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

Study Overview
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Brief Summary
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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
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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.

Official Title
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Nonmyeloablative Hematopoietic Cell Transplantation (HCT) for Patients With Hematologic Malignancies Using Related, HLA-Haploidentical Donors: A Phase II Trial of Peripheral Blood Stem Cells (PBSC) as the Donor Source

Conditions
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Acute Biphenotypic Leukemia, Acute Erythroid Leukemia in Remission, Acute Leukemia in Remission, Acute Lymphoblastic Leukemia in Remission, Acute Myeloid Leukaemia With Prior Myelodysplastic Syndrome, Acute Myeloid Leukemia in Remission, Acute Myeloid Leukemia With FLT3/ITD Mutation, Acute Myeloid Leukemia With Inv(3)(Q21Q26.2); RPN1-EVI1, Acute Myeloid Leukemia With Multilineage Dysplasia, Acute Myeloid Leukemia With t(6;9), Acute Undifferentiated Leukemia, Adult Acute Lymphoblastic Leukemia in Complete Remission, B Acute Lymphoblastic Leukemia With T(1;19)(Q23;P13.3); E2A-PBX1 (TCF3-PBX1), Ph+ ALL, Burkitt Lymphoma, Childhood Acute Lymphoblastic Leukemia in Complete Remission, DS Stage II Plasma Cell Myeloma, DS Stage III Plasma Cell Myeloma, Myelodysplastic Syndrome, Recurrent Anaplastic Large Cell Lymphoma, Blasts Under 5 Percent of Bone Marrow Nucleated Cells, Recurrent Follicular Lymphoma, Recurrent Hodgkin Lymphoma, Recurrent Mantle Cell Lymphoma, Recurrent Marginal Zone Lymphoma, Recurrent Plasma Cell Myeloma, Refractory Plasma Cell Myeloma, Secondary Acute Myeloid Leukemia, T Lymphoblastic Lymphoma, Hematopoietic Cell Transplant Recipient

Intervention / Treatment
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* 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


Participation Criteria
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Eligibility Criteria
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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
Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (nonmyeloablative HCT, TBI)<br>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. | Drug: Cyclophosphamide<br>* Given IV<br>* Other names: WR- 138719;Biological: Filgrastim<br>* Given SQ<br>* Other names: Zarxio;Drug: Fludarabine Phosphate<br>* Given IV<br>* Other names: SH T 586;Drug: Mycophenolate Mofetil<br>* Given PO<br>* Other names: MMF;Procedure: Nonmyeloablative Allogeneic Hematopoietic Stem Cell Transplantation<br>* Undergo PBSC<br>* Other names: NST;Procedure: Peripheral Blood Stem Cell Transplantation<br>* Undergo PBSC<br>* Other names: Peripheral Stem Cell Transplantation;Drug: Tacrolimus<br>* Given IV or PO<br>* Other names: Protopic;Radiation: Total-Body Irradiation<br>* Undergo total-body irradiation (TBI)<br>* Other names: Whole-Body Irradiation;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Non-relapse Mortality at 1 Year | Cumulative incidence of death without evidence of disease progression at 1 year | Up to 1 year | 
| Percentage of Participants With Chronic Graft Versus Host Disease | Scored according to the National Cancer Institute criteria. Mild-to-severe chronic GVHD at 2 years. | Up to 2 years post-transplant | 
| Incidence of Grades III/IV Acute Graft Versus Host Disease | 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. | At day 84 | 
| Relapse of Malignancy After Transplantation | 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. | Up to 7 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Neutrophil Recovery | 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. | Up to day 84 post-transplant | 
| Time to Platelet Recovery | The first day of a sustained platelet count > 20,000/mm^3 with no platelet transfusions in the preceding seven days. | Up to day 84 post-transplant | 
| Incidence of Primary Graft Failure | 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. | At day 84 | 
| Disease-free Survival | 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 | 3 years from the date of transplant | 
| Toxicity of Treatment Regimen Determined by Number of Adverse Events Per Organ System | 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. | Up to day 90 | 
| Number of Red Blood Cell Transfusions | Number of units of RBCs given to the patient between day 0 and day 100 post transplant | Day 0-100 | 
| Number of Platelet Transfusions | Number platelet transfusions given to the patient between day 0 and day 100 post transplant | Day 0-100 | 
| Point Estimate of Overall Survival at 3 Years | Kaplan Meier estimate of the percentage of participants with overall survival at 3 years | 3 years |