Monocytes Matter: Impact of Monocyte Recovery on Allogeneic Hematopoietic Stem Cell Transplant Outcomes with Post-Transplantation Cyclophosphamide As Graft Versus Host Disease Prophylaxis
Authors: Desai Nihar , Alfaro Moya Tommy , Law Arjun , Lam Wilson , Novitzky-Basso Igor , Pasic Ivan , Michelis Fotios , Gerbitz Armin , Kim Dennis Dong Hwan , Kumar Rajat , Mattsson Jonas , Viswabandya Auro 
Published: December 2024

Background: Monocytopenia has been associated with inferior survival following allogeneic hematopoietic stem cell transplantation (allo-HCT). Post-transplantation cyclophosphamide (PTCy) for graft versus host disease (GVHD) prophylaxis has been associated with delayed neutrophil and platelet engraftment but its effect on monocyte recovery has not been documented (2). Previous research has identified monocyte recovery as a predictor of overall survival, but not in the context of PTCy-based GVHD prophylaxis. In this study, we aim to evaluate if monocyte recovery predicts favorable outcomes in patients receiving PTCy and anti-thymocyte globulin (ATG) GVHD prophylaxis.

Methods: We retrospectively analyzed patients undergoing allo-HCT between January 2019 and October 2023 from matched unrelated donors (MUD) using a combination of ATG and PTCy for GVHD prophylaxis. Categorical variables were presented as numbers and percentages, and continuous variables were summarized using median and range. Overall survival (OS) and GVHD-free/relapse-free survival (GRFS) were calculated using the Kaplan-Meier product-limit method and differences were assessed using the log-rank test.

The absolute monocyte count (AMC) at D+28, D+100, and D+180 were recorded from the complete blood cell count. The primary endpoint was to assess the impact of AMC on overall survival. For the outcome analyses, we defined a cutoff AMC value of &lt;0.3 x 109/L. Multivariable Cox regression analysis (MVA) assessed risk factors for OS and GRFS. Fine-gray regression was used for non-relapse mortality (NRM), cumulative incidence of relapse (CIR), and GVHD. A p-value of &lt;0.05 was considered statistically significant, and analyses were conducted using EZR (version 1.62).

Results: A total of 295 patients were included in this study. The median age was 58 years (18 - 74), 162 (54.9%) were male. Acute myeloid leukemia was the most common indication (51.8%). Most (66.4%) received reduced-intensity conditioning. The GVHD prophylaxis was uniform across the cohort and included a combination of ATG and PTCy with a calcineurin inhibitor. Peripheral blood stem cell grafts were used in all patients. The median CD34+ cell dose was 7.36 x 106/kg (1.7 - 13.2). Sixty-three (21.3%) received cryopreserved grafts. The HCT-CI score was ≥3 in 85 (28.8%) patients. The disease risk index (DRI) was high - very high in 46 (15.6%).

At the time of analysis, 66 (22.3%) patients have relapsed, and 84 (28.5%) have died. The median follow-up of survivors was 18.1 months (1 - 57.3). Engraftment occurred in 289 (97.9%) patients. The median time to neutrophil and platelet engraftment were 18 (17 - 19) and 23.5 days (21- 25), respectively. The OS, GRFS, and the cumulative incidence of relapse at 2 years was 68.1% (95% CI: 61.5 - 73.9), 47.1% (95% CI: 40.4 - 53.4), and 22.5% (95% CI: 17.3 - 28.1) respectively. At 1 year, the NRM was 14.5 % (95% CI: 10.5 - 19). The D+100 cumulative incidence of grade II-IV, and grade III-IV aGVHD were 24.4% (95% CI: 19.6 - 29.6), and 6.8% (95% CI: 4.2 - 10.3) respectively.

Patients with AMC &gt;0.3 x 109/L at D+100 had a significantly higher 2-year OS [80.7% (73.2- 86.2) vs 55.9% (36.6 - 71.5), p=0.002], and GRFS [58.1% (50 -65) vs 28.9% (15 - 45) p=0.001]. The NRM at 1 year for patients with AMC &gt;0.3 x 109/L was 3.6 % (1.5 - 7.3) and 16.3% (12.9 - 41.9) for those with AMC &lt;0.3 x 109/L (p&lt;0.001). Infections were the most common cause of NRM, followed by GVHD. The cumulative incidence of relapse, and acute and chronic GVHD was not significantly different between the groups.

On univariate analysis, high-very high DRI, higher HCT-CI score, acute GVHD grade III-IV, and day +100 AMC &gt;0.3 x 109/L were associated with OS. On MVA, day +100 AMC &gt;0.3 x 109/L was predictive of improved OS, HR 0.37 (0.19 - 0.69), p=0.002. High-very high DRI was associated with inferior OS, HR 2.45 (1.2 - 4.9), p=0.01.

The use of cryopreserved grafts, aGVHD, and D+100 AMC were significant for NRM on UVA. On the MVA, D+100 AMC &gt;0.3 x 109/L was associated with improved NRM, HR 0.11 (0.4 - 2.9), p&lt;0.001.

Conclusion: Our study demonstrates that monocyte recovery by day 100 post-allo-HCT is a significant predictor of OS and NRM in patients receiving PTCY and ATG for GVHD prophylaxis. These findings underscore the importance of monocyte recovery as a marker for favorable post-transplant outcomes and highlight the continued importance of monitoring monocyte recovery post-allo-HCT in patients receiving PTCy.