Donor Lymphocyte Infusion After Allogeneic Hematopoietic Cell Transplantation for High-Risk Hematologic Malignancies
- Conditions
- Hematologic Neoplasms
- Interventions
- Procedure: donor lymphocyte infusion
- Registration Number
- NCT05327023
- Lead Sponsor
- National Cancer Institute (NCI)
- Brief Summary
Background:
People with blood cancers often receive blood or bone marrow transplants. But even with these treatments, the risk of relapse is high. Researchers want to see if giving the transplant recipient an infusion of lymphocytes (a type of white blood cell) from their transplant donor early after the transplant can reduce that risk.
Objective:
To learn if giving donor lymphocytes early after a transplant will help reduce the risk of relapse for people with certain blood cancers.
Eligibility:
Adults aged 18-65 with high-risk leukemia, lymphoma, myelodysplastic syndrome, or multiple myeloma that does not respond well to standard treatments and/or has a high risk of relapse. Healthy potential bone marrow and lymphocyte donor relatives aged 12 and older are also needed.
Design:
Participants will be screened with:
Physical exam
Blood and urine tests
Spinal tap
Eye exam
Dental exam
Heart and lung tests
Imaging scans. A radioactive substance may be injected in their arm if a PET scan is needed.
Bone marrow aspiration and biopsy
Some screening tests will be repeated during the study.
Participants will stay at the NIH hospital for about 4 weeks. They will receive a central venous catheter. They will get chemotherapy and other drugs starting 6 days before transplant. Then they will have their transplant. They will receive donor white blood cells 7 days later. They will give blood, bone marrow, urine, and stool samples for research. They must stay near NIH for at least 100 days after transplant.
Participants will have periodic follow-up visits for 5 years.
Healthy donors will have 2-3 visits. They will give blood, bone marrow, white blood cells, and stool samples for research.
Participation will last for 5 years....
- Detailed Description
Background:
* High-risk hematologic malignancies generally are incurable without an allogeneic hematopoietic cell transplant (HCT), but even HCT is associated with high risk of relapse and very poor overall survival.
* Prophylactic donor lymphocyte infusions (DLI) have been used to prevent relapse in high-risk diseases; preemptive DLIs have been used for MRD positivity or decreasing donor chimerism post-transplant; and, therapeutic DLIs have been used to treat overt morphologic relapse post-transplant.
* Prophylactic, preemptive, and therapeutic DLIs can cause significant graft-versus-host disease (GVHD), both acute and chronic, based on the dose of lymphocytes, timing of the infusion, and use of preparative chemotherapy, although these same factors also may impact on the therapeutic efficacy (graft-versus-tumor immunity of the DLI).
* Post-transplantation cyclophosphamide (PTCy) reduces rates of severe acute and chronic graft-versus-host disease (GVHD) and the immunosuppressive burden after HCT.
* In pre-clinical HCT models, very large DLI doses can be given after PTCy, even as early as 24 hours after PTCy treatment, and significant GVHD is not induced, different from that seen for DLI infusions in mice treated with T-cell-depleted HCT, in which fatal GVHD is rapidly induced. This effect in PTCy-treated mice is dependent on Foxp3+ regulatory T cells.
* In patients treated at the NIH Clinical Center, DLI has been given for clinical reasons as early as 1 month post-transplant in PTCy-treated patients for infection, falling chimerism, or relapse and did not cause GVHD in these settings when additional conditioning was not given and T-cell-depleting antibodies were not used, both of which may disrupt the regulatory mechanisms induced after PTCy that are needed to control GVHD.
* The early integration of immunotherapeutic strategies, such as DLIs, after PTCy has the potential to prevent relapse in patients with high-risk hematologic malignancies, which may result in improved survival in such patients.
Objectives:
-To determine the maximally tolerated dose of DLI that can be safely administered after HLA-matched-related HCT and after HLA-haploidentical HCT
Eligibility:
-Recipient Participant:
* Histologically or cytologically confirmed hematologic malignancy classified as high or very high disease risk by the Refined Disease Risk Index for HCT
* Age 18-65
* At least one potentially suitable human leukocyte antigen (HLA)-matched related or HLA-haploidentical donor.
* Karnofsky performance score \>=60
* Adequate organ function
Design:
* Open-label, single-center, non-randomized, phase I/II study
* All recipient participants will receive myeloablative conditioning, HLA-matched-related or HLA-haploidentical bone marrow HCT, GVHD prophylaxis including post- transplantation cyclophosphamide, and prophylactic donor lymphocyte infusion
* There will be 2 cohorts of recipient participants: one with HLA-matched-related donors and one with HLA-haploidentical donors
* For HLA-matched HCT, the study will proceed to a small, three-level \[1) DLI: 1 x 10\^6 CD3+ cells/kg on day +7, 2) DLI: 3 x 10\^6 CD3+ cells/kg on day +7, 3) DLI: 1 x 10\^7 CD3+ cells/kg on day +7\] phase I dose escalation study based on the standard 3+3 approach
* For HLA-haploidentical HCT, the study will proceed to a small, three-level \[1) DLI: 1 x 10\^5 CD3+ cells/kg on day +7, 2) DLI: 3 x 10\^5 CD3+ cells/kg on day +7, 3) DLI: 1 x 10\^6 CD3+ cells/kg on day +7\] phase I dose escalation study based on the standard 3+3 approach
* Recipient participants will be evaluated for development of steroid-refractory grade III- IV acute GVHD (aGVHD) at day +60 as the dose-limiting toxicity.
* Phase II will proceed with DLI at the dose level (separately determined for each HLA cohort) which is associated with 0-1 of 6 recipient participants with steroid refractory grade III-IV aGVHD at day +60 and the least amount of toxicity.
* Simon optimal two-stage phase II trial design, to rule out excess steroid refractory grade III-IV aGVHD with the addition of prophylactic DLI, will be used in the phase II portion of the study which will enroll an additional 14 evaluable subjects in each cohort.
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 430
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SEQUENTIAL
- Arm && Interventions
Group Intervention Description Phase I Dose Escalation, Cohort 2 (haploidentical) Busulfan DLI at escalating doses (1 x 10\^5 CD3+ cells/kg, 3 x 10\^5 CD3+ cells/kg, and 1 x 10\^6 CD3+ cells/kg) on day +7 or +21 to assess for safety and determine Phase II dose (up to 18 evaluable patients) Phase I Dose Escalation, Cohort 1 (matched) donor lymphocyte infusion DLI at escalating doses (1 x 10\^6 CD3+ cells/kg, 3 x 10\^6 CD3+ cells/kg, and 1 x 10\^7 CD3+ cells/kg) on day +7 or +21 to assess for safety and determine Phase II dose (up to 18 evaluable patients) Phase I Dose Escalation, Cohort 2 (haploidentical) donor lymphocyte infusion DLI at escalating doses (1 x 10\^5 CD3+ cells/kg, 3 x 10\^5 CD3+ cells/kg, and 1 x 10\^6 CD3+ cells/kg) on day +7 or +21 to assess for safety and determine Phase II dose (up to 18 evaluable patients) Phase II Efficacy, Cohort 1 (matched) Mycophenolate mofetil DLI at maximally tolerated, safe dose (from Phase I) to assess secondary clinical outcomes at this dosing level (up to 14 additional evaluable patients in each cohort) Phase II Efficacy, Cohort 1 (matched) donor lymphocyte infusion DLI at maximally tolerated, safe dose (from Phase I) to assess secondary clinical outcomes at this dosing level (up to 14 additional evaluable patients in each cohort) Phase II Efficacy, Cohort 2 (haploidentical) donor lymphocyte infusion DLI at maximally tolerated, safe dose (from Phase I) to assess secondary clinical outcomes at this dosing level (up to 14 additional evaluable patients in each cohort) Phase I Dose Escalation, Cohort 1 (matched) Busulfan DLI at escalating doses (1 x 10\^6 CD3+ cells/kg, 3 x 10\^6 CD3+ cells/kg, and 1 x 10\^7 CD3+ cells/kg) on day +7 or +21 to assess for safety and determine Phase II dose (up to 18 evaluable patients) Phase I Dose Escalation, Cohort 1 (matched) Mycophenolate mofetil DLI at escalating doses (1 x 10\^6 CD3+ cells/kg, 3 x 10\^6 CD3+ cells/kg, and 1 x 10\^7 CD3+ cells/kg) on day +7 or +21 to assess for safety and determine Phase II dose (up to 18 evaluable patients) Phase I Dose Escalation, Cohort 1 (matched) Fludarabine DLI at escalating doses (1 x 10\^6 CD3+ cells/kg, 3 x 10\^6 CD3+ cells/kg, and 1 x 10\^7 CD3+ cells/kg) on day +7 or +21 to assess for safety and determine Phase II dose (up to 18 evaluable patients) Phase I Dose Escalation, Cohort 1 (matched) Cyclophosphamide DLI at escalating doses (1 x 10\^6 CD3+ cells/kg, 3 x 10\^6 CD3+ cells/kg, and 1 x 10\^7 CD3+ cells/kg) on day +7 or +21 to assess for safety and determine Phase II dose (up to 18 evaluable patients) Phase I Dose Escalation, Cohort 1 (matched) Sirolimus DLI at escalating doses (1 x 10\^6 CD3+ cells/kg, 3 x 10\^6 CD3+ cells/kg, and 1 x 10\^7 CD3+ cells/kg) on day +7 or +21 to assess for safety and determine Phase II dose (up to 18 evaluable patients) Phase I Dose Escalation, Cohort 2 (haploidentical) Cyclophosphamide DLI at escalating doses (1 x 10\^5 CD3+ cells/kg, 3 x 10\^5 CD3+ cells/kg, and 1 x 10\^6 CD3+ cells/kg) on day +7 or +21 to assess for safety and determine Phase II dose (up to 18 evaluable patients) Phase I Dose Escalation, Cohort 2 (haploidentical) Fludarabine DLI at escalating doses (1 x 10\^5 CD3+ cells/kg, 3 x 10\^5 CD3+ cells/kg, and 1 x 10\^6 CD3+ cells/kg) on day +7 or +21 to assess for safety and determine Phase II dose (up to 18 evaluable patients) Phase I Dose Escalation, Cohort 2 (haploidentical) Mycophenolate mofetil DLI at escalating doses (1 x 10\^5 CD3+ cells/kg, 3 x 10\^5 CD3+ cells/kg, and 1 x 10\^6 CD3+ cells/kg) on day +7 or +21 to assess for safety and determine Phase II dose (up to 18 evaluable patients) Phase I Dose Escalation, Cohort 2 (haploidentical) Sirolimus DLI at escalating doses (1 x 10\^5 CD3+ cells/kg, 3 x 10\^5 CD3+ cells/kg, and 1 x 10\^6 CD3+ cells/kg) on day +7 or +21 to assess for safety and determine Phase II dose (up to 18 evaluable patients) Phase II Efficacy, Cohort 1 (matched) Cyclophosphamide DLI at maximally tolerated, safe dose (from Phase I) to assess secondary clinical outcomes at this dosing level (up to 14 additional evaluable patients in each cohort) Phase II Efficacy, Cohort 1 (matched) Busulfan DLI at maximally tolerated, safe dose (from Phase I) to assess secondary clinical outcomes at this dosing level (up to 14 additional evaluable patients in each cohort) Phase II Efficacy, Cohort 1 (matched) Fludarabine DLI at maximally tolerated, safe dose (from Phase I) to assess secondary clinical outcomes at this dosing level (up to 14 additional evaluable patients in each cohort) Phase II Efficacy, Cohort 1 (matched) Sirolimus DLI at maximally tolerated, safe dose (from Phase I) to assess secondary clinical outcomes at this dosing level (up to 14 additional evaluable patients in each cohort) Phase II Efficacy, Cohort 2 (haploidentical) Cyclophosphamide DLI at maximally tolerated, safe dose (from Phase I) to assess secondary clinical outcomes at this dosing level (up to 14 additional evaluable patients in each cohort) Phase II Efficacy, Cohort 2 (haploidentical) Busulfan DLI at maximally tolerated, safe dose (from Phase I) to assess secondary clinical outcomes at this dosing level (up to 14 additional evaluable patients in each cohort) Phase II Efficacy, Cohort 2 (haploidentical) Fludarabine DLI at maximally tolerated, safe dose (from Phase I) to assess secondary clinical outcomes at this dosing level (up to 14 additional evaluable patients in each cohort) Phase II Efficacy, Cohort 2 (haploidentical) Mycophenolate mofetil DLI at maximally tolerated, safe dose (from Phase I) to assess secondary clinical outcomes at this dosing level (up to 14 additional evaluable patients in each cohort) Phase II Efficacy, Cohort 2 (haploidentical) Sirolimus DLI at maximally tolerated, safe dose (from Phase I) to assess secondary clinical outcomes at this dosing level (up to 14 additional evaluable patients in each cohort)
- Primary Outcome Measures
Name Time Method determine the maximally tolerated dose of DLI that can be safely administered after HLA-matched-related HCT and after HLA-haploidentical HCT 60 days fraction of evaluable patients who experience steroid-refractory grade III-IV aGVHD at day +60 will be determined and reported along with 80% and 95% two-sided confidence intervals.
- Secondary Outcome Measures
Name Time Method determine, at the maximally tolerated dose in the phase II portion of the study, the cumulative incidences of chronic GVHD at 1 year for HLA-matched-related and HLA-haploidentical 1 year To evaluate chronic GVHD
determine, at the maximally tolerated dose in the phase II portion of the study, the cumulative incidences of non-relapse mortality at 100 days and 1 year for HLA-matched-related and HLA-haploidentical Day 100 and 1 year To evaluate non-relapse mortality
determine, at the maximally tolerated dose in the phase II portion of the study, the cumulative incidences of Steroid-refractory Grades II-IV and Grades III-IV aGVHD at days +100 and +200 for HLA-matched-related and HLA-haploidentical Day 100 and 200 To evaluate steroid-refractory grade II-IV and grade III-IV acute GVHD at day 100 and 200.
determine, at the maximally tolerated dose in the phase II portion of the study, the cumulative incidences of overall survival (OS) and disease-free survival (DFS) at 1 year for HLA-matched-related and HLA-haploidentical 1 year To evaluate survival
determine, at the maximally tolerated dose in the phase II portion of the study, the cumulative incidences of Grades II-IV and Grades III-IV aGVHD at days +100 and +200 for HLA-matched-related and HLA-haploidentical Day 100 and 200 To evaluate grade II-IV and grade III-IV acute GVHD at day 100 and 200.
determine, at the maximally tolerated dose in the phase II portion of the study, the cumulative incidences of relapse at 1 year for HLA-matched-related and HLA-haploidentical 1 year To evaluate relapse
determine, at the maximally tolerated dose in the phase II portion of the study, the cumulative incidences of primary engraftment (including time to neutrophil and platelet engraftment) for HLA-matched-related and HLA-haploidentical Day 28 and 100 Rate and timing of neutrophil and platelet engraftment reported as median engraftment times for each and cumulative incidences of each at days +28 and +100
Trial Locations
- Locations (1)
National Institutes of Health Clinical Center
🇺🇸Bethesda, Maryland, United States