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Low-Dose Total Body Irradiation and Donor Peripheral Blood Stem Cell Transplant Followed by Donor Lymphocyte Infusion in Treating Patients With Non-Hodgkin Lymphoma, Chronic Lymphocytic Leukemia, or Multiple Myeloma

Primary Purpose

Adult Nasal Type Extranodal NK/T-cell Lymphoma, Anaplastic Large Cell Lymphoma, Angioimmunoblastic T-cell Lymphoma

Status
Completed
Phase
Not Applicable
Locations
International
Study Type
Interventional
Intervention
chemotherapy
total-body irradiation
peripheral blood stem cell transplantation
cyclosporine
mycophenolate mofetil
allogeneic hematopoietic stem cell transplantation
therapeutic allogeneic lymphocytes
Sponsored by
Fred Hutchinson Cancer Center
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Adult Nasal Type Extranodal NK/T-cell Lymphoma

Eligibility Criteria

50 Years - 65 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria: Patients aged > 49 years and < 66 years with NHL, CLL and multiple myeloma who are not eligible for autologous transplantation or have failed prior autologous transplantation; patients with NHL and CLL must have failed prior therapy with an alkylating agent and/or fludarabine; patients with multiple myeloma must have stage II or III disease and received prior chemotherapy Patients < 50 years of age with NHL, CLL and multiple myeloma at high risk of regimen related toxicity through prior autologous transplant or through pre-existing chronic disease affecting kidneys, liver, lungs, and heart will be considered on a case by case basis and presented to professional clinical counselor (PCC) Patients < 66 years of age with other diseases treatable by allogeneic bone marrow transplant (BMT) whom through pre-existing chronic disease affecting kidneys, liver, lungs, and heart are considered to be at high risk for regimen related toxicity using standard high dose regimens; autografting must also be contraindicated in these patients and they must be approved for this protocol by both PCC and by the principal investigator; the following diseases are the likely candidates but other less common diseases may be considered and approved by PCC: Myelodysplastic syndromes Myeloproliferative syndromes Acute leukemia in remission Chronic myelogenous leukemia (CML) in 2nd chronic phase Hodgkin's disease Selected patients with any of the above diagnosis who are (a) older than 65 years and < 75 years with a Karnofsky score >= 70 and who, apart from age, fulfill eligibility criteria, or (b) < 66 years but ineligible solely because of renal dysfunction; these patients must be approved for transplant by both PCC and the principal investigator DONOR: Human leukocyte antigen (HLA) genotypically identical sibling DONOR: Donor must consent to filgrastim (G-CSF) administration and leukapheresis DONOR: Donor must have adequate veins for leukapheresis or agree to placement of central venous catheter (femoral, subclavian) DONOR: Age < 75 Exclusion Criteria: Eligible for autologous transplantation Patients with rapidly progressive high grade NHL History of central nervous system (CNS) involvement with disease Fertile men or women unwilling to use contraceptive techniques during and for 12 months following treatment Females who are pregnant Patients with a creatinine clearance < 50 ml/min Cardiac ejection fraction < 40% or cardiac failure requiring therapy Severe defects in pulmonary function testing (defects are currently categorized as mild, moderate and severe) as defined by the pulmonary consultant, or receiving supplementary continuous oxygen Total bilirubin > 2 x the upper limit of normal Serum glutamate pyruvate transaminase (SGPT) and serum glutamic oxaloacetic transaminase (SGOT) 4 x the upper limit of normal Karnofsky score < 50 Patients with poorly controlled hypertension DONOR: Identical twin DONOR: Age less than 12 years DONOR: Pregnancy DONOR: Infection with human immunodeficiency virus (HIV) DONOR: Inability to achieve adequate venous access DONOR: Known allergy to G-CSF DONOR: Current serious systemic illness DONOR: Failure to meet Fred Hutchinson Cancer Research Center (FHCRC) criteria for donation as described in the Standard Practice Guidelines

Sites / Locations

  • City of Hope Medical Center
  • Stanford University Hospitals and Clinics
  • Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium
  • Universitaet Leipzig
  • University of Torino

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Treatment (irradiation, transplant, immunosuppression, DLI)

Arm Description

CYTOREDUCTION: If necessary, patients with advanced malignancies undergo cytoreductive chemotherapy to reduce tumor size at discretion of primary physician and study investigators. CONDITIONING REGIMEN: Patients undergo low-dose total-body irradiation followed by allogeneic PBSC transplant on day 0. IMMUNOSUPPRESSION: Patients receive cyclosporine IV BID on days -1 to 0 and then PO BID on days 1-35 with taper to day 56. Patients also receive mycophenolate mofetil PO BID on days 0-27. POST-TRANSPLANT DLI: Patients with mixed chimerism on day 56 and no evidence of GVHD undergo DLI over 30 minutes on day 65 and may receive up to 3 additional infusions in the absence of GVHD and disease progression or persistence. Patients who have not achieved mixed chimerism at day 56 undergo DLI if complete response is not obtained after a 2 month monitoring period.

Outcomes

Primary Outcome Measures

Incidence of GVHD, myelosuppression, and infections
At the conclusion of the study, all unexpected toxicities will be summarized and reported.
Greater than 10% incidence of treatment-related mortality (TRM) after PBSC infusion, defined as death without evidence of disease progression
Greater than 20% incidence of TRM after DLI, defined as death without evidence of disease progression
Proportion of patients who successfully achieve mixed chimerism
The proportion of patients who successfully establish mixed chimerism in each group (patients with NHL, CLL or multiple myeloma vs patients with other malignancies) will be estimated and corresponding confidence intervals will be presented.
Proportion of patients with mixed chimerism who successfully achieve full donor chimerism
The proportion of patients with mixed chimerism who are successfully converted to full donor chimerism in each group (patients with NHL, CLL or multiple myeloma vs patients with other malignancies) will be estimated and corresponding confidence intervals will be presented.

Secondary Outcome Measures

Response of malignancy to DLI
Examined separately in the two groups of patients, and reported in a descriptive manner with confidence intervals presented.
Incidence of myelosuppression after initial PBSC transplant
Defined as (absolute neutrophil count [ANC] < 500 for > 2 days, platelets < 20,000 for > 2 days). Examined separately in the two groups of patients, and reported in a descriptive manner with confidence intervals presented.
Incidence of aplasia after DLI
Examined separately in the two groups of patients, and reported in a descriptive manner with confidence intervals presented.
Incidence of grades 2-4 acute GVHD after DLI
Examined separately in the two groups of patients, and reported in a descriptive manner with confidence intervals presented.
Incidence of grades 2-4 acute GVHD after PBSC infusion
Examined separately in the two groups of patients, and reported in a descriptive manner with confidence intervals presented.
Incidence of chronic extensive GVHD after DLI
Examined separately in the two groups of patients, and reported in a descriptive manner with confidence intervals presented.
Dose of cluster of differentiation (CD)3+ cells required to convert mixed to full lymphoid chimeras
Examined separately in the two groups of patients, and reported in a descriptive manner with confidence intervals presented.
Incidence of non-relapse mortality
Examined separately in the two groups of patients, and reported in a descriptive manner with confidence intervals presented.

Full Information

First Posted
November 1, 1999
Last Updated
December 24, 2019
Sponsor
Fred Hutchinson Cancer Center
Collaborators
National Heart, Lung, and Blood Institute (NHLBI), National Cancer Institute (NCI)
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1. Study Identification

Unique Protocol Identification Number
NCT00003196
Brief Title
Low-Dose Total Body Irradiation and Donor Peripheral Blood Stem Cell Transplant Followed by Donor Lymphocyte Infusion in Treating Patients With Non-Hodgkin Lymphoma, Chronic Lymphocytic Leukemia, or Multiple Myeloma
Official Title
Induction of Mixed Hematopoietic Chimerism in Older Patients With B-Cell Malignancies and in Selected Other Diseases, Using Low Dose TBI , PBSC Infusion and Post-Transplant Immunosuppression With Cyclosporine and Mycophenolate Mofetil to be Followed by Donor Lymphocyte Infusion: A Pilot Study.
Study Type
Interventional

2. Study Status

Record Verification Date
December 2019
Overall Recruitment Status
Completed
Study Start Date
September 1997 (Actual)
Primary Completion Date
April 2002 (Actual)
Study Completion Date
April 2002 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Fred Hutchinson Cancer Center
Collaborators
National Heart, Lung, and Blood Institute (NHLBI), National Cancer Institute (NCI)

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
This pilot clinical trial studies low-dose total body irradiation and donor peripheral blood stem cell transplant followed by donor lymphocyte infusion in treatment patients with non-Hodgkin lymphoma, chronic lymphocytic leukemia, or multiple myeloma. Giving total-body irradiation before a donor peripheral blood stem cell transplant helps stop the growth of cells in the bone marrow, including normal blood-forming cells (stem cells) and cancer cells. When healthy stem cells from a donor are infused into the patient they may help the patient's bone marrow make stem cells, red blood cells, white blood cells, and platelets. Once the donated stem cells begin working, the patient's immune system may see the remaining cancer cells as not belonging in the patient's body and destroy them. Giving an infusion of the donor's white blood cells (donor lymphocyte infusion) may boost this effect.
Detailed Description
PRIMARY OBJECTIVES: I. To determine whether mixed hematopoietic chimerism can be safely established using a non-myeloablative conditioning regimen in patients with non-Hodgkin lymphoma (NHL), chronic lymphocytic leukemia (CLL) and multiple myeloma. II. To determine whether mixed chimerism, established with non- myeloablative conditioning regimens, can be safely converted to full donor hematopoietic chimerism by infusions of donor lymphocytes (DLI). OUTLINE: CYTOREDUCTION: If necessary, patients with advanced malignancies undergo cytoreductive chemotherapy to reduce tumor size at discretion of primary physician and study investigators. CONDITIONING REGIMEN: Patients undergo low-dose total-body irradiation followed by allogeneic peripheral blood stem cell (PBSC) transplant on day 0. IMMUNOSUPPRESSION: Patients receive cyclosporine intravenously (IV) twice daily (BID) on days -1 to 0 and then orally (PO) BID on days 1-35 with taper to day 56. Patients also receive mycophenolate mofetil PO BID on days 0-27. POST-TRANSPLANT DLI: Patients with mixed chimerism on day 56 and no evidence of graft-vs-host disease (GVHD) undergo DLI over 30 minutes on day 65 and may receive up to 3 additional infusions in the absence of GVHD and disease progression or persistence. Patients who have not achieved mixed chimerism at day 56 undergo DLI if complete response is not obtained after a 2 month monitoring period. After completion of study treatment, patients are followed up at 4, 6, 12, 18, and 24 months and then annually thereafter.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Adult Nasal Type Extranodal NK/T-cell Lymphoma, Anaplastic Large Cell Lymphoma, Angioimmunoblastic T-cell Lymphoma, Cutaneous B-cell Non-Hodgkin Lymphoma, Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue, Hepatosplenic T-cell Lymphoma, Intraocular Lymphoma, Nodal Marginal Zone B-cell Lymphoma, Noncutaneous Extranodal Lymphoma, Peripheral T-cell Lymphoma, Recurrent Adult Acute Lymphoblastic Leukemia, Recurrent Adult Burkitt Lymphoma, Recurrent Adult Diffuse Large Cell Lymphoma, Recurrent Adult Diffuse Mixed Cell Lymphoma, Recurrent Adult Diffuse Small Cleaved Cell Lymphoma, Recurrent Adult Grade III Lymphomatoid Granulomatosis, Recurrent Adult Immunoblastic Large Cell Lymphoma, Recurrent Adult Lymphoblastic Lymphoma, Recurrent Adult T-cell Leukemia/Lymphoma, Recurrent Cutaneous T-cell Non-Hodgkin Lymphoma, Recurrent Grade 1 Follicular Lymphoma, Recurrent Grade 2 Follicular Lymphoma, Recurrent Grade 3 Follicular Lymphoma, Recurrent Mantle Cell Lymphoma, Recurrent Marginal Zone Lymphoma, Recurrent Mycosis Fungoides/Sezary Syndrome, Recurrent Small Lymphocytic Lymphoma, Refractory Chronic Lymphocytic Leukemia, Refractory Hairy Cell Leukemia, Refractory Multiple Myeloma, Small Intestine Lymphoma, Splenic Marginal Zone Lymphoma, Stage II Multiple Myeloma, Stage III Multiple Myeloma, Testicular Lymphoma, Waldenström Macroglobulinemia

7. Study Design

Primary Purpose
Treatment
Study Phase
Not Applicable
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
63 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Treatment (irradiation, transplant, immunosuppression, DLI)
Arm Type
Experimental
Arm Description
CYTOREDUCTION: If necessary, patients with advanced malignancies undergo cytoreductive chemotherapy to reduce tumor size at discretion of primary physician and study investigators. CONDITIONING REGIMEN: Patients undergo low-dose total-body irradiation followed by allogeneic PBSC transplant on day 0. IMMUNOSUPPRESSION: Patients receive cyclosporine IV BID on days -1 to 0 and then PO BID on days 1-35 with taper to day 56. Patients also receive mycophenolate mofetil PO BID on days 0-27. POST-TRANSPLANT DLI: Patients with mixed chimerism on day 56 and no evidence of GVHD undergo DLI over 30 minutes on day 65 and may receive up to 3 additional infusions in the absence of GVHD and disease progression or persistence. Patients who have not achieved mixed chimerism at day 56 undergo DLI if complete response is not obtained after a 2 month monitoring period.
Intervention Type
Drug
Intervention Name(s)
chemotherapy
Other Intervention Name(s)
chemo
Intervention Description
Undergo cytoreductive chemotherapy
Intervention Type
Radiation
Intervention Name(s)
total-body irradiation
Other Intervention Name(s)
TBI
Intervention Description
Undergo TBI
Intervention Type
Procedure
Intervention Name(s)
peripheral blood stem cell transplantation
Other Intervention Name(s)
PBPC transplantation, PBSC transplantation, peripheral blood progenitor cell transplantation, transplantation, peripheral blood stem cell
Intervention Description
Undergo allogeneic PBSC transplant
Intervention Type
Drug
Intervention Name(s)
cyclosporine
Other Intervention Name(s)
ciclosporin, cyclosporin, cyclosporin A, CYSP, Sandimmune
Intervention Description
Given IV or PO
Intervention Type
Drug
Intervention Name(s)
mycophenolate mofetil
Other Intervention Name(s)
Cellcept, MMF
Intervention Description
Given PO
Intervention Type
Procedure
Intervention Name(s)
allogeneic hematopoietic stem cell transplantation
Intervention Description
Undergo allogeneic PBSC transplant
Intervention Type
Biological
Intervention Name(s)
therapeutic allogeneic lymphocytes
Other Intervention Name(s)
ALLOLYMPH
Intervention Description
Undergo DLI
Primary Outcome Measure Information:
Title
Incidence of GVHD, myelosuppression, and infections
Description
At the conclusion of the study, all unexpected toxicities will be summarized and reported.
Time Frame
Up to 5 years
Title
Greater than 10% incidence of treatment-related mortality (TRM) after PBSC infusion, defined as death without evidence of disease progression
Time Frame
Within 65 days of transplant
Title
Greater than 20% incidence of TRM after DLI, defined as death without evidence of disease progression
Time Frame
Within 12 months of DLI
Title
Proportion of patients who successfully achieve mixed chimerism
Description
The proportion of patients who successfully establish mixed chimerism in each group (patients with NHL, CLL or multiple myeloma vs patients with other malignancies) will be estimated and corresponding confidence intervals will be presented.
Time Frame
Up to 5 years
Title
Proportion of patients with mixed chimerism who successfully achieve full donor chimerism
Description
The proportion of patients with mixed chimerism who are successfully converted to full donor chimerism in each group (patients with NHL, CLL or multiple myeloma vs patients with other malignancies) will be estimated and corresponding confidence intervals will be presented.
Time Frame
Up to 5 years
Secondary Outcome Measure Information:
Title
Response of malignancy to DLI
Description
Examined separately in the two groups of patients, and reported in a descriptive manner with confidence intervals presented.
Time Frame
Up to 5 years
Title
Incidence of myelosuppression after initial PBSC transplant
Description
Defined as (absolute neutrophil count [ANC] < 500 for > 2 days, platelets < 20,000 for > 2 days). Examined separately in the two groups of patients, and reported in a descriptive manner with confidence intervals presented.
Time Frame
Up to day 56
Title
Incidence of aplasia after DLI
Description
Examined separately in the two groups of patients, and reported in a descriptive manner with confidence intervals presented.
Time Frame
Up to day 90
Title
Incidence of grades 2-4 acute GVHD after DLI
Description
Examined separately in the two groups of patients, and reported in a descriptive manner with confidence intervals presented.
Time Frame
Up to day 90 post-DLI
Title
Incidence of grades 2-4 acute GVHD after PBSC infusion
Description
Examined separately in the two groups of patients, and reported in a descriptive manner with confidence intervals presented.
Time Frame
Up to day 56
Title
Incidence of chronic extensive GVHD after DLI
Description
Examined separately in the two groups of patients, and reported in a descriptive manner with confidence intervals presented.
Time Frame
Up to 1 year post-DLI
Title
Dose of cluster of differentiation (CD)3+ cells required to convert mixed to full lymphoid chimeras
Description
Examined separately in the two groups of patients, and reported in a descriptive manner with confidence intervals presented.
Time Frame
Up to 5 years
Title
Incidence of non-relapse mortality
Description
Examined separately in the two groups of patients, and reported in a descriptive manner with confidence intervals presented.
Time Frame
Up to 5 years

10. Eligibility

Sex
All
Minimum Age & Unit of Time
50 Years
Maximum Age & Unit of Time
65 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Patients aged > 49 years and < 66 years with NHL, CLL and multiple myeloma who are not eligible for autologous transplantation or have failed prior autologous transplantation; patients with NHL and CLL must have failed prior therapy with an alkylating agent and/or fludarabine; patients with multiple myeloma must have stage II or III disease and received prior chemotherapy Patients < 50 years of age with NHL, CLL and multiple myeloma at high risk of regimen related toxicity through prior autologous transplant or through pre-existing chronic disease affecting kidneys, liver, lungs, and heart will be considered on a case by case basis and presented to professional clinical counselor (PCC) Patients < 66 years of age with other diseases treatable by allogeneic bone marrow transplant (BMT) whom through pre-existing chronic disease affecting kidneys, liver, lungs, and heart are considered to be at high risk for regimen related toxicity using standard high dose regimens; autografting must also be contraindicated in these patients and they must be approved for this protocol by both PCC and by the principal investigator; the following diseases are the likely candidates but other less common diseases may be considered and approved by PCC: Myelodysplastic syndromes Myeloproliferative syndromes Acute leukemia in remission Chronic myelogenous leukemia (CML) in 2nd chronic phase Hodgkin's disease Selected patients with any of the above diagnosis who are (a) older than 65 years and < 75 years with a Karnofsky score >= 70 and who, apart from age, fulfill eligibility criteria, or (b) < 66 years but ineligible solely because of renal dysfunction; these patients must be approved for transplant by both PCC and the principal investigator DONOR: Human leukocyte antigen (HLA) genotypically identical sibling DONOR: Donor must consent to filgrastim (G-CSF) administration and leukapheresis DONOR: Donor must have adequate veins for leukapheresis or agree to placement of central venous catheter (femoral, subclavian) DONOR: Age < 75 Exclusion Criteria: Eligible for autologous transplantation Patients with rapidly progressive high grade NHL History of central nervous system (CNS) involvement with disease Fertile men or women unwilling to use contraceptive techniques during and for 12 months following treatment Females who are pregnant Patients with a creatinine clearance < 50 ml/min Cardiac ejection fraction < 40% or cardiac failure requiring therapy Severe defects in pulmonary function testing (defects are currently categorized as mild, moderate and severe) as defined by the pulmonary consultant, or receiving supplementary continuous oxygen Total bilirubin > 2 x the upper limit of normal Serum glutamate pyruvate transaminase (SGPT) and serum glutamic oxaloacetic transaminase (SGOT) 4 x the upper limit of normal Karnofsky score < 50 Patients with poorly controlled hypertension DONOR: Identical twin DONOR: Age less than 12 years DONOR: Pregnancy DONOR: Infection with human immunodeficiency virus (HIV) DONOR: Inability to achieve adequate venous access DONOR: Known allergy to G-CSF DONOR: Current serious systemic illness DONOR: Failure to meet Fred Hutchinson Cancer Research Center (FHCRC) criteria for donation as described in the Standard Practice Guidelines
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
David Maloney
Organizational Affiliation
Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium
Official's Role
Principal Investigator
Facility Information:
Facility Name
City of Hope Medical Center
City
Duarte
State/Province
California
ZIP/Postal Code
91010
Country
United States
Facility Name
Stanford University Hospitals and Clinics
City
Stanford
State/Province
California
ZIP/Postal Code
94305
Country
United States
Facility Name
Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium
City
Seattle
State/Province
Washington
ZIP/Postal Code
98109
Country
United States
Facility Name
Universitaet Leipzig
City
Leipzig
ZIP/Postal Code
D-04103
Country
Germany
Facility Name
University of Torino
City
Torino
ZIP/Postal Code
10126
Country
Italy

12. IPD Sharing Statement

Citations:
PubMed Identifier
32499241
Citation
Cooper JP, Storer BE, Granot N, Gyurkocza B, Sorror ML, Chauncey TR, Shizuru J, Franke GN, Maris MB, Boyer M, Bruno B, Sahebi F, Langston AA, Hari P, Agura ED, Lykke Petersen S, Maziarz RT, Bethge W, Asch J, Gutman JA, Olesen G, Yeager AM, Hubel K, Hogan WJ, Maloney DG, Mielcarek M, Martin PJ, Flowers MED, Georges GE, Woolfrey AE, Deeg JH, Scott BL, McDonald GB, Storb R, Sandmaier BM. Allogeneic hematopoietic cell transplantation with non-myeloablative conditioning for patients with hematologic malignancies: Improved outcomes over two decades. Haematologica. 2021 Jun 1;106(6):1599-1607. doi: 10.3324/haematol.2020.248187.
Results Reference
derived

Learn more about this trial

Low-Dose Total Body Irradiation and Donor Peripheral Blood Stem Cell Transplant Followed by Donor Lymphocyte Infusion in Treating Patients With Non-Hodgkin Lymphoma, Chronic Lymphocytic Leukemia, or Multiple Myeloma

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