Two-stage randomized clinical trials with a right-censored endpoint: Comparison of frequentist and Bayesian adaptive designs.

Adaptive randomized clinical trials are of major interest when dealing with a time-to-event outcome in a prolonged observation window. No consensus exists either to define stopping boundaries or to combine p $$ p $$ values or test statistics in the terminal analysis in the case of a frequentist design and sample size adaptation. In a one-sided setting, we compared three frequentist approaches using stopping boundaries relying on α $$ \alpha $$ -spending functions and a Bayesian monitoring setting with boundaries based on the posterior distribution of the log-hazard ratio. All designs comprised a single interim analysis with an efficacy stopping rule and the possibility of sample size adaptation at this interim step. Three frequentist approaches were defined based on the terminal analysis: combination of stagewise statistics (Wassmer) or of p $$ p $$ values (Desseaux), or on patientwise splitting (Jörgens), and we compared the results with those of the Bayesian monitoring approach (Freedman). These different approaches were evaluated in a simulation study and then illustrated on a real dataset from a randomized clinical trial conducted in elderly patients with chronic lymphocytic leukemia. All approaches controlled for the type I error rate, except for the Bayesian monitoring approach, and yielded satisfactory power. It appears that the frequentist approaches are the best in underpowered trials. The power of all the approaches was affected by the violation of the proportional hazards (PH) assumption. For adaptive designs with a survival endpoint and a one-sided alternative hypothesis, the Wassmer and Jörgens approaches after sample size adaptation should be preferred, unless violation of PH is suspected.

Drug combinations screening using a Bayesian ranking approach based on dose-response models.

Drug combinations have been of increasing interest in recent years for the treatment of complex diseases such as cancer, as they could reduce the risk of drug resistance. Moreover, in oncology, combining drugs may allow tackling tumor heterogeneity. Identifying potent combinations can be an arduous task since exploring the full dose-response matrix of candidate combinations over a large number of drugs is costly and sometimes unfeasible, as the quantity of available biological material is limited and may vary across patients. Our objective was to develop a rank-based screening approach for drug combinations in the setting of limited biological resources. A hierarchical Bayesian 4-parameter log-logistic (4PLL) model was used to estimate dose-response curves of dose-candidate combinations based on a parsimonious experimental design. We computed various activity ranking metrics, such as the area under the dose-response curve and Bliss synergy score, and we used the posterior distributions of ranks and the surface under the cumulative ranking curve to obtain a comprehensive final ranking of combinations. Based on simulations, our proposed method achieved good operating characteristics to identifying the most promising treatments in various scenarios with limited sample sizes and interpatient variability. We illustrate the proposed approach on real data from a combination screening experiment in acute myeloid leukemia.

Effectiveness of heat treatment in rapid control of bed bugs in environmental conditions resembling their natural habitats.

We evaluated lethal temperatures and times for killing bed bugs in diverse covered and uncovered conditions simulating their natural habitats. A total of 5400 adult bed bugs were collected alive from 17 infested locations in Paris. They were morphologically identified in laboratory as Cimex lectularius. They were then distributed in multiple sets of 30 specimens to examine in covered (tissue, furniture, mattress or blanket) and uncovered (direct exposure) conditions and in diverse step-function temperatures (50, 55 and 60°C) and times (15, 30, 60 and 120 minutes), replicated three times. Effective mortality was observed in 1080 specimens exposed directly to 50°C for 60 minutes. In specimens covered by tissue (1080 specimens), furniture (1080) or mattress (1080), all were dead at 60°C within 60 minutes. The specimens covered by blanket (1080) at the same temperature were dead after 120 minutes. A 60-minutes delay in reaching to lethal temperature within blanket compared to uncovered thermometer was observed.

A fixed-duration, measurable residual disease-guided approach in CLL: follow-up data from the phase 2 ICLL-07 FILO trial.

Trials assessing first-line, fixed-duration approaches in chronic lymphocytic leukemia (CLL) are yielding promising activity, but few long-term data are available. We report follow-up data from a phase 2 trial (ICLL07 FILO) in previously untreated, medically fit patients (N = 135). Patients underwent obinutuzumab-ibrutinib induction for 9 months; then, following evaluation (N = 130 evaluable), those in complete remission and with bone marrow measurable residual disease (BM MRD) <0.01% (n = 10) received ibrutinib for 6 additional months; those in partial remission and/or with BM MRD ≥0.01%, the majority (n = 120), also received 4 cycles of immunochemotherapy (fludarabine/cyclophosphamide-obinutuzumab). Beyond end of treatment, responses were assessed every 3 month and peripheral blood MRD every 6 months. At median follow-up 36.7 months from treatment start, progression-free and overall survival rates (95% confidence interval) at 3 years were 95.7% (92.0% to 99.5%) and 98% (95.1% to 100%), respectively. Peripheral blood MRD <0.01% rates were 97%, 96%, 90%, 84%, and 89% at months 16, 22, 28, 34, and 40, respectively. No new treatment-related or serious adverse event occurred beyond end of treatment. Thus, in previously untreated, medically fit patients with CLL, a fixed-duration (15 months), MRD-guided approach achieved high survival rates, a persistent MRD benefit beyond the end of treatment, and low long-term toxicity. This trial was registered at www.clinicaltrials.gov as #NCT02666898.

Identification of the Axis ß-Catenin-BTK in the Dynamic Adhesion of Chronic Lymphocytic Leukemia Cells to Their Microenvironment.

In the microenvironment, cell interactions are established between different cell types to regulate their migration, survival and activation. ß-Catenin is a multifunctional protein that stabilizes cell-cell interactions and regulates cell survival through its transcriptional activity. We used chronic lymphocytic leukemia (CLL) cells as a cellular model to study the role of ß-catenin in regulating the adhesion of tumor cells to their microenvironment, which is necessary for tumor cell survival and accumulation. When co-cultured with a stromal cell line (HS-5), a fraction of the CLL cells adhere to stromal cells in a dynamic fashion regulated by the different levels of ß-catenin expression. In non-adherent cells, ß-catenin is stabilized in the cytosol and translocates into the nucleus, increasing the expression of cyclin D1. In adherent cells, the level of cytosolic ß-catenin is low but membrane ß-catenin helps to stabilize the adhesion of CLL to stromal cells. Indeed, the overexpression of ß-catenin enhances the interaction of CLL with HS-5 cells, suggesting that this protein behaves as a regulator of cell adhesion to the stromal component and of the transcriptional regulation of cell survival. Inhibitors that block the stabilization of ß-catenin alter this equilibrium and effectively disrupt the support that CLL cells receive from the cross-talk with the stroma.

Prevalence of BTK and PLCG2 mutations in a real-life CLL cohort still on ibrutinib after 3 years: a FILO group study.

Mutational analyses performed following acquired ibrutinib resistance have suggested that chronic lymphocytic leukemia (CLL) progression on ibrutinib is linked to mutations in Bruton tyrosine kinase (BTK) and/or phospholipase Cγ2 (PLCG2) genes. Mutational information for patients still on ibrutinib is limited. We report a study aimed to provide a "snapshot" of the prevalence of mutations in a real-life CLL cohort still on ibrutinib after at least 3 years of treatment. Of 204 patients who initiated ibrutinib via an early-access program at 29 French Innovative Leukemia Organization (FILO) centers, 63 (31%) were still on ibrutinib after 3 years and 57 provided a fresh blood sample. Thirty patients had a CLL clone ≥0.5 × 109/L, enabling next-generation sequencing (NGS); BTK and PLCG2 mutations were detected in 57% and 13% of the NGS samples, respectively. After median follow-up of 8.5 months from sample collection, the presence of a BTK mutation was significantly associated with subsequent CLL progression (P = .0005 vs no BTK mutation). Our findings support that mutational analysis should be considered in patients receiving ibrutinib who have residual clonal lymphocytosis, and that clinical trials are needed to evaluate whether patients with a BTK mutation may benefit from an early switch to another treatment.

Treating secondary antibody deficiency in patients with haematological malignancy: European expert consensus.

OBJECTIVES: Secondary antibody deficiency (SAD), associated with severe, recurrent or persistent infections, is common in patients with haematological malignancies (HM), but unifying guidance on immunoglobulin replacement therapy (IgRT) in these patients is lacking. We aimed to develop consensus statements for the use of IgRT in patients with HM. METHODS: A Delphi exercise was employed to test the level of agreement on statements developed by a Task Force based on available data and their clinical experience. In Round 1, an Expert Panel, comprising specialist EU physicians caring for patients with HM, helped to refine the statements. In Round 2, experts rated their agreement with the statements. In Round 3, experts who had scored their agreement as ≤4 were invited to review their agreement based on the overall feedback. RESULTS: Three definitions and 20 statements were formulated and tested for consensus, covering measurement of IgG levels, initiation and discontinuation of IgRT, dosing, and the use of subcutaneous IgG. Consensus (agreement ≥70% on Likert-type scale) was reached for all three definitions and 18 statements. CONCLUSIONS: Recommendations have been developed with the aim of providing guidance for the use of IgRT to prevent severe, recurrent or persistent infections in patients with HM and SAD.

In vitro maturation is a viable option for urgent fertility preservation in young women with hematological conditions.

Fertility preservation embraces different techniques developed to improve young women chances of becoming mothers after healing. Among them, in vitro maturation (IVM) procedure is based on oocyte retrieval without any gonadotropin treatment, feasible under locoregional or local anesthesia, with very low operative complications. The present retrospective analysis of a preliminary case series of 25 women diagnosed with Hodgkin or non-Hodgkin lymphoma aims to evaluate the feasibility of IVM for urgent fertility preservation purposes in hematological context. A median of five mature oocytes was cryopreserved after one cycle of IVM, performed without delaying the start of the chemotherapy (median delay from histological diagnosis to start of the chemotherapy 17.5 days). No association was found between lymphomas' characteristics and the number of recovered or frozen oocytes. Although experimental, this technique could be relevant when fertility preservation has to be performed within a short time frame and without additional surgery nor any risk of malignant cells reintroduction.

Feasibility of combining two individualized lung recruitment maneuvers at birth for very low gestational age infants: a retrospective cohort study.

BACKGROUND: Lung recruitment at birth has been advocated as an effective method of improving the respiratory transition at birth. Sustained inflations (SI) and dynamic positive end-expiratory pressure (PEEP) were assessed in clinical and animal studies to define the optimal level. Our working hypothesis was that very low gestational age infants (VLGAI) < 32 weeks' gestation require an individualized lung recruitment based on combining both manoeuvers. METHODS: Between 2014 and 2016, 91 and 72 inborn VLGAI, requiring a respiratory support beyond a continuous positive airway pressure (CPAP) = 5 cmH2O, were enrolled before and after introducing these manoeuvers based on progressive increase in SI up to 15 s, with simultaneous gradual increase in PEEP up to 15 cmH2O, according to the cardiorespiratory response. Retrospective comparisons of the incidence of mechanical ventilation (MV) < 72 h of life, short-term and before discharge morbidity were then performed. RESULTS: Among extremely low gestational age infants (ELGAI) < 29 weeks' gestation, the following outcomes decreased significantly: intubation (90 to 55%) and surfactant administration (54 to 12%) in the delivery room, MV (92 to 71%) and its mean duration < 72 h of life (45 h to 13 h), administration of a 2nd dose of surfactant (35 to 12%) and postnatal corticosteroids (52 to 19%), and the rate of bronchopulmonary dysplasia (23 to 5%). Among VLGAI, all of these results were also significant. Neonatal mortality and morbidity were not different. CONCLUSIONS: In our setting, combining two individualized lung recruitment maneuvers at birth was feasible and may be beneficial on short-term and before discharge pulmonary outcomes. A randomized controlled trial is needed to confirm these results.

Ethnic differences in normal retinal capillary density and foveal avascular zone measurements.

BACKGROUND: The purpose of this study was to quantify retinal capillary density and foveal avascular zone (FAZ) area in healthy subjects according to their ethnicity, using optical coherence tomography angiography (OCTA). METHODS: In this cross-sectional study, all eyes underwent swept-source OCTA (Triton, Topcon, Tokyo, Japan). Macular OCTA scans (3 × 3 mm) were obtained in healthy white Caucasian and black African subjects. The FAZ area and capillary density in both the superficial (SCP) and deep capillary plexuses (DCP) were automatically measured using a custom-made software combining vessel binarization and skeletonization. RESULTS: Twelve eyes of 12 healthy Caucasians and 15 eyes of 15 healthy black Africans were included in the analysis. The mean FAZ area was significantly smaller, and the overall vessel density (VD) was higher in the SCP and DCP of Caucasians compared to black Africans. The mean FAZ area was 0.26 ± 0.008 mm2 in the SCP and 0.25 ± 0.05 mm2 in the DCP in Caucasians versus 0.33 ± 0.08 mm2 in the SCP (p = 0.01) and 0.37 ± 0.1 mm2 in the DCP (p = 0.03) in Africans. In the SCP and DCP, the mean VD was, respectively, 40.5 ± 0.8% and 47.1 ± 0.5% in Caucasians versus 34.3 ± 1% (p = 0.008) and 40.6 ± 0.9% in Africans (p < 0.001). DISCUSSION/CONCLUSION: In the SCP and DCP, VD is lower in black Africans compared to Caucasians. In OCTA studies on vascular diseases, ethnicity-matched measurements from healthy subjects should be used for comparisons.

A French observational study describing the use of human polyvalent immunoglobulins in hematological malignancy-associated secondary immunodeficiency.

OBJECTIVE: To describe the characteristics of patients suffering from secondary immunodeficiencies (SID) associated with hematological malignancies (HM), who started immunoglobulin replacement therapy (IgRT), physicians' expectations regarding IgRT, and IgRT modalities. METHODS: Non-interventional, prospective French cross-sectional study. RESULTS: The analysis included 231 patients (66 ± 12 years old) suffering from multiple myeloma (MM) (N = 64), chronic lymphoid leukemia (CLL) (N = 84), aggressive non-Hodgkin B-cell lymphoma (aNHL) (N = 32), indolent NHL (N = 39), acute leukemia (N = 6), and Hodgkin disease (N = 6). Of the HM, 47% were currently treated, 42% were relapsing or refractory, 23% of patients had received an autologous hematopoietic stem-cell transplant, and 1% had received an allograft. Serum immunoglobulin trough levels in 195 individuals were less than 5 g/L in 68.7% of cases. Most patients had a history of recurrent infections. Immunoglobulin dose was about 400 mg/kg/mo. Half of patients started with subcutaneous infusion. When starting IgRT, physicians mainly expected to prevent severe and moderate infections. They also anticipated improvement in quality of life and survival which is beyond evidence-based medicine. CONCLUSION: NHL is a frequent condition motivating IgRT besides well-recognized indications. Physicians mainly based the decision of starting IgRT on hypogammaglobulinemia and recurrence of infections but, irrespective of current recommendations, were also prepared to start IgRT prophylactically even in the absence of a history of infections.

Management of central nervous system involvement in chronic lymphocytic leukaemia: a retrospective cohort of 30 patients.

Central nervous system involvement (CNSi) is a rare and poorly reported complication of chronic lymphocytic leukaemia (CLL). Establishing cause and effect between the CLL and the neurological symptoms remains challenging. We have analysed a retrospective cohort of 30 CLL patients with CNSi, documented by lymphocytic infiltration either by flow cytometry of the cerebrospinal fluid (CSF; n = 29) or CNS biopsy (n = 1). Neurological symptoms were heterogeneous. At the time of CNSi, less than half of the patients had a progressive CLL and 20 had never been treated for CLL. Initial treatment with fludarabine-based immuno-chemotherapy, with or without intra-CSF therapy, led to durable response in eight out of nine untreated patients. In contrast, 50% patients receiving various prior treatments needed additional therapy within a median of 4 months (1-16). Ibrutinib led to complete response in 4/4 heavily pre-treated patients. From CNSi, 5-year overall survival was 72% and 48% for treatment-naïve and previously treated patients respectively (P = 0·06); 5-year progression-free survival (PFS) was 43% and 0% (P = 0·125). 17p deletion was significantly associated with poor PFS (P = 0·006). CNSi may be the only sign of progression of CLL and should be considered an initiation criterion of systemic treatment. Prognosis seemed to be related to CLL characteristics rather than to CNSi itself.

Atrial fibrillation in CLL patients treated with ibrutinib. An international retrospective study.

Atrial fibrillation (AF) occurs in 5-9% of patients treated with ibrutinib for chronic lymphocytic leukaemia (CLL); the clinical consequences and optimal management are unclear. We retrospectively studied 56 CLL patients who received ibrutinib and developed AF. Median time to onset was 3·8 months. AF was persistent in 35/56 (62%) cases despite treatment. Clinical consequences included: three episodes of severe cardiac failure (one fatal) and one stroke; eight non-thrombocytopenic patients (14%) experienced severe bleeding adverse events. Altogether, ibrutinib was permanently discontinued in 26/56 cases (46%). Data to guide optimal management are lacking and clinical practice guidelines are urgently needed.

Efficacy and long-term toxicity of the rituximab-fludarabine-cyclophosphamide combination therapy in Waldenstrom's macroglobulinemia.

Waldenstrom's macroglobulinemia is generally treated with alkylating agents, purine analogs and monoclonal antibodies, alone or in combination. We report the outcomes of 82 patients (median age 61 years) treated with the RFC combination. Twenty-five patients were treatment-naive. RFC was administered every 4 weeks, for a median of five cycles. At treatment discontinuation, the overall response rate was 85.4%. The responses improved after treatment discontinuation in 25 patients, with a median time to best response achievement of 10.8 months, raising the major response rate (PR, VGPR and CR) from 64.6% to 76.8%. With a median follow-up of 47 months, the median progression-free survival time had not been reached (67% PFS at 48 months) and was influenced by age and treatment status before RFC. Likewise, the median time to next therapy had not been reached. Two cases of myelodysplastic syndrome/AML and 3 cases of transformation to aggressive lymphoma occurred. Thirteen patients died. The 3-year overall survival rate was 90%. Long-lasting cytopenias occurred in 19 patients. The RFC combination thus gave a high response rate and durable responses, even in heavily treatment-experienced patients. The high incidence of long-lasting cytopenia might be reduced by giving fewer courses and thereby minimizing myelotoxicity. Am. J. Hematol. 91:782-786, 2016. © 2016 Wiley Periodicals, Inc.

Outcomes after a 1-Year Treatment with Ranibizumab for Diabetic Macular Edema in a Clinical Setting.

PURPOSE: The aim of this study was to assess the efficacy and safety of ranibizumab in patients with diabetic macular edema (DME). METHODS: We conducted a retrospective analysis of consecutive patients with vision loss due to DME who were treated with ranibizumab. All patients received a loading dose of 3 monthly injections followed by re-treatments on an as-needed basis. The primary endpoint was the change in best-corrected visual acuity (BCVA) at 12 months. Secondary endpoints were the change in central retinal thickness (CRT) and the number of intravitreal injections (IVI) at 12 months. RESULTS: One hundred and six eyes of 78 patients were included. BCVA changed from 48.3 (20/100) letters at baseline to 59.0 letters (20/63) at 12 months (p < 0.0001; mean gain: +10.7 letters), and 38% of the patients had a final BCVA >70 letters. CRT decreased from 519 µm at baseline to 355 µm at 12 months (p < 0.0001). The threshold of the first quartile of the baseline VA was 40 letters. Patients with a baseline VA >40 letters had a higher final VA of 66 ± 14 letters (20/50) versus 43 ± 18 letters (20/125) for patients with a baseline VA ≤40 letters (p < 0.0001). A mean number of 5.4 (3-10) IVI were administered. CONCLUSION: This study conducted in a clinical setting confirms the results of previous randomized trials. The final BCVA was mainly influenced by the baseline BCVA, which supports the utility of early DME treatment before patients experience a severe vision loss.

Bendamustine and rituximab combination in the management of chronic lymphocytic leukemia-associated autoimmune hemolytic anemia: a multicentric retrospective study of the French CLL intergroup (GCFLLC/MW and GOELAMS).

We report our experience on bendamustine and rituximab (BR) combination in 26 patients with chronic lymphocytic leukemia (CLL) complicated by autoimmune hemolytic anemia (AIHA). At the time of BR initiation, 88% of the patients had already been treated for AIHA and CLL was progressive regardless of AIHA in all patients but one. Overall response rates were 81% for AIHA and 77% for CLL. Median time to next treatment was 28.3 months and 26.2 months for AIHA and CLL, respectively. BR therapy may represent a good and safe therapeutic option in this setting where adequate control of CLL seems important for long-term AIHA response.

Old DAT and new data: positive direct antiglobulin test identifies a subgroup with poor outcome among chronic lymphocytic leukemia stage A patients.

Only a minority of chronic lymphocytic leukemia (CLL) patients harboring a positive direct antiglobulin test (DAT) will develop autoimmune hemolytic anemia (AIHA). In a single institution cohort of 378 CLL patients, 56 patients (14.8%) had at least one positive DAT during the course of the disease, either at diagnosis or later. We found no relationship between the time of the first positive DAT and overall survival (OS). However, patients with a positive DAT who did not develop AIHA had the same adverse outcome as patients who developed AIHA. Of the patients who were in Binet stage A at diagnosis, those with a positive DAT had a significantly shorter OS, regardless of their IGHV mutational status, however, there was a strong association with VH1-69. By multivariate analysis, a positive DAT was found to be an independent adverse prognostic factor for OS. Thus, DAT represents a strong adverse prognostic factor and its determination should be repeated during follow-up.

The degree of BCR and NFAT activation predicts clinical outcomes in chronic lymphocytic leukemia.

B-cell antigen receptor (BCR)-mediated signaling plays a critical role in chronic lymphocytic leukemia (CLL) pathogenesis and gives an in vitro survival advantage to B cells isolated from patients with unfavorable prognostic factors. In this study, we undertook to elucidate the signaling intermediates responsible for this biologic alteration. In responding cells only, in vitro BCR engagement triggers global phosphorylation of Syk, activation of phospholipase Cγ2, and intracellular calcium mobilization, reflecting competency of BCR signaling. The calcium-calcineurin-dependent transcription factor NFAT2 is up-regulated and to some extent constitutively activated in all CLL B cells. In contrast, its DNA-binding capacity is enhanced on IgM stimulation in responding cells only. NFAT inhibition using the VIVIT peptide prevents induction of CD23 target gene and IgM-induced survival, converting responding cells to unresponsive status. At the opposite, ionomycin-induced NFAT activity allows survival of nonresponding cells. These results demonstrate that the functional heterogeneity relies on variability of protein levels establishing BCR-dependent thresholds and NFAT-dependent activation. Finally, status of the BCR-NFAT pathway for each patient reveals its relevance for CLL clinical outcome and points out to BCR-NFAT intermediates as promising functional therapeutic targets.

Recommendations of the SFH (French Society of Haematology) for the diagnosis, treatment and follow-up of hairy cell leukaemia.

Hairy cell leukaemia (HCL) is a rare haematological malignancy, with approximately 175 new incident cases in France. Diagnosis is based on a careful examination of the blood smear and immunophenotyping of the tumour cells, with a panel of four markers being used specifically to screen for hairy cells (CD11c, CD25, CD103 and CD123). In 2011, the V600E mutation of the BRAF gene in exon 15 was identified in HCL; being present in HCL, it is absent in the variant form of HCL (HCL-v) and in splenic red pulp lymphoma (SRPL), two entities related to HCL. The management of patients with HCL has changed in recent years. A poorer response to purine nucleoside analogues (PNAs) is observed in patients with more marked leukocytosis, bulky splenomegaly, an unmutated immunoglobulin variable heavy chain (IgVH) gene profile, use of VH4-34 or with TP53 mutations. We present the recommendations of a group of 11 experts belonging to a number of French hospitals. This group met in November 2013 to examine the criteria for managing patients with HCL. The ideas and proposals of the group are based on a critical analysis of the recommendations already published in the literature and on an analysis of the practices of clinical haematology departments with experience in managing these patients. The first-line treatment uses purine analogues: cladribine or pentostatin. The role of BRAF inhibitors, whether or not combined with MEK inhibitors, is discussed. The panel of French experts proposed recommendations to manage patients with HCL, which can be used in a daily practice.