Engraftment Syndrome during Autologous Stem Cell Transplant in Hodgkin Lymphoma Patients Treated with Checkpoint Inhibitors: A Multi-Center Retrospective Analysis

Background: Engraftment Syndrome (ES) has traditionally been considered a rare complication of autologous stem cell transplant (ASCT) in patients (pts) with relapsed/refractory Hodgkin lymphoma (HL). There have been several attempts to define ES, but diagnostic criteria have not been unified. Diagnosis of ES is considered in pts developing non-infectious fever coinciding with neutrophil recovery, typically with at least one other inflammatory finding such as pulmonary infiltrates, diarrhea, rash, or transaminitis. The proposed pathogenesis of ES involves production of inflammatory cytokines by activated leukocytes, which may ultimately be suppressed by treatment with systemic corticosteroids. Recent clinical trials in HL have suggested that exposure to immune checkpoint inhibitors (ICI) before ASCT may increase the risk of developing ES.

Methods: We conducted a retrospective study at several U.S. academic institutions to better characterize ES in HL pts undergoing ASCT in the era of ICIs. Eligibility criteria included age > 18, diagnosis with relapsed/refractory HL, treatment with an ICI as part of pre-transplant salvage therapy, and ASCT between January 1, 2015 and February 1, 2023. Inflammatory symptoms and timing of symptom onset were assessed by medical record review. ES was defined by Maiolino criteria (Maiolino et al. Bone Marrow Transpl, 2003) as at least two symptoms within 48 hours of engraftment not attributable to other causes, including fever in combination with diarrhea, rash, or pulmonary infiltrates. We assessed the incidence of inflammatory symptoms and ES, and evaluated potential risk factors associated with developing these symptoms.

Results: A total of 53 pts with HL were identified. Pts had a median age of 33 (range 19-72), 49% were female, 75% White, and 11% Black. The majority (87%) had the nodular sclerosis subtype and were treated with ABVD (68%) or BV-AVD (23%) in the frontline setting, with a majority achieving CR (53%) or PR (15%). At relapse, 57% received BV-nivolumab and 13% received pembrolizumab-GVD. Overall, 70% received nivolumab prior to ASCT, and 30% received pembrolizumab. None of the pts in this reported cohort were treated on a clinical trial. On pre-ASCT PET, 77% achieved CR, after which all were mobilized with GCSF, with 42% also receiving plerixafor. An average of 9.57 million CD34+ cells/kg (median 7.28) were infused on day 0.

Pts were hospitalized for an average of 20 days (range 2-99). All pts successfully engrafted, with a median time-to-engraftment (ANC 500) and time-to-platelet-recovery of 10 days.

A majority of pts (70%) experienced at least one non-infectious inflammatory finding at engraftment, but only 21% met Maiolino criteria for ES. The frequency of non-infectious inflammatory findings is described in Figure 1. Of the 11 pts clinically diagnosed with ES by the treating physician, 7 received high-dose steroids for treatment, for a median of 8 days. There were no deaths attributed to ES. Following transplant, 91% achieved CR, with 5 pts experiencing progressive disease. Over a median follow-up of 15 months (range 1-57 months), 5 pts relapsed and 4 died.

The outcomes of the entire cohort were excellent, with 2-year PFS of 78% (95% CI: 67-90%) and 2-year OS of 90% (95% CI 81-100%). There were no differences in survival based on ES status. We explored potential risk factors for developing ES, including number of cells infused, duration of ICI exposure/timing in relation to ASCT, and plerixafor use, but none achieved statistical significance.

Conclusions: In this non-trial cohort of HL pts receiving ICI-based salvage before transplant, a minority of patients (21%) developed ES by traditional diagnostic criteria, but the majority of pts (70%) developed non-infectious inflammatory findings in the peri-engraftment period. Most pts experiencing ES were treated with steroids and had favorable outcomes similar to those without ES. With increasing use of ICI-based regimens in the pre-transplant setting, further studies with larger patient cohorts are needed to better characterize this entity, develop unified reporting and diagnostic criteria, identify pts at high risk for severe ES, and develop effective prophylactic and therapeutic strategies.