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A retrospective study was conducted to evaluate the incidence of latent tuberculosis (TB) infection in patients with multiple myeloma (MM) who were treated with novel drugs. The study used the LIAISON QuantiFERON-TB Gold Plus assay to detect interferon-gamma produced by T-lymphocytes in response to specific antigens of Mycobacterium tuberculosis. Out of 180 patients, 26 (14.4%) tested positive for latent TB infection, with only three patients being foreign-born. Prophylactic treatment was administered to 80.8% of patients with latent TB, and no cases of TB reactivation were observed during or after MM treatment. The study suggests that TB screening and prophylaxis are important for MM patients receiving novel drugs to prevent reactivation of latent TB. [Extracted from the article]

Introduction: Interferon regulatory factor 4 (IRF4) is a transcriptional factor with a key role in the modulation of inflammation and immune surveillance. The IRF4 gene is downregulated in Philadelphia-negative myeloproliferative neoplasms, and its expression is associated with prognosis and response to treatment. Methods: We evaluated the IRF4 expression kinetics during tyrosine kinase inhibitor (TKI) treatment in a cohort of 116 chronic myeloid leukemia (CML) patients to elucidate its role in the disease course. Results: A relationship between the IRF4 expression and the disease burden was observed at various disease stages. A correlation analysis between the International Scale (IS) and IRF4 values confirmed this close association. A significant increase is detected after 3 months of TKI treatment. Patients achieving an early molecular response (EMR) had higher IRF4 values at both diagnosis and after 3 months of therapy as compared to those failing the EMR target. Patients achieving treatment-free remission did not show IRF4 fluctuations during monitoring, while a decreased IRF4 expression emerged at the time of molecular relapse. Conclusion: Our data seem to confirm the relevance of IRF4 in the pathogenesis of CML, suggesting a pivotal role at the disease onset and a predictive value during the CML course. [ABSTRACT FROM AUTHOR]

BCR-ABL1 and JAK2 V617F coexistence in myeloproliferative neoplasms has been described as concomitant or sequential events. Despite this, we present a unique case of chronic myeloid leukemia (CML) not referable to either of the known scenarios. BCR-ABL1 molecular monitoring was performed by real-time quantitative PCR (RQ-PCR). At the time of molecular relapse, a targeted next-generation sequencing analysis with a customized panel of 26 genes commonly mutated in myeloid diseases was performed. To investigate the kinetics of the JAK2 variant and its association with the BCR-ABL1 rearrangement, RQ-PCR was performed at different time points during the patient's follow-up. While negative at CML diagnosis, the JAK2 mutation was first detected 9 years later (VAF: 7.2%). The mutational burden of JAK2 remained stable in multiple determinations, with minor fluctuations independent of BCR-ABL1 kinetics. At the last available time point, the patient was in deep molecular response (MR4), the JAK2 mutational burden was 7%, and no clinical-laboratory findings of Ph-MPN were detectable. In the presented case, the JAK2variantoccurring during the course of the disease seems to stay in the shadows of CML, just as a bystander. The impact of this event (that may be considered suggestive of clonal hematopoiesis of indeterminate potential) on the disease outcome, even if seemingly irrelevant, has still to be explored. [ABSTRACT FROM AUTHOR]

Il quadro linguistico italiano legato all’atavico plurilinguismo proprio del nostro Paese – per la ricchissima presenza di dialetti e minoranze linguistiche storiche – negli ultimi decenni si è ulteriorimente complicato per l’aggiunta di ulteriori lingue, che hanno dato vita a quello che viene definito da Vedovelli “neoplurilinguismo” dovuto proprio al nuovo ruolo centripeto dell’Italia rispetto ai movimenti migratori. In questo contesto la scuola, luogo di formazione e crescita per eccellenza, ha il ruolo importantissimo di valorizzare e di promuovere un’educazione plurilingue e interculturale affinché non si corra il rischio di lasciare alcuni studenti nel solco di una rottura che potrebbe dar vita ad identità monche. Tuttavia, spesso essa incontra difficoltà nell’attuazione di quelle che pur sono direttive e indicazioni che vengono da più parti. Come dar voce, dunque, a queste nuove presenze? L’autobiografia, nello specifico linguistica, è un valido strumento che ha avuto una buona diffusione negli ultimi decenni come dispositivo per affrontare il passato, risanare e proiettare in avanti l’individuo che scrive migliorando il rapporto con il proprio bagaglio linguistico nel riconoscimento di un’identità multipla. In questo articolo si riporta un’esperienza didattica che ha visto la realizzazione di un percorso in una scuola superiore di un quartiere periferico di Padova nell’a. s. 2020-2021 in cui si è avuto come punto di arrivo finale proprio la scrittura da parte degli studenti della propria autobiografia linguistica. Sfruttando il doppio filone in cui le AL sono state impiegate già precedentemente, cioè quello più proprio della realtà italiana legato alla dimensione dialettale e quello nell’insegnamento dell’italiano L2, si è potuto coinvolgere interamente il gruppo classe di tre sezioni diverse dando agli studenti la possibilità di raccontarsi attraverso le lingue in cui “abitano”. A tool for de-invisibilizing students' identities and languages: linguistic autobiographies in a high school in Padua The Italian linguistic framework linked to the atavistic multilingualism of our country – due to the very rich presence of dialects and historical linguistic minorities – has been further complicated in recent decades by the addition of more languages, which have given rise to what Vedovelli calls “neoplurilingualism” due precisely to Italy’s new centripetal role with respect to migratory movements. In this context, the school, the place for training and growth par excellence, has the very important role of valuing and promoting plurilingual and intercultural education so that there is no risk of leaving some students in a rut that could give rise to stunted identities. However, it often encounters difficulties in implementing what are nevertheless directives and directions coming from many quarters. How, then, to give voice to these new presences? Autobiography, specifically linguistic autobiography, is a valuable tool that has been popular in recent decades as a device for dealing with the past, healing and projecting forward for the individual through writing, by improving the relationship with one's linguistic background as recognition of a multiple identity. In this paper, we report on an educational experience that involved the implementation of a course in a high school in a suburban district of Padua during the 2020-2021 school year where the students’ writing on their linguistic autobiography was the final point of arrival. Taking advantage of the double thread in which ALs have been employed before, namely the one more specific to the Italian reality related to the dialectal dimension and one to the teaching of Italian L2, it was possible to fully involve three different class groups by giving students the opportunity to tell their stories through the languages in which they “live”.

We applied Charlson comorbidity index (CCI) stratification on a large cohort of chronic myeloid leukemia (CML) very elderly patients (>75 years) treated with imatinib, in order to observe the impact of concomitant diseases on both compliance and outcome. One hundred and eighty-one patients were recruited by 21 Italian centers. There were 95 males and 86 females, median age 78.6 years (range 75–93.6). According to Sokal score, 106 patients were classified as intermediate risk and 55 as high risk (not available in 20 patients). According to CCI stratification, 71 patients had score 0 and 110 a score ≥ 1. Imatinib standard dose was reduced at start of therapy (200–300 mg/day) in 68 patients independently from the evaluation of baseline comorbidities, but based only on physician judgement: 43.6% of these patients had score 0 compared to 34% of patients who had score ≥ 1. Significant differences were found in terms of subsequent dose reduction (39% of patients with score 0 compared to 53% of patients with score ≥ 1) and in terms of drug discontinuation due to toxicity (35% of patients with score 0 vs 65% of patients with score ≥ 1). We did not find significant differences as regards occurrence of hematologic side effects, probably as a consequence of the initial dose reduction: 39% of patients with score 0 experienced grade 3/4 hematologic toxicity (most commonly anemia) compared to 42% of patients with score ≥ 1. Independently from the initial dose, comorbidities again did not have an impact on development of grade 3/4 non-hematologic side effects (most commonly skin rash, muscle cramps and fluid retention): 62% of patients with score 0 compared to 52.5% of patients with score ≥ 1. Notwithstanding the reduced dose and the weight of comorbidities we did not find significant differences but only a trend in terms of efficacy: 66% of patients with score 0 achieved a CCyR compared to 54% of patients with score ≥ 1. Comorbidities appeared to have an impact on median OS (40.8 months for patients with score 0 vs 20.16 months for patients with score ≥ 1) on EFS and on non-CML death rate. Our results suggest that treatment of very elderly CML patients might be influenced by personal physician perception: evaluation at baseline of comorbidities according to CCI should improve initial decision-making in this subset of patients. [ABSTRACT FROM AUTHOR]

Graft-versus-host disease (GVHD), mediated by mature T cells present in the donor graft, remains a major complication after allogeneic peripheral blood stem cell transplantation (PBSCT). Regulatory T cells (Tregs) (CD4+CD25highFoxp3+) are believed to maintain tolerance and to inhibit GVHD after allogeneic PBSCT (allo-PBSCT). In this study, we analyzed the graft CD3+/Tregs ratio (gCD3/Tregs R) and evaluated its impact on acute GVHD (aGVHD) and immunologic recovery after myeloablative allo-PBSCT. We analyzed 65 consecutive patients who underwent transplantation with unmanipulated peripheral blood stem cells from an HLA-identical related donor (n = 45) or an HLA-identical unrelated donor (n = 20). The median CD3+ and Tregs doses administered were 256 × 106/kg of body weight (range, 67-550 × 106/kg) and 12 × 106/kg (range, 2-21 × 106/kg), respectively; the median gCD3/Tregs R value was 18 (range, 8-250). Patients were subdivided into a high gCD3/Tregs R (≥36) group (HR; n = 26) and a low gCD3/Tregs R (<36) group (LR; n = 39). The incidence of aGVHD (grade II-IV) was lower in the LR group compared with the HR group (8/39 [20%] versus 22/26 [84%]; P < .001). Median cytomegalovirus-specific CD8+ T lymphocytes were significantly higher in the LR group than in the HR group at 1 month (2 cells/μL versus 0 cells/μL; P < .001), 2 months (6 cells/μL versus 1 cell/μL; P < .001), and 3 months (15 cells/μL versus 3 cells/μL; P < .001) months. Moreover, cytomegalovirus infection/disease was observed in 15% of patients in the LR group versus 69% of patients in the HR group (P < .001). At multivariate logistic regression, gCD3/Tregs R was correlated both with aGVHD (odds ratio, 2.50; 95% confidence interval, 1.30-4.50; P = .05) and with cytomegalovirus infection/disease (odds ratio, 2.35; 95% confidence interval, 0.9-5.00; P = .05). Taken together, our data may suggest that the balance in favor of graft Tregs content is able to mediate protective effects against aGVHD and to maintain an optimal microenviroment for the reconstitution of functional immunity. [Copyright &y& Elsevier]

Abstract: To highlight dasatinib role in the elderly, 125 unselected patients with CP-CML aged >60 years resistant/intolerant to imatinib were retrospectively evaluated. Grade 3–4 haematological and extra-haematological toxicities were reported in 39 (31.2%) and 34 (27.2%) patients; grade 3–4 haematological toxicity was higher in patients with 140mg starting dose (50.0% vs 19.6%, p =0.001). Grade 3–4 pleuro-pericardial effusions occurred in 10 patients (8.0%). Dose reductions were more common in patients with 140mg (88.4% vs 26.7%, p <0.001). Of 122 evaluable patients, 72 (59.1%) had cytogenetic response [12 (9.8%) partial, 60 (49.3%) complete]. Overall, 38/60 patients in complete CyR also achieved a molecular response. Cumulative OS at 24 and 48 months were 93.1% (95% CI 88.4–97.8) and 84.2% (95% CI 74.6–93.7). Dasatinib, at the recommended dose of 100mg/day, is effective and safe also in unselected elderly subjects. [Copyright &y& Elsevier]

Recovery of cytomegalovirus (CMV)-specific CD8+ T cells after allogeneic stem cell transplantation (SCT) is critical for protection against CMV infection and disease. Moreover, Foxp3+CD4+CD25high regulatory T cells (Tregs) are a major regulator of adaptive immunity, preventing graft-versus-host disease (GVHD) and so promoting timely and complete immune recovery. The aim of our study was to evaluate the recovery of circulating tetramer-based CMV-specific CD8+ T cells and T regs in 46 patients after allogeneic peripheral blood SCT (PBSCT). CMV infection and/or disease was observed in 7% and 94% of patients with or without CMV-specific CD8+ T cells recovery (P < .001), and in 77% and 4% of patients with or without acute GVHD (aGVHD) (P < .001), respectively. T regs values were higher in patients without than with CMV infection and/or disease at 2 (P < .001) and 3 months (P < .001) after allogeneic PBSCT, respectively. Moreover, we observed a positive correlation between T regs and the recovery of CMV-specific CD8+ T cells at 2 (r = .61, P < .0001) and 3 (r = .72, P < .00001) months, respectively. Tregs were higher in patients without than with aGVHD at 1, 2 (P < .001) and 3 months (P < .0001), respectively. At multivariate logistic regression, aGVHD (odds ratio [OR]: 2.60, 95% confidence interval [CI] [1.3-5.0], P = .0006) and CMV-specific CD8+ T cells recovery (OR:2.25, 95% CI [1.2-4.8], P = .05) were correlated with CMV infection and/or disease, whereas no correlation was found for Tregs, absolute neutrophil count, patients'' and donors'' age, disease status pretransplantation, type of disease, and CMV serology. Taken together, our data may suggest the existence of a correlation between Tregs and the recovery of CMV-specific CD8+ T cells; Tregs may preserve an optimal microenvironment for the reconstitution of functional immunity and mediate protective effects against aGVHD. [Copyright &y& Elsevier]

Inflammatory bowel diseases (IBDs) are a group of chronic conditions of the gastrointestinal tract in which nationwide studies have revealed a higher risk of hematological malignancies (HMs). Clonal hematopoiesis (CH) is a premalignant condition defined by the presence of an acquired somatic mutation characterized by a variant allele frequency (VAF) of ≥2%, in a gene frequently associated with HMs. A growing body of evidence suggests a correlation between inflammation and CH; its occurrence in the context of IBD has been previously demonstrated. With the aim to assess CH possible co-occurrence in patients with an IBD associated with HMs, we performed a targeted next-generation sequencing analysis in a cohort of thirteen patients who were referred to our center with IBD associated with HMs. Eleven (85%) patients showed one or more mutations in CH-associated genes; DNMT3A was the most frequently mutated gene, followed by ASXL1 and JAK2. These results may suggest that the mechanisms at the basis of the inflammatory environment could potentially select for the growth of hematopoietic clones harboring specific mutations. In this context, CH emergence may be boosted by the proinflammatory IBD environment, thus acting as a biological link between IBD and the HM onset. If these data are confirmed, IBD patients screened and positive for CH should undergo a hematologic follow-up to assess the risk of developing HM. Future study will clarify the relationship between these conditions., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Cumbo, Tarantini, Zagaria, Anelli, Minervini, Coccaro, Tota, Impera, Parciante, Conserva, Redavid, Carluccio, Delia, Giordano, Longo, Perrone, Rossi, Specchia, Musto and Albano.)

For monitoring minimal residual disease (MRD) in chronic myeloid leukemia (CML) the most recommended method is quantitative RT-PCR (RT-qPCR) for measuring BCR-ABL1 transcripts. Several studies reported that a DNA-based assay enhances the sensitivity of detection of the BCR-ABL1 genomic rearrangement, even if its characterization results difficult. We developed a DNA-based method for detecting and quantifying residual BCR-ABL1 positive leukemic stem cells in CML patients. We propose two alternative approaches: the first one is a fluorescence in situ hybridization (FISH)-based step followed by Sanger sequencing; the second one employs MinION, a single molecule sequencer based on nanopore technology. Finally, after defining the BCR-ABL1 genomic junction, we performed the target CML patient-specific quantification, using droplet digital PCR (ddPCR). FISH and MinION steps, respectively, together with ddPCR analysis, greatly reduce the complexity that has impeded the use of "personalized monitoring" of CML in clinical practice. Our report suggests a feasible pipeline, in terms of costs and reproducibility, aimed at characterizing and quantifying the genomic BCR-ABL1 rearrangement during MRD monitoring in CML patients., Competing Interests: CONFLICTS OF INTEREST The authors declare no conflicts of interest.

Background: Patients with primary refractory or first relapse acute myeloid leukemia (AML) are considered to have worse clinical outcomes after treatment. For these patients, the achievement of complete remission appears crucial for them to be able to undergo allotransplantation, which might be the only possible treatment., Patients and Methods: We used the FLAG-Ida (fludarabine, cytarabine [cytosine arabinoside], granulocyte colony-stimulating factor, idarubicin) regimen in patients with primary refractory/first relapse AML as a bridge to transplantation. We studied its efficacy in terms of overall response and overall survival to assess which variables (age, lactate dehydrogenase, bone marrow blast count, peripheral blood blast count, platelet count, white blood cell count, de novo or secondary AML, molecular-cytogenetic risk, duration of response, and relapsed or refractory disease) might have an effect on outcome., Results: We analyzed the data from 108 consecutive adult patients (52 males, 66 females; median age, 49 years; range, 17-72 years) with newly diagnosed AML refractory to standard induction regimens or relapse after first complete remission, who had received the FLAG-Ida protocol as salvage therapy from January 2005 to December 2015. An overall response was achieved in 48 patients (44%). On multivariate analysis, the variables with a positive effect on the response rate were molecular-cytogenetic risk (P = .009), duration of first response in relapsed AML (P = .003), AML status (relapsed or refractory; P = .047), and peripheral blood blast count (P = .016). On multivariate analysis, overall survival was significantly associated with FLAG-Ida response (hazard ratio, 0.343; P = .001) and receipt of allotransplantation (hazard ratio, 0.277; P < .001)., Conclusion: Our data seem to confirm the value of FLAG-Ida in this setting and might suggest its best usage as bridge therapy for patients awaiting allotransplantation., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: About 40% of all patients with chronic myeloid leukemia are currently old or very old. They are effectively treated with imatinib, even though underrepresented in clinical studies. Furthermore, as it happens in the general population, they often receive multiple drugs for associated chronic illnesses. Aim of this study was to assess whether or not in imatinib-treated patients aged >75 years the exposure to polypharmacy (5 drugs or more) had an impact on cytogenetic and molecular response rates, event-free and overall survival, as well as on hematological or extra-hematological toxicity., Methods: 296 patients at 35 Italian hematological institutions were evaluated., Results: Polypharmacy was reported in 107 patients (36.1%), and drugs more frequently used were antiplatelets, diuretics, proton pump inhibitors, ACE-inhibitors, beta-blockers, calcium channel blockers, angiotensin II receptors blockers, statins, oral hypoglycemic drugs and alpha blockers. Complete cytogenetic response was obtained in 174 patients (58.8%), 78 (26.4%) within 6 month, 63 (21.3%) between 7 and 12 months. Major molecular response was obtained in 153 patients (51.7%), 64 (21.6%) within the 12 month. One hundred and twenty-eight cases (43.2%) of hematological toxicity were recorded, together with 167 cases (56.4%) of extra-hematological toxicity. Comparing patients exposed to polypharmacy to those without, no difference was observed pertaining to the dosage of imatinib, cytogenetic and molecular responses and hematological and extra-hematological toxicity., Conclusion: Notwithstanding the several interactions reported in the literature between imatinib and some of the medications considered herewith, this fact does not seem to have a clinical impact on response rate and outcome.

Graft-versus-host disease (GVHD), mediated by mature T cells present in the donor graft, remains a major complication after allogeneic peripheral blood stem cell transplantation (PBSCT). Regulatory T cells (Tregs) (CD4(+)CD25(high)Foxp3(+)) are believed to maintain tolerance and to inhibit GVHD after allogeneic PBSCT (allo-PBSCT). In this study, we analyzed the graft CD3(+)/Tregs ratio (gCD3/Tregs R) and evaluated its impact on acute GVHD (aGVHD) and immunologic recovery after myeloablative allo-PBSCT. We analyzed 65 consecutive patients who underwent transplantation with unmanipulated peripheral blood stem cells from an HLA-identical related donor (n = 45) or an HLA-identical unrelated donor (n = 20). The median CD3(+) and Tregs doses administered were 256 × 10(6)/kg of body weight (range, 67-550 × 10(6)/kg) and 12 × 10(6)/kg (range, 2-21 × 10(6)/kg), respectively; the median gCD3/Tregs R value was 18 (range, 8-250). Patients were subdivided into a high gCD3/Tregs R (≥36) group (HR; n = 26) and a low gCD3/Tregs R (<36) group (LR; n = 39). The incidence of aGVHD (grade II-IV) was lower in the LR group compared with the HR group (8/39 [20%] versus 22/26 [84%]; P < .001). Median cytomegalovirus-specific CD8(+) T lymphocytes were significantly higher in the LR group than in the HR group at 1 month (2 cells/μL versus 0 cells/μL; P < .001), 2 months (6 cells/μL versus 1 cell/μL; P < .001), and 3 months (15 cells/μL versus 3 cells/μL; P < .001) months. Moreover, cytomegalovirus infection/disease was observed in 15% of patients in the LR group versus 69% of patients in the HR group (P < .001). At multivariate logistic regression, gCD3/Tregs R was correlated both with aGVHD (odds ratio, 2.50; 95% confidence interval, 1.30-4.50; P = .05) and with cytomegalovirus infection/disease (odds ratio, 2.35; 95% confidence interval, 0.9-5.00; P = .05). Taken together, our data may suggest that the balance in favor of graft Tregs content is able to mediate protective effects against aGVHD and to maintain an optimal microenviroment for the reconstitution of functional immunity., (Copyright © 2012 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

The in vivo effect of recombinant human erythropoietin (rHuEpo) and granulocyte colony-stimulating factor (G-CSF) combined treatment on CD34(+) cells was evaluated by fluorescence in situ hybridization (FISH) in 13 myelodysplastic syndrome (MDS) patients with known cytogenetic abnormalities. After treatment, responsive patients presented a significantly lower proportion of FISH abnormal CD34(+) cells than before treatment (P = 0.003), and in comparison with unresponsive cases (P = 0.007). Response to treatment was associated with a reduced degree of apoptosis in CD34(+) cells (P = 0.021): however, no difference in telomere length was observed in responsive patients after growth factor administration. Although the number of patients analysed was relatively small, the present data suggest that, in MDS patients, response to rHuEpo and G-CSF may be related to the proliferation of karyotypically normal but potentially defective CD34(+) progenitor cells.