Novel CD4+ Donor Lymphocyte Therapy Shows Promising Remission Rates in High-Risk Myeloid Malignancies

In a groundbreaking phase 1 trial, a novel first-in-human CD4+ mismatched unrelated donor lymphocyte infusion (CD4+ MMUDLI) treatment achieved complete remission rates of more than 50% in treatment-refractory myelodysplastic syndrome (MDS) and secondary acute myeloid leukemia (sAML), offering new hope for these challenging cases.

High-risk MDS and sAML remain notoriously difficult to treat, especially among patients for whom treatment with hypomethylating agents (HMAs) has failed. Survival for these individuals is often limited to months. Hany Elmariah, MD, MS, Moffitt Cancer Center, Tampa, Florida, and collaborators presented a first-in-human study of CD4+ MMUDLI therapy designed to reverse immune tolerance and elicit a robust antitumor response without the long-term complications of graft-versus-host disease (GVHD).^1,2

The phase 1 study included 19 patients (16 with sAML and three with MDS) without prior allogeneic hematopoietic cell transplants. Most participants harbored high-risk mutations, such as TP53 mutations, or complex cytogenetics. The trial employed a 3+3 dose-escalation design, administering the CD4+ MMUDLI therapy after induction chemotherapy. CD8+ T cells were selectively depleted to minimize GVHD risks, and donors were chosen based on specific human leukocyte antigen mismatches.

At the highest dose (5 × 10⁷ CD4+ cells/kg), more than half of patients, including those with adverse risk mutations, achieved complete remission. Notably, three patients with TP53 mutations, a group often resistant to standard treatments, achieved remission. Among these, two demonstrated no minimal residual disease and proceeded to successful allogeneic transplants. Twelve-month progression-free survival for responders was 73%, compared with 0% for nonresponders.

Notably, the therapy was well tolerated, with no severe cases of GVHD or cytokine release syndrome reported. Two patients experienced grade 2 cytokine release syndrome that resolved with administration of tocilizumab. Cytokine analysis indicated that higher levels of interleukin (IL)–6, IL-2, IL-15, and other markers shortly after infusion correlated with treatment response.

This innovative approach addresses the unmet need for effective therapies for high-risk MDS and sAML. The encouraging results of this phase 1 study reported by Dr. Elmariah and colleagues support the further development of CD4+ MMUDLI therapy for the treatment of MDS and sAML.

REFERENCES:

1. Elmariah H, Kim J, Reid K, et al. Non-engrafting CD8-depleted human leukocyte antigen (HLA) mismatched unrelated donor lymphocyte infusion (DLI) achieves remissions in transplant-naive myelodysplastic syndrome (MDS) and secondary acute myeloid leukemia (sAML). Abstract #2071. Presented at the American Society of Hematology Annual Meeting; December 7-10, 2024; San Diego, California.
2. Symons HJ, Levy MY, Wang J, et al. The allogeneic effect revisited: exogenous help for endogenous, tumor-specific T cells. Biol Blood Marrow Transplant. 2008 14(5):499-509. doi: 10.1016/j.bbmt.2008.02.013