is a key tumor suppressor gene with protean functions associated with preservation of genomic balance, including regulation of cellular senescence, apoptotic pathways, metabolism functions, and DNA ...repair. The vast majority of
acute myeloid leukemia (AML) present unaltered
alleles. However,
mutations are frequently detected in AML related to an increased genomic instability, such as therapy-related (t-AML) or AML with myelodysplasia-related changes. Of note,
mutations are associated with complex cytogenetic abnormalities, advanced age, chemoresistance, and poor outcomes. Recent breakthroughs in AML research and the development of targeted drugs directed at specific mutations have led to an explosion of novel treatments with different mechanisms. However, optimal treatment strategy for patients harboring
mutations remains a critical area of unmet need. In this review, we focus on the incidence and clinical significance of
mutations in
and t-AML. The influence of these alterations on response and clinical outcomes as well as the current and future therapeutic perspectives for this hardly treatable setting are discussed.
The clinical outcome, response to treatment, and occurrence of acute complications were retrospectively investigated in 308 primary autoimmune hemolytic anemia (AIHA) cases and correlated with ...serological characteristics and severity of anemia at onset. Patients had been followed up for a median of 33 months (range 12-372); 60% were warm AIHA, 27% cold hemagglutinin disease, 8% mixed, and 5% atypical (mostly direct antiglobulin test negative). The latter 2 categories more frequently showed a severe onset (hemoglobin Hb levels ≤6 g/dL) along with reticulocytopenia. The majority of warm AIHA patients received first-line steroid therapy only, whereas patients with mixed and atypical forms were more frequently treated with 2 or more therapy lines, including splenectomy, immunosuppressants, and rituximab. The cumulative incidence of relapse was increased in more severe cases (hazard ratio 3.08; 95% confidence interval, 1.44-6.57 for Hb ≤6 g/dL; P < .001). Thrombotic events were associated with Hb levels ≤6 g/dL at onset, intravascular hemolysis, and previous splenectomy. Predictors of a fatal outcome were severe infections, particularly in splenectomized cases, acute renal failure, Evans syndrome, and multitreatment (4 or more lines). The identification of severe and potentially fatal AIHA in a largely heterogeneous disease requires particular experienced attention by clinicians.
•Mixed, atypical, and warm immunoglobulin G plus C AIHA (∼30% of cases) more frequently have a severe onset (Hb ≤6 g/dL) and require multiple therapy lines.•Infections, particularly after splenectomy, acute renal failure, Evans syndrome, and multitreatment, were predictors of fatal outcome.
Highlights • 34% of adult B-lineage ALL without aberrations have high CRLF2 expression levels. • In adult B-ALL, CRLF2 expression has prognostic significance. • Also in adult B-ALL, CRLF2 is ...associated with JAK/STAT and IKZF1 lesions.
Early recognition of Ph-like acute lymphoblastic leukemia cases could impact on the management and outcome of this subset of B-lineage ALL. To assess the prognostic value of the Ph-like status in a ...pediatric-inspired, minimal residual disease (MRD)-driven trial, we screened 88 B-lineage ALL cases negative for the major fusion genes (BCR-ABL1, ETV6-RUNX1, TCF3-PBX1 and KTM2Ar) enrolled in the GIMEMA LAL1913 front-line protocol for adult BCR/ABL1-negative ALL. The screening - performed using the BCR/ABL1-like predictor - identified 28 Ph-like cases (31.8%), characterized by CRLF2 overexpression (35.7%), JAK/STAT pathway mutations (33.3%), IKZF1 (63.6%), BTG1 (50%) and EBF1 (27.3%) deletions, and rearrangements targeting tyrosine kinases or CRLF2 (40%). The correlation with outcome highlighted that: i) the complete remission (CR) rate was significantly lower in Ph-like compared to non-Ph-like cases (74.1% vs 91.5%, p=0.044); ii) at time point 2 (TP2), decisional for transplant allocation, 52.9% of Ph-like cases vs 20% of non-Ph-like were MRD-positive (p=0.025); iii) the Ph-like profile was the only parameter associated with a higher risk of being MRD-positive at TP2 (p=0.014); iv) at 24 months, Ph-like patients had a significantly inferior event-free and disease-free survival compared to non-Ph-like patients (33.5% vs 66.2%, p=0.005 and 45.5% vs 72.3%, p=0.062, respectively). This study documents that Ph-like patients have a lower CR rate, EFS and DFS, as well as a greater MRD persistence also in a pediatric-oriented and MRD-driven adult ALL protocol, thus reinforcing that the early recognition of Ph-like ALL patients at diagnosis is crucial to refine risk-stratification and to optimize therapeutic strategies.
Myelodysplastic syndromes/neoplasms (MDSs) encompass a range of hematopoietic malignancies, commonly affecting elderly individuals. Molecular alterations in the hematopoietic stem cell compartment ...drive disease pathogenesis. Recent advancements in genomic profiling have provided valuable insights into the biological underpinnings of MDSs and have expanded therapeutic options, particularly for specific molecularly defined subgroups. This review highlights the diagnostic principles, classification updates, prognostic stratification systems, and novel treatments, which could inform future clinical trials and enhance the management of adult MDS patients, particularly for specific molecularly defined subgroups.
Chimeric antigen receptors (CAR)-T-cell therapy represents the most important innovation in onco-hematology in recent years. The progress achieved in the management of complications and the latest ...generations of CAR-T-cells have made it possible to anticipate in second-line the indication of this type of treatment in large B-cell lymphoma. While some types of B-cell lymphomas and B-cell acute lymphoid leukemia have shown extremely promising results, the same cannot be said for myeloid leukemias-in particular, acute myeloid leukemia (AML), which would require innovative therapies more than any other blood disease. The heterogeneities of AML cells and the immunological complexity of the interactions between the bone marrow microenvironment and leukemia cells have been found to be major obstacles to the clinical development of CAR-T in AML. In this review, we report on the main results obtained in AML clinical trials, the preclinical studies testing potential CAR-T constructs, and future perspectives.
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