In acute myeloid leukemia (AML) many patients experience relapse, despite the achievement of morphological complete remission; therefore, conventional morphologic criteria are currently considered inadequate for assessing the quality of the response after treatment. Quantification of measurable residual disease (MRD) has been established as a strong prognostic marker in AML and patients that test MRD negative have lower relapse rates and better survival than those who test positive. Different techniques, varying in their sensitivity and applicability to patients, are available for the measurement of MRD and their use as a guide for selecting the most optimal post-remission therapy is an area of active investigation. Although still controversial, MRD prognostic value promises to support drug development serving as a surrogate biomarker, potentially useful for accelerating the regulatory approval of new agents. In this review, we will critically examine the methods used to detect MRD and its potential role as a study endpoint.

Secondary acute myeloid leukemia (AML) comprises heterogeneous entities, unified by poor prognosis. We evaluated the associations of genetic profiles with blast counts and patients’ history in a cohort of 924 patients with myelodysplastic syndrome (MDS)/AML or AML, classified according to the International Consensus Classification (ICC). The cohort included 109 patients with “mutated TP53,” 497 with “myelodysplasia-related (MDR) gene mutation,” 93 with “MDR-cytogenetic abnormality,” 77 were therapy-related, and 136 controls, categorized as “not otherwise specified” (NOS) AML. Exploring the ICC hierarchy, AML and MDS/AML categories with “mutated TP53” and “MDR-cytogenetic abnormality” presented similar biology and prognosis, irrespective of blast counts. Conversely, in MDS/AML with “MDR gene mutation” and NOS, profiles significantly differed from AML and were characterized by a higher number of mutations in STAG2, SRSF2, ASXL1 and TET2. This corresponded to improved survival in MDS/AML vs AML (MDR-gene mutation: median overall survival 24.8 vs 13.6 months, P< .0001; and NOS: 49.9 vs 19.2 months, P = .028). Within each ICC-defined AML category, a prior MDS history vs de novo onset did not impact on patients’ prognosis. We then analyzed secondary AML, defined by “prior MDS or MDS/MPN” or “therapy-related” (t-AML), as diagnostic qualifiers. According to European LeukemiaNet (ELN) 2022, AML progressing from MDS or MDS/myeloproliferative neoplasm (MPN) (AML post-MDS) mostly clustered in the adverse-risk group (84.1%), whereas t-AML showed more heterogeneous ELN profiles (12.9% favorable, 33.8% intermediate, and 53.3% adverse risk) reflecting diverse overall survival. Our findings underscore that genetic features and the ICC classification reliably capture disease biology, refine risk stratification, and ultimately guide treatment decisions in most secondary AML and MDS/AML.

CPX-351, a novel liposomal formulation of cytarabine and daunorubicin, represents the standard of care in fit patients with acute myeloid leukemia with myelodysplasia–related changes (AML-MRC) and therapy-related AML (t-AML). Considering its better safety profile than conventional intensive chemotherapy, we investigated its cost-to-benefit ratio, in terms of overall survival and of mortality, in a large multicentric series of AML-MRC and t-AML receiving CPX-351 outside clinical trials between 2019 and 2022. Patients were classified as fit or unfit for intensive chemotherapy through a comprehensive evaluation of age, comorbidities, and performance status by adopting Italian Society of Hematology/Italian Society of Experimental Hematology/Gruppo Italiano per il Trapianto di Midollo Osseo (SIE/SIES/GITMO) criteria. Disease risk was defined according to the European LeukemiaNet 2017 classification. Before treatment start, 328 of 403 (81.4%) patients were classified as fit and 75 of 403 (18.6%) as unfit. Three hundred and ninety-six had a full genetic/cytogenetic profile, with 17 (4%) being categorized as favorable risk, 162 (41%) intermediate risk, and 217 (55%) adverse risk according to European LeukemiaNet 2017. After induction, 230 of 403 (57.1%) patients achieved complete remission, with no differences between fit (57.3%) and unfit (56%) patients. However, the 2 groups significantly differed in terms of survival (median overall survival, 18 months vs 8 months for fit and unfit patients, respectively) and of 28- and 100-day mortality (4.6% vs 10.7% at 28 days and 14.3% vs 32% at 100 days for fit and unfit patients, respectively). In conclusion, the SIE/SIES/GITMO criteria distinguished patient subgroups with different short- and long-term outcomes after treatment with CPX-351. The update or design of dedicated fitness criteria could represent a future and valid strategy to optimize the use of this specific treatment.

Background: Acute myeloid leukemia (AML) necessitates timely treatment, yet the impact of prolonged time to treatment (TTT) on clinical outcomes remains debated, especially its impact on achieving measurable residual disease (MRD) negativity, a powerful prognostic indicator in AML. Methods: This retrospective study analyzed 196 adult AML patients treated with intensive chemotherapy, evaluating the effect of TTT on outcome measures and quality of response. TTT was categorized arbitrarily into 14 days. Results: Results showed a median TTT of 11 days. Median overall survival (OS) was 414 days, with no significant differences among TTT groups (p = 0.48). Complete remission rate was 75.5%, with significantly higher rates in patients treated within 14 days (p = 0.004 and p = 0.006 for 8–14 and 14 days. MRD was assessed in 140 patients, with 35% achieving negativity, and no significant differences observed among TTT groups. Conclusions: This study suggests that a treatment delay of up to 14 days does not negatively impact OS or MRD negativity. This timeframe potentially allows for thorough patient evaluation, including detailed genetic profiling and comorbidity assessment, facilitating a more personalized and optimized therapeutic strategy.

Myelodysplastic syndromes/neoplasms (MDS) are a heterogeneous group of blood disorders characterized by distinctive biological and clinical features. Diagnosis typically relies on bone marrow examination and cytogenetic/molecular analysis. However, a small subset of patients lacks detectable cytogenetic or genetic abnormalities, making diagnosis challenging and reliant solely on marrow dysplasia and cytopenia. Here, we conducted a multicenter retrospective study investigating the clinical and hematological features of patients with MDS lacking detectable cytogenetic or molecular alterations. From a cohort of 329 MDS patients who underwent genetic testing at our laboratory of "Diagnostica Avanzata Oncoematologica", we selected 62 patients presenting with unexplained cytopenia, suspected MDS, and a non-informative cytogenomic profile. Of these, 26 were ultimately diagnosed with alternative conditions such as aplastic anemia, drug/radiation toxicity, multiple myeloma, and others. The patients with non-informative genetic profile had a median age of 60 years and a female predominance (67 %). Autoimmune diseases (AD) were the most frequently observed comorbidities (26 %), and neutropenia was the most common type of cytopenia (56 %), followed by thrombocytopenia (22 %), and anemia (19 %). Most patients had bi-lineage or tri-lineage dysplasia, and had low-risk disease according to IPSS-R and IPSS-M. Only one patient progressed to AML at a median follow-up of 12 months (IQR for the test cohort: 2-25). MDS lacking classical myeloid clonal alteration represent a unique clinical-biological subtype whereby marrow assessment along with a thorough clinical workup is crucial.

Background: Perianal infections (PIs) are a serious threat in patients with acute myeloid leukemia (AML). While CPX-351 is designed to reduce gastrointestinal toxicity, its impact on the incidence of PIs is unknown. This study aims to evaluate the incidence and characteristics of PIs in a cohort of CPX-351-treated AML patients. Methods: We enrolled 22 adult patients diagnosed with secondary AML receiving CPX-351 between May 2020 and July 2025 at Policlinico Tor Vergata Hospital. Statistical analysis used descriptive statistics and multivariate analysis. Results: The incidence of PIs in the cohort was 31.8%. Microbiological cultures from the lesions commonly yielded Klebsiella pneumoniae and Enterococcus species. The development of a PI was associated with a significantly longer hospital stay (mean, 49.6 vs. 37.7 days; p = 0.034). An increased odds ratio of having PIs was noted for mucositis and positive rectal swabs (17.961, p = 0.062; 5.554, p = 0.391, respectively), with two patients (28.5%) having a positive pre-infection swab for Klebsiella pneumoniae. Surgical intervention was guided by patient pain levels and hematological criteria. Surgical patients had significantly higher pain levels (p = 0.001) and a platelet count greater than 20 × 10⁹/L (p = 0.028). All patients were alive at 30 days, with low rates of septic shock (14.2%, n = 1) and no infection-related mortality or recurrence. Conclusions: Despite CPX-351’s known reduced gastrointestinal toxicity, our study showed a significantly higher incidence of PIs compared to literature data. While the outcomes were favorable, PIs led to prolonged hospitalization. Routine rectal swab surveillance could be a valuable tool for risk stratification and preemptive strategies.