How are granulocytes for transfusion best used? The past, the present and the future.

Granulocyte transfusions continue to be used in clinical practice, predominantly for treatment of refractory infection in the setting of severe neutropenia. There is biological plausibility for effectiveness in these patients with deficiencies of neutrophils, either as a consequence of disease or treatment. However, there is a chequered history of conducting and completing interventional trials to define optimal use, and many uncertainties remain regarding schedule and dose. Practice and clinical studies are severely limited by the short shelf life and viability of current products, which often restricts the timely access to granulocyte transfusions. In the future, methods are needed to optimise donor-derived granulocyte products. Options include use of manufactured neutrophils, expanded and engineered from stem cells. Further possibilities include manipulation of neutrophils to enhance their function and/or longevity. Granulocyte transfusions contain a heterogeneous mix of cells, and there is additional interest in how these transfusions may have immunomodulatory effects, including for potential uses as adjuncts for anti-cancer effects.

Granulocyte transfusion during cord blood transplant for relapsed, refractory AML is associated with massive CD8+ T-cell expansion, significant cytokine release syndrome and induction of disease remission.

In high-risk myeloid malignancy, relapse is reduced using cord blood transplant (CBT) but remains the principal cause of treatment failure. We previously described T-cell expansion in CBT recipients receiving granulocyte transfusions. We now report the safety and tolerability of such transfusions, T-cell expansion data, immunophenotype, cytokine profiles and clinical response in children with post-transplant relapsed acute leukaemia who received T-replete, HLA-mismatched CBT and pooled granulocytes within a phase I/II trial (ClinicalTrials.Gov NCT05425043). All patients received the transfusion schedule without significant clinical toxicity. Nine of ten patients treated had detectable measurable residual disease (MRD) pre-transplant. Nine patients achieved haematological remission, and eight became MRD negative. There were five deaths: transplant complications (n = 2), disease (n = 3), including two late relapses. Five patients are alive and in remission with 12.7 months median follow up. Significant T-cell expansion occurred in nine patients with a greater median lymphocyte count than a historical cohort between days 7-13 (median 1.73 × 109 /L vs. 0.1 × 109 /L; p < 0.0001). Expanded T-cells were predominantly CD8+ and effector memory or TEMRA phenotype. They exhibited markers of activation and cytotoxicity with interferon-gamma production. All patients developed grade 1-3 cytokine release syndrome (CRS) with elevated serum IL-6 and interferon-gamma.

An International Registry of Granulocyte Transfusions.

INTRODUCTION: Granulocyte transfusions are used to either treat or prevent life-threatening infections in neutropenic patients. Current evidence from clinical trials does not support or reject efficacy, nor guide practice. METHODS: A group of investigators have led the efforts to create an online registry to gather information on granulocyte transfusion practices from as broad a range of international settings. The data forms were adapted from an on-going study in England for electronic data management. Data is collected at the time of the request for granulocytes, weekly, at 28 days, and at 6 months. Information collected includes donor, granulocyte unit, patient and illness characteristics, and outcomes. RESULTS: The PROspective GRanulocyte usage and outcomEs Survey (ProGrES) is currently open for data entry. Centres across the UK have collected data on 80 subjects. Five institutions from 4 countries (2 from the US, 1 each from Brazil, and national services in Canada and France) are in the process of joining the study. Other countries have expressed interest. CONCLUSION: It is feasible to develop an international registry of granulocyte transfusions to characterise current practices and describe outcomes. This registry would provide a platform to explore the relationship between intervention and outcomes, and to generate evidence to inform granulocyte transfusion efficacy.