SETD2 loss of function as a new marker of advanced disease in systemic mastocytosis: biological and clinical implications

This project stems from the results of a WES analysis of a rare case of KIT mutation-negative mast cell leukemia (MCL), that identified biallelic inactivating mutations of the SETD2 gene. SETD2 is a tumor suppressor whose loss of function is implicated in solid tumors and leukemias. We thus moved to investigate the prevalence, the underlying mechanisms, the pathogenetic role and the ‘druggability’ of SETD2 loss of function in SM, and its clinical relevance. Screening of a validation cohort of 57 patients with various forms of SM for H3K36 trimethylation levels as a surrogate marker for SETD2 loss of function by WB showed reduced or absent levels in all cases with AdvSM, and significantly lower median SETD2 and H3K36 trimethylation levels resulted in patients with advanced SM as compared to patients with indolent SM. Thus, SETD2 impaired/loss of function can be considered a general phenomenon in SM, correlating with the aggressiveness of the disease. Interestingly, we uncovered a novel post-translational mechanism of hyperubiquitination and enhanced degradation of the protein, and that inhibition of proteasome-mediated degradation is able to rescue SETD2 expression and function. We explored the MDM2 ubiquitin role and the p53 checkpoint involvement. We demonstrated that phosphorylation by Aurora kinase A is the main trigger for this mechanism. We then tested proteasome inhibitor, MDM2 and AKA inhibitors in vitro in cell lines and primary patient cells aimed to revert SETD2 non genomic loss of function. We also explored the cellular effect of midostaurin. Finally, we investigated the clinical significance of SETD2 loss of function in a cohort of 88 patients with various forms of SM assessing the prognostic value of SET2 and H3K36 trimethylation levels in the context of other relevant clinical and laboratory variables, and found that reduced SETD2 and H3K36 trimethylation levels significantly correlate with shorter overall survival

Low dose gemtuzumab ozogamicin for relapsed acute myeloid leukaemia in elderly

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Association of 3q21q26 syndrome with different RPN1/EVI1 fusion transcripts

Patients with acute myeloblastic leukemia (AML) with features of myelodysplastic syndrome and abnormalities of megakaryocytopoiesis often have cytogenetic aberrations of 3q21 and 3q26 bands involving the paracentric inversion [inv(3) (q21q26)] or a reciprocal translocation [t(3;3) (q21;q26)]. These abnormalities frequently cause inappropriate expression of the EVI1 gene located at 3q26. Other genes that have been implicated at the rearrangement breakpoint are GR6 and RPN1 (both on 3q21). The aim of this study was to investigate the expression of the EVI1 fusion genes in AML patients with 3q21q26 syndrome

Familial occurrence of systemic and cutaneous mastocytosis in an adult multicentre series

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The efficacy of imatinib mesylate in patients with FIP1L1-PDGFRα-positive hypereosinophilic syndrome. Results of a multicenter prospective study

BACKGROUND AND OBJECTIVES: The hypereosinophilic syndrome (HES) may be associated with the fusion of the platelet derived growth factor receptor a (PDGFRalpha) gene with the FIP1L1 gene in chromosome 4 coding for a constitutively activated PDGFRalpha tyrosine kinase. These cases with FIP1L1-PDGFRalpha rearrangement have been reported to be very sensitive to the tyrosine kinase inhibitor imatinib mesylate. DESIGN AND METHODS: A prospective multicenter study of idiopathic or primary HES was established in 2001 (Study Protocol Registration no. NCT 0027 6929). One hundred and ninety-six patients were screened, of whom 72 where identified as having idiopathic or primary HES and 63 were treated with imatinib 100 to 400 mg daily. RESULTS: Twenty-seven male patients carried the FIP1L1-PDGFRalpha rearrangement. All 27 achieved a complete hematologic remission (CHR) and became negative for the fusion transcripts according to reverse transcriptase polymerase chain reaction (RT-PCR) analysis. With a median follow-up of 25 months (15-60 months) all 27 patients remain in CHR and RT-PCR negative, and continue treatment at a dose of 100 to 400 mg daily. In three patients imatinib treatment was discontinued for few months, the fusion transcript became rapidly detectable, and then again undetectable upon treatment reassumption. Thirty-six patients did not carry the rearrangement; of these, five (14%) achieved a CHR, which was lost in all cases after 1 to 15 months. INTERPRETATION AND CONCLUSIONS: All patients meeting the criteria for idiopathic or primary HES should be screened for the FIP1L1-PDGFRalpha rearrangement. For all patients with this rearrangement, chronic imatinib treatment at doses as low as 100 mg daily ensures complete and durable responses

Multicenter Observational Retrospective Study on Febrile Events in Patients with Acute Myeloid Leukemia Treated with Cpx-351 in "Real-Life": The SEIFEM Experience

: In the present study, we aimed to evaluate the absolute risk of infection in the real-life setting of AML patients treated with CPX-351. The study included all patients with AML from 30 Italian hematology centers of the SEIFEM group who received CPX-351 from July 2018 to June 2021. There were 200 patients included. Overall, 336 CPX-351 courses were counted: all 200 patients received the first induction cycle, 18 patients (5%) received a second CPX-351 induction, while 86 patients (26%) proceeded with the first CPX-351 consolidation cycle, and 32 patients (10%) received a second CPX-351 consolidation. A total of 249 febrile events were recorded: 193 during the first or second induction, and 56 after the first or second consolidation. After the diagnostic work-up, 92 events (37%) were classified as febrile neutropenia of unknown origin (FUO), 118 (47%) were classifiable as microbiologically documented infections, and 39 (17%) were classifiable as clinically documented infections. The overall 30-day mortality rate was 14% (28/200). The attributable mortality-infection rate was 6% (15/249). A lack of response to the CPX-351 treatment was the only factor significantly associated with mortality in the multivariate analysis [p-value: 0.004, OR 0.05, 95% CI 0.01-0.39]. Our study confirms the good safety profile of CPX-351 in a real-life setting, with an incidence of infectious complications comparable to that of the pivotal studies; despite prolonged neutropenia, the incidence of fungal infections was low, as was infection-related mortality

New Horizons in Immunology and Immunotherapy of Acute Leukemias and Related Disorders

Accumulating data have shown that molecular aberrations have the potential to trigger the development of acute leukemia, and that the routine application of novel molecular biology technologies has facilitated the development of investigational drugs which target driver genetic mutations [...

New monoclonal antibodies and tyrosine kinase inhibitors in B-cell acute lymphoblastic leukemia

reserved9noPatients with acute lymphoblastic leukemia (ALL) are characterized by an unfavorable outcome in the majority of adult cases. Several clinical trials have confirmed the usefulness of a pediatric-type therapy applied to adult patients. Adults present with higher risk features at diagnosis that predispose them to chemotherapy resistance and disease relapse after an initial achievement of complete remission. The recent introduction of novel immune-targeted therapies, including monoclonal antibodies (MoAbs) targeting B cell-associated antigens such as CD19 (blinatumumab) and CD22 (inotuzumab), tyrosine kinase inhibitors targeting BCR-ABL1 tyrosine kinase, bispecific antibodies and chimeric antigen receptor T- cell therapy (CAR-T), circumvent B-ALL cell chemo-refractoriness through novel mechanisms of action, potentially eradicating minimal residual disease (MRD) and enabling more patients to receive allogeneic hematopoietic stem cell transplantation and to achieve a better clinical outcome.mixedLanza, Francesco; Maffini, Enrico; Saraceni, Francesco; Massari, Evita; Rondoni, Michela; Daghia, Giulia; Olivieri, Attilio; Cerchione, Claudio; Martinelli, GiovanniLanza, Francesco; Maffini, Enrico; Saraceni, Francesco; Massari, Evita; Rondoni, Michela; Daghia, Giulia; Olivieri, Attilio; Cerchione, Claudio; Martinelli, Giovann

Instillazione diretta intranasale di amfotericina B liposomiale nella terapia delle micosi nasali.

Le infezioni fungine viscerali sono una severa complicanza durante la chemioterapia nei pazienti con leucemia acuta mieloide (LAM) (1). In particolare, le Aspergillus spp. e le Candida species sono spesso responsabili di gravi infezioni in questo tipo di pazienti, durante le fasi di agranulocitosi. Il polmone ed i seni nasali sono le sedi più frequentemente interessate da questi patogeni. Entrambi questi tipi di infezione possono essere letali, essendo possibili eventi terminali drammatici l’interessamento dei vasi bronchiali principali (con conseguente emottisi massiva) e l’infiltrazione del sistema nervoso centrale attraverso la lamina cribrosa dell’osso etmoide. Anche l’interessamento epato-splenico è un evento non raro. Il recupero granulocitario ed un tempestivo trattamento specifico per via sistemica sono necessari per controllare l’infezione.Al momento, l’amfotericina-B deossicolato per e.v. è il farmaco più comunemente impiegato per il trattamento di queste forme; peraltro, la nefrotossicità e le reazioni infusionali sono effetti indesiderati molto comuni (2). La formulazione liposomiale dell’amfotericina- B (AmBisome) (GILEAD SCIENCE) si è rivelata particolarmente efficace e con un favorevole profilo di tossicità e viene pertanto comunemente utilizzata per i pazienti che risultino intolleranti alla formulazione convenzionale (3). Questi due farmaci possono essere impiegati anche in forma di aerosol, al fine di aumentare la concentrazione a livello polmonare riducendo la tossicità sistemica (4, 5). Inoltre, sono stati riportati successi con l’instillazione diretta di agenti antifungini in aspergillomi polmonari (6). In casi selezionati, per aspergillomi isolati,può essere proposta una terapia chirurgica.Infine, in caso di micosi invasiva, possono essere utilizzate anche trasfusioni di granulociti (7).Alcuni nuovi farmaci, sviluppati recentemente, hanno mostrato risultati promettenti, ma, allo stato attuale, non sono ancora comunemente adottati. Noi abbiamo utilizzato con successo AmBisome, e. v. e per la prima volta anche per diretta instillazione intranasale, in due pazienti con LAM e micosi dei seni nasali. In un caso, è stata anche associata la trasfusione di granulociti