Noninfectious Pulmonary Toxicity after Allogeneic Hematopoietic Cell Transplantation

Sagar S. Patel, Kwang Woo Ahn, Manoj Khanal, Caitrin Bupp, Mariam Allbee-Johnson, Navneet S. Majhail, Betty K. Hamilton, Seth J. Rotz, Hasan Hashem, Amer Beitinjaneh, Hillard M. Lazarus, Maxwell M. Krem, Tim Prestidge, Neel S. Bhatt, Akshay Sharma, Shahinaz M. Gadalla, Hemant S. Murthy, Larisa Broglie, Taiga Nishihori, César O. FreytesGerhard C. Hildebrandt, Usama Gergis, Sachiko Seo, Baldeep Wirk, Marcelo C. Pasquini, Bipin N. Savani, Mohamed L. Sorror, Edward A. Stadtmauer, Saurabh Chhabra

Research output: Contribution to journalArticlepeer-review

10 Scopus citations


Noninfectious pulmonary toxicity (NPT), a significant complication of allogeneic hematopoietic cell transplantation (alloHCT), includes idiopathic pneumonia syndrome (IPS), diffuse alveolar hemorrhage (DAH), and cryptogenic organizing pneumonia (COP), with an overall incidence ranging from 1% to 15% in different case series and a variable mortality rate. A registry study of the epidemiology and outcomes of NPT after alloHCT has not been conducted to date. The primary objective of the present study was to assess the incidence of and risk factors for IPS, DAH, and COP; the secondary objective was to assess overall survival (OS) in patients developing NPT. This retrospective study included adult patients who underwent alloHCT between 2008 and 2017 and reported to the Center for International Blood and Marrow Transplant Research. Multivariable Cox proportional hazards regression models were developed to identify the risk factors for development of NPT and for OS, by including pretransplantation clinical variables and time-dependent variables of neutrophil and platelet recovery, and acute graft-versus-host disease (GVHD) post-transplantation. This study included 21,574 adult patients, with a median age of 55 years. According to the HCT Comorbidity Index (HCT-CI), 24% of the patients had moderate pulmonary comorbidity and 15% had severe pulmonary comorbidity. The cumulative incidence of NPT at 1 year was 8.1% (95% confidence interval [CI], 7.7% to 8.5%). Individually, the 1-year cumulative incidences of IPS, DAH, and COP were 4.9% (95% CI, 4.7% to 5.2%), 2.1% (95% CI, 1.9% to 2.3%), and .7% (95% CI, .6% to .8%), respectively. Multivariable analysis showed that severe pulmonary comorbidity, grade II-IV acute GVHD, mismatched unrelated donor and cord blood transplantation, and HCT-CI score ≥1 significantly increased the risk of NPT. In contrast, alloHCT performed in 2014 or later, non-total body irradiation (TBI)- and TBI-based nonmyeloablative conditioning and platelet recovery were associated with a decreased risk. In a landmark analysis at day+100 post-transplantation, the risk of DAH was significantly lower in patients who had platelet recovery by day +100. Multivariable analysis for OS demonstrated that NPT significantly increased the mortality risk (hazard ratio, 4.2; P < .0001).

Original languageEnglish
Pages (from-to)310-320
Number of pages11
JournalTransplantation and Cellular Therapy
Issue number6
StatePublished - Jun 2022

Bibliographical note

Funding Information:
Other members of the Working Committee: Catherine Lee, Robert Peter Gale, Peiman Hematti, Zachariah DeFilipp, Marjolein van der Poel, Shatha Farhan, Miguel Angel Diaz, Sherif Badawy, Jane Liesveld, Amy K. Keating, Jan Cerny, Jean-Yves Cahn, David A Rizzieri, Siddhartha Ganguly, Hisham Abdel-Azim, Mahmoud Aljurf, Sunita Nathan, Kasiani Myers, Muhammad Bilal Abid, Jean Yared, and Attaphol Pawarode, Financial disclosure: The CIBMTR is supported primarily by Public Health Service Award U24CA076518 from the National Cancer Institute (NCI), the National Heart, Lung and Blood Institute (NHLBI), and the National Institute of Allergy and Infectious Diseases (NIAID); Award HHSH250201700006C from the Health Resources and Services Administration (HRSA); and Awards N00014-20-1-2705 and N00014-20-1-2832 from the Office of Naval Research. Support is also provided by Be the Match Foundation, the Medical College of Wisconsin, the National Marrow Donor Program, and the following commercial entities: AbbVie; Accenture; Actinium Pharmaceuticals, Adaptive Biotechnologies, Adienne SA; Allovir, Amgen, Astellas Pharma US, bluebird bio, Bristol Myers Squibb, CareDx, CSL Behring, CytoSen Therapeutics, Daiichi Sankyo, Eurofins Viracor (DBA Eurofins Transplant Diagnostics), Fate Therapeutics, Gamida Cell, Gilead, GlaxoSmithKline, HistoGenetics, Incyte, Iovance, Janssen Research & Development, Janssen/Johnson & Johnson, Jasper Therapeutics, Jazz Pharmaceuticals, Kadmon, Karius, Karyopharm Therapeutics, Kiadis Pharma, Kite Pharma, Kite Pharma, Kyowa Kirin, Legend Biotech, Magenta Therapeutics, Medac, Medexus, Merck & Co, Millennium, Miltenyi Biotec, MorphoSys,; Novartis Pharmaceuticals, Omeros, OncoImmune, Oncopeptides, OptumHealth, Orca Biosystems, Ossium Health, Pfizer, Pharmacyclics, Priothera, Sanofi Genzyme, Seagen, Stemcyte, Takeda Pharmaceuticals, Talaris Therapeutics, Terumo Blood and Cell Technologies, TG Therapeutics, Tscan, Vertex, Vor Biopharma, and Xenikos BV. Conflict of interest statement: N.S.M. has served as a consultant for Incyte. A.S. is the St. Jude Children's Research Hospital site principal investigator of clinical trials for genome editing of SCD sponsored by Vertex Pharmaceuticals/CRISPR Therapeutics ( identifier NCT03745287) and by Novartis (NCT04443907). The industry sponsors provide funding for the clinical trial, which includes salary support paid to the St. Jude Children's Research Hospital. A.S. also is a paid consultant for Spotlight Therapeutics and Medexus and has received research funding from CRISPR Therapeutics. H.M. reports consultation for and research funding from CRISPR Therapeutics. T.N. reports institutional research support from Novartis (clinical trial support) and Karyopharm (drug supply for clinical trial) but no direct support. H.M.L. reports advisory board membership for Jazz Pharmaceuticals. M.S. reports advisory board membership for Jazz Pharmaceuticals. S.C. reports payment or honoraria from GSK and Sanofi and institutional research support for clinical trials from Amgen, Janssen, BMS, Syndax, and Sanofi. Authorship statement: S.S.P. NS.M. B.K.H. K.W.A. and S.C. designed the study; C.B. acquired the data; K.W.A. M.K. S.S.P. and S.C. analyzed and interpreted the data; S.S.P. drafted the manuscript; and S.C. critically reviewed and revised the manuscript. All authors reviewed, critiqued, and approved the final manuscript. Data use statement: The CIBMTR supports the accessibility of research in accordance with the National Institutes of Health's Data Sharing Policy and the National Cancer Institute's Cancer Moonshot Public Access and Data Sharing Policy. The CIBMTR only releases deidentified datasets that comply with all relevant global regulations regarding privacy and confidentiality. Financial disclosure: See Acknowledgments on page 319.

Publisher Copyright:
© 2022 The American Society for Transplantation and Cellular Therapy


  • Allogeneic hematopoietic cell transplantation
  • Cryptogenic organizing pneumonia
  • Diffuse alveolar hemorrhage
  • Idiopathic pneumonia syndrome
  • Noninfectious pulmonary toxicity

ASJC Scopus subject areas

  • Immunology and Allergy
  • Molecular Medicine
  • Hematology
  • Cell Biology
  • Transplantation


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