Monocytosis as prognostic factor for chronic graft versus host disease

Abstract INTRODUCTION Chronic graft-versus-host disease (cGvHD) is the main cause of long-term morbidity and mortality after allogeneic hematopoietic stem cell transplantation (HSCT). Although some biomarkers have been identified for acute GvHD (aGvHD), no reliable markers are available for cGvHD. A prognostic biomarker for cGvHD would enable tailored prophylaxis, optimized immunosuppression, and monitoring. However, most biomarkers described—alloantibodies, microRNAs, extracellular vesicles, or immune cell subsets—have limitations regarding feasibility in routine settings. Monocytes play a key role in cGvHD pathogenesis via antigen presentation, cytokine release (e.g., IL-1, TNF-α), and downstream immune activation leading to tissue damage. Elevated and activated monocyte levels have been documented in cGvHD and therapies such as CSF-1R inhibition with axatilimab have shown benefit in refractory cases. In this context, absolute monocyte count may serve as a simple and cost-effective biomarker. We previously suggested this hypothesis in a single-center study; here, we validate this finding in a multicenter study. METHODS We conducted a retrospective, multicenter study including patients who underwent allo-HSCT in 8 Spanish centers between 2014–2017. Those who died within the first 100 days post-transplant were excluded. A total of 477 patients were analyzed. Monocytosis was defined as a monocyte count > 1 × 10⁹/L, occurring during post-transplant follow-up any time prior to the onset of cGvHD or 6 months before cGvHD onset. RESULTS The median age at diagnosis was 50 years (IQR 25–75: 40–58 years), with a mean age of 47.5 years (SD = 13.2). Regarding sex, 59.0% of the patients were male. Most patients received a reduced-intensity conditioning (RIC) regimen (67.4%). The donor type was predominantly matched related (sibling) in 34.8% of cases, followed by matched unrelated donors in 32.5%. Male donors accounted for 64.5% of cases. The primary source of hematopoietic stem cells was peripheral blood (92.4%). Regarding disease status at the time of transplantation, 57.9% of patients were in complete remission (CR), 17.3% were in partial remission, and 14.6% had active disease. Overall mortality was 36.3%, and the relapse rate was 30.6% at 8 years. A highly significant association was observed between the presence of prior monocytosis and the development of cGvHD (p < 0.001). Among patients who developed cGvHD, 44.8% had prior monocytosis, compared to only 1.3% of those who did not. The risk of cGvHD at 36 months was 93.6% (range: 87-96.9%) vs 41% (range: 35.3-46.2%) for patients with or without monocytosis [HR 3.29 (95% CI 2.55-4.24), p < 0.001]. Chronic GvHD flared at a median of 10 months in patients with monocytosis and it was not reached during follow-up in patients with lower counts (p < 0.0001). In addition, monocyte count proved to be a strong prognostic factor not only for the incidence but also for the severity of cGvHD. At 36 months, the cumulative incidence of moderate-to-severe cGvHD was 83.6% (range 71.4–90.6%) in patients with monocytosis at any time post-transplant and prior to cGvHD onset, compared to 29.3% (23.9–34.3%) in those without [HR 3.39 (95% CI 2.50-4.59), p < 0.001]. For severe cGvHD, the respective incidences were 47.2% (range 30.7–59.7%) and 14.3% (range 9.9–18.4%) [HR 2.93 (95% CI 1.84-4.65), p < 0.001]. Upon considering monocytosis occurring within 6 months prior to the onset of cGvHD these values were: HR 4.13 (95% CI 2.86-5.97), p < 0.001 for moderate to severe and HR 4.26 (95% CI 2.46-7.37), p < 0.001 for severe cGvHD. The positive predictive value (PPV) was 97.4%, therefore, most patients with monocytosis developed cGvHD. Again, considering monocytosis occurring within 6 months prior to the onset of cGvHD PPV was also 97.4%. Finally, we performed a multivariate analysis for overall cGvHD including monocytes count, GvHD prophylaxis, stem cell source, donor type, conditioning regimens and prior aGvHD. Patients with monocytosis during follow-up had 2.51 times higher risk of developing cGvHD than those without it (HR 2.51, IC 95%: 1.92–3.29; p < 0,001). CONCLUSIONS In conclusion, monocytosis onset following allo-HSCT is a prognostic biomarker of cGvHD. Monocytes' count ≥ 1.0 109/ L may help to identify patients at a higher risk of cGvHD, particularly those with moderate and severe forms.