Yi Luo

Chronic graft-versus-host disease (cGVHD) remains the leading cause of late non-relapse mortality and long-term disability after allogeneic hematopoietic cell transplantation (allo-HCT), affecting 30–70% of long-term survivors. Despite its substantial morbidity and the toxicities associated with prolonged corticosteroid use, therapeutic advances have accelerated considerably. This review synthesizes current mechanistic insights and clinical evidence within the framework of the well-established three-phase pathogenesis model of cGVHD. Phase 1 (early inflammation) involves tissue injury and innate immune activation; Phase 2 (months 2–12) is characterized by impaired central and peripheral tolerance with aberrant B- and T-cell responses; Phase 3 (>1 year) features macrophage-driven fibrosis and end-organ damage. Recognizing that these phases are conceptual and frequently overlap in clinical practice, we explore the alignment of contemporary biomarkers with each phase—ST2/CXCL9 (Phase 1), BAFF/autoantibodies (Phase 2), and MMP3/TGF-β (Phase 3)—and discuss how FDA-approved agents (ibrutinib, ruxolitinib, belumosudil, axatilimab) may target phase-specific pathways. A conceptual, risk-stratified treatment algorithm is proposed to link pathobiology to clinical decision-making, with the important caveat that biomarker-guided selection remains investigational and currently complements, rather than replaces, comprehensive clinical assessment. Notably, the adoption of prophylaxis and upfront strategies to prevent cGVHD has substantially reduced cGVHD incidence in modern cohorts.

Background: Although inotuzumab ozogamicin (InO) has been approved as an effective agent for patients with refractory/relapsed (r/r) B‐cell acute lymphoblastic leukemia (B‐ALL), data in the context of post chimeric antigen receptor (CAR)‐T cell therapy and allogeneic hematopoietic stem cell transplantation (allo‐HSCT) relapse are lacking. Case: We report on a series of three heavily pretreated r/r B‐ALL patients who relapsed after CAR‐T therapy and allo‐HSCT and were salvage treated with InO. All achieved bone marrow (BM) remission with negative minimal residual disease (MRD) after the first InO cycle; of note, one patient with extensive extramedullary involvement before InO treatment experienced a remarkable tumor regression on PET/CT imaging. They all completed 2 cycles of InO. Two patients experienced relapse 8 and 9.5 months after InO initiation (one central nervous system relapse, the other breast relapse). Treatment‐related adverse events (AEs) were primarily hematologic and manageable. Crucially, no sinusoidal obstruction syndrome (SOS) developed in any of the patients during the whole course of InO therapy and beyond. Conclusion: InO appears to be a promising and well‐tolerated salvage regimen for inducing remission in heavily pretreated B‐ALL patients who have relapsed after both CAR‐T therapy and allo‐HSCT.

This study aimed to define the incidence of Clostridioides difficile infection (CDI), identify its risk factors, and evaluate its association with early post-transplant complications and overall clinical outcomes. To characterize CDI in the allogeneic hematopoietic stem cell transplantation (allo-HSCT) setting, we retrospectively analyzed a cohort of 539 recipients who experienced diarrhea in the peri-transplant period (from conditioning to discharge from laminar flow). Among these diarrheic recipients, 64 patients developed CDI, the cumulative incidence of CDI was 12.1%, with a median onset of day -1 (range, -7 to +26) relative to HSCT. In a multivariate analysis, older age was independently associated with a lower risk of CDI (HR, 0.97; P = 0.008) among diarrheic recipients. The incidence of CDI stratified by the median onset time revealed that pre-transplant CDI was an independent risk factor for grade 1-4 lower gastrointestinal acute graft-versus-host disease (lower-GI aGVHD) (HR, 2.43; P=0.024). Furthermore, pre-transplant CDI was associated with a markedly increased risk of severe fungal infection (HR,6.97; P=0.026) and 100-day non-relapse mortality (NRM) (HR, 3.13; P=0.046). In conclusion, this study highlights a critical, timing-dependent distinction in CDI-associated severe complications and mortality in allo-HSCT recipients with diarrhea.

Relapse is the predominant cause of treatment failure after allogeneic hematopoietic cell transplantation (allo-HCT) in FLT3-ITD-mutated AML. Although measurable residual disease (MRD) is increasingly used for risk stratification, optimal FLT3-ITD MRD assessment, the prognostic value of peri-transplant MRD dynamics, and their implications to transplant-related decision-making remain unclear. We conducted a multicenter retrospective study of 219 patients with FLT3-ITD-mutated AML in morphologic complete remission at transplantation, assessing peri-transplant MRD by PCR-next-generation sequencing (PCR-NGS). Pre-transplant MRD positivity (≥ 0.001% by PCR-NGS) was associated with inferior outcomes versus MRD negativity (2-year relapse-free survival [RFS], 56.8% vs. 86.5%; cumulative incidence of relapse [CIR], 30.0% vs. 6.9%; overall survival [OS], 65.9% vs. 88.4%; all p<0.001). Peri-transplant MRD dynamics outperformed single time-point assessments, identifying high-risk patients such as those with post-HCT MRD conversion. And post-HCT FLT3 inhibitor maintenance independently improved RFS (p = 0.003), with greatest benefit observed in MRD-positive patients. These findings support PCR-NGS-based molecular MRD assessment to refine risk stratification and guide individualized transplant strategies in FLT3-ITD-mutated AML.

Background: The optimal regimens for older adults with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) before allogeneic hematopoietic stem cell transplantation (allo‐HSCT) remain uncertain. Methods: The authors conducted a multicenter phase 2 trial to evaluate the novel venetoclax, fludarabine, and melphalan (VFM) regimen in patients with AML or MDS aged 50 years and older. The VFM regimen consisted of venetoclax (400 mg daily on days −8 to −2), fludarabine (30 mg/m ² daily on days −7 to − 3), and melphalan (120–140 mg/m ² daily on day −2). Results: Sixty patients (median age, 58 years; age range, 51–66 years) received the novel VFM conditioning regimen. The 2‐year disease‐free survival (DFS) rate was 75.0% (95% confidence interval [CI], 64.8%–86.8%), which was the primary end point. Two‐year rates of overall survival, graft‐versus‐host disease (GVHD)–free and recurrence‐free survival, nonrelapse mortality, and relapse were 78.3% (95% CI, 68.6%–89.5%), 61.6% (95% CI, 50.5%–75.3%), 13.3% (95% CI, 6.1%–23.3%), and 11.7% (95% CI, 5.1%–21.3%), respectively. Treatment‐related grade 2–3 nonhematologic adverse events occurred in 58% of patients, with no grade 4–5 nonhematologic toxicities. The cumulative incidence of grade 2–4 and grade 3–4 acute GVHD at day 100 was 5.0% (95% CI, 1.3%–12.7%) and 1.7% (95% CI, 0.1%–7.9%), respectively. The 2‐year cumulative incidence of moderate‐to‐severe chronic GVHD was 16.7% (95% CI, 8.5%–27.3%). Conclusions: These findings support the feasibility of incorporating venetoclax into a fludarabine and melphalan conditioning regimen in older adults with AML/MDS. Notably, the low rates of GVHD and relapse associated with this venetoclax‐based conditioning regimen support further study of this platform [ClinicalTrials.gov Identifier: NCT05084027].

Antibodies targeting foreign HLA molecules can be detrimental in transplantation. Nonetheless, existing desensitisation methods for anti‐HLA antibodies frequently prove insufficient. We conducted a single‐arm pilot study to evaluate CD19/B cell maturation antigen (BCMA) chimeric antigen receptor T (CAR‐T) cell therapy for desensitising anti‐HLA antibodies prior to transplantation. Seven patients diagnosed with acute leukaemia participated in the study, comprising four individuals with acute myeloid leukaemia (AML) and three with acute B lymphoblastic leukaemia (B‐ALL). Among them, one patient was treated with BCMA CAR‐T cells, while six received CD19 CAR‐T cells. No instances of neurotoxicity or severe cytokine release syndrome (grade ≥ 3) were noted. CAR‐T cell expansion was observed in six patients (86%), with the exception of patient 3. Among the seven patients with pre‐infusion anti‐HLA‐I antibodies, five (71%) showed a decrease in mean fluorescence intensity (MFI), including three (43%) who experienced a reduction greater than 75%. Among the six patients confirmed to exhibit CAR‐T cell expansion in vivo, three presented with donor‐specific anti‐HLA antibodies (DSAs) prior to CAR‐T cell infusion. The median MFI level of DSA declined from 15797.8 (7750.3–21106.0) to 3831.1 (523.3–13197.0) ( p < 0.001) in the three patients studied. Two patients with decreased DSA levels after CD19 CAR‐T cell infusion underwent combined desensitisation before haematopoietic stem cell transplantation. This pilot study illustrates the potential safety and efficacy of CD19 and BCMA CAR‐T cells in desensitising anti‐HLA antibodies in patients with AML or B‐ALL. However, only one patient received BCMA CAR‐T cells in our cohort, so further research with an expanded sample size is essential for comprehensively evaluating the safety and efficacy of CD19/BCMA CAR‐T cell therapy for anti‐HLA antibody sensitisation.

Sequential allogeneic hematopoietic stem cell transplantation (allo‐HSCT) is a critical approach to enhance the efficacy of chimeric antigen receptor T cell (CAR‐T) therapy for relapsed/refractory acute lymphoblastic leukemia (R/R ALL). The long‐term survival rates following allo‐HSCT after CAR‐T cell therapy remain controversial. We previously reported the results of 122 patients with R/R B‐ALL who achieved minimal residual disease negative (MRD−) complete remission (CR) after anti‐CD19 CAR‐T, including 67 patients without subsequent transplantation (non‐transplant group) and 55 patients with subsequent haplo‐HSCT (transplant group). Here, we present the extended follow‐up of this cohort, with a median of 72.9 months. Compared with the non‐transplant group, transplantation recipients had a higher 5‐year LFS (50.5% vs. 25.7%; p < 0.001) and OS (53.5% vs. 25.6%; p < 0.001). Multivariable analysis identified MRD positivity at transplantation as an independent factor associated with worse LFS, OS, and a higher cumulative incidence rate of relapse (CIR). MRD‐negative patients before transplant (MRD− group) had a lower 5‐year CIR compared to MRD‐positive patients (MRD+ group) (20.8% vs. 50.0%; p = 0.014). The 5‐year LFS rates in the MRD+ and MRD− groups were 26.7% and 59.4%, respectively ( p = 0.003). The 5‐year OS of the MRD− group was higher than that of the MRD+ group (62.0% vs. 30.5%; p = 0.006). For patients who achieve CR after CAR‐T therapy, haplo‐HSCT with pre‐transplant MRD negativity was associated with better long‐term survival. However, infections emerged as a significant complication that may reduce the long‐term survival benefits. Trial Registration: ClinicalTrials.gov identifier: ChiCTR1900023957.