Early Versus Standard Initiation of Immunosuppressive Therapy for Graft Versus Host Disease Prophylaxis in Haploidentical Allogeneic Stem Cell Transplantation: Incidence and Severity of Cytokine Release Syndrome and Related Outcomes
Authors: Carvalho Luisa V. , Americo André Dias , Isoppo Camila Carminati , Pittol Isabella , Prats João A. G. G. , Rosa Eurides L. , Lima Germano , Fumagalli Natalia , Zenero Paula Lucafo , Figueiroa Hegta R. , Ayoub Fauze Lutfe , Pessoa Juliana Matos , Filho Jose Ulysses A. , Kerbauy Fabio R. , Scheinberg Phillip 
Published: December 2024

INTRODUCTION: Haploidentical stem cell transplant (haplo-HSCT) is associated with a high incidence of Cytokine Release Syndrome (CRS). Severe forms of CRS (grade 3-5) can evolve with serious organ damage, increased treatment-related mortality (TRM) and a higher risk of bloodstream infections. Standard haplo prophylaxis for graft-versus-host disease (GvHD) includes post transplant cyclophosphamide (PTCy) on days +3 and +4, and mycophenolate mofetil [MMF] and calcineurin inhibitor [CNI] from day +5 until day +35. Recent studies (Hunter et al., 2022) show that earlier immunosuppression initiation (IST) may reduce CRS incidence and improve outcomes.
OBJECTIVE: To evaluate the incidence and severity of CRS (graded by CTCAE 5.0) and Intensive Care Unit (ICU) admissions after the implementation of an early IST protocol for GvHD prophylaxis. This protocol starts CNI on day -1 and MMF on day 0 (early), with PTCy infusion on days +3 and +4, compared to the standard GvHD prophylaxis regimen.
STUDY DESIGN: This retrospective analysis includes 136 patients over 18 years old who underwent haplo-HSCT between 2016 and 2023 at Hospital A Beneficência Portuguesa de São Paulo, Brazil. Of these, 106 received standard GvHD prophylaxis. From January 2023 onwards, 30 patients received the early IST protocol. Data on microbiologically or clinically confirmed viral, bacterial, and fungal infections, and febrile neutropenia in absence of a clinically or microbiologically documented infection until day +100 were recorded. The study was approved by the local Ethics in Research Committee.
RESULTS: The median ages were 47 and 45 years in standard and early GvHD prophylaxis groups, respectively. Over 90% of patients in both groups received peripheral blood stem cells. The most common diagnoses were acute myeloid leukemia (39,6% in standard vs 36,7% early prophylaxis), acute lymphoblastic leukemia (19,8% vs 33,3%) and Hodgkin's lymphoma (9,4% vs 10%). 34,9% patients in the standard group and 45,2% in the early IST group underwent myeloablative conditioning (p=0,30). The median follow up was 380 days. The overall incidence of CRS was 81.6% in standard vs. 60% in early prophylaxis group (p=0.008). The incidence of severe CRS was 5.6% in the standard group, with no cases in the early prophylaxis group (p=0.027). ICU admissions within the first 35 days post-transplant were not significantly different between cohorts (25% standard vs. 14% early prophylaxis, p=0.4). Overall survival at 180 days was similar between the groups (63% standard vs. 65% early prophylaxis, p=0.7). Engraftment failure at 45 days was also comparable (2.9% standard vs. 3.4% early prophylaxis, p=0.5). Acute GvHD grades II-IV was 35.8% in the standard vs 46.7% in the early prophylaxis group, with more severe cases (III-IV) in the latter (7,5% vs. 30%). The rate of infections and febrile neutropenia was high, 3.38 events per 100 patient-days, and it was higher for patients receiving early prophylaxis (rate ratio=1.38, 95% CI 1.11-1.72, p=0.003)
CONCLUSIONS: Our study demonstrated that early initiation of CNI and MMF is associated with a reduced incidence of CRS, particularly in its severe form. However, we could not show an association with reduced ICU admissions or TRM with the current sample size in both groups. An increased incidence of severe GvHD was observed, which requires further investigation due to potential collection bias related to the study's retrospective nature. The incidence of infections until day+100 might also be higher with early prophylaxis, although there was no difference in short-term overall survival.