Silvia Park

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only curative treatment for myelodysplastic neoplasms (MDS). While matched sibling donors (MSD) have traditionally been preferred, the impact of donor type on transplant outcomes under anti-thymocyte globulin (ATG)-based graft-versus-host disease (GVHD) prophylaxis remains unclear. We analyzed 391 adult MDS patients receiving allo-HSCT with fludarabine–busulfan conditioning and ATG between 2009 and 2019. Donors included MSD (n = 155), unrelated donors (UD; n = 134), and haploidentical donors (HID; n = 102). At a median follow-up of 108 months, the 5-year overall survival (OS) and relapse-free survival (RFS) rates were 63.0% and 58.4%. While OS and non-relapse mortality (NRM) did not significantly differ by donor type, MSD recipients had a higher cumulative incidence of relapse compared to UD and HID recipients (34.3% vs. 16.4% and 16.8% at 5 years, p < 0.001), with a trend toward inferior RFS. In multivariate analysis, MSD was independently associated with increased relapse risk and a lower incidence of GVHD, which may reflect a reduced graft-versus-leukemia effect. In this single-center large cohort, MSD transplants were associated with higher relapse risk compared with alternative donors under ATG-based prophylaxis.

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare clonal hematopoietic stem cell disorder characterized by complement-mediated hemolysis and thrombotic complications. The introduction of complement inhibitors has markedly improved survival outcomes by reducing intravascular hemolysis and thrombotic risk. We report the case of a 73-year-old man with PNH and myelodysplastic neoplasm (MDS) who developed severe thromboembolic and hemolytic events following the discontinuation of ravulizumab. His disease had previously evolved from aplastic anemia to MDS. Despite prior resolution of PNH-related thrombosis and maintained clinical stability, the cessation of treatment precipitated rebound hemolysis and multiple thrombotic events 8 months after discontinuation. These events included ischemic enterocolitis, necrotic gingivitis, ischemic epididymo-orchitis, and portal vein thrombosis. Resumption of complement inhibition with ravulizumab successfully halted the progression of PNH-related complications. This case emphasizes the life-threatening risks associated with the withdrawal of complement blockade in patients with a prior thromboembolic history and highlights the critical importance of continuous therapy, even in the context of bone marrow failure.

Background/Objectives: Myeloid neoplasms encompass a diverse group of disorders. In this study, we aimed to analyze the clinical and genomic data of patients with myeloproliferative neoplasm (MPN), myelodysplastic neoplasm (MDS), and their overlapping conditions, such as MDS/MPN and aplastic anemia (AA), to help redefine the disease classification. Methods: Clinico-genomic data of 1585 patients diagnosed with MPN (n = 715), MDS (n = 698), MDS/MPN (n = 78), and AA (n = 94) were collected. Patterns of 53 recurrent genomic abnormalities were compartmentalized into 10 groups using a Dirichlet process (DP). Results: These genomic groups were correlated with specific genomic features, survival outcomes, and disease subtypes. Groups DP1 and DP5, characterized by JAK2 and CALR mutations, respectively, showed very favorable prognoses among the patients with MPN. Groups DP2, DP7, and DP9 demonstrated very adverse prognoses across the disease subtypes. DP2 included patients with MDS harboring TP53 mutations and complex karyotypes; DP9 comprised patients with acute myeloid leukemia-related mutations, including NPM1; and DP7 included patients with SETBP1 mutations. Groups DP10 and DP8, linked to SF3B1 and DDX41 mutations or chromosome 1q derivatives, presented a favorable risk profile. Improved survival was observed with transplantation in groups DP2, DP7, and DP9. Conclusions: These findings highlight the role of genomic classifications in guiding personalized treatment strategies, ultimately enhancing the understanding and management of myeloid neoplasms.

Given the limited comprehensive data on the bone marrow (BM) immune environment in acute myeloid leukemia (AML), we analyzed the distribution and phenotype of T cell subsets, including γδ T cells, and their immune checkpoint (IC) ligands on blasts. We performed multiparametric flow cytometry with BM samples taken from 89 AML patients at the time of diagnosis, remission, and relapse/refractory status after chemotherapy and 13 healthy controls (HCs) to identify immune-related risk factors. Compared to the HCs, the T cells of the AML patients exhibited exhausted features including higher TIGIT levels and similar levels of PD-1 and TIM-3. The γδ T cells were exhausted by the upregulation of TIGIT and/or TIM-3 and downregulation of NKG2D and NKp30, with different patterns in the Vδ1 and Vδ2 subtypes. A successful chemotherapeutic response partially restored the exhausted phenotypes of the T cell subsets. The simultaneous analysis of IC receptors on the T cell subsets and their ligands on blasts showed the prognostic value of a specific IC receptor–ligand pair and the feasibility of risk stratification based on their diverse patterns. Our findings clarified the BM T cell landscape in AML, unveiling the prognostic value of γδ T cells in both diagnosis and remission predictions.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potential cure for myelodysplastic neoplasms (MDSs) and other hematologic malignancies. This study investigates post-transplantation genetic evolution and telomere dynamics in hematopoietic cells, with a focus on clonal hematopoiesis (CH). We conducted a longitudinal analysis of 21 MDS patients who underwent allo-HSCT between September 2009 and February 2015. Genetic profiles of hematopoietic cells from both recipients and donors were compared at equivalent pre- and post-transplantation time points. Targeted sequencing identified CH-associated mutations, and real-time quantitative PCR measured telomere length. Furthermore, we compared CH incidence between recipients and age-matched controls from the GENIE cohort from routine health checkups. Post-allo-HSCT, 38% of recipients developed somatic mutations not detected before transplantation, indicating de novo CH originating from donor cells. Compared to age-matched healthy controls, recipients showed a significantly higher incidence of CH, suggesting increased susceptibility to genetic changes post-transplant. Telomere length analysis also revealed accelerated shortening in transplanted cells, highlighting the heightened stress and proliferation demands in the new microenvironment. Our findings reveal a notable incidence of donor-derived CH in allo-HSCT recipients, alongside significant telomere attrition. This suggests the potential influence of the marrow microenvironment on genetic and molecular changes in hematopoietic cells.

Hepatic graft-versus-host disease (GVHD) significantly impacts morbidity and mortality among allogeneic hematopoietic stem cell transplant recipients. However, the relationship between clinical and immunopathological phenotypes and their influence on clinical outcomes in hepatic GVHD is not well understood. In this study, we aimed to study the implications of portal T-cell infiltration on the clinical outcomes in hepatic GHVD and its similarities to autoimmune liver disease. We analyzed 78 patients with biopsy-confirmed hepatic GVHD (n = 38) or autoimmune liver disease (n = 40) between 2016 and 2021. The cholestatic variant was defined by an R-value < 2.0, based on the ratio of alanine aminotransferase to alkaline phosphatase. The primary outcome was the biochemical response at 4 (early) and 8–12 (late) weeks after corticosteroid treatment. In hepatic GVHD patients, the hepatitic variant (n = 19) showed greater CD3⁺ T-cell infiltration than the cholestatic variant (n = 19; p < 0.001). No significant differences were observed in the infiltration of CD20⁺, CD38⁺, or CD68⁺ cells. The hepatitic variant had significantly better early and late responses and higher liver-related event-free survival than the cholestatic variants (p < 0.05). Concerning autoimmune liver diseases, the autoimmune hepatitis (AIH) group had significantly more portal T-cell infiltration and better treatment responses than the primary biliary cholangitis (PBC) group. In conclusion, higher portal T-cell infiltration may be associated with better clinical outcomes in patients with hepatic GVHD. Additionally, this study highlights similarities in portal T-cell infiltration and treatment response patterns between AIH and the hepatitic variant, as well as PBC and the cholestatic variant.

The recently approved BCL2 inhibitor venetoclax (VEN) has achieved promising outcomes in new and relapsed/refractory (R/R) acute myeloid leukemia (AML). Although its use is not well established in R/R AML with extramedullary disease (EMD), some reports have shown promising outcomes. We retrospectively analyzed 11 patients of R/R AML with EMD (with (n = 4) or without (n = 7) concurrent marrow involvement), who were treated with VEN plus decitabine (n = 9) or low-dose cytarabine (n = 2) between May 2020 and October 2020 in Seoul St. Mary’s Hospital. The median number of prior treatment lines was 3 (1–6), and most (n = 9, 81.8%) had multiple sites of EMD. Nine patients (81.8%) received concurrent therapy for extramedullary (EM) involvement sites with radiotherapy (RT) (n = 4), surgery (n = 1), and both of them (n = 4). Among 11 patients, 4 patients (36.4%) had either marrow or EM responses to VEN combination; EM response was seen in 1 patient (9.1%, partial response) who had received concurrent RT (25 Gy, 10 fx) during the 1st cycle of VEN combination, and other 3 patients showed marrow response without EM response. After median follow-up of 27.0 months, the median overall survival was estimated to be 5.4 months. To conclude, VEN combination regimens have shown only modest efficacy in EM recurrence of AML with little impact on eliciting EM response.

The prevention and management of cytomegalovirus (CMV) reactivation is important to improve the outcomes of allogeneic hematopoietic cell transplantation (allo-HCT) recipients. The aim of this study was to analyze real-world data regarding the incidence and characteristics of CMV infections until 1 year after allo-HCT under 100-day letermovir prophylaxis. A single-center retrospective study was conducted between November 2020 and October 2021. During the study period, 358 patients underwent allo-HCT, 306 of whom received letermovir prophylaxis. Cumulative incidence of clinically significant CMV infection (CS-CMVi) was 11.4%, 31.7%, and 36.9% at 14 weeks, 24 weeks, and 1 year post-HCT, respectively. Through multivariate analysis, the risk of CS-CMVi increased with graft-versus-host disease (GVHD) ≥ grade 2 (adjusted odds ratio 3.640 [2.036–6.510]; p < 0.001). One-year non-relapse mortality was significantly higher in letermovir breakthrough CS-CMVi patients than those with subclinical CMV reactivation who continued receiving letermovir (p = 0.002). There were 18 (15.9%) refractory CMV infection cases in this study population. In summary, letermovir prophylaxis is effective at preventing CS-CMVi until day 100, which increased after the cessation of letermovir. GVHD is still a significant risk factor in the era of letermovir prophylaxis. Further research is needed to establish individualized management strategies, especially in patients with significant GVHD or letermovir breakthrough CS-CMVi.

Prevention and management of cytomegalovirus (CMV) reactivation is important to improve outcome of allogeneic hematopoietic cell transplantation (allo-HCT) recipients. The aim of this study was to analyze real-world data for incidence and characteristics of CMV infections until 1-year after allo-HCT under 100-day letermovir prophylaxis. A single-center retrospective study was conducted between November 2020 and October 2021. During the study period, 358 patients underwent allo-HCT, 306 of whom received letermovir prophylaxis. Cumulative incidence of clinically significant CMV infection (CS-CMVi) was 11.4%, 31.7%, and 36.9% at 14-weeks, 24-weeks, and 1-year post-HCT, respectively. In multivariate analysis, risk of CS-CMVi increased with graft-versus-host disease (GVHD) ≥ grade 2 (adjusted odds ratio 3.640 [2.036–6.510]; P < 0.001). One-year non-relapse mortality was significantly higher in letermovir breakthrough CS-CMVi patients than those with subclinical CMV reactivation who continued letermovir (P = 0.002). There were 18 (15.9%) refractory CMV infection in this study population. In summary, letermovir prophylaxis is effective in preventing CS-CMVi until day 100, which increased after cessation of letermovir. GVHD is still a significant risk factor in letermovir prophylaxis era. Further research is needed to establish individualized management strategies especially in patients with significant GVHD or letermovir breakthrough CS-CMVi.

Recently, the combination of VEN-HMA has been shown to achieve durable responses in patients with both newly diagnosed (ND) and R/R-AML. We retrospectively evaluated the post-allo-HCT outcomes of 50 patients who received VEN-HMA therapy. In total, 10 were ND and 40 were R/R and, at the time of HCT, the median age was 53 years. In the ND- and R/R-AML groups, the percentage of patients who achieved CR/CRi or MLFS was 90% and 92.5%, respectively. In all, after a median follow-up of 13.7 months, the probabilities of overall survival (OS), relapse-free survival (RFS), cumulative incidence of relapse (CIR), and nonrelapse mortality (NRM) at 1 year were 63.7%, 59.3%, 28.5%, and 12.2%, respectively. In addition, the cumulative incidences of grade II–IV acute graft-versus-host disease (GVHD) and moderate–severe chronic GVHD at 1 year were 28.4% and 37.4%, respectively. In multivariate analysis, the factors associated with a statistically significant impact on OS were VEN-HMA cycle (p = 0.021), ELN risk group (p = 0.041), and the response to VEN-HMA therapy before allo-HCT (p = 0.003). Although 80% of our patients had R/R-AML and 30% underwent a second allo-HCT, our data still suggest that allo-HCT following VEN-HMA therapy is a safe and effective treatment option.