Engraftment Syndrome Incidence after Immune Checkpoint Inhibitor Therapy in Pts with Classical Hodgkin Lymphoma Undergoing Autologous Stem Cell Transplantation: A Single Institutional Review
Authors: Odetola Oluwatobi , Adekola Kehinde , Moreira Jonathan , Karmali Reem , Ma Shuo , Carson Kenneth R. , Mehta Jayesh , Winter Jane N. , Gordon Leo I. , Lin Adam Yuh 
Published: December 2023

Introduction: After receiving frontline chemotherapy for classical Hodgkin lymphoma, up to 30% of patients (pts) relapse. Salvage chemotherapy and autologous stem cell transplantation (ASCT) are the standard of care. Immune Checkpoint inhibitors (ICIs) have become essential to salvage therapy with improved complete response (CR) rates. However, ICIs have been linked to an increased risk of engraftment syndrome (ES), reported in as many as 68-78% of cases (Moskowitz et al. 2021; Park et al. 2021), while others have reported lower rates 3-12% (Bryan et al. 2023; Mei et al. 2022). The variability is connected to the definition of ES. The more stringent Spitzers criteria require 3 major (non-infectious fever (NIF), skin rash, pulmonary edema, or hypoxia) or 2 major and 1 minor criteria within 96 hours of engraftment, while the more lenient Maiolino criteria require a NIF with skin rash, pulmonary infiltrates, or diarrhea. Early diagnosis of ES and early intervention with corticosteroids is important to minimize toxicity during the ASCT. Here, we evaluate ES incidence at our institution during ASCT with or without the inclusion of ICI during salvage therapy.

Method: The institutional database was queried for pts with relapsed/refractory cHL who underwent ASCT between 2018 and 2023. ES is broadly defined as the presence of non-infectious fever with skin rash, diarrhea, or pulmonary infiltrates (Maiolino Criteria) or clinical suspicion requiring corticosteroids.

Results: A total of 47 pts underwent ASCT during this period and were included in the final analysis. Twenty-nine pts received ICI during salvage therapy (72%). Regarding basic patient characteristics: the median age at ASCT was 31 [19-72], 27 pts were female (57.5%), 35 pts were white (74.5%), the most common subtype was nodular sclerosis (n=42; 89.4%), with 23 pts (50%) initially presenting with advanced-stage disease. The most common initial therapy was ABVD (n=42, 89.4%), with one patient being treated with an ICI-based therapy on clinical trial (SWOG 1826). Thirty pts (63.8%) had a CR after frontline treatment and 16 pts with primary refractory disease. For the CR pts, the median time to progression was 159 [13-3864] days.

Thirty-five pts achieved a CR after salvage therapy (74.5%), 25 receiving ICI (71.4%), most commonly pembrolizumab. Regarding conditioning regimens, the most used and our institutional standard is total lymphoma irradiation (TLI) followed by high-dose chemotherapy (CCV) (n=34; 72.3%), which we have reported having high and durable response rates (10-yr PFS 68.5% and OS 68.0%). (Paudel et al. 2019) The median time to neutrophil engraftment is 10 days [7-30]. The rate of post-ASCT relapse was higher in the chemotherapy-only conditioning group (31%) compared to TLI-CCV (3.3%). All pts who received TLI-CCV are still alive, with two deaths in the chemotherapy only conditioning group (Total OS 95.7%).

Out of 47 evaluable pts, no pts qualified with a diagnosis of ES using the stringent Spitzers criteria. However, 17 received corticosteroids using the broader diagnosis criteria for ES (36%). Looking specifically at pts who received ICI (n=29), 14 pts had ES (48.3%), while of the 18 pts who did not receive ICI, 3 had ES (16.7%). Of the pts who did develop ES (n=17), 16 pts received TLI-CCV (94%), the median time to onset was 9 [2-11] days, the median time to resolution was 6 [2-19] days, the median time to neutrophil engraftment was 10 [8-12] days. When evaluating pts who received TLI-CCV conditioning, 24 pts received ICI during treatment before ASCT, with 13 pts having ES (54.2%). By comparison, 3 (33%) of the 9 ICI-naïve pts who received TLI-CCV were diagnosed with ES. The incidence of ES with or without ICI exposure was not statistically significant (p = 0.2549). Overall, the median time to ES onset is 9 days, and the duration of 6 days. There was no recorded mortality from ES. Only 3 pts relapsed post-ASCT (8.8%), with two receiving ICIs. Even with the small number of pts in this retrospective study, there was an increase in ES incidence between the use of ICI during salvage therapy (p=0.0279).

Conclusions: In this single-institution retrospective analysis, we found that the addition of ICI during salvage therapy increased the incidence of a broadly defined ES, with an increase in corticosteroid use. ES must be recognized early and treated with corticosteroids aggressively.