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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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]