Chronic lymphocytic leukaemia and Richter's transformation: multimodal review and new imaging paradigms.

Chronic lymphocytic leukaemia (CLL) is the most common leukaemia in adults. It is a malignancy of CD5 B-cells characterised by small, mature-appearing lymphocytes accumulating in the blood, bone marrow, and lymphoid tissues. Richer transformation (RT) is an important adverse complication. Detection of RT is critical to allow initiation of appropriate therapy. CLL staging and response evaluation is complicated and nuanced. From our extensive tertiary centre experience of several hundred CLL cases over the last decade, we detail key computed tomography (CT) and positron-emission tomography (PET) imaging features of the natural history of CLL. The authors present an original imaging-based patient-management paradigm for the investigation of potential RT, which will inform global practice. Potential applications of whole-body diffusion weighted imaging, novel PET radiotracers, minimal residual disease, and ct-DNA are addressed.

B and T cell prolymphocytic leukaemia.

Prolymphocytic leukaemias B-PLL and T-PLL are rare disorders, typically with an aggressive clinical course and poor prognosis. Combining morphology, immunophenotyping, cytogenetic and molecular diagnostics reliably separates B-PLL and T-PLL from one another and other disorders. In T-PLL discovery of frequent mutations in the JAK-STAT pathway have increased understanding of disease pathogenesis. Alemtuzumab (anti-CD52) produces excellent response rates but long-term remissions are only achieved in a minority following consolidation with allogeneic stem cell transplant. Molecular abnormalities in B-PLL are less understood. Disruption of TP53 is a key finding, conveying chemotherapy resistance requiring novel therapies such as B-cell receptor inhibitors (BCRi). Both conditions require improved pathobiological knowledge to identify new treatment targets and guide therapy with novel pathway inhibitors.

The epidemiology of respiratory syncytial virus: A retrospective review from Steve Biko Academic Hospital 2013 - 2016.

BACKGROUND: Respiratory syncytial virus (RSV) bronchiolitis is a seasonal disease that has an enormous burden on health systems across the world. RSV disease manifestations in children range from mild upper respiratory tract infections to severe lower respiratory tract infections, including pneumonia and bronchiolitis. In South Africa, the seasonality of RSV disease causing both upper and lower respiratory tract illness is well documented. OBJECTIVES: To describe the incidence of RSV bronchiolitis among patients ≤24 months of age who presented to a tertiary institution with a diagnosed viral bronchiolitis over a 4-year period. Secondary aims included determining: (i) the risk factors for the development of RSV bronchiolitis; (ii) the fatality rates and risk factors associated with mortality; (iii) the correlation with c-reactive protein values and risk of comorbid bacterial infection; and (iv) the impact of seasonality on RSV incidence. METHODS: A retrospective chart-based analysis of laboratory-confirmed RSV cases in children ≤24 months, presenting to Steve Biko Academic Hospital from January 2013 to December 2016, was undertaken. Epidemiology, risk factors and local weather data were collected as part of the analysis. RESULTS: During the 4-year period, a total of 1 127 nasopharyngeal aspirates (NPAs) was collected. RSV was isolated from 162 NPAs by either immunofluorescence (84%) or polymerase chain reaction (16%). Of the 162 patients with RSV bronchiolitis, 131 (80.9%) had a known HIV status. Only 2 (1.5%) of the patients whose status was known were HIV-infected; 26 (19.8%) were HIV-exposed and confirmed negative; and 103 (78.6%) HIV-unexposed. Forty-nine patients (30.2%) with RSV required intensive care unit (ICU, either paediatric or neonatal) admission. Thirty-four (69.4%) of these were <6 months old. Prematurity (27.8%) and cardiac lesions (13%) were the most common risk factors for acquiring the disease identified in patients with RSV bronchiolitis. CONCLUSION: RSV is still a commonly detected virus among infants who are admitted for bronchiolitis. Significant risk factors associated with admission due to RSV bronchiolitis were prematurity, being <6 months of age and congenital cardiac disease. Male gender and HIV status did not appear to increase the risk of RSV bronchiolitis. In fact, HIV seems to have a protective effect against specifically RSV bronchiolitis in children <2 years of age. Young babies, especially premature infants with RSV bronchiolitis, are at considerable risk of requiring ICU admission, which leads to a significant increase in admission costs.

Hematopoietic stem cell transplantation in T-prolymphocytic leukemia: a retrospective study from the European Group for Blood and Marrow Transplantation and the Royal Marsden Consortium.

T-prolymphocytic leukemia (T-PLL) has a very poor prognosis with conventional immunochemotherapy. Incidental reports suggest that allogeneic hematopoietic stem cell transplantation (allo-HSCT) might have a role in this disease. Therefore, the purpose of the present study was to analyze the outcome of transplants for T-PLL registered with the European Group for Blood and Marrow Transplantation database and the Royal Marsden Consortium. Eligible were 41 patients with a median age of 51 (24-71) years; median time from diagnosis to treatment was 12 months, and in complete remission (CR) (11), partial remission (PR) (12), stable or progressive disease (13) and unknown in 5 patients. A total of 13 patients (31%) received reduced-intensity conditioning. Donors were HLA-identical siblings in 21 patients, matched unrelated donors in 20 patients. With a median follow-up of surviving patients of 36 months, 3-year relapse-free survival (RFS) and OS was 19% (95% CI, 6-31%) and 21% (95% CI, 7-34%), respectively. Multivariate analysis identified TBI and a short interval between diagnosis and HSCT as factors associated with favorable RFS. Three-year non relapse mortality and relapse incidence were each 41% with the majority of relapses occurring within the first year. These data indicate that allo-HSCT may provide effective disease control in selected patients with T-PLL.

Management guidelines for the use of alemtuzumab in chronic lymphocytic leukemia.

The consensus views of an expert roundtable meeting are presented as updated management guidelines for using alemtuzumab in chronic lymphocytic leukemia. Since the publication of previous management guidelines in 2004, clinical experience with alemtuzumab has grown significantly, especially regarding its efficacy and safety, management of cytomegalovirus (CMV) reactivation, identification of patient subgroups likely to benefit from alemtuzumab therapy and subcutaneous administration of alemtuzumab. The updated recommendations include (1) alemtuzumab monotherapy can be safely used as first-line therapy; (2) suitable patient subgroups for alemtuzumab therapy include elderly patients, patients with 17p deletion, patients with refractory autoimmune cytopenias and patients with profound pancytopenia at baseline due to heavily infiltrated bone marrow; (3) alemtuzumab treatment should be continued for 12 weeks (36 doses) whenever possible, and bone marrow examination may be considered at week 12 to evaluate response; (4) monitoring CMV reactivation by weekly PCR is mandated during therapy; when CMV reactivation becomes symptomatic or viremia increases, alemtuzumab therapy should be interrupted and anti-CMV therapy started; (5) subcutaneous administration is safe, easy to perform and appears equally effective compared with intravenous infusion and (6) our strong recommendation is that alemtuzumab combination therapy and consolidation therapy shall not be used outside carefully controlled clinical studies.

An early CT-diagnosis-based treatment strategy for invasive fungal infection in allogeneic transplant recipients using caspofungin first line: an effective strategy with low mortality.

Empirical antifungal therapy is frequently used in allogeneic transplant patients who have persistent febrile neutropenia and can be associated with high cost, toxicity and breakthrough infections. There are limited reports of strategies for early diagnosis of invasive fungal infection (IFI) and, to our knowledge, no reports of treatment strategies based only on high-resolution computerized tomography (HRCT) scans. We used an early treatment strategy for IFI in 99 consecutive patients undergoing allogeneic transplantation. Patients received caspofungin if they had antibiotic-resistant neutropenic fever for more than 72 h and a positive HRCT scan. Fifty-three of 99 patients (54%) had antibiotic-resistant neutropenic fever at 72 h and would have received parenteral antifungal treatment if an empirical approach had been used. The HRCT-based strategy reduced the use of parenteral antifungal agents to 17/99 patients (17%), a 68% reduction. No subsequent diagnoses of IFI occurred within 100 days in patients with a negative HRCT. Only one patient died from IFI within 100 days. These data suggest that this non-empirical strategy may be feasible and that caspofungin may be effective in this setting. A randomized controlled trial is warranted to further assess these results.

High-grade transformation in splenic marginal zone lymphoma with circulating villous lymphocytes: the site of transformation influences response to therapy and prognosis.

In a series of 48 patients with splenic marginal zone lymphoma (SMZL) with circulating villous lymphocytes, we describe the clinical and laboratory features of nine cases that transformed to high-grade B-cell lymphoma. These patients had a significantly greater incidence of peripheral lymph node involvement at diagnosis when compared to SMZL patients who did not transform (P < 0.03). While transformation in the bone marrow is frequently refractory to therapy and associated with poor outcome in SMZL, lymph node transformation responds well to chemotherapy with durable progression-free and overall survival.

Prolymphocytic leukaemia of B- and T-cell subtype: a state-of-the-art paper.

Prolymphocytic leukaemias of B and T cell subtype are rare diseases. Despite recent advances in immunophenotyping and molecular cytogenetics, leading to a better understanding of the underlying cell biology of the prolymphocytic leukaemias, prognosis for these patients remains poor. Purine analogues and monoclonal antibodies have shown efficacy in B-cell prolymphocytic leukaemia although further studies are warranted. Monoclonal antibody therapy with alemtuzumab has significantly improved outcome in T-cell prolymphocytic leukaemia (T-PLL) but responses are still transient and further disease progression is inevitable. While allogeneic stem cell transplant is an attractive option, due to the older age group of T-PLL patients the morbidity and mortality associated with the procedure is significant.

The Met Office Hadley Centre climate modelling capability: the competing requirements for improved resolution, complexity and dealing with uncertainty.

Predictions of future climate change require complex computer models of the climate system to represent the full range of processes and interactions that influence climate. The Met Office Hadley Centre uses 'families' of models as part of the Met Office Unified Model Framework to address different classes of problems. The HadGEM family is a suite of state-of-the-art global environment models that are used to reduce uncertainty and represent and predict complex feedbacks. The HadCM3 family is a suite of well established but cheaper models that are used for multiple simulations, for example, to quantify uncertainty or to test the impact of multiple emissions scenarios.

Assessment of fludarabine plus cyclophosphamide for patients with chronic lymphocytic leukaemia (the LRF CLL4 Trial): a randomised controlled trial.

BACKGROUND: Previous studies of patients with chronic lymphocytic leukaemia reported high response rates to fludarabine combined with cyclophosphamide. We aimed to establish whether this treatment combination provided greater survival benefit than did chlorambucil or fludarabine. METHODS: 777 patients with chronic lymphocytic leukaemia requiring treatment were randomly assigned to fludarabine (n=194) or fludarabine plus cyclophosphamide (196) for six courses, or chlorambucil (387) for 12 courses. The primary endpoint was overall survival, with secondary endpoints of response rates, progression-free survival, toxic effects, and quality of life. Analysis was by intention to treat. This study is registered as an International Standard Randomised Controlled Trial, number NCT 58585610. FINDINGS: There was no significant difference in overall survival between patients given fludarabine plus cyclophosphamide, fludarabine, or chlorambucil. Complete and overall response rates were better with fludarabine plus cyclophosphamide than with fludarabine (complete response rate 38%vs 15%, respectively; overall response rate 94%vs 80%, respectively; p<0.0001 for both comparisons), which were in turn better than with chlorambucil (complete response rate 7%, overall response rate 72%; p=0.006 and 0.04, respectively). Progression-free survival at 5 years was significantly better with fludarabine plus cyclophosphamide (36%) than with fludarabine (10%) or chlorambucil (10%; p<0.00005). Fludarabine plus cyclophosphamide was the best combination for all ages, including patients older than 70 years, and in prognostic groups defined by immunoglobulin heavy chain gene (V(H)) mutation status and cytogenetics, which were tested in 533 and 579 cases, respectively. Patients had more neutropenia and days in hospital with fludarabine plus cyclophosphamide, or fludarabine, than with chlorambucil. There was less haemolytic anaemia with fludarabine plus cyclophosphamide (5%) than with fludarabine (11%) or chlorambucil (12%). Quality of life was better for responders, but preliminary analyses showed no significant difference between treatments. A meta-analysis of these data and those of two published phase III trials showed a consistent benefit for the fludarabine plus cyclophosphamide regimen in terms of progression-free survival. INTERPRETATION: Fludarabine plus cyclophosphamide should now become the standard treatment for chronic lymphocytic leukaemia and the basis for new protocols that incorporate monoclonal antibodies.

Lack of clinical efficacy of rituximab in the treatment of autoimmune neutropenia and pure red cell aplasia: implications for their pathophysiology.

We describe 11 patients with severe refractory autoimmune cytopenias treated with the anti-CD20 monoclonal antibody rituximab. Six patients had autoimmune neutropenia (AIN), two had pure red cell aplasia (PRCA), one had AIN and autoimmune haemolytic anaemia, one had AIN and immune thrombocytopaenia purpura (ITP) and one had PRCA and ITP. Rituximab was administered at a dose of 375 mg/m(2) as an intravenous infusion weekly for 4 weeks. Six of eight patients with AIN and all three patients with PRCA did not respond. Two patients died: one with resistant AIN and autoimmune haemolytic anaemia died of pneumocytis pneumonia infection, and one with PRCA and ITP died of an acute exacerbation of bronchiectasis. Rituximab in AIN and PRCA appears to be less effective than Campath-1H when compared to historical data from our group. This supports the hypothesis that T cells may be important in the pathophysiology of AIN and PRCA.