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Propranolol inhibits molecular risk markers in HCT recipients: a phase 2 randomized controlled biomarker trial. Blood Adv 2020 02 11;4(3):467-476

Date

02/07/2020

Pubmed ID

32027744

Pubmed Central ID

PMC7013267

DOI

10.1182/bloodadvances.2019000765

Scopus ID

2-s2.0-85082178004   4 Citations

Abstract

Preclinical research shows that stress-induced activation of the sympathetic nervous system can promote hematopoietic malignancies via β-adrenoreceptor-mediated molecular pathways. Hematopoietic cell transplant (HCT) recipients exposed to conditions of chronic stress show activation of a conserved transcriptional response to adversity (CTRA) gene expression profile, which in turn is associated with increased relapse and decreased disease-free survival. We conducted a randomized controlled phase 2 biomarker trial testing the impact of the nonselective β-antagonist propranolol on CTRA-related gene expression of 25 individuals receiving an autologous HCT for multiple myeloma. Propranolol was administered for 1 week prior to and 4 weeks following HCT. Blood was collected at baseline, day -2, and day +28. Intention-to-treat analyses controlling for demographic characteristics, high-risk disease (International Myeloma Working Group risk score), and tumor stage tested effects on a 53-gene CTRA indicator profile and measures of CTRA-related cellular processes in peripheral blood mononuclear cells. Twelve participants were randomized to the intervention and 13 to the control. Relative to the control group, propranolol-treated patients showed greater decreases from baseline to HCT day -2 and day +28 for both CTRA gene expression (P = .017) and bioinformatic measures of CD16- classical monocyte activation (P = .005). Propranolol-treated patients also showed relative upregulation of CD34+ cell-associated gene transcripts (P = .011) and relative downregulation of myeloid progenitor-containing CD33+ cell-associated gene transcripts (P = .001). Ancillary analyses identified nonsignificant trends toward accelerated engraftment and reduced posttransplant infections in propranolol-treated patients. Peri-HCT propranolol inhibits cellular and molecular pathways associated with adverse outcomes. Changes in these pathways make propranolol a potential candidate for adjunctive therapy in cancer-related HCT.

Author List

Knight JM, Rizzo JD, Hari P, Pasquini MC, Giles KE, D'Souza A, Logan BR, Hamadani M, Chhabra S, Dhakal B, Shah N, Sriram D, Horowitz MM, Cole SW

Authors

Saurabh Chhabra MD Associate Professor in the Medicine department at Medical College of Wisconsin
Anita D'Souza MD Associate Professor in the Medicine department at Medical College of Wisconsin
Binod Dhakal MD Associate Professor in the Medicine department at Medical College of Wisconsin
Mehdi H. Hamadani MD Professor in the Medicine department at Medical College of Wisconsin
Parameswaran Hari MD Chief, Professor in the Medicine department at Medical College of Wisconsin
Mary M. Horowitz MD, MS Center Director, Professor in the Medicine department at Medical College of Wisconsin
Jennifer M. Knight MD Associate Professor in the Psychiatry department at Medical College of Wisconsin
Brent R. Logan PhD Director, Professor in the Institute for Health and Equity department at Medical College of Wisconsin
Marcelo C. Pasquini MD, MS Professor in the Medicine department at Medical College of Wisconsin
J. Douglas D. Rizzo MD, MS Director, Center Associate Director, Professor in the Medicine department at Medical College of Wisconsin
Nirav N. Shah MD Associate Professor in the Medicine department at Medical College of Wisconsin




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