Immunoglobulin and granulocyte-colony stimulating factor affecting infection and hematopoietic reconstruction in allogeneic hematopoietic stem cell transplantation

To the Editor: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is an important treatment for hematologic disease. High-intensity preconditioning in allo-HSCT patients significantly increases the risk of severe infection, which is an important cause of early transplant-related death. Granulocyte-colony stimulating factor (G-CSF) infusion can promote hematopoiesis, accelerate reconstruction of the immune system, reduce the duration of febrile neutropenia (FN), and decrease the incidence of infections. In addition, the increased risk of infection is thought to be partly due to hypogammaglobulinemia after HSCT. Therefore, some centers argue that prophylactic administration of intravenous immunoglobulin (IVIG) after HSCT is the standard of care. In 2008, Department of Hematology, First Affiliated Hospital of the Army Medical University partly employed IVIG addition to G-CSF after allo-HSCT to evaluate its effectiveness in shortening the period of agranulocytosis and decreasing the risk of severe infection. Based on the characteristics of the IVIG and G-CSF, we used the combination therapy to observe the effect on infection and hematopoietic reconstruction. In addition, there has been no comparison in safety and efficacy between IVIG and G-CSF treatment after allo-HSCT. Therefore, the effect of G-CSF combined with IVIG after allo-HSCT is still unclear. In our cohort study, we evaluated the effect and safety of three regimens (G-CSF alone, IVIG alone, and IVIG combined with G-CSF) on hematopoietic reconstruction in the post-transplant period. A retrospective study design was adopted. The studies involving human participants were reviewed and our study was approved by the Ethics Committee of the First Affiliated Hospital of Army Military Medical University (No. KY2021065). Patients/participants provided their written informed consent to participate in this study. All the participants had the opportunity to discuss any questions or issues. Patients who received allo-HSCT at the Department of Hematology of the First Affiliated Hospital of Army Medical University from 2008 to 2021 due to aplastic anemia, acute myelocytic leukemia, acute lymphoid leukemia, myelodysplastic syndrome, and chronic myeloid leukemia were included. Pre-treatment was divided into myeloablative and non-myeloablative regimens. Among the patients, 46 received G-CSF injections, 48 received IVIG injections, and 72 received G-CSF and IVIG injections. All of the patients underwent primary HSCT. The patients received an infusion of CD34+ cells at a dose ≥2.0 × 106/kg. Hematopoietic recovery such as time to neutrophil recovery, time to platelet recovery, time of agranulocytosis, time of fever, and FN were observed. Severe agranulocytosis was defined as absolute neutrophil count (ANC) <0.5 × 109/L, while extremely severe agranulocytosis was defined as ANC <0.1 × 109/L.[1] FN was defined as a fever >38.4°C once or >38.2°C on three consecutive readings with an ANC <0.5 × 109/L.[1] The incidence of adverse events was compared between the three groups along with the pain index, acute graft-versus-host disease (aGVHD) and the rates of ostalgia or myalgia. The day of the stem cell infusions was defined as day 0. Patients received IVIG starting on the day after transplantation: day +1; day +11; and day +21, at a dose of 400 mg/kg. G-CSF was injected subcutaneously from day +4 at a dose of 6 mg/kg/d until the neutrophil count rose >0.5 × 109 or the WBC count >2.0 × 109. All statistical analyses were performed using SPSS 22.0 software (Armonk, NY, USA). Data having normal distribution were described as mean ± standard deviation. Data having non normal distribution were described as median (Q1–Q3). Kruskal–Wallis tests were used for continuous variables’ data not having a normal distribution. Date having normal distribution were performed using Z tests. The 2-year follow up of overall survival (OS) and disease free survival (DFS) were estimated by Kaplan–Meier analysis. Log-rank tests were used to compare the OS and DFS curves between the three groups. P value <0.05 was considered statistically significant. The patients’ median age was 32.0 years (range: 6.2–57.8 years). Among the 166 patients, ten were diagnosed with aplastic anemia (AA; 6.0%); 65 were diagnosed with acute myelocytic leukemia (39.2%); 35 were diagnosed with acute lymphocytic leukemia (21.1%); 37 were diagnosed with chronic myeloid leukemia (22.3%); and 19 were diagnosed with myelodysplastic syndrome (11.4%). A total of 90 patients achieved complete response status before HSCT (54.2%). The three groups of patients had no statistically significant differences in age, gender, leukemia diagnostic classification, disease status before HSCT, number of chemotherapies before HSCT, or viral infection conditions before HSCT. The three groups of patients had no statistically significant differences in human leukocyte antigen (HLA) compatibility or the number of infused CD34+ cells. There were no statistically significant differences in gender or type of donor among the three groups. HLA-matched HSCT was performed in 119 cases, and allo-HSCT was performed in 47 cases. There were more male than female donors. Most of donors were siblings (133/166). The mean dose of infused CD34+ cells was 5.5 (4.7–6.1) × 106/kg. There was a statistical difference in the time to neutrophil recovery (P < 0.01, Supplementary Table 1, https://links.lww.com/CM9/B444); the time to neutrophil recovery was 14.0 (12.0–16.0) days, 15.0 (13.0–17.0) days and 12.0 (10.0–14.0) days, respectively, in the G-CSF, IVIG, and IVIG+G-CSF groups. No statistically difference was observed in time to platelet recovery (P = 0.07). The average time of agranulocytosis was 18.0 (16.0–20.0) days, 20.0 (17.0–23.8) days, and 16.0 (14.0–18.0) days, respectively, in the G-CSF, IVIG, and IVIG + G-CSF groups, which was statistically different among the three groups (P < 0.01, Supplementary Table 1, https://links.lww.com/CM9/B444). The average time of fever and FN were 5.0 (3.0–9.0) days and 3.0 (1.0–5.3) days, 7.0 (5.0–11.8) days and 4.5 (2.0–8.8) days, and 4.0 (2.2–7.8) days and 2.0 (1.0–4.8) days, respectively, in the G-CSF, IVIG, and IVIG + G-CSF groups, which were both statistically different among the three groups (both P < 0.01, Supplementary Table 1, https://links.lww.com/CM9/B444). We analyzed the average time of agranulocytosis (severe) and the average time of agranulocytosis (extremely severe), which were 5.0 (4.0–7.3) days and 9.0 (5.0–10.0) days, 4.0 (3.0–6.0) days and 11.0 (7.0–14.8) days, and 3.0 (2.0–5.0) days and 5.0 (4.0–9.0) days, respectively, in G-CSF, IVIG, and IVIG + G-CSF groups, and the differences among the three groups were statistically significant (both P < 0.01, Supplementary Table 1, https://links.lww.com/CM9/B444). There were no statistical differences in the rates of signs and symptoms of infection (P = 0.75), the rates of ostalgia or myalgia (P = 0.85) and the rates of aGVHD (P = 0.31, Supplementary Table 1, https://links.lww.com/CM9/B444) among the three groups, implying that there were no significant differences in terms of side effects of drugs during the post-transplant period. Severe infection is one of the major causes of HSCT failure and patient death. Hematopoietic reconstruction after HSCT can minimize the occurrence of infection. Recently, many studies have suggested that the use of G-CSF or IVIG can promote immune system reconstruction and reduce the average time of hematopoietic reconstruction, which drastically reduces the rate of infection and hospitalization expenses.[2] However, the best way to use IVIG or G-CSF to achieve hematopoietic reconstruction after HSCT has not been recognized. In addition, there are few studies evaluating the use of IVIG combined with G-CSF in HSCT patients. Our results indicated that IVIG combined with G-CSF has a better effect on hematopoietic reconstruction than IVIG alone or G-CSF alone. Meanwhile, there were no statistically significant differences between the IVIG combined with G-CSF group and the IVIG alone group or the G-CSF alone group in the side effects of IVIG and G-CSF, which indicated that the use of IVIG combined with G-CSF complied with medication safety. One meta-analysis showed that the use of IVIG alone has no advantage in terms of survival or infection prevention in HSCT.[3] Some studies have shown that patients with high Fcγ receptor (FcγR) had a significantly lower quality of life compared to patients with low FcγR after allo-HSCT due to poor hematopoietic reconstruction.[4] Recent research shows that IVIG contains an anti-FcγR antibody.[5] We hypothesized that IVIG eliminated excess FcγR, providing an advantageous environment for G-CSF in hematopoietic reconstruction. Moreover, after a 2-year follow-up period, IVIG + G-CSF treatment statistically significantly increased the rates of DFS and OS compared with the G-CSF and IVIG groups [Figures 1A–B]. We considered that the long-term benefits of G-CSF combined with IVIG were associated with rapid hematopoietic reconstitution after allo-HSCT.Figure 1: The 2-year follow-up after transplantation. (A) Disease-free survival and (B) overall survival of patients in the three groups. ∗ P < 0.01. A: G-CSF: 51.1 (95% CI: 34.1–63.6); IVIG: 64.6 (95% CI: 48.5–73.7); IVIG+G-CSF: 80.3 (95% CI: 69.5–87.6). B: G-CSF: 54.7 (95% CI: 38.7–68.3); IVIG: 69.1 (95% CI: 52.4–74.0); IVIG+G-CSF: 84.2 (95% CI: 77.7–94.5). CI: Confidence interval; G-CSF: Granulocyte-colony stimulating factor; IVIG: Intravenous immunoglobulin; n.s: Not statistically significant.Funding This work was supported by the Intramural Research Project (Nos. AWS17J007 and 2020XQN13). Conflicts of interest None.