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Summary: Secondary primary malignancies (SPM) have been reported after anti‐BCMA or anti‐CD19 chimeric antigen receptor (CAR)‐T‐cell therapies. While the cytotoxic effect of antecedent therapies, including chemotherapy and radiotherapy, has been well established, few data are available on risk related to CAR‐T immunotherapies. The study aimed to analyse the incidence of SPM in 651 patients enrolled in the Italian prospective observational CART‐SIE study. SPMs were documented in 4.3% (28/651), and the most frequent SPMs were haematological malignancies. In conclusion, the frequency of SPMs in our cohort of heavily pretreated patients receiving CAR‐T was relatively low and consistent with previous studies. [ABSTRACT FROM AUTHOR]

Experts often play a fundamental role in decision‐making processes. They are the bearers of an epistemic authority, which is primarily grounded on what we may call scientific naturalism. The main tenets of this view can clash though with other values characterising our pluralist societies. This may lead to conflicts but also to a devaluation or to a rejection of the sort of knowledge and advise offered by experts. In this paper we propose a new accommodation between scientific naturalism and the values of our democratic societies. In Section 1, we present a case study highlighting the problematicity of experts' decisions based on mere epistemic soundness. In Section 2, we frame our analysis of expertise in the context of a post‐truth world. Section 3 looks at the relations between scientific naturalism and democracy, while Section 4 focuses on the potential clash between scientific naturalism and the normative character of other forms of knowledge. In Sections 5 and 6, we present practical instances of this clash (additional case studies), involving religious, bioethical, and cultural values. We show that in some cases these values ought to be granted full citizenship in a democratic state. This, (Section 7), leads us to a stalemate that seems to threaten the functioning of modern democracies. In Section 8, to overcome this stalemate, we propose to resort to a more inclusive form of naturalism, namely liberal naturalism. This form of naturalism cannot do without experts' scientific recommendations and yet does not end up excluding (a priori) alternatives forms of knowledge. We conclude, Section 9, by advocating a more liberal ecology of mechanisms for the regulation of decision‐making processes; one that also encompasses socially inclusive (not necessarily scientific) processes of deliberation and judgment. [ABSTRACT FROM AUTHOR]

Consolidation treatment in acute myeloid leukemia (AML) patients achieving complete remission (CR) is warranted. High‐dose cytarabine (HDAC) is considered first choice in favorable risk and an option in intermediate‐risk AML. However, its optimal dose and schedule, as well as the benefit of additional chemotherapy agents remain controversial. Herein, we report on the long‐term outcome of consecutive unselected AML patients treated with repeated courses of HDAC, with the addition of idarubicin, followed by autologous peripheral blood stem cell (PBSC) support, in order to limit toxicity, according to Northern Italy Leukemia Group (NILG) AML‐01/00 study (EUDRACT number 00400673). Among 338 patients consecutively diagnosed from 2001 to 2017 at our center, 148 with high‐risk AML (adverse cytogenetic, isolated FLT3‐internal tandem duplication mutation, refractory to first induction) were addressed to allogeneic stem cell transplant. All other cases, 186 patients (55%), median age 53 (range 19–75), were considered standard‐risk and received the NILG AML‐01/00 program. After achieving CR, patients were mobilized with cytarabine 8 g/sqm to collect autologous CD34+‐PBSC and received three consolidation cycles with HDAC (20 g/sqm) plus idarubicin (20 mg/sqm) per cycle, followed by reinfusion of limited doses of CD34+ PBSC (1‐2x106/kg). The program was completed by 160 (86%) patients. Toxicity was acceptable. Neutrophils recovered a median of 10 days. Treatment‐related mortality was 3/160 (1.8%). After a median follow‐up of 66.4 months, overall survival (OS) and relapse‐free survival (RFS) at 5‐years were 61.4% and 52.4%, respectively. Twenty‐eight selected patients aged >65 had similar outcomes. According to European leukemia net‐2010 classification, the OS and RFS at 5‐years were 76.4% and 65% in favorable risk, without differences between molecular subgroups, 52.3% and 47.2% in Intermediate‐I, 45.2% and 36.5% in Intermediate‐II risk patients, respectively. In conclusion, consolidation including repeated courses of high dose cytarabine and idarubicin, with limited PBSC support, proved feasible and very effective in nonhigh risk patients. The incorporation of novel agents in its backbone may be tested to further improve patient's prognosis. [ABSTRACT FROM AUTHOR]

Background: Stopping tyrosine kinase inhibitor (TKI) treatment has become a realistic and safe objective for patients who have chronic myeloid leukemia (CML). Both a sustained deep molecular response (sDMR) and the lack of a molecular recurrence after TKI discontinuation are required to reach a durable treatment‐free remission (TFR). Methods: The potential predictive role of BCR‐ABL transcripts in attaining an sDMR and a TFR was analyzed in a strictly consecutive, unselected series of 194 patients who were diagnosed and treated with TKIs at the authors' center. Results: Of 173 fully evaluable patients, 67 (38.7%) had the e13a2 transcript, and 106 (61.3%) had the e14a2 transcript. Complete cytogenetic and major molecular remissions were not affected, whereas the achievement of both a DMR (P = .008) and an sDMR (P = .004) was favored significantly in patients who had the e14a2 transcript. After a median of 68 months, the sDMR rate was 39.6% in those with the e14a2 transcript and 19.4% in those with the e13a2 transcript. In addition to transcript type, both the early achievement of a molecular response and starting treatment with a second‐generation TKI positively affected the attainment of an sDMR in multivariate analysis. The use of a second‐generation TKI as frontline treatment increased the sDMR rate in both transcript types. However, in patients who had the e13a2 transcript, the probability of attaining an sDMR was 37% after 60 months and did not increase further despite continuing therapy. Among 51 of 60 patients who attained an sDMR after discontinuing TKIs, 24 experienced a molecular relapse, but all regained molecular remission after resuming TKI treatment. Again, transcript type influenced TFR maintenance (P = .005), because only 2 patients (3%) with the e13a2 transcript enjoyed a durable TFR compared with 25 (23.5%) of those with the e14a2 transcript. Conclusions: The e13a2 transcript hinders the achievement of deep responses and the possibility of stopping TKI treatment in patients with CML. Among patients who have chronic myeloid leukemia and receive treatment with tyrosine kinase inhibitors, the likelihood of obtaining a sustained deep molecular response and a durable treatment‐free remission is lower in those who have the e13a2 BCR‐ABL transcript. After 5 years of treatment, the probability that patients with the e13a2 transcript will achieve a sustained deep molecular response is 17.4% with imatinib and 36.2% with second‐generation tyrosine kinase inhibitors. [ABSTRACT FROM AUTHOR]

Treatment‐free remission (TFR) by tyrosine kinase inhibitors (TKI) discontinuation in patients with deep molecular response (DMR) is a paramount goal in the current chronic myeloid leukemia (CML) therapeutic strategy. The best DMR level by real‐time quantitative PCR (RT‐qPCR) for TKI discontinuation is still a matter of debate. To compare the accuracy of digital PCR (dPCR) and RT‐qPCR for BCR‐ABL1 transcript levels detection, 142 CML patients were monitored for a median time of 24 months. Digital PCR detected BCR‐ABL1 transcripts in the RT‐qPCR undetectable cases. The dPCR analysis of the samples, grouped by the MR classes, revealed a significant difference between MR4.0 and MR4.5 (P = 0.0104) or MR5.0 (P = 0.0032). The clinical and hematological characteristics of the patients grouped according to DMR classes (MR4.0 vs MR4.5‐5.0) were superimposable. Conversely, patients with dPCR values <0.468 BCR‐ABL1 copies/µL (as we previously described) showed a longer DMR duration (P = 0.0220) and mainly belonged to MR4.5‐5.0 (P = 0.0442) classes compared to patients with higher dPCR values. Among the 142 patients, 111 (78%) discontinued the TKI treatment; among the 111 patients, 24 (22%) lost the MR3.0 or MR4.0. RT‐qPCR was not able to discriminate patients with higher risk of MR loss after discontinuation (P = 0.8100). On the contrary, according to dPCR, 12/25 (48%) patients with BCR‐ABL1 values ≥0.468 and 12/86 (14%) patients with BCR‐ABL1 values <0.468 lost DMR in this cohort, respectively (P = 0.0003). Treatment‐free remission of patients who discontinued TKI with a dPCR <0.468 was significantly higher compared to patients with dPCR ≥ 0.468 (TFR at 2 years 83% vs 52% P = 0.0017, respectively). In conclusion, dPCR resulted in an improved recognition of stable DMR and of candidates to TKI discontinuation. [ABSTRACT FROM AUTHOR]

Mucosa-associated lymphoid tissue (MALT) lymphoma is an indolent lymphoma with good prognosis and variable fluorine-18 fluorodeoxyglucose (18 F-FDG) avidity. Many possible prognostic factors have been investigated with controversial results, but the possible prognostic role of 18 F-FDG positron emission tomography/computed tomography (PET/CT) remains unclear. Our aim was to evaluate the prognostic impact of qualitative and semiquantitative baseline PET/CT parameters on outcome of MALT lymphoma. We retrospectively enrolled 161 patients with histologically confirmed MALT lymphoma who underwent 18 F-FDG PET/CT before any treatment. PET images were qualitatively and semiquantitatively analyzed by measuring the maximum standardized uptake value body weight (SUVbw), lean body mass (SUVlbm), body surface area (SUVbsa), metabolic tumor volume (MTV), and total lesion glycolysis (TLG). The Kaplan-Meier method was used to estimate the progression-free survival (PFS) and overall survival (OS) times. Cox regression models were performed to determine the relation between PET/CT features and OS and PFS. Ninety-eight patients had positive 18 F-FDG PET/CT showing 18 F-FDG uptake (mean SUVbw, 10.1; SUVlbm, 7.2; SUVbsa, 2.7; MTV, 88.8; and TLG, 526); the remaining 63 were not 18 F-FDG avid. 18 F-FDG avidity was significantly correlated with tumor size and Ki-67 score. Relapse/progression of disease occurred in 47 patients with an average time of 40.2 months; death occurred in 12 patients with an average of 59 months. At a median follow-up of 62 months, median PFS and OS were 52 and 62 months, respectively. Advanced tumor stage and extragastric site were demonstrated to be independent prognostic factors for PFS, while only tumor stage for OS. Instead, PET/CT parameters were not related to survival, despite positive correlation at univariate analysis between MTV and TLG with PFS and positive PET/CT with PFS and OS. In conclusion, a 61% rate of PET avidity in biopsy-confirmed MALT lymphoma was found, and it was correlated with tumor size and Ki-67 score. Only tumor stage and localization were independently correlated with PFS and OS. [ABSTRACT FROM AUTHOR]

Adult onset hemophagocytic lymphohistiocytosis (HLH) is a hyperinflammatory syndrome, which can develop as a complication of many disorders. Early diagnosis is essential in order to avoid a fatal outcome. To confirm the diagnosis of acquired HLH made in a single institution series of adult patients with HLH-04 criteria, we applied the HScore and evaluated prognostic factors associated with clinical outcome. The median age of 35 patients was 54 (range 17-81), M/F ratio was 20/15. In 26/35 (74.3%) patients, an underlying haematological disease was present (2 Multicentric Castleman Disease, 10 B-cell Non-Hodgkin Lymphoma [NHL] and 14 T/NK-cell NHL); an autoimmune disorder was observed in four (11.4%) patients (one Still Disease, one undifferentiated connective tissue disease and two haemolytic anaemia); in five (14.3%), no underlying disease was identified. A concomitant infection by EBV was observed in 10 patients (28.6%), CMV in 8 (22.9%), HHV8 in 6 (17.1%) and HIV in 1 (2.9%). Hyperferritinemia, fever and splenomegaly were present in more than 90% of patients, whereas bone marrow hemophagocytosis in 51% of cases only. According to HScore, 34/35 patients had a >75% and 32/35 >93% probability of HLH. Four-year overall survival and HLH-free survival were 17.8% (CI 1.9-33.8) and 23.8% (CI 7.3-40.3), respectively. By multivariate analysis, presence of oedema and hyperbilirubinemia were predictors of death, whereas there was a statistically significant trend for viral infection as predictor of poor prognosis. B-NHL diagnosis was confirmed as associated to a better prognosis in comparison with T/NK lymphoma (4-year HFS 53.3% vs. 0%, p = 0.09) and similar to other aetiologies. Copyright © 2016 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Background Methods Results Conclusions Ruxolitinib (RUX) is a JAK1/2 inhibitor approved for the therapy of myelofibrosis (MF) based on clinical trials including only intermediate2‐high risk (INT2/HIGH) patients. However, RUX is commonly used in intermediate‐1 (INT1) patients, with scarce information on responses and outcome.The authors investigated the benefit of RUX in 1055 MF patients, included in the “RUX‐MF” retrospective study.At baseline (BL), 595 (56.2%) patients were at INT1‐risk according to DIPSS (PMF) or MYSEC‐PM (SMF). The spleen was palpable at <5 cm, between 5 and 10 cm, and >10 cm below costal margin in 5.9%, 47.4%, and 39.7% of patients, respectively; 300 (54.1%) were highly symptomatic (total symptom score ≥20). High‐molecular‐risk (HMR) mutations (IDH1/2, ASXL‐1, SRSF2, EZH2, U2AF1Q157) were detected in 77/167 patients. A total of 101 (19.2%) patients had ≥1 cytopenia (Hb < 10 g/dL: n.36; PLT <100 x 109/L: n = 43; white blood cells <4 x 109/L: n = 40). After 6 months on RUX, IWG‐MRT–defined spleen and symptoms response rates were 26.8% and 67.9%, respectively. In univariate analysis, predictors of SR at 6 months were no HMR mutations odds ratio [OR], 2.0, p = .05], no cytopenia (OR, 2.10; p = .01), and blasts <1% (OR, 1.91; p = .01). In multivariate analysis, absence of HMR maintained a significant association (OR, 2.1 [1.12–3.76]; p = .01).In INT1 patients, responses were more frequent and durable, whereas toxicity rates were lower compared to INT2/high‐risk patients. Presence of HMR mutations, cytopenia, and peripheral blasts identified less‐responsive INT1 patients, who may benefit for alternative therapeutic strategies. [ABSTRACT FROM AUTHOR]

Mucosa-associated lymphoid tissue (MALT) lymphoma is an indolent lymphoma with good prognosis and variable fluorine-18 fluorodeoxyglucose ( 18 F-FDG) avidity. Many possible prognostic factors have been investigated with controversial results, but the possible prognostic role of 18 F-FDG positron emission tomography/computed tomography (PET/CT) remains unclear. Our aim was to evaluate the prognostic impact of qualitative and semiquantitative baseline PET/CT parameters on outcome of MALT lymphoma. We retrospectively enrolled 161 patients with histologically confirmed MALT lymphoma who underwent 18 F-FDG PET/CT before any treatment. PET images were qualitatively and semiquantitatively analyzed by measuring the maximum standardized uptake value body weight (SUVbw), lean body mass (SUVlbm), body surface area (SUVbsa), metabolic tumor volume (MTV), and total lesion glycolysis (TLG). The Kaplan-Meier method was used to estimate the progression-free survival (PFS) and overall survival (OS) times. Cox regression models were performed to determine the relation between PET/CT features and OS and PFS. Ninety-eight patients had positive 18 F-FDG PET/CT showing 18 F-FDG uptake (mean SUVbw, 10.1; SUVlbm, 7.2; SUVbsa, 2.7; MTV, 88.8; and TLG, 526); the remaining 63 were not 18 F-FDG avid. 18 F-FDG avidity was significantly correlated with tumor size and Ki-67 score. Relapse/progression of disease occurred in 47 patients with an average time of 40.2 months; death occurred in 12 patients with an average of 59 months. At a median follow-up of 62 months, median PFS and OS were 52 and 62 months, respectively. Advanced tumor stage and extragastric site were demonstrated to be independent prognostic factors for PFS, while only tumor stage for OS. Instead, PET/CT parameters were not related to survival, despite positive correlation at univariate analysis between MTV and TLG with PFS and positive PET/CT with PFS and OS. In conclusion, a 61% rate of PET avidity in biopsy-confirmed MALT lymphoma was found, and it was correlated with tumor size and Ki-67 score. Only tumor stage and localization were independently correlated with PFS and OS., (© 2018 John Wiley & Sons, Ltd.)