Successful neutrophil engraftment supported by granulocyte transfusion in adult allogeneic transplant patients with peri-transplant active infection

Abstract

Active infection at the time of allogeneic hematopoietic stem cell transplantation (HSCT) is a risk for non-relapse mortality (NRM) after HSCT. Granulocyte transfusion (GTX) has been used to prevent or treat life-threatening infections in patients with severe neutropenia. However, data are limited on the clinical benefits of GTX during HSCT. We retrospectively analyzed the transplant outcomes of HSCT patients who had undergone GTX between 2012 and 2020. Altogether, 20 patients with documented infection had received 55 GTXs during HSCT. No adverse events were observed during the GTX infusion. The average number of granulocytes was 0.40 (range, 0.10–1.59) × 10⁹/kg. The median neutrophil increment one day after GTX was 515 (range, −6 to 6630)/μl, which was significantly correlated with the infused granulocyte dose (p = 0.0007). A total of 17 of 20 patients achieved neutrophil engraftment. The number of infused granulocytes tended to higher in clinical responders (p = 0.12), and patients receiving ≥ 0.5 × 10⁹/kg showed trend toward to better transplant outcomes (GTX-high vs. GTX-low, 1-year OS; 33% vs. 11%, p = 0.19. 1-year NRM; 44% vs.77%, p = 0.11). The type of red blood sedimenting agents was significantly correlated with the amounts of granulocyte collection. In conclusion, GTX, especially with a high amount of containing granulocytes, could be a safe bridging therapy for neutrophil engraftment after HSCT in patients with active infection.

Introduction

Allogeneic hematopoietic stem cell transplantation (HSCT) is a curative treatment strategy for patients with various hematological diseases [1]. Despite the improvement of supportive care, including the introduction of new drugs over the last decade, infection remains a major complication and a cause of mortality following HSCT [2].

Granulocyte transfusion (GTX) has been used as a prophylaxis or treatment strategy for patients with neutropenia since the 1970s [3]. Pioneer studies have demonstrated clinical benefits but were limited by their study sizes, heterogeneous patient cohorts, and low granulocyte doses [4], [5]. Later, with the ability to collect larger cell doses after the combined administration of granulocyte-colony stimulating factor (G-CSF) and steroids to the donor, there has been renewed interest in this treatment method [6], [7]. An optimal granulocyte apheresis regimen enables the harvesting of a sufficient dose of granulocytes; however, it remains unclear whether GTX affects the clinical outcomes [6], [8], [9], [10], especially in the setting of neutropenia pre- and post-HSCT. The RING (Resolving Infection in Neutropenia with Granulocytes) trial, a multicenter randomized controlled trial, addressed the clinical benefit of GTX in patients with neutropenia [11]. In the RING trial, neutropenic patients were randomly assigned to either standard antibiotic therapy or standard antibiotic therapy, and GTX from donors stimulated with G-CSF and dexamethasone. Although the primary endpoint of the study was not different between these two groups, subjects who received an average dose per transfusion of ≥ 0.6 × 10⁹/kg showed better outcomes than lower doses suggesting that a higher number of GTX may improve the outcomes of neutropenic patients with infections.

Patients with hematological malignancies candidates for HSCT receive multiple courses of chemotherapies to control underlying diseases before HSCT. Consequently, these pretransplant chemotherapies may result in bacterial or fungal infections before HSCT due to long-term immune suppression. Active infection at the time of HSCT is one of the risk factors of transplant-related mortality after HSCT [12]. Prolonged neutropenia after HSCT is also life-threatening situation and often leads to primary graft failure, a fatal complication after transplantation [13]. In theory, GTX is an attractive option for a neutropenic patient with an active infection during the early period of HSCT, especially until neutrophil engraftment. However, statistical evidence on the efficacy of GTX in the context of HSCT setting is limited [9], [14], [15], [16], [17], [18]. In the RING trial, 8 patients (16%) in the control group, and 8 patients in the GTX group (17%) underwent HSCT, but the effect of GTX in HSCT recipients were not described [11].

In our institution, we have been performing GTX for neutropenic patients with active documented infections since 2012. To evaluate the effect of GTX for the transplant outcomes, we have herein reported a case series of patients who received GTX during the peri-transplant period.