Donor Peripheral Blood Stem Cell Transplant in Treating Patients With Hematologic Malignancies

Phase 2

Terminated

Conditions: Acute Myeloid Leukaemia With Prior Myelodysplastic Syndrome
Acute Myeloid Leukemia in Remission
Acute Myeloid Leukemia With Multilineage Dysplasia
Acute Undifferentiated Leukemia
Recurrent Follicular Lymphoma
T Lymphoblastic Lymphoma
Acute Erythroid Leukemia in Remission
Acute Myeloid Leukemia With FLT3/ITD Mutation
Ph+ ALL
Acute Myeloid Leukemia With Inv(3)(Q21Q26.2); RPN1-EVI1

Interventions: Drug: Cyclophosphamide
Biological: Filgrastim
Drug: Fludarabine Phosphate
Drug: Mycophenolate Mofetil
Procedure: Nonmyeloablative Allogeneic Hematopoietic Stem Cell Transplantation
Procedure: Peripheral Blood Stem Cell Transplantation
Drug: Tacrolimus
Radiation: Total-Body Irradiation

Registration Number: NCT01028716

Lead Sponsor: Fred Hutchinson Cancer Center

Brief Summary: This phase II trial studies how well donor peripheral blood stem cell (PBSC) transplant works in treating patients with hematologic malignancies. Cyclophosphamide when added to tacrolimus and mycophenolate mofetil is safe and effective in preventing severe graft-versus-host disease (GVHD) in most patients with hematologic malignancies undergoing transplantation of bone marrow from half-matched (haploidentical) donors. This approach has extended the transplant option to patients who do not have matched related or unrelated donors, especially for patients from ethnic minority groups. The graft contains cells of the donor's immune system which potentially can recognize and destroy the patient's cancer cells (graft-versus-tumor effect). Rejection of the donor's cells by the patient's own immune system is prevented by giving low doses of chemotherapy (fludarabine phosphate and cyclophosphamide) and total-body irradiation before transplant. Patients can experience low blood cell counts after transplant. Using stem cells and immune cells collected from the donor's circulating blood may result in quicker recovery of blood counts and may be more effective in treating the patient's disease than using bone marrow.

Detailed Description: PRIMARY OBJECTIVES:

I. To demonstrate that use of PBSC in place of marrow as the source of lymphocytes and stem cells for nonmyeloablative transplants from related, haploidentical donors will not result in unacceptable rates of high-grade acute or chronic GVHD, non-relapse mortality or relapse compared to historical data on nonmyeloablative transplants from unrelated donors.

SECONDARY OBJECTIVES:

I. Estimates of the rates of neutrophil and platelet recovery, number of red blood cell (RBC) and platelet transfusions, incidences of graft failure, transplant-related toxicities, disease-free survival and overall survival.

OUTLINE:

Patients receive fludarabine intravenously (IV) over 30-60 minutes daily on days -6 through -2 and cyclophosphamide IV over 1-2 hours on days -6, -5, and 3-4. Patients undergo total-body irradiation on day -1. Patients undergo donor peripheral blood stem cell transplant on day 0. Patients then receive tacrolimus IV once daily or orally (PO) twice daily (BID) on days 5-180 (may be continued if active GVHD is present), mycophenolate mofetil IV or PO thrice daily (TID) on days 5-35 (may be continued if GVHD present), and filgrastim IV beginning on day 5 until the absolute neutrophil count (ANC) is \>= 1,000/mm\^3 for three consecutive days.

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

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 46

Inclusion Criteria

Molecular based human leukocyte antigen (HLA) typing will be performed for the HLA-A, -B, -Cw, -DRB1 and -DQB1 loci to the resolution adequate to establish haplo-identity; a minimum match of 5/10 is required; an unrelated donor search is not required for a patient to be eligible for this protocol if the clinical situation dictates an urgent transplant; clinical urgency is defined as 6-8 weeks from referral or low-likelihood of finding a matched, unrelated donor
Acute leukemias (includes T lymphoblastic lymphoma); remission is defined as < 5% blasts with no morphological characteristics of acute leukemia (e.g., Auer rods) in a bone marrow with > 20% cellularity, peripheral blood counts showing ANC > 1000/ul, including patients in complete remission with incomplete platelet recovery (CRp); if the marrow has < 20% cellularity due to treatment related cytotoxicity, but still has < 5% blasts, an exception may be made to include this patient up to principal investigator (PI) discretion
Acute lymphoblastic leukemia in high risk first complete remission (CR1) as defined by at least one of the following:
- Adverse cytogenetics including but not limited to t(9;22), t(1;19), t(4;11), mixed lineage leukemia (MLL) rearrangements
- White blood cell counts > 30,000/mcL
- Patients over 30 years of age
- Time to complete remission > 4 weeks
- Presence of extramedullary disease
- Minimal residual disease
- Other risk factors determined by the patient's attending physician to be high risk features requiring transplantation
Acute myelogenous leukemia in high risk CR1 as defined by at least one of the following:
- Greater than 1 cycle of induction therapy required to achieve remission
- Preceding myelodysplastic syndrome (MDS)
- Presence of fms-like tyrosine kinase receptor-3 (Flt3) abnormalities
- French-American-British (FAB) M6 or M7 leukemia, or
- Adverse cytogenetics for overall survival such as:
  - Those associated with MDS
  - Complex karyotype (>= 3 abnormalities); or
  - Any of the following: inv(3) or t(3;3), t(6;9), t(6;11), + 8 [alone or with other abnormalities except for t(8;21), t(9;11), inv(16) or t(16;16)], t(11;19)(q23;p13.1)]
- Other risk factors determined by the patient's attending physician to be high risk features requiring transplantation
Acute leukemias in second (2nd) or subsequent remission
Biphenotypic/undifferentiated leukemias in first (1st) or subsequent complete remission (CR)
High-risk MDS status-post cytotoxic chemotherapy
Burkitt's lymphoma: second or subsequent CR
Chemotherapy-sensitive (at least stable disease) large cell, mantle cell or Hodgkin's lymphomas that have failed at least 1 prior regimen of multi-agent chemotherapy and are ineligible for an autologous transplant
Marginal zone B-cell lymphoma or follicular lymphoma that has progressed after at least two prior therapies (excluding single agent Rituxan)
Multiple myeloma (MM) stage II or III patients who have progressed after an initial response to chemotherapy or autologous hematopoietic stem cell transplantation (HSCT) or MM patients with refractory disease who may benefit from tandem autologous-nonmyeloablative allogeneic transplant
Left ventricular ejection fraction at rest must be >= 35%
Bilirubin =< 2.5 mg/dL
Alanine aminotransferase (ALT) < 5 x upper limit of normal (ULN)
Aspartate aminotransferase (AST) < 5 x ULN
Alkaline phosphatase < 5 x ULN
Serum creatinine within normal range for age, or if serum creatinine outside normal range for age, then renal function (creatinine clearance or glomerular filtration rate [GFR]) > 40 mL/min/1.73m^2
Forced expiratory volume in one second (FEV1), forced vital capacity (FVC), diffusion capacity of carbon monoxide (DLCO) (diffusion capacity) >= 40% predicted (corrected for hemoglobin); if unable to perform pulmonary function tests, then oxygen (O2) saturation > 92% on room air
Karnofsky/Lansky score >= 60%
Patients who have received a prior allogeneic HSCT and who have either rejected their grafts or who have become tolerant of their grafts with no active GVHD requiring immunosuppressive therapy
Patients will undergo standard pre-transplant work-up as dictated by standard practice guidelines the results of which may be used for screening for this study
DONOR: Donors must be HLA-haploidentical first-degree relatives of the patient; eligible donors include biological parents, siblings, or children, or half-siblings
DONOR: Age >= 12 years
DONOR: Weight >= 40 kg
DONOR: Ability of donors < 18 years of age to undergo apheresis without use of a vascular access device; vein check must be performed and verified by an apheresis nurse prior to arrival at the Seattle Cancer Care Alliance (SCCA)
DONOR: Donors must meet the selection criteria as defined by the Foundation for the Accreditation of Cell Therapy (FACT) and will be screened per the American Association of Blood Banks (AABB) guidelines

Exclusion Criteria

HLA-matched or single allele-mismatched donor able to donate
Pregnancy or breast-feeding
Current uncontrolled bacterial, viral or fungal infection (currently taking medication with evidence of progression of clinical symptoms or radiologic findings)
Patients with primary idiopathic myelofibrosis
DONOR: Positive anti-donor HLA antibody

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Treatment (nonmyeloablative HCT, TBI)	Mycophenolate Mofetil	Patients receive fludarabine IV over 30-60 minutes daily on days -6 through -2 and cyclophosphamide IV over 1-2 hours on days -6, -5, and 3-4. Patients undergo total-body irradiation on day -1. Patients undergo donor peripheral blood stem cell transplant on day 0. Patients then receive tacrolimus IV once daily or PO BID on days 5-180 (may be continued if active GvHD is present), mycophenolate mofetil IV or PO TID on days 5-35 (may be continued if GvHD present), and filgrastim IV beginning on day 5 until the ANC is \>= 1,000/mm\^3 for three consecutive days.
Treatment (nonmyeloablative HCT, TBI)	Filgrastim	Patients receive fludarabine IV over 30-60 minutes daily on days -6 through -2 and cyclophosphamide IV over 1-2 hours on days -6, -5, and 3-4. Patients undergo total-body irradiation on day -1. Patients undergo donor peripheral blood stem cell transplant on day 0. Patients then receive tacrolimus IV once daily or PO BID on days 5-180 (may be continued if active GvHD is present), mycophenolate mofetil IV or PO TID on days 5-35 (may be continued if GvHD present), and filgrastim IV beginning on day 5 until the ANC is \>= 1,000/mm\^3 for three consecutive days.
Treatment (nonmyeloablative HCT, TBI)	Nonmyeloablative Allogeneic Hematopoietic Stem Cell Transplantation	Patients receive fludarabine IV over 30-60 minutes daily on days -6 through -2 and cyclophosphamide IV over 1-2 hours on days -6, -5, and 3-4. Patients undergo total-body irradiation on day -1. Patients undergo donor peripheral blood stem cell transplant on day 0. Patients then receive tacrolimus IV once daily or PO BID on days 5-180 (may be continued if active GvHD is present), mycophenolate mofetil IV or PO TID on days 5-35 (may be continued if GvHD present), and filgrastim IV beginning on day 5 until the ANC is \>= 1,000/mm\^3 for three consecutive days.
Treatment (nonmyeloablative HCT, TBI)	Peripheral Blood Stem Cell Transplantation	Patients receive fludarabine IV over 30-60 minutes daily on days -6 through -2 and cyclophosphamide IV over 1-2 hours on days -6, -5, and 3-4. Patients undergo total-body irradiation on day -1. Patients undergo donor peripheral blood stem cell transplant on day 0. Patients then receive tacrolimus IV once daily or PO BID on days 5-180 (may be continued if active GvHD is present), mycophenolate mofetil IV or PO TID on days 5-35 (may be continued if GvHD present), and filgrastim IV beginning on day 5 until the ANC is \>= 1,000/mm\^3 for three consecutive days.
Treatment (nonmyeloablative HCT, TBI)	Total-Body Irradiation	Patients receive fludarabine IV over 30-60 minutes daily on days -6 through -2 and cyclophosphamide IV over 1-2 hours on days -6, -5, and 3-4. Patients undergo total-body irradiation on day -1. Patients undergo donor peripheral blood stem cell transplant on day 0. Patients then receive tacrolimus IV once daily or PO BID on days 5-180 (may be continued if active GvHD is present), mycophenolate mofetil IV or PO TID on days 5-35 (may be continued if GvHD present), and filgrastim IV beginning on day 5 until the ANC is \>= 1,000/mm\^3 for three consecutive days.
Treatment (nonmyeloablative HCT, TBI)	Cyclophosphamide	Patients receive fludarabine IV over 30-60 minutes daily on days -6 through -2 and cyclophosphamide IV over 1-2 hours on days -6, -5, and 3-4. Patients undergo total-body irradiation on day -1. Patients undergo donor peripheral blood stem cell transplant on day 0. Patients then receive tacrolimus IV once daily or PO BID on days 5-180 (may be continued if active GvHD is present), mycophenolate mofetil IV or PO TID on days 5-35 (may be continued if GvHD present), and filgrastim IV beginning on day 5 until the ANC is \>= 1,000/mm\^3 for three consecutive days.
Treatment (nonmyeloablative HCT, TBI)	Fludarabine Phosphate	Patients receive fludarabine IV over 30-60 minutes daily on days -6 through -2 and cyclophosphamide IV over 1-2 hours on days -6, -5, and 3-4. Patients undergo total-body irradiation on day -1. Patients undergo donor peripheral blood stem cell transplant on day 0. Patients then receive tacrolimus IV once daily or PO BID on days 5-180 (may be continued if active GvHD is present), mycophenolate mofetil IV or PO TID on days 5-35 (may be continued if GvHD present), and filgrastim IV beginning on day 5 until the ANC is \>= 1,000/mm\^3 for three consecutive days.
Treatment (nonmyeloablative HCT, TBI)	Tacrolimus	Patients receive fludarabine IV over 30-60 minutes daily on days -6 through -2 and cyclophosphamide IV over 1-2 hours on days -6, -5, and 3-4. Patients undergo total-body irradiation on day -1. Patients undergo donor peripheral blood stem cell transplant on day 0. Patients then receive tacrolimus IV once daily or PO BID on days 5-180 (may be continued if active GvHD is present), mycophenolate mofetil IV or PO TID on days 5-35 (may be continued if GvHD present), and filgrastim IV beginning on day 5 until the ANC is \>= 1,000/mm\^3 for three consecutive days.

Primary Outcome Measures

Name	Time	Method
Percentage of Participants With Chronic Graft Versus Host Disease	Up to 2 years post-transplant	Scored according to the National Cancer Institute criteria. Mild-to-severe chronic GVHD at 2 years.
Incidence of Grades III/IV Acute Graft Versus Host Disease	At day 84	Grading determined by organ system stages. Grade III/IV acute graft versus host disease is defined as skin: stage IV, liver: stages II-IV, and/or gastrointestinal tract: stages II-IV.
Relapse of Malignancy After Transplantation	Up to 7 years	Defined by either morphological or cytogenetic evidence of acute leukemia consistent with pre-transplant features, or radiologic evidence of lymphoma progression. When in doubt, the diagnosis of recurrent or progressive lymphoma should be documented by tissue biopsy.
Non-relapse Mortality at 1 Year	Up to 1 year	Cumulative incidence of death without evidence of disease progression at 1 year

Secondary Outcome Measures

Name	Time	Method
Number of Platelet Transfusions	Day 0-100	Number platelet transfusions given to the patient between day 0 and day 100 post transplant
Time to Platelet Recovery	Up to day 84 post-transplant	The first day of a sustained platelet count \> 20,000/mm\^3 with no platelet transfusions in the preceding seven days.
Point Estimate of Overall Survival at 3 Years	3 years	Kaplan Meier estimate of the percentage of participants with overall survival at 3 years
Time to Neutrophil Recovery	Up to day 84 post-transplant	Achievement of an absolute neutrophil count greater or equal to 500/mm\^3 for three consecutive measurements on different days. The first of the three days will be designated the day of neutrophil recovery.
Incidence of Primary Graft Failure	At day 84	Defined as \< 5% donor CD3 chimerism. Chimerism will be measured by short tandem repeat-polymerase chain reaction on peripheral blood sorted into CD3 and CD33 cell fractions.
Disease-free Survival	3 years from the date of transplant	Defined as being alive and in remission by \< 5% blasts by bone marrow morphology for patients with myeloid malignancies and CT or PET imaging for patients with lymphoid malignancies at the time of the assessment
Toxicity of Treatment Regimen Determined by Number of Adverse Events Per Organ System	Up to day 90	Assessed by Common Terminology Criteria for Adverse Events version 3.0. The incidence of all adverse events greater or equal to grade 3 was determined.
Number of Red Blood Cell Transfusions	Day 0-100	Number of units of RBCs given to the patient between day 0 and day 100 post transplant