Dietary interventions may improve gut microbial diversity and HCT prognosis. Lysozyme, an antimicrobial protein highly expressed in human milk, supports the establishment of a healthy gut microbiota. Maga et al., at UC Davis developed the Artemis line of transgenic goats producing milk with human lysozyme (hLZ), which showed improve clinical outcomes, intestinal mucosa integrity, and gut microbiota in piglets with E. coli-induced severe diarrhea.In our ongoing pilot trial (NCT03531281) with the primary objective to evaluate the safety/feasibility of hLZ consumption, 41 evaluable patients (pts; median age=61 years; range: 22-78 years) with ALL (n=14), AML (n=8), or MPN or MDS (n=19) have been enrolled. The trial included a safety lead-in segment (SLI; n=6) followed by a randomized segment with pts receiving standard HCT care alone (SOC; n=17) or SOC+hLZ (n=18). Grafts were PBSC (n=40) or bone marrow (n=1) from matched related (n=11) or unrelated (n=30) donors. All SLI pts received myeloablative conditioning (FTBI), but most randomized pts (80%) received reduced intensity conditioning. GVHD prophylaxis was tacrolimus/sirolimus.Data from the SLI showed the feasible hLZ volume for consumption in the randomized segment is 450ml daily from admission to HCT and 300ml daily from HCT to discharge. These doses correspond to 2-3x naturally produced lysozyme in saliva in healthy individuals. There were no hLZ-related serious adverse events. Overall AEs were similar in the SLI, SOC and hLZ arms. Blood stream infections occurred in 4 pts by day 100 (SLI n=1, SOC n=2, hLZ n=1). Grade 3-4 infections occurred in 4 pts in SOC vs 1 in hLZ (p=0.18).At a median follow-up duration of 11.4 months (range 0.2-25.5) for surviving pts, all pts engrafted; median of 14 days to neutrophil recovery. In the randomized segment, day 180 non-relapse mortality (NRM) was 0% in the hLZ and 12% in the SOC arm (p=0.16). One-year overall survival (OS) was 90% for hLZ and 88% for SOC. Cumulative incidence of G3-4 aGVHD was 6% (95%CI: 0.4-26%) in SOC and 0% in hLZ pts. Lower GI GVHD was seen in 3 pts (SOC=1, hLZ=2).Shotgun metagenome sequencing analysis of stool samples showed a trend for better preservation of gut microbial diversity in hLZ pts at day 14 post-HCT vs. SOC pts, particularly among those who developed aGVHD. Some pathobionts such as E. coli (day 30, 100) Prevotella (Admit – day 100), Klebsiella (day 30,100), Staphylococcus (day 30) and Enterococcus (day 14) were more enriched in SOC vs hLZ pts. The dominance of antimicrobial resistance (AMR) genes by group and aGVHD changes over time, with SOC aGVHD+ exhibiting the greatest domination of select AMR genes.Our preliminary data establishes the safety & feasibility of hLZ in HCT pts. While survival outcomes were similar between hLZ and SOC in this interim analysis, we observed promising low rates of G3-4 infections, G3-4 aGVHD, and NRM, associated with reduced disruption of microbial communities.
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