Engraftment Syndrome, an Unusual Complication during Autologous Peripheral Stem Cell Transplantation in Relapsed/Refractory Hodgkin's Lymphoma Patients Receiving Checkpoint Inhibitors As Salvage Therapy in the Pre-Transplant Setting
Authors: Ibrahim Ahmad , Youssef Ali , Ibrahim Jad , Khalil Charbel , Makdessi Joseph 
Published: December 2024

Background:
Autologous peripheral stem cell transplantation (APSCT) after PD-1- blockade resulted in favorable outcomes in patients (pts) with multiply refractory / relapsed (R/R) Hodgkin's lymphoma (HL). Response to PD-1- blockade by immune checkpoint inhibitors (ICI), and not chemotherapy sensitivity, best predicted post- APSCT PFS for these pts (Mariotti J. et al. Cells, 2024 - Maranzano M. et al. Frontiers Oncology, 2023).
Engraftment syndrome (ES) is a non-infectious complication which has traditionally been considered as rare after APSCT in pts auto transplanted for R/R HL. The proposed pathogenesis of ES involves production of inflammatory cytokines by activated leukocytes. The diagnosis criteria of ES have not been unified. However, ES can be defined by Maiolino criteria (Maiolino A. et al. Bone marrow transplant, 2003) as at least two symptoms within 48 hours of engraftment not attributable to other causes including fever, in combination with rash, pulmonary infiltrates and diarrhea. Few reports were published on ES post APSCT in R/R HL suggesting that exposure to ICI before APSCT may increase the risk of developing ES (Taranto E. et al. ASH 2023).
Methods:
We conducted between October 2017 and June 2024, a retrospective study including pts aged ≥ 18 yo with R/R HL who underwent APSCT following ICI as salvage therapy. Data related to diagnosis and management of ES were assessed by medical record review. ES was defined according to Maiolino criteria.
Results:
A total of 11 pts were identified. Pts had a median age of 33 yo (range 21-40). Six pts (55%) were females. Nine pts (82%) had the nodular sclerosis subtype. The pts received a median of 3 lines of therapy (range 3-5) before APSCT. ICI was the last line of therapy prior to APSCT, and consisted in pembrolizumab alone in 7 pts (64%) and nivolumab alone in 4 pts (36%). All the pts achieved complete remission (CR) on pre-APSCT PET.
Mobilization consisted in G-CST alone in 3 pts (27%) and G-CSF with plerixafor in 8 pts (73%). High dose chemotherapy consisted in TEAM regimen (thiotepa, etoposide, aracytine, melphalan). The median number of CD 34 + cells infused on day 0 was 4.2 106/ kg (range 3 -5.1). All pts successfully engrafted with a median time to neutrophil and platelets recovery of 14 days (d) (range 10-20) and 17 d (range 8-32), respectively.
All the pts experienced at least two non - infectious inflammatory findings at engraftment; 3 pts (27%) developed fever and rash, 6 pts (55%) developed fever, rash and pulmonary infiltrates and 2 pts (18%) fever, rash, pulmonary infiltrates and diarrhea. On the onset of ES, ten pts (91%) received steroids at the dose of 2 mg/ kg/ d which induced a total resolution of symptoms within 5 to 8 days. One pt (9%) didn't receive steroids and died 10 days after the onset of ES. Biopsy of skin lesions performed in 3 pts showed pathological findings similar to those of acute graft-vs-disease which occurs after allogeneic hematopoietic stem cell transplantation (HSCT).
The outcome of the entire cohort was excellent with 2-year PFS of 73% and 2-year OS of 82%. Among the 10 pts who were treated successfully with steroids, 9 pts are alive in CR with a median follow up of 47 months (m) (range 4-81). 2 pts relapsed at 13 m and 17 m after APSCT; 1 pt died of HL at 15 m after APSCT and the other pt underwent haploidentical allogeneic HSCT and is still in CR at 42 m after APSCT.
Conclusion:
ES, an unusual complication occurring during APSCT for HL, has been more frequently reported in R/R HL pts treated with ICI-based regiments in the pre-APSCT setting. In our non-trial cohort of R/R HL pts autotransplanted after ICI as salvage therapy, pts developing ES were sensitive to early steroids administration and had favorable outcomes. Further studies are needed to better characterize, prevent, and manage this complication.