Search Results (125)

Azacytidine is the only approved treatment for patients with higher-risk myelodysplastic syndromes (MDS); yet less than half of the patients will achieve a response, whereas the duration of response is highly heterogeneous and there are no predictors for response duration. The aim of this study is to estimate the patient’s time to loss of response (LoR) to azacytidine based on clinical measurements during treatment. To this end, a personalized prediction framework is proposed that estimates the LoR of a new patient using a patient similarity-based approach. Namely, the new patient’s clinical data—represented as a multivariate time series—are compared to a reference set of patients. The comparison uses distance metrics that quantify how similar two patients’ time series are, assuming patients with similar trajectories tend to have similar LoR. Then, the LoR of the new patient is predicted by averaging the outcomes of the most similar reference patients. The pipeline includes a data normalization strategy that centers each feature on its baseline value and scales it to highlight relative changes and distance metrics to quantify similarity. Both real-world and simulated data were utilized to evaluate the proposed methodology, employing the leave-one-out validation and the Mean Absolute Percentage Error (MAPE) to assess accuracy. The estimated MAPE was found to be 30.52% and 11.82% in the real-world and simulated dataset, respectively. The best and most robust predictions were achieved using the Euclidean distance metric and setting the number of most similar patients around three to five. This study proposes a personalized predictive approach for the LoR to azacitidine in the MDS clinical setting, demonstrating potential for a serviceable prediction of LoR and forming the foundation for further research. Full article

Background and Clinical Significance: The occurrence of acute myeloid leukemia (AML) in pregnancy represents a diagnostic and management challenge in the attempt to balance and achieve both maternal and fetal wellbeing. Pregnancy-specific manifestations mimic the initial symptoms of leukemia and may lead to a delay in diagnosis, especially during the first trimester of pregnancy. Decision-making strategies involve the patient and couples counseling with a multidisciplinary team of hematologists, obstetricians, neonatologists and psychologists. Maternal outcome depends on the disease subtype, progression and response to medication. Fetal outcome depends on other potential pregnancy complications, possible teratogenicity, gestational age at delivery and sometimes iatrogenic prematurity. Case Presentation: We present the case of a 38-year-old multiparous patient with a late first trimester, with an AML diagnosis presenting with hyperemesis gravidarum-like symptoms. Genetic testing revealed the presence of an Fms-like tyrosine kinase 3-internal tandem duplication mutation (FLT3-ITD). Following that, a repeatedly refused termination of pregnancy and rapid disease progression with azacitidine therapy was initiated. Elective cesarean delivery was performed at 34 weeks of gestation due to progressive leukocytosis, which persisted postpartum, requiring the use of first-, second-, and eventually third-line chemotherapy. Fetal outcome was favorable at 3 months postpartum. Conclusions: Cases of AML in pregnancy require a tailored approach according to guidelines, but also patient/couple preferences, while the choice of chemotherapy is limited considering its potential teratogenic effects. This is a case with a misleading first presentation and a challenging therapeutic choice due to its genetic subtype and maternal treatment postponement. Full article

Background/Objectives: Relapsed acute myeloid leukemia (AML) is often characterized by clonal evolution and acquired genomic abnormalities, which can inform prognosis and direct therapeutic decisions. The emergence of high-risk chromosomal rearrangements during relapse is of particular significance, yet the impact of rare and complex events remains poorly understood. This report details a case of relapsed AML that demonstrated rare MYC and MECOM rearrangements and additional features that were not observed at initial diagnosis, emphasizing the clinical relevance of serial cytogenetic assessments. Case Description: A 70-year-old man was initially diagnosed with AML, exhibiting monocytic differentiation, an 11q23 deletion involving KMT2A loss, and a U2AF1 mutation. After achieving remission with azacitidine and venetoclax, the patient relapsed within ten months, necessitating reevaluation and modification of therapy. Repeat cytogenetic analysis at relapse revealed a distinct t(3;8)(q26.2;q24.3) exhibiting MYC and MECOM rearrangements, features that were absent at initial diagnosis. Conclusions: This case underscores the importance of serial cytogenetic and molecular profiling in relapsed AML. The emergence of new abnormalities upon relapse suggested underlying genomic instability and clonal evolution. MYC rearrangements are notably rare in AML, especially with concurrent MECOM rearrangements, highlighting a unique feature of this case. The identification of novel abnormalities at relapse may carry prognostic and therapeutic significance and may be used to refine risk stratification. Thus, ongoing cytogenetic monitoring is essential to adapt management approaches in evolving disease contexts. Full article

Background and Clinical Significance: Acute megakaryoblastic leukemia (AMKL) is a rare and aggressive hematologic malignancy. The presence of genetic abnormalities often increases the complexity of AMKL. Among these, patients with monosomy 7 constitute a high-risk group associated with a poorer prognosis and greater chemoresistance. We report the case of a 10-year-old boy who had AMKL along with monosomy 7 and familial GATA2 deficiency. The case highlights the diagnostic and therapeutic challenges faced, as well as the critical importance of early genetic screening and timely hematopoietic stem cell transplantation (HSCT). Case Presentation: A 10-year-old boy presented with easy bruising and pancytopenia. AMKL was diagnosed with the help of a bone marrow biopsy and immunophenotyping. Genetic testing showed a GATA2 mutation and monosomy 7. Two induction cycles with daunorubicin and cytarabine were administered but failed to eliminate residual disease. The patient also developed pneumonia of a fungal origin. HSCT was delayed due to liver toxicity and elevated minimal residual disease (MRD). Azacitidine and venetoclax stabilized the disease, thereby allowing for successful haploidentical HSCT. The patient achieved complete remission with full donor chimerism. Conclusions: This case emphasizes the importance of early molecular diagnostics in pediatric AMKL. Identifying GATA2 mutations and monosomy 7 early can help guide risk stratification and the timing of HSCT. Multimodal therapy, which includes the use of infection control and targeted agents, is important for improving the outcomes in high-risk patients. Full article

Background/Objectives: After first-line treatment, elderly patients with acute myeloid leukemia (AML) often become unfit to continue intensive chemotherapy despite having achieved a response. This trial aimed to determine the efficacy of maintenance treatment with azacitidine in AML patients who are ineligible to continue intensive treatment after remission. Methods: A single-arm, multicenter, phase II clinical trial (EudraCT: 2010-020432-18) including patients with AML with complete (CR) or partial remission (PR) after one or two cycles of intensive induction chemotherapy and ineligible to continue intensive treatment was conducted. Efficacy was measured as the response rate, progression-free survival (PFS), and overall survival (OS), and was assessed in the intention-to-treat (ITT) population (all patients). Quality of life was also assessed. Results: Thirty-two patients were included, with a mean age of 73.3 years (SD 3.8) (53.1% male); sixteen patients (50.0%) reached the sixth treatment cycle. The best response was CR in 11 patients (68.8%) and PR in 2 patients (12.5%) at cycle six, and CR in 15 patients (46.9%) and PR in 5 patients (15.6%) overall. The median PFS was 6.7 months (95% CI 3.1–8.7), and OS was 11.5 months (95% CI 6.6–15.9). The daily function (p = 0.0296), cognitive function (p = 0.0412), and social function (p = 0.0275) scales of the EORTC QLQ-C30 questionnaire significantly improved. Thirty-one patients (96.9%) experienced adverse events; six (1.9%) were serious. Conclusions: Azacitidine is a safe and well-tolerated maintenance treatment option for AML patients unfit for intensive therapy following a response to induction, although the single-arm phase II design precludes direct causal inference. Patients achieved promising results regarding PFS and remission rates, with improved quality of life. Full article

VEXAS syndrome (Vacuoles, E1-enzyme, X-linked, Autoinflammation, and Somatic) is a recently identified late-onset autoinflammatory disorder characterized by a unique interplay between hematological and inflammatory manifestations. It results from somatic mutations in the UBA1 gene, located on the short arm of the X chromosome. Initially, females were considered mere carriers, with the syndrome primarily affecting males over 50. However, recent evidence indicates that heterozygous females can exhibit symptoms as severe as those seen in hemizygous males. The disease manifests as systemic inflammation, macrocytic anemia, thrombocytopenia, chondritis, neutrophilic dermatoses, and steroid-dependent inflammatory symptoms. Due to its overlap with autoimmune and hematologic disorders such as relapsing polychondritis, Still’s disease, and myelodysplastic syndromes, misdiagnosis is common. At the molecular level, VEXAS syndrome is driven by impaired ubiquitination pathways, resulting in dysregulated immune responses and clonal hematopoiesis. A key diagnostic marker is the presence of cytoplasmic vacuoles in myeloid and erythroid precursors, though definitive diagnosis requires genetic testing for UBA1 mutations. Traditional immunosuppressants and TNF inhibitors are generally ineffective, while JAK inhibitors and IL-6 blockade provide partial symptom control. Azacitidine and decitabine have shown promise in reducing disease burden, but hematopoietic stem cell transplantation (HSCT) remains the only curative treatment, albeit with significant risks. This review provides a comprehensive analysis of VEXAS syndrome, examining its clinical features, differential diagnoses, diagnostic challenges, and treatment approaches, including both pharmacological and non-pharmacological strategies. By enhancing clinical awareness and optimizing therapeutic interventions, this article aims to bridge emerging genetic insights with practical patient management, ultimately improving outcomes for those affected by this complex and often life-threatening disease. Full article

Background: Myelodysplastic syndromes are clonal hematopoietic disorders characterized by ineffective hematopoiesis and risk of progression to acute myeloid leukemia. Accurate prognostic stratification is essential to guide treatment, with several scoring systems in clinical use: IPSS, IPSS-R, and WPSS. Objective: We aimed to evaluate the prognostic accuracy of IPSS, IPSS-R, and WPSS in a real-world Romanian MDS cohort by comparing risk classifications with observed overall survival and progression-free survival. Methods: We conducted a retrospective analysis of 117 patients diagnosed with MDS treated in our clinic between 2018 and 2022. All patients had confirmed diagnoses based on bone marrow biopsy and cytogenetic testing. Data were used to assign risk categories based on IPSS, IPSS-R, and WPSS. Survival outcomes were analyzed using Kaplan–Meier curves and log-rank tests. Results: The median age of the cohort was 70 years; gender distribution was balanced. Transfusion dependence was present in 73.5%, and 49.6% had cytogenetic abnormalities. Overall, low-risk classification was assigned in 58.1% (IPSS), 38.5% (IPSS-R), and 38.5% (WPSS) of patients. Median OS was 20 months, and median PFS was 35 months. Although no statistically significant overall survival differences were observed across scoring systems, IPSS-R demonstrated a trend toward stronger prognostic discrimination in multivariable analysis. Reclassification of patients initially categorized as IPSS intermediate-1 revealed a significant survival impact: patients reclassified as lower-risk by IPSS-R and WPSS had a median OS of 67.5 months versus 15 months for those reclassified as higher-risk (IPSS-R: HR = 0.24; p = 0.0017; WPSS: HR = 0.26; p = 0.0031). Similarly, leukemic transformation occurred in 13.6% of reclassified lower-risk patients vs. 52.2% in higher-risk patients (IPSS-R: HR = 0.13; p = 0.0021; WPSS: HR = 0.12; p = 0.002), with a median PFS of 21 months in the higher-risk group. In multivariable Cox regression analysis, IPSS-R stratification remained a strong independent predictor for both OS (HR = 3.22; p = 0.000003) and PFS (HR = 4.77; p < 0.00001), while azacitidine treatment was associated with significantly improved survival (OS: HR = 0.43; p = 0.00002) and reduced risk of progression (PFS: HR = 0.36; p = 0.013). Full article

Background: Relapsed/refractory acute myeloid leukemia (R/R AML) remains a therapeutic challenge due to disease heterogeneity, resistance mechanisms, and poor tolerability to intensive regimens. Venetoclax (VEN), a BCL-2 inhibitor, has shown promise in combination with hypomethylating agents (HMAs), but data on response timing in the R/R setting are limited. The aim of this study was to assess the efficacy, safety, and kinetics of response to HMA-VEN therapy in a real-world cohort of R/R AML patients, with particular focus on early versus late responders. Methods: This prospective single-center study included 33 adult patients with R/R AML treated with VEN plus either azacitidine (AZA) or decitabine (DEC) from 2018 to 2021. The primary endpoint was the composite complete remission (cCR) rate and the rate of early and late response, respectively, occurring within two cycles of therapy or later; secondary endpoints included overall survival (OS), relapse-free survival (RFS), time to relapse (TTR), and safety. Results: The cCR was 58%, with complete remission (CR) or CR with incomplete recovery (CRi) achieved in 52% of patients. Median OS was 9 months. No significant differences in OS or TTR were observed between early (≤2 cycles) and late (>2 cycles) responders. Eight responders (42%) underwent allogeneic hematopoietic stem cell transplantation (HSCT), with comparable transplant rates in both groups of responders. Toxicity was manageable. Grade 3–4 neutropenia occurred in all patients, and febrile neutropenia occurred in 44% of patients. An Eastern Cooperative Oncology Group (ECOG) score >2 was associated with inferior response and shorter treatment duration. Conclusions: HMA-VEN therapy is effective and safe in R/R AML, including for patients with delayed responses. The absence of a prognostic disadvantage for late responders supports flexible treatment schedules and suggests that the continuation of therapy may be beneficial even without early blast clearance. Tailored approaches based on performance status and comorbidities are warranted, and future studies should incorporate minimal residual disease (MRD)-based monitoring to refine response assessment. Full article

Continuous development of molecular and immunophenotypic techniques enables more precise diagnoses and more accurate assessment of prognosis in myelodysplastic syndromes (MDS). However, the relationship between genetic alterations and immunophenotype remains very poorly understood. The analysis included 30 patients diagnosed at a tertiary center who were eligible for azacitidine treatment. Next-generation sequencing (NGS) was performed at the start of the study to assess the mutation status of 40 genes associated with MDS pathogenesis. In addition, multiparametric flow cytometry (MFC) was performed to assess the ELN score (Ogata score) and, additionally, to detect an abnormal CD11b/HLA-DR and CD11b/CD13 expression pattern. In the studied patient population, higher ELN score results were found in patients with mutations in epigenetic modifiers and pathogenic mutations of the tumor suppressor genes. Signal pathway mutations were associated with lower platelet counts at diagnosis. The results of this study indicate a correlation between molecular abnormalities and deviations in cell immunophenotype. Investigating this correlation may, in the future, allow the development of new scales that allow a more sensitive and specific diagnosis of MDS and a more precise prediction of its course. 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 met 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

Myelodysplastic syndromes (MDSs) comprise a diverse group of clonal hematopoietic stem cell disorders characterized by ineffective hematopoiesis, cytopenia in the peripheral blood, and an increased risk of transformation into acute myeloid leukemia (AML). Despite extensive research, the mechanisms underlying MDS pathogenesis remain unclear. In the present study, we explored the role of autophagy and apoptosis in the development of MDS and assessed the impact of azacitidine on these processes in vitro. First, we assessed the expression of proteins involved in both autophagic and apoptotic pathways in MDS patients with different prognoses. Furthermore, using the MDS-L cell line as a model, we investigated the in vitro effects of azacitidine treatment on these processes. We report that MDS, irrespective of risk classification, is associated with the dysregulation of autophagy and apoptosis. Notably, azacitidine treatment restored these cellular processes, accompanied by modulation of key signaling phosphoproteins. Overall, these findings provide evidence that impaired autophagy and apoptosis contribute to MDS pathogenesis and that azacitidine helps restore cellular homeostasis by activating both processes. Furthermore, our study highlights the potential therapeutic benefits of targeting these mechanisms and suggests that combining azacitidine with agents that modulate autophagy and apoptosis could enhance the treatment efficacy for MDS patients. 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 and Clinical Significance: Intermediate- to high-risk Myelodysplastic Syndrome (MDS), according to the Revised International Prognostic Scoring System (IPSS-M), confers a high risk of progression into acute myeloid leukemia. Treatment with hypomethylating agents, including azacitidine and decitabine, represents the current standard of care. In eligible patients, hypomethylating agents are used as a bridge for allogeneic stem cell transplantation, currently the only curative approach in these malignancies. The most common side effects of hypomethylating agents are myelosuppression, cutaneous injection site reactions (when azacitidine is given subcutaneously), and gastrointestinal symptoms. Uncommon, disabling, and long-lasting side effects represent a threat to effective treatment in this group of patients. Case Presentation: We describe the case of a 49-year-old male patient with IPSS-M intermediate-risk MDS, intended to receive first-line treatment with azacitidine followed by allogeneic stem cell transplantation. The first, late-onset azacitidine reaction was observed 48 h after the first exposure, with cutaneous and respiratory toxicity, followed by the late-onset recurrence of symptoms after azacitidine withdrawal and decitabine introduction. Conclusions: This case highlights atypical, disabling, and long-lasting drug reactions to two hypomethylating agents, with the persistence of hypersensitivity manifestations months after medication withdrawal. 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: Magrolimab (Magro) is a humanized naked anti-CD47 monoclonal antibody that blocks the SIRPα CD47 interaction, allowing macrophages to target and destroy cancer cells. To evaluate its preclinical efficacy in vivo, Magro was tested as a single agent and in combination with conventional chemotherapy drugs, Cytarabine (Ara-C) or Azacitidine (Aza), in three pediatric AML (pAML) patient-derived xenograft (PDX) models—AML006 (KMT2A::MLLT1), AML010 (+10, WT1), and AML013 (KMT2A::MLLT4). Methods: After PDX model establishment, mice were assigned to treatment groups hulgG4 (VC, vehicle control for Magro), Magro, Ara-C + VC, Aza + VC, Ara-C + Magro, and Aza + Magro, and then followed for survival. Mice that met humane euthanasia endpoints and at the culmination of experimental timelines had tissues harvested to measure disease burden. Results: Magro alone significantly improved survival in AML006 (p < 0.0001) and AML013 (p = 0.003) and decreased bone marrow (BM) disease burden in AML006 (p = 0.009) and AML013 (p = 0.002). Ara-C + Magro therapy led to significantly improved survival in all three models and significantly decreased BM disease burden in AML006 (p < 0.0001) and AML013 (p = 0.048). Aza + Magro therapy led to significantly improved survival in AML013 (p = 0.047) and AML010 (p = 0.017) and significantly lower BM disease burden in AML010 (p = 0.001). Conclusions: Interestingly, the two models that demonstrated improvement in survival with Magro harbored KMT2A rearrangements, suggesting a subset of patients that may be more responsive to the effects of CD47 blockade. As this drug is being evaluated for use in other malignancies, future studies may focus on investigating the importance of biomarker-based patient selection. Full article