Search Results (82)

Introduction: Acute Myeloid Leukemia (AML) is a hematologic malignancy characterized by the clonal expansion of myeloid progenitors. While it primarily affects the bone marrow, extramedullary relapse occurs in 3–5% of cases, and it is linked to poor prognosis. Central nervous system (CNS) involvement presents diagnostic challenges due to nonspecific symptoms. CNS manifestations include leptomeningeal dissemination, nerve infiltration, parenchymal lesions, and myeloid sarcoma, occurring at any disease stage and frequently asymptomatic. Methods: A 62-year-old man with a recent history of AML in remission presented with diplopia and aching paresthesias in the left periorbital region spreading to the left frontal area. The diagnostic workup included neurological and hematological evaluation, lumbar puncture, brain CT, brain magnetic resonance imaging (MRI) with contrast, and dermatological evaluation with skin biopsy due to the appearance of nodular skin lesions on the abdomen and thorax. Results: Neurological evaluation showed hypoesthesia in the left mandibular region, consistent with left trigeminal nerve involvement, extending to the periorbital and frontal areas, and impaired adduction of the left eye with divergent strabismus in the primary position due to left oculomotor nerve palsy. Brain MRI showed an equivocal thickening of the left oculomotor nerve without enhancement. Cerebrospinal fluid (CSF) analysis initially showed elevated protein (47 mg/dL) with negative cytology; a repeat lumbar puncture one week later detected leukemic cells. Skin biopsy revealed cutaneous AML localization. A diagnosis of AML relapse with CNS and cutaneous localization was made. Salvage therapy with FLAG-IDA-VEN (fludarabine, cytarabine, idarubicin, venetoclax) and intrathecal methotrexate, cytarabine, and dexamethasone was started. Subsequent lumbar punctures were negative for leukemic cells. Due to high-risk status and extramedullary disease, the patient underwent allogeneic hematopoietic stem cell transplantation. Post-transplant aplasia was complicated by septic shock; the patient succumbed to an invasive fungal infection. Conclusions: This case illustrates the diagnostic complexity and poor prognosis of extramedullary AML relapse involving the CNS. Early recognition of neurological signs, including cranial nerve dysfunction, is crucial for timely diagnosis and management. Although initial investigations were negative, further analyses—including repeated CSF examinations and skin biopsy—led to the identification of leukemic involvement. Although neuroleukemiosis cannot be confirmed without nerve biopsy, the combination of clinical presentation, neuroimaging, and CSF data strongly supports the diagnosis of extramedullary relapse of AML. Multidisciplinary evaluation remains essential for detecting extramedullary relapse. Despite treatment achieving CSF clearance, the prognosis remains unfavorable, underscoring the need for vigilant clinical suspicion in hematologic patients presenting with neurological symptoms. Full article

Background/Objectives: The combination of venetoclax (VEN) and hypomethylating agents (HMA), such as azacitidine (AZA) or decitabine (DEC), has transformed the treatment landscape for acute myeloid leukemia (AML) in patients unfit for intensive chemotherapy. However, optimal management of neutropenia and the impact of post-remission treatment interruptions (washouts) remain unclear. This study aimed to evaluate the safety and efficacy of post-remission washouts and their effect on clinical outcomes. Methods: We conducted a retrospective single-center study of 44 AML patients treated with HMA/VEN between 2020 and 2021. Clinical, molecular, and treatment-related data were collected, including treatment duration, post-remission washout duration, response rates, disease-free survival (DFS), and overall survival (OS). Statistical analyses included Fisher’s exact test and univariate and multivariate Cox models. Results: Overall, 61% of patients responded to therapy, with significantly higher response rates among those potentially eligible for the VIALE-A trial (86% vs. 39%, p = 0.002). Neither treatment duration nor post-remission washout length was associated with DFS or OS. DFS was significantly longer in patients treated with AZA compared to DEC (p = 0.006). Median OS was 7.7 months, with longer OS observed in patients who did not meet VIALE-A trial eligibility criteria (p = 0.021). Achieving complete remission (CR) was associated with improved OS (14.5 months). Conclusions: Post-remission treatment interruptions (washouts) did not negatively impact DFS or OS, suggesting they may be a safe strategy to support hematologic recovery. However, the choice of HMA appears to influence response duration, with AZA outperforming DEC in maintaining disease control. Full article

Background: Chronic lymphocytic leukemia (CLL) is a prevalent hematologic malignancy that predominantly affects elderly individuals, posing significant clinical challenges due to patient comorbidities and inherent resistance to conventional chemotherapy. The emergence of targeted therapies combining venetoclax, a selective inhibitor of the anti-apoptotic protein BCL-2, with anti-CD20 monoclonal antibodies has dramatically transformed the treatment landscape. Methods: This retrospective observational study analyzed the differential impacts of first-line venetoclax-obinutuzumab (VenO) and second-line venetoclax-rituximab (VenR) on immunoglobulin G (IgG) levels and absolute neutrophil count (ANC) in CLL patients. Results: Our findings indicate that during first-line VenO therapy, a significant improvement in ANC levels from baseline was observed, whereas patients undergoing second-line VenR therapy demonstrated limited impact on ANC and the decreasing tendency in IgG levels. Patients treated with VenR had a longer disease history and previous exposure to other treatment regimens, primarily chemoimmunotherapy, which could negatively influence immune recovery, making direct comparisons between these two treatment lines challenging. Although this observational study did not directly compare infection rates, the observed enhancement of ANC levels in patients receiving VenO suggests a potential for lower infection risk compared to pretreated VenR patients. Conclusions: These results underscore the clinical significance of considering both the treatment line and the patient’s prior therapeutic history when selecting venetoclax-based regimens for CLL. The potential association of first-line VenO with improved immunological parameters and the complex impact of prior therapies on immunological recovery with second-line VenR warrant further prospective investigation into the correlation between treatment regimen, patient history, immune function, and infectious complications. Full article

The treatment of acute myeloid leukemia (AML) in Jehovah’s Witness (JW) patients poses unique challenges due to their refusal of blood transfusions. This case series reports the outcomes of four older JW patients with AML treated with azacitidine (Aza) and venetoclax (Ven), including two with hyperleukocytosis and FLT3-ITD mutations. Three patients achieved initial remission; one of these patients subsequently received gilteritinib in combination with Ven and Aza, also achieving remission. All but one therapy cycle was administered in an outpatient setting, and hematologic recovery occurred in all patients without bleeding, ischemic events, or fungal infections. Three patients experienced disease relapse at 179, 301, and 392 days post-diagnosis, while one patient remains alive 706 days post-diagnosis. This report is among the first to demonstrate that Ven and Aza can safely achieve remissions, some of which were durable, in older JW patients with AML, even those with proliferative features like hyperleukocytosis and FLT3-ITD mutations. Our central finding is that Ven and Aza represent safe and effective transfusion-sparing therapeutic options in this population, with triplet therapy incorporating gilteritinib also proving feasible with dose modifications. These findings underscore the clinical relevance of such approaches, suggesting that transfusion refusal should not preclude treatment initiation, offering meaningful clinical outcomes and potentially enhancing quality of life in this population. Full article

Background/Objectives: Bendamustine (BEN) combined with rituximab (RTX) remains a standard first-line therapy for transplant-ineligible patients with newly diagnosed mantle cell lymphoma (MCL). Meanwhile, novel targeted therapies such as Bruton tyrosine kinase inhibitors (BTKis) are increasingly used in the treatment of relapsed/refractory (R/R) MCL. We recently reported that a novel oral formulation of BEN exhibits comparable efficacy to the intravenous counterpart. In this study, we investigated the efficacy of oral BEN administered alone or in combination with the oral BCL-2 inhibitor Venetoclax (VEN) and/or the oral BTKi Acalabrutinib (ACAL), against two human MCL cell lines (Jeko-1 and Z-138) representative of the R/R disease subtype. Methods: We performed in vitro analyses using MTS viability and Annexin V/PI apoptosis assays. For the in vivo studies, all treatments were administered via oral gavage in xenograft mouse models. Therapeutic efficacy was evaluated by monitoring tumor growth and survival. Results: BEN induced significant cytotoxicity in both cell lines at low, clinically relevant concentrations. In contrast, VEN demonstrated limited efficacy as monotherapy, with Z-138 showing sensitivity only at high doses. However, combining BEN with VEN with or without ACAL, enhanced apoptosis and cytotoxicity, with more pronounced effects in Z-138. In vivo, oral BEN significantly reduced tumor growth and prolonged survival in both xenograft models. In the Z-138 model, the addition of VEN ± ACAL further improved survival outcomes. Conclusions: Our findings support the efficacy of oral BEN as both a monotherapy and as part of an all-oral treatment regimen for MCL. These results warrant further investigation into the clinical potential of oral BEN, particularly in combination with targeted agents. Full article

Acute myeloid leukemia (AML) has traditionally been linked to a poor prognosis, particularly in older patients who are ineligible for intensive chemotherapy. The advent of Venetoclax, a powerful oral BH3 mimetic targeting anti-apoptotic protein BCL2, has significantly advanced AML treatment. Its combination with the hypomethylating agent azacitidine (AZA/VEN) has become a standard treatment for this group of AML patients, demonstrating a 65% overall response rate and a median overall survival of 14.7 months, compared to 22% and 8 months with azacitidine monotherapy, respectively. However, resistance and relapses remain common, representing a significant clinical challenge. Recent studies have identified molecular alterations, such as mutations in FLT3-ITD, NRAS/KRAS, TP53, and BAX, as major drivers of resistance. Additionally, other factors, including metabolic changes, anti-apoptotic protein expression, and monocytic or erythroid/megakaryocytic differentiation status, contribute to treatment failure. Clinical trials are exploring strategies to overcome venetoclax resistance, including doublet or triplet therapies targeting IDH and FLT3 mutations; novel epigenetic approaches; menin, XPO1, and MDM2 inhibitors; along with immunotherapies like monoclonal antibodies and antibody–drug conjugates. A deeper understanding of the molecular mechanisms of resistance through single-cell analysis will be crucial for developing future therapeutic strategies. Full article

Background/Objectives: Venlafaxine (VEN) is a serotonin and norepinephrine reuptake inhibitor (SNRI) antidepressant. Arterial hypertension (HTN), heart failure (HF), and arrhythmias are side effects of VEN. Cardiotoxicity (CTOX) as a feature of VEN-associated side-effects has only rarely been described. Methods: We conducted a search of our database for cases of VEN-associated CTOX, analyzing symptoms, echocardiographic findings, and laboratory results. Results: We identified five patients (three females, two males) with VEN-associated CTOX, aged 51 to 87 years at presentation. VEN dose was 150 and 375 mg daily and treatment duration was 1.5 to 15 years. Presenting features were HTN in three, “hypertrophic cardiomyopathy” in two, heart failure in three, and atrial fibrillation in three patients. Symptoms and signs of CTOX were reversible in all patients after discontinuation or dose reduction of VEN, suggesting a causal relationship between VEN and CTOX. Conclusions: VEN-associated CTOX can occur and progress to severe cardiomyopathy or heart failure. Potential risk factors include cardiac sympathetic stimulation, high VEN dosage, and prolonged treatment duration; however, CTOX may also occur at standard doses. Therefore, patients taking VEN should be routinely monitored for signs of cardiotoxicity, including monitoring of serum concentrations of VEN. Full article

Azacitidine and venetoclax (Aza-Ven) are part of a new standard of care for elderly patients with Acute Myeloid Leukemia (AML) [In line with recommendations, patients with AML at our centre were routinely admitted during initiation of Aza-Ven for close monitoring for tumour lysis syndrome (TLS). However, hospitalization impacts patient experience and is a significant resource burden. The objectives of this study were to evaluate the incidence of TLS in this population and identify patients who could safely initiate therapy in our outpatient facility. Of the 48 patients who commenced Aza-Ven as inpatients, the incidence of TLS was 25% using Cairo–Bishop (CB) diagnostic criteria but was mostly due to transient increases in uric acid, phosphate or potassium that remained within the normal laboratory reference range. Using Howard diagnostic criteria, TLS incidence was only 2%. Patients who developed CB TLS had a significantly higher baseline white blood count (WBC; p = 0.01). Patients with WBC of less than 30 × 10⁹/L subsequently completed outpatient initiation of Aza-Ven (n = 15). Only one of these patients developed mild, transient TLS by CB criteria but not by Howard criteria. Our results demonstrate that a significant portion of patients could safely initiate Aza-Ven in our outpatient facility and avoid unnecessary hospitalization. Full article

Background: The long-term follow-up of clinical trials of novel first-line (1L) therapies for chronic lymphocytic leukemia (CLL) demonstrates 6–10-year progression-free survival. We describe the effectiveness of 1L CLL treatments in real-world settings, with an emphasis on the important real-world outcome of time to next treatment or death (TTNT-D). Methods: This retrospective, observational study utilized de-identified electronic health records from the ConcertAI RWD360™ database with linked administrative open claims. Adults with CLL who initiated an approved 1L CLL therapy (June 2019–March 2023) were included. Duration of therapy (DoT), TTNT-D, and overall survival were assessed. Results: At 1L, 39.8% of 1843 patients received first-generation covalent Bruton tyrosine kinase inhibitors (cBTKis), 23.0% second-generation cBTKis, 12.4% venetoclax-obinutuzumab (VenO), 7.4% chemotherapy/chemoimmunotherapy (CT/CIT), and 17.4% anti-CD20 monotherapy. Median (range) follow-up in months was 24.9 (13.1–36.6) for first-generation cBTKis, 13.4 (7.3–21.7) for second-generation cBTKis, 16.0 (8.4–27.8) for VenO, 21.8 (11.2–32.7) for CT/CIT, and 19.7 (10.0–33.4) for anti-CD20 monotherapy. Median (range) DoT was 11.5 (4.2–25.0) and 8.6 (3.0–16.1), 9.1 (5.9–12.2), 5.6 (3.2–5.8), and 1.6 (1.6–4.5) months for first- and second-generation cBTKis, VenO, CT/CIT, and anti-CD20 monotherapy, respectively. Regarding TTNT-D, at 2 years’ follow-up, 69.1%, 82.5%, 86.3%, 79.1%, and 53.0% of patients treated with first- and second-generation cBTKis, VenO, CT/CIT, and anti-CD20 monotherapy, respectively, had not initiated subsequent treatment or experienced death. Conclusions: TTNT-D is an important real-world outcome in CLL. Our findings demonstrated the utility of time-limited VenO, with potentially more time off treatment, relative to continuous 1L cBTKi therapies. Full article

Purpose: This study aimed to investigate the efficacy and the clinical and molecular predictors of response and survival following venetoclax plus hypomethylating agents (VEN + HMAs) in adult relapsed/refractory acute myeloid leukemia (R/R AML) patients. Methods: We retrospectively analyzed 197 adult R/R AML patients who received the VEN + HMAs regimen. Molecular profiling was performed using targeted next-generation sequencing (NGS) of 139 genes to explore potential response and survival genetic predictors. Results: The median treatment cycle was 1 (1–4) cycle. The composite complete remission (CRc) rate, encompassing complete remission (CR) and CR with incomplete hematologic recovery (CRi), was 44.7%, while the overall response rate (ORR) reached 59.9%. With a median follow-up period of 14.0 months (range: 0.7–54.0 months), the 1-year and 2-year overall survival (OS) rates were 55.4% and 40.2%, respectively. Multivariate analyses revealed that mutations in NPM1 and SRSF2 were significantly associated with improved response rates. Conversely, prior exposure to HMA therapy, early relapse, and the presence of GATA2 mutations were linked to lower response rates. Regarding survival outcomes, the CBFB-MYH11 fusion gene, as well as mutations in NPM1 and IDH1/2, were found to be favorable prognostic factors for OS, whereas mutations in FLT3-ITD, TP53, DNMT3A, and GATA2 were associated with worse OS. Conclusions: The VEN + HMAs regimen demonstrated considerable efficacy in the treatment of R/R AML patients, with both response rates and overall survival being influenced by distinct genetic features. These findings provide valuable insights into optimizing personalized treatment strategies for this challenging patient population. Full article

Background/Objectives: Venlafaxine (VEN) is commonly used in young and elderly patients. Bupropion (BUP) is occasionally added to depression treatments with VEN. BUP’s inhibitory potential toward CYP2D6, VEN’s main metabolic pathway, may provoke a higher risk for toxic or adverse drug effects. Therefore, the question arises if a dose reduction in VEN or BUP is needed to avoid clinically relevant changes in exposure to VEN and its metabolite O-desmethylvenlafaxine (ODV). Methods: The literature-based PBPK models of VEN, BUP and their active metabolites under single-dose and steady-state conditions were created by using PK-Sim^®. To evaluate the DDI model‘s predictive performance, trough plasma concentrations (<65 years, n = 54 and ≥65 years, n = 13) of VEN/ODV were extracted from the TDM database KONBEST. DDI’s clinical extent was assessed by AUC changes in VEN, ODV and active moiety (AM). The prediction was compared to the results of SCHOLZ Databank’s MDDI calculator (MDDIcalc). Results: Models accurately describe VEN’s and BUP’s pharmacokinetics and BUP’s effect on VEN’s metabolism in the age strata. The model predicts higher exposure to VEN (+110% to 132%), lower exposure to ODV (−50.0% to −61.5%) and a negligible change in AM (−1.02% to −2.40%). The AUC changes increase with higher BUP doses but is independent of patients’ age. Because of the missing AUC change in the AM, the DDI is considered clinically irrelevant. The MDDIcalc predicts no relevant effect on the AUC of AM with BUP. Conclusions: Both PBPK and MDDIcalc provide, in their own way, valuable tools to predict the DDI’s extent. Further research is needed regarding elderly patients, renal or hepatic impairment and polymorphisms, especially CYP2D6, CYP2C9, CYP2C19 and UGT. Full article

Elucidating the gene regulatory mechanisms underlying the gut–brain axis is critical for uncovering novel gut–brain interaction pathways and developing therapeutic strategies for gut bacteria-associated neurological disorders. Most studies have primarily investigated how gut bacteria modulate host epigenetics and gene expression; their impact on host alternative splicing, particularly in the brain, remains largely unexplored. Here, we investigated the effects of the gut-associated probiotic Lacidofil^® on alternative splicing across 10 regions of the rat brain using published RNA-sequencing data. The Lacidofil^® altogether altered 2941 differential splicing events, predominantly, skipped exon (SE) and mutually exclusive exon (MXE) events. Protein–protein interactions and a KEGG analysis of differentially spliced genes (DSGs) revealed consistent enrichment in the spliceosome and vesicle transport complexes, as well as in pathways related to neurodegenerative diseases, synaptic function and plasticity, and substance addiction across brain regions. Using the PsyGeNET platform, we found that DSGs from the locus coeruleus (LConly), medial preoptic area (mPOA), and ventral dentate gyrus (venDG) were enriched in depression-associated or schizophrenia-associated genes. Notably, we highlight the App gene, where Lacidofil^® precisely regulated the splicing of two exons causally involved in amyloid β protein-based neurodegenerative diseases. Although the splicing factors exhibited both splicing plasticity and expression plasticity in response to Lacidofil^®, the overlap between DSGs and differentially expressed genes (DEGs) in most brain regions was rather low. Our study provides novel mechanistic insight into how gut probiotics might influence brain function through the modulation of RNA splicing. Full article

Background: Even though venetoclax in combination with azacitidine (VenAza) is considered a low-intensity regimen, its patients present a high incidence of cytopenia and infections during the first courses, making the initial management a challenging phase. Methods: This difficulty in our center led to the establishment of an At-Home (AH) program for ramp-up and follow-up patients during the VenAza combination induction phase focused on therapy administration, patient and caregiver education, and management of adverse events (AEs). A total of 70 patients with newly diagnosed acute myeloid leukemia (ND-AML) or relapsed/refractory AML (R/R AML) were treated with VenAza from March 2019 to May 2022. We compared outcomes between patients managed with a hospital-based (inpatient) approach and those managed through the AH program. Results: Despite most patients experiencing grade 3–4 cytopenias (96.9%), the incidence of serious infections and other AEs was comparable between both groups, with no significant difference in febrile neutropenia (42.3% vs. 27.8%, p = 0.38). Overall, the AH cohort demonstrated a significantly lower hospital readmission rate after ramp-up (29.5% vs. 84.6%, p = 0.001). Moreover, the inpatient cohort’s admission days were longer than in the AH cohort (13 vs. 8, p = 0.28). Conclusions: AH management was feasible and safe, leading to better resource use, enhanced patient comfort, and improved treatment compliance. The potential of AH programs for managing low-intensity chemotherapy regimens can reduce hospital admissions and subsequently improve patient and caregiver well-being. Full article

Background/Objectives: Patients with chronic lymphocytic leukemia (CLL) are susceptible to infections that can affect their clinical outcomes. Aims: The aims of this study were to assess the following: (1) the incidence of pneumonia in CLL patients treated with venetoclax-based regimens in a real-world setting, (2) the risk factors for event-free survival (EFS), and (3) overall survival (OS). Methods: This multicenter study included 322 patients from eight centers. Univariable and multivariable analyses (MVA) were performed, with the development of pneumonia during venetoclax-based treatment and OS as outcomes. Results: The most common complication was neutropenia (59%). During treatment with venetoclax-based regimens, 66 (20%) patients developed pneumonia—50 (23%) patients in the rituximab-plus-venetoclax (R-VEN) group and 13 (16%) patients in the obinutuzumab-plus-venetoclax (O-VEN) group (p = 0.15). Chronic obstructive pulmonary disease (COPD)/asthma, splenomegaly, elevated creatinine, and anemia < 8 g/dL were the risk factors for EFS in MVA (HR = 2.08, 95%CI 1.16–3.74, p = 0.014; HR 1.73, 95%CI 1.08–2.78, p = 0.02; HR 2.13, 95%CI 1.10–4.11, p = 0.03, HR 3.58, 95%CI 2.18–5.89, p < 0.001, respectively). Relapsed/refractory (R/R) CLL patients treated with R-VEN with pneumonia had worse OS than those without (p < 0.001). In patients treated with O-VEN, median OS did not differ between patients with and without pneumonia (p = 0.45). Conclusions: Our real-world study showed that pneumonia during venetoclax treatment occurs more frequently than reported in registration trials and has a negative impact on OS, especially in patients with R/R CLL who are treated with R-VEN. Neutropenia is not a risk factor for pneumonia. Full article

Our previous studies have demonstrated that pegcrisantaspase (PegC), a long-acting Erwinia asparaginase, synergizes with the BCL-2 inhibitor Venetoclax (Ven) in vitro and in vivo; however, the anti-leukemic activity of E. coli-derived asparaginases in combination with BCL-2 inhibition, and potential synergy with inhibitors of MCL-1, a key resistance factor of BCL-2 inhibition, has yet to be determined. Using a combination of human AML cells lines, primary samples, and in vivo xenograft mouse models, we established the anti-leukemic activity of the BCL-2 inhibitor S55746 and the MCL-1 inhibitor S63845, alone and in combination with the long-acting E. coli asparaginase calaspargase pegol-mknl (CalPegA). We report that CalPegA enhances the anti-leukemic effect of S55746 but does not impact the activity of S63845. The S55746-CalPegA combination inhibited protein synthesis and increased eIF4E/4EBP1 interaction, suggesting an inhibition of translational complex formation. These results support the clinical evaluation of CalPegA in combination with BCL-2 inhibition for AML. Full article