A shorter time to the first treatment may be predicted by the absolute number of regulatory T-cells in patients with Rai stage 0 chronic lymphocytic leukemia

Regulatory T-cells (Tregs) are increased in chronic lymphocytic leukemia(CLL) and correlates with clinical and biological features of active/progressive disease. However, little is known about their ability to predict the time to first treatment (TFT). We evaluated 75 patients with Rai stage 0 CLL, in whom the absolute number of Tregs was determined at diagnosis, and correlated to main clinical and biological features, as well as to the need of receiving any specific therapy during the course of the disease. After a median follow-up of 30 months, 12 patients(16%) required therapy at some time from the diagnosis. Treated patients showed a significant higher number of peripheral white blood cells and B-lymphocytes, platelet count, cases with unmutated immunoglobulin heavy chain status, and high-risk cytogenetic abnormalities,as well as lower hemoglobin values, than patients who did not need therapy. A greater number of circulating Tregs was detected in treated patients (P < 0.001). Multivariate analysis confirmed that the absolute number of Tregs was an independent predictor of TFT in these patients, the best predictive cut-off being 41/mL. These data show that the absolute Tregs cell number is able to identify Rai stage 0 CLL patients at higher risk of requiring therapy.     

Monoclonal gammopathy and serum immunoglobulin levels as prognostic factors in chronic lymphocytic leukaemia

The relationship between chronic lymphocytic leukaemia (CLL) and qualitative/quantitative gammaglobulin abnormalities is well established. Nevertheless, in order to better understand this kind of connection, we examined 1505 patients with CLL and divided them into four subgroups on the basis of immunoglobulin (Ig) aberrations at diagnosis. A total of 73 (4·8%), 149 (10%), 200 (13·2%) and 1083 (72%) patients were identified with IgM monoclonal gammopathy (IgM/CLL), IgG monoclonal gammopathy (IgG/CLL), hypogammaglobulinaemia (hypo-γ) and normal Ig levels (γ-normal) respectively. IgM paraprotein was significantly associated with a more advanced Binet/Rai stage and del(17p)/TP53 mutation, while IgG abnormalities correlated with a higher occurrence of trisomy 12. Patients with any type of Ig abnormality had shorter treatment-free survival (TFS) but no significant impact affecting overall survival (OS) compared to those with normal Ig levels.     

Impaired nodal shrinkage and apoptosis define the independent adverse outcome of NOTCH1 mutated patients under ibrutinib therapy in chronic lymphocytic leukemia

The introduction of agents inhibiting the B-cell receptor-associated kinases such as ibrutinib has dramatically changed treatments algorithms of chronic lymphocytic leukemia (CLL) as well as the role of different adverse prognosticators. We evaluated the efficacy of ibrutinib as a single agent, in a real-life context, in 180 patients with CLL mostly pretreated, recruited from three independent cohorts from Italy. Patients received 420 mg oral ibrutinib once daily until progression or occurrence of unacceptable side effects. Seventy-three patients discontinued ibrutinib for progression or for adverse events. NOTCH1 mutations (NOTCH1 M) were correlated with a reduced redistribution lymphocytosis, calculated at 3 months on ibrutinib (P=0.022). Moreover, NOTCH1 M patients showed inferior nodal response at 6 months on ibrutinib compared to NOTCH1 wild-type patients (P<0.0001). Significant shorter progression free survival (PFS) and overall survival (OS) were observed in NOTCH1 M patients (P=0.00002 and P=0.001). Interestingly, NOTCH1 M plus a lower BAX/BCL-2 ratio identified a CLL subset showing the worst PFS and OS (P=0.0002 and P=0.005). In multivariate analysis of PFS and OS, NOTCH1 M were confirmed an independent prognosticator (P=0.00006 and P=0.0039). In conclusion, NOTCH1 M are strongly associated with a lower BAX/BCL-2 ratio, consistent with defective apoptosis, lower redistribution lymphocytosis and lower nodal shrinkage under ibrutinib treatment, this last paramter being responsible for partial responses, subsequent relapses, as well as shorter PFS and OS. Either new small molecule combination approaches or antibodies targeting NOTCH1 could be future therapeutic options for NOTCH1 M patients.     

“SIMBurns”: A high-fidelity simulation program in emergency burn management developed through international collaboration

Acute management of a severely burned patient is an infrequent and stressful situation that requires medical knowledge as well as immediate coordinated action. Many adverse events in health care result from issues related to the application of ‘non-technical' skills such as communication, teamwork, leadership and decision making rather than lack of medical knowledge. Training in these skills is known as Crisis Resource Management (CRM) training.In order to create well-prepared burn teams, it is critical to teach CRM principles through high-fidelity simulation (HFS).While CRM teaches foundational non-technical skills, HFS incorporates lifelike, whole-body, fully-responsive mannequins in order to provide a realistic emergency situation.The aim of the study is to describe the development of a novel high-fidelity simulation course called “SIMBurns: High Fidelity Simulation Program for Emergency Burn Management” that uses CRM as its foundation and is focused on management of burn injuries. The course was designed by a panel of simulation and burns experts from Meyer Children’s Hospital in Italy and Birmingham Children’s Hospital in the U.K. Simulation Program experts were certified by Boston Children’s Hospital’s Simulation Program. In this paper, we describe the course’s design, development, structure, and participant’s assessment of the course. Since the creation of the SIMBurns course in 2013, 9 courses have been conducted and 101 participants have attended the course. The course was well-received and its “Overall Satisfaction” was rated at 4.8/5. The primary objective in the SIMBurns course – to teach teamwork and CRM skills to medical staff involved in emergency burn care – was also met at 4.8/5. Participants felt that the course developed their ability to interact with other team members, further improved their understanding of how to appropriately use resources, emphasized the importance of role clarity and developed their communication skills. Additional quantitative and qualitative analyses obtained from participants were also reviewed after each course. The SIMBurns course aims to contribute to the education of those in healthcare in order to improve patient safety and to continue advancing the education of our emergency burn care teams.     

Factors predicting survival in chronic lymphocytic leukemia patients developing Richter syndrome transformation into Hodgkin lymphoma

We hereby report the clinical and biologic features of 33 of 4680 (0.7%) patients with chronic lymphocytic leukemia (CLL), managed at 10 Italian centers, who developed Hodgkin lymphoma (HL), a rare variant of Richter syndrome. The median age at CLL and at HL diagnosis were 61 years (range 41‐80) and 70 years (range 46‐82), respectively, with a median interval from CLL to the diagnosis of HL of 90 months (range 0‐258). In 3 cases, CLL and HL were diagnosed simultaneously. Hl was characterized by advanced stage in 79% of cases, International Prognostic Score (IPS) ≥4 in 50%, extranodal involvement in 39%, B symptoms in 70%. Prior treatment for CLL had been received by 82% of patients and included fludarabine in 67%. Coexistence of CLL and HL was detected in the same bioptic tissue in 87% of cases. The most common administered treatment was the ABVD regimen given to 22 patients (66.6%). The complete response (CR) rate after ABVD was 68%, and was influenced by the IPS (P = .03) and interval from the last CLL treatment (P = .057). Survival from HL was also influenced by the IPS (P = .006) and time from the last CLL treatment (P = .047). The achievement of CR with ABVD was the only significant and independent factor predicting survival (P = .037). Taken together, our results show that the IPS and the interval from the prior CLL treatment influence the likelihood of achieving CR after ABVD, which is the most important factor predicting survival of patients with CLL developing HL.     

Autologous peripheral blood stem cell transplantation and the role of lenalidomide in patients affected by poems syndrome

POEMS syndrome is a rare paraneoplastic condition, with a poorly understood pathogenesis. High dose chemotherapy followed by autologous stem cell transplantation (ASCT) has been reported to be an effective therapeutic option for patients with good performance status. Here, we review the role of ASCT for POEMS syndrome and discuss indications together with advantages and disadvantages, and related issues such lenalidomide given before or after ASCT, VEGF levels as a marker of disease, and different regimens for stem cell mobilization.     

CD200 included in a 4‐marker modified Matutes score provides optimal sensitivity and specificity for the diagnosis of chronic lymphocytic leukaemia

CD200, a transmembrane type Ia glycoprotein belonging to the immunoglobulin superfamily, has been shown to have a differential expression in B‐cell neoplasms. Here, we retrospectively assessed the diagnostic relevance of CD200 on 427 patients with B‐cell chronic neoplasms in leukemic phase (median age, 69 y; range, 35‐97 y). The final diagnosis based on the investigator's assessment was chronic lymphocytic leukaemia (CLL) in 75% of cases and non‐CLL in 25% of cases. Sensitivity and specificity for the diagnosis of CLL (vs non‐CLL) were calculated for the following markers: CD200, CD5, CD22, CD23, CD79b, FMC7, and SmIg. CD23 was the only marker without a statistically significant difference between the investigator assessment and the flowcytometric analysis. The other markers were unable—when individually evaluated—to discriminate between CLL and non‐CLL, requiring the integration into a scoring system. The modified score no. 1 (addition of CD200) showed superimposable sensitivity and specificity compared with the Matutes score. The substitution of CD79b (modified score no. 2), surface membrane immunoglobulins (SmIg) (modified score no. 3), and CD79b and FMC7 (modified score no. 4) with CD200 showed that only the modified score no. 4 had both higher sensitivity and higher specificity compared with standard Matutes score. In conclusion, this work defines a simplified score, compared with the classical Matutes score, for the differential diagnosis of chronic B‐cell leukaemia—which only requires 4 markers instead of 5 (CD5, CD23, CD200, and SmIg).