The Effect of Smoking and Pre-Transplant Pulmonary Comorbidity on the Incidence of Lung Graft Versus Host Disease and Post Transplant Outcomes
Authors: Kawari Mohammed , Pinto Pereira Mariana , Remberger Mats , Lau Ambrose , Law Arjun , Kumar Rajat , Novitzky-Basso Igor , Lam Wilson , Pasic Ivan , Gerbitz Armin , Viswabandya Auro , Kim Dennis Dong Hwan , Mattsson Jonas , Michelis Fotios 
Published: December 2024

Introduction:
Allogeneic hematopoietic cell transplantation (Allo-HCT) is the curative treatment for various hematological disorders. Despite advancements in supportive care, graft-versus-host disease (GVHD) continues to be a challenging complication. Smoking is linked with various pulmonary diseases, also elevates the risk of pulmonary complications and overall mortality in Allo-HCT recipients. However, it remains unclear whether smoking adversely affects Allo-HCT outcomes independently of pre-transplant underlying lung conditions.
Methodology:
We conducted a retrospective analysis of 407 patients (pts) who underwent Allo-HCT at Princess Margaret Cancer Centre, Toronto between January 2019 and May 2021. This analysis examined the impact of pre-transplant pulmonary comorbidities, smoking history, and total smoking dose on transplant outcomes. Pre-transplant pulmonary comorbidity was defined according to HCT-specific comorbidity index: DLCO and/or FEV1 less than 80%, or dyspnea on slight activity.
Four groups were formed based on smoking history and pre-transplant pulmonary comorbidity.
Group A: smoker with pre-transplant pulmonary comorbidity, 40 pts (9.8%).
Group B: non-smoker with pre-transplant pulmonary comorbidity, 71 pts (17.4%).
Group C: smoker with no pre-transplant pulmonary comorbidity, 105 pts (25.8%).
Group D: non-smoker with no pre-transplant pulmonary comorbidity, 191 pts (46.9%).
Smokers were categorized into three groups based on their smoking history &lt;10 pack-years (59 pts, 14.5%), 10 to 25 pack-years (50 pts, 12.3%), and &gt;25 pack-years (35 pts, 8.6%).
The primary end point is the incidence of lung GVHD. Secondary end points are the 3 year-overall survivor (OS) and Non-Relapse Mortality (NRM).
Results:
Among the 407 pts, the median age was 58 years (18-76). Of these patients, 94 (23.1%) received grafts from matched related donors, 195 (47.9%) had match unrelated graft, while 79 (19.4%) and 39 (9.6%) had haploidenitcal donor and mismatch unrelated donor, respectively. Two-thirds of the patients, 264 (64.9%), received dual T cell depletion for GVHD prophylaxis, consisting of antithymocyte globulin (ATG) and post-transplant cyclophosphamide (PTCy). Additionally, 81 pts (19.9%) received only ATG, while 54 pts (13.3%) received only PTCy.
The median number of readmission days in the first year was 45 days for the group A, compared to 36, 31, and 34 days in group B, C and D, respectively (p=0.007). However, there was no difference in the ICU admissions across the four groups (p=0.2).
The 3-year OS for the entire cohort is 65.3% (95% CI: 60.5-69.8), with a NRM of 18.0% (95% CI: 14.4-21.9). The incidence of chronic GVHD is 37.9% (95% CI: 33.0-42.9). The 3-year OS is lowest in Group A at 45.0% (95% CI: 29.3-59.5), compared to 70.4% (95% CI: 58.3-79.6) in Group B, 62.4% (95% CI: 52.3-70.9) in Group C, and 69.4% (95% CI: 62.3-75.5) in Group D (p=0.006). The combination of smoking and pre-transplant pulmonary comorbidities adversely affects NRM, which is 37.5% (95% CI: 22.6-52.3) in this group, while it is 15.5% (95% CI: 8.2-24.9), 18.2% (95% CI: 11.5-26.2), 14.7% (95% CI: 10.1-20.1) in group B, C, and D, respectively (p=0.001).
There were no significant differences among the four groups in the incidence of grade II-IV acute GVHD or chronic GVHD, with p-values of 0.32 and 0.75, respectively. However, Group A had a higher incidence of chronic lung GVHD compared to the other groups (p=0.01).
Patients with &gt;25 pack-years smoking history had the lowest 3-year OS at 45.5% (95% CI: 28.7-60.9), compared to 49.5% (95% CI: 35.0-62.5) for those with 11-25 pack-years and 70.5% (95% CI: 56.8-80.5) for those with &lt;10 pack-years (p=0.02). There were no differences in NRM among the three smoking history groups (p=0.26). Nonetheless, relapse-free survival (RFS) was higher in the group with a lower smoking history of &lt;10 pack-years (p=0.02).
In the multivariate analysis (MVA), a longer smoking history of &gt;10 pack-years is associated with higher mortality and reduced RFS.
Conclusion:
The results exhibit the combination of smoking and pre-transplant pulmonary comorbidities increases the incidence of chronic lung GVHD. This association also correlates with a lower 3-year OS and higher NRM. Moreover, a higher smoking dose is associated with reduced OS. Further research is required to determine the ideal intervention for optimizing outcomes in smokers with pre-transplant pulmonary comorbidities.