We compared the efficacy of azacitidine (AZA) and decitabine (DEC) in elderly patients with untreated AML, diagnosed according to WHO criteria. In the two groups, we evaluated complete remission (CR), overall survival (OS) and disease free survival (DFS). The AZA and DEC groups included 139 and 186 patients, respectively. To minimize the effects of treatment selection bias, adjustments were made using the propensity-score matching method, which yielded 136 patient pairs. In the AZA and DEC cohort, median age was 75 years in both, (IQR, 71-78 and 71-77), median WBCc at treatment onset 2.5 x 109/L (IQR, 1.6-5.8) and 2.9 x 109/L (IQR, 1.5-8.1), median bone marrow (BM) blast count 30% (IQR, 24-41%) and 49% (IQR, 30-67%), 59 (43%) and 63 (46%) patients had a secondary AML, respectively. Karyotype was evaluable in 115 and 120 patients: 80 (59%) and 87 (64%) had intermediate-risk, 35 (26%) and 33 (24%) an adverse risk karyotype, respectively. Median number of cycles delivered was 6 (IQR, 3.0-11.0) and 4 (IQR, 2.0-9.0), CR rate was 24% vs 29%, median OS and 2-year OS rates 11.3 (95% CI 9.5-13.8) vs 12.0 (95% CI 7.1-16.5) months and 20% vs 24%, respectively. No differences in CR and OS were found within the following subgroup: intermediate-and adverse-risk cytogenetic, frequency of WBCc at treatment >= 5 x 10<^>9 L and < 5 x 10<^>9/L, de novo and secondary AML, BM blast count < and >= 30%. Median DFS for AZA and DEC treated patients was 9.2 vs 12 months, respectively. Our analysis indicates similar outcomes with AZA compared to DEC.

Material and methodsAccording to WHO classification, diagnosis of systemic mastocytosis (SM) can be made if the major criterion (multifocal dense infiltrates of mast cells (MCs) in bone marrow (BM) and/or other extracutaneous organ) and at least one minor criterion (>25% of atypical MCs on BM smears or spindle-shaped MC in visceral organs infiltrates; cKIT D816V mutation; CD2 and/or CD25 positivity on MCs; baseline serum tryptase level >20 ng/mL) are present, or 3 minor criteria are detected 1 .EPICOVIDEHA is an online platform developed to gather epidemiological data of patients with hematological malignancies and SARS-CoV-2 infection from 132 hematological wards across 32 countries all over the world 2 .Since the first report of 6 patients with mastocytosis among almost four thousand patients included 3 , 20 patients affected by mastocytosis were recruited and specific information were required.We retrospectively investigated the characteristics of these patients, to assess the overall survival (OS), identify factors associated with severity of symptoms of infection and compare the OS according to concomitant treatment for SM.The diagnosis of coronavirus disease 2019 (COVID-19) was made according to the international recommendations of the World Health Organization (WHO) 4 .At the time of the survey design, no well-defined criteria were yet available to establish a degree of infection severity.Therefore, the following definitions have been included: asymptomatic (no clinical signs or symptoms); mild (non-pneumonia and mild pneumonia); severe (dyspnea, respiratory frequency ≥ 30 breaths per min, SpO2 ≤ 93%, PaO2/FiO2 < 300, or lung infiltrates > 50%), and critical (patients admitted in intensive care for respiratory failure, septic shock, or multiple organ dysfunction or failure).However, our grading definition was very similar to the one suggested by the China Centers for Disease Control and Prevention definitions 5 .

Background: Combination of venetoclax and hypomethylating agents (HMAs) has become a standard of care in adult patients with acute myeloid leukemia (AML) who are aged≥75 years or who have comorbidities that preclude use of intensive induction chemotherapy. Few promising data are available in the setting of relapsed/refractory (R/R) AML, while the utility of venetoclax in the post-transplant setting remains poorly investigated. Aims: To investigate clinical outcome and safety of venetoclax-based combinations in AML patients treated outside of clinical trials. Methods: We conducted a monocentric retrospective analysis on adult patients affected by treatment-naïve AML not eligible for standard induction therapy or R/R AML, who started venetoclax combination regimens between November 2017 and December 2021. AML genetic risk stratification and response criteria were assessed according to 2017 European Leukemia Net (ELN) consensus. Venetoclax was administered at the dose of 400 mg daily after a short ramp-up. The venetoclax dosage was reduced to 50 or 100 mg daily in case of concomitant strong CYP3A4 inhibitors (e.g. posaconazole) and 200 mg daily in case of moderate CYP3A4 inhibitors (e.g. isavuconazole). Disease free survival (DFS) and overall survival (OS) were assessed using the Kaplan-Meier method and compared between groups using the log-rank test; p values <0.05 were considered significant. Results: A total of 60 consecutive AML patient treated with venetoclax-based combinations were considered in the study. Twenty-three patients (38%) were affected by treatment-naïve AML and 37 patients (62%) by R/R AML. The median age was 70 years and 67% of the patients were ≥65 years old. The majority of patients showed an intermediate ELN genetic risk, while adverse ELN risk was found in 39% of treatment-naïve patients and 32% of R/R group. Among patients with R/R AML, 62% were treated in the salvage-2 setting or later and 37% had received a prior allogenic stem cell transplantation (allo-SCT). In combination with venetoclax, 51 patients (85%) received azacitidine 75 mg/m2 days 1-7. Eight patients (13%) added venetoclax to HMAs after progression during hypomethylating treatment previously administered for pre-leukemic conditions. Antifungal prophylaxis and subsequent venetoclax dose reduction were performed in 32 patients (53%). Overall response rate was 60% with a complete remission (CR) rate of 53% (78% for treatment-naïve group and 49% for R/R group, p 0.017). The best response was achieved after a median of one months. Median OS was 130 days for R/R patients and 269 days for treatment-naïve patients; median DFS was 199 days for treatment-naïve patients and 145 days for R/R cohort. Genetic adverse risk had a significant worst survival (p 0.02, Figure 1). Among patients who were treated after allo-SCT venetoclax lead to a CR rate of 36%. Overall, 11 patients (18%) received an allo-SCT after venetoclax combinations (7 as consolidation of a first line therapy). Most common grade 3 or 4 adverse events were hematological or infectious toxicities (31% and 64%). One event of severe tumor lysis syndrome was reported. Image:Summary/Conclusion: The results of this real-life monocentric study confirmed that venetoclax-based regimens are a viable and safe option as first-line therapy for AML unfit patients and a valid rescue therapy in the R/R setting. Furthermore, the association of venetoclax and hypomethylating agents proved to be a feasible bridging therapy to transplantation in elderly AML patients.

Background: The hypomethylating agents (HMAs) are an important therapeutic option for older patients (pts) with AML and have become the backbone for combination regimens (eg, with Venetoclax). However, there are very limited real-life prospective studies regarding clinical outcome of these pts, including infectious complications and infection related mortality (IRM) during treatment. Aims: To investigate the infectious complications and clinical outcome in AML patients treated with HMAs± Venetoclax (V) outside of clinical trials. Methods: The recruitment of this prospective multicentric study (CE-Id-study:2908) has been completed on December 31, 2020. We enrolled 230 AML pts with a median age of 75 years (range 25-94); 157 pts (68%) had >2 relevant comorbidities. Of the 230 cases, 132 (57%) received a first-line therapy with a combination of HMAs+V while 98 (43%) were treated with HMAs monotherapy (azacitidine or decitabine). A total of 1550 cycles of HMAs have been administered (680/1550 with HMAs+V). Results: The best response achieved, with HMAs treatment, was: CR in 44% of cases (57,6% with HMAs+V and 25,5% with HMAs alone, P=0,0001), PR in 17% and SD in 14% of cases (ORR 61%; 72% in HMAS+V and 46% in HMAs alone, P=0,0007). The microbiological or radiological proven infectious complications (almost one) occurred in 160/230 (70%) of pts, mainly pneumonia (in 42% of pts) and/or bacteremia/sepsis (one or more events in 29% of pts). Febrile neutropenia (one or more episodes) occurred in 38% of pts and 14 cases of Covid-19 (6%) were reported. After a median follow-up of 9 months (1-24) from the start of HMAs therapy, 144 (63%) pts died and 86 (37%) were alive. The 1 yr OS probability was 46% with a median OS of 10,3 months (11 months in HMAs+V and 9 months in HMAs alone; P=ns). The primary causes of death were: progression of AML (42%), Infection (26%-37/144), Infection+AML (24%), other causes (8%). The IRM was 26% and 19/144 (13%) pts died of infectious complication while in CR/PR (16 in HMAs+V group and only 3 in HMAs group; P=0,005). Data on antibiotic prophylaxis, hospitalization, drug-doses modulation, are available and analyzed in this study. Summary/Conclusion: The results of this real-life, multicentric, prospective study, confirm a higher CR rate in pts treated with HMAs+V compared to HMAs alone (P=0,0001). However, we found a high rate of infectious complications and IRM (26%) with a higher infection related deaths in patients in CR/PR who were treated with HMAs+V (P=0,005). Findings from this study highlight the critical relevance of infection prevention in reducing infectious mortality, which adversely impacts the OS of this frail AML population.

Mastocytosis represents a group of clonal disorders characterized by abnormal proliferation and infiltration of mast cells in various tissues, particularly skin and haematopoietic organs, ranging from skin-limited diseases to systemic and more aggressive variants.1 Its clonal nature relies on somatic, gain-of-function mutations in exon 17, causing constitutive activation of the c-KIT proto-oncogene and detected in most patients.2 More than 80% of adult patients with a systemic disease carry a somatic aspartate-to-valine substitution in codon 816 (D816V) of the KIT gene.1 Although it is a putative, non-hereditary disease, familial cases have been reported in paediatric series, with an estimated frequency of 11–13%.3, 4 However, data about the familial occurrence in adults are still lacking. This retrospective, observational, multicentre study aimed first at assessing the prevalence of familial disease in a large cohort of adult patients with mastocytosis and, second, at describing the clinical and molecular features of familial cases. Our cohort included 1541 adult patients followed by eight Italian Institutions, diagnosed with systemic or cutaneous mastocytosis, according to 2016 WHO criteria.5 All patients were asked about the occurrence of mastocytosis in relatives. When achievable, KIT mutational status was assessed both in index patients and relatives. Clinical data were collected retrospectively. Informed consent was obtained from participants, according to the guidelines of the local ethics committee Azienda Ospedaliera Universitaria Integrata di Verona. Among 1541 patients, we identified 23 clustered cases, resulting in an estimated prevalence of 1·5% familial cases. The median age at diagnosis of index patients was 44 years (range 16–70). Diagnosis was systemic mastocytosis (SM) in 16 cases (69·5%) and cutaneous mastocytosis (CM) in four cases (17·4%). Three patients (13·6%) who refused bone marrow biopsy were diagnosed with mastocytosis in the skin (MIS). Ten out of 16 SM patients (62·5%) had indolent systemic mastocytosis (ISM), four (25%) had bone marrow mastocytosis (BMM), one had aggressive SM (ASM) and one had systemic mastocytosis with associated haematological neoplasm (SM-AHN). KIT D816V mutation was found in either bone marrow (BM) or peripheral blood (PB) in all but one patient with SM (93·7%). Relatives with mastocytosis had a median age at diagnosis of 20 years (range 0–70), i.e., they were younger than the index cases. Seven patients (30·4%) had SM (ISM, n = 3; SM-AHN, n = 2; smouldering systemic mastocytosis (SSM), n = 1; BMM, n = 1); 13 patients (52·2%) had a cutaneous variant of mastocytosis [maculo-papular cutaneous mastocytosis (MPCM), n = 7; cutaneous mastocytoma, n = 6] and three patients had a diagnosis of MIS. The KIT mutational status was available only in four of seven relatives with SM, and three of them were KIT D816V mutated; five relatives with MPCM and one with MIS were negative for KIT D816V mutation in BM or PB. In eight out of 23 clustered cases, the KIT mutational status had been assessed in BM in both index patient and relative: concordant results were documented only in four out of eight cases, three D816V mutated and one wild-type. In the remaining cases, the index case carried the D816V mutation, whereas the relative was found to be negative. Finally, the index/relative relationships were: eight out of 23 parent and child (34·8%), eight out of 23 siblings (34·8%) and seven out of 23 other relationship (30·4%). Index and relative patients' clinical and molecular characteristics are listed in Table I. In our series, the clinical phenotype was highly heterogeneous, without any clear correlation in the disease presentation among members of the same familial cluster (see Fig 1). Moreover, 11 out of 23 clustered cases (47·8%) had the disease onset during adulthood, whereas in six cases (26·1%) symptoms appeared in childhood. In six families (26·1%) symptoms appeared either in childhood in the index case and in adulthood in relative or vice versa. Finally, in one case, both the index patient and her sister had an SM-AHN, associated with a triple-negative myeloproliferative neoplasm (MPN) and chronic myeloid leukaemia (CML), respectively. In the index case, the KIT D816V mutation was detected in PB, whereas neither the mutational status nor symptoms' age at onset was available for the relative. To our knowledge, this is the largest report on the prevalence and characteristics of familial mastocytosis in an adult population. Interestingly, in most of our index cases, we identified the KIT D816V mutation, which has never been shown to be inherited. Familial cases described so far were mainly paediatric CM lacking KIT lesions or harbouring uncommon KIT mutations, often positioned outside the exon 17 (i.e. A533D, K509I).3 Both somatic and germline KIT mutations have been reported in a few familial cases of gastrointestinal stromal tumor and mastocytosis.6, 7 Our group and Broesby-Olsen et al. have previously described two systemic mastocytosis clusters affecting two adult members of the same family, both carrying a somatic KIT D816V mutation.8, 9 The same mutation was reported in two paediatric familial cases, one of them harbouring a somatic D816V KIT mutation.3 Unfortunately, due to the retrospective nature of our study and the higher frequency of pediatric cases, data about relatives' mutational status were limited. Among SM patients, the KIT D816V mutation rate was of 93·3% and 42·9% in index cases and relatives, respectively; however, this mutation was not documented in any tested CM cases. Unfortunately, the KIT mutational status was available for both relatives and index cases only in eight families, with concordant results documented in four cases. Since the majority of the relatives had been tested for the KIT D816V mutation in other centres, information about the technique used for mutational analysis is lacking. Therefore, we cannot rule out an incidence underestimation related to low-sensitivity methods. In our series, the different time of onset of the disease, as well as the heterogeneity of mutational status and clinical variants in the same families, suggest the presence of other potential genetic factors favouring the acquisition of a somatic activating KIT mutation, such as another KIT germline mutation, as well as polymorphisms of genes coding for mast cell growth factors and or their receptors.10 Future studies of familial cases of CM, including complete sequencing of the KIT gene, genetic analyses on skin biopsy samples and exome sequencing could identify new molecular determinants of CM. We acknowledge Associazione Italiana Mastocitosi Onlus (ASIMAS) for donations and support in managing patients affected by mastocytosis. The authors declare that they have no competing interests. Ilaria Tanasi designed the research study, collected and analyzed data and wrote the paper. Massimiliano Bonifacio analyzed data and reviewed the paper. Federica Irene Grifoni, Mariarita Sciumè, Chiara Elena, Pietro Benvenuti, Francesco Mannelli, Roberta Parente, Donatella Schena, Luigi Scaffidi, Patrizia Bonadonna, Cristina Papayannidis, Michela Rondoni, Marianna Criscuolo, Alessandro M. Vannucchi, Massimo Triggiani, and Giovanni Martinelli, provided clinical data. Mauro Krampera reviewed the paper. Roberta Zanotti designed the research study, analyzed data and reviewed the paper. All authors read and approved the final manuscript.

Background:The prognosis of refractory/relapsed B acute lymphoblastic leukemia (R/R B‐ALL) still represents a clinical challenge. In this setting, therapy with the bispecific T cell engager blinatumomab or the anti‐CD22 antibody‐drug conjugate inotuzumab‐ozogamicin (IO) showed promising results.Aims:We aimed to describe our clinical experience in the use of blinatumomab and/or IO in a monocentric series of relapsed/refractory R/R B‐ALL.Methods:Adult patients with R/R B‐ALL treated with blinatumomab and/or IO for disease reappearance (morphologic or molecular) were selected from the institutional database.Results:We identified 13 R/R B‐ALL patients who received blinatumomab and/or IO for disease relapse. At diagnosis median age was 61 years (23‐75); 9 patients had a very‐high‐risk disease (4 Philadelphia chromosome–positive‐Ph+ ALL) and 4 patients a standard risk ALL. Five cases received sequentially blinatumomab and IO, while 6 patients were treated with only blinatumomab and 2 with only IO. Blinatumomab was given as continuous IV infusion at a dose of 28 μg/m2/d for 4 weeks, with a 2 week break. IO was given IV at a dose of 1.8 mg/m2 for the first cycle and then 1.5 mg/m2, divided in three weekly doses, every 3‐4 weeks. At blinatumomab start, median number of prior therapy lines was 2 (1‐5). Ph+ ALL patients were treated with multiple tyrosine kinase inhibitors, 1 received prior allogeneic stem cell transplantation (allo‐HSCT). Median number of blinatumomab cycles was 3 (1‐5). After 2 cycles 10 patients achieved a complete remission (CR); 8 of them were in complete cytofluorimetric or molecular remission. The remaining one patient was a Ph+ ALL who developed a progressive disease with lymph‐nodes involvement, without bone marrow morphologic or molecular evidence of ALL. Four patients experienced a cytokine release syndrome grade 1/2, while 2 patients experienced a grade 3 neurological toxicity. In 2 cases blinatumomab was used as bridge to transplant. Relapse occurred in 5 cases after CR achievement: 2 molecular relapses (1 after allo‐HSCT) and 3 morphologic bone marrow relapse. CD19 expression was lost in 2 cases. Median progression‐free‐ survival (PFS), time to next treatment (TTNT) and overall survival (OS) from blinatumomab start were 268, 278, 393 days, respectively. Three patients died due to progressive disease and all of them were exposed to IO salvage treatment after blinatumomab. Regarding the 7 patients treated with IO, median number of prior therapy lines was 4 (3‐8), including blinatumomab in all cases except one. The median IO cycles was 2 (1‐6). Only one patient experienced progressive disease during IO, the remaining 6 patients achieved a morphologic CR since first cycle. Negative cytofluorimetric or molecular disease was achieved in 2 patients. IO therapy was safe: one patient had a QT prolongation during concomitant use of IO and amiodarone, while a grade 2 transaminases elevation was seen in another case. Two patients received IO as bridge to transplant; three cases relapsed after a CR achievement and 2 of these relapses occurred after allo‐HSCT. Median PFS, TTNT and OS were all 58 days.Summary/Conclusion:This monocentric survey underlies the feasibility and efficacy of immunotherapy in the setting of R/R B‐ALL, also in a sequential use mode.

Background:Mastocytosis refers to a group of clonal disorders characterized by abnormal proliferation of mast cells infiltrating various tissues, especially skin and hematopoietic organs. Clinical presentation is heterogeneous and may vary from skin‐limited disease to more aggressive variants. The clonal nature of mastocytosis has been largely demonstrated by the identification of gain‐of‐function mutations in exon 17 causing constitutive activation of the c‐KIT protooncogene. In the large majority of patients with systemic disease a somatic aspartate‐to‐valine substitution in codon 816 (D816 V) of the KIT gene is demonstrable. Typically, mastocytosis is considered a non‐hereditary disease, although clustered cases were reported in pediatric series with an estimated frequency of 8–10%, in the absence or presence of c‐KIT mutations, generally located outside the exon 17. Prevalence data about familial cases in adults are lacking. To our knowledge, somatic D816 V KIT mutation was reported only in two adult clusters and in two pediatric familial cases.Aims:In this retrospective, observational, multicenter study we sought: a) to estimate the prevalence of familial disease in a series of 1541 patients with mastocytosis referred in adulthood (>16 years old) to 8 Italian Institutions, and b) to describe the clinical and molecular characteristics of clustered cases.Methods:Diagnosis of mastocytosis was made according to the 2016 World Health Organization criteria. All patients were asked for the occurrence of the same disease in relatives. Clinical and molecular data were recorded in all patients and in the affected relatives, when available.Results:Familial occurrence of mastocytosis was reported in 22 patients (1.4% of the whole cohort). Clinical and molecular characteristics are reported in table I. Index cases were 12 males and 10 females, median age at diagnosis was 43 years (range 16–65 years). Diagnosis in index patients was systemic mastocytosis (SM) (n = 15), mastocytosis in the skin (MIS) (n = 3), and maculo‐papular cutaneous mastocytosis (MPCM) (n = 4). All but one SM patients harbored D816V KITmutation. Each index case reported a single affected relative: they were 14 males and 8 females, with median age at diagnosis of 20 years (range 0–70 years). Diagnosis in relatives was SM (n = 7), MIS (n = 3), MCPM (n = 6) and Mastocytoma (n = 6). The relationship between index and relatives was mainly “parent and child” (41%) and “siblings” (27%). Notably, 4 SM patients had one child who developed single or multiple mastocytoma; in other two families index and/or relatives developed an associated hematological neoplasia.Summary/Conclusion:To our knowledge, this is the largest report about the prevalence and the characteristics of familial cases in an adult population of patients with mastocytosis. Familial occurrence of mastocytosis with different clinical and molecular characteristics between indices and relatives suggests that D816 V KIT mutations may be a secondary genetic event. Further studies, including search for mutations in all patients with skin‐limited disease and genotyping of D816V‐mutated patients, are needed to confirm our hypothesis.image

Background:Isavuconazole (ISV) has been reported as safe and effective in the SECURE trial (Maertens 2016).Aims:To confirm the efficacy and safety of ISV in hematological patients in a clinical care setting.Methods:We planned a multicenter retrospective study, collecting all cases of invasive fungal infections (IFI) occurring in hematological patients (pts) treated with ISV in 17 Centers between Jul‐16 and Nov‐18. IFI were categorized as possible (PS), probable (PB) or proven (PV) according to EORTC/MSG criteria. The impact of age, gender, type and status of disease at IFI (diagnosis [Dx], complete and partial remission [CR/PR], relapse/refractory [r/r]), type of IFI, allogeneic stem cell transplantation (alloSCT), neutropenia and timing of ISV treatment were evaluated.Results:One‐hundred and twenty‐eight pts were enrolled (M/F ratio: 76/52, median age 57y, range 18–80). AL were 88 (68%) (myeloid 57%; lymphoblastic 12%), lymphoma 28 (22%), myeloma 4 (3%), aplastic anemia 3 (2%) and myelodysplastic syndromes 5 (4%) pts. Thirty‐one (24%) patients developed IFI at Dx, 54 (42%) while on CR/PR and 43 (34%) with r/r disease; alloSCT pts were 50 (39%). IFI were PS in 54 (42%), PB in 61 (48%) and PV in 13 (10%) cases. Aspergillus spp was responsible for 67 (91%) of PB/PV IFI; in the remaining 7 cases, 1 Rhizomucor and 1 Fusarium spp were isolated and in 5 histologically PV IFI no specific agent was identified. Lung was the more frequent site of IFI (110, 86%), followed by paranasal sinuses (13, 10%). ISV was employed as 1st line therapy in 44 (34%) and as subsequent line in 84 (66%) pts. The median duration of previous treatments was 18d (range 3–1110). Reasons for ISV use were failure in 45 (54%) and intolerance in 17 (20%) of 84 cases. In 17 (20%) ISV was chosen because of the need to switch to oral antifungal agent and in 5 (6%) for a favorable drug‐interaction profile. Median duration of ISV treatment was 50d (2–375). Clinical and radiological overall response rate (ORR) was 82 of 118 evaluable pts (69%); it was similar when using ISV as 2nd line with refractory IFI or not (respectively: 67% vs 77%). In multivariate analysis, underlying disease status was confirmed as a predictive factor for ORR to ISV (rec/ref HR 0.259, CI 0.111–0.604). After a median follow‐up of 4.2mo, 44 (34%) pts died; IFI‐attributable mortality was 13/128 (10%). The estimated 1‐year overall survival (OS) from IFI diagnosis of the entire cohort was 50% (CI 0.22–0.45); figures were similar for PS vs PB/PV IFI (52.8% vs 48.7%), AL vs no AL (49% vs 51%) and first vs subsequent line use of ISV (49% vs 51%). OS was significantly lower for pts with refractory IFI (36% vs 58%, p = 0.05) (Fig.1), with r/r hematological disease (r/r 19% vs CR/PR 71%, p = 0.0007, or vs Dx 59%, p = 0.016) and in alloSCT pts (38% vs 58%, p = 0.029). Response to ISV was associated to better OS (HR 0.102, CI 0.04–0.26), while r/r disease showed a trend toward statistically significant negative impact on OS (rel/ref HR 2.344, CI 0.932–5.899). Adverse events (AE) were reported in 15/128 pts (11.7%) (hepatic in 5, cutaneous in 3, gastroenteric in 7 and hypokaliemia in 3); grade 3–4 AE were reported in 5 (4%) cases and led to permanent ISV discontinuation.Summary/Conclusion:ISV is used in hematological pts also in diseases other than acute myeloid leukemia and it is overall well tolerated. ORR to ISV is at least comparable with other antifungal agents. Having an IFI refractory to other antifungal agents does not seem to compromise the response to ISV, although this condition, together with a r/r underlying disease, negatively impacts on survival.image

Background:Acute myeloid leukemia (AML) with mutated NPM1 was recently recognized as a distinct entity. The most common NPM1 mutation is type A, generally considered of favorable prognosis in the absence of additional internal tandem duplication (ITD) in FLT3 gene. So far little is known about the prognostic relevance of non‐A type.Aims:We aimed to evaluate the relevance of A type and non‐A type NPM1 mutations on clinical profiles and outcomes in a monocentric AML cohort.Methods:Adult patients with newly diagnosed NPM1‐mutated AML were selected from the institutional database. NPM1 mutations were detected by Sanger sequencing and molecular minimal residual disease (MRD) was determined by real‐time quantitative polymerase chain reaction analysis (sensitivity 10‐5). Genetic risk classification and response to treatment were assessed according to the 2017 European LeukemiaNet guidelines. The chi‐squared test was used for testing relationships between categorical variables; p ≤ 0.05 were considered significant. Overall survival (OS) curve was estimated using the Kaplan–Meier method.Results:We identified 32 consecutive patients seen in a 4‐year period. Median age at AML diagnosis was 67 years and male/female ratio was 15/17. Median white blood cell count was 32x109/L. Type A NPM1 mutations was found in 21 (66%) and non‐A type in 11 cases (34%), including B type (4 cases), D type (2 cases) and other rare mutations (5 cases). One of the latter was this following novel mutation c.870_873delGAGGinsCTTCTCCC. Hyperleukocytosis occurred in 4 type A (19%) and 2 non‐A type (18%) cases (p not significant, NS). M4 was the most represented morphology (17 cases, 53%). The karyotype was normal in all cases and favorable genetic risk was found in 15 type A (71%) and 8 non‐A type (73%) cases, whereas intermediate in 6 type A (29%) and 3 non‐A type (27%) cases (p NS). All intermediate risk had a FLT3‐ITD mutation. Sixteen patients (50%) were treated with antracycline‐cytarabine‐based chemotherapy (8 type A, 8 non‐A type) and 3 of them received also midostaurin (all non‐A type). Eleven patients (34%) were treated with hypomethylating agents (9 type A, 2 non‐A type), 5 patients (16%) died before AML treatment start (4 type A, 1 non‐A type). Complete remission (CR) was observed in 13 cases (41%) treated with intensive chemotherapy (6 type A, 7 non‐A type) and in 2 cases (18%) who received a hypomethylating agent (all type A) (p 0.014), without significant difference between the two mutation groups. A relapse occurred in 5 of the 15 patients who achieved a CR, 3 cases treated with intensive chemotherapy (1 type A, 2 non‐A type) and 2 cases with hypomethylating agents (all type A). Molecular MRD was available in 11 cases (4 type A, 7 non‐A type); at the end of first line treatment it was negative for 3 patients (27%, 1 type A, 2 non‐A type), who had also a flow‐cytometry MRD negativity. After a median follow‐up of 26.5 months, median OS and median disease free survival were both 5 months; using the Kaplan–Meier method a significant OS difference was observed between type A and non‐A type cases (Fig. 1), DFS was not significant different between the two groups. During the follow‐up 18 patients died (56%, 14 type A, 4 non‐A type), mainly due to AML progression (9 cases) or hemorrhagic complications (4 cases).Summary/Conclusion:Our results in a small retrospective and monocentric series of NPM1 mutated AML showed similar clinical‐biological features among cases with type A and non‐A type mutations, albeit a better OS was associated to non‐A type mutations.image