A Study of Withdrawal of Immunosuppression and Donor Lymphocyte Infusions Following Allogeneic Transplant for Pediatric Hematologic Malignancies

• Sponsor: University of California, San Francisco (Other)
• Overall Status: Completed
• CT.gov ID: NCT01036009
• Collaborator: Johns Hopkins All Children's Hospital (Other)
• Enrollment: 43
• Locations: 2
• Arms: 2
• Duration (Months): 69
• Patients Per Site: 21.5
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

There is no curative therapy once acute leukemia patients relapse after transplant. Patients who develop clinically significant graft versus host disease (GVHD) have a lower rate of relapse than those who do not develop GVHD. We are initiating this study of post-transplant fast withdrawal of immunosuppression and donor lymphocyte infusions, with a goal of achieving full donor chimerism in children with hematologic malignancies. If our hypothesis that full donor chimerism results in leukemia-free survival is correct, using immune modulation to achieve full donor chimerism should decrease relapse rate and thus increase survival. The goal of this Phase II study is to identify if achieving full donor chimerism in whole blood CD3+ and leukemia-specific (CD14/15+, CD19+, CD33+ and CD34+) subset may decrease the risk of relapse of patients undergoing allogeneic transplant for hematologic malignancy.

Condition or Disease	Intervention/Treatment	Phase
Acute Leukemia; Acute Myeloid Leukemia; Acute Lymphoblastic Leukemia; Biphenotypic Leukemia; Pre-leukemic Syndromes; Monosomy 7; Bone Marrow Clonal Malformations; Juvenile Myelomonocytic Leukemia; Myelodysplastic Syndromes; Chronic Myelogenous Leukemia	Other: Withdrawal of immunosuppression and donor lymphocyte infusion	Phase 2

Detailed Description

The goal of this Phase II study is to identify if achieving full donor chimerism in whole blood, CD3+, and leukemia-specific subset (CD3+, CD14/15+, CD19+, CD33+ and CD34+ subset) may decrease the risk of relapse of patients undergoing allogeneic transplant for hematologic malignancy.

We estimate that total of 50 recipient patients will need to be enrolled. Of these 50 recipient patients an observation group and an intervention group will be formed. We want to enroll 25 recipient patients in the intervention group, this group will receive study intervention and their outcomes will be the focus of statistical analysis for this study. Intervention will involve fast withdrawal of immunosuppression following transplant and donor lymphocyte infusion (DLI) until full donor chimerism is achieved. Chimerism is a genetic test that measures the proportion of donor's and recipient's cells in blood or bone marrow. Twenty five patients will undergo fast withdrawal of immunosuppression and 33 -50% of them (8-13) will undergo DLI following fast withdrawal of immunosuppression.

Patients will have peripheral blood (PB) chimerism tested upon engraftment. A confirmatory test from PB and bone marrow (BM) will be done on day 45±7. Minimal residual disease (MRD) will be examined by immunoflow, FISH, cytogenetics or PCR. Patients with positive MRD will be on a faster schedule of immune intervention than patients with negative MRD. Interventions will be carried on until 1 year post transplant. If confirmatory testing shows no evidence of MRD and full donor chimerism is present in all subsets, the patient will be part of the "observation" group and be observed until 2 years post transplant. Chimerism will be repeated at 12 and 24 months post transplant. If the patient has mixed chimerism on both confirmatory tests (PB and BM), the patient will be part of the "intervention" group and fast withdrawal of immunosuppression will be initiated. If the patient has mixed chimerism on one of the confirmatory tests (PB or BM), the test will be repeated in 2 weeks and the patient will proceed with either observation or intervention, based on the result of the repeated test. Patients will be followed for the incidence of acute and chronic Graft Versus Host Disease (GVHD) and relapse until 2 years post transplant. The study will be considered successful if the relapse rate at 2 years post transplant is ≤20% for the entire study or ≤ 40% for the intervention group.

Study Design

• Study Type: Interventional
• Actual Enrollment: 43 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase II Study of Preemptive Fast Withdrawal of Immunosuppression and Donor Lymphocyte Infusions for Achieving Complete Donor Chimerism Following Allogeneic Transplant for Pediatric Hematologic Malignancies
• Study Start Date: Oct 1, 2009
• Actual Primary Completion Date: Jul 1, 2014
• Actual Study Completion Date: Jul 1, 2015

Arms and Interventions

Arm	Intervention/Treatment
No Intervention: Group I: Observation Group I (observation): Patients with full donor chimerism and no evidence of MRD continue to undergo clinical monitoring for acute and chronic graft-vs-host disease and relapse until 3 years post-transplant. Patients undergo repeat chimerism testing at 12 and 24 months post-transplant.
Experimental: Group II: Intervention Group II (intervention): Patients undergo withdrawal of immunosuppression and receive donor lymphocyte infusions between days 60-365 post-transplant (or until full donor chimerism is achieved). Patients also undergo clinical monitoring and repeat chimerism testing as in group I.	Other: Withdrawal of immunosuppression and donor lymphocyte infusion; Intervention will involve fast withdrawal of immunosuppression and DLI until full donor chimerism is achieved.

Outcome Measures

Primary Outcome Measures

1. Relapse at 2 Years Post-transplant. [2 years post transplant.]

   Definition of relapse was >5 % blasts in bone marrow

Secondary Outcome Measures

1. 2 Years Post-transplant Survival. [2 years post transplant]

2. The Incidence of Acute Graft Versus Host Disease (aGVHD). [2 years post transplant]

   Definition and diagnostic criteria of aGVHD according to: 1994 Consensus Conference on Acute GVHD Grading. Przepiorka D1, Weisdorf D, Martin P, Klingemann HG, Beatty P, Hows J, Thomas ED. Bone Marrow Transplant. 1995 Jun;15(6):825-8. In this system, patients are divided into one of four grades (I-IV) depending on the degree, or stage, of involvement in three organs. The skin is staged with percent body surface involved, the liver is staged with degree of bilirubin elevation, and the gastrointestinal tract is staged with amount of diarrhea.

3. The Incidence of Chronic GVHD (cGVHD). [2 years post transplant]

   Diagnostic criteria of cGVHD from: Filipovich AH, Weisdorf D, Pavletic S et al. National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-host disease: I Diagnosis and Staging Working Group Report. Biology of Blood and Marrow Transplantation 2005;11:945-955. The diagnosis of chronic GVHD requires the following: 1) Distinction from acute GVHD; 2) Presence of at least 1 diagnostic clinical sign of chronic GVHD or presence of at least 1 distinctive manifestation confirmed by pertinent biopsy or other relevant tests; 3) Exclusion of other possible diagnoses. Scoring of organ manifestations requires careful assessment of signs, symptoms, laboratory values, and other study results. A clinical scoring system (0-3) is used for evaluation of the involvement of individual organs and sites. Global assessment of severity (mild, moderate, or severe) is derived by combining organ- and site-specific scores.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 6 Months to 25 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Age 6 months - 25 years.

• Diagnoses of acute leukemia (AML, ALL, biphenotypic leukemia), pre-leukemic syndromes (monosomy 7 or other bone marrow clonal malformations), JMML, myelodysplastic syndromes or CML.

• Undergoing an allogeneic transplant as standard care.

• Performance status: Karnofsky/Lansky>60%.

• Availability of pre-transplant recipient's DNA and donor's DNA for chimerism testing. This could be DNA or material from which DNA could be extracted. Frozen blood would be preferred. For some patients, post transplant specimens that are not infiltrated with donor cells may be used.

• Bone marrow or PBMTC as stem cell source.HLA matching: donor and recipient should be matched at a minimum of 7/8 antigens (A,B,C and DrB1) for bone marrow and PBMTC transplants.

• No history of ≥grade III acute GVHD.

Exclusion Criteria:

• Treatment on other experimental protocols, if withdrawal of immunosuppression interferes with procedures of follow-up on the primary study.

• Leukemia relapse defined as > 5% blasts on bone marrow exam or >1% leukemia cells by immunoflow MRD, or presence of extramedullary leukemia.

• History of acute GVHD ≥ stage III or with any degree of active acute or cGVHD.

• On steroids for any reason.

• Any condition that compromises compliance with the objectives and procedures of this protocol, as judged by the principal investigator.

• Cells for DLI cannot be obtained from the donor.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of California	San Francisco	California	United States	94115
2	All Children's Hospital	St. Petersburg	Florida	United States	33701

Sponsors and Collaborators

• University of California, San Francisco
• Johns Hopkins All Children's Hospital

Investigators

• Principal Investigator: Biljana Horn, M.D., University of California, San Francisco

Study Documents (Full-Text)

None provided.

More Information

Publications

• Horn B, Soni S, Khan S, Petrovic A, Breslin N, Cowan M, Pelle-Day G, Cooperstein E, Baxter-Lowe LA. Feasibility study of preemptive withdrawal of immunosuppression based on chimerism testing in children undergoing myeloablative allogeneic transplantation for hematologic malignancies. Bone Marrow Transplant. 2009 Mar;43(6):469-76. doi: 10.1038/bmt.2008.339. Epub 2008 Oct 27.

• Responsible Party: University of California, San Francisco
• ClinicalTrials.gov Identifier: NCT01036009
• Other Study ID Numbers: CC# 09082; NCT00975598
• First Posted: Dec 21, 2009
• Last Update Posted: Jun 23, 2016
• Last Verified: May 1, 2016

• Keywords provided by University of California, San Francisco: Hematologic; Malignancy; Leukemia; Pre-leukemic; Allogeneic; Transplant; Pediatric
• Additional relevant MeSH terms: Leukemia; Neoplasms; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Myeloid; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Hematologic Neoplasms; Leukemia, Myelomonocytic, Juvenile; Myelodysplastic Syndromes; Syndrome; Monosomy

Study Results

Participant Flow

Pre-assignment Detail	5 eligible patients relapsed/died before assignment to a study arm

Arm/Group Title	Group I: Observation	Group II: Intervention
Arm/Group Description	Group I (observation): Patients with full donor chimerism and no evidence of MRD continue to undergo clinical monitoring for acute and chronic graft-vs-host disease and relapse until 3 years post-transplant. Patients undergo repeat chimerism testing at 12 and 24 months post-transplant.	Group II (intervention): Patients undergo withdrawal of immunosuppression and receive donor lymphocyte infusions between days 60-365 post-transplant (or until full donor chimerism is achieved). Patients also undergo clinical monitoring and repeat chimerism testing as in group I. Withdrawal of immunosuppression and donor lymphocyte infusion: Intervention will involve fast withdrawal of immunosuppression and DLI until full donor chimerism is achieved.
Period Title: Overall Study
STARTED	17	26
COMPLETED	17	26
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Group I: Observation	Group II: Intervention	Total
Arm/Group Description	Group I (observation): Patients with full donor chimerism and no evidence of MRD continue to undergo clinical monitoring for acute and chronic graft-vs-host disease and relapse until 3 years post-transplant. Patients undergo repeat chimerism testing at 12 and 24 months post-transplant.	Group II (intervention): Patients undergo withdrawal of immunosuppression and receive donor lymphocyte infusions between days 60-365 post-transplant (or until full donor chimerism is achieved). Patients also undergo clinical monitoring and repeat chimerism testing as in group I. Withdrawal of immunosuppression and donor lymphocyte infusion: Intervention will involve fast withdrawal of immunosuppression and DLI until full donor chimerism is achieved.	Total of all reporting groups
Overall Participants	17	26	43
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	10.12 (7.25)	11.3 (6)	10.84 (6.5)
Sex: Female, Male (Count of Participants)
Female	8 47.1%	12 46.2%	20 46.5%
Male	9 52.9%	14 53.8%	23 53.5%
Region of Enrollment (participants) [Number]
United States	17 100%	26 100%	43 100%

Outcome Measures

1. Primary Outcome

Title	Relapse at 2 Years Post-transplant.
Description	Definition of relapse was >5 % blasts in bone marrow
Time Frame	2 years post transplant.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Group I: Observation	Group II: Intervention
Arm/Group Description	Group I (observation): Patients with full donor chimerism and no evidence of MRD continue to undergo clinical monitoring for acute and chronic graft-vs-host disease and relapse until 3 years post-transplant. Patients undergo repeat chimerism testing at 12 and 24 months post-transplant.	Group II (intervention): Patients undergo withdrawal of immunosuppression and receive donor lymphocyte infusions between days 60-365 post-transplant (or until full donor chimerism is achieved). Patients also undergo clinical monitoring and repeat chimerism testing as in group I. Withdrawal of immunosuppression and donor lymphocyte infusion: Intervention will involve fast withdrawal of immunosuppression and DLI until full donor chimerism is achieved.
Measure Participants	17	26
Number [participants]	6 35.3%	4 15.4%

2. Secondary Outcome

Title	2 Years Post-transplant Survival.
Time Frame	2 years post transplant

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Group I: Observation	Group II: Intervention
Arm/Group Description	Group I (observation): Patients with full donor chimerism and no evidence of MRD continue to undergo clinical monitoring for acute and chronic graft-vs-host disease and relapse until 3 years post-transplant. Patients undergo repeat chimerism testing at 12 and 24 months post-transplant.	Group II (intervention): Patients undergo withdrawal of immunosuppression and receive donor lymphocyte infusions between days 60-365 post-transplant (or until full donor chimerism is achieved). Patients also undergo clinical monitoring and repeat chimerism testing as in group I. Withdrawal of immunosuppression and donor lymphocyte infusion: Intervention will involve fast withdrawal of immunosuppression and DLI until full donor chimerism is achieved.
Measure Participants	17	26
Number [participants]	11 64.7%	21 80.8%

3. Secondary Outcome

Title	The Incidence of Acute Graft Versus Host Disease (aGVHD).
Description	Definition and diagnostic criteria of aGVHD according to: 1994 Consensus Conference on Acute GVHD Grading. Przepiorka D1, Weisdorf D, Martin P, Klingemann HG, Beatty P, Hows J, Thomas ED. Bone Marrow Transplant. 1995 Jun;15(6):825-8. In this system, patients are divided into one of four grades (I-IV) depending on the degree, or stage, of involvement in three organs. The skin is staged with percent body surface involved, the liver is staged with degree of bilirubin elevation, and the gastrointestinal tract is staged with amount of diarrhea.
Time Frame	2 years post transplant

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Group I: Observation	Group II: Intervention
Arm/Group Description	Group I (observation): Patients with full donor chimerism and no evidence of MRD continue to undergo clinical monitoring for acute and chronic graft-vs-host disease and relapse until 3 years post-transplant. Patients undergo repeat chimerism testing at 12 and 24 months post-transplant.	Group II (intervention): Patients undergo withdrawal of immunosuppression and receive donor lymphocyte infusions between days 60-365 post-transplant (or until full donor chimerism is achieved). Patients also undergo clinical monitoring and repeat chimerism testing as in group I. Withdrawal of immunosuppression and donor lymphocyte infusion: Intervention will involve fast withdrawal of immunosuppression and DLI until full donor chimerism is achieved.
Measure Participants	17	26
Number [participants]	11 64.7%	5 19.2%

4. Secondary Outcome

Title	The Incidence of Chronic GVHD (cGVHD).
Description	Diagnostic criteria of cGVHD from: Filipovich AH, Weisdorf D, Pavletic S et al. National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-host disease: I Diagnosis and Staging Working Group Report. Biology of Blood and Marrow Transplantation 2005;11:945-955. The diagnosis of chronic GVHD requires the following: 1) Distinction from acute GVHD; 2) Presence of at least 1 diagnostic clinical sign of chronic GVHD or presence of at least 1 distinctive manifestation confirmed by pertinent biopsy or other relevant tests; 3) Exclusion of other possible diagnoses. Scoring of organ manifestations requires careful assessment of signs, symptoms, laboratory values, and other study results. A clinical scoring system (0-3) is used for evaluation of the involvement of individual organs and sites. Global assessment of severity (mild, moderate, or severe) is derived by combining organ- and site-specific scores.
Time Frame	2 years post transplant

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Group I: Observation	Group II: Intervention
Arm/Group Description	Group I (observation): Patients with full donor chimerism and no evidence of MRD continue to undergo clinical monitoring for acute and chronic graft-vs-host disease and relapse until 3 years post-transplant. Patients undergo repeat chimerism testing at 12 and 24 months post-transplant.	Group II (intervention): Patients undergo withdrawal of immunosuppression and receive donor lymphocyte infusions between days 60-365 post-transplant (or until full donor chimerism is achieved). Patients also undergo clinical monitoring and repeat chimerism testing as in group I. Withdrawal of immunosuppression and donor lymphocyte infusion: Intervention will involve fast withdrawal of immunosuppression and DLI until full donor chimerism is achieved.
Measure Participants	17	26
Number [participants]	6 35.3%	2 7.7%

5. Post-Hoc Outcome

Title	Late Relapses
Description	The number of patients who relapsed after 2-year primary endpoint. To assess a potential for late relapse-rate in the intervention arm only, patients in the intervention arm were provided additional follow-up until 3-yrs post transplant. The criterion for relapse was >5% blasts in bone marrow.
Time Frame	24-36 months post-transplant

Outcome Measure Data

Analysis Population Description

surviving patients in the intervention arm who had not relapsed as of 24 months were followed for an additional 12 months (until 3 years post-transplant)

Arm/Group Title	Group II: Intervention
Arm/Group Description	Group II (intervention): Patients undergo withdrawal of immunosuppression and receive donor lymphocyte infusions between days 60-365 post-transplant (or until full donor chimerism is achieved). Patients also undergo clinical monitoring and repeat chimerism testing as in group I. Withdrawal of immunosuppression and donor lymphocyte infusion: Intervention will involve fast withdrawal of immunosuppression and DLI until full donor chimerism is achieved.
Measure Participants	21
Number [participants]	4 23.5%

6. Post-Hoc Outcome

Title	Time Until Late Relapse
Description	Number of months post-transplant until late relapse, in intervention patients relapsing after the 2-year primary study endpoint. Relapse defined as >5% blasts in bone marrow
Time Frame	24-36 months post-transplant

Outcome Measure Data

Analysis Population Description

intervention patients who relapsed after the 2 year primary study endpoint

Arm/Group Title	Group II: Intervention
Arm/Group Description	Group II (intervention): Patients undergo withdrawal of immunosuppression and receive donor lymphocyte infusions between days 60-365 post-transplant (or until full donor chimerism is achieved). Patients also undergo clinical monitoring and repeat chimerism testing as in group I. Withdrawal of immunosuppression and donor lymphocyte infusion: Intervention will involve fast withdrawal of immunosuppression and DLI until full donor chimerism is achieved.
Measure Participants	4
Mean (Full Range) [months]	32.025

Adverse Events

Time Frame	2 years
Adverse Event Reporting Description	Due to the severity of illness in this patient population, this study collected and reported Adverse Events only if at least possibly related to study participation, and only in patients undergoing study intervention (intervention arm).
Arm/Group Title	Group I: Observation		Group II: Intervention
Arm/Group Description	Group I (observation): Patients with full donor chimerism and no evidence of MRD continue to undergo clinical monitoring for acute and chronic graft-vs-host disease and relapse until 3 years post-transplant. Patients undergo repeat chimerism testing at 12 and 24 months post-transplant.		Group II (intervention): Patients undergo withdrawal of immunosuppression and receive donor lymphocyte infusions between days 60-365 post-transplant (or until full donor chimerism is achieved). Patients also undergo clinical monitoring and repeat chimerism testing as in group I. Withdrawal of immunosuppression and donor lymphocyte infusion: Intervention will involve fast withdrawal of immunosuppression and DLI until full donor chimerism is achieved.
All Cause Mortality
	Group I: Observation		Group II: Intervention
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Group I: Observation		Group II: Intervention
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/0 (NaN)		1/26 (3.8%)
Respiratory, thoracic and mediastinal disorders
intervention-related-death	0/0 (NaN)	0	1/26 (3.8%)	1
Other (Not Including Serious) Adverse Events
	Group I: Observation		Group II: Intervention
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/0 (NaN)		9/26 (34.6%)
Blood and lymphatic system disorders
progressive disease	0/0 (NaN)	0	4/26 (15.4%)	4
Immune system disorders
aGVHD grade I-III	0/0 (NaN)	0	3/26 (11.5%)	3
cGVHD	0/0 (NaN)	0	2/26 (7.7%)	2

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.