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

• ClinicalTrials.gov Identifier: NCT01028716
• Recruitment Status: Recruiting
• First Posted: December 9, 2009
• Last Update Posted: January 20, 2021
• Sponsor: Fred Hutchinson Cancer Research Center
• Collaborator: National Cancer Institute (NCI)
• Information provided by (Responsible Party): Fred Hutchinson Cancer Research Center

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Acute Biphenotypic Leukemia; Acute Erythroid Leukemia in Remission; Acute Leukemia in Remission; Acute Lymphoblastic Leukemia in Remission; Acute Myeloid Leukemia Arising From Previous Myelodysplastic Syndrome; Acute Myeloid Leukemia in Remission; Acute Myeloid Leukemia With FLT3/ITD Mutation; Acute Myeloid Leukemia With Inv(3) (q21.3;q26.2); GATA2, MECOM; Acute Myeloid Leukemia With Multilineage Dysplasia; Acute Myeloid Leukemia With t(6;9) (p23;q34.1); DEK-NUP214; 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); B Acute Lymphoblastic Leukemia With t(9;22)(q34.1;q11.2); BCR-ABL1; 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	Drug: Cyclophosphamide; Biological: Filgrastim; Drug: Fludarabine Phosphate; Procedure: Laboratory Biomarker Analysis; Drug: Mycophenolate Mofetil; Procedure: Nonmyeloablative Allogeneic Hematopoietic Stem Cell Transplantation; Procedure: Peripheral Blood Stem Cell Transplantation; Drug: Tacrolimus; Radiation: Total-Body Irradiation; Drug: Fludarabine	Phase 2

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 Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 50 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: 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
• Actual Study Start Date: February 8, 2010
• Estimated Primary Completion Date: January 4, 2023
• Estimated Study Completion Date: January 4, 2023

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures :

1. Cumulative incidence of non-relapse mortality, defined as death without evidence of disease progression [ Time Frame: Up to 1 year ]
2. Incidence of chronic graft versus host disease [ Time Frame: Up to 1 year post-transplant ]
   Scored according to the National Cancer Institute criteria. The time to onset of limited and extensive chronic graft versus host disease will be recorded.
3. Incidence of grades III/IV acute graft versus host disease [ Time Frame: 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.
4. Relapse of malignancy after transplantation [ Time Frame: 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.

Secondary Outcome Measures :

1. Donor cell engraftment [ Time Frame: Up to day 84 post-transplant ]
   Donor chimerism in the T-cell (CD3-positive) and granulocyte (CD33-positive) fractions of sorted peripheral blood greater or equal to 50%.
2. Infections [ Time Frame: Up to 7 years ]
   Reported by anatomic site, date of onset, organism and resolution, if any.
3. Neutrophil recovery [ Time Frame: 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.
4. Platelet recovery [ Time Frame: 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.
5. Primary graft failure [ Time Frame: 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.
6. Progression-free survival [ Time Frame: Time interval to relapse/recurrence, to death or to last follow-up, assessed for up to 7 years ]
   Defined as the minimum time interval to relapse/recurrence, to death or to last follow-up.
7. Secondary graft failure [ Time Frame: Up to day 84 post-transplant ]
   Initial recovery followed by neutropenia with < 5% donor chimerism. If no chimerism assays were performed and absolute neutrophil count is less than 500/mm^3, then it will be counted as a secondary graft failure.
8. Toxicity of treatment regimen [ Time Frame: 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 will be determined.

Eligibility Criteria

• Ages Eligible for Study: Child, Adult, Older Adult
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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

Contacts and Locations

Contacts

Contact: Rachel B. Salit; 206-667-1317; rsalit@fredhutch.org

Locations

United States, Washington

VA Puget Sound Health Care System; Withdrawn

Seattle, Washington, United States, 98101

Fred Hutch/University of Washington Cancer Consortium; Recruiting

Seattle, Washington, United States, 98109

Contact: Rachel B. Salit 206-667-1317 rsalit@fredhutch.org

Principal Investigator: Rachel B. Salit

Sponsors and Collaborators

Fred Hutchinson Cancer Research Center

National Cancer Institute (NCI)

Investigators

• Principal Investigator: Rachel B. Salit; Fred Hutch/University of Washington Cancer Consortium

More Information

• Responsible Party: Fred Hutchinson Cancer Research Center
• ClinicalTrials.gov Identifier: NCT01028716
• Other Study ID Numbers: 2372.00; NCI-2009-01433 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) ); 2372; 2372.00 ( Other Identifier: Fred Hutch/University of Washington Cancer Consortium ); P30CA015704 ( U.S. NIH Grant/Contract ); RG9213052 ( Other Identifier: Fred Hutch/University of Washington Cancer Consortium )
• First Posted: December 9, 2009
• Last Update Posted: January 20, 2021
• Last Verified: January 2021

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

Additional relevant MeSH terms:

Burkitt Lymphoma; Lymphoma; Leukemia; Leukemia, Myeloid; Multiple Myeloma; Neoplasms, Plasma Cell; Leukemia, Myeloid, Acute; Preleukemia; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Lymphoid; Lymphoma, Mantle-Cell; Hematologic Neoplasms; Lymphoma, Large-Cell, Anaplastic; Leukemia, Erythroblastic, Acute; Leukemia, Biphenotypic, Acute; Myelodysplastic Syndromes; Syndrome; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Disease; Pathologic Processes; Hemostatic Disorders; Vascular Diseases; Cardiovascular Diseases; Paraproteinemias; Blood Protein Disorders