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Stable to improved cardiac and pulmonary function in children with high-risk sickle cell disease following haploidentical stem cell transplantation

Bone Marrow Transplantation volume 56, pages 2221–2230 (2021)Cite this article

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Abstract

Children with sickle cell disease (SCD) are at high-risk of progressive, chronic pulmonary and cardiac dysfunction. In this prospective multicenter Phase II trial of myeloimmunoablative conditioning followed by haploidentical stem cell transplantation in children with high-risk SCD, 19 patients, 2.0–21.0 years of age, were enrolled with one or more of the following: history of (1) overt stroke; (2) silent stroke; (3) elevated transcranial Doppler velocity; (4) multiple vaso-occlusive crises; and/or (5) two or more acute chest syndromes and received haploidentical transplants from 18 parental donors. Cardiac and pulmonary centralized cores were established. Pulmonary function results were expressed as percent of the median of healthy reference cohorts, matched for age, sex, height and race. At 2 years, pulmonary functions including forced expiratory volume (FEV), FEV1/ forced vital capacity (FVC), total lung capacity (TLC), diffusing capacity of lung for carbon monoxide (DLCO) were stable to improved compared to baseline values. Importantly, specific airway conductance was significantly improved at 2 years (p < 0.004). Left ventricular systolic function (fractional shortening) and tricuspid regurgitant velocity were stable at 2 years. These results demonstrate that haploidentical stem cell transplantation can stabilize or improve cardiopulmonary function in patients with SCD.

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Fig. 1: Specific conductance (% predicted) before and after myeloimmunoablative conditioning and haploidentical stem cell transplantation (HISCT).
Fig. 2: Tricuspid regurgitation gradient before and after myeloimmunoablative conditioning and haploidentical stem cell transplantation (HISCT).

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Acknowledgements

This study was supported in large part by FDA R01FD004090 held by Dr. Cairo and in small part by the Pediatric Cancer Research Foundation, held by Dr. Cairo. We would like to thank Virginia Davenport, RN for her superb editorial assistance. We would also like to thank the patients and families who participated in this clinical trial and all the members of the external data safety monitoring committee and external advisory committee (Supplementary Fig. 3).

Funding

This study was supported in large part by FDA R01FD004090 held by MSC and in small part by the Pediatric Cancer Research Foundation, held by MSC.

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  1. These authors contributed equally: Deborah Friedman, Allen J. Dozor

Authors and Affiliations

  1. Department of Pediatrics, New York Medical College, Valhalla, NY, USA

    Deborah Friedman, Allen J. Dozor, Jordan Milner, Marise D’Souza, Suzanne Braniecki, Janet Ayello, Allyson Flower, Erin Morris, Harshini Mahanti, Sandra Fabricatore, Liana Klejmont, Carmella van de Ven & Mitchell S. Cairo

  2. Pediatrics, Medical College of Wisconsin, Milwaukee, WI, USA

    Julie-An Talano

  3. Department of Pediatrics, University of California Los Angeles, Los Angeles, CA, USA

    Theodore B. Moore

  4. Department of Pediatrics, Washington University, St. Louis, MO, USA

    Shalini Shenoy

  5. Epidemiology & Community Health, New York Medical College, Valhalla, NY, United States

    Qiuhu Shi

  6. Department of Pediatrics, UCSF Benioff Children’s Hospital, Oakland, CA, USA

    Mark C. Walters & Elliott Vichinsky

  7. Departments of Medicine and Pediatrics, Tufts Medical Center, Boston, USA

    Susan K. Parsons

  8. Radiation Medicine, New York Medical College, Valhalla, NY, USA

    Chitti R. Moorthy

  9. Department of Pathology, Children’s Hospital of Los Angeles, Los Angeles, CA, USA

    Lee Ann Baxter-Lowe

  10. Departments of Medicine, New York Medical College, Valhalla, NY, United States

    Mitchell S. Cairo

  11. Departments of Pathology, New York Medical College, Valhalla, NY, United States

    Mitchell S. Cairo

  12. Departments of Microbiology & Immunology, New York Medical College, Valhalla, NY, United States

    Mitchell S. Cairo

  13. Departments of Cell Biology & Anatomy, New York Medical College, Valhalla, NY, United States

    Mitchell S. Cairo

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Contributions

MSC, AJD, DF, MD, JM, QS and CV had full access to all the data in the study and take responsibility for the integrity of the data and accuracy of the data analysis. MSC, JT, TBM, MCW and SS contributed to the concept and design of study. MSC, DF, AJD, MD, QS, CVV and JM collected, analyzed and interpreted the data. MSC, AJD, DF, MD, JM, CVV, and EM drafted the manuscript. MSC, AJD, DF, MD, JM, CVV and EM drafted the manuscript. MSC, AJD, DF, MD, JM, JT, TBM, SS, QS, MCW, EV, SP, SB, CM, JA, AF, EM, HM, SB, LK, CVV and LBL critically revised the manuscript for important intellectual content. QS and CVV provided the statistical analysis. MSC obtained the funding and Miltenyi generously provided the CD34 enriched reagents for this study. All authors contributed to the writing of this manuscript and have approved this submitted version of the manuscript.

Corresponding author

Correspondence to Mitchell S. Cairo.

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Conflict of interest

MSC has received funding from the FDA (R01FD004090), the Pediatric Cancer Research Foundation (PCRF), Otsuka and Miltenyi. Although not related to this study, MCW is a consultant for Bluebird Bio, Inc., Bioverativ, Sangamo, Veevo, Editas Medicine and is medical director for AllCells, Inc. Biosciences. SKP is a consultant to Seattle Genetics, also unrelated to this study. EV is a consultant for ApoPharma, on the advisory committee for Global Blood Therapeutics and receives royalties from UptoDate. All other authors declare no conflicts of interest.

Ethics

The protocol was approved at each institutional review board, informed consent was obtained and assent was obtained if clinically applicable and the study was registered at ClinicalTrials.gov NCT01461837. This research has been presented in part at the American Society of Hematology (ASH), December 2017, San Diego, CA.

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Friedman, D., Dozor, A.J., Milner, J. et al. Stable to improved cardiac and pulmonary function in children with high-risk sickle cell disease following haploidentical stem cell transplantation. Bone Marrow Transplant 56, 2221–2230 (2021). https://doi.org/10.1038/s41409-021-01298-7

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