Donor Lymphocyte Infusion After Allogeneic Hematopoietic Cell Transplantation for High-Risk Hematologic Malignancies

Hematologic Neoplasms Clinical Trial

Official title: Phase I/II Study Using Prophylactic Donor Lymphocyte Infusion Early Post-Transplant After Allogeneic Hematopoietic Cell Transplantation Using Post-Transplantation Cyclophosphamide for High-Risk Hematologic Malignancies

Status Recruiting

Clinical Trial 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....

Clinical Trial 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. ;

Related Conditions & MeSH terms

• Hematologic Neoplasms

• NCT number: NCT05327023
• Study type: Interventional
• Source: National Institutes of Health Clinical Center (CC)
• Contact: Amy H Chai
• Phone: (301) 219-7105
• Email: amy.chai@nih.gov
• Status: Recruiting
• Phase: Phase 1/Phase 2
• Start date: May 23, 2022
• Completion date: July 2, 2029