Acute LeukemiaPhase 2NCT01036009
A Study of Withdrawal of Immunosuppression and Donor Lymphocyte Infusions Following Allogeneic Transplant for Pediatric Hematologic Malignancies
A Phase 2 study testing Withdrawal of immunosuppression and donor lymphocyte infusion in people with Acute Leukemia and Acute Myeloid Leukemia, run by University of California, San Francisco at 2 sites in United States.
Trial 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. Read more about this study
- Who is it for?
- Ages 6 months to 25 years
- Conditions the study is for
- Acute Leukemia, Acute Myeloid Leukemia, Acute Lymphoblastic Leukemia
- What is being tested?
- Withdrawal of immunosuppression and donor lymphocyte infusion
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 43 participants
- Where
- 2 sitesUnited States
- Study dates
- Oct 2009to Jul 2015
- Phase
- Phase 2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 6 months to 25 years
- All sexes
- No healthy volunteers
- Child, Adult
Who may be able to join
- 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.
Who cannot join
- 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.
Trial locations and contacts
2 sites in 1 country.
United States2 sites
University of California
San Francisco, California, 94115
All Children's Hospital
St. Petersburg, Florida, 33701
About this study
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
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.
Read the 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.
- Conditions
- Acute Leukemia, Acute Myeloid Leukemia, Acute Lymphoblastic Leukemia, Biphenotypic Leukemia, Pre-leukemic Syndromes, Monosomy 7
- Being tested
- Withdrawal of immunosuppression and donor lymphocyte infusion
- Keywords
- Hematologic, Malignancy, Leukemia, Pre-leukemic, Allogeneic, Transplant, Pediatric
- Medical subject headings
- Leukemia, Myeloid, Acute, Precursor Cell Lymphoblastic Leukemia-Lymphoma, Chromosome 7, monosomy, Leukemia, Myelomonocytic, Juvenile, Myelodysplastic Syndromes, Leukemia, Myelogenous, Chronic, BCR-ABL Positive, Neoplasms, Leukemia
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Withdrawal of immunosuppression and donor lymphocyte infusionOther
Intervention will involve fast withdrawal of immunosuppression and DLI until full donor chimerism is achieved.
| Study group | Role | What they receive |
|---|---|---|
| Group I: Observation | No intervention | 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 | Experimental | 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. Receives: Other: Withdrawal of immunosuppression and donor lymphocyte infusion |
What is being measured
The primary outcome is the main question the study is designed to answer.
Relapse at 2 Years Post-transplant.
Definition of relapse was >5 % blasts in bone marrow
Measured: 2 years post transplant.
Secondary outcomes (3)
2 Years Post-transplant Survival.
Measured: 2 years post transplant
The Incidence of Acute Graft Versus Host Disease (aGVHD).
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.
Measured: 2 years post transplant
The Incidence of Chronic GVHD (cGVHD).
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:
- 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.
Measured: 2 years post transplant
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted21 Dec 2009 (estimated)
- Study startOct 2009
- Primary completionJul 2014
- Study completionJul 2015
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (2)Papers the sponsor has linked to this study.
- Other trials for Acute LeukemiaStudies of the same condition, open and under way.
- More trials run by University of California, San FranciscoThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 43 participants (actual)
Sponsor and investigators
- Lead sponsor
- University of California, San Francisco
- Sponsor type
- University, hospital or other
- Collaborators
- Johns Hopkins All Children's Hospital
- Responsible party
- Sponsor
- Investigators
- Biljana Horn, M.D., Principal investigator, University of California, San Francisco
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01036009
- Sponsor's protocol ID
- CC# 09082
- Status last verified
- May 2016
- First submitted
- 17 Dec 2009
- Last updated
- 23 Jun 2016
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
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.
PubMed 18955982Horn B, Petrovic A, Wahlstrom J, Dvorak CC, Kong D, Hwang J, Expose-Spencer J, Gates M, Cowan MJ. Chimerism-based pre-emptive immunotherapy with fast withdrawal of immunosuppression and donor lymphocyte infusions after allogeneic stem cell transplantation for pediatric hematologic malignancies. Biol Blood Marrow Transplant. 2015 Apr;21(4):729-37. doi: 10.1016/j.bbmt.2014.12.029. Epub 2015 Jan 31.
PubMed 25644958
Study at a glance
From the registry record, last updated by the sponsor on 23 Jun 2016. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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
- ClinicalTrials.gov ID
- NCT01036009
- Acronym / sponsor ID
- CC# 09082
- Conditions
- Acute Leukemia, Acute Myeloid Leukemia, Acute Lymphoblastic Leukemia, Biphenotypic Leukemia, Pre-leukemic Syndromes, Monosomy 7
- Keywords
- Hematologic, Malignancy, Leukemia, Pre-leukemic, Allogeneic, Transplant, Pediatric
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 43 participants (actual)
- Lead sponsor
- University of California, San FranciscoUniversity, hospital or other
- Collaborators
- Johns Hopkins All Children's Hospital
- Study start
- Oct 2009
- Primary completion
- Jul 2014 (actual)
- Study completion
- Jul 2015 (actual)
- First posted
- 21 Dec 2009 (estimated)
- Results
- Posted 31 Oct 2014
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
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
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Group I: Observation | No intervention | –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 | Experimental | Other: Withdrawal of immunosuppression and donor lymphocyte infusionGroup 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. |
Who may qualify
- Ages
- 6 months to 25 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult
Key inclusion criteria (7 listed)
- 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.
Key exclusion criteria (6 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Withdrawal of immunosuppression and donor lymphocyte infusionIntervention will involve fast withdrawal of immunosuppression and DLI until full donor chimerism is achieved. | Other | Group II: Intervention |
Primary outcome
Relapse at 2 Years Post-transplant.
Time frame: 2 years post transplant.
Definition of relapse was >5 % blasts in bone marrow
3 secondary outcomes
2 Years Post-transplant Survival.
Time frame: 2 years post transplant
The Incidence of Acute Graft Versus Host Disease (aGVHD).
Time frame: 2 years post transplant
The Incidence of Chronic GVHD (cGVHD).
Time frame: 2 years post transplant
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 23 Jun 2016.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Background: PubMed 18955982Horn 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.
- Derived from this study: PubMed 25644958Horn B, Petrovic A, Wahlstrom J, Dvorak CC, Kong D, Hwang J, Expose-Spencer J, Gates M, Cowan MJ. Chimerism-based pre-emptive immunotherapy with fast withdrawal of immunosuppression and donor lymphocyte infusions after allogeneic stem cell transplantation for pediatric hematologic malignancies. Biol Blood Marrow Transplant. 2015 Apr;21(4):729-37. doi: 10.1016/j.bbmt.2014.12.029. Epub 2015 Jan 31.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Biljana Horn, M.D. principal investigator
University of California, San Francisco
2 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Withdrawal of immunosuppression and donor lymphocyte infusion in people with Acute Leukemia and Acute Myeloid Leukemia, run by University of California, San Francisco at 2 sites in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 7 inclusion and 6 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 23 Jun 2016. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 2 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 31 Oct 2014). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Relapse at 2 Years Post-transplant. (time frame: 2 years post transplant.). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT01036009, which also lists 2 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 23 Jun 2016.