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Background: Post-transplant cyclophosphamide (PTCY) is widely used as graft versus host disease (GvHD) prophylaxis in allogeneic hematopoietic stem cell transplant (HSCT) recipients, with reported clinical benefits in patients who underwent transplant from a matched unrelated donor (MUD). However, real-life data on clinical efficacy and safety of PTCY in haploidentical and MUD transplantations are still poor. Methods: In our real-life retrospective observational study, we included a total of 40 consecutive adult patients who underwent haploidentical or MUD HSCT for various hematological malignancies and who received PTCY (n = 24) or ATG (n = 16) as GvHD prophylaxis at Hematology Units from hospitals of Salerno and Avellino, Italy, and clinical outcomes were compared. Results: We showed protective effects of PTCY against disease relapse with the relapse rate after transplantation of 16% versus 50% in the ATG arm (p = 0.02). All-cause mortality was lower (36% vs. 75%; p = 0.02) and the 2-year overall survival was slightly superior in patients administered PTCY (61% vs. 42%; p = 0.26). Conclusions: We support the use of PTCY, even in a real-life setting; however, the optimization of this protocol should be further investigated to better balance relapse prevention and GvHD prophylaxis. [ABSTRACT FROM AUTHOR]

Background: Splicing modifications, genomic instability, and hypomethylation are central mechanisms promoting myelodysplasia and acute myeloid leukemia (AML). In this real-life retrospective study, to elucidate pathophysiology of clonal hemopoiesis in hematological malignancies, we investigated clinical significance of mutations in leukemia-related genes of known pathogenetic significance and of variants of uncertain clinical significance (VUS) in a cohort of patients with MDS and AML. Methods: A total of 59 consecutive subjects diagnosed with MDS, 48 with AML, and 17 with clonal cytopenia with unknown significance were screened for somatic mutations in AML-related genes by next-generation sequencing. Results: We showed that TET2, SETBP1, ASXL1, EZH2, RUNX1, SRSF2, DNMT3A, and IDH1/2 were commonly mutated. MDS patients also showed a high genetic complexity, especially for SETBP1. Moreover, the presence of SETBP1 wild-type or two or more simultaneous VUS variants identified a subgroup of AML and MDS patients with better outcome, while the presence of single SETBP1 VUS variant was related to a worse prognosis, regardless TET2 mutational status. Conclusions: In conclusions, we linked both pathogenic and VUS variants in AML-related genes to clonal hematopoiesis; therefore, we proposed to consider those variants as prognostic markers in leukemia and myelodysplasia. However, further studies in larger prospective cohorts are required to validate our results. [ABSTRACT FROM AUTHOR]

Oxidative stress is important in the pathogenesis of atopic dermatitis (AD); it can damage keratinocytes, increase dermal inflammation, and reduce skin barrier function, the hallmarks of atopic dermatitis pathogenesis. Measuring oxidative stress is possible by identifying peripheral markers, which could have a predictive value of disease severity, disease progression and response to therapy, with a potentially significant impact on patient management. Our review explored this fascinating field of research, focusing on old and new possible biomarkers that may represent an effective tool to investigate the inflammatory-oxidative axis in AD, adding clinically important information to patient care. [ABSTRACT FROM AUTHOR]

Background: Current chronic lymphocytic leukemia (CLL) International Prognostic Index (IPI) stratifies patients based on clinical, molecular, and biochemical features; however, B‐cell markers also influence CLL outcomes. Here, prognostic roles of CD11c, CD38, and CD49d were first evaluated, and then an immunophenotypic score was combined with CLL‐IPI for risk stratification of CLL patients. Methods: A total of 171 CLL subjects were included, and surface marker expression was assessed by flow cytometry. Levels ≥30% were chosen as cut‐off of positivity to a marker; then values of 1 (for CD11c and CD38) or 3 (for CD49d) were assigned and scores determined for each patient's clone immunophenotype. Results: CD49d positivity was significantly associated with simultaneous expression of CD11c and/or CD38, unmutated IGHV status, and higher β2‐microglobulin levels compared to those with CD49d negativity. Moreover, CD49d+ patients experienced a shorter progression‐free survival and time to treatment. When the immunophenotypic score was combined with CLL‐IPI, patients with high‐risk immunophenotype had a significantly lower time‐to‐treatment regardless CLL‐IPI. Conclusions: Our results suggested clinical utility of an integrated prognostic score for better risk stratification of CLL patients. These results require further validation in prospective larger studies. [ABSTRACT FROM AUTHOR]

Treatment of relapsed/refractory or elderly unfit acute myeloid leukemia (AML) is still challenging, and hypomethylating agents in combination with venetoclax, an oral selective BCL2 inhibitor, might be successfully used as salvage therapy. However, clinical trials evaluating the efficacy and safety of this combination in the setting of multiresistant AML treatment also as a bridge to transplant are still ongoing. Here, we reported a 50-year-old male diagnosed with AML with normal cytogenetics and wild type for fms-like tyrosine kinase 3, nucleophosmin 1, and KIT, and treated with decitabine and venetoclax as the fifth line of therapy and after a relapse post-allogeneic transplant. The patient achieved a complete remission and successfully underwent a haploidentical transplant with an overall survival of 48.6 months. [ABSTRACT FROM AUTHOR]

Background: Viral reactivations are frequent in hematologial patients due to their cancer‐related and drug‐induced immunosuppressive status. Daratumumab, an anti‐CD38 monoclonal antibody, is used for multiple myeloma (MM) treatment, and causes immunosuppression by targeting CD38‐expressing normal lymphocytes. In this single‐center two‐arm real‐life experience, we evaluated incidence of cytomegalovirus (CMV) reactivation in MM patients treated with daratumumab‐based regimens as first‐ or second‐line therapy. Methods: A total of 101 consecutive MM patients were included in this study and were divided into two cohorts: daratumumab and nondaratumumab‐based (control) regimens. Patients treated with >2 lines of therapies were excluded to reduce the confounding factor of multi‐treated cases. Primary endpoint was the CMV reactivation rate. Results: CMV reactivation rate was significantly higher in the daratumumab cohort compared to control group (33% vs. 4%; p < 0.001), also with higher CMV‐DNA levels (>1000 UI/mL in 12% of cases; p < 0.05). However, only one subject developed a CMV disease with severe pneumonia, while 12% of patients were successfully treated with preemptive therapy with valganciclovir. No subjects in the control cohort required anti‐CMV agents (p = 0.02). Conclusion: Our single‐center retrospective experience showed that daratumumab might significantly increase the risk of CMV reactivation in MM, while currently underestimated and related to morbility and mortality in MM patients under treatments. However, further validation on larger and prospective clinical trials are required. [ABSTRACT FROM AUTHOR]

This article discusses a case study of a patient with refractory multiple myeloma who developed psoriasis as a side effect of lenalidomide treatment. The patient was successfully treated with narrowband ultraviolet B phototherapy (NB-UVB) without discontinuing the lenalidomide. The article highlights the efficacy and safety of NB-UVB in managing lenalidomide-induced psoriasis and suggests that NB-UVB can be considered as a therapeutic option for psoriasis secondary to anti-multiple myeloma agents. However, further validation through larger prospective trials is needed. [Extracted from the article]

Isatuximab, a novel anti‐CD38 monoclonal antibody, is approved in combination with carfilzomib and dexamethasone (Isa‐Kd) in relapsed/refractory multiple myeloma (RRMM) patients. Because of its recent introduction, real‐world efficacy and safety are poorly reported. In this Italian multicenter real‐life observational retrospective study, efficacy and safety of the Isa‐Kd regimen were evaluated in a cohort of 103 RRMM patients. Overall response rate (ORR) was 85%, with stringent (sCR) or complete response (CR) in 18% of cases and very good partial response (VGPR) in 39%. Median PFS and OS were not reached within the study period, while 1‐year PFS and OS were 72% and 77%, respectively. Hematological toxicities were observed in 42% of subjects, and cardiac toxicities occurred in 24% of cases. Moreover, we conducted a subanalysis on patients (N = 69) treated with Isa‐Kd after one prior line of therapy, showing an ORR of 88%, with sCR + CR in 20% of subjects, VGPR in 46%, and PR in 22% of patients. In this group, median PFS and OS were not reached, while 1‐year PFS and OS were 92% and 95%, respectively. In conclusions, our study confirmed Isa‐Kd as an effective treatment option for RRMM with a manageable safety profile even in real‐life settings. [ABSTRACT FROM AUTHOR]

The achievement of complete remission (CR) is crucial for acute myeloid leukemia (AML) patients undertaking curative therapy, but relapse often occurs within months, highlighting the need for strategies to prolong disease-free survival (DFS). Our phase III study compared the efficacy and safety of azacitidine (AZA) to best supportive care (BSC) in elderly AML patients who achieved CR following intensive induction and consolidation therapy. This ancillary study (QOL-ONE Trans-2) evaluated biological changes in bone marrow using Next-Generation Sequencing (NGS). We analyzed baseline, randomization, and 6-month post-remission samples from 24 patients (median age of 71 and 12 males). High-throughput NGS targeted 350 myeloid malignancy-related genes, considering variants with a variant allele frequency ≥ 4%. At diagnosis, all patients had 5 to 17 (median = 10) mutations, with DNMT3A (42%), NPM1 (33%), and TET2 (33%) being most frequent. FANCA mutations in four patients were linked to a higher relapse risk (HR = 4.96, p = 0.02) for DFS at both 2 and 5 years. Further HLA-specific NGS analyses are ongoing to confirm these results and their therapeutic implications. [ABSTRACT FROM AUTHOR]

Blinatumomab is a bispecific T-cell engager approved for relapsed/refractory and minimal residual disease positive B-cell Acute Lymphoblastic Leukemia. We conducted a retrospective study evaluating the outcome of Blinatumomab. The impact of clinical and treatment-related variables on cumulative incidence of relapse/progression (CIRP), event-free (EFS) and overall survival (OS) was analyzed. From January 2016 to December 2022 50 Ph'- (37) and Ph+ (13) B-ALL patients received Blinatumomab. The median age was 37. Indications to blinatumomab were relapsed/refractory B-ALL in 29 and MRD-positive in 21 patients. Blinatumomab was the 2nd and 3rd line in 40 and in 10 patients, respectively. Twenty patients were treated pre-transplantation, ten were treated for relapse after transplant, twenty were not eligible for transplant. Out of 29 patients treated for relapsed/refractory disease, 16 (55%) achieved complete response and 12 achieved MRD-negativity. Out of 21 patients treated for MRD, 16 (76%) achieved MRD-negativity. At a median follow-up of 46 months the median EFS and OS were 11.5 and 16.2 months. The CIRP was 50%. In univariate analysis age, disease-status (overt vs. minimal disease) at blinatumomab, bridging to transplant after blinatumomab and MRD-response resulted significant for EFS and OS. In multivariate analysis only disease-status and MRD-response retained significance both for EFS and OS. Disease-status and MRD-response resulted significant for EFS and OS also after censoring at HSCT. This retrospective study on B-ALL patients treated with blinatumomab confirms a superior outcome for MRD-responsive over MRD non-responsive patients. Survival depends also on the disease-status prior treatment. [ABSTRACT FROM AUTHOR]

Cytomegalovirus (CMV) reactivation during chemotherapy or after organ or hematopoietic stem cell transplantation is a major cause of morbidity and mortality, and the risk of reactivation increases with patients’ age. Bendamustine, an alkylating agent currently used for treatment of indolent and aggressive non-Hodgkin lymphomas, can augment the risk of secondary infections including CMV reactivation. In this real-world study, we described an increased incidence of CMV reactivation in older adults (age >60 years old) with newly diagnosed and relapsed/refractory indolent and aggressive diseases treated with bendamustine-containing regimens. In particular, patients who received bendamustine plus rituximab and dexamethasone were at higher risk of CMV reactivation, especially when administered as first-line therapy and after the third course of bendamustine. In addition, patients with CMV reactivation showed a significant depression of circulating CD4+ T cell count and anti-CMV IgG levels during active infection, suggesting an impairment of immune system functions which are not able to properly face viral reactivation. Therefore, a close and early monitoring of clinical and laboratory findings might improve clinical management and outcome of non-Hodgkin lymphoma patients by preventing the development of CMV disease in a subgroup of subjects treated with bendamustine more susceptible to viral reactivation. [ABSTRACT FROM AUTHOR]

Infections caused by antibiotic-resistant bacteria represent a serious threat to global public health. Recently, due to its increased resistance to carbapenems and β-lactams, Klebsiella pneumoniae has become one of the main causes of septicemia, pneumonia, and urinary tract infections. It is crucial to take immediate action and implement effective measures to prevent further spread of this issue. This study aims to report the prevalence and antibiotic resistance rates of K. pneumoniae strains isolated from clinical specimens from 2015 to 2020 at the University Hospital of Salerno, Italy. More than 3,800 isolates were collected from urine cultures, blood cultures, respiratory samples, and others. K. pneumoniae isolates showed broad resistance to penicillin and cephalosporins, and increased susceptibility to fosfomycin and gentamicin. Extended spectrum beta-lactamase (ESBL) isolates accounted for 20–22%. A high percentage of strains tested were resistant to carbapenems, with an average of 40% to meropenem and 44% to ertapenem. The production of ESBLs and resistance to carbapenems is one of the major public health problems. Constant monitoring of drug-resistant isolates is crucial for developing practical approaches in implementing antimicrobial therapy and reducing the spread of K. pneumoniae in nosocomial environments. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented related to valganciclovir as CMV reactivation prophylaxis in patients receiving alemtuzumab for marrow failure syndromesis presented.

Introduction: Fine needle aspiration cytology (FNAC) combined with rapid on‐site evaluation (ROSE) and ancillary techniques is an accurate diagnostic tool for many pathologies. However, in some cases, it may not be sufficient for actionable diagnoses or molecular testing, especially for cases that require large immunohistochemical panels or cases in which histological features are mandatory for the diagnosis. Core needle biopsy (CNB), on the contrary, provides samples that are suitable for histological features and sufficient for all ancillary studies. However, CNB is often performed by radiologists or clinicians without the direct participation of cytopathologists, which can lead to missed or delayed diagnoses. This study reports on the experience of combining FNAC and CNB performed in one setting by cytopathologists. The aim was to evaluate the impact of CNB on FNAC and the diagnostic efficiency of the combined procedures. Materials and Methods: One hundred forty‐two FNAC and CNB procedures performed in the same setting over a period of 2 years were analysed. The FNAC diagnoses were compared and integrated with the subsequent CNB diagnoses. The impact of CNB was categorized as follows: non‐contributory, in cases of inadequate samples; confirmed, when the CNB and FNAC diagnoses were the same; improved, when the CNB diagnosis was consistent with the FNAC diagnosis and further specified the corresponding entity; allowed, when CNB produced a diagnosis that could not be reached by FNAC; changed, when the CNB changed the previous FNAC diagnosis. Results: CNB confirmed the FNAC diagnosis in 40.1% of cases (n = 57/142). CNB improved the FNAC diagnosis in 47.2% of cases (n = 67/142). CNB allowed a diagnosis that could not be performed on FNAC in 2.1% of cases (n = 3/142). CNB changed a previous FNAC diagnosis in 2.1% of cases (n = 3/142). CNB was non‐contributory in 8.4% of cases (n = 12/142). CNB produced a positive impact on the whole diagnostic procedure in 51.4% of total cases (n = 73/142). The combined FNAC and CNB resulted in actionable diagnoses in 91.5% of all cases (n = 130/142). A complete molecular assessment was successfully performed in 14.7% of cases (n = 21/142) utilizing either FNAC or CNB material. Conclusions: The combined use of FNAC and CNB in one setting improves the diagnostic accuracy of both procedures. This approach exploits the advantages of each procedure, enhancing the accuracy of the final diagnosis. [ABSTRACT FROM AUTHOR]

Daratumumab, an anti-CD38 monoclonal antibody, is worldwide approved for treatment of newly diagnosed and relapsed/refractory multiple myeloma (MM) patients and is available as intravenous or subcutaneous formulations. Intravenous daratumumab is associated with frequent infusion-related reactions, while eye complications, especially refractive shifts, are very rare, with only previously reported cases. Here, we described a rare case of multi-refractory MM who developed transient myopic shift during intravenous daratumumab infusion successfully treated only with cycloplegic collyrium not requiring infusion rate lowering or drug discontinuation. This conservative therapeutic approach allowed termination of induction therapy and autologous hematopoietic stem-cell transplantation resulting in durable complete remission. [ABSTRACT FROM AUTHOR]

The microenvironment plays an essential role in multiple myeloma (MM) development, progression, cell proliferation, survival, immunological escape, and drug resistance. Mesenchymal stromal cells and macrophages release tolerogenic cytokines and favor anti-apoptotic signaling pathway activation, while the urokinase plasminogen activator receptor (uPAR) system contributes to migration through an extracellular matrix. Here, we first summarized the role of macrophages and the uPAR system in MM pathogenesis, and then we reported the potential therapeutic effects of uPAR inhibitors in a case series of primary MM-derived adherent cells. Our preliminary results showed that after uPAR inhibitor treatments, interleukein-6 (mean ± SD, 8734.95 ± 4169.2 pg/mL vs. 359.26 ± 393.8 pg/mL, pre- vs. post-treatment; p = 0.0012) and DKK-1 levels (mean ± SD, 7005.41 ± 6393.4 pg/mL vs. 61.74 ± 55.2 pg/mL, pre- vs. post-treatment; p = 0.0043) in culture medium were almost completely abolished, supporting further investigation of uPAR blockade as a therapeutic strategy for MM treatment. Therefore, uPAR inhibitors could exert both anti-inflammatory and pro-immunosurveillance activity. However, our preliminary results need further validation in additional in vitro and in vivo studies. [ABSTRACT FROM AUTHOR]

Simple Summary: Azacitidine (AZA) is a hypomethylating agent with well-known antileukemic activity. Due to its favorable safety profile, AZA is widely used alone or in association with other drugs for the frontline treatment of patients with acute myeloid leukemia (AML) unfit for intensive chemotherapy. To date, only a few studies have used AZA as maintenance therapy during complete remission in patients with AML. In our phase-3 randomized multicenter trial, AZA improved disease-free survival (DFS) up to 2 and 5 years in patients aged >68 years compared to best supportive care (BSC). No patients died before leukemic relapse and no differences in patient-reported outcome measures between AZA and BSC patient groups were observed. The most frequent side effect seen in patients was low neutrophil count. In summary, AZA given as a post-remission therapy was found to provide benefit in AML patients aged >68 years. This phase-3 randomized multicenter trial evaluated the efficacy of subcutaneous azacitidine (AZA) post-remission therapy vs. best supportive care (BSC) in elderly acute myeloid leukemia (AML) patients. The primary endpoint was the difference in disease-free survival (DFS) from complete remission (CR) to relapse/death. Patients with newly diagnosed AML aged ≥61 years received two courses of induction chemotherapy ("3+7" daunorubicin and cytarabine) followed by consolidation (cytarabine). At CR, 54 patients were randomized (1:1) to receive BSC (N = 27) or AZA (N = 27) at a dose of 50 mg/m2 for 7 days every 28 days and the dose increased after the 1st cycle to 75 mg/m2 for a further 5 cycles, followed by cycles every 56 days for 4.5 years. At 2 years, median DFS was 6.0 (95% CI: 0.2–11.7) months for patients receiving BSC vs. 10.8 months (95% CI: 1.9–19.6, p = 0.20) months for AZA. At 5 years, DFS was 6.0 (95% CI: 0.2–11.7) months in the BSC arm vs. 10.8 (95% CI: 1.9–19.6, p = 0.23) months in the AZA arm. Significant benefit was afforded by AZA on DFS at 2 and 5 years in patients aged >68 years (HR = 0.34, 95% CI: 0.13–0.90, p = 0.030 and HR = 0.37, 95% CI: 0.15–0.93, p = 0.034, respectively). No deaths occurred prior to leukemic relapse. Neutropenia was the most frequent adverse event. There were no differences in patient-reported outcome measures between study arms. In conclusion, AZA post-remission therapy was found to provide benefit in AML patients aged >68 years. [ABSTRACT FROM AUTHOR]

Mast cells (MCs) are immune cells distributed in many organs and tissues and involved in the pathogenesis of allergic and inflammatory diseases as a major source of pro-inflammatory and vasoactive mediators. MC-related disorders are heterogeneous conditions characterized by the proliferation of MC within tissues and/or MC hyper-reactivity that leads to the uncontrolled release of mediators. MC disorders include mastocytosis, a clonal disease characterized by tissue MC proliferation, and MC activation syndromes that can be primary (clonal), secondary (related to allergic disorders), or idiopathic. Diagnosis of MC disorders is difficult because symptoms are transient, unpredictable, and unspecific, and because these conditions mimic many other diseases. Validation of markers of MC activation in vivo will be useful to allow faster diagnosis and better management of MC disorders. Tryptase, being the most specific MC product, is a widely used biomarker of proliferation and activation. Other mediators, such as histamine, cysteinyl leukotrienes, and prostaglandin D2, are unstable molecules and have limitations in their assays. Surface MC markers, detected by flow cytometry, are useful for the identification of neoplastic MC in mastocytosis but, so far, none of them has been validated as a biomarker of MC activation. Further studies are needed to identify useful biomarkers of MC activation in vivo. [ABSTRACT FROM AUTHOR]

Introduction: We describe a case of intrathecal methotrexate toxicity and perform a literature review of existing cases. Case presentation: A 23-year-old man who received diagnosis of acute lymphoblastic leukemia and started chemotherapy according to the LAL1913 protocol underwent CNS prophylaxis with intrathecal methotrexate. About 1 month after, he developed a flaccid paraparesis. CSF analysis showed albumin/cytological dissociation. Spinal MRI showed thickening of the ventral roots of the cauda equina with contrast enhancement. Nerve conduction studies showed severe lower limb motor axonal neuropathy. Needle examination showed acute denervation involving L3-S1 roots. Methotrexate was stopped, and the patient was treated with intravenous immunoglobulins, followed by high-dose intravenous methylprednisolone, with a gradual improvement. Three months later, the spine MRI was normal. Electrophysiological and imaging findings were indicative of pure motor L3-S1 polyradiculopathy. Discussion: Literature review of existing cases confirm the relatively selective involvement of lumbosacral ventral roots in intrathecal methotrexate toxicity. Pathophysiologic mechanisms suggest either a direct toxicity with localized folate deficiency or an immune-mediated mechanism, the latter consistent, in our patient, with the albumin/cytological dissociation and response to immunomodulatory treatments. Pure motor polyradiculopathy of the lower limbs is rare but predictable complication of intrathecal methotrexate, which can benefit from early withdrawal and immunomodulatory treatments. [ABSTRACT FROM AUTHOR]

Fine-needle aspiration cytology (FNAC)is commonly used to obtain a pre-surgical pathological diagnosis in many organs, but its cost-effectiveness in lymphadenopathy has not been studied yet. We calculated the cost and diagnostic accuracy of a diagnostic algorithm that uses FNAC as a first-line procedure and compared it to a purely surgical approach in 545 consecutive lymphadenopathies. In 74% of the cases, FNAC alone can obtain a sufficiently detailed diagnosis, avoiding the surgical biopsy. In doing so, the average cost of diagnosis is cut to less than one-third, the patient avoids an invasive procedure and the diagnosis is reached earlier. In conclusion, the systematic use of lymph node-FNAC in the initial assessment of lymphadenopathy is clinically and economically advantageous as it avoids surgical biopsies in cases where cytology can suffice. [ABSTRACT FROM AUTHOR]

Hairy cell leukemia (HCL) treatment in elderly, frail subjects is still unsatisfactory, and interferons, old-fashioned therapies, can be effectively used in this subset of patients. Here, to the best of our knowledge, we report for the first time an old, frail HCL patient effectively and safely treated with pegylated interferon-α-2a in monotherapy as a first-line treatment. At diagnosis, the patient arrived in a life-threating condition due to severe neutropenia and splenomegaly with high risk of splenic rupture. However, splenectomy was proposed and refused by the patient; therefore, a therapy with pegylated interferon-α-2a was initiated. After six months of therapy, the patient displayed the disappearance of palpable splenomegaly and of peripheral hairy cells at morphological examination without any drug-related adverse event. Our case report supports the use of pegylated interferon-α-2a in monotherapy as an effective and safe alternative therapeutic option in frail, elderly patients not eligible for purine analogous or targeted therapies. [ABSTRACT FROM AUTHOR]

The management of older patients with chronic primary immune thrombocytopenia (ITP) is still very challenging because of the fragility of older patients who frequently have severe comorbidities and/or disabilities. Corticosteroid-based first-line therapies fail in most of the cases and patients require a second-line treatment, choosing between rituximab, thrombopoietin-receptor agonists and splenectomy. The choice of the best treatment in elderly patients is a compromise between effectiveness and safety and laparoscopic splenectomy may be a good option with a complete remission rate of 67% at 60 months. But relapse and complication rates remain higher than in younger splenectomized ITP patients because elderly patients undergo splenectomy with unfavorable conditions (age >60 year-old, presence of comorbidities, or multiple previous treatments) which negatively influence the outcome, regardless the hematological response. For these reasons, a good management of concomitant diseases and the option to not use the splenectomy as the last possible treatment could improve the outcome of old splenectomized patients. [ABSTRACT FROM AUTHOR]

Richter's syndrome represents the progression of chronic lymphocytic leukemia (CLL) to more aggressive diseases, most frequently diffuse large B-cell lymphoma, while Hodgkin's lymphoma (HL) and hairy cell leukemia (HCL) are rarely described. The first case involved a 67-year-old man with a diagnosis of a high-risk stage-II CLL treated with rituximab and ibrutinib, developed a HL nodular sclerosis variant after three months of therapy for CLL. After achieving a complete remission for HL and ibrutinib cessation because of drug-related cardiotoxicity, the patient relapsed after five months off-therapy and died due to disease progression after two cycles of brentuximab-vedotin. The second case involved an 83-year-old female with a diagnosis of stage-IV CLL treated with rituximab plus bendamustine who developed a HCL eight years later. Pentostatin was unsuccessfully employed as upfront HCL therapy, and the patient was then switched to rituximab while in remission for CLL. In conclusion, Richter's transformation risk rate might be higher in patients treated with novel targeted therapies, and multiparametric flow cytometry and lymph node biopsy at relapse could help in early identifying small clones. The treatment of predominant neoplasia is mandatory, and disease-specific drugs are administered; however, clinical efficacy might be lower in these patients. [ABSTRACT FROM AUTHOR]

Beyond well-assessed risk factors, cardiovascular events could be also associated with the presence of epigenetic and genetic alterations, such as the methylenetetrahydrofolate-reductase (MTHFR) C677T polymorphism. This gene variant is related to increased circulating levels of homocysteine (Hcy) and cardiovascular risk. However, heterozygous carriers have an augmented risk of cardiovascular accidents independently from normal Hcy levels, suggesting the presence of additional deregulated processes in MTHFR C677T carriers. Here, we hypothesize that targeting Sirtuin 1 (SIRT1) could be an alternative mechanism to control the cardiovascular risk associated to MTHFR deficiency condition. Flow Mediated Dilatation (FMD) and light transmission aggregometry assay were performed in subjects carrying MTHFR C677T allele after administration of resveratrol, the most powerful natural clinical usable compound that owns SIRT1 activating properties. MTHFR C677T carriers with normal Hcy levels revealed endothelial dysfunction and enhanced platelet aggregation associated with SIRT1 downregulation. SIRT1 activity stimulation by resveratrol intake was able to override these abnormalities without affecting Hcy levels. Impaired endothelial function, bleeding time, and wire-induced thrombus formation were rescued in a heterozygous Mthfr-deficient (Mthfr+/–) mouse model after resveratrol treatment. Using a cell-based high-throughput multiplexed screening (HTS) assay, a novel selective synthetic SIRT1 activator, namely ISIDE11, was identified. Ex vivo and in vivo treatment of Mthfr+/– mice with ISIDE11 rescues endothelial vasorelaxation and reduces wire-induced thrombus formation, effects that were abolished by SIRT1 inhibitor. Moreover, platelets from MTHFR C677T allele carriers treated with ISIDE11 showed normalization of their typical hyper-reactivity. These results candidate SIRT1 activation as a new therapeutic strategy to contain cardio and cerebrovascular events in MTHFR carriers. [ABSTRACT FROM AUTHOR]

Kaposi's sarcoma is associated with immunosuppression and human herpesvirus 8 infection, while rarely described in myeloid malignancies. Here, we illustrate a rare case of chronic myeloid leukemia treated with imatinib, a tyrosine kinase inhibitor, who developed a human herpesvirus 8‐related Kaposi's sarcoma. [ABSTRACT FROM AUTHOR]

An alemtuzumab-based experimental immunosuppressive treatment (IST) regimen was investigated in 35 patients with severe aplastic anaemia (SAA), pure red cell (PRCA) or pure white cell aplasia (PWCA). Alemtuzumab total dose was 73–103 mg s.c., followed by cyclosporine. No serious toxicity due to the regimen was observed. Adverse events were clinically irrelevant; infectious events were rare. The total response rate was 58%, 84% and 100% in SAA, PRCA and PWCA, respectively, with corresponding 6 months cumulative response probabilities of 84%, 84% and 100%. Subcutaneous alemtuzumab is a feasible and sufficiently safe IST regimen for patients suffering from immune-mediated marrow failures. [ABSTRACT FROM AUTHOR]

Adult acute lymphoblastic leukemia (ALL) with BCR-ABL1 rearrangement (Philadelphia chromosome, Ph) is a hematological aggressive disease with a fatal outcome in more than 50% of cases. Tyrosine kinase inhibitors (TKIs) targeting the activity of BCR-ABL1 protein have improved the prognosis; however, relapses are frequent because of acquired somatic mutations in the BCR-ABL1 kinase domain causing resistance to first, second and third generation TKIs. Axitinib has shown in vitro and ex vivo activity in blocking ABL1; however, clinical trials exploring its efficacy in ALL are missing. Here, we presented a 77-year-old male with a diagnosis of Ph positive ALL resistant to ponatinib and carrying a rare threonine to leucine (T315L) mutation on BCR-ABL1 gene. The patient was treated with axitinib at 5 mg/twice daily as salvage therapy showing an immediate although transient benefit with an overall survival of 9.3 months. Further dose-finding and randomized clinical trials are required to assess the real efficacy of axitinib for adult Ph positive ALL resistant to third generation TKIs. [ABSTRACT FROM AUTHOR]

Ruxolitinib is a JAK 1/2 inhibitor approved in 2011 by the Food and Drug Administration (FDA) for the treatment of patients with myelofibrosis. Currently, side effects related to the use of ruxolitinib are routinely managed through therapeutic dose adjustment and blood count monitoring. However, the evaluation of plasma concentration of this compound and other tyrosine kinase inhibitors is becoming of increasing importance, since the therapeutic efficacy of this class of drugs is characterized by a marked variability caused by the presence of genetic polymorphisms, drug–drug interactions, and potential poor patient adherence. Therapeutic drug monitoring of these compounds is thus required to ensure both an optimal response and the reduction of potential adverse effects. In this manuscript, we describe the development and validation of a reverse-phase high-performance liquid chromatography (RP-HPLC) method for the quantification of ruxolitinib in plasma, using a liquid chromatographic system equipped with a fluorometric detector (FL) and a mobile phase at pH 4.8 composed of 67:33 water:acetonitrile. The excitation and emission wavelengths were set to 320 nm and 386 nm, respectively. The lower limit of quantification in plasma was 0.1 ng/mL, and the response was linear across the concentration range from 0.2 to 500 ng/mL. The developed methodology, based on a simple extraction procedure and on a rapid chromatographic analysis involving a 5 minutes total analysis time, was validated according to the European Medicines Agency (EMA) guidelines, and may be considered as alternative and complementary to other previously proposed approaches. [ABSTRACT FROM AUTHOR]

Harmonization of flow cytometry protocols from instrument settings to antibody panel and reagents is highly encouraged for inter-laboratory data comparison in both research and clinical settings, especially for minimal residual disease monitoring evaluation in hematological diseases across centers. Here, we described inter-intra instrument comparison of two standardized 10-color staining dried tubes for B- and T-cell lymphoproliferative disorder diagnosis and monitoring on two different flow cytometers, a Beckman Coulter NaviosEx and a Beckman Coulter DxFlex. A total of 47 consecutive patients were enrolled, and 39 of them were evaluable for further studies. We show highly comparable results between the two cytometers for cell frequency and fluorescence intensity signals for both standardized 10-color staining dried tubes. For this latter, fluorescence of each antibody and subject was normalized on the mean value obtained from the entire study cohort thus reducing the effects of biological variability and allowing comparison between instruments with different detector sensitivity. In summary, dried tubes were confirmed as an optimal standardized diagnostic tool, especially when associated with EuroFlow standardized procedures by minimizing technical and biological variability. However, data analysis is still operator-dependent, and more efforts are needed to develop automated or semi-automated software for flow cytometry data analysis for diagnostic purposes. [ABSTRACT FROM AUTHOR]

Autoimmune hemolytic anemia (AIHA) is a rare hematologic disease, primarily affecting adults or children with immunodeficiency disease. First-line therapy consists of long course of steroids administration, with an early complete response rate (CRr) of 75-80%, but up to 20-30% of patients requires a second-line therapy. Rituximab is the first choice in refractory old AIHA patients, because of its safety and efficacy (early CRr at 80-90% and at 68% at 2-3 years). For this reason, splenectomy is even less chosen as second-line therapy in elderly, even though laparoscopic technique decreased complication and mortality rates. However, splenectomy can be still considered a good therapeutic option with a CRr of 81% at 35.6 months in patients older than 60 year-old, when rituximab administration cannot be performed. [ABSTRACT FROM AUTHOR]

Two patients with acute promyelocytic leukemia (APL) relapsed at 111 and 84 months after achievement of complete remission (CR) induced by a combination of all-trans retinoic acid and chemotherapy. In both patients molecular remission, obtained after consolidation, had been confirmed at 60 months from CR achievement. At relapse, morphological, immunophenotypic, cytogenetic, and molecular analyses showed findings identical to those at diagnosis. Hematological and molecular remission was induced with the identical treatment applied at diagnosis. We conclude that, although infrequently, patients with APL treated with modern combination therapy can experience very late relapse and can be rescued with treatment similar to that administered at diagnosis. [ABSTRACT FROM AUTHOR]