Pulmonary Engraftment Syndrome: A Unique Complication of Allogeneic Hematopoietic Cell Transplantation for Myelofibrosis

Background: In myelofibrosis patients undergoing alloHCT, we have observed a pulmonary infiltrate predominant engraftment syndrome with or without hypoxemia. Therefore, we sought to characterize this unique syndrome further and determine its association with pre-HCT patient and disease characteristics and determine its impact on HCT outcome.

Methods: From our HCT database, we identified 83 patients with primary/secondary myelofibrosis who underwent alloHCT at our institution from 2015 to 2020 at City of Hope. Data on patient demographics, disease characteristics, disease status at HCT, mutations, HCT-related variables and outcome measures were collected from patient medical records. Pulmonary ES (PES) was defined as the combination of new onset of pulmonary opacities in the absence of infection, fluid overload, and cardiac dysfunction with or without hypoxemia occurring between ten to twenty days after stem cell infusion. All statistical analysis was performed using SAS statistical software.

Results: Among the 83 patients included in this study, 49% had PMF, and 51% had secondary MF. Their median age was 62 years (range 55-68) and the majority of the patients were male (n=53,64%). The JAK2 V617F mutation was detected in 65% (n=54) of patients. Prior to an alloHCT, 61% (n= 51) had received treatment with ruxolitinib. The median spleen size was 20 cm (range 16-23 cm).

Graft source for allo-HCT was matched unrelated donor (MUD) in 54%, followed by matched related donor (MRD) in 23%, mis-matched unrelated (MMUD) in 12%, and Haplo-identical donor in 11%. Mobilized peripheral blood stem cells were used as a graft source in 97.6% of donors. Most patients (94%) received a non-myeloablative/reduced-intensity conditioning regimen. Tacrolimus/sirolimus was used in more than half of the patients (57.8%, n=48). The median CD34+ and CD3 cells were infused at a median 6x10^6 cells/kg (range: 2.49 - 12.96) and 2.21x10^8 cells/kg (range: 0.25 - 4.90) respectively. The median time for neutrophil engraftment was 20.0 days.

25 patients (30%) had new pulmonary infiltrates between days 10 and 20 of HCT. 22% (n=18) met the criteria for PES. Nine of those patients (50%) required an ICU admission. A majority (n=12) of patients with PES required systemic steroid therapy.

Demographic factors and transplant characteristics did not reveal any risk factors for PES. Pre-HCT CT scan chest was reported as normal in 87% of patients. There was no association between abnormal CT chest before HCT and occurrence of pulmonary ES (OR 0.29, 95% CI 0.01 - 2.52, p 0.42).

Pulmonary artery hypertension (defined as PASP ≥35 mmHg) was observed in 61 patients (77%) in this cohort. PAH was associated with increased risk of PES with an odds ratio 3.68 (95% CI 1.13,12; P=0.04). An abnormal pulmonary function test (PFT), defined as FEV1<80%, FEV1/FVC<70%, and DLCO< 80 were found in 19%, 23% and 72% patients during pre-HCT testing, respectively. No association was seen between PFT abnormalities and the occurrence of PES (FEV1 p=0.25 95% CI 2.60 0.50-13.32, FEV1/FVC p=1.00, 95% CI 0.84 0.08-5.40, DLCO p=0.74 95% CI 0.18-4.10).

12-month OS and 2-yr OS was 65% and 63%, respectively. Patients who experienced PES had no difference in overall survival (OS) and Non-Relapse Mortality (NRM) in comparison to those who did not have PES (HR;1.93, 95% CI 0.94-3.97, P 0.074 and HR 1.63; 95% CI 0.70- 3.83, P 0.26, respectively). There was a significant difference in ICU stay by PES (50% vs 17%, p=0.01). But length of ICU stays were not significantly different by PES (median 18 days vs 5 days, p = 0.13). Patients with median PASP>35 and pre-HCT spleen size >20 cm had worse OS in multivariate analysis (HR 2.58, 95% CI 1.24-5.40, P<0.001, and HR 4.14, 95% CI 1.83-9.36, p<0.001), while pre-HCT median PASP of greater or equal with 35 mmHg was associate with worse NRM (HR 2.42, 95% CI 1.04-5.62, p 0.040)

Conclusion: In this study, we describe a novel variation of engraftment syndrome consisting of predominantly pulmonary infiltrates, occurring around the time of neutrophil engraftment in patients undergoing alloHCT for MF. Although this syndrome was not associated with decreased overall survival or increased non-relapse mortality, it was associated with significant morbidity and requires early recognition to initiate corticosteroid therapy.

Ball:Oncovalent: Membership on an entity's Board of Directors or advisory committees. Nakamura:Sanofi: Consultancy; Omeros: Consultancy; BluebirdBio: Consultancy; Helocyte Inc: Research Funding; Magenta Therapeutics: Consultancy; Kadmon: Consultancy. Marcucci:Abbvie: Other: Speaker and advisory scientific board meetings; Lynx: Membership on an entity's Board of Directors or advisory committees. Ali:Incyte Corporation: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees. Pullarkat:Amgen, Dova, and Novartis: Consultancy, Other: Advisory Board Member; AbbVie, Amgen, Genentech, Jazz Pharmaceuticals, Novartis, Pfizer, and Servier: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.