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Allogeneic Transplantation Using Total Lymphoid Irradiation (TLI) and Anti-Thymocyte Globulin (ATG) for Older Patients With Hematologic Malignancies

Primary Purpose

Blood Cancer, Leukemia

Status
Completed
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Cyclosporine
Anti-thymocyte globulin (ATG)
Mycophenolate mofetil (MMF)
Filgrastim
Total Lymphoid Irradiation (TLI)
Sponsored by
Stanford University
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Blood Cancer

Eligibility Criteria

50 Years - 70 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

INCLUSION CRITERIA: Any patient with one of the following hematolymphoid malignancies or syndromes in whom allogeneic hematopoietic stem cell transplant (HST) is warranted. Specific disease categories include: Indolent advanced stage non-Hodgkin lymphomas Mantle cell lymphoma Chronic lymphocytic leukemia Hodgkin disease (Hodgkin's lymphoma) Acute leukemias in complete remission Aplastic anemia Paroxysmal nocturnal hemoglobinuria Myelodysplastic or myeloproliferative syndromes. Other selected malignancies/disorders may also be considered but must be approved by the transplant team and the Principal Investigator. Age > 50 years, or if < 50 years of age, considered to be at high risk for regimen-related toxicity associated with conventional myeloablative transplants due to pre-existing medical conditions or prior therapy. A fully human leukocyte antigen (HLA)-identical sibling or matched unrelated donor is available. Potential participants with one antigen mismatched donors can be considered but only after discussion with the transplant team and the Principal Investigator. Participant must be competent to give consent. EXCLUSION CRITERIA: Progressive hematolymphoid malignancies despite conventional therapies, or acute leukemias not in complete remission. Uncontrolled central nervous system (CNS) involvement with disease Fertile men or women unwilling to use contraceptive techniques during and for 12 months following treatment Pregnant Cardiac ejection fraction < 30% Uncontrolled cardiac failure Pulmonary diffusing capacity (DLCO) < 40% predicted Elevation of bilirubin to > 3 mg/dL Transaminases > 4 x the upper limit of normal Creatinine clearance < 50 cc/min (24-hour urine collection) Karnofsky performance score < 60% Poorly controlled hypertension on multiple antihypertensives Documented fungal disease that is progressive despite treatment HIV-positive. Other viral infections, ie, Hepatitis B- and C- positive, evaluated on a case-by-case basis Psychiatric disorders or psychosocial problems which in the opinion of the primary physician or Principal Investigator would place the patient at unacceptable risk from this regimen.

Sites / Locations

  • Stanford University School of Medicine

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Non-myeloablative transplantation

Arm Description

Pre-transplant total lymphoid irradiation (TLI) and anti-thymocyte globulin (ATG) infusion with Day 0 allogeneic hematopoietic cell transplant (HCT), followed by post-transplant immunosuppression by cyclosporine and mycophenolate mofetil.

Outcomes

Primary Outcome Measures

Acute Graft vs Host Disease (GvHD)
The incidence of acute GvHD after transplantation was assessed per Glucksberg GvHD grade, a compound scale based on the following combinations of disease stages. Skin Stages 0: No rash 1: Maculopapular (MP) rash <25% of body surface area 2: MP rash on 25-50% of body surface area 3: Generalized erythroderma (ED) 4: Generalized ED with bullous formation and desquamation Liver Stages (Bilirubin in mg/dL) 0: <2 1: 2-3 2: 3.01-6 3: 6.01-15.0 4: >15 Gastrointestinal (GI) Stages (diarrhea) 0: None or < 500 mL/day 1: 500-999 mL/day 2: 1000-1499 mL/day 3: >1500 mL/day 4: Severe abdominal pain, with or without ileus Glucksberg Overall grade Grade 1: Skin 1/2; GI 0; Liver 0; Karnofsky performance scale (KPS) 90-100% Grade 2: Skin 1-3; GI 1; Liver 1; KPS 70-80 Grade 2: Skin 2/3; GI 2/3; Liver 2-4; KPS 50-60 Grade 4: Skin 2-4; GI 2-4; Liver 2-4; KPS 30-40

Secondary Outcome Measures

Acute Graft vs Host Disease (GvHD), All Evaluable
The incidence of acute GvHD after transplantation was assessed per Glucksberg GvHD grade, a compound scale based on the following combinations of disease stages. Skin Stages 0: No rash 1: Maculopapular (MP) rash <25% of body surface area 2: MP rash on 25-50% of body surface area 3: Generalized erythroderma (ED) 4: Generalized ED with bullous formation and desquamation Liver Stages (Bilirubin in mg/dL) 0: <2 1: 2-3 2: 3.01-6 3: 6.01-15.0 4: >15 Gastrointestinal (GI) Stages (diarrhea) 0: None or < 500 mL/day 1: 500-999 mL/day 2: 1000-1499 mL/day 3: >1500 mL/day 4: Severe abdominal pain, with or without ileus Glucksberg Overall grade Grade 1: Skin 1/2; GI 0; Liver 0; Karnofsky performance scale (KPS) 90-100% Grade 2: Skin 1-3; GI 1; Liver 1; KPS 70-80 Grade 2: Skin 2/3; GI 2/3; Liver 2-4; KPS 50-60 Grade 4: Skin 2-4; GI 2-4; Liver 2-4; KPS 30-40
Incidence of Relapse
Reports the overall rate of disease relapse, occurring any time within 3 years after transplant
Overall Survival (OS)
Event-free Survival (EFS)
Reports the number and proportion of participants who neither died due to any cause nor experienced relapse.
Transplant-related Mortality
Reports the proportion of participants who expired within 1 year due to any complication or failure of the transplant.

Full Information

First Posted
September 12, 2005
Last Updated
June 24, 2021
Sponsor
Stanford University
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1. Study Identification

Unique Protocol Identification Number
NCT00185640
Brief Title
Allogeneic Transplantation Using Total Lymphoid Irradiation (TLI) and Anti-Thymocyte Globulin (ATG) for Older Patients With Hematologic Malignancies
Official Title
Allogeneic Hematopoietic Cell Transplantation Using a Non-Myeloablative Preparative Regimen of Total Lymphoid Irradiation and Anti-Thymocyte Globulin for Older Patients With Hematologic Malignancies
Study Type
Interventional

2. Study Status

Record Verification Date
June 2021
Overall Recruitment Status
Completed
Study Start Date
March 2003 (undefined)
Primary Completion Date
April 2014 (Actual)
Study Completion Date
January 2016 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Stanford University

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
To measure how frequently and to what degree a complication of transplant cell acute graft versus host disease (GvHD) occurs.
Detailed Description
This study evaluated whether TLI-ATG conditioning followed by allogeneic hematpoietic cell transplant (HCT), which has provided excellent overall survival for patients with relapsed lymphoma after failed autologous HCT, provides a similar benefit in the setting of elderly patients with hematologic malignancies.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Blood Cancer, Leukemia

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
303 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Non-myeloablative transplantation
Arm Type
Experimental
Arm Description
Pre-transplant total lymphoid irradiation (TLI) and anti-thymocyte globulin (ATG) infusion with Day 0 allogeneic hematopoietic cell transplant (HCT), followed by post-transplant immunosuppression by cyclosporine and mycophenolate mofetil.
Intervention Type
Drug
Intervention Name(s)
Cyclosporine
Other Intervention Name(s)
Cyclosporin, Cyclosporin A
Intervention Description
Starting day -3 at a dose of 5 mg/kg orally twice daily with a target trough level of 350 to 450 ng/mL
Intervention Type
Drug
Intervention Name(s)
Anti-thymocyte globulin (ATG)
Other Intervention Name(s)
Thymoglobulin
Intervention Description
1.5 mg/kg for total dose of 7.5mg/kg, IV starting on day -11 to day -7 before HCT
Intervention Type
Drug
Intervention Name(s)
Mycophenolate mofetil (MMF)
Other Intervention Name(s)
CellCept
Intervention Description
Begins on day 0 after HCT at a dose of 15 mg/kg. Transplant recipients who received related donor grafts received MMF twice daily and those who received unrelated donor grafts received MMF 3 times daily.
Intervention Type
Drug
Intervention Name(s)
Filgrastim
Other Intervention Name(s)
Neupogen, Granulocyte-colony stimulating factor (G-CSF; GCSF), colony-stimulating factor 3 (CSF-3)
Intervention Description
Donors mobilized with 16 µg/kg/day filgrastim. As needed, myelosuppression in transplant recipients will be managed with subcutaneous filgrastim 5 µg/kg/day
Intervention Type
Radiation
Intervention Name(s)
Total Lymphoid Irradiation (TLI)
Intervention Description
0.8 Gy/day from day -11 to day -7 (inclusive) from day -4 to day -2 (inclusive) with 2 additional fractions of 0.8 Gy delivered on day -1 for total dose of 8 Gy.
Primary Outcome Measure Information:
Title
Acute Graft vs Host Disease (GvHD)
Description
The incidence of acute GvHD after transplantation was assessed per Glucksberg GvHD grade, a compound scale based on the following combinations of disease stages. Skin Stages 0: No rash 1: Maculopapular (MP) rash <25% of body surface area 2: MP rash on 25-50% of body surface area 3: Generalized erythroderma (ED) 4: Generalized ED with bullous formation and desquamation Liver Stages (Bilirubin in mg/dL) 0: <2 1: 2-3 2: 3.01-6 3: 6.01-15.0 4: >15 Gastrointestinal (GI) Stages (diarrhea) 0: None or < 500 mL/day 1: 500-999 mL/day 2: 1000-1499 mL/day 3: >1500 mL/day 4: Severe abdominal pain, with or without ileus Glucksberg Overall grade Grade 1: Skin 1/2; GI 0; Liver 0; Karnofsky performance scale (KPS) 90-100% Grade 2: Skin 1-3; GI 1; Liver 1; KPS 70-80 Grade 2: Skin 2/3; GI 2/3; Liver 2-4; KPS 50-60 Grade 4: Skin 2-4; GI 2-4; Liver 2-4; KPS 30-40
Time Frame
100 days post-transplant
Secondary Outcome Measure Information:
Title
Acute Graft vs Host Disease (GvHD), All Evaluable
Description
The incidence of acute GvHD after transplantation was assessed per Glucksberg GvHD grade, a compound scale based on the following combinations of disease stages. Skin Stages 0: No rash 1: Maculopapular (MP) rash <25% of body surface area 2: MP rash on 25-50% of body surface area 3: Generalized erythroderma (ED) 4: Generalized ED with bullous formation and desquamation Liver Stages (Bilirubin in mg/dL) 0: <2 1: 2-3 2: 3.01-6 3: 6.01-15.0 4: >15 Gastrointestinal (GI) Stages (diarrhea) 0: None or < 500 mL/day 1: 500-999 mL/day 2: 1000-1499 mL/day 3: >1500 mL/day 4: Severe abdominal pain, with or without ileus Glucksberg Overall grade Grade 1: Skin 1/2; GI 0; Liver 0; Karnofsky performance scale (KPS) 90-100% Grade 2: Skin 1-3; GI 1; Liver 1; KPS 70-80 Grade 2: Skin 2/3; GI 2/3; Liver 2-4; KPS 50-60 Grade 4: Skin 2-4; GI 2-4; Liver 2-4; KPS 30-40
Time Frame
100 days post-transplant
Title
Incidence of Relapse
Description
Reports the overall rate of disease relapse, occurring any time within 3 years after transplant
Time Frame
3 years
Title
Overall Survival (OS)
Time Frame
3 and 5 years
Title
Event-free Survival (EFS)
Description
Reports the number and proportion of participants who neither died due to any cause nor experienced relapse.
Time Frame
3 and 5 years
Title
Transplant-related Mortality
Description
Reports the proportion of participants who expired within 1 year due to any complication or failure of the transplant.
Time Frame
1 year

10. Eligibility

Sex
All
Minimum Age & Unit of Time
50 Years
Maximum Age & Unit of Time
70 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
INCLUSION CRITERIA: Any patient with one of the following hematolymphoid malignancies or syndromes in whom allogeneic hematopoietic stem cell transplant (HST) is warranted. Specific disease categories include: Indolent advanced stage non-Hodgkin lymphomas Mantle cell lymphoma Chronic lymphocytic leukemia Hodgkin disease (Hodgkin's lymphoma) Acute leukemias in complete remission Aplastic anemia Paroxysmal nocturnal hemoglobinuria Myelodysplastic or myeloproliferative syndromes. Other selected malignancies/disorders may also be considered but must be approved by the transplant team and the Principal Investigator. Age > 50 years, or if < 50 years of age, considered to be at high risk for regimen-related toxicity associated with conventional myeloablative transplants due to pre-existing medical conditions or prior therapy. A fully human leukocyte antigen (HLA)-identical sibling or matched unrelated donor is available. Potential participants with one antigen mismatched donors can be considered but only after discussion with the transplant team and the Principal Investigator. Participant must be competent to give consent. EXCLUSION CRITERIA: Progressive hematolymphoid malignancies despite conventional therapies, or acute leukemias not in complete remission. Uncontrolled central nervous system (CNS) involvement with disease Fertile men or women unwilling to use contraceptive techniques during and for 12 months following treatment Pregnant Cardiac ejection fraction < 30% Uncontrolled cardiac failure Pulmonary diffusing capacity (DLCO) < 40% predicted Elevation of bilirubin to > 3 mg/dL Transaminases > 4 x the upper limit of normal Creatinine clearance < 50 cc/min (24-hour urine collection) Karnofsky performance score < 60% Poorly controlled hypertension on multiple antihypertensives Documented fungal disease that is progressive despite treatment HIV-positive. Other viral infections, ie, Hepatitis B- and C- positive, evaluated on a case-by-case basis Psychiatric disorders or psychosocial problems which in the opinion of the primary physician or Principal Investigator would place the patient at unacceptable risk from this regimen.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Robert Lowsky
Organizational Affiliation
Stanford University
Official's Role
Principal Investigator
Facility Information:
Facility Name
Stanford University School of Medicine
City
Stanford
State/Province
California
ZIP/Postal Code
94305
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
No
Citations:
PubMed Identifier
16192477
Citation
Lowsky R, Takahashi T, Liu YP, Dejbakhsh-Jones S, Grumet FC, Shizuru JA, Laport GG, Stockerl-Goldstein KE, Johnston LJ, Hoppe RT, Bloch DA, Blume KG, Negrin RS, Strober S. Protective conditioning for acute graft-versus-host disease. N Engl J Med. 2005 Sep 29;353(13):1321-31. doi: 10.1056/NEJMoa050642. Erratum In: N Engl J Med. 2006 Feb 23;354(8):884.
Results Reference
result
PubMed Identifier
20528878
Citation
Jones CD, Arai S, Lowsky R, Tyan DB, Zehnder JL, Miklos DB. Complete donor T-cell engraftment 30 days after allogeneic transplantation predicts molecular remission in high-risk chronic lymphocytic leukaemia. Br J Haematol. 2010 Sep;150(5):637-9. doi: 10.1111/j.1365-2141.2010.08252.x. Epub 2010 Jun 7. No abstract available.
Results Reference
result
PubMed Identifier
26146806
Citation
Rezvani AR, Kanate AS, Efron B, Chhabra S, Kohrt HE, Shizuru JA, Laport GG, Miklos DB, Benjamin JE, Johnston LJ, Arai S, Weng WK, Negrin RS, Strober S, Lowsky R. Allogeneic hematopoietic cell transplantation after failed autologous transplant for lymphoma using TLI and anti-thymocyte globulin conditioning. Bone Marrow Transplant. 2015 Oct;50(10):1286-92. doi: 10.1038/bmt.2015.149. Epub 2015 Jul 6.
Results Reference
result
PubMed Identifier
19423725
Citation
Kohrt HE, Turnbull BB, Heydari K, Shizuru JA, Laport GG, Miklos DB, Johnston LJ, Arai S, Weng WK, Hoppe RT, Lavori PW, Blume KG, Negrin RS, Strober S, Lowsky R. TLI and ATG conditioning with low risk of graft-versus-host disease retains antitumor reactions after allogeneic hematopoietic cell transplantation from related and unrelated donors. Blood. 2009 Jul 30;114(5):1099-109. doi: 10.1182/blood-2009-03-211441. Epub 2009 May 7.
Results Reference
result
PubMed Identifier
24607552
Citation
Benjamin J, Chhabra S, Kohrt HE, Lavori P, Laport GG, Arai S, Johnston L, Miklos DB, Shizuru JA, Weng WK, Negrin RS, Lowsky R. Total lymphoid irradiation-antithymocyte globulin conditioning and allogeneic transplantation for patients with myelodysplastic syndromes and myeloproliferative neoplasms. Biol Blood Marrow Transplant. 2014 Jun;20(6):837-43. doi: 10.1016/j.bbmt.2014.02.023. Epub 2014 Mar 7.
Results Reference
result

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Allogeneic Transplantation Using Total Lymphoid Irradiation (TLI) and Anti-Thymocyte Globulin (ATG) for Older Patients With Hematologic Malignancies

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