Donor Lymphocyte Infusion in Treating Patients With Persistent, Relapsed, or Progressing Cancer After Donor Hematopoietic Cell Transplant

• Sponsor: Fred Hutchinson Cancer Center (Other)
• Overall Status: Completed
• CT.gov ID: NCT00068718
• Collaborator: National Cancer Institute (NCI) (NIH)
• Enrollment: 35
• Locations: 4
• Arm: 1
• Actual Duration (Months): 119
• Patients Per Site: 8.8
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

This phase I/II trial studies the side effects of donor lymphocyte infusion and to see how well it works in treating patients with persistent, relapsed (disease that has returned), or progressing cancer after donor hematopoietic cell transplantation. White blood cells from donors may be able to kill cancer cells in patients with cancer that has come back (recurrent) after a donor hematopoietic cell transplant.

Condition or Disease	Intervention/Treatment	Phase
Blast Phase Chronic Myelogenous Leukemia, BCR-ABL1 Positive; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Recurrent Hodgkin Lymphoma; Recurrent Non-Hodgkin Lymphoma; Recurrent Plasma Cell Myeloma	Biological: Therapeutic Allogeneic Lymphocytes	Phase 1/Phase 2

Detailed Description

PRIMARY OBJECTIVES:

1. To assess the safety of donor lymphocyte infusion (DLI) as adoptive immunotherapy for persistent or relapsed malignant diseases in patients after related or unrelated nonmyeloablative transplantation.

SECONDARY OBJECTIVES:

1. To determine disease response, progression free and overall survival, chimerism, grade of graft-versus-host disease (GVHD), and infections.

OUTLINE:

Patients undergo unirradiated DLI over 15-30 minutes on day 0. Patients then undergo restaging on day 28 and may undergo a second DLI after at least 4 weeks if no significant GVHD develops and disease status worsens or after at least 8 weeks if disease status is unchanged and persistent donor T-cells are documented.

After completion of study treatment, patients are followed up periodically.

Study Design

• Study Type: Interventional
• Actual Enrollment: 35 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Donor Lymphocyte Infusion for the Treatment of Malignancy After Hematopoietic Cell Transplantation Using Nonmyeloablative Conditioning - A Multi-center Trial
• Actual Study Start Date: May 1, 2003
• Actual Primary Completion Date: Apr 1, 2013
• Actual Study Completion Date: Apr 1, 2013

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Treatment (DLI) Patients undergo unirradiated DLI over 15-30 minutes on day 0. Patients then undergo restaging on day 28 and may undergo a second DLI after at least 4 weeks if no significant GVHD develops and disease status worsens or after at least 8 weeks if disease status is unchanged and persistent donor T-cells are documented.	Biological: Therapeutic Allogeneic Lymphocytes; Given IV; Other Names: Allogeneic Lymphocytes

Outcome Measures

Primary Outcome Measures

1. Safety of DLI Following a Non-myeloablative Transplant, Defined as Incidence of Grade IV Acute GVHD [100 days after DLI]

   Percentage of Participants with Grade IV Acute GVHD

Secondary Outcome Measures

1. Incidence of Graft Rejection [100 days after DLI]

   Percentage patients with graft rejection.

2. Incidence of Relapse/Progression [1 year after DLI]

   CML New cytogenetic abnormality and/or development of accelerated phase or blast crisis. The criteria for accelerated phase will be defined as unexplained fever >38.3°C, new clonal cytogenetic abnormalities in addition to a single Ph-positive chromosome, marrow blasts and promyelocytes >20%. CMML, AML, ALL >30% BM blasts w/ deteriorating performance status, or worsening of anemia, neutropenia, or thrombocytopenia. CLL ≥1 of: Physical exam/imaging studies ≥50% increase or new, circulating lymphocytes by morphology and/or flow cytometry ≥50% increase, and lymph node biopsy w/ Richter's transformation. NHL >25% increase in the sum of the products of the perpendicular diameters of marker lesions, or the appearance of new lesions. MM ≥100% increase of the serum myeloma protein from its lowest level, or reappearance of myeloma peaks that had disappeared w/ treatment; or definite increase in the size or number of plasmacytomas or lytic bone lesions.

3. Incidence of Grade II-IV GVHD in Patients Undergoing DLI Following a Non-myeloablative Transplant [100 days after DLI]

   Percentage of Participants with II-IV Acute GVHD

4. Incidence of Infections in Patients Undergoing DLI Following a Non-myeloablative Transplant [100 days after DLI]

   Percentage of Participants with infections.

5. Overall Survival [1 year after DLI]

   Percentage patients surviving 1 year post-transplant.

6. Progression-free Survival [1 year after DLI]

   Percentage of patients with progression-free survival

Eligibility Criteria

Criteria

• Ages Eligible for Study: N/A and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Only patients having received a preceding nonmyeloablative allogeneic transplantation with fludarabine/2 Gy total-body irradiation (TBI) - 4 Gy TBI or 2 Gy TBI - 4 Gy TBI conditioning from either a related or unrelated donor are eligible for this protocol

• Patients with persistent, relapsed or progressing malignancy after nonmyeloablative allogeneic transplantation; persistent disease will be defined as a failure to achieve a response as compared to baseline

• Patients with rapidly progressing malignancies (acute myeloid leukemia [AML], acute lymphocytic leukemia [ALL], blastic phase chronic myelogenous leukemia [CML-BC] intermediate-high-grade non-Hodgkin lymphoma [NHL], Hodgkin's lymphoma or aggressive multiple myeloma [MM]) should receive salvage chemotherapy or radiation before DLI according to the recommendation made in this protocol; any form of salvage chemotherapy should be discontinued no less than 3 weeks before DLI; therapy with Gleevec or interferon (IFN)-alpha should be discontinued prior to DLI; after salvage chemotherapy restaging is performed, patients with progressive disease and patients not meeting the inclusion criteria of the study after chemotherapy will be excluded from the study; patients are allowed to receive further doses of chemotherapy after DLI administration if they are scheduled for further DLI; after additional therapy the patients must be restaged and must again meet inclusion criteria to receive further DLI

• Patients must be able to tolerate a taper of systemic steroids to a dosage of less than or equal to 0.25 mg/kg/day; all other immunosuppressive therapy must have been discontinued for at least two weeks without significant flares in GVHD (i.e., increase of acute GVHD by one or more grades)

• Patients must have persistent donor cluster of differentiation (CD)3 cells (> 5% donor CD3 cells by a deoxyribonucleic acid [DNA]-based assay that compares the profile of amplified fragment length polymorphisms [ampFLP] [or fluorescent in situ hybridization (FISH) studies or variable number tandem repeat (VNTR)])

• DONOR: Alternatively to a fresh unmodified leukapheresis product, previously collected cryopreserved peripheral blood stem cells (PBSC) after mobilization with granulocyte colony-stimulating factor (G-CSF) or cryopreserved unmodified leukapheresis product from the original donor can be used; if cryopreserved product is not available, the DLI product must be from the original donor of hematopoietic cell transplantation

• DONOR: Original donor of hematopoietic cell transplantation

• DONOR: Donor must give consent to leukapheresis

• DONOR: Donor must have adequate veins for leukapheresis or agree to placement of central venous catheter (femoral or subclavian)

• DONOR: Donor must be medically fit to undergo the apheresis procedure (institutional guidelines for apheresis)

Exclusion Criteria:

• Current grade II to IV acute GVHD or extensive chronic GVHD

• Karnofsky score < 50%

• Lansky Play-Performance Score < 40 for pediatric patients

• DONOR: Donors who are not suitable for medical reasons to donate peripheral blood mononuclear cells (PBMC) by continuous centrifugation according to the criteria of the American Association of Blood Banks (AABB)

• DONOR: Pregnancy

• DONOR: Human immunodeficiency virus (HIV) or human T-lymphotrophic virus (HTLV) infection

• DONOR: Recent immunization may require a delay

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	VA Puget Sound Health Care System	Seattle	Washington	United States	98101
2	Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium	Seattle	Washington	United States	98109
3	Universitaet Leipzig	Leipzig		Germany	D-04103
4	University of Torino	Torino		Italy	10126

Sponsors and Collaborators

• Fred Hutchinson Cancer Center
• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Brenda Sandmaier, Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Brenda Sandmaier, Principal Investigator, Fred Hutchinson Cancer Center
• ClinicalTrials.gov Identifier: NCT00068718
• Other Study ID Numbers: 1803.00; NCI-2010-00163; 1803.00; P01CA078902; P30CA015704
• First Posted: Sep 11, 2003
• Last Update Posted: Jan 31, 2020
• Last Verified: Jan 1, 2020

• Additional relevant MeSH terms: Lymphoma; Leukemia; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Myeloid; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Multiple Myeloma; Blast Crisis; Recurrence

Study Results

Participant Flow

Arm/Group Title	Treatment (DLI)
Arm/Group Description	Patients undergo unirradiated DLI over 15-30 minutes on day 0. Patients then undergo restaging on day 28 and may undergo a second DLI after at least 4 weeks if no significant GVHD develops and disease status worsens or after at least 8 weeks if disease status is unchanged and persistent donor T-cells are documented. Therapeutic Allogeneic Lymphocytes: Given IV
Period Title: Overall Study
STARTED	35
COMPLETED	35
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Treatment (DLI)
Arm/Group Description	Patients undergo unirradiated DLI over 15-30 minutes on day 0. Patients then undergo restaging on day 28 and may undergo a second DLI after at least 4 weeks if no significant GVHD develops and disease status worsens or after at least 8 weeks if disease status is unchanged and persistent donor T-cells are documented. Therapeutic Allogeneic Lymphocytes: Given IV
Overall Participants	35
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	28 80%
>=65 years	7 20%
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	59.2
Sex: Female, Male (Count of Participants)
Female	15 42.9%
Male	20 57.1%
Region of Enrollment (participants) [Number]
United States	26 74.3%
Italy	9 25.7%

Outcome Measures

1. Primary Outcome

Title	Safety of DLI Following a Non-myeloablative Transplant, Defined as Incidence of Grade IV Acute GVHD
Description	Percentage of Participants with Grade IV Acute GVHD
Time Frame	100 days after DLI

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment (DLI)
Arm/Group Description	Patients undergo unirradiated DLI over 15-30 minutes on day 0. Patients then undergo restaging on day 28 and may undergo a second DLI after at least 4 weeks if no significant GVHD develops and disease status worsens or after at least 8 weeks if disease status is unchanged and persistent donor T-cells are documented. Therapeutic Allogeneic Lymphocytes: Given IV
Measure Participants	35
Number [percentage of participants]	5.7 16.3%

2. Secondary Outcome

Title	Incidence of Graft Rejection
Description	Percentage patients with graft rejection.
Time Frame	100 days after DLI

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment (DLI)
Arm/Group Description	Patients undergo unirradiated DLI over 15-30 minutes on day 0. Patients then undergo restaging on day 28 and may undergo a second DLI after at least 4 weeks if no significant GVHD develops and disease status worsens or after at least 8 weeks if disease status is unchanged and persistent donor T-cells are documented. Therapeutic Allogeneic Lymphocytes: Given IV
Measure Participants	35
Number [percentage of participants]	5.7 16.3%

3. Secondary Outcome

Title	Incidence of Relapse/Progression
Description	CML New cytogenetic abnormality and/or development of accelerated phase or blast crisis. The criteria for accelerated phase will be defined as unexplained fever >38.3°C, new clonal cytogenetic abnormalities in addition to a single Ph-positive chromosome, marrow blasts and promyelocytes >20%. CMML, AML, ALL >30% BM blasts w/ deteriorating performance status, or worsening of anemia, neutropenia, or thrombocytopenia. CLL ≥1 of: Physical exam/imaging studies ≥50% increase or new, circulating lymphocytes by morphology and/or flow cytometry ≥50% increase, and lymph node biopsy w/ Richter's transformation. NHL >25% increase in the sum of the products of the perpendicular diameters of marker lesions, or the appearance of new lesions. MM ≥100% increase of the serum myeloma protein from its lowest level, or reappearance of myeloma peaks that had disappeared w/ treatment; or definite increase in the size or number of plasmacytomas or lytic bone lesions.
Time Frame	1 year after DLI

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment (DLI)
Arm/Group Description	Patients undergo unirradiated DLI over 15-30 minutes on day 0. Patients then undergo restaging on day 28 and may undergo a second DLI after at least 4 weeks if no significant GVHD develops and disease status worsens or after at least 8 weeks if disease status is unchanged and persistent donor T-cells are documented. Therapeutic Allogeneic Lymphocytes: Given IV
Measure Participants	35
Number [percentage of participants]	71.4 204%

4. Secondary Outcome

Title	Incidence of Grade II-IV GVHD in Patients Undergoing DLI Following a Non-myeloablative Transplant
Description	Percentage of Participants with II-IV Acute GVHD
Time Frame	100 days after DLI

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment (DLI)
Arm/Group Description	Patients undergo unirradiated DLI over 15-30 minutes on day 0. Patients then undergo restaging on day 28 and may undergo a second DLI after at least 4 weeks if no significant GVHD develops and disease status worsens or after at least 8 weeks if disease status is unchanged and persistent donor T-cells are documented. Therapeutic Allogeneic Lymphocytes: Given IV
Measure Participants	35
Number [percentage of participants]	14.3 40.9%

5. Secondary Outcome

Title	Incidence of Infections in Patients Undergoing DLI Following a Non-myeloablative Transplant
Description	Percentage of Participants with infections.
Time Frame	100 days after DLI

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment (DLI)
Arm/Group Description	Patients undergo unirradiated DLI over 15-30 minutes on day 0. Patients then undergo restaging on day 28 and may undergo a second DLI after at least 4 weeks if no significant GVHD develops and disease status worsens or after at least 8 weeks if disease status is unchanged and persistent donor T-cells are documented. Therapeutic Allogeneic Lymphocytes: Given IV
Measure Participants	35
Number [percentage of participants]	88.6 253.1%

6. Secondary Outcome

Title	Overall Survival
Description	Percentage patients surviving 1 year post-transplant.
Time Frame	1 year after DLI

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment (DLI)
Arm/Group Description	Patients undergo unirradiated DLI over 15-30 minutes on day 0. Patients then undergo restaging on day 28 and may undergo a second DLI after at least 4 weeks if no significant GVHD develops and disease status worsens or after at least 8 weeks if disease status is unchanged and persistent donor T-cells are documented. Therapeutic Allogeneic Lymphocytes: Given IV
Measure Participants	35
Number [percentage of participants]	71.4 204%

7. Secondary Outcome

Title	Progression-free Survival
Description	Percentage of patients with progression-free survival
Time Frame	1 year after DLI

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment (DLI)
Arm/Group Description	Patients undergo unirradiated DLI over 15-30 minutes on day 0. Patients then undergo restaging on day 28 and may undergo a second DLI after at least 4 weeks if no significant GVHD develops and disease status worsens or after at least 8 weeks if disease status is unchanged and persistent donor T-cells are documented. Therapeutic Allogeneic Lymphocytes: Given IV
Measure Participants	35
Number [percentage of participants]	28.6 81.7%

Adverse Events

Time Frame	AEs: Conditioning through Day 100; SAEs: Conditioning through Day 200
Arm/Group Title	Treatment (DLI)
Arm/Group Description	Patients undergo unirradiated DLI over 15-30 minutes on day 0. Patients then undergo restaging on day 28 and may undergo a second DLI after at least 4 weeks if no significant GVHD develops and disease status worsens or after at least 8 weeks if disease status is unchanged and persistent donor T-cells are documented. Therapeutic Allogeneic Lymphocytes: Given IV
All Cause Mortality
	Treatment (DLI)
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Treatment (DLI)
	Affected / at Risk (%)	# Events
Total	6/35 (17.1%)
Cardiac disorders
Myocardial infaction	1/35 (2.9%)	1
Immune system disorders
GVHD	3/35 (8.6%)	3
Investigations
Blood bilirubin increased	1/35 (2.9%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Secondary Malignancy	1/35 (2.9%)	1
Other (Not Including Serious) Adverse Events
	Treatment (DLI)
	Affected / at Risk (%)	# Events
Total	7/35 (20%)
Blood and lymphatic system disorders
Spleen disorder	1/35 (2.9%)	1
Cardiac disorders
Atrial fibrillation	1/35 (2.9%)	1
Gastrointestinal disorders
Abdominal pain	1/35 (2.9%)	1
Ileal obstruction	1/35 (2.9%)	1
Hepatobiliary disorders
Cholecystitis	1/35 (2.9%)	1
Immune system disorders
GVHD	1/35 (2.9%)	1
Investigations
Blood bilirubin increased	1/35 (2.9%)	1
Neutrophil count decreased	1/35 (2.9%)	1
Metabolism and nutrition disorders
Metabolism and nutrition disorders - Other (Elevated tacrolimus level)	1/35 (2.9%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Treatment related secondary malignancy	1/35 (2.9%)	1
Renal and urinary disorders
Respiratory, thoracic, and mediastrinal disorders - Other (Unknown)	1/35 (2.9%)	1
Respiratory, thoracic and mediastinal disorders
Hypoxia	2/35 (5.7%)	3
Vascular disorders
Hypotension	2/35 (5.7%)	2
Thromboembolic event	1/35 (2.9%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE 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.