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Offers insight into the different transforming power of the three hybrid BCR/ABL proteins. History of the hybrid BCR/ABL gene; Molecular structure of BCR/ABL genes; Correlation of BCR breakpoint positions with leukemic phenotype; Structure and biological features of proteins, ABL, BCR and of the various BCR/ABL fusion proteins.

The advent of immunological therapies has revolutionized the treatment of solid and haematological cancers over the last decade. Licensed therapies which activate the immune system to target cancer cells can be broadly divided into two classes. The first class are antibodies that inhibit immune checkpoint signalling, known as immune checkpoint inhibitors (ICIs). The second class are cell‐based immune therapies including chimeric antigen receptor T lymphocyte (CAR‐T) cell therapies, natural killer (NK) cell therapies, and tumour infiltrating lymphocyte (TIL) therapies. The clinical efficacy of all these treatments generally outweighs the risks, but there is a high rate of immune‐related adverse events (irAEs), which are often unpredictable in timing with clinical sequalae ranging from mild (e.g. rash) to severe or even fatal (e.g. myocarditis, cytokine release syndrome) and reversible to permanent (e.g. endocrinopathies).The mechanisms underpinning irAE pathology vary across different irAE complications and syndromes, reflecting the broad clinical phenotypes observed and the variability of different individual immune responses, and are poorly understood overall. Immune‐related cardiovascular toxicities have emerged, and our understanding has evolved from focussing initially on rare but fatal ICI‐related myocarditis with cardiogenic shock to more common complications including less severe ICI‐related myocarditis, pericarditis, arrhythmias, including conduction system disease and heart block, non‐inflammatory heart failure, takotsubo syndrome and coronary artery disease. In this scientific statement on the cardiovascular toxicities of immune therapies for cancer, we summarize the pathophysiology, epidemiology, diagnosis, and management of ICI, CAR‐T, NK, and TIL therapies. We also highlight gaps in the literature and where future research should focus. [ABSTRACT FROM AUTHOR]

Summary Ruxolitinib is a JAK1/JAK2 inhibitor approved for the treatment of myelofibrosis (MF)‐related splenomegaly or symptoms. The recommended starting dose depends on platelet count, regardless of haemoglobin level at baseline. In the recent years, an overall survival (OS) advantage was reported in patients treated with ruxolitinib compared with best available therapy. We analysed a large Italian cohort of 3494 patients identified by Agenzia Italiana del Farmaco (AIFA) monitoring registries. Of them, 2337 (66.9%) started at reduced dose: these patients were older (median age 70 vs. 67), with increased incidence of large splenomegaly (longitudinal diameter 20 vs. 19.1 cm, median volume 1064 cm3 vs. 1016 cm3), with higher IPSS risk (30.9% vs. 26.1%), and worse ECOG score (more than 1 in 14.3% vs. 9.8%). After balancing for baseline characteristics, Kaplan–Meier analysis showed a median OS of 78.2 months (95% CI 65.9–89) for patients who started at full dose and 52.6 (95% CI 49–56.6) months for patients who started with reduced dose (p < 0.001). Group analysis also showed a substantial difference in patients with intermediate‐2 and high IPSS risk. The majority of MF patients in real‐world analysis started with a reduced dose of ruxolitinib, which is associated with less favourable outcomes. [ABSTRACT FROM AUTHOR]

In multiple myeloma (MM) bone marrow infiltration by monoclonal plasma cells can occur in both focal and diffuse manner, making staging and prognosis rather difficult. The aim of our study was to test whether texture analysis of 18 F-2-deoxy-d-glucose positron emission tomography/computed tomography (18F-FDG PET/CT) images can predict survival in MM patients. Forty-six patients underwent 18 F-FDG-PET/CT before treatment. We used an automated contouring program for segmenting the hottest focal lesion (FL) and a lumbar vertebra for assessing diffuse bone marrow involvement (DI). Maximum standardized uptake value (SUVmax), mean standardized uptake value (SUVmean) and texture features such as Coefficient of variation (CoV), were obtained from 46 FL and 46 DI. After a mean follow-up of 51 months, 24 patients died of myeloma and were compared to the 22 survivors. At univariate analysis, FL SUVmax (p = 0.0453), FL SUVmean (p = 0.0463), FL CoV (p = 0.0211) and DI SUVmax (p = 0.0538) predicted overall survival (OS). At multivariate analysis only FL CoV and DI SUVmax were retained in the model (p = 0.0154). By Kaplan-Meier method and log-rank testing, patients with FL CoV below the cut-off had significantly better OS than those with FL CoV above the cut-off (p = 0.0003), as well as patients with DI SUVmax below the threshold versus those with DI SUVmax above the threshold (p = 0.0006). Combining FL CoV and DI SUVmax by using their respective cut-off values, a statistically significant difference was found between the resulting four survival curves (p = 0.0001). Indeed, patients with both FL CoV and DI SUVmax below their respective cut-off values showed the best prognosis. Conventional and texture parameters derived from 18F-FDG PET/CT analysis can predict survival in MM patients by assessing the heterogeneity and aggressiveness of both focal and diffuse infiltration. [ABSTRACT FROM AUTHOR]

The author reflects on various developments in treatment of chronic myeloid leukemia (CML), a cancer of white blood cells (WBCs). Topics discussed include development of targeted treatments for CML such as by targeting the tyrosine kinase inhibitors (TKIs), history of treatment of CML such as by using chemotherapy, radiation, and allogeneic stem cell transplantation (SCT), and development of several TKI such as imatinib, a medicine, which target BCR-ABL1 activity of the kinase.

Classic Hodgkin lymphoma (cHL) consists of a heterogeneous group of haematological disorders that covers undifferentiated B cell neoplasms originating from germinal centre B cells. The HL molecular characterization still represents an ongoing challenge due to the low fraction of tumour Hodgkin and Reed–Sternberg cells mixed with a plethora of non‐tumour haematological cells. In this scenario, next generation sequencing of liquid biopsy samples is emerging as a useful tool in HL patients' management. In this review, we aimed to overview the clinical and methodological topics regarding the implementation of molecular analysis in cHL, focusing on the role of liquid biopsy in diagnosis, follow‐up, and response prediction. [ABSTRACT FROM AUTHOR]

In patients with low-risk polycythemia vera, exposure to low-dose Ropeginterferon alfa-2b (Ropeg) 100 µg every 2 weeks for 2 years was more effective than the standard treatment of therapeutic phlebotomy in maintaining target hematocrit (HCT) (< 45%) with a reduction in the need for phlebotomy without disease progression. In the present paper, we analyzed drug survival, defined as a surrogate measure of the efficacy, safety, adherence, and tolerability of Ropeg in patients followed up to 5 years. During the first 2 years, Ropeg and phlebotomy-only (Phl-O) were discontinued in 33% and 70% of patients, respectively, for lack of response (12 in the Ropeg arm vs. 34 in the Phl-O arm) or adverse events (6 vs. 0) and withdrawal of consent in (3 vs. 10). Thirty-six Ropeg responders continued the drug for up to 3 years, and the probability of drug survival after a median of 3.15 years was 59%. Notably, the primary composite endpoint was maintained in 97%, 94%, and 94% of patients still on drug at 3, 4, and 5 years, respectively, and 60% of cases were phlebotomy-free. Twenty-three of 63 Phl-O patients (37%) failed the primary endpoint and were crossed over to Ropeg; among the risk factors for this failure, the need for more than three bloodletting procedures in the first 6 months emerged as the most important determinant. In conclusion, to improve the effectiveness of Ropeg, we suggest increasing the dose and using it earlier driven by high phlebotomy need in the first 6 months post-diagnosis. [ABSTRACT FROM AUTHOR]

Unmet needs remain in later lines chronic myeloid leukemia (CML): the response rate and the overall survival of resistant patients in the chronic phase who changed a second-generation TKI in the second line with another TKI with similar action are usually poor, while the off-target toxicities and the potential development of mutations increase. The recent approval of asciminib, a STAMP inhibitor, in the third line, has the potential to soon change the therapeutic algorithm for this subset of patients. Here, we report the results of a GIMEMA survey assessing the number of patients currently treated in the third line in Italy, the current approach in later lines by Italian physicians, and the future role of this drug according to the reason to switch to asciminib (resistance and/or intolerance), as well as the perceptions about the future position of this agent. [ABSTRACT FROM AUTHOR]

Chronic lymphocytic leukaemia (CLL) is characterised by the expansion of a neoplastic mature B cell clone. CLL clinical outcome is very heterogeneous, with some subjects never requiring therapy and some showing an aggressive disease. Genetic and epigenetic alterations and pro-inflammatory microenvironment influence CLL progression and prognosis. The involvement of immune-mediated mechanisms in CLL control needs to be investigated. We analyse the activation profile of innate and adaptive cytotoxic immune effectors in a cohort of 26 CLL patients with stable disease, as key elements for immune-mediated control of cancer progression. We observed an increase in CD54 expression and interferon (IFN)-γ production by cytotoxic T cells (CTL). CTL ability to recognise tumour-targets depends on human leukocyte antigens (HLA)-class I expression. We observed a decreased expression of HLA-A and HLA-BC on B cells of CLL subjects, associated with a significant reduction in intracellular calnexin that is relevant for HLA surface expression. Natural killer (NK) cells and CTL from CLL subjects show an increased expression of the activating receptor KIR2DS2 and a reduction of 3DL1 and NKG2A inhibiting molecules. Therefore, an activation profile characterises CTL and NK cells of CLL subjects with stable disease. This profile is conceivable with the functional involvement of cytotoxic effectors in CLL control. [ABSTRACT FROM AUTHOR]

The discovery that Philadelphia-negative classical myeloproliferative neoplasms (MPNs) present with several molecular abnormalities, including the mostly represented JAK2V617F mutation, opened new horizons in the diagnosis, prognosis, and monitoring of these disorders. However, the great strides in the knowledge on molecular genetics need parallel progresses on the best approach to methods for detecting and reporting disease-associated mutations, and to shape the most effective and rationale testing pathway in the diagnosis, prognosis and monitoring of MPNs. The MPN taskforce of the Italian Society of Hematology (SIE) assessed the scientific literature and composed a framework of the best, possibly evidence-based, recommendations for optimal molecular methods as well as insights about the applicability and interpretation of those tests in the clinical practice, and clinical decision for testing MPNs patients. The issues dealt with: source of samples and nucleic acid template, the most appropriate molecular abnormalities and related detection methods required for diagnosis, prognosis, and monitoring of MPNs, how to report a diagnostic molecular test, calibration and quality control. For each of these issues, practice recommendations were provided. [ABSTRACT FROM AUTHOR]

Simple Summary: Central vein catheter (CVC) insertion is a main risk factor for deep vein thrombosis and blood stream infection in patients undergoing induction chemotherapy for acute leukemia. The decision of the treating physician to catheterize the basilica/brachial vein site as the frontline central vascular access has an important effect in minimizing morbidity and likely health care costs related to CVC complications in hematologic patients with severe and prolonged neutropenia. The basilic/brachial (BBV), internal jugular (IJV), and subclavian veins (SCV) are commonly used as central venous catheter (CVC) sites. A BBV approach [peripherally inserted central catheter (PICC)] is increasingly used for short- to intermediate-term CVCs for acute leukemias undergoing cytotoxic intensive regimens. In this retrospective study, the catheterization of the BBV, IJV, and SCV in patients with previously untreated acute leukemia was assessed. The primary outcome was the composite incidence of catheter-related symptomatic deep-vein thrombosis (sDVT) and bloodstream infection (BSI) from catheterization up to 30 days later. In a 10-year period, 336 CVC were inserted in the BBV (n = 115), IJV (n = 111), and SCV (n = 110) in 336 patients suffering from AML (n = 201) and ALL (n = 135) and undergoing induction chemotherapy. The primary outcome events were 8, 20, and 27 in the BBV, SCV and IJV cohorts (2.6, 6.9, and 9.6 per 1000 catheter-days, respectively; p = 0.002). The primary outcome risk was significantly higher in the IJV-cohort than in the BBV-cohort (HR, 3.6; 95% CI, 1.6 to 7.9; p = 0.001) and in the SCV-cohort than in the BBV-cohort (HR, 2.6; 95% CI, 1.2 to 5.9; p = 0.02). PICC was a valid CVC for the induction chemotherapy of acute leukemia for the lowest risk of sDVT and BSI. [ABSTRACT FROM AUTHOR]

Background: Emergence of dysplastic haematopoietic precursor/s, cytopenia and variable leukaemia risk characterise myelodysplastic syndromes (MDS). Impaired immune‐regulation, preferentially affecting cytotoxic T cells (CTL), has been largely observed in MDS. Recently, we described the TR3−56 T cell subset, characterised by the co‐expression of CD3 and CD56, as a novel immune‐regulatory population, able to modulate cytotoxic functions. Here, we address the involvement of TR3−56 cells in MDS pathogenesis/progression. Objectives: To analyse the relationship between TR3−56 and CTL activation/expansion in bone marrow (BM) of very‐low/low‐risk MDS subjects. Methods: Peripheral blood and BM specimens, obtained at disease onset in a cohort of 58 subjects, were analysed by immune‐fluorescence and flow cytometry, to preserve the complexity of the biological sample. Results: We observed that a trend‐increase of BM TR3−56 in high/very‐high MDS stage, as compared with very‐low/low group, associates with a decreased activation of BM resident CTL; significant correlation of TR3−56 with BM blasts has been also revealed. In addition, in very‐low/low‐risk subjects the TR3−56 amount in BM inversely correlates with the presence of activated BM CTL showing a skewed Vβ T‐cell repertoire. Conclusions: These data add TR3−56 to the immune‐regulatory network involved in MDS pathogenesis/progression. Better knowledge of the immune‐mediated processes associated with the disease might improve MDS clinical management. [ABSTRACT FROM AUTHOR]

Summary: Real‐world data on daily practice management, treatment modifications and outcome of a large cohort of chronic myeloid leukaemia (CML) patients treated with ponatinib was performed through monitoring Registries of the Italian Medicines Agency (AIFA). Overall, 666 CML subjects were included in the ponatinib registry from February 2015 to December 2020 and were eligible for analysis: 515 in chronic phase (CP), 50 in accelerated phase (AP) and 101 in blast crisis (BC). Median age at baseline was 58.7 years with a predominance of male subjects (57.1%). The median time from diagnosis to start of ponatinib was 2.35 years: 259 (38.9%) subjects had received two previous lines of treatment, 260 (39.0%) three lines and 147 (22.1%) four or more lines. A molecular response [from major molecular response (MMR) to a score of ≤0.01% on the international reporting scale (IS)] was reported for 59% of patients out of 593 patients analysed. With a median follow‐up of 14.4 months, 136 subjects (20.4%) required at least one dose reduction due to adverse events (AEs), whereas 309 patients (46.4%) required dose reduction in the absence of any evidence of side effects. Treatment discontinuation occurred in 261 patients (39%). This real‐life analysis shows that dose reductions were made primarily as a precaution rather than due to the occurrence of adverse reactions. [ABSTRACT FROM AUTHOR]

Cardio-oncology is a relatively new discipline that focuses on the cardiovascular sequelae of anti-tumour drugs. As any other young adolescent discipline, cardio-oncology struggles to define its scientific boundaries and to identify best standards of care for cancer patients or survivors at risk of cardiovascular events. The International Colloquium on Cardio-Oncology was held in Rome, Italy, 12-14 March 2014, with the aim of illuminating controversial issues and unmet needs in modern cardio-oncology. This colloquium embraced contributions from different kind of disciplines (oncology and cardiology but also paediatrics, geriatrics, genetics, and translational research); in fact, cardio-oncology goes way beyond the merging of cardiology with oncology. Moreover, the colloquium programme did not review cardiovascular toxicity from one drug or the other, rather it looked at patients as we see them in their fight against cancer and eventually returning to everyday life. This represents the melting pot in which anti-cancer therapies, genetic backgrounds, and risk factors conspire in producing cardiovascular sequelae, and this calls for screening programmes and well-designed platforms of collaboration between one key professional figure and another. The International Colloquium on Cardio-Oncology was promoted by the Menarini International Foundation and co-chaired by Giorgio Minotti (Rome), Joseph R Carver (Philadelphia, Pennsylvania, United States), and Steven E Lipshultz (Detroit, Michigan, United States). The programme was split into five sessions of broad investigational and clinical relevance (what is cardiotoxicity?, cardiotoxicity in children, adolescents, and young adults, cardiotoxicity in adults, cardiotoxicity in special populations, and the future of cardio-oncology). Here, the colloquium chairs and all the session chairs briefly summarised what was said at the colloquium. Topics and controversies were reported on behalf of all members of the working group of the International Colloquium on Cardio-Oncology. [ABSTRACT FROM AUTHOR]

Mutational analysis, available for 100 patients out of 190 (52.6%), showed a T315I only in 7 patients (7.0%; 3.7% overall) and other mutations in 28 patients (14.7%), the most represented being T315A, Y253H, F359V, F317L, and E255K. After a median follow-up of 12 months, 85% of patients improved the level of response, with 10 patients achieving a deep molecular response (MR4-4.5). At the start of ponatinib, 19.5% of patients were affected by hypertension in treatment, 1.1% and 1.6% of patients had a previous history of arterial and/or venous thrombosis and ischemic heart disease, respectively, and less than 1% of patients had suffered from a congestive heart failure. [Extracted from the article]

Simple Summary: Our retrospective collection from the database registry of the Hematology Unit of the Federico II University Medical School of Naples (Italy) of all patients referring to our center (from 1 January 2009 to 31 January 2019) for lymph node biopsy-proven lymphoma and one or more distinct splenic lesions, visible at baseline ultrasonographic scans and submitted to CEUS, could be a great asset in the diagnostic approach for splenic lymphoma. For the first time, based on a robust sample size of 260 nodules (with final diagnoses uniformly controlled by clinical laboratory imaging follow-up, in the cases not directly biopsy-proven) we showed that CEUS can achieve the diagnosis of splenic malignant lymphoma with excellent accuracy. Contrast-enhanced ultrasonography (CEUS) use for detecting lymphoma in the spleen was questioned because of the risk of its inadequate diagnostic accuracy. The aim of the present study was to validate CEUS exam for the identification of spleen involvement by lymphoma in patients at risk. A total of 260 nodules from the spleens of 77 patients with lymph node biopsy-proven non-Hodgkin lymphoma (NHL; n = 44) or Hodgkin lymphoma (HL; n = 33) at staging (n = 56) or follow-up (n = 21) were collected in a hematology Italian center and retrospectively analyzed. Nodules were classified as malignant lymphoma if ≥0.5 cm (long axis) with arterial phase isoen-hancement and early (onset <60 s after contrast agent injection) wash-out of marked (≤120 s after contrast agent injection) degree. Other perfusional combinations at CEUS scans qualified lesions as benign or inconclusive. Diagnostic reference standard was clinical laboratory imaging monitoring for 230 nodules, and/or histology for 30 nodules. The median nodule size was 1.5 cm (range 0.5–7 cm). According to the reference standard, 204 (78%) nodules were lymphomas (aggressive-NHL (a-NHL), 122; classic-HL (c-HL), 65; indolent (i)-NHL, 17) and 56 (22%) were benign (inflammation, infection, and/or mesenchymal) lesions. Sensitivity, specificity, positive predictive value, negative predictive value, and overall diagnostic accuracy of CEUS for detecting lymphoma in the spleen were 95%, 100%, 100%, 85%, and 96%, respectively. Marked wash-out range of 55–90 s (median, 74 s), 92–120 s (median, 100 s), and 101–120 s (median, 114.5 s) was 100%, 96.6%, and 77% predictive of a-NHL, c-HL, and i-NHL splenic nodular infiltration, respectively. The CEUS perfusional pattern of arterial phase isoenhancement with early wash-out of marked degree was highly accurate for the detection of lymphomatous invasion of spleen in patients at risk, enabling its use for a confident non-invasive diagnosis. [ABSTRACT FROM AUTHOR]

This study aimed at evaluating the role of consolidation radiation in a setting of Hodgkin's lymphoma (HL) patients, using event-free survival (EFS) as end point. Among 260 patients treated with induction chemotherapy for bulky HL, 160 patients achieved negative residual masses at 2-[18F]fluoro-2-deoxy-d-glucose positron emission tomography (FDG-PET) scans. They were randomly divided into two well-matched groups to receive either 32 Gy radiotherapy to bulky area or no further therapy. At a median follow-up of 40 months, histology showed a malignancy in 14% of patients in the chemotherapy-only group (HL, 11 patients) and in 4% of patients in the chemotherapy + radiotherapy group (HL, 2 patients; carcinoma in previously irradiated area, 1 patient) (P = 0.03). All the relapses in the chemotherapy-only group involved the bulky site and the contiguous nodal regions. Thus, the overall diagnostic accuracy of FDG-PET to exclude future relapses in the patients nonprotected by radiotherapy was 86% with a false-negative rate of 14%. Our study suggests that the addition of irradiation helps improve EFS in HL patients with post-chemotherapy FDG-PET-negative residual masses. [ABSTRACT FROM AUTHOR]

Objectives: Several studies suggested that CD30 expression is a favorable prognostic marker in transformed mycosis fungoides (tMF). However, evidence in this field is still unclear. This systematic review and meta-analysis aimed to evaluate the prognostic significance of CD30 in tMF.Methods: Electronic databases were searched from their inception to June 2020 for all studies assessing the prognostic value of CD30 in tMF. Pooled hazard ratio (HR) for death was calculated; a P value less than .05 was considered significant. Inconsistency index (I2) was used to assess statistical heterogeneity among studies.Results: Seven studies with 323 patients were included. CD30 expression in tMF was significantly associated with a decreased hazard of death both on univariate (HR, 0.459; 95% confidence interval [CI], 0.319-0.660; P < .001) and multivariate analysis (HR, 0.503; 95% CI, 0.345-0.734; P < .001), and the statistical heterogeneity among studies was null in all analyses (I2 = 0%).Conclusions: tMF cases with CD30 expression in large cells have a hazard of death two times lower than CD30-negative cases. [ABSTRACT FROM AUTHOR]

By contrast, the sensitivity rate for lymph node malignant status was 98-8% (95% CI 95-9-99-9%) for PDUS-guided CNB with a false-negative rate of 1-1% (two of 174 patients with lymph nodes positive for malignancy were not identified). The authors emphasised the value of lymph node excisional biopsy as the "gold standard", with the need of a tight partnership with surgical colleagues as part of a multidisciplinary team that can facilitate the surgery excisional biopsy decision-making process. Randomized comparison of power Doppler ultrasound-directed excisional biopsy with standard excisional biopsy for the characterization of lymphadenopathies in patients with suspected lymphoma. [Extracted from the article]

The use of dasatinib and nilotinib in the treatment of patients with chronic myeloid leukemia represents a valid therapeutic option for patients resistant or intolerant to imatinib. In this multicentre study, adherence, persistence and efficacy in real life over two years of treatment were evaluated. Adherence to treatment was calculated as the ratio between the dose received and the prescribed dose. The dose received was calculated using pharmacy refill data. The persistence with treatment was calculated as the difference between the end and the beginning of the treatment. Efficacy was assigned as Progression-Free Survival (PFS) and Events-Free Survival (EFS) and represented through the Kaplan-Meier curve. The number of patients analysed was 117, 70 treated with dasatinib and 47 with nilotinib. Adherence to treatment for dasatinib and nilotinib at two years was 0.91 and 0.82 respectively. Persistence at two years was 77% while the PFS was 92% for both drugs in the study. Adherence to the treatment calculated over two years showed a superiority of dasatinib over nilotinib. Nevertheless, the efficacy in terms of PFS and EFS is superimposable between the two drugs in the study. [ABSTRACT FROM AUTHOR]

The introduction of tyrosine kinase inhibitors (TKIs) has improved the overall survival of chronic myeloid leukemia patients in chronic phase (CP-CML) and reduced the rate of disease-related mortality. Conflicting results have been however reported between data emerged from sponsored clinical trials and from population-based registries. Moreover, no data are so far available for patients treated with frontline second-generation TKIs, excluding those from sponsored studies. We analyzed the mortality rate of 2315 CP-CML patients treated with frontline second-generation TKIs through the Italian Medicines Agency (AIFA) registries and compared it with the ISTAT mortality rate of the general population. The estimated differences show that the increased rate of mortality in CP-CML patients is less than 1% for the class 0–29 years, stable around 2% for the intervals 30–44 years and 45–59 years, and 1.4% for the interval 60–74 years; interestingly this rate is reduced for patients aged 75 years and more as compared to the general population (− 0.65%). The difference between potential and estimated deaths is higher among women in the age classes between 30 and 74 years. [ABSTRACT FROM AUTHOR]

Development of the highly selective targeted tyrosine kinase inhibitors (TKIs) has expanded the therapeutic options for chronic myeloid leukemia (CML). Patients undergoing TKI therapy should be closely monitored to ensure that the best therapeutic response and quality of life are achieved, and to control suboptimal responses and adverse events. Despite the high rate of response using current first‐line TKIs, treatment failure may still occur, and resistance is considered a challenge in the treatment of patients with CML. The third‐generation TKI, ponatinib, is a potent orally bioavailable pan BCR‐ABL inhibitor that inhibits both wild‐type and mutant BCR‐ABL1 kinase, including the "gatekeeper" T315I mutation, which is resistant to all other currently available TKIs. This paper reviews the effectiveness, feasibility, and safety of ponatinib in the real‐life clinical management of CML. Potential prognostic factors in identifying patients most likely to benefit from ponatinib treatment will be discussed, and case presentations illustrating situations encountered in real‐life clinical practice are described. Ponatinib is effective in patients who have received prior TKIs in clinical studies as well as under real‐life conditions. Nevertheless, the risk/benefit balance must be evaluated for each patient, particularly considering disease state, mutational status, treatment line, intolerance/resistance to prior TKIs, age, frailty, and specific comorbidities. [ABSTRACT FROM AUTHOR]

The frequency of patients who switch to a second‐line therapy from a frontline second‐generation (2gen) tyrosine kinase inhibitor (TKI) such as dasatinib and nilotinib, is still substantially unknown. We retrospectively investigated a large series of chronic phase chronic myeloid leukemia (CP‐CML) patients initially treated with 2gen TKIs monitored through the Italian Medicines Agency (AIFA Agenzia Italiana del farmaco) registries. Overall, 2420 patients were analyzed over a period of 6 years. One hundred and fifty‐seven patients (16.3%) treated with dasatinib and 164 treated with nilotinib (11.3%) have switched to another drug, with an overall frequency of 13.2%. In the dasatinib cohort, 39.4% of patients changed treatment for failure and 36.3% for intolerance as compared to 45.7% and 27.4% respectively in the nilotinib cohort. Overall, the median time to switch due to resistance was 293 days, whereas it was 317 days in case of intolerance. Resistance was observed mainly in younger male patients with high‐risk features, while intolerance was not related to any baseline parameter. After resistance/intolerance to nilotinib, the majority of patients switched to dasatinib (53.8%) whereas in case of frontline dasatinib to ponatinib (43.2%). To the best of our knowledge these data provide the first report on the frequency of discontinuation of frontline 2gen TKIs and on the main causes and pattern of choice to a second‐line therapy in the real‐life setting. [ABSTRACT FROM AUTHOR]

Objectives: Sjögren syndrome (SS) is considered as a major etiologic factor for primary salivary gland lymphoma (SGL). However, the percentage of SGL that is caused by SS (and thus the real impact of SS on SGL epidemiology) is unclear. We aimed to assess the prevalence of SS in patients with SGL through a systematic review and meta-analysis.Methods: Electronic databases were searched for studies assessing the presence of SS in patients with SGL. Pooled prevalence of SS in SGL was calculated, with a subgroup analysis based on histotype (mucosa-associated lymphoid tissue [MALT] vs non-MALT).Results: Sixteen studies with 665 SGLs were included. Pooled prevalence of SS in SGL was 18.2%, with high heterogeneity among studies. In MALT SGL, the prevalence of SS was 29.5%, with moderate heterogeneity. In non-MALT SGL, the prevalence of SS was 0%, with null heterogeneity.Conclusions: SS seems to be responsible for a significant but minor portion of SGLs. SS appears involved in MALT-type SGL but not in other histotypes. [ABSTRACT FROM AUTHOR]

Emergence of clones carrying point mutations in the BCR‐ABL1 kinase domain (KD) is a common mechanism of resistance to tyrosine kinase inhibitor (TKI)‐based therapies in Philadelphia chromosome‐positive (Ph+) acute lymphoblastic leukemia (ALL). Sanger sequencing (SS) is the most frequently used method for diagnostic BCR‐ABL1 KD mutation screening, but it has some limitations—it is poorly sensitive and cannot robustly identify compound mutations. Next‐generation sequencing (NGS) may overcome these problems. NSG is increasingly available and has the potential to become the method of choice for diagnostic BCR‐ABL1 KD mutation screening. A group discussion within an ad hoc constituted Panel of Experts has produced a series of consensus‐based statements on the potential value of NGS testing before and during first‐line TKI‐based treatment, in relapsed/refractory cases, before and after allo‐stem cell transplantation, and on how NGS results may impact on therapeutic decisions. A set of minimal technical and methodological requirements for the analysis and the reporting of results has also been defined. The proposals herein reported may be used to guide the practical use of NGS for BCR‐ABL1 KD mutation testing in Ph+ ALL. [ABSTRACT FROM AUTHOR]

Objectives: To assess the prevalence of Chlamydia psittaci, Chlamydia pneumoniae, and Chlamydia trachomatis in ocular adnexa lymphoma (OAL) determined by molecular testing in different countries and the potential association of Chlamydia infection with mucosa-associated lymphoid tissue (MALT) histotype by performing a systematic review and meta-analysis.Methods: Electronic databases were searched for studies assessing the presence of Chlamydia in OAL. Pooled prevalence of the three Chlamydia species was calculated in each country. An odds ratio was calculated for the association between Chlamydia and MALT histotype, with a significant P < .05.Results: Thirty-seven studies with 1,188 OALs were included. Pooled prevalence of C psittaci, C pneumoniae, and C trachomatis by country was done. Chlamydia infection was significantly associated with MALT histotype (odds ratio, 2.183; P = .027).Conclusions: The involvement of C psittaci in OAL is highly variable, with the highest prevalence in Italy and Korea. Chlamydia is associated with MALT histotype. [ABSTRACT FROM AUTHOR]

Treatment-free remission (TFR) in patients with chronic myeloid leukemia in chronic phase (CML-CP) is considered a feasible option, especially with the ability of second-generation tyrosine kinase inhibitors to induce higher rates of sustained deep molecular response (DMR). DASFREE is an open-label, single-arm, multicenter phase II trial assessing TFR after dasatinib discontinuation in patients with CML-CP (N = 84). At 2 years, TFR was 46% in all patients. Multivariate analyses revealed statistically significant associations between 2-year TFR and duration of prior dasatinib (≥median; p =.0051), line of therapy (first line; p =.0138), and age (>65 years; p =.0012). No disease transformation occurred, and the most common adverse events experienced off treatment were musculoskeletal (observed in 30 patients); however, dasatinib withdrawal events were reported in nine patients (11%) by the investigator. Overall, these findings support the feasibility of discontinuing dasatinib for patients with CML-CP in sustained DMR in the first line and beyond. [ABSTRACT FROM AUTHOR]

Objectives: To assess the prevalence of Hashimoto thyroiditis (HT) in primary thyroid lymphoma (PTL) and whether it differs between mucosa-associated lymphoid tissue (MALT) lymphoma and diffuse large B-cell lymphoma (DLBCL).Methods: Electronic databases were searched for studies assessing HT prevalence in PTL, based on antithyroid antibodies, clinical history, or pathology. Pooled prevalence of HT and its association with histotype (MALT or DLBCL) were calculated.Results: Thirty-eight studies with 1,346 PTLs were included. Pooled prevalence results were 78.9% (any HT evidence), 65.3% (antithyroid antibodies), 41.7% (clinical history), and 64% (pathology). HT prevalence was significantly higher in MALT lymphoma than in DLBCL (P = .007) and in mixed DLBCL/MALT than in pure DLBCL (P = .002).Conclusions: Overall, 78.9% of patients with PTL have any HT evidence, but only half of these had been clinically followed. The difference in HT prevalence suggests that a subset of DLBCL may not derive from MALT lymphoma. [ABSTRACT FROM AUTHOR]

In multiple myeloma (MM) patients, 18F-FDG-PET/CT allows either the detection of disease spread by using visual parameters based on the Italian Myeloma criteria for PET Use (IMPeTUs) or the direct measurement of metabolic tumor burden by volume-based parameters such as metabolic tumor volume (MTV). The purpose is to evaluate the contribution of visual and volumetric parameters in the prediction of progression-free survival (PFS) and overall survival (OS) in MM patients. Forty-seven patients in stage IIIA who had undergone whole-body 18F-FDG-PET/CT were retrospectively evaluated. In each patient, visual parameters were determined and compared with volumetric parameters for PFS and OS prediction after a mean follow-up period of 53 months. Among the visual and volumetric parameters tested, a statistically significant difference was found between maximum standardized uptake value, MTV, total lesion glycolysis, and number of lytic lesions of patients with (n = 26) or without (n = 21) progression (p = 0.0400, p = 0.0065, p = 0.015, and p = 0.0220, respectively) and of dead (n = 24) vs survivors (n = 23) (p = 0.0171, p = 0.0037, p = 0.0060, and p = 0.0270, respectively). At univariate and multivariate analysis, MTV and hemoglobin were predictive of both PFS (p = 0.008) and OS (p = 0.0026). The best MTV discriminative value assessed by receiver operating characteristic curve analysis for predicting both PFS and OS was 39.4 ml. By Kaplan-Meier analysis and log-rank test, PFS and OS were significantly better in patients with MTV ≤ 39.4 ml (p = 0.0004 and p = 0.0001, respectively) as compared with those having an MTV higher than the cutoff. The volume-based parameter MTV determined by 18F-FDG-PET/CT may be used in the prediction of PFS and OS in myeloma patients. [ABSTRACT FROM AUTHOR]

The authors underscored that HBV prophylaxis extended over 1 year should be given for HBsAg-positive patients undergoing HSCT for hematological malignancies, regardless of the type of drug against HBV prescribed. After a median follow-up of 80 months, no emergent HBV DNA or exacerbation of HBV replication was registered in any of the 45 patients, in addition, none of the patients developed acute hepatitis. Hepatitis B reactivation in hematopoietic stem cell transplanted patients: 20 years of experience of a single center from a middle endemic country. [Extracted from the article]

Reduced regulatory T cells (Treg) in bone marrow preferentially associate with the expansion of cytotoxic T lymphocytes in low risk MDS patients. Bone marrow CD3+CD56+regulatory T lymphocytes (TR3-56 cells) are inversely associated with activation and expansion of bone marrow cytotoxic T cells in IPSS-R very-low/low risk MDS patients. [Extracted from the article]

Ruxolitinib is the only commercially available JAK1/2 inhibitor approved for the treatment of myelofibrosis-related splenomegaly and symptoms. During treatment, as rare conditions, leukocytosis and/or thrombocytosis could develop and the management of these situations is not well established. We report here 53 myelofibrosis patients that received a combination of hydroxyurea and ruxolitinib because of uncontrolled myeloproliferation. Both drugs were administered outside clinical trials. At 48 weeks, a significant reduction in leucocyte and platelet counts was observed (p = 0.02 and p = 0.04, respectively). Additionally, the spleen volume decreased from a median value of 10 cm below the left costal margin (range, 0-10) to 6 cm (range, 0-15). The rate of spleen response increased from 14% at the start of the combination to 45% after 48 weeks. The safety profile of the combination was consistent with that observed with ruxolitinib single agent. These data require further confirmation in large cohorts of patients prospectively assessed. [ABSTRACT FROM AUTHOR]

• Candidates to ibrutinib or idelalisib should undergo HBV and HCV screening. • Co-trimoxazole prophylaxis against P.jirovecii is recommended during idelalisib. • Immunoglobulins when IgG <400 mg/dL and history of serious bacterial infections. • Pneumococcal vaccination is recommended in candidates to ibrutinib/idelalisib. The introduction of new therapeutic agents in chronic lymphocytic leukemia (CLL), including the new kinase inhibitors (KIs) ibrutinib and idelalisib, has changed the therapeutic landscape of the disease. The new KIs have also changed frequency and epidemiology of infections, that represent a major cause of morbidity and mortality of the disease. Hence, the great strides in the indications and use of new KIs need parallel amelioration of prophylaxis and supportive treatment for infections. Moving from the recognition that infection control represents an unmet need, the Italian Society of Hematology (SIE) convened a panel of experts who had published and/or expressed an interest in infection complications in CLL. The goal of the project was to provide practice recommendations for the management of the infectious complications of CLL during ibrutinib or idelalisib therapy. The present publication represents the results of a series of email correspondences and meetings held during 2017 and 2018. Three domains of infectious complications during KIs therapy for CLL were explored: risk assessment, risk management and risk monitoring. We hope these recommendations will help to minimize infectious adverse events, and we believe that an optimal management of them will be rewarded by better outcomes, and better quality of life. [ABSTRACT FROM AUTHOR]

Ruxolitinib, an orally bioavailable and selective inhibitor of Janus kinase 1 (JAK1) and JAK2, significantly reduces splenomegaly and disease‐related symptoms in patients with myelofibrosis (MF). However, no clear survival benefit has been demonstrated, which may in part reflect suboptimal drug exposure related to lower dosages needed to minimize hematological toxicity, specifically cytopenias. Furthermore, the optimal management of specific conditions such as leukocytosis or thrombocytosis in patients under ruxolitinib therapy is still undefined. In these cases, combining ruxolitinib with a cytoreductive agent like hydroxyurea might improve hematological response. This observational multi‐center study enrolled 20 adult patients with intermediate‐ or high‐risk primary MF, post‐ polycythemia vera MF, or postessential thrombocythemia MF with hyperproliferative manifestations of the disease and WBC and/or platelet counts not controlled by ruxolitinib therapy. The patients received treatment with a combination of ruxolitinib and hydroxyurea. A clinical response of any type was obtained in 8 patients (40%) during ruxolitinib monotherapy and in 17 patients (85%) during ruxolitinib‐hydroxyurea combination (P = 0.003). After a median duration of 12.4 months of combination therapy, 16/20 patients had a hematological response; 14/17 patients who had started combination therapy to control WBC count and 2/3 who started in order to reduce platelets count. The number of patients requiring ruxolitinib dosage reduction or discontinuations was lower during combination therapy and, at the end of follow‐up the median ruxolitinib dose was increased in 50% of patients. In conclusion, the combination of hydroxyurea with ruxolitinib yielded a high clinical response rate and increased ruxolitinib exposure in patients with hyperproliferative forms of MF. [ABSTRACT FROM AUTHOR]

The article offers information on reducing regulatory T cells in bone marrow preferentially associate with the expansion of cytotoxicT lymphocytes in low risk myelodysplastic syndromes (MDS) patients; and mentions the myelodysplastic syndromes (MDS) include clonal bone marrow (BM) disorders characterised by the emergence of dysplastic progenitors in the context of ineffective haematopoiesis, peripheral cytopenias and increased risk of acute myeloid leukaemia (AML).

Efficacy and infection morbidity of front-line immuno-chemotherapy in follicular lymphoma. Thus, during the 3-year infection follow-up, bendamustine-based regimens led to a high rate of patients experiencing any grade of infection and a high number of infection-related admissions. Primary vigorous anti-infective prophylaxis to reduce the rate of infections and related chemotherapy disruptions in patients with untreated follicular lymphoma. [Extracted from the article]

Dear editor, I Stenotrophomonas maltophilia i infection is an increasing and feared complication in immunocompromised patients due to the intrinsic multidrug resistance and potential toxicity of conventional treatments [[1]]. At our knowledge, this is the first report of successful treatment of MDR I S. maltophilia i pneumonia with a cefiderocol-based regimen in a hematologic patient. [Extracted from the article]

Despite novel agents, multiple myeloma is still an incurable disease, especially for elderly and frail patients, who are difficult to manage for concomitant comorbidities as the therapeutic options are limited and the response to chemotherapy is often short. We report our evaluations upon safety and efficacy of domestic subcutaneous bortezomib in elderly and frail patients candidate to bortezomib-melphalan-prednisone (VMP) regimen. We confirmed that overall incidence of adverse events, including peripheral neuropathy, was low, and in no case required admission to emergency service, contributing to reduce the rate of therapy discontinuation. These results confirm the effectiveness and safety of subcutaneous bortezomib, in a real-life-experience, and define a new possibility of safe auto-administration in a comfortable domestic setting. We suggest that domestic treatment can significantly improve the quality of life of the patients, avoiding unnecessary transfer to the hospital without reducing treatment efficacy. [ABSTRACT FROM AUTHOR]

The article reports on a study which found that apart from controlling haematocrit and improving splenomegaly, ruxolitinib also provides broad haematological control in patients with polycythaemia vera. According to authors, regular and comprehensive haematological control might be linked to improving outcomes in the long term.

Cancer patients may experience nonvalvular atrial fibrillation (AF) as a manifestation of cardiotoxicity. AF may be a direct effect of a neoplasm or, more often, appear as a postsurgical complication, especially after thoracic surgery. AF may also develop as a consequence of anticancer therapy (chemotherapy or radiotherapy), a condition probably underestimated. Cancer patients with AF require amultidisciplinary approach involving oncologists/hematologists, cardiologists, and coagulation experts. An echocardiogram should be performed to detect possible abnormalities of left ventricular systolic and diastolic function, as well as left atrial dilation and the existence of valvular heart disease, to determine pretest probability of sinus rhythm restoration, and identify the best treatment. The choice of antiarrhythmic treatment in cancer patients may be difficult because scanty information is available on the interactions between anticancer agents and antiarrhythmic drugs. A careful evaluation of the antithrombotic strategy with the best efficacy/safety ratio is always needed. The use of vitamin K antagonists (VKAs) may be problematic because of the unpredictable therapeutic response and high bleeding risk in patients with active cancer who are undergoing chemotherapy and who may experience thrombocytopenia and changes in renal or hepatic function. Low molecular weight heparins (in particular for short and intermediate periods) and non-VKA oral anticoagulants (NOACs) should be preferred. However, the possible pharmacological interactions of NOACs with both anticancer and antiarrhythmic drugs should be considered. Based on all these considerations, antiarrhythmic and anticoagulant therapy for AF should be tailored individually for each patient. [ABSTRACT FROM AUTHOR]

Neutropenic enterocolitis ( NEC) is an abdominal infection reported primarily in patients with acute myeloid leukemia ( AML) following chemotherapy, especially cytarabine, a notable efficacious cytotoxic agent for AML remission. Specific data regarding the impact of different cytarabine schedules and/or antibacterial regimens for NEC are sparse. The aim of the study was to identify the predictors of outcome within 30 days of NEC onset. NEC episodes were retrospectively pinpointed among 440 patients with newly diagnosed AML hospitalized in our Institution, over a 10-year period, for receiving chemotherapy protocols with 100-6000 mg/m2 daily of cytarabine. Two subgroups, survivors versus nonsurvivors, were compared by using logistic regression analysis. NEC was documented in 100 of 420 (23.8%) analyzed patients: 42.5% had received high-dose cytarabine, whereas 19% and 15% intermediate-dose and standard-dose cytarabine, respectively ( P < 0.001). The 30-day NEC attributable mortality rate was 23%. In univariate analysis, antileukemic protocols containing robust dosages of cytarabine were significantly associated with high mortality ( P < 0.001); whereas, standard-dose cytarabine and prompt initiation (at the ultrasonographic appearance of intestinal mural thickening) of NEC therapy with antibiotic combinations including tigecycline were significantly associated with low mortality. In multivariate analysis, high-dose cytarabine-containing chemotherapy was the independent predictor of poor outcome (odds ratio [ OR]: 0.109; 95% confidence interval [ CI]: 0.032-0.364; P < 0.001), whereas ultrasonography-driven NEC therapy with antibiotic regimens including tigecycline was associated with a favorable outcome ( OR: 13.161; 95% CI: 1.587-109.17; P = 0.017). Chemotherapy schedules with robust dosages of cytarabine for AML remission are associated with a high rate of NEC incidence and attributable. Vigorous antibacterial therapy, triggered off pathologic ultrasonographic findings, with drug combinations which have broad antimicrobial coverage and good gut penetration, specifically those also including tigecycline, may be effective in improving 30-day survival rate after NEC onset. [ABSTRACT FROM AUTHOR]

Ponatinib (Iclusig, ARIAD Pharmaceuticals-Incyte Co.) is a third-generation structure-guided tyrosine kinase inhibitor that is approved for treatment of Philadelphia chromosome-positive leukaemias resistant or intolerant to other inhibitors. The clinical use of ponatinib is complicated by the possible development of cardiovascular events, primarily hypertension and arterial or venous thrombotic events. The US Food and Drug Administration and the European Medicine Agency recommend that the cardiovascular profile of patients candidate for ponatinib should be carefully evaluated. For patients deemed to carry a high risk of cardiovascular events, other life-saving therapeutic options should be considered. When alternative options are not available, treatment with ponatinib is indicated but requires that haematologists and cardiologists collaborate and identify modalities of surveillance and risk mitigation in the best interest of the patient. This article reports on the expert opinion provided by a panel of Italian haematologists, cardiologists and clinical pharmacologists. It summarises suggestions that may help to improve the therapeutic index of ponatinib, primarily in the settings of chronic-phase chronic myeloid leukaemia. [ABSTRACT FROM AUTHOR]

Background: In this prospective study, the impact of granulocyte colony-stimulating factors (G-2 CSF) administered during induction treatment with bendamustine plus rituximab for indolent non- Hodgkin Llymphoma (NHL) was evaluated by comparing patients who received secondary prophylaxis with filgrastim (control group) versus. patients who received pegfilgrastim as primary prophylaxis (peg-group). The primary endpoint was the incidence rate of febrile neutropenia (FN)- related chemotherapy disruptions (regarding dose-dense and/or dose-intensity of schedule). The Ssecondary endpoint included days of hospitalization due to FN, and G-CSF-related side effects (grade ≥3 WHO toxicity criteria) in each group.Methods: One hundred twenty-two: 122 consecutive patients, with untreated indolent NHL, were referred to our outpatient unit for remission induction immuno-chemotherapy with bendamustine-rituximab. During the first period, 61 patients received secondary prophylaxis with filgrastim, given "on demand" if ANC was <1000/mm3. During the second period, 61 patients received primary prophylaxis with pegfilgrastim in a single administration.Results: Pegfilgrastim was significantly associated with fewer incidence rate of FN-related chemotherapy disruptions (11.4% in the control group vs. 1.6% in the peg-group, p = 0.04) and fewer days of hospitalization due to FN (median number 18 days in the control group vs. 6 in the peg-group, p = 0.04). In terms of G-CSF-related extra-hematological grade III side effects, no significant difference has been found in the two groups (9.8% in the control group vs. 11.5% in the peg-group, p = 0.77). Only one patient stopped the treatment in the peg-group due to intolerance.Conclusions: In patients with indolent NHL, in front-line treatment with bendamustine plus rituximab, primary prophylaxis with pegfilgrastim seems to reduce the incidence of chemotherapy disruptions due to FN, and the days of hospitalization. Moreover, it is well- tolerated and may increase the opportunity to maintain the planned schedule of treatment. These results make pegfilgrastim an advantageous option in most cases both in terms of cost-effectiveness and quality of life. These preliminary observations need to be validated by controlled clinical trials. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented on the case of acquired hemoglobin H (Hb) disease associated with primary myelofibrosis in a woman.

A letter to the editor is presented in response to the article "Salvage therapy with pegylated liposomial doxorubicin, bortezomib, cyclophosphamide, and dexamethasone in relapsed/ refractory myeloma patients," by A. Romano and colleagues in the 2014 issue.