Post Transplant Donor Lymphocyte Infusion

• Sponsor: Masonic Cancer Center, University of Minnesota (Other)
• Overall Status: Terminated
• CT.gov ID: NCT00167180
• Collaborator: (none)
• Enrollment: 57
• Location: 1
• Arms: 2
• Duration (Months): 179.7
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

The purpose of this study is to test the hypothesis that a pre-infusion preparative regimen of cyclophosphamide and fludarabine will improve the effectiveness of DLI in patients with blood cancers.

Condition or Disease	Intervention/Treatment	Phase
Leukemia, Myeloid, Chronic; Lymphomas; Multiple Myeloma; Myelodysplastic Syndrome; Leukemia, Lymphocytic, Acute; Leukemia, Lymphocytic, Chronic; AML	Procedure: Donor Lymphocyte Infusion; Drug: Induction Chemotherapy	Phase 2

Detailed Description

When cancer relapses after donor bone marrow transplantation, regular dose chemotherapy offers little hope of prolonged survival. However, there is evidence that lymphocytes can attack cancer cells. There is considerable evidence that this immune attack on cancer cells is associated with graft-versus-host disease. Although graft-versus-host disease can cause problems, this immune reaction may, in part, be the way that bone marrow transplantation cures cancer. In this study we hope that infusion of immune cells from the subject's bone marrow donor plus a chemotherapy regimen of cyclophosphamide and fludarabine will activate the subject's immune system to attack their cancer.

Study Design

• Study Type: Interventional
• Actual Enrollment: 57 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Use of Cyclophosphamide/Fludarabine to Promote in Vivo Expansion of Donor Lymphocyte Infusions (DLI) to Enhance Efficacy After Allogeneic Transplant
• Study Start Date: Jan 1, 2004
• Actual Primary Completion Date: Nov 21, 2017
• Actual Study Completion Date: Dec 24, 2018

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: CML Patients with Chronic Myelogenous Leukemia (CML) who have failed or refused Gleevec(TM) therapy and will receive Donor Lymphocyte Infusion.	Procedure: Donor Lymphocyte Infusion; donor cells infused over 2 hrs at cell dose of 0.5 dx 10^8 CD3+T-cells/kg; Other Names: DLI
Active Comparator: Non-CML or CML that Relapsed after Donor Lymphocyte Infusion Patients with non-CML or CML who have failed Donor Lymphocyte Infusion (DLI) and will receive induction chemotherapy plus DLI.	Procedure: Donor Lymphocyte Infusion; donor cells infused over 2 hrs at cell dose of 0.5 dx 10^8 CD3+T-cells/kg; Other Names: DLI ; Drug: Induction Chemotherapy; Fludarabine 25 mg/m2 IV Cyclosphosphamide 60 mg/kg IV; Other Names: Fludara Endoxan, Cytoxan, Neosar, Procytox, Revimmune, cytophosphane

Outcome Measures

Primary Outcome Measures

1. Number of Patients Alive [1 Year]

   The percentage of people in a study or treatment group who are alive for a certain period of time after they were diagnosed with or treated for a disease, such as cancer. Also called survival rate. Overall survival will be defined as time from date of enrollment to date of death or censored at the date of last documented contact for patients still alive.

Secondary Outcome Measures

1. Number of Patients Alive Without Disease [1 Year]

   The number of patients alive one year after treatment without any signs or symptoms of the cancer being treated or any other type of cancer. In a clinical trial, measuring the disease-free survival is one way to see how well a new treatment works.

2. Number of Participants With Complete Remission [one year]

   In complete remission, all signs and symptoms of cancer that can be detected with modern technology have disappeared, although cancer still may be in the body.

3. Number of Patients With Acute Graft-Versus-Host Disease [Day 100]

   Acute Graft-Versus-Host Disease is a severe short-term complication created by infusion of donor cells into a foreign host.

4. Number of Patients With Bone Marrow Aplasia [Day 100]

   Aplastic anemia is a disorder in which the bone marrow greatly decreases or stops production of blood cells. In aplastic anemia, the basic structure of the marrow becomes abnormal, and those cells responsible for generating blood cells (hematopoietic cells) are greatly decreased in number or absent. These hematopoietic cells are replaced by large quantities of fat.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 1 Year to 70 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Patients (age > or = 1 years) with a diagnosis of relapse after related or unrelated allogeneic stem cell transplantation for a hematological malignancy.

• For CML, relapse will be defined as any cytogenetic evidence of a Philadelphia chromosome or persistence of BCR/ABL rearrangements by molecular testing on at least two measurements over a 6 month interval. If cytogenetics are normal and there is PCR evidence of a BCR/ABL fusion, patients will be eligible if they have evidence of a quantitative increase in CML measured either by quantitative PCR or by fluorescent in situ hybridization (FISH).

• For non-CML, relapse will be defined based on disease specific morphologic criteria from a bone marrow biopsy and aspirate or recurrence of disease specific cytogenetics. For disease specific definition of relapse, see appendix 3. Relapse can be determined morphologically with less than 5 percent blasts if definitive relapse can be determined. Equivocal results for relapse should result in a repeated test after an appropriate time interval (suggested 1 month) to determine eligibility.

Post-transplant lymphoproliferative diseases (often referred to as EBV-associated lymphomas) are NOT eligible for this protocol.

• For Chronic Phase CML patients only

• • must have failed (no response in 3 months or incomplete response at 6 months) or refused treatment with Gleevec
• • if no prior DLI, CML patients will first have DLI- if relapse occurs after DLI, DLI with chemotherapy per this protocol will be offered

• Patients must be within one year of identification of relapse or if beyond that time period, must have at least 10% donor DNA by RFLP or cytogenetics.

• Same allogeneic donor (sibling or URD) used for transplantation is available for lymphocyte donation.

• No severe organ damage (by laboratory or clinical assessment) as measured by:

• • blood creatinine ≤ 2.0 mg/dL
• • liver function tests < 5 x normal
• • left ventricular ejection fraction > 40% (testing required only if symptomatic or prior known impairment).
• • pulmonary functions > 50% (testing required only if symptomatic or prior known impairment). Oxygen saturation (>92%) can be used in child where PFT's cannot be obtained.
• • chest x-ray without evidence of active infection

• Off prednisone and other immunosuppressive agents (given for any reason) for at least 3 days prior to DLI infusions.

• Performance status ≥ 60%

• Women must not be pregnant or lactating. The agents used in this study may be teratogenic to a fetus and there is no information on the excretion of agents into breast milk All females of childbearing potential must have a blood test or urine study within 2 weeks prior to registration to rule out pregnancy

• Women of childbearing potential and sexually active males are strongly advised to use an accepted and effective method of contraception

• Patient must given written informed consent indicating understanding of the nature of the treatment and its potential risks

Exclusion Criteria:

• Concurrent signs of acute or chronic graft-versus-host disease requiring ongoing treatment at the time of relapse will be ineligible.

• Patients being treated for GVHD with prednisone, cyclosporine, Imuran or other immunosuppressive medications are not eligible until these medications are discontinued for at least 2 weeks without a flare of GVHD.

• Active CNS leukemia

• Active fungal infection or pulmonary infiltrates (stable prior treated disease is allowable)

• HIV positive

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Masonic Cancer Center, University of Minnesota	Minneapolis	Minnesota	United States	55455

Sponsors and Collaborators

• Masonic Cancer Center, University of Minnesota

Investigators

• Principal Investigator: Jeffrey Miller, MD, Masonic Cancer Center, University of Minnesota

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Oct 10, 2008

More Information

Publications

None provided.

• Responsible Party: Masonic Cancer Center, University of Minnesota
• ClinicalTrials.gov Identifier: NCT00167180
• Other Study ID Numbers: 2004LS006; MT2003-15; 0401M55207; NCT00303693
• First Posted: Sep 14, 2005
• Last Update Posted: Jul 30, 2019
• Last Verified: Jul 1, 2019

• Keywords provided by Masonic Cancer Center, University of Minnesota: donor lymphocyte infusions; BMT; bone marrow transplant
• Additional relevant MeSH terms: Leukemia; Multiple Myeloma; Leukemia, Myeloid; Leukemia, Lymphoid; Leukemia, Lymphocytic, Chronic, B-Cell; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Myelodysplastic Syndromes; Cyclophosphamide

Study Results

Participant Flow

Pre-assignment Detail	During the recruitment period of the study, the donor lymphocyte infusion (DLI) was reduced from 1.0 x 10^8 CD3+ T-cells/kg to 0.5 x 10^8 CD3+ T-cells/kg due to an excess rate and intensity of graft vs. host disease.

Arm/Group Title	Chronic Myelogenous Leukemia (CML)	Non-CML or CML Failing Donor Lymphocyte Infusion
Arm/Group Description	Patients who have failed or refused Gleevec (TM) therapy and will receive Donor Lymphocyte Infusion. Donor Lymphocyte Infusion: donor cells infused over 2 hrs at cell dose of 0.5 dx 10^8 CD3+T-cells/kg	Patients with non-CML or CML who have failed DLI and will receive Induction Chemotherapy + DLI. Induction Chemotherapy + DLI: Fludarabine 25 mg/m2 IV Cyclosphosphamide 60 mg/kg IV Donor Lymphocyte Infusion (DLI)
Period Title: Overall Study
STARTED	0	57
COMPLETED	0	57
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	DLI Cell Dose of 1.0 x 10^8 CD3+ T-cells/kg	DLI Cell Dose of 0.5 x 10^8 CD3+ T-cells/kg	Total
Arm/Group Description	Cyclophosphamide 60mg/kg IV over 2 hours Fludarabine 25 mg/m2 IV over 30 minutes DLI Cell Dose 1.0 x 10^8 CD3+ T-cells/kg	Cyclophosphamide 60mg/kg IV over 2 hours Fludarabine 25 mg/m2 DLI Cell Dose 0.5 x 10^8 CD3+ T-cells/kg	Total of all reporting groups
Overall Participants	15	42	57
Age (Count of Participants)
<=18 years	1 6.7%	2 4.8%	3 5.3%
Between 18 and 65 years	14 93.3%	36 85.7%	50 87.7%
>=65 years	0 0%	4 9.5%	4 7%
Sex: Female, Male (Count of Participants)
Female	7 46.7%	18 42.9%	25 43.9%
Male	8 53.3%	24 57.1%	32 56.1%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	3 7.1%	3 5.3%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	0 0%	1 2.4%	1 1.8%
White	15 100%	38 90.5%	53 93%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%

Outcome Measures

1. Primary Outcome

Title	Number of Patients Alive
Description	The percentage of people in a study or treatment group who are alive for a certain period of time after they were diagnosed with or treated for a disease, such as cancer. Also called survival rate. Overall survival will be defined as time from date of enrollment to date of death or censored at the date of last documented contact for patients still alive.
Time Frame	1 Year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	DLI Cell Dose of 1.0 x 10^8 CD3+ T-cells/kg	DLI Cell Dose of 0.5 x 10^8 CD3+ T-cells/kg
Arm/Group Description	Cyclophosphamide 60mg/kg IV over 2 hours Fludarabine 25 mg/m2 IV over 30 minutes DLI Cell Dose 1.0 x 10^8 CD3+ T-cells/kg	Cyclophosphamide 60mg/kg IV over 2 hours Fludarabine 25 mg/m2 DLI Cell Dose 0.5 x 10^8 CD3+ T-cells/kg
Measure Participants	15	42
Count of Participants [Participants]	3 20%	20 47.6%

2. Secondary Outcome

Title	Number of Patients Alive Without Disease
Description	The number of patients alive one year after treatment without any signs or symptoms of the cancer being treated or any other type of cancer. In a clinical trial, measuring the disease-free survival is one way to see how well a new treatment works.
Time Frame	1 Year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	DLI Cell Dose of 1.0 x 10^8 CD3+ T-cells/kg	DLI Cell Dose of 0.5 x 10^8 CD3+ T-cells/kg
Arm/Group Description	Cyclophosphamide 60mg/kg IV over 2 hours Fludarabine 25 mg/m2 IV over 30 minutes DLI Cell Dose 1.0 x 10^8 CD3+ T-cells/kg	Cyclophosphamide 60mg/kg IV over 2 hours Fludarabine 25 mg/m2 DLI Cell Dose 0.5 x 10^8 CD3+ T-cells/kg
Measure Participants	15	42
Count of Participants [Participants]	2 13.3%	10 23.8%

3. Secondary Outcome

Title	Number of Participants With Complete Remission
Description	In complete remission, all signs and symptoms of cancer that can be detected with modern technology have disappeared, although cancer still may be in the body.
Time Frame	one year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	DLI Cell Dose of 1.0 x 10^8 CD3+ T-cells/kg	DLI Cell Dose of 0.5 x 10^8 CD3+ T-cells/kg
Arm/Group Description	Cyclophosphamide 60mg/kg IV over 2 hours Fludarabine 25 mg/m2 IV over 30 minutes DLI Cell Dose 1.0 x 10^8 CD3+ T-cells/kg	Cyclophosphamide 60mg/kg IV over 2 hours Fludarabine 25 mg/m2 DLI Cell Dose 0.5 x 10^8 CD3+ T-cells/kg
Measure Participants	15	42
Count of Participants [Participants]	7 46.7%	22 52.4%

4. Secondary Outcome

Title	Number of Patients With Acute Graft-Versus-Host Disease
Description	Acute Graft-Versus-Host Disease is a severe short-term complication created by infusion of donor cells into a foreign host.
Time Frame	Day 100

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	DLI Cell Dose of 1.0 x 10^8 CD3+ T-cells/kg	DLI Cell Dose of 0.5 x 10^8 CD3+ T-cells/kg
Arm/Group Description	Cyclophosphamide 60mg/kg IV over 2 hours Fludarabine 25 mg/m2 IV over 30 minutes DLI Cell Dose 1.0 x 10^8 CD3+ T-cells/kg	Cyclophosphamide 60mg/kg IV over 2 hours Fludarabine 25 mg/m2 DLI Cell Dose 0.5 x 10^8 CD3+ T-cells/kg
Measure Participants	15	42
Count of Participants [Participants]	10 66.7%	10 23.8%

5. Secondary Outcome

Title	Number of Patients With Bone Marrow Aplasia
Description	Aplastic anemia is a disorder in which the bone marrow greatly decreases or stops production of blood cells. In aplastic anemia, the basic structure of the marrow becomes abnormal, and those cells responsible for generating blood cells (hematopoietic cells) are greatly decreased in number or absent. These hematopoietic cells are replaced by large quantities of fat.
Time Frame	Day 100

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	DLI Cell Dose of 1.0 x 10^8 CD3+ T-cells/kg	DLI Cell Dose of 0.5 x 10^8 CD3+ T-cells/kg
Arm/Group Description	Cyclophosphamide 60mg/kg IV over 2 hours Fludarabine 25 mg/m2 IV over 30 minutes DLI Cell Dose 1.0 x 10^8 CD3+ T-cells/kg	Cyclophosphamide 60mg/kg IV over 2 hours Fludarabine 25 mg/m2 DLI Cell Dose 0.5 x 10^8 CD3+ T-cells/kg
Measure Participants	15	42
Count of Participants [Participants]	0 0%	1 2.4%

Adverse Events

Time Frame	1 Year
Arm/Group Title	DLI Cell Dose of 1.0 x 10^8 CD3+ T-cells/kg		DLI Cell Dose of 0.5 x 10^8 CD3+ T-cells/kg
Arm/Group Description	Cyclophosphamide 60mg/kg IV over 2 hours Fludarabine 25 mg/m2 IV over 30 minutes DLI Cell Dose 1.0 x 10^8 CD3+ T-cells/kg		Cyclophosphamide 60mg/kg IV over 2 hours Fludarabine 25 mg/m2 DLI Cell Dose 0.5 x 10^8 CD3+ T-cells/kg
All Cause Mortality
	DLI Cell Dose of 1.0 x 10^8 CD3+ T-cells/kg		DLI Cell Dose of 0.5 x 10^8 CD3+ T-cells/kg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	12/15 (80%)		22/42 (52.4%)
Serious Adverse Events
	DLI Cell Dose of 1.0 x 10^8 CD3+ T-cells/kg		DLI Cell Dose of 0.5 x 10^8 CD3+ T-cells/kg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	8/15 (53.3%)		3/42 (7.1%)
General disorders
Death, NOS	1/15 (6.7%)		0/42 (0%)
Acute Graft vs. Host Disease	7/15 (46.7%)		1/42 (2.4%)
Graft vs. Host Disease, NOS	0/15 (0%)		1/42 (2.4%)
Infections and infestations
Infection, NOS	1/15 (6.7%)		0/42 (0%)
Acute Sepsis	1/15 (6.7%)		0/42 (0%)
Respiratory, thoracic and mediastinal disorders
Pulmonary Failure	0/15 (0%)		1/42 (2.4%)
Other (Not Including Serious) Adverse Events
	DLI Cell Dose of 1.0 x 10^8 CD3+ T-cells/kg		DLI Cell Dose of 0.5 x 10^8 CD3+ T-cells/kg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	12/15 (80%)		11/42 (26.2%)
Blood and lymphatic system disorders
Hypovolemia	0/15 (0%)		1/42 (2.4%)
Cardiac disorders
Atrial Flutter	0/15 (0%)		1/42 (2.4%)
Bradycardic Arrest	0/15 (0%)		1/42 (2.4%)
Cardiac Arrhythmia	0/15 (0%)		1/42 (2.4%)
New Q Wave	0/15 (0%)		1/42 (2.4%)
Pericardial Effusion	0/15 (0%)		1/42 (2.4%)
Systolic Ejection Murmur	0/15 (0%)		1/42 (2.4%)
Tachycardia	0/15 (0%)		1/42 (2.4%)
Eye disorders
Retinal Hemorrhage	1/15 (6.7%)		0/42 (0%)
Gastrointestinal disorders
Gastrointestinal Hemorrhage	1/15 (6.7%)		2/42 (4.8%)
Pancreatitis, NOS	0/15 (0%)		1/42 (2.4%)
Small Bowel Obstruction	0/15 (0%)		1/42 (2.4%)
Tubular Adenoma, Rectum	1/15 (6.7%)		0/42 (0%)
General disorders
Acute Graft vs. Host Disease	6/15 (40%)		0/42 (0%)
Chronic Graft vs. Host Disease	1/15 (6.7%)		0/42 (0%)
Graft vs. Host Disease, NOS	0/15 (0%)		1/42 (2.4%)
Multi-System Organ Failure	0/15 (0%)		1/42 (2.4%)
Immune system disorders
Anaphylactic Reaction to Anti-Thymocyte Globulin	1/15 (6.7%)		0/42 (0%)
Infections and infestations
Bacterial Infection, NOS	3/15 (20%)		2/42 (4.8%)
Blood Infection, Bacterial	1/15 (6.7%)		2/42 (4.8%)
Blood Infection, Viral	1/15 (6.7%)		3/42 (7.1%)
Bone Marrow Infection, Viral	0/15 (0%)		1/42 (2.4%)
Eye Infection, NOS	0/15 (0%)		1/42 (2.4%)
Fungal Infection, NOS	1/15 (6.7%)		0/42 (0%)
Gastrointestinal Infection, Bacterial	0/15 (0%)		1/42 (2.4%)
Gastrointestinal Infection, Fungal	1/15 (6.7%)		0/42 (0%)
Genitourinary Infection, Bacterial	3/15 (20%)		1/42 (2.4%)
Genitourinary Infection, Fungal	0/15 (0%)		1/42 (2.4%)
Genitourinary Infection, Viral	0/15 (0%)		1/42 (2.4%)
Mucosal Infection, Viral	1/15 (6.7%)		0/42 (0%)
Nervous System Infection, Viral	1/15 (6.7%)		0/42 (0%)
Pneumonia	3/15 (20%)		4/42 (9.5%)
Respiratory Infection, Bacterial	0/15 (0%)		1/42 (2.4%)
Respiratory Infection, NOS	1/15 (6.7%)		2/42 (4.8%)
Sepsis	0/15 (0%)		1/42 (2.4%)
Viral Infection, NOS	0/15 (0%)		3/42 (7.1%)
Wound Infection, Bacterial	2/15 (13.3%)		0/42 (0%)
Musculoskeletal and connective tissue disorders
Scoliosis	0/15 (0%)		1/42 (2.4%)
Nervous system disorders
Difficulty with Speech	0/15 (0%)		1/42 (2.4%)
Neuropathy	0/15 (0%)		1/42 (2.4%)
Pachymeningeal Thickening	0/15 (0%)		1/42 (2.4%)
Seizures	0/15 (0%)		1/42 (2.4%)
Slow Thinking and Movement	0/15 (0%)		1/42 (2.4%)
Status Epilepticus after Seizures	0/15 (0%)		1/42 (2.4%)
Psychiatric disorders
Decreased Consciousness and Delirium	1/15 (6.7%)		0/42 (0%)
Renal and urinary disorders
Acute Renal Failure	0/15 (0%)		1/42 (2.4%)
Genitourinary Hemorrhage	0/15 (0%)		1/42 (2.4%)
Hemorrhagic Cystitis	0/15 (0%)		1/42 (2.4%)
Requires Dialysis, NOS	1/15 (6.7%)		1/42 (2.4%)
Respiratory, thoracic and mediastinal disorders
Acute Respiratory Distress Syndrome	0/15 (0%)		1/42 (2.4%)
Fibrous Pneumonitis	0/15 (0%)		1/42 (2.4%)
Pneumothorax	0/15 (0%)		1/42 (2.4%)
Pulmonary Hemorrhage	0/15 (0%)		2/42 (4.8%)
Pulmonary Hypertension	0/15 (0%)		1/42 (2.4%)
Respiratory Arrest	2/15 (13.3%)		1/42 (2.4%)
Respiratory Distress	0/15 (0%)		1/42 (2.4%)
Vascular disorders
Brain Infarction	0/15 (0%)		1/42 (2.4%)
Deep Vein Thrombosis	1/15 (6.7%)		1/42 (2.4%)
Splenic Infarcts	0/15 (0%)		1/42 (2.4%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.