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

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

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.

Study Overview

• Status: Terminated
• Conditions: Recurrent Hodgkin Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Burkitt Lymphoma; Secondary Acute Myeloid Leukemia; Myelodysplastic Syndrome; Refractory Plasma Cell Myeloma; Recurrent Plasma Cell Myeloma; Acute Leukemia in Remission; Acute Undifferentiated Leukemia; Acute Biphenotypic Leukemia; DS Stage II Plasma Cell Myeloma; DS Stage III Plasma Cell Myeloma; Acute Myeloid Leukemia With FLT3/ITD Mutation; Recurrent Follicular Lymphoma; Acute Myeloid Leukemia in Remission; T Lymphoblastic Lymphoma; Acute Lymphoblastic Leukemia in Remission; Hematopoietic Cell Transplant Recipient; Recurrent Anaplastic Large Cell Lymphoma; Acute Myeloid Leukemia With Multilineage Dysplasia; Blasts Under 5 Percent of Bone Marrow Nucleated Cells; Adult Acute Lymphoblastic Leukemia in Complete Remission; Acute Erythroid Leukemia in Remission; Childhood Acute Lymphoblastic Leukemia in Complete Remission; Ph+ ALL; Acute Myeloid Leukaemia With Prior Myelodysplastic Syndrome; Acute Myeloid Leukemia With Inv(3)(Q21Q26.2); RPN1-EVI1; Acute Myeloid Leukemia With t(6;9); B Acute Lymphoblastic Leukemia With T(1;19)(Q23;P13.3); E2A-PBX1 (TCF3-PBX1)
• Intervention / Treatment: Drug: Cyclophosphamide; Drug: Mycophenolate Mofetil; Drug: Fludarabine Phosphate; Drug: Tacrolimus; Procedure: Nonmyeloablative Allogeneic Hematopoietic Stem Cell Transplantation; Procedure: Peripheral Blood Stem Cell Transplantation; Radiation: Total-Body Irradiation; Biological: Filgrastim

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.

• Study Type: Interventional
• Enrollment (Actual): 46
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Washington
    • Seattle, Washington, United States, 98109
      • Fred Hutch/University of Washington Cancer Consortium

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Treatment (nonmyeloablative HCT, TBI); 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; Given IV; Other Names: Cytoxan; CTX; (-)-Cyclophosphamide; 2H-1,3,2-Oxazaphosphorine, 2-[bis(2-chloroethyl)amino]tetrahydro-, 2-oxide, monohydrate; Carloxan; Ciclofosfamida; Ciclofosfamide; Cicloxal; Clafen; Claphene; CP monohydrate; CYCLO-cell; Cycloblastin; Cycloblastine; Cyclophospham; Cyclophosphamid monohydrate; Cyclophosphamidum; Cyclophosphan; Cyclophosphane; Cyclophosphanum; Cyclostin; Cyclostine; Cytophosphan; Cytophosphane; Fosfaseron; Genoxal; Genuxal; Ledoxina; Mitoxan; Neosar; Revimmune; Syklofosfamid; WR- 138719; Drug: Mycophenolate Mofetil; Given PO; Other Names: Cellcept; MMF; Drug: Fludarabine Phosphate; Given IV; Other Names: 2-F-ara-AMP; Beneflur; Fludara; 9H-Purin-6-amine, 2-fluoro-9-(5-O-phosphono-.beta.-D-arabinofuranosyl)-; SH T 586; Drug: Tacrolimus; Given IV or PO; Other Names: Prograf; Hecoria; FK 506; Fujimycin; Protopic; Procedure: Nonmyeloablative Allogeneic Hematopoietic Stem Cell Transplantation; Undergo PBSC; Other Names: NST; Non-myeloablative allogeneic transplant; Nonmyeloablative Stem Cell Transplantation; Procedure: Peripheral Blood Stem Cell Transplantation; Undergo PBSC; Other Names: PBPC transplantation; Peripheral Blood Progenitor Cell Transplantation; Peripheral Stem Cell Support; Peripheral Stem Cell Transplantation; Peripheral Stem Cell Transplant; Radiation: Total-Body Irradiation; Undergo total-body irradiation (TBI); Other Names: Whole-Body Irradiation; TOTAL BODY IRRADIATION; Biological: Filgrastim; Given SQ; Other Names: G-CSF; r-metHuG-CSF; Neupogen; Recombinant Methionyl Human Granulocyte Colony Stimulating Factor; rG-CSF; Tevagrastim; Zarxio; Filgrastim XM02; Tbo-filgrastim; Filgrastim-sndz

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Fred Hutchinson Cancer Center
• Investigators: Principal Investigator: Rachel B. Salit, Fred Hutch/University of Washington Cancer Consortium

Study record dates

Study Major Dates

• Study Start (Actual): May 19, 2010
• Primary Completion (Actual): October 7, 2021
• Study Completion (Actual): October 7, 2021

Study Registration Dates

• First Submitted: December 8, 2009
• First Submitted That Met QC Criteria: December 8, 2009
• First Posted (Estimate): December 9, 2009

Study Record Updates

• Last Update Posted (Actual): January 23, 2023
• Last Update Submitted That Met QC Criteria: January 4, 2023
• Last Verified: January 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Cardiovascular Diseases; Vascular Diseases; Virus Diseases; Infections; Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Lymphoma, Non-Hodgkin; Neoplasms by Site; Disease Attributes; Disease; Bone Marrow Diseases; Hematologic Diseases; Hemorrhagic Disorders; Myeloproliferative Disorders; Hemostatic Disorders; Paraproteinemias; Blood Protein Disorders; DNA Virus Infections; Tumor Virus Infections; Precancerous Conditions; Epstein-Barr Virus Infections; Herpesviridae Infections; Lymphoma, B-Cell; Lymphoma, T-Cell; Lymphoma; Syndrome; Myelodysplastic Syndromes; Hematologic Neoplasms; Multiple Myeloma; Neoplasms, Plasma Cell; Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Recurrence; Preleukemia; Burkitt Lymphoma; Lymphoma, Mantle-Cell; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Lymphoid; Leukemia, Erythroblastic, Acute; Lymphoma, Large-Cell, Anaplastic; Leukemia, Biphenotypic, Acute; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Antirheumatic Agents; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Anti-Bacterial Agents; Adjuvants, Immunologic; Antibiotics, Antineoplastic; Antitubercular Agents; Antibiotics, Antitubercular; Calcineurin Inhibitors; Cyclophosphamide; Lenograstim; Fludarabine; Fludarabine phosphate; Tacrolimus; Mycophenolic Acid
• Other Study ID Numbers: 2372.00 (Other Identifier: Fred Hutch/University of Washington Cancer Consortium); NCI-2009-01433 (Other Identifier: CTRP (Clinical Trial Reporting Program)); 2372; RG9213052 (Other Identifier: Fred Hutch/University of Washington Cancer Consortium)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No