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

Fred Hutchinson Cancer Center (FHCC)

Status and phase: Completed; Phase 2

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

Treatments: Drug: cyclosporine; Drug: busulfan; Procedure: allogeneic hematopoietic stem cell transplantation; Drug: fludarabine phosphate; Drug: cyclophosphamide; Procedure: peripheral blood stem cell transplantation; Radiation: total-body irradiation

Study type: Interventional

Funder types: Other; NIH

Identifiers

NCT01427881

NCI-2011-02459 (Registry Identifier)

2541.00

P30CA015704 (U.S. NIH Grant/Contract)

Details and patient eligibility

About

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.

Full 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.

Enrollment: 43 patients

Sex: All

Ages: Under 65 years old

Volunteers: No Healthy Volunteers

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

Trial design

Primary purpose: Treatment

Allocation: N/A

Interventional model: Single Group Assignment

Masking: None (Open label)

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43 participants in 1 patient group

Treatment (TBI, PBSCT, and cyclophosphamide GVHD prophylaxis)

Experimental group

Description:

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.

Treatment:

Radiation: total-body irradiation

Procedure: peripheral blood stem cell transplantation

Drug: fludarabine phosphate

Drug: cyclophosphamide

Procedure: allogeneic hematopoietic stem cell transplantation

Drug: busulfan

Drug: cyclosporine