Kristina Maas-Bauer

Chronic graft-versus-host disease (GvHD) is a significant risk factor for late morbidity and mortality after allogeneic stem cell transplantation. In Europe, so far there were no standard treatment options available after failure of corticosteroids and ruxolitinib. The selective ROCK-2 inhibitor belumosudil, a novel FDA-, and recently EMA-approved agent, has shown efficacy in phase-2 trials and had been made available to German and Austrian patients within a managed-access program (MAP). In a retrospective multicenter study, we analyzed 144 patients with predominately severe chronic GvHD (72%) receiving belumosudil within the MAP after a median of four prior therapeutic agents. The objective response rate at one and six months was partial remission or better in 53 and 52 patients (37% and 56%). Responses were observed across all organ systems. Median time to response was 1.3 months. At six months, steroids could be discontinued in 35% and reduced in 33% of patients. Failure-free survival was 81.9% and 75.8% at six and nine months. Six months overall survival was 96.9%. Treatment-emergent adverse reactions CTCAE grade III-IV were mostly infectious complications and occurred in 28 patients (22%). This retrospective analysis of a large real-world cohort demonstrates efficacy and safety of belumosudil in refractory chronic GvHD patients.

TP53 mutations define a clinically distinct subset of acute myeloid leukaemia (AML) associated with complex cytogenetics and therapy resistance. We performed a retrospective single-centre analysis of 61 consecutive TP53-altered AML patients undergoing first allogeneic haematopoietic cell transplantation (allo-HCT) at the Medical Center Freiburg (2007–2025), compared with 636 TP53-wild-type controls. TP53-altered patients had markedly inferior overall survival (median 379 vs. 1694 days; 5-year OS 18% vs. 50%; p < 0.001). Excess relapse was the primary driver (5-year cumulative incidence 55% vs. 33%; p < 0.001), whereas non-relapse mortality did not differ (28.5% vs. 23%; p = 0.426). On multivariable Cox analysis, TP53 alteration was the strongest independent predictor of inferior OS (HR 2.54, 95% CI 1.77–3.64; p < 0.001), and this association persisted after adjustment for cytogenetic risk and for the refined Disease Risk Index. In an exploratory hierarchical clustering analysis extended by seven patients from a second centre, two subgroups emerged: a del(17p)-enriched cluster ( n = 12; median OS 5.7 months) and a TP53 point mutation-enriched cluster ( n = 56; median OS 15.1 months). TP53-altered AML is confirmed as the strongest independent adverse prognostic factor after allo-HCT, and molecular heterogeneity within this subtype may inform trial stratification and targeted post-transplant interventions.

Acute graft-versus-host disease (aGVHD) is a major cause of death after allogeneic hematopoietic cell transplantation, and patients with steroid-refractory aGVHD have a dismal prognosis. We have previously shown that the enteroendocrine hormone glucagon-like peptide-2 has tissue regenerative activity in the lower gastrointestinal tract in mice and patients with steroid-refractory aGVHD. Here, we explored the tissue protective effect of the enteroendocrine hormone gastrin for aGVHD of the stomach. We observed that aGVHD caused a loss of gastrin-producing G-cells and parietal cells (PCs) and an increase in pH in the stomach, and allogeneic T cells had infiltrated the stomach wall. Pentagastrin treatment of aGVHD mice rescued the loss of PCs, normalized the pH in the stomach, increased stomach stem cell marker expression and abundance of LGR5+ cells. Gastrin also increased the viability of stomach and small intestine organoids in vitro. Compared with wild-type mice, Gast−/− mice experienced more severe aGVHD in the intestine and liver, which was rescued by pentagastrin treatment. In patients developing aGVHD, low gastrin levels in stomach biopsies were connected to reduced survival. Moreover, gastrin expression in the stomach correlated with aGVHD severity and tissue damage scores in independent patient cohorts. This study delineates the protective role of gastrin in aGVHD of the stomach in mice and patients and provides a rationale for the therapeutic use of pentagastrin in a clinical trial of patients with aGVHD.

Relapse of acute myeloid leukemia (AML) following allogeneic hematopoietic cell transplantation (allo-HCT) remains a life-threatening complication and is influenced by the underlying biology of the AML and possibly by genetic alterations. In this retrospective multicenter study, we evaluated mutational dynamics of AML cells in 57 patients with relapse after allo-HCT. We observed that 68% of patients exhibited genetic instability, characterized by acquisition or loss of mutations, most frequently involving FLT3-ITD, NRAS , and KRAS , while founding lesions such as DNMT3A were usually retained. Clonal evolution patterns varied, with constant profiles (35.0%), linear (29.8%), branching (22.8%), and parallel (12.3%) evolution. However, these evolutionary categories were not associated with differences in progression-free or overall survival. In contrast, relapse timing was highly prognostic: early relapse ( ≤ 6 months) conferred a significant higher mortality risk compared to late relapse, independent of evolution model. Our findings indicate that while relapse after allo-HCT in AML is genetically diverse, timing of recurrence remains the most critical determinant of outcome. Given that certain genetic changes may inform therapeutic options, these findings highlight the relevance of longitudinal molecular monitoring especially during the early post-transplant period.

Acute myeloid leukemia (AML) carrying chromosomal rearrangements involving the lysine methyltransferase 2A (KMT2A) gene frequently relapse after allogeneic hematopoietic cell transplant (allo-HCT). Pharmacological blockade of the menin-KMT2A interaction disrupts the assembly of oncogenic KMT2A complexes on chromatin, thereby attenuating aberrant self-renewal and inducing myeloid differentiation. We found that beyond this antileukemic mechanism, menin inhibition induced class II transactivator and major histocompatibility complex II (MHC-II) expression in KMT2A-rearranged and NPM1-mutated AML cells in vitro and in vivo. Increased MHC-II expression sensitized AML cells to T-cell–mediated elimination after allo-HCT in mice. Menin inhibition also increased MHC-II expression on primary human AML cells, and enhanced the graft-versus-leukemia (GVL) effect in human xenograft models. Mechanistically, menin inhibition increased expression of multiple human endogenous retroviruses (HERV), leading to consecutive interferon-stimulated gene upregulation and enhanced MHC-II expression. Additionally, menin inhibition directly promoted antitumor effector functions of donor T cells, causing increased tumor necrosis factor-alfa, interferon-gamma, perforin, and granzyme A/B production and cytolytic activity. T-cell exhaustion and menin-KMT2A binding to genes encoding for negative regulators of T-cell activation were reduced by menin inhibition. These findings indicate that menin inhibition enhances the GVL effect via the HERV/MHC-II axis in AML cells and promotes cytotoxicity of donor T cells, which provides a rationale for a clinical trial using menin inhibition as maintenance after allo-HCT.

Allogeneic hematopoietic cell transplantation (allo-HCT) following complete remission (CR) after induction chemotherapy has traditionally been the only curative approach for high-risk acute myeloid leukemia (AML). Recent advances have expanded allo-HCT eligibility to older patients. However, the requirement of achieving CR before transplant is increasingly being challenged. We retrospectively analyzed outcomes of 106 AML patients who underwent allo-HCT between 2010 and 2023 at our center, regardless of remission status. Patients received either hypomethylating agents (HMA, n = 42), HMA plus venetoclax (HMA + Ven, n = 24), or no prior therapy (upfront, n = 40). CR at the time of transplant was achieved in 19% of HMA and 38% of HMA + Ven patients. One-year non-relapse mortality (NRM) was significantly higher in the HMA group (26.2%) compared to HMA + Ven (4.2%, p = 0.0062) and upfront (5.0%, p = 0.0061) groups. However, the one-year cumulative incidence of relapse was similar across cohorts (HMA 19.1%, HMA + Ven 16.7%, upfront 15.0%). Three-year overall survival was 47.6% (HMA), 61.7% (HMA + Ven), and 71.8% (upfront). These findings support the feasibility of allo-HCT in AML patients treated with low-intensity pretransplant regimens, even without prior CR, and highlight the need for prospective trials to to avoid excluding patients with active disease from potentially curative options.

Intestinal glucocorticoid-refractory (SR) acute (a) graft-versus-host disease (GVHD) causes high non-relapse mortality (NRM) in patients after allogeneic hematopoietic cell transplantation (allo-HCT). Recent preclinical data indicate that acute GVHD causes a loss of intestinal neuroendocrine L-cells leading to reduced levels of glucagon-like peptide-2 (GLP-2). GLP-2 substitution improved GVHD severity and increased Paneth cells and intestinal stem cells in mice. This motivated us to treat patients with refractory intestinal aGHVD using the GLP-2-analogon teduglutide. In this retrospective multicenter survey, 17 patients received teduglutide as salvage-therapy for SR-intestinal aGVHD. The best response (CR or PR) at any time point during and after treatment was 64.7% (11/17) including 41.2% (7/17) CR and 23.5% (4/17) PR. At a median follow-up of 28 weeks after teduglutide 10/17 patients are alive. Most patients experienced an increase of the albumin serum level within 2 months after the first teduglutide dose, including patients who clinically did not respond to teduglutide treatment. No specific teduglutide-related toxicity was observed. Our retrospective analysis suggests that teduglutide is safe and has activity in a fraction of patients with intestinal SR-aGVHD, which needs validation in a prospective trial.

Immunological reconstitution after allogeneic hematopoietic cell transplantation (alloHCT) is critical for patient survival. We compared short- and long-term immune reconstitution and clinical endpoints in adult recipients of haploidentical or mismatched T cell replete peripheral blood stem cell transplants (PBSCT) with post-transplant cyclophosphamide as GvHD prophylaxis (PTCY, n = 68) to: (a) patients receiving matched unrelated grafts and anti-T lymphocyte globulin (ATLG) (MUD/ATLG, n = 280); (b) patients with a mismatched donor and ATLG (MM/ATLG, n = 54); and (c) recipients of matched related grafts without ATLG (MRD/NoATLG, n = 97). PTCY was associated with delayed neutrophil engraftment, low NK-cell counts on day 30 and reduced CD8+ cells on days 60–80. In terms of long-term reconstitution, PTCY recipients demonstrated significantly higher CD4+ counts from day 100–365, primarily derived from naïve T cells. Additionally, B-lymphocyte counts at one year were highest in the PTCY group. Early morbidity and mortality due to infectious complications (viral reactivation, (blood stream) infections) were most frequent in PTCY patients during the first three months. However, beyond three months, no PTCY patient suffered a fatal infection. Our study highlights the pattern of early immunodeficiency followed by robust long-term immune reconstitution in PTCY recipients, identifying critical time periods of risk that could be targeted to optimise patient survival and reduce infectious complications.