NCT05327023

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

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
• Phase: Phase 1 / Phase 2
• Study type: Interventional
• Enrollment: 430 (estimated)
• Sponsor: National Cancer Institute (NCI) · NIH
• Sex: All
• Age: 12 Years – 120 Years
• Healthy volunteers: Accepted

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.

Conditions

• Hematologic Neoplasms

Interventions

Type	Name	Description
PROCEDURE	donor lymphocyte infusion	The DLI will be given on Day +7 (Day +21 for dose level -1). If a recipient participant is deemed too critically ill/unstable to receive DLI on the protocol specified day, the DLI will be delayed up to 4 days at the discretion of the PI and given within this time frame once the recipient participant s clinical status has stabilized or improved. If the DLI cannot be given during this time frame, the recipient participant will be taken off study and not considered evaluable for DLT, outcomes, or adverse events since the experimental intervention will not have been given.
DRUG	Cyclophosphamide	HLA-matched: 50 mg/kg IV once daily over 2 hours on days +3 and +4a Cyclophosphamide will be dosed according to ideal body weight. HLA haploidentical: 25 mg/kg IV once daily over 2 hours on days +3 and +4a Cyclophosphamide will be dosed according to ideal body weight.
DRUG	Busulfan	AUC targeted dose based on busulfan test dose, with a default dose of 130 mg/m2/day, given as IV infusion over 3 hours each day for 4 days Transplant days -6 through day -3
DRUG	Mycophenolate mofetil	15 mg/kg orally or IV three times daily (max 1000 mg/dose) starting on day +5, continued through day +35. Dosing will be according to actual body weight.
DRUG	Fludarabine	40 mg/m2 IV infusion over 30-60 minutes once daily for 4 days Transplant days -6 through -3
DRUG	Sirolimus	Loading dose of 6 mg orally given on day +5 (calculated based on actual body weight, maximum initial dose 6 mg), then maintenance dose starting at 2 mg orally daily on day +6 with dose adjustments to maintain a trough of 5-12 ng/ml, continued through day +70 with no taper. Doses should be modified as appropriate for drug interactions.

Timeline

• Start date: 2022-05-23
• Primary completion: 2028-07-03
• Completion: 2029-07-02
• First posted: 2022-04-14
• Last updated: 2026-01-26

Locations

1 site across 1 country: United States

Regulatory

• FDA-regulated drug study