Complex Restrictive Lung Disease Patterns Affecting Survival and Outcomes in Patients Undergoing Allogeneic Stem Cell Transplant: A Single-Institution Retrospective Analysis

Background: Allogeneic stem cell transplant is the only curative therapy for some patients with hematologic malignancies. While pulmonary function impairment related to diffusion capacity and air flow obstruction is part of the predictive Hematopoietic Cell Transplant-Comorbidity Index (HCT-CI), restrictive changes are poorly reflected. A new entity known as complex restrictive lung disease (CRLD) refers to a discrepancy between Forced Vital Capacity percent predicted (FVCpp) and Total Lung Capacity percent predicted (TLCpp). FVCpp being disproportionately lower than TLCpp occurs due to impaired lung emptying from neuromuscular disease, obesity, bronchiectasis, occult obstruction, pulmonary hypertension and chest wall limitations. In simple restrictive lung disease (SRLD) such as pulmonary fibrosis, FVCpp is proportionately decreased compared to TLCpp.

Methods: Over three years, 124 patients received myeloablative (MA) or reduced intensity conditioning (RIC) followed by matched unrelated donor (MUD) or matched related donor (MRD) grafts. Patients had complete pulmonary function tests (PFT) within 60 days prior to transplant and 6 months post-transplant. Simple Restriction was defined as TLCpp - FVCpp <10%. Complex Restriction was defined as TLCpp - FVCpp >10%. Our primary outcome in this study was Median Overall Survival (mOS). Median follow up was 14 months.

Results: For the 124 enrolled patients, demographics included median age of 55 years (range: 18-70), 60% male, MUD status (73%) with male donor (75%); half received RIC (52%) with fludarabine melphalan (62%) vs fludarabine/busulfan (FLU/BU2) (32%) compared to MA (40%) with FLU/BU4 conditioning (77%). The demographics of diagnosis include Acute Myeloid Leukemia (40%), Lymphoma (17%) and Acute Lymphoblastic Lymphoma (16%) and Myelodysplastic Syndrome (16%). The median HCT-CI/Age score was 4 (0-11). Half (62) developed acute graft-versus-host disease (aGVHD) with 80% as Grade 1-2. One patient was lost to follow up, 65 patients were still alive and 22 had relapse of their initial disease with 17 deaths related to relapse. Out of 58 deaths in this study, 41 deaths (71%) were attributed to non-relapse mortality (NRM) with NRM at 33% and relapse mortality rate at 14%.

Out of 124 patients, 10 patients had complex restriction prior to transplant and 9 patients developed complex restriction at 6 months post-transplant. The mOS was 7 months for patients with CRLD prior to transplant (1-14 months) compared to 13 months for patients without CRLD (1- 36 months) (p=0.0026). Eight patients with CRLD before transplant were deceased at follow-up of 14 months, with four (50%) out of those eight deaths related to acute respiratory distress syndrome (25%) and hypoxic respiratory failure (25%). The non-relapse mortality rate for this population was 60% and relapse mortality rate was 10%.

For all patients with aGVHD, mOS was greater than 30 months for aGVHD Grades 0-1, 16 months for Grade 2, 6 months for Grade 3 and 5 months for Grade 4 (p=0.0048). Six out of six patients with GVHD and CRLD prior to transplant died from acute respiratory distress syndrome (ARDS) hypoxia, or other cause. Out of the 4 patients with CRLD without GVHD, one patient developed respiratory failure as cause of death.

There was no statistical difference in mOS due to BMI (p=0.2895). Nonsmokers and past smokers had a m0S of 22 months, with current smokers at 10 months m0S (p=0.13). We found no statistical difference in survival for the 9 patients who developed CRLD after transplant (p=0.45), the 10 patients with simple restriction prior to transplant (p=0.55), the 21 patients who developed Bronchiolitis Obliterans Syndrome (B0S) after transplant (p=0.25), or the 26 patients with Chronic Obstructive Pulmonary Disease (COPD) prior to transplant compared to normal PFT (p=0.14). The mOS for these groups was 12 months.

Conclusion: Patients with complex restrictive lung disease prior to allogeneic stem cell transplant are at high risk for poor outcomes from respiratory and non-respiratory disease when compared to the overall population. As complex restriction is not included in the current HCT-CI, patients with this lung disease should have closer monitoring and scrutiny prior to allogeneic stem cell transplantation. Based on the results of this study, addition of complex restrictive lung disease to the HCT-CI to improve predictability of HCT outcomes warrants further investigation.

Hildebrandt:Axim Biotechnologies: Current holder of stock options in a privately-held company; GW Pharmaceutical: Current equity holder in private company; Cardinal Health: Current equity holder in private company; Clovis Oncology: Current equity holder in private company; Cellectis: Current holder of stock options in a privately-held company; CVS Health: Current equity holder in private company; Bluebird Bio: Current equity holder in private company; Pfizer: Current equity holder in private company; Charlottes Webb: Current equity holder in private company; Aimmune Therapeutics: Current holder of stock options in a privately-held company; Medical PPTYS: Current holder of stock options in a privately-held company; Caretrust Reit Inc: Current holder of stock options in a privately-held company; Moderna: Current equity holder in private company; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; Jannsen Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; RAPA Therapeutics: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Membership on an entity's Board of Directors or advisory committees.