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Here, we present a novel case of a patient with chronic lymphocytic leukemia (CLL) who received CTLA-4 and then PD-1 immune-checkpoint blockade (ICB) as treatment for concomitant metastatic melanoma. Whereas the metastatic melanoma was responsive to ICB, the CLL rapidly progressed (but responded to ICB cessation and ibrutinib). There were no new genetic mutational drivers to explain the altered clinical course. PD-1/PD-L1/PD-L2 and CTLA-4/CD80/CD86 expression was not increased in CLL B cells, CD8+ or CD4+ T-cell subsets, or monocytes. The patient's CLL B cells demonstrated strikingly prolonged in vitro survival during PD-1 blockade, which was not observed in samples taken before or after ICB, or with other patients. To our knowledge, a discordant clinical course to ICB coupled with these biological features has not been reported in a patient with dual malignancies. [ABSTRACT FROM AUTHOR]

Anti-CD20 antibody treatments, such as obinutuzumab, have been associated with infusion-related reactions (IRRs). In the phase 3 iLLUMINATE study of ibrutinib-obinutuzumab versus chlorambucil-obinutuzumab in first-line chronic lymphocytic leukemia/small lymphocytic lymphoma, IRRs were substantially reduced with ibrutinib-obinutuzumab versus chlorambucil-obinutuzumab. We prospectively analyzed inflammatory cytokines to evaluate the impact of ibrutinib on circulating cytokine levels following obinutuzumab infusion. In iLLUMINATE, ibrutinib or chlorambucil was given approximately 30-120 min before the first obinutuzumab infusion. Cytokines evaluated were IFNγ, IL-6, IL-8, IL-10, IL-18, MCP-1, MIP-1α, MIP-1β, and TNFα. Changes in peak cytokine levels from baseline (immediately before obinutuzumab) to post-obinutuzumab infusion were compared between arms and between patients with versus without IRRs using Wilcoxon rank sum test. Of 228 treated patients, 95 on ibrutinib-obinutuzumab (15 with IRRs, 80 without) and 88 on chlorambucil-obinutuzumab (45 with IRRs, 43 without) with cytokine data were included. Irrespective of IRR occurrence, median increase in cytokines was lower with ibrutinib-obinutuzumab versus chlorambucil-obinutuzumab for all cytokines (P < 0.01) except MIP-1β. Across treatment arms, post-obinutuzumab median increase in all cytokines except MIP-1β was greater in patients with versus without IRRs (P < 0.001). IL-6 and IL-8 elevations were associated with IRRs in both treatment arms. Among patients with IRRs, those receiving ibrutinib-obinutuzumab had lower post-obinutuzumab increases in IL-6, IL-8, IL-10, and MCP-1 (P < 0.04) than patients receiving chlorambucil-obinutuzumab. For patients in the ibrutinib-treatment arm, we observed a reduction in both the rate of clinically apparent IRRs and the levels of IRR-related cytokines and chemokines. This observation supports an immunomodulatory mechanism of action for ibrutinib. Clinical Trial Registration: NCT02264574. [ABSTRACT FROM AUTHOR]

Targeted antibody therapies improve outcomes for chronic lymphocytic leukemia (CLL) patients. However, resistance often develops. We have previously shown that resistance to therapeutic antibodies, by monocyte derived macrophages (referred to as nurse like cells, NLCs), from CLL patients is characterized by suppression of antibody dependent phagocytosis (ADP). The mechanism(s) contributing to the muted ADP responses remain unresolved. In this regard, an innate immune checkpoint was recently described that uses the CD47:SIRPα axis to suppress phagocytic responses by macrophages. In this study we examine whether the SIRPα axis regulates ADP responses to the anti-CD20 antibody, obinutuzumab, by NLCs. Using siRNA depletion strategies we show that SIRPα is a suppressor of ADP responses. Moreover, we show that this innate immune checkpoint contributes to the resistance phenotype in NLCs derived from CLL patients. Finally, we show that SIRPα suppression is mediated via the phosphatase, Shp1, which in turn suppresses SYK-dependent activation of ADP. Thus, we identify a druggable pathway that could be exploited to enhance sensitivity to existing therapeutic antibodies used in CLL. This is the first study to show that activation of the CD47:SIRPα innate immune checkpoint contributes to ADP resistance in NLCs from CLL patients. [ABSTRACT FROM AUTHOR]

Antibody therapies are important treatment options for Chronic lymphocytic leukemia (CLL). Paradoxically, MDMs also play a critical role in tumor cell killing either through a) recognition and phagocytosis of tumor cells mediated I via i pattern recognition receptors [[6]] or b) Fc R-dependent phagocytosis of tumor cells that have been opsonized with a therapeutic antibody (e.g. obinituzumab) [[7]]. Given the evidence that macrophages are key effector cells that clear opsonized CLL cells [[9]] it is surprising that little attention has focused on characterizing the phenotype of the MDMs responsible. [Extracted from the article]

Prognosis of CLL patients has historically been determined by categorization into Rai or Binet risk groups based on physical examination and blood counts, however given heterogeneity within Rai or Binet risk categories, these prognostic tools have limitations predicting clinical course and response to therapy. CLL cells express low levels of FasR and FasL, and high sera levels of sFasR have been associated with progressive CLL [[5]], however little is known about sFasL and how this impacts CLL treatment response and survival. Cytokines for which serum levels are significantly different when untreated CLL patients are analyzed according to Rai and Binet staging, serum 2-microglobulin levels, IGHV mutation status and CLL-IPI risk groups. [Extracted from the article]

Background. The optimal reduction of immunosuppressive therapy (IST) in renal transplant patients with post-transplant lymphoproliferative disorders (PTLDs) is uncertain. As chemotherapy is immunosuppressive, IST may be stopped during this time without compromising graft function. Subsequent longterm reduction of IST reduces relapse risk, but may increase risk of graft rejection. Methods. We performed a retrospective, matched cohort study of adult renal transplant patients in whom IST was ceased during chemotherapy and resumed at lower dose (calcineurin inhibitor at 50%, prednisolone =10 mg daily, no third agent) approximately 6 weeks after chemotherapy. Outcomes were compared with those of renal transplant patients without PTLD, matched for creatinine at equivalent time post-transplant that PTLD was diagnosed in cases, as well as for age, gender and year of transplant. Results. Twenty-four cases of PTLD occurring at a median of 9.2 years post-transplant were compared with 83 matched controls. PTLD cases were followed for a median of 11.9 years. Using competing risks analysis, time to 25% increase in serum creatinine was not significantly different between the two groups [adjusted hazard ratio (HR) 1.8, 95% confidence interval (CI) 0.89-3.6]. Similar results were obtained using multivariable Cox regression analysis (HR 1.19, 95% CI 0.44-3.23). Only one PTLD case experienced a =25% increase in creatinine <6 months after IST cessation in the setting of progressive PTLD and death. Three cases recommenced dialysis, compared with three controls (HR 2.5, 95% CI 0.47-13.00). Five-year patient survival rates for cases and controls were 70 and 94%, respectively (P = 0.01). Conclusions. IST can be safely ceased during chemotherapy for PTLD in renal transplant patients. Furthermore, long-term reduction in IST is not associated with a significant difference in renal function deterioration. Prospective trials are needed to address the optimal reduction of IST in PTLDs. [ABSTRACT FROM AUTHOR]

We conducted a randomized phase III trial to compare the efficacy and safety of two purine analogs, cladribine and fludarabine, with high-dose chlorambucil, in patients with previously untreated chronic lymphocytic leukemia (CLL). Between 1997 and 2004, 223 patients with CLL were randomly assigned to cladribine, fludarabine or chlorambucil, for six cycles of therapy with frequent health-related quality of life assessments. There was no statistical difference for the primary endpoint of overall response with cladribine (70%), fludarabine (67%) and chlorambucil (59%), or complete remission (12%, 7% and 8%), respectively. However, the median progression-free survival (25, 10, 9 months) and median time to second treatment (40, 22, 21 months) were superior with cladribine. There was no significant difference in overall survival (96, 82 and 91 months), nor in toxicity or HRQoL assessments. Monotherapy with cladribine gives superior PFS and longer response duration than fludarabine and chlorambucil as first-line treatment of CLL. [ABSTRACT FROM AUTHOR]

Chronic lymphocytic leukemia (CLL) is predominantly a disease of accumulation rather than rapid proliferation. To date, no cell lines exist, as CLL cells undergo rapid apoptosis when cultured in vitro, suggesting that a favorable in vivo microenvironment is required. To identify survival signals we cultured primary CLL peripheral blood mononuclear cells (PBMCs) at high density, which has previously been shown to dramatically improve survival. Using antibody arrays we measured the level of 42 cytokines in culture supernatants and showed that inerleukin-6 (IL-6), IL-8, CXCL2 and CCL2 were highly up-regulated in culture. This is the first report to describe a role for CCL2 and CXCL2 in CLL cell survival. Importantly, CXCL2, IL-6 and IL-8 were significantly up-regulated in primary patient plasma. The addition of either CXCL2 or CCL2 enhanced CLL cell survival, while antibodies blocking these chemokines reduced survival. Co-culture of CLL cells and PBMC accessory cells separated by transwells provided a similar degree of survival protection compared to normal culture, whereas CLL cells cultured alone died rapidly. Interestingly, CCL2 and CXCL2 appeared to be produced by CLL cells but only when co-cultured with accessory cells. Thus, we speculate that accessory cells release soluble factors that promote the production of these pro-survival chemokines from CLL cells and physical interactions are not required. Our data support the concept that the CLL microenvironment is critical, and suggests that soluble factors are more important than physical interactions. [ABSTRACT FROM AUTHOR]

Elderly patients with acute myeloid leukemia (AML) have a poor prognosis. The authors examined the in vitro and clinical activity of the histone deacetylase inhibitor valproic acid (VA) combined with cytosine arabinoside (AraC) in elderly patients with AML unsuited to intensive therapy. For the in vitro studies, primary AML cells from 11 patients were treated with AraC and VA and analyzed for apoptosis, cytostatic effects, differentiation and acetyl histone H3 induction. VA (alone and with AraC) enhanced apoptosis and induced acetyl histone H3. VA inhibited cell proliferation. For the clinical trial, 15 patients were treated with VA and subcutaneous AraC and assessed for toxicity and response. No complete or partial remissions were achieved. In concusion, VA has in vitro activity against AML and has additional activity with AraC. However, in this study, this combination demonstrated limited clinical activity in elderly patients with AML. [ABSTRACT FROM AUTHOR]

The optimal initial therapy for treatment of adult acute lymphoblastic leukemia is yet to be defined. Hyper-CVAD has become a widely used treatment for adult acute lymphoblastic leukemia, although publication of outcomes is largely limited to single-center experience. We performed a retrospective analysis of 63 patients treated with Hyper-CVAD at two Australian institutions between 1995 and 2007. Complete remission was obtained in 86% of patients, with an induction mortality of 8%. Treatment-related toxicity was high, resulting in premature cessation of planned treatment in 29% of patients achieving CR. Survival estimates were comparable to previously published experience, with estimated 5-year overall and progression-free survival of 48% and 42%, respectively. Allogeneic stem cell transplant was performed in 22% of patients in first complete remission, with encouraging survival outcomes (estimated 5-year overall survival 75%, progression free survival 82%). Hyper-CVAD is an effective and tolerable induction strategy for adult ALL, and is suitable for use prior to allogeneic stem cell transplant in first complete remission. [ABSTRACT FROM AUTHOR]

Alpha interferon has proven efficacy in prolonging remissions in patients with follicular non-Hodgkin lymphoma (NHL) when given concurrently with or after conventional-dose anthracycline-based chemotherapy, but there are limited data on its use after myeloablative conditioning. We prospectively evaluated the toxicity and efficacy of interferon given thrice weekly for up to 5 years post-engraftment in patients with relapsed follicular NHL undergoing autologous stem cell transplant using busulfan–melphalan conditioning. Thirty-seven patients were enrolled in this Australasian Leukaemia & Lymphoma Group study and transplanted between 1995 and 1999. Only one patient had received prior rituximab. Two patients died of transplant-related toxicity; 28 of the remainder commenced interferon, but it was discontinued prematurely in most patients due to toxicity (mainly fatigue and depression) or relapse. While the majority of patients (29/36 evaluable: 81%) achieved a complete remission based on clinical and CT scan criteria post-transplant, most relapsed relatively early, with a median progression-free survival of 2.4 years. The overall survival at 7 years was 49%. Eight patients (22%), however, remain alive a median of 9.3 years post-transplant, having never relapsed, and another six patients (16%) remain alive in durable remission after salvage therapy. These results demonstrate that interferon is poorly tolerated post-autograft and hence is unlikely to positively contribute to patient outcome. Long-term follow-up demonstrates that autografting may result in durable remissions in a meaningful minority of patients with relapsed follicular NHL. [ABSTRACT FROM AUTHOR]

Introduction: Activated Protein C [APC] improves outcome in immunocompetent patients with severe sepsis particularly in those who are perceived to have high mortality risk. Before embarking on a trial of APC administration in immunocompromised septic patients, a preliminary study on plasma levels of protein C in this cohort is essential. Objective: To assess serum Protein C concentrations in immunocompromised patients as compared to immunocompetent patients during sepsis, severe sepsis, septic shock and recovery. Methods: Prospective cohort study in a tertiary hospital. Patients satisfying inclusion criteria were enrolled after informed consent. Clinical variables were noted with sample collection when patients met criteria for sepsis, severe sepsis, septic shock and recovery. Protein C levels were measured using monoclonal antibody based fluorescence immunoassay. Results: Thirty one patients participated in this study (22 immunocompromised, 9 immunocompetent). Protein C levels were found to be significantly lower in the immunocompromised group compared to the immunocompetent group, particularly observed in severe sepsis [2.27 (95% CI: 1.63-2.9) vs 4.19 (95% CI: 2.87-5.52) mcg/ml] (p = 0.01) and sepsis [2.59 (95% CI: 1.98-3.21) vs 3.64 (95% CI: 2.83-4.45) mcg/ml] (p = 0.03). SOFA scores were similar in both the groups across sepsis, severe sepsis and septic shock categories. Protein C levels improved significantly in recovery (p = 0.001) irrespective of immune status. Conclusion: Protein C levels were significantly lower in immunocompromised patients when compared to immunocompetent patients in severe sepsis and sepsis categories. Our study suggests a plausible role for APC in severely septic immunocompromised patients which need further elucidation. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented regarding a prognosticator for post-transplant lymphoproliferative disorders in patients undergone renal transplantation.

Core binding factor acute myeloid leukemia (CBF AML), with t(8;21)(q22;q22), inv(16)(p13q22) or t(16;16)(p13;q22) and the associated fusion gene transcripts AML1/ETO or CBFβ/MYH11, has a favourable clinical prognosis although significant numbers of patients still suffer relapse. We examined the prognostic utility of serial bone marrow minimal residual disease (MRD) monitoring by RQ-PCR in a cohort of patients with CBF AML with long term clinical follow-up. Twenty-nine patients were evaluated with a median follow of 34 months. Twelve relapses occurred at a median of 11 months (range 4 - 17) from diagnosis. RQ-PCR levels at diagnosis, post-induction chemotherapy and post-consolidation were not predictive of outcome. However, a ≥1 log10 rise at any stage in transcript level relative to the level from a remission bone marrow sample correlated with inferior leukemia free survival (LFS) and imminent morphologic relapse (hazard ratio 8.6). Relapses occurred a median of 60 days (range 45 - 272) after a log10 rise. A ≥1 log10 rise in transcript levels strongly predicts subsequent morphologic relapse in CBF AML and therefore defines molecular relapse. Our data support a simple RQ-PCR model for prediction of impending relapse which has the potential for widespread clinical applicability. Prospective identification of high risk patients will enable clinical trials to assess the efficacy of treatment initiated at molecular relapse. [ABSTRACT FROM AUTHOR]

Immunosuppression following solid organ transplantation results in impaired T-cell immunity and risk of Epstein–Barr virus (EBV)-positive post-transplant lymphoproliferative disorders (PTLD). The B-cell targeting antibody rituximab has efficacy in PTLD. As B cells are the principle reservoir for EBV, we investigated the effect of rituximab on the persistence of EBV-specific CD8+ T-cell immunity. To avoid the confounding factor of concurrent immunosuppression to prevent transplant rejection, immunity was analysed in non-transplanted lymphoma patients (i.e. a non-PTLD setting). Cytomegalovirus-specific T-cell immunity was assessed as an internal control. Our data demonstrated that circulating B cells were not critical for maintaining EBV-specific T-cell immunity. [ABSTRACT FROM AUTHOR]

The Hyper-CVAD chemotherapy regimen is being increasingly applied to a number of haematological malignancies. We assessed the impact of Hyper-CVAD on peripheral blood stem cell (PBSC) yields and examined the optimal timing of PBSC collection when using this regimen. Seventy-four consecutive patients were identified in whom an attempt was made to collect PBSC, usually on recovery from cycle A or B. Where PBSC collection was attempted after cycle 3B, only 18% (3/17) of patients successfully mobilized. Fifty-seven patients were mobilized on recovery from cycle 1B ( n = 13), 2A ( n = 22), 2B ( n = 14) or 3A ( n = 8). Compared with cycle 2A, 1B was not superior in achieving the minimum of ≥2 × 106/kg CD34+ cells (100% vs. 77%, p = 0.13), but was superior in terms of total CD34+ yield (21.4 vs. 3.2 × 106/kg, p < 0.001), achieving the target CD34+ cell count of ≥5 × 106/kg (92% vs 36%, p = 0.002), and obtaining both a minimum (92% vs. 18%, p < 0.001) and target (77% vs. 0%, p < 0.001) graft with a single apheresis. There were no significant differences in PBSC yields following cycles 2A, 2B and 3A. Hyper-CVAD has substantial stem cell toxicity which can be readily circumvented by using the early chemotherapy cycles for mobilization. Copyright © 2006 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Pegfilgrastim (Neulasta®) has proven efficacy as supportive therapy in a variety of 21-day chemotherapy regimens, but has not been studied in dose intensive, rapidly cycling regimens utilising cell-cycle active drugs (e.g. anti-metabolites) such as hyper-CVAD. This study examined whether pegfilgrastim was safe and lead to similar kinetics of neutrophil recovery as daily granulocyte colony stimulating factor (G-CSF). Using retrospective analysis, patients receiving pegfilgrastim (6 mg) were matched with controls (G-CSF 5 μg kg-1 per day) for a cycle of chemotherapy, prior chemotherapy, dose of cytarabine received, age (<60 or >60 years), diagnosis and bone marrow involvement. The primary endpoint was duration of grade IV neutropenia (absolute neutrophil count, ANC < 500 μl-1). Secondary endpoints included time to neutrophil recovery, incidence of febrile neutropenia, positive blood cultures and delay in subsequent chemotherapy. This study identified 124 pegfilgrastim supported cycles in 43 patients and successfully matched them to 124 G-CSF supported cycles from 38 patients treated between January 1999 and July 2005. There were no significant differences between pegfilgrastim and G-CSF groups in baseline or treatment-related variables. The median duration of grade IV neutropenia was 4 days in both groups (P = 0.55). Time to neutrophil recovery, incidence of febrile neutropenia, positive blood cultures and delay in subsequent chemotherapy were similar in both groups. Once per cycle dosing of pegfilgrastim appears safe and as effective as daily G-CSF for supporting the hyper-CVAD chemotherapy regimen. [ABSTRACT FROM AUTHOR]

Summary. Re-treatment with rituximab for B-cell non-Hodgkin's lymphoma (NHL) relapsing after previous rituximab therapy has recently been shown to be clinically efficacious. Although the mechanism of resistance to rituximab re-treatment in non-responding patients is unknown, it is possible that loss of CD20 expression in the relapsed NHL could be important in some patients. We examined the incidence and nature of CD20 negative relapses following rituximab therapy in aggressive B-cell NHL treated at our institution. Of a total of 18 patients who received rituximab, 13 have relapsed, with 10 patients subsequently undergoing repeat tissue biopsy. Six of these 10 patients (60%) were shown to have lost CD20 expression by either immunohistochemistry and/or flow cytometry. Furthermore, three of the six patients who relapsed with CD20-negative NHL also suffered relapses at unusual anatomical sites. We conclude that loss of CD20 expression in aggressive B-cell NHL relapsing post-rituximab therapy is common. As such, repeat tissue biopsy should be undertaken to document CD20 expression by both flow cytometry and immunohistochemistry prior to considering repeated courses of rituximab in relapsed aggressive lymphomas. [ABSTRACT FROM AUTHOR]

The article presents information on a phase II study of risk-adapted intravenous melphalan in patients having AL amyloidosis. It shows Haematological toxicity associated with intermediate dose melphalan and dexamethasone. Under the study, seven ASCT-eligible patients underwent transplantation, three with 140 mg/m sq. and four with 200 mg/m sq. IV melphalan.

An amendment to this paper has been published and can be accessed via a link at the top of the paper. [ABSTRACT FROM AUTHOR]

Arsenic trioxide has recently been used in the treatment of both relapsed and de novo acute promyelocytic leukaemia (APML). Molecular remissions have been attained using arsenic trioxide with minimal associated haematological toxicity, making protocols utilizing this drug an attractive option for Jehovah's Witnesses with APML. A 62-year-old female Jehovah's Witness with de novo APML was treated with all-trans retinoic acid induction followed by combined arsenic trioxide/ATRA consolidation, and achieved molecular remission with minimal haematological toxicity and no blood product support. [ABSTRACT FROM AUTHOR]

We report the laser operation of a thin-film waveguide structure grown by the pulsed laser deposition technique. A 2.7-μm-thick crystalline film of neodymium doped Gd3Ga5O12 (Nd:GGG) lases at a wavelength centered at 1.06 μm when pumped by a Ti:sapphire laser at 808 nm. © 1996 American Institute of Physics. [ABSTRACT FROM AUTHOR]

Fusion genes are a major cause of cancer. Their rapid and accurate diagnosis can inform clinical action, but current molecular diagnostic assays are restricted in resolution and throughput. Here, we show that targeted RNA sequencing (RNAseq) can overcome these limitations. First, we establish that fusion gene detection with targeted RNAseq is both sensitive and quantitative by optimising laboratory and bioinformatic variables using spike-in standards and cell lines. Next, we analyse a clinical patient cohort and improve the overall fusion gene diagnostic rate from 63% with conventional approaches to 76% with targeted RNAseq while demonstrating high concordance for patient samples with previous diagnoses. Finally, we show that targeted RNAseq offers additional advantages by simultaneously measuring gene expression levels and profiling the immune-receptor repertoire. We anticipate that targeted RNAseq will improve clinical fusion gene detection, and its increasing use will provide a deeper understanding of fusion gene biology. Rapid and accurate detection of fusion genes is important in cancer diagnostics. Here, the authors demonstrate that targeted RNA sequencing provides fast, sensitive and quantitative gene fusion detection and overcomes the limitations of approaches currently in clinical use. [ABSTRACT FROM AUTHOR]

The article reports that Ermysted's Grammar School in Skipton, North Yorkshire, England, hosted its first physics summer school. A total of 35 year-12 students gave up four days of their summer holidays to attend lectures on topics including classical mechanics and quantum physics. The aim was to cover material in enough depth to allow students to discover the analytical power of physics. The core aim of the course was to redress the lack of mathematics in current physics specifications. Students gained an insight into the role of differential and integral calculus in mechanics and were shown how to solve first-order and second order differential equations.

A letter to the editor is presented which discusses acute promyelocytic leukaemia (APML) cases on three Jehovah's Witness (JW) patients and seeks recommendations for APML management.