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: Not yet recruiting
• Trial end date: 2029-07-02

Summary

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 patients for infection, falling chimerism, or relapse and does not cause GVHD in these settings when additional conditioning is not given and T-cell-depleting antibodies are not used, both of which may disrupt the regulatory mechanisms 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.

• Phase: Phase 1/Phase 2

Details

• Lead Sponsor: National Cancer Institute (NCI)
• Treatments: Busulfan; Cyclophosphamide; Fludarabine; Mycophenolic Acid; Sirolimus