A pilot study of nicotinamide riboside supplementation in allogeneic bone marrow transplantation

Abstract

Abstract Allogeneic hematopoietic cell transplantation requires intensive chemotherapy conditioning followed by donor-derived hematopoietic cell rescue. As compared to peripheral blood stem cell (PBSC) grafts bone marrow (BM) has been associated with slower neutrophil and platelet count recovery. Efforts to hasten engraftment are critical to improve transplant-related morbidity and mortality. Nicotinamide adenine dinucleotide (NAD+) is important to increase sirtuins, which assist with the differentiation process of stem cells. Nicotinamide riboside (NR) has been shown in pre-clinical and clinical studies to safely increase NAD+ levels. In the murine system, NR supplementation resulted in a significantly enlarged pool of progenitors, accelerated blood count recovery and improved survival (Cell Stem Cell. 2019 Mar 7;24(3):405-418.e7). In the human umbilical cord blood setting, nicotinamide-based cell expansion technology (NiCord) has been used ex-vivo to expand the number of donor cells, while maintaining their function. Patients treated with NiCord had more rapid hematopoietic recovery and shorter hospital length of stay (LOS) as compared to transplant with standard cord blood units (J Clin Oncol. Feb 10 2019;37(5):367-374). We hypothesized that NR supplementation during the peri-transplant conditioning regimen administration for allogeneic BM transplant (alloBMT) is safe and tolerable, while hastening engraftment and shortening hospital LOS. A single center pilot study (NCT04332341) was designed to test 4 study cohorts (5 patients per cohort) with dose escalation of oral NR as follows: observation group (cohort 1), 500 mg BID Day -14 to day +7 (cohort 2), +14 (cohort 3), or +21 (cohort 4). The primary objective was to evaluate safety and tolerability of NR in this population. The secondary objective evaluated neutrophil (NE) and platelet engraftment (PE), which were compared to contemporary control patients who received BM and PBSC grafts. We here report the interim results of the trial which is currently in cohort 3. Pre-clinical correlative studies were performed with BM and peripheral blood mononuclear cells (PBMCs) from patients pre- and post-treatment to measure NAD+, NADPH and associated metabolite levels that reflected the overall cellular redox state. Colony forming unit assays were performed with and without NR from the donor PBMCs at screening. Thirteen adult hematologic malignancy patients who received myeloablative HLA matched related or unrelated alloBMT were enrolled from 4/13/23-4/14/25. NR was safe and well-tolerated with no treatment-related adverse events. As compared to cohort 2, cohort 3 patients had more rapid platelet engraftment (PE) at a median of 18 vs. 22 days (p=.024), and shorter LOS (median 21 vs. 25 days, p=.072). There were no differences in these outcomes between cohort 2 and BM control patients (which included cohort 1). Cohort 3 had more rapid PE (median 18 vs. 21 days, p=.022) and shorter LOS (21 vs. 24 d, p=.047) compared to BM controls. PBSC controls had more rapid NE (median 12 vs. 16 d, p=.031) and shorter LOS (median 21 vs. 25 d, p=.028) than cohort 2, but no significant differences were observed compared to cohort 3. At a median follow-up of 8.4 months no study patients relapsed and only 1 death occurred in a cohort 2 patient at day +47 from pneumonia unrelated to NR. Median NAD+/NADPH levels were stable from day -14 to day +30 for cohort 1. However, compared to day -14 these levels increased 2-fold on day 0 (p=0.02) and 3-fold on day 30 for cohort 2. At the time of analysis cohort 3 had a 1.6-fold (p=0.02), 2.5 (p= 0.05) and 3.5-fold (p= 0.03) increase of these levels on days -7, 0 and +30, respectively. In the pre-clinical set-up, donor PBMCs exposed to 1mM NR in a colony forming assay using Methocult™, for 14 days had a nearly 40% increase (p=<.0001) in the number of colonies compared to vehicle controls, consistent with prior reports of NR for ex vivo hematopoietic cellular expansion. We conclude that NR supplementation is safe and well tolerated in alloBMT with dose dependent increases in NAD+/NADPH levels that preliminarily are associated with more rapid PE and shorter LOS. These findings may have implications for improved resource utilization and cost-effectiveness in alloBMT, which will be further assessed as the trial proceeds to cohort 4.