Propranolol inhibits molecular risk markers in HCT recipients: a phase 2 randomized controlled biomarker trial.

Preclinical research shows that stress-induced activation of the sympathetic nervous system can promote hematopoietic malignancies via ß-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 ß-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.

Repurposing existing medications as cancer therapy: design and feasibility of a randomized pilot investigating propranolol administration in patients receiving hematopoietic cell transplantation.

BACKGROUND: Repurposing existing medications for antineoplastic purposes can provide a safe, cost-effective, and efficacious means to further augment available cancer care. Clinical and preclinical studies suggest a role for the ß-adrenergic antagonist (ß-blocker) propranolol in reducing rates of tumor progression in both solid and hematologic malignancies. In patients undergoing hematopoietic cell transplantation (HCT), the peri-transplant period is a time of increased activity of the ß-adrenergically-mediated stress response. METHODS: We conducted a proof-of-concept randomized controlled pilot study assessing the feasibility of propranolol administration to patients between ages 18-75 who received an autologous HCT for multiple myeloma. Feasibility was assessed by enrollment rate, tolerability, adherence, and retention. RESULTS: One hundred fifty-four patients underwent screening; 31 (20%) enrolled in other oncology trials that precluded dual trial enrollment and 9 (6%) declined to enroll in the current trial. Eighty-nine (58%) did not meet eligibility requirements and 25 (16%) were eligible; of the remaining eligible patients, all were successfully enrolled and randomized. The most common reasons for ineligibility were current ß-blocker use, age, logistics, and medical contraindications. 92% of treatment arm patients tolerated and remained on propranolol for the study duration; 1 patient discontinued due to hypotension. Adherence rate in assessable patients (n = 10) was 94%. Study retention was 100%. CONCLUSIONS: Findings show that it is feasible to recruit and treat multiple myeloma patients with propranolol during HCT, with the greatest obstacle being other competing oncology trials. These data support further studies examining propranolol and other potentially repurposed drugs in oncology populations. TRIAL REGISTRATION: This randomized controlled trial was registered at clinicaltrials.gov with the identifier NCT02420223 on April 17, 2015.