Azacitidine in combination with shortened venetoclax treatment cycles in patients with acute myeloid leukemia.

The combination of venetoclax with hypomethylating agents is currently the standard of care for elderly patients with acute myeloid leukemia (AML) ineligible for intensive chemotherapy. Despite its favorable efficacy, clinical use is often associated with post-remission cytopenia, frequently necessitating treatment delays and dose modifications. This study aims to evaluate the efficacy and safety of shortened venetoclax treatment durations. A multicenter analysis was conducted involving 20 adult AML patients receiving venetoclax (7 or 14 days with 9 and 11 patients, respectively) combined with 5-azacitidine (5-7 days) between 2021 and 2024. The cohort included patients from four German academic centers all treated in first line. Outcome measures included bone marrow response, transfusion dependence, overall survival (OS) and progression-free survival (PFS). Median age was 73.5 years, with 70% of patients having secondary AML. Adverse molecular risk was observed in 75% of patients. The overall response rate (ORR) was 100%, with a composite complete remission rate of 78%. No significant differences in response rates were observed between the 7-day and 14-day venetoclax regimens. Median OS for the cohort was 15 months. Infection-related complications were observed in 55% of patients, with severe sepsis in 20% of cases. In this cohort, shortened venetoclax regimens demonstrated efficacy comparable to standard treatment protocols, with a potential reduction in hematologic toxicity. These findings support the individualization of treatment regimens to optimize clinical outcomes while potentially minimizing adverse effects.

Isolation of Hafnia paralvei co-harbouring blaNDM-1 and blaVIM-1 in a woman who underwent allogeneic hematopoietic stem cell transplantation.

Metallo-ß-lactamases (MBL) are a threat to public health, since they dramatically limit the use of ß-lactams. We report the isolation of a multidrug-resistant Hafnia paralvei strain from urine and a rectal swab of a female patient after allogeneic hematopoietic stem cell transplantation for myelodysplastic syndrome. Antimicrobial susceptibility testing yielded resistance to trimethoprim/sulfamethoxazole, colistin, fosfomycin and all ß-lactams, except cefiderocol. Whole genome sequencing revealed the presence of plasmid-encoded NDM-1 and VIM-1 carbapenemases. This finding highlights the importance of epidemiological surveillance and new therapeutic options for MBL.

Outcomes after allogeneic haematopoietic stem cell transplantation in young adults in Germany.

Young adults (YA) represent a minority among recipients of allogeneic haematopoietic stem cell transplantation (HSCT). In order to describe the outcome of YA following HSCT in Germany, 9299 patients who were registered with the German Registry for Stem Cell Transplantation were included in this retrospective analysis of the years 1998-2019. The impact of the variables, such as patient age and sex, sex differences, stem cell source, donor type, conditioning, year of HSCT, the diagnosis, and the achieved remission status were tested in univariable and multivariable analysis for overall, event-free and relapse-free survival as well as for the cumulative incidences of non-relapse and therapy-related mortality. Altogether, the outcome of YA after HSCT improved over time and was determined by the underlying disease, the age at disease onset, stem cell source, and donor type. Patients were most likely to die from relapse, and survival of HSCT recipients after 10 years was reduced by more than half in comparison to the general population of YA. Deeper understanding of modifiable risk factors may be gained by studies comparing the outcome of YA post-HSCT with that of children, adolescents and elderly patients. A deliberate and strong patient selection may further improve mortality rates.

Psychosocial distress in young adults surviving hematological malignancies: a pilot study.

PURPOSE: Survivors of cancer during young adulthood face multiple psychosocial challenges following treatment. This study explores psychosocial distress and unmet needs among young adult survivors treated of hematological malignancies. METHODS: A total of 85 young adults aged between 18 and 39 years at time of diagnosis, were invited to join the survey after the completion of treatment with curative intent. Sociodemographic data and the need for advice were gathered with a self-report questionnaire. A set of standardized questionnaires for quality of life (EORTC QLQ-C30), psychosocial stressors (PHQ-S), fear of progression (PA-F-KF), cancer-related fatigue (EORTC QLQ-FA12), and symptoms of anxiety (GAD-7) or depression (PHQ-9) was employed. Descriptive statistics and multivariate analysis were conducted. RESULTS: Forty-seven young adult cancer survivors responded. A quarter of patients (26%) reported depressive symptoms, 15% suffered from anxiety, 36% from fear of progression, and 21% reported increased psychosocial stressors. They had a lower QoL than the general population and reported poorer outcomes on all single-item and multi-symptom scales. Employment was significantly associated with lower levels of psychosocial distress, anxiety, fatigue, and better QoL. CONCLUSION: Young adult cancer survivors exhibited a high disposition for psychosocial distress. They reported excessive demands in everyday life and resumption of work. However, a longitudinal study of young adult cancer survivors is needed to confirm the results of this pilot study. In future, psycho-oncological and social support need to become an inherent part of the aftercare of survivors of young adult cancer survivors.

Sex-Disaggregated Analysis of Biology, Treatment Tolerability, and Outcome of Multiple Myeloma in a German Cohort.

INTRODUCTION: Multiple myeloma (MM) is a plasma cell disease that affects more men than women. Although there is an obvious imbalance in incidence, knowledge of differences in biology and outcome between the sexes is surprisingly rare. METHODS: We performed a unicentric retrospective analysis of patients with MM treated at a tertiary cancer centre between 2003 and 2018. RESULTS: We present a sex-disaggregated analysis of the characteristics and outcome of MM in a cohort of 655 patients (median age at diagnosis 62 years; 363 men with a median age at diagnosis 62 years and 292 women with a median age at diagnosis 63 years, p = 0.086). Most patients (n = 561, 86%) received myeloma-specific treatment. Median overall survival was 76 months (95% CI 63-89) (72 months in men [95% CI 54-90] and 83 months in women [95% CI 66-100], p = ns). Apart from a higher incidence of moderate and severe anaemia in women (p < 0.001), there were no statistically significant differences in the biology of the underlying MM. Similarly, in the group of patients who received high-dose therapy with autologous stem-cell transplantation (ASCT, n = 313), no statistically significant differences apart from more frequent anaemia in women were detected regarding the biology of the disease. However, there was a trend toward a higher plasma cell infiltration of the bone marrow and toward more frequent high-risk features in women. In contrast, relevant comorbidities were significantly more common in men (for example, coronary heart disease in 13% of men vs. 2% of women, p < 0.001). Toxicities after ASCT were not significantly different between the sexes with the exception of severe mucositis, which occurred in 22% of men versus 40% of women (p = 0.001). CONCLUSION: In conclusion, this first sex-disaggregated analysis of MM patients in Germany supports previous findings that survival is comparable amongst sexes, but women experience more toxicity of high-dose therapy. The higher incidence of clinically relevant anaemia in women warrants further investigation to exclude underlying treatable causes.

Treosulfan plus fludarabine versus TEAM as conditioning treatment before autologous stem cell transplantation for B-cell Non-Hodgkin lymphoma.

Conditioning with treosulfan and fludarabine (Treo/Flu) has been proven to be feasible and efficient in several types of malignancies before allogeneic hematopoietic stem cell transplantation (allo-HSCT). Given its favorable reduced toxicity profile, we introduced Treo/Flu as conditioning before autologous HSCT (auto-HSCT) in patients with B-cell Non-Hodgkin lymphoma (NHL). The aim of this study was to evaluate the efficacy and safety of Treo/Flu in comparison to TEAM. Fifty-seven patients with NHL received auto-HSCT after conditioning with either Treo/Flu (n = 22) or TEAM (n = 35). All patients achieved sustained engraftment. PFS, EFS and OS were not significant in both groups. Of note is that patients in the Treo/Flu group were less dependent on thrombocyte transfusions (p = 0.0082), significantly older (in median 11 years, p < 0.0001) and suffered less frequently from infectious complications (p = 0.0105), mucositis and stomatitis (p < 0.0001). This study is the first to present efficacy, feasibility, and safety of conditioning with Treo/Flu preceding auto-HSCT in patients with NHL. Since it demonstrated a lack of significant difference in comparison to TEAM conditioning it might be a valuable alternative especially in elderly patients with B-cell NHL and comorbidities. Further evaluation by prospective clinical trials is warranted.

Clinical experience with venetoclax in patients with newly diagnosed, relapsed, or refractory acute myeloid leukemia.

BACKGROUND: Diagnosis of acute myeloid leukemia (AML) is associated with poor outcome in elderly and unfit patients. Recently, approval of the BCL-2 inhibitor venetoclax (VEN) in combination with hypo-methylating agents (HMA) led to a significant improvement of response rates and survival. Further, application in the relapsed or refractory (r/r) AML setting or in context of allogeneic stem cell transplantation (alloHSCT) seems feasible. METHODS AND PATIENTS: Fifty-six consecutive adult AML patients on VEN from January 2019 to June 2021 were analyzed retrospectively. Patients received VEN either as first-line treatment, as subsequent therapy (r/r AML excluding prior alloHSCT), or at relapse after alloHSCT. VEN was administered orally in 28-day cycles either combined with HMA or low-dose cytarabine (LDAC). RESULTS: After a median follow-up of 11.5 (range 6.1-22.3) months, median overall survival (OS) from start of VEN treatment was 13.3 (2.2-20.5) months, 5.0 (0.8-24.3) months and 4.0 (1.5-22.1) months for first-line, subsequent line treatment and at relapse post-alloHSCT, respectively. Median OS was 11.5 (10-22.3) months from start of VEN when subsequent alloHSCT was carried out. Relapse-free survival (RFS) for the total cohort was 10.2 (2.2 - 24.3) months. Overall response rate (composite complete remission + partial remission) was 51.8% for the total cohort (61.1% for VEN first-line treatment, 52.2% for subsequent line and 42.8% at relapse post-alloHSCT). Subgroup analysis revealed a significantly reduced median OS in FLT3-ITD mutated AML with 3.4 (1.9-4.9) months versus 10.4 (0.8-24.3) months for non-mutated cases, (HR 4.45, 95% CI 0.89-22.13, p = 0.0002). Patients harboring NPM1 or IDH1/2 mutations lacking co-occurrence of FLT3-ITD showed a survival advantage over patients without those mutations (11.2 (5-24.3) months versus 5.0 (0.8-22.1) months, respectively, (HR 0.53, 95% CI 0.23 - 1.21, p = 0.131). Multivariate analysis revealed mutated NPM1 as a significant prognostic variable for achieving complete remission (CR) (HR 19.14, 95% CI 2.30 - 436.2, p < 0.05). The most common adverse events were hematological, with grade 3 and 4 neutropenia and thrombocytopenia reported in 44.6% and 14.5% of patients, respectively. CONCLUSION: Detailed analyses on efficacy for common clinical scenarios, such as first-line treatment, subsequent therapy (r/r AML), and application prior to and post-alloHSCT, are presented. The findings suggest VEN treatment combinations efficacious not only in first-line setting but also in r/r AML. Furthermore, VEN might play a role in a subgroup of patients with failure to conventional chemotherapy as a salvage regimen aiming for potential curative alloHSCT.

Combination of treosulfan, fludarabine and cytarabine as conditioning in patients with acute myeloid leukemia, myelodysplastic syndrome and myeloproliferative neoplasms.

PURPOSE: Treosulfan and fludarabine (Treo/Flu) were successfully introduced into toxicity-reduced conditioning for SCT. However, the risk of post-SCT relapse remains a matter of concern. We report the results of a novel individual treatment approach with Treo/Flu and cytarabine (Treo/Flu/AraC) conditioning prior to allogeneic SCT in patients with acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), or myeloproliferative neoplasms (MPN). METHODS: Seventy-seven patients (median age 54 years) at high risk of disease relapse due to unfavorable cytogenetics or failure to achieve complete remission prior to SCT were included. Median follow-up was 3.2 years. RESULTS: The 1-, 2- and 3-year RFS rates were 49.4%, 41.7%, and 37.6% and OS rates were 59.3%, 49.3%, and 45.4%, respectively. Cumulative incidence of NRM was 10% at 100 days, 18.8% at 1 year and 20.1% at 2 years. The cumulative incidence of relapse increased from 31% at 1 year to 38.5% after 3 years. The cumulative incidences of engraftment, chimerism, graft-versus-host disease (GvHD) and toxicities were acceptable and comparable with similar patients conditioned with Treo/Flu or FLAMSA-RIC. CONCLUSION: In conclusion, Treo/Flu/AraC provides tolerable, feasible, and effective conditioning for patients with AML, MDS or MPN, even in advanced disease states. The incidence of NRM and relapse is acceptable in this heavily pre-treated population with high-risk disease. Future research will aim to confirm these initial findings and include a larger number of participants in a prospective trial.

Outcome of patients with relapsed or refractory acute myeloid leukemia treated with Mito-FLAG salvage chemotherapy.

PURPOSE: Curative intended treatment is challenging in patients with relapsed or refractory acute myeloid leukemia (r/r AML) and associated with a dismal prognosis for long-term survival. Despite novel treatment options, the majority of patients are treated with chemotherapy-based regimens. Although widely used, little data exist on the combination of fludarabine, cytarabine, granulocyte colony stimulating factor (FLAG) and mitoxantrone as salvage strategy for r/r AML. MATERIALS AND METHODS: Sixty-six patients receiving Mito-FLAG for r/r AML treated at a German tertiary care center between 2009 and 2019 were analyzed with regard to response rates, survival and safety profile. RESULTS: Overall response rate was 75.8% with 56.1% of patients achieving complete remission (CR) and 19.7% partial remission (PR). After a median follow-up of 54 months, median overall survival (OS) was 13 months. Patients transitioned to allogeneic hematopoietic stem cell transplantation (alloHSCT) (75.8%) showed a significant improvement in OS with a median OS of 17 (95% CI 8.5-25.4) months vs 3 (95% CI 1.7-4.3) months (p < 0.001). 30- and 60-day mortality rates for all patients after the initial cycle of Mito-FLAG were 4.5% and 7.6%, respectively. CONCLUSION: The Mito-FLAG salvage protocol represents an effective and feasible treatment regimen for r/r AML. Importantly, a high rate of transition to successful alloHSCT with the aim of long-term disease-free survival has been shown.

Impact of induction chemotherapy with intermediate-dosed cytarabine and subsequent allogeneic stem cell transplantation on the outcome of high-risk acute myeloid leukemia.

BACKGROUND: Acute myeloid leukemia (AML) with antecedent hematological disease (s-AML) and treatment-related AML (t-AML) predicts poor prognosis. Intensive treatment protocols of those high-risk patients should consider allogeneic stem cell transplantation (allo-HSCT) in first complete remission (CR). Despite allo-HSCT, relapse rate remains high. Induction chemotherapy with liposomal cytarabine and daunorubicin (CPX-351) has been approved for patients with AML with myeloid-related changes (AML-MRC) or t-AML based on improved survival and remission rates compared to standard 7 + 3 induction. PATIENTS AND METHODS: 110 patients with newly diagnosed s-AML or t-AML at a university hospital were analyzed retrospectively. Median age was 62 years (24-77 years). A total of 65 patients with s-AML after MDS (59%) and 23 patients (20.9%) with t-AML were included. Induction chemotherapy consisted of intermediate-dosed cytarabine (ID-AraC) in combination with idarubicin (patients up to 60 years) or mitoxantrone (patients over 60 years). In patients subsequently undergoing allo-HSCT, reduced conditioning regimens (RIC) were applied prior to transplantation in 47 of 62 patients (76%). RESULTS: Induction chemotherapy with ID-AraC resulted in an overall response rate of 83% including complete remission (CR/CRi) in 69 patients (63%) with a low rate of early death (2.7%). Most relevant non-hematologic toxicity consisted of infectious complications including sepsis with need of intensive care treatment in five patients (4.5%) and proven or probable invasive fungal disease in eight patients (7.2%). Relapse-free survival (RFS), event-free survival (EFS) and overall survival (OS) of the whole cohort were 19 months (0-167), 10 months (0-234) and 15 months (0-234), respectively (p < 0.0001). A significant improvement of OS was observed in patients who underwent allo-HSCT compared to those without subsequent allo-HSCT: 9 vs. 46 months, p < 0.0001. Rate of transplantation-related mortality (TRM) in the early phase post allo-HSCT was low (0.9% at day 30 and 1.8% at day 90, respectively). RIC conditioning results in OS rate of 60% after 60 months post allo-HSCT (median OS not reached). CONCLUSION: S-AML and t-AML patients receiving induction chemotherapy with intermediate-dosed cytarabine showed satisfactory response rate and consolidation therapy with allo-HSCT after full or reduced-intensity conditioning further improved survival in these patients with similar outcome as reported for CPX-351.

Improved gene delivery to K-562 leukemia cells by lipoic acid modified block copolymer micelles.

Although there has been substantial progress in the research field of gene delivery, there are some challenges remaining, e.g. there are still cell types such as primary cells and suspension cells (immune cells) known to be difficult to transfect. Cationic polymers have gained increasing attention due to their ability to bind, condense and mask genetic material, being amenable to scale up and highly variable in their composition. In addition, they can be combined with further monomers exhibiting desired biological and chemical properties, such as antioxidative, pH- and redox-responsive or biocompatible features. By introduction of hydrophobic monomers, in particular as block copolymers, cationic micelles can be formed possessing an improved chance of transfection in otherwise challenging cells. In this study, the antioxidant biomolecule lipoic acid, which can also be used as crosslinker, was incorporated into the hydrophobic block of a diblock copolymer, poly{[2-(dimethylamino)ethyl methacrylate]101-b-[n-(butyl methacrylate)124-co-(lipoic acid methacrylate)22]} (P(DMAEMA101-b-[nBMA124-co-LAMA22])), synthesized by RAFT polymerization and assembled into micelles (LAMA-mic). These micelles were investigated regarding their pDNA binding, cytotoxicity mechanisms and transfection efficiency in K-562 and HEK293T cells, the former representing a difficult to transfect, suspension leukemia cell line. The LAMA-mic exhibited low cytotoxicity at applied concentrations but demonstrated superior transfection efficiency in HEK293T and especially K-562 cells. In-depth studies on the transfection mechanism revealed that transfection efficiency in K-562 cells does not depend on the specific oncogenic fusion gene BCR-ABL alone. It is independent of the cellular uptake of polymer-pDNA complexes but correlates with the endosomal escape of the LAMA-mic. A comparison of the transfection efficiency of the LAMA-mic with structurally comparable micelles without lipoic acid showed that lipoic acid is not solely responsible for the superior transfection efficiency of the LAMA-mic. More likely, a synergistic effect of the antioxidative lipoic acid and the micellar architecture was identified. Therefore, the incorporation of lipoic acid into the core of hydrophobic-cationic micelles represents a promising tailor-made transfer strategy, which can potentially be beneficial for other difficult to transfect cell types.

Extra-medullary recurrence of myeloid leukemia as myeloid sarcoma after allogeneic stem cell transplantation: impact of conditioning intensity.

Myeloid sarcoma (MS) as a solid extra-medullary (EM) manifestation of acute myeloid leukemia (AML), myeloproliferative or myelodysplastic syndromes is a rare presentation of relapse after allogeneic hematopoietic stem cell transplantation (HSCT). The databases of the Departments of Hematology and Oncology of the University Hospitals of Jena and Rostock were screened for patients aged 18 years or older for onset of MS after HSCT for myeloid malignancies between 2002 and 2019. Nineteen patients with MS were identified, the majority of whom had received reduced-intensity conditioning (RIC). The median onset of MS was 425 days after HSCT and the median overall survival since MS was 234 days. Although MS is associated with a poor prognosis, three patients survived more than two years and one more than 11 years after MS onset. These results indicate that RIC protocols may be associated with a higher risk of EM relapse. Since EM relapse occurred in the presence of Graft-versus-host-disease, these observations also demonstrate the limitations of graft-versus-tumor effects after HSCT. In conclusion, occurrence of MS after HSCT is associated with a poor prognosis, as multimodal curative concepts including intensive chemotherapy and another HSCT are often not viable.

SIRT7: an influence factor in healthy aging and the development of age-dependent myeloid stem-cell disorders.

Molecular alterations within the hematopoietic system influence cellular longevity and development of age-related myeloid stem-cell disorders like acute myeloid leukemia (AML) and chronic myeloid leukemia (CML). A reduced SIRT7-expression in aged murine hematopoietic stem cells (HSC) resulted in reduced longevity and increased proliferation. In this study we investigated age-related changes of SIRT7-expression in healthy humans and relevant pathomechanisms in AML and CML. SIRT7-expression in leukocytes of healthy people decreased in an age-dependent manner. Low SIRT7 mRNA levels were also detected in AML and CML patients. With positive treatment response, SIRT7-expression increased, but showed reduction when patients progressed or relapsed. Pharmacologic inhibition of driver mutations in AML (FLT3-ITD) or CML (BCR-ABL) also restored SIRT7 levels in cell lines and patient samples. Furthermore, SIRT7-expression increased with time during PMA-mediated monocyte differentiation of THP-1 cells. SIRT7-overexpression in THP-1 cells resulted in increased expression of differentiation markers. BCR-ABL, FLT3-ITD, and differentiation-associated SIRT7-expression in general were positively regulated by C/EBPα, -ß, and -ε binding to two different C/EBP-binding sites within the SIRT7 promoter. SIRT7 is important in human hematopoietic cell aging and longevity. It might act as tumor suppressor and could potentially serve as general biomarker for monitoring treatment response in myeloid stem-cell disorders.

Phosphorylation-Dependent Differences in CXCR4-LASP1-AKT1 Interaction between Breast Cancer and Chronic Myeloid Leukemia.

The serine/threonine protein kinase AKT1 is a downstream target of the chemokine receptor 4 (CXCR4), and both proteins play a central role in the modulation of diverse cellular processes, including proliferation and cell survival. While in chronic myeloid leukemia (CML) the CXCR4 is downregulated, thereby promoting the mobilization of progenitor cells into blood, the receptor is highly expressed in breast cancer cells, favoring the migratory capacity of these cells. Recently, the LIM and SH3 domain protein 1 (LASP1) has been described as a novel CXCR4 binding partner and as a promoter of the PI3K/AKT pathway. In this study, we uncovered a direct binding of LASP1, phosphorylated at S146, to both CXCR4 and AKT1, as shown by immunoprecipitation assays, pull-down experiments, and immunohistochemistry data. In contrast, phosphorylation of LASP1 at Y171 abrogated these interactions, suggesting that both LASP1 phospho-forms interact. Finally, findings demonstrating different phosphorylation patterns of LASP1 in breast cancer and chronic myeloid leukemia may have implications for CXCR4 function and tyrosine kinase inhibitor treatment.

Knockout of LASP1 in CXCR4 expressing CML cells promotes cell persistence, proliferation and TKI resistance.

Chronic myeloid leukaemia (CML) is a clonal myeloproliferative stem cell disorder characterized by the constitutively active BCR-ABL tyrosine kinase. The LIM and SH3 domain protein 1 (LASP1) has recently been identified as a novel BCR-ABL substrate and is associated with proliferation, migration, tumorigenesis and chemoresistance in several cancers. Furthermore, LASP1 was shown to bind to the chemokine receptor 4 (CXCR4), thought to be involved in mechanisms of relapse. In order to identify potential LASP1-mediated pathways and related factors that may help to further eradicate minimal residual disease (MRD), the effect of LASP1 on processes involved in progression and maintenance of CML was investigated. The present data indicate that not only overexpression of CXCR4, but also knockout of LASP1 contributes to proliferation, reduced apoptosis and migration as well as increased adhesive potential of K562 CML cells. Furthermore, LASP1 depletion in K562 CML cells leads to decreased cytokine release and reduced NK cell-mediated cytotoxicity towards CML cells. Taken together, these results indicate that in CML, reduced levels of LASP1 alone and in combination with high CXCR4 expression may contribute to TKI resistance.

A Mosquito Bite with Devastating Complications in an Immunocompromised Patient.

Infectious complications such as invasive aspergillosis or infection with Stenotrophomonas maltophilia (SM) in immunocompromised patients are associated with a high mortality rate. Our report concerns a 40-year-old male newly diagnosed very severe aplastic anemia (vSAA) who in consequence of a mosquito bite was suffering from skin lesion and consecutive soft tissue phlegmon subsequent to the administration of antithymocyte globulin; a full-thickness autologous meshed skin graft successfully performed to cover skin ulcera after allogeneic stem cell transplantation (SCT). This unusual case illustrates the importance of appropriate diagnosis, anti-infective therapy and close interdisciplinary diagnostic algorithms to minimalize side effects and the selection of resistant strains and to improve patients' outcome.

In Vivo Emergence of UL56 C325Y Cytomegalovirus Resistance to Letermovir in a Patient with Acute Myeloid Leukemia after Hematopoietic Cell Transplantation.

CMV associated tissue-invasive disease is associated with a considerable risk of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (HSCT). Recently, the terminase inhibitor letermovir (LMV) has been approved for prophylaxis of CMV infection in HSCT. We hereby report a 60-year-old female experiencing CMV reactivation after HSCT in a CMV seronegative donor-constellation. Due to ongoing elevated CMV viral load and drug-associated myelosuppression, which prevented ganciclovir therapy, treatment was replaced by foscarnet. Due to nephrotoxicity, foscarnet was switched to LMV. The patient developed skin GvHD and prednisolone was started. Subsequently, CMV viremia worsened despite LMV therapy. Genotyping revealed the mutation C325Y of the CMV UL56 terminase being associated with high-level resistance against LMV. Prolonged uncontrolled low-level viremia due to prednisolone treatment may have favored the selection of drug-resistant CMV. Despite the excellent toxicity profile of LMV, physicians should be aware of risk factors for the emergence of resistance.