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

Chronic Myelomonocytic Leukemia Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01427881
• Other study ID #: 2541.00
• Secondary ID: NCI-2011-02459P3
• Status: Completed
• Phase: Phase 2
• First received: August 31, 2011
• Last updated: May 17, 2017
• Start date: September 2011
• Est. completion date: July 2015

Study information

• Verified date: May 2017
• Source: Fred Hutchinson Cancer Research Center
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 43
• Est. completion date: July 2015
• Est. primary completion date: June 2014
• Accepts healthy volunteers: No
• Gender: All
• Age group: N/A to 65 Years

Eligibility

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

Related Conditions & MeSH terms

• Accelerated Phase Chronic Myelogenous Leukemia
• Adult Acute Lymphoblastic Leukemia in Remission
• Adult Acute Megakaryoblastic Leukemia (M7)
• Adult Acute Myeloid Leukemia in Remission
• Adult Erythroleukemia (M6a)
• Adult Nasal Type Extranodal NK/T-cell Lymphoma
• Adult Pure Erythroid Leukemia (M6b)
• Anaplastic Large Cell Lymphoma
• Angioimmunoblastic T-cell Lymphoma
• Blast Crisis
• Blastic Phase Chronic Myelogenous Leukemia
• Burkitt Lymphoma
• Childhood Acute Erythroleukemia (M6)
• Childhood Acute Lymphoblastic Leukemia in Remission
• Childhood Acute Megakaryocytic Leukemia (M7)
• Childhood Acute Myeloid Leukemia in Remission
• Childhood Burkitt Lymphoma
• Childhood Chronic Myelogenous Leukemia
• Childhood Diffuse Large Cell Lymphoma
• Childhood Immunoblastic Large Cell Lymphoma
• Childhood Myelodysplastic Syndromes
• Childhood Nasal Type Extranodal NK/T-cell Lymphoma
• Chronic Myelomonocytic Leukemia
• Chronic Phase Chronic Myelogenous Leukemia
• Cutaneous B-cell Non-Hodgkin Lymphoma
• de Novo Myelodysplastic Syndromes
• Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue
• Graft vs Host Disease
• Hepatosplenic T-cell Lymphoma
• Hodgkin Disease
• Intraocular Lymphoma
• Leukemia
• Leukemia, Erythroblastic, Acute
• Leukemia, Lymphocytic, Chronic, B-Cell
• Leukemia, Lymphoid
• Leukemia, Megakaryoblastic, Acute
• Leukemia, Myelogenous, Chronic, BCR-ABL Positive
• Leukemia, Myeloid
• Leukemia, Myeloid, Acute
• Leukemia, Myeloid, Chronic-Phase
• Leukemia, Myelomonocytic, Chronic
• Leukemia, T-Cell
• Leukemia-Lymphoma, Adult T-Cell
• Lymphoma
• Lymphoma, B-Cell
• Lymphoma, B-Cell, Marginal Zone
• Lymphoma, Extranodal NK-T-Cell
• Lymphoma, Follicular
• Lymphoma, Large B-Cell, Diffuse
• Lymphoma, Large-Cell, Anaplastic
• Lymphoma, Large-Cell, Immunoblastic
• Lymphoma, Mantle-Cell
• Lymphoma, Non-Hodgkin
• Lymphoma, T-Cell
• Lymphoma, T-Cell, Cutaneous
• Lymphoma, T-Cell, Peripheral
• Lymphomatoid Granulomatosis
• Lymphoproliferative Disorders
• Multiple Myeloma
• Mycoses
• Mycosis Fungoides
• Myelodysplastic Syndromes
• Neoplasm Metastasis
• Nodal Marginal Zone B-cell Lymphoma
• Noncutaneous Extranodal Lymphoma
• Peripheral T-cell Lymphoma
• Philadelphia Chromosome
• Philadelphia Chromosome Negative Chronic Myelogenous Leukemia
• Plasmablastic Lymphoma
• Post-transplant Lymphoproliferative Disorder
• Precursor Cell Lymphoblastic Leukemia-Lymphoma
• Preleukemia
• Previously Treated Myelodysplastic Syndromes
• Recurrent Adult Acute Lymphoblastic Leukemia
• Recurrent Adult Acute Myeloid Leukemia
• Recurrent Adult Burkitt Lymphoma
• Recurrent Adult Diffuse Large Cell Lymphoma
• Recurrent Adult Diffuse Mixed Cell Lymphoma
• Recurrent Adult Diffuse Small Cleaved Cell Lymphoma
• Recurrent Adult Grade III Lymphomatoid Granulomatosis
• Recurrent Adult Hodgkin Lymphoma
• Recurrent Adult Immunoblastic Large Cell Lymphoma
• Recurrent Adult Lymphoblastic Lymphoma
• Recurrent Adult T-cell Leukemia/Lymphoma
• Recurrent Childhood Acute Lymphoblastic Leukemia
• Recurrent Childhood Acute Myeloid Leukemia
• Recurrent Childhood Anaplastic Large Cell Lymphoma
• Recurrent Childhood Grade III Lymphomatoid Granulomatosis
• Recurrent Childhood Large Cell Lymphoma
• Recurrent Childhood Lymphoblastic Lymphoma
• Recurrent Childhood Small Noncleaved Cell Lymphoma
• Recurrent Cutaneous T-cell Non-Hodgkin Lymphoma
• Recurrent Grade 1 Follicular Lymphoma
• Recurrent Grade 2 Follicular Lymphoma
• Recurrent Grade 3 Follicular Lymphoma
• Recurrent Mantle Cell Lymphoma
• Recurrent Marginal Zone Lymphoma
• Recurrent Mycosis Fungoides/Sezary Syndrome
• Recurrent Small Lymphocytic Lymphoma
• Recurrent/Refractory Childhood Hodgkin Lymphoma
• Relapsing Chronic Myelogenous Leukemia
• Secondary Acute Myeloid Leukemia
• Secondary Myelodysplastic Syndromes
• Sezary Syndrome
• Small Intestine Lymphoma
• Splenic Marginal Zone Lymphoma
• Stage III Multiple Myeloma
• Syndrome
• Testicular Lymphoma
• Waldenstrom Macroglobulinemia
• Waldenström Macroglobulinemia

Intervention

Drug:
• cyclophosphamide
Given IV
• cyclosporine
Given IV

Procedure:
• peripheral blood stem cell transplantation
Undergo allogeneic PBSCT

Radiation:
• total-body irradiation
Undergo TBI

Drug:
• fludarabine phosphate
Given IV
• busulfan
Given IV

Procedure:
• allogeneic hematopoietic stem cell transplantation
Undergo allogeneic PBSCT

Locations

Country	Name	City	State
United States	Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium	Seattle	Washington

Sponsors (2)

Lead Sponsor	Collaborator
Fred Hutchinson Cancer Research Center	National Cancer Institute (NCI)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Chronic GVHD Requiring Systemic Immunosuppressive Treatment	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	Donor Engraftment	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
Secondary	Grades II-IV and III-IV Acute GVHD	Grades II-IV and III-IV GVHD will be assessed with the use of cumulative incidence plots.	Through day +100 post-transplant
Secondary	Duration of Systemic Immunosuppressive Treatment	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
Secondary	Persistent or Recurrent Malignancy After HCT	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
Secondary	Non-relapse Mortality	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
Secondary	Overall Survival	Overall survival will be evaluated as Kaplan-Meier estimates.	At 1 year post-transplant
Secondary	Disease-free Survival	Disease-free survival will be evaluated as Kaplan-Meier estimates.	At 1 year post-transplant
Secondary	Hematologic Recovery	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
Secondary	Graft Failure	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