Clinical trial NCT01427881: Cyclophosphamide for Prevention of Graft-Versus-Host Disease After Allogeneic Peripheral Blood Stem Cell Transplantation in Patients With Hematological Malignancies
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: 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
Blastic Phase Chronic Myelogenous Leukemia
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
Hepatosplenic T-cell Lymphoma
Intraocular Lymphoma
Nodal Marginal Zone B-cell Lymphoma
Noncutaneous Extranodal Lymphoma
Peripheral T-cell Lymphoma
Philadelphia Chromosome Negative Chronic Myelogenous Leukemia
Post-transplant Lymphoproliferative Disorder
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
Small Intestine Lymphoma
Splenic Marginal Zone Lymphoma
Stage III Multiple Myeloma
Testicular Lymphoma
Waldenström Macroglobulinemia
Lead sponsor: Fred Hutchinson Cancer Center
Sponsor class: OTHER
Collaborators: name: National Cancer Institute (NCI)
First posted: 2011-09-02
Enrollment: 43
Sex: ALL
Maximum age (years): 65
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief 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.

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.

Eligibility criteria: 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

Primary outcomes:
measure: Chronic GVHD Requiring Systemic Immunosuppressive Treatment
timeFrame: At 1 year after transplantation
Secondary outcomes:
measure: Donor Engraftment
timeFrame: At day 28
measure: Grades II-IV and III-IV Acute GVHD
timeFrame: Through day +100 post-transplant
measure: Duration of Systemic Immunosuppressive Treatment
timeFrame: Up to 5 years
measure: Persistent or Recurrent Malignancy After HCT
timeFrame: At 2 years
measure: Non-relapse Mortality
timeFrame: At 2 years
measure: Overall Survival
timeFrame: At 1 year post-transplant
measure: Disease-free Survival
timeFrame: At 1 year post-transplant
measure: Hematologic Recovery
timeFrame: Up to day +100
measure: Graft Failure
timeFrame: By greater than or equal to 28 days post-transplant
Other outcomes:
Locations:
city: Seattle
country: United States
facility: Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium
state: Washington
Study officials:
affiliation: Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium
name: Marco Mielcarek
role: PRINCIPAL_INVESTIGATOR
References:
citation: Mielcarek M, Furlong T, O'Donnell PV, Storer BE, McCune JS, Storb R, Carpenter PA, Flowers ME, Appelbaum FR, Martin PJ. Posttransplantation cyclophosphamide for prevention of graft-versus-host disease after HLA-matched mobilized blood cell transplantation. Blood. 2016 Mar 17;127(11):1502-8. doi: 10.1182/blood-2015-10-672071. Epub 2016 Jan 13.