AML typical mutations (CEBPA, FLT3, NPM1) identify a high-risk chronic myelomonocytic leukemia independent of CPSS molecular [Retrospective study].

Highlights

●       Mutations commonly associated with acute myeloid leukemia (AML), such as CEBPA, FLT3, IDH1/ 2, and NPM1, are rarely found in chronic myelomonocytic leukemia (CMML), and their prognostic significance in CMML has not been clearly identified.

●       Patients with CMML harboring CEBPA, FLT3, and/or NPM1 mutations (mutCFN) more frequently had the myeloproliferative subtype, a high prevalence of severe cytopenia, and elevated blast counts.

●       The genetic profile of these mutCFN patients with CMML closely resembled that of patients with AML, with higher-risk clinical characteristics.

Next-generation sequencing and polymerase chain reaction data were analyzed from bone marrow samples collected at CMML diagnosis in 127 patients.

Hypomethylating agents for patients with VEXAS without myelodysplastic syndrome: Clinical outcome and longitudinal follow-up of vacuolization and UBA1 clonal dynamics [Case series].

Highlights:

●       Hypomethylating agents (HMA) have shown promise in VEXAS syndrome (a haemato-inflammatory disease caused by somatic UBA1 mutations and characterized by cytoplasmic vacuoles in myeloid and erythroid precursor cells) patients with concomitant myelodysplastic syndrome (MDS), while the efficacy of HMA in VEXAS patients without MDS is mainly unknown.

●       This study showed the effectiveness of the HPAs in VEXAS patients without concomitant MDS. It contributes to increasing the knowledge on treating this syndrome, indicating an important role in the longitudinal follow-up of the variant allele frequency (VAF) of UBA1.

The authors evaluated the efficacy of HMA in four VEXAS patients without MDS and performed longitudinal analyses of the VAF of UBA1 and vacuolization during treatment. They speculate that unlike anti-inflammatory therapies, HMA may well act as a disease-modifying treatment. If these findings are confirmed in further studies, it could lead to the early use of HMA in the treatment of all VEXAS patients-with or without MDS.

Surrogate endpoints in mature B-cell neoplasms – meaningful or misleading? [Perspective].

This perspective article discusses the validation of surrogate endpoints and available data for mature B-cell neoplasms, followed by an outlook on the potential of precise tools such as measurable residual disease (MRD) assessment as novel surrogate candidates.

Key points:

●       Overall survival (OS) differences are increasingly difficult to capture within the practical timeframe of clinical trials, especially in mature B-cell neoplasms.

●       When trying to validate endpoints, even with large datasets, the correlation of surrogate candidates such as progression-free survival (PFS), time to next treatment (TTNT), response rates, or MRD with OS is difficult to evaluate due to few events and the efficacy of relapse treatments, especially in the setting of novel agents.

●       Novel approaches to assess MRD with a higher resolution such as NGS-based/CAPP-sequencing approaches (cancer personalized profiling by deep sequencing), which showed higher prognostic value, might eventually lead to the granularity needed to validate MRD as a true surrogate endpoint for OS.

●       Even if analyses ultimately show only a moderate or weak correlation, PFS or MRD and their impact on a patient’s quality of life should not be underestimated, especially when a long-lasting remission is achieved through a well-tolerated time-limited treatment.

The Heterogeneous Syndrome of Noninfectious Causes of Persistent Fever in Neutropenic Patients With Hematologic Malignancy: Another Opportunity for Stewardship? [Commentary].  

Key points:

●       Serological tests for human immunodeficiency virus, hepatitis B virus, hepatitis C virus, hepatitis A virus, hepatitis E virus, cytomegalovirus (CMV), Epstein-Barr virus, herpes simplex virus, varicella-zoster virus, and Toxoplasma gondii should be performed before proceeding with cytotoxic chemotherapy or hematopoietic stem cell transplantation (HSCT). HSCT candidates who have traveled to areas endemic for helminthiases (e.g., strongyloidiasis) should be screened by serological tests. Patient history for exposure should be obtained for tuberculosis, and screening tests should be performed for latent tuberculosis in patients at risk. Colonization for methicillin-resistant Staphylococcus aureus, vancomycin-resistant enterococci, and multidrug-resistant (MDR) gram-negative bacteria should be screened for in high-risk settings.

●       [18F] Fluorodeoxyglucose positron emission tomography (FDG-PET) was associated with more frequent antimicrobial cessation or de-escalation than conventional computed tomography in hematological malignancy patients with persistent neutropenic fever after chemotherapy or transplant conditioning. Additionally, new research areas include its potential role in the cessation of antifungal therapy in invasive fungal infections and the use of PET in uncovering occult infections. In patients with no evidence of a bacterial or fungal infection either suspected clinically and/or microbiologically documented, several occult infections (e.g., MDR culture-negative bacterial and fungal) and mycobacterial infections in those coming from endemic regions, as well as opportunistic viruses (e.g., CMV, adenoviruses) and other rare infectious causes (e.g., Toxoplasma), should be considered in the differential diagnosis.

●       Persistent fever of unknown etiology in patients with hematological malignancy is a complex, nonstatic, and heterogeneous entity where infectious and noninfectious etiologies can be encountered, coexist, or develop sequentially. See Table 1 in the original article.

●       Continuing unnecessary antibiotics beyond a time-limited trial, especially when a noninfectious cause of fever is apparent, could result in toxicity, expense, and selection of resistance and is a lost opportunity for diagnostic and therapeutic stewardship intervention.

How I Treat Higher-Risk MDS [Review].

Key points:

●       Identifying driver mutations is a critical first step when diagnosing and managing myelodysplastic syndromes (MDS), as it not only aids in classification but also provides valuable clinical and prognostic information. For instance, in the World Health Organization (WHO)-2022 classification, subtypes like MDS with fibrosis and MDS with biallelic TP53 mutations, and in the International Classification Consensus (ICC), MDS/acute myeloid leukemia with MDS-related genes and MDS with mutated TP53, are linked to higher-risk disease.

●       Higher-risk (HR)-MDS encompasses diseases with International Prognostic Scoring Systems-Revised (IPSS-R) scores >3.5, as well as the clinical-molecular prognostic (IPSS-Molecular [IPSS-M]) risk categories of moderate-high, high, and very-high. Patients with HR-MDS have a high likelihood of leukemic transformation, resistance to standard therapies, and a median overall survival of approximately 18 months. Notably, 74% of patients were upstaged by the IPSS-M, with 21% of those previously classified as intermediate by IPSS-R reclassified as very high-risk by IPSS-M, highlighting the significant impact of incorporating mutational data into clinical decision-making. Consequently, the diagnostic workup for suspected MDS should include a next-generation sequencing panel of ~50 genes.

●       Patients classified as low-risk by conventional prognostic tools but presenting with features such as increased blasts (≥5%), bone marrow fibrosis, transfusion dependence, severe cytopenias, or resistance to multiple lines of therapy may still be considered higher risk. These patients could benefit from more intensive treatment strategies typically reserved for high-risk diseases.

●       In HR-MDS, the therapeutic approach is geared toward delaying leukemic transformation and prolonging survival. For over a decade, the hypomethylating agents (HMA) azacitidine and decitabine have been the standard of care, and when feasible, allogeneic hematopoietic stem cell transplantation (AHSCT) should be considered. However, treatment-related mortality is a major concern and can be as high as 40%, especially in older patients, who constitute the majority of MDS patients.

●       Multi-hit TP53-mutated MDS patients have a very poor prognosis. Our approach follows treatment principles in line with the general management of HR-MDS:(1) AHSCT remains the only potentially curative option for these patients;(2) HMA therapy before AHSCT is encouraged with the aim of clearing the mutant TP53 clone;(3) post-transplant maintenance therapy with an HMA might be beneficial; and (4) eligible patients should be referred to a clinical trial.