure and secondary graft failure. Primary graft failure is defined as failure to achieve a sustained neutrophil count of >= 500/uL by >= 28 days post-transplant. Secondary graft failure is defined as the decline in neutrophil count to < 500/uL after achieving engraftment which is unrelated to infection or drug effect and is unresponsive to stimulation by growth factors.
By greater than or equal to 28 days post-transplant

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Fred Hutchinson Cancer Center

Collaborators

National Cancer Institute (NCI)

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

September 1, 2011

Primary Completion (Actual)

June 1, 2014

Study Completion (Actual)

July 1, 2015

Study Registration Dates

First Submitted

August 31, 2011

First Submitted That Met QC Criteria

September 1, 2011

First Posted (Estimate)

September 2, 2011

Study Record Updates

Last Update Posted (Actual)

May 19, 2017

Last Update Submitted That Met QC Criteria

May 17, 2017

Last Verified

May 1, 2017

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 2541.00
  • P30CA015704 (U.S. NIH Grant/Contract)
  • NCI-2011-02459 (Registry Identifier: CTRP (Clinical Trial Reporting Program))

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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