Relapse after allogeneic hematopoietic stem cell transplantation (HSCT) remains the dominant cause of treatment failure in leukemia. This perspective reviews evidence that adjuvant, non‑engrafting allogeneic leukocytes—delivered as transfusions, granulocyte pools, or via a second cord unit—can prime immune responses that influence post‑transplant leukemia control. The article synthesizes historical reports, solid‑organ transplant parallels, and cord blood transplantation observations to propose mechanisms and highlight translational opportunities.
Allogeneic HSCT confers benefit largely through an immunologic mechanism: donor‑derived immune cells, principally T cells, recognize and eliminate recipient leukemic cells (the graft‑versus‑leukemia, GVL, effect). Donor T cells detect mismatch at major HLA loci and minor histocompatibility antigens (MiHA). Strategies that deplete donor T cells or apply high levels of immunosuppression reduce GVL and are associated with higher relapse. Conversely, donor lymphocyte infusions (DLI) can re‑induce remission in some relapsed patients, underlining the central role of donor T cells in disease control.
Despite improvements in supportive care and targeted agents, relapse occurs in a substantial proportion of transplant recipients, with reported rates varying widely by disease subtype, donor characteristics, pre‑transplant measurable residual disease (MRD), and conditioning intensity. Existing options to augment GVL, such as DLI, are limited by the risk of graft‑versus‑host disease (GVHD) and treatment‑related morbidity and mortality. There is therefore a need for approaches that better focus donor immunity on malignant cells while sparing normal tissues.
A range of immunotherapies is now in routine use or clinical development for cancer, including cellular therapies (allogeneic HCT, CAR‑T, TCR‑engineered T cells, tumour infiltrating lymphocytes), antibody‑based approaches (monoclonal antibodies, antibody‑drug conjugates), bispecific T‑cell engagers (BiTEs), immune checkpoint inhibitors, and tumour vaccines. These modalities reaffirm that antigen‑directed immunity can control haemato‑oncologic disease and provide context for exploring how transferred leukocytes might be used to harness or redirect immune responses after transplant.
Reports from the 1960s described remissions and remissions prolongation following leukocyte‑replete blood transfusions in patients with acute leukemia. Observations that leukocyte reduction methods (irradiation or filtration) attenuated the anti‑leukemic signal support the importance of transferred donor leukocytes in these responses. More recent case reports document spontaneous or sustained cytogenetic and morphological remissions after repeated irradiated granulocyte infusions in poor‑risk acute myeloid leukemia (AML) patients, followed in some cases by successful allogeneic transplant consolidation. These clinical anecdotes suggest that transient, non‑engrafting leukocyte exposure can trigger meaningful anti‑leukemic immunity in selected cases.
Experience from solid‑organ transplantation shows that transfusion‑related leukocyte transfer is highly immunogenic: blood transfusions can lead to HLA sensitization and development of donor‑specific antibodies, which are associated with graft rejection and reduced organ survival. Studies in renal transplantation link post‑transplant blood transfusion with de novo donor‑specific HLA antibodies and graft loss, indicating that transferred leukocytes prime antigen‑specific responses. The authors draw a parallel: if transferred leukocytes prime anti‑HLA T‑cell responses in solid‑organ recipients, similar mechanisms might account for anti‑leukemic effects when third‑party leukocytes encounter host leukemic cells.
Cord blood (CB) transplantation, particularly when performed with T‑cell replete cord blood (TRCB), has been associated in retrospective series with reduced relapse and improved relapse‑free outcomes in high‑risk pediatric AML cohorts, notably those with measurable residual disease at transplant. TRCB transplants are often HLA‑mismatched but can show lower chronic GVHD rates and superior graft‑versus‑host–free/relapse‑free survival compared with other donor sources in some series. A proposed mechanism is that HLA mismatches in CB are distributed across both haplotypes, making genomic loss of mismatched HLA by the leukemic clone less likely than after haploidentical transplant, thereby preserving GVL.
In double cord blood transplant (DCBT), two units are infused and typically one unit becomes the dominant engrafting graft while the other is rejected. Registry analyses indicate that when the rejected (“losing”) unit shares HLA mismatches with the host, the immune response generated during rejection may be transferred and mediate anti‑leukemic effects, with some series reporting markedly reduced relapse risk—particularly when shared mismatches include HLA‑A. Importantly, these observations did not demonstrate an accompanying increase in GVHD or transplant‑related mortality unless shared mismatches involved certain class II loci. These findings support the concept that a second, non‑engrafting cell source can modulate post‑transplant immunity.
The literature uses varying terms for these approaches, including “non‑engrafting alloreactive cellular therapy (NEACT)”. Potential sources of non‑engrafting leukocytes include leukocyte‑replete blood transfusions, granulocyte pools, and additional cord units. Evidence suggests that such transfers can prime antigen‑specific T‑cell responses that may target leukemic cells, but the mechanisms are incompletely defined. Observational data and case reports indicate potential benefit in selected settings; however, prospective studies are required to delineate the optimal sources, timing, HLA relationships, and safety profile—specifically the balance between enhanced GVL and the risk of GVHD or allo‑sensitization.
There is converging historical, registry, and mechanistic rationale to support further investigation of third‑party or non‑engrafting leukocyte exposures as an adjunct to allogeneic HSCT for leukemia. Improved understanding of how these cells prime and redirect donor immunity could enable transplant strategies that reduce relapse while minimizing GVHD. The authors advocate prospective mechanistic and clinical studies to define the conditions under which non‑engrafting leukocytes can be safely and effectively deployed to enhance anti‑leukemic immunity.