The effect of hyaluronic acid in embryo transfer media in donor oocyte cycles and autologous oocyte cycles: a systematic review and meta-analysis.

STUDY QUESTION: Does the addition of hyaluronic acid (HA) to embryo transfer medium improve pregnancy outcomes in both autologous and oocyte donation IVF cycles? SUMMARY ANSWER: The best available evidence indicates that the addition of HA to embryo transfer medium is clinically beneficial in cycles with autologous oocytes. WHAT IS KNOWN ALREADY: There is a known clinical benefit of HA addition to embryo transfer media but it is not known if HA affects donor and autologous oocyte cycles differently. STUDY DESIGN, SIZE, DURATION: A systematic review with meta-analysis was performed. The Cochrane Gynaecology and Fertility Group Trials Register, CENTRAL via Cochrane Register of Studies Online (CRSO), MEDLINE, Embase and PsycINFO electronic databases (until 8 January 2020) were searched for randomized controlled trials (RCTs) examining the effect of HA in embryo transfer medium on pregnancy outcomes. PARTICIPANTS/MATERIALS, SETTING, METHODS: RCTs with separate donor and autologous oocyte data that compared embryo transfer medium with functional HA concentrations (0.5 mg/ml) to those containing no or low HA concentrations (0.125 mg/ml) were included. Two review authors independently selected trials for inclusion, extracted data and assessed the included studies using the Cochrane risk of bias assessment tool. Pooled risk ratios and 95% CIs were calculated. A summary of findings table was generated using Grading of Recommendations, Assessment, Development and Evaluation criteria. Judgements about evidence quality were justified and incorporated into the reported results for each outcome. MAIN RESULTS AND THE ROLE OF CHANCE: Fifteen studies, totalling 4686 participants, were analysed. In autologous oocyte cycles, live birth increased from 32% to 39% when embryo transfer media contained functional HA concentrations (risk ratio (RR) 1.22, 95% CI 1.11-1.34; nine studies, 3215 participants, I2 = 39%, moderate-quality evidence (number needed to treat (NNT) 14). HA-enriched media increased clinical pregnancy and multiple pregnancy rates by 5% and 8%, respectively (RR 1.11, 95% CI 1.04-1.18; 13 studies, 4014 participants, I2 = 0%, moderate-quality evidence, NNT 21) and (RR 1.49, 95% CI 1.27-1.76; 5 studies, 2400 participants, I2 = 21%, moderate-quality evidence, number needed to harm 13). Conversely, in donor oocyte cycles, HA addition showed little effect on live birth and clinical pregnancy (RR 1.12 95% CI 0.86-1.44; two studies, 317 participants, I2 = 50%, low-quality evidence) and (RR 1.06, 95% CI 0.97-1.28; three studies, 351 participants, I2 = 23%, low-quality evidence). There was insufficient available information on multiple pregnancy in donor oocyte cycles and on total adverse effects in both groups to draw conclusions. LIMITATIONS, REASONS FOR CAUTION: There were limited studies with separate data on donor oocyte cycles and limited information on oocyte quality. Additionally, one-third of the included studies did not include the main outcome, live birth rate. WIDER IMPLICATIONS OF THE FINDINGS: There is a moderate level of evidence to suggest that functional HA concentration in embryo transfer medium increases clinical pregnancy, live birth and multiple pregnancy rates in IVF cycles using autologous oocytes. This effect was not seen in donor oocyte cycles, indicating either intrinsic differences between donor and autologous oocytes or lack of statistical power. The combination of HA addition to transfer media in cycles using autologous oocytes and a single embryo transfer policy might yield the best combination, with higher clinical pregnancy and live birth rates without increasing the chance of multiple pregnancies. STUDY FUNDING/COMPETING INTEREST(S): No financial assistance was received. The authors have no competing interests. REGISTRATION NUMBER: N/A.

Hyaluronic acid in embryo transfer media for assisted reproductive technologies.

BACKGROUND: This is an update of a Cochrane Review first published in the Cochrane Library (2010, Issue 7). To increase the success rate of assisted reproductive technologies (ARTs), adherence compounds such as hyaluronic acid (HA) have been introduced into subfertility management. Adherence compounds are added to the embryo transfer medium to increase the likelihood of embryo implantation, with the potential for higher clinical pregnancy and live birth rates. OBJECTIVES: To determine whether adding adherence compounds to embryo transfer media could improve pregnancy outcomes, including improving live birth and decreasing miscarriage, in women undergoing assisted reproduction. SEARCH METHODS: We searched the Cochrane Gynaecology and Fertility Group Trials Register, CENTRAL, MEDLINE, Embase, and PsycINFO electronic databases on 7 January 2020 for randomised controlled trials that examined the effects of adherence compounds in embryo transfer media on pregnancy outcomes. Furthermore, we communicated with experts in the field, searched trials registries, checked reference lists of relevant studies, and conference abstracts were handsearched. SELECTION CRITERIA: Only truly randomised controlled trials comparing embryo transfer media containing functional concentrations of adherence compounds to media with no or low adherence compound concentrations were included. DATA COLLECTION AND ANALYSIS: Two review authors selected trials for inclusion according to the above criteria, after which the same two review authors independently extracted data for subsequent analysis. Statistical analysis was performed according to the guidelines developed by Cochrane. We combined data to calculate pooled risk ratios (RRs) and 95% confidence intervals (CIs). We assessed statistical heterogeneity using the I² statistic. We used GRADE methods to assess the overall quality of evidence for the main comparisons. MAIN RESULTS: We analysed 26 studies with a total of 6704 participants. Overall, the certainty of evidence was low to moderate: the main limitations were imprecision and/or heterogeneity. Compared to embryos transferred in media containing no or low (0.125 mg/mL) HA, the addition of functional (0.5 mg/mL) HA concentrations to the transfer media probably increases the live birth rate (RR 1.21, 95% CI 1.1 to 1.31; 10 RCTs, N = 4066; I² = 33%; moderate-quality evidence). This suggests that if the chance of live birth following no HA addition in media is assumed to be 33%, the chance following HA addition would be between 37% and 44%. The addition of HA may slightly decrease miscarriage rates (RR 0.82, 95% CI 0.67 to 1.00; 7 RCTs, N = 3091; I² = 66%; low-quality evidence). Nevertheless, when only studies with low risk of bias were included in the analysis, there was no conclusive evidence of a difference in miscarriage rates (RR 0.96, 95% CI 0.75 to 1.23; N = 2219; I² = 36%). Adding HA to transfer media probably results in an increase in both clinical pregnancy (RR 1.16, 95% CI 1.09 to 1.23; 17 studies, N = 5247; I² = 40%; moderate-quality evidence) and multiple pregnancy rates (RR 1.45, 95% CI 1.24 to 1.70; 7 studies, N = 3337; I² = 36%; moderate-quality evidence). We are uncertain of the effect of HA added to transfer media on the rate of total adverse events (RR 0.86, 95% CI 0.40 to 1.84; 3 studies, N = 1487; I² = 0%; low-quality evidence). AUTHORS' CONCLUSIONS: Moderate-quality evidence shows improved clinical pregnancy and live birth rates with the addition of HA as an adherence compound in embryo transfer media in ART. Low-quality evidence suggests that adding HA may slightly decrease miscarriage rates, but when only studies at low risk of bias were included in the analysis, the results were inconclusive. HA had no clear effect on the rate of total adverse events. The increase in multiple pregnancy rates may be due to combining an adherence compound and transferring more than one embryo. Further studies of adherence compounds with single embryo transfer need to be undertaken.

Bendamustine for patients with indolent B cell lymphoproliferative malignancies including chronic lymphocytic leukaemia - an updated meta-analysis.

The question of which chemotherapy induction provides the best results for indolent lymphoma patients is yet unanswered. Different regimens have been compared, none of which has been shown to improve overall survival. The use of bendamustine is growing. A number of trials evaluated its efficacy for patients with indolent B-cell lymphoid neoplasms, including chronic lymphocytic leukaemia (CLL). To evaluate the efficacy of bendamustine in that population we performed a systematic review and meta-analysis of 9 randomised controlled trials (2726 patients). Bendamustine was compared to fludarabine-containing regimens, CVP (cyclophosphamide, vincristine, prednisolone), CHOP (CVP+ doxorubicin) and chlorambucil. Due to insufficient reported data, six of the nine trials were included in analysis of overall survival. Bendamustine was associated with a prolonged overall survival, (hazard ratio 0·79, 95% confidence interval 0·65-0·95). Data regarding quality of life was reported for two trials, therefore too scarce to pool. The risk of neutropenia was reduced with bendamustine treatment compared to other chemotherapy. Bendamustine induction is an efficacious option for patients with indolent lymphoma, and CLL. Maintenance therapy was not evaluated after bendamustine induction, and potentially there is an interaction between the two. Chemotherapy-free approach was shown to be efficacious for patients with CLL, while toxicity with that approach is not negligible.

The role of maintenance therapy in patients with diffuse large B cell lymphoma: A systematic review and meta-analysis.

Randomized trials of maintenance therapy (MT) in diffuse large B cell lymphoma (DLBCL) are inconclusive regarding its effect on overall survival (OS) and disease control. We aimed to examine the efficacy and safety of MT in this meta-analysis. Systematic review and meta-analysis of randomized controlled trials comparing MT with observation or placebo, in patients with DLBCL, who achieved complete response (CR) or partial response (PR) after first-line chemotherapy with or without rituximab. Primary outcome was OS. Secondary outcomes included relapse rate, disease control (defined as progression-free survival, event-free survival, or disease-free survival, as reported in the original trials), and safety. Our search yielded 14 trials including 5122 patients. Median age of patients was 49 to 70 years. Six trials included rituximab as the MT; three included Interferon alfa; other trials include thalidomide, lenalidomide, cyclophosphamide and prednisone, serine threonine kinase inhibitor enzastaurin, and mTOR inhibitor everolimus. MT did not improve OS compared to observation, OR 0.91, (95% CI 0.78-1.07). Results were the same in a subgroup analysis by the type of maintenance (rituximab vs other). MT did decreased relapse rate, RR 0.76 (95% CI 0.65-0.89) and improved disease control, OR 0.74 (95% CI 0.65-0.84). Disease control was significantly improved in the subgroup of studies evaluating rituximab as maintenance OR 0.61 (95% CI 0.47-0.79) and in the subgroup of R-CHOP induction studies OR 0.77 (95% CI 0.67-0.88). Serious or grade III/IV adverse events including neutropenia and infections were significantly more common in the maintenance arm, RR = 1.69 (95% CI 1.29-2.22). MT in patients with DLBCL achieving CR or PR after induction therapy did not affect OS, yet it decreased relapse rate and improved disease control at the cost of higher infection rate. Our data do not support routine administration of MT in patients with DLBCL.

Spontaneous Regression of Hodgkin Lymphoma: Case Report and Review of the Literature.

Spontaneous regression of Hodgkin lymphoma (HL) is a rare event. We describe a 32-year-old woman with spontaneous regression of HL and review the literature. The patient presented with cervical lymphadenopathy and was diagnosed with stage IIA classical HL. The patient refused to receive any treatment for her disease. Positron emission tomography/computed tomography carried out 2 years later showed complete regression of the lymphadenopathy, without pathological uptake of fluorodeoxyglucose. At the last follow-up, 3.5 years after the initial presentation, the patient is with no evidence of disease. During workup for the HL, concomitant papillary thyroid carcinoma was diagnosed, for which the patient refused treatment as well. The thyroid malignancy has remained stable throughout the follow-up.

Utility of PET-CT for Evaluation of Patients With Peripheral T-cell Lymphoma.

BACKGROUND: Fluorine-18 fluorodeoxyglucose (FDG) avidity varies in peripheral T-cell lymphoma (PTCL). We evaluated FDG avidity of pretreatment positron emission tomography/computed tomography (P-PET/CT), to appraise the prognostic significance of interim PET/CT (I-PET/CT) and end of treatment PET/CT (E-PET/CT) in PTCL. PATIENTS AND METHODS: We performed a retrospective cohort study of patients with newly diagnosed or relapsed PTCL who had received any chemotherapy regimen from 2008 to 2015 in a tertiary center. P-PET/CT, I-PET/CT, and E-PET/CT studies were centrally reviewed. The primary outcomes were the prognostic role of I-PET/CT and E-PET/CT on progression-free survival (PFS) and overall survival (OS). The secondary outcomes were P-PET/CT avidity, the prognostic role of other baseline characteristics, and the correlation between the PET/CT and bone marrow biopsy findings. RESULTS: We included 40 patients in the present analysis. The median OS and PFS for the whole cohort was 39 and 16 months, respectively. Of the 40 patients, 36 had positive P-PET/CT findings. A total of 23 patients underwent I-PET/CT, with positive findings for 10. Of the 40 patients, 34 underwent E-PET/CT, 26 of which had positive findings. The sensitivity, specificity, and negative predictive value of P-PET/CT for bone marrow involvement was 40%, 83%, and 89%, respectively. The factors significantly associated with PFS and OS on univariate analysis included elevated lactate dehydrogenase, and low lymphocyte, hemoglobin, and albumin levels. On multivariate analysis, only lymphopenia remained prognostic for PFS and OS. The E-PET/CT and I-PET/CT results were not prognostic for PFS or OS. CONCLUSION: Our study has shown that 90% of PTCL cases will be FDG avid. However, PET/CT was not predictive for PFS or OS at any point. The only predictive factor was the presence of lymphopenia.

PET-adapted therapy for advanced Hodgkin lymphoma - systematic review.

INTRODUCTION: Positron emission tomography-computed tomography (PET-CT) performed after two chemotherapy cycles (PET-2) has become an accepted prognostic tool in Hodgkin lymphoma (HL). We evaluated the effect of PET-adapted strategy on outcome in advanced stage HL. METHODS: In August 2017, we searched electronic databases, conference proceedings and ongoing trials. We included all studies in which treatment modification for advanced HL was performed based on the results of the interim PET scan. The primary analysis included randomized controlled trials (RCTs). Outcomes were progression-free survival (PFS) and overall survival (OS). RESULTS: We identified 13 studies (4 RCTs, 7 phase II and 2 retrospective studies), conducted between 1999 and 2014, including 6856 patients. Of the four RCTS: one used therapy escalation, one did de-escalation and two trials performed both. Outcomes were assessed at different time point between 2 and 5 years. Three RCTs for de-escalating therapy, obtained similar outcomes despite reducing therapy, with a 2-year PFS of 88-92% (6 escalated BEACOPP (EB) vs. 4 ABVD cycles), a 5-year PFS of 91-92% (6/8 EB vs. 4 EB cycles) and a 5-year PFS of 80-82% (6 ABVD vs. omitting bleomycin after two successful ABVD cycles). Two RCTs implemented escalation. The randomization was between adding rituximab or not. In both trials, it did not affect outcome, with a 4-year PFS of 68-69% (addition of rituximab to BEACOPP after 2 ABVD cycles) and 5-year PFS of 88-90% (addition of rituximab to EB after 2 EB cycles). Performing true randomization between PET-adapted and a standard ABVD control arm was not feasible, given historical data. CONCLUSIONS: This systematic review of PET-adapted therapy, mainly based on RCTs, suggests that a change to the treatment paradigm is appropriate in advanced HL.

The effect of R-CHOP dose reduction on overall survival of elderly patients with DLBCL - comparative study.

R-CHOP is the standard therapy for patients with diffuse large B-cell lymphoma (DLBCL). We evaluated the effect of reduced intensity R-CHOP on survival, and toxicity in patients 70 years or older with DLBCL. The retrospective analysis included 140 patients (median age 78 years). We showed that patients with a good performance status treated with reduced adriamycin dose had a statistically significant worse overall survival. In multivariable model, the HR with any 10% increase adriamycin-relative dose in the first cycle was, 0.81, 95% CI 0.70-0.94. Age, gender, albumin and IPI were also associated with overall survival. Hospitalizations of patients treated with reduced R-CHOP were longer; however, the rate of infection did not differ between the groups. Based on current data, the optimal treatment for elderly patients with DLBCL remains unclear, but it is apparent that the dose of chemotherapy should be tailored individually according to performance status.

Maintenance Treatment for Patients With Mantle Cell Lymphoma: A Systematic Review and Meta-analysis of Randomized Trials.

Current treatment of patient with mantle cell lymphoma (MCL) is insufficient and does not result in cure. To assess the efficacy and safety of maintenance therapy for patients with MCL, we performed a systematic review and meta-analysis of randomized controlled trials. Six trials randomizing 858 patients were included in the meta-analysis. In 5 trials, maintenance therapy consisted of rituximab. The pooled hazard ratio (HR) of death with rituximab maintenance compared to observation was 0.79, 95% CI 0.58 to 1.06 (4 trials, 737 patients). Progression free survival was longer with rituximab maintenance in each of the trials and in the pooled analysis (HR 0.58, 95% CI 0.45-0.73). The risk of neutropenia was higher with maintenance compared to observation risk ratio (RR) 1.31, 95% CI 1.03 to 1.66. None of the trials reported on quality of life outcomes. The grade 3 to 4 infection rate was 7% in each of the treatment groups. The risk of grade 3 to 4 infection was not affected by allocation to maintenance. Rituximab maintenance is recommended after R-CHOP or R-cytarabine-containing induction in the frontline setting for transplant eligible and ineligible patients, and after R-CHOP in the relapse setting. It is unclear if maintenance is of benefit after different induction chemotherapy such as bendamustine or fludarabine. It is too early to conclude on other type of maintenance for MCL patients.

Acute myeloid leukemia during pregnancy: a systematic review and meta-analysis.

Data regarding clinical characteristics, therapy, maternal and fetal outcomes of pregnancy-associated acute myeloid leukemia (PA-AML) are limited. This study (including 138 cases published between 1955 and 2013) provides comprehensive assessment of these clinical parameters and may serve as a platform for developing management recommendations. Most patients (58%) received anthracycline-cytarabine-based regimens (ACBRs), which were associated with significantly increased complete remission (CR: 91%). Yet, the maternal overall survival (OS: ∼30%) was relatively low, probably reflecting reduced application of risk-adapted consolidation and allogeneic stem cell transplantation (allo-SCT). Fetal exposure to ACBRs resulted in a live birth rate of 87%, with complications (16%) diagnosed only in chemotherapy-subjected neonates. This study demonstrates safety and efficacy of ACBRs during pregnancy. Therapy and delivery schedule should allow early referral of high-risk patients to allo-SCT. Generation of a pool of high-quality data on PA-AML could contribute to providing evidence-based therapy and lead to improved maternal and fetal survival.

Empirical antibiotics targeting gram-positive bacteria for the treatment of febrile neutropenic patients with cancer.

BACKGROUND: The pattern of infections among neutropenic patients with cancer has shifted in the last decades to a predominance of gram-positive infections. Some of these gram-positive bacteria are increasingly resistant to beta-lactams and necessitate specific antibiotic treatment. OBJECTIVES: To assess the effectiveness of empirical anti-gram-positive (antiGP) antibiotic treatment for febrile neutropenic patients with cancer in terms of mortality and treatment failure. To assess the rate of resistance development, further infections and adverse events associated with additional antiGP treatment. SEARCH METHODS: For the review update we searched the Cochrane Central Register of Controlled Trials (CENTRAL) (2017, Issue 2), MEDLINE (May 2012 to 2017), Embase (May 2012 to 2017), LILACS (2012 to 2017), conference proceedings, ClinicalTrials.gov trial registry, and the references of the included studies. We contacted the first authors of all included and potentially relevant trials. SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing one antibiotic regimen versus the same regimen with the addition of an antiGP antibiotic for the treatment of febrile neutropenic patients with cancer. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trial eligibility and risk of bias, and extracted all data. Risk ratios (RR) with 95% confidence intervals (CIs) were calculated. A random-effects model was used for all comparisons showing substantial heterogeneity (I2 > 50%). Outcomes were extracted by intention-to-treat and the analysis was patient-based whenever possible. MAIN RESULTS: Fourteen trials and 2782 patients or episodes were included. Empirical antiGP antibiotics were tested at the onset of treatment in 12 studies, and for persistent fever in two studies. The antiGP treatment was a glycopeptide in nine trials. Eight studies were assessed in the overall mortality comparison and no significant difference was seen between the comparator arms, RR of 0.90 (95% CI 0.64 to 1.25; 8 studies, 1242 patients; moderate-quality data). Eleven trials assessed failure, including modifications as failures, while seven assessed overall failure disregarding treatment modifications. Failure with modifications was reduced, RR of 0.72 (95% CI 0.65 to 0.79; 11 studies, 2169 patients; very low-quality data), while overall failure was the same, RR of 1.00 (95% CI 0.79 to 1.27; 7 studies, 943 patients; low-quality data). Sensitivity analysis for allocation concealment and incomplete outcome data did not change the results. Failure among patients with gram-positive infections was reduced with antiGP treatment, RR of 0.56 (95% CI 0.38 to 0.84, 5 studies, 175 patients), although, mortality among these patients was not changed.Data regarding other patient subgroups likely to benefit from antiGP treatment were not available. Glycopeptides did not increase fungal superinfection rates and were associated with a reduction in documented gram-positive superinfections. Resistant colonisation was not documented in the studies. AUTHORS' CONCLUSIONS: Based on very low- or low-quality evidence using the GRADE approach and overall low risk of bias, the current evidence shows that the empirical routine addition of antiGP treatment, namely glycopeptides, does not improve the outcomes of febrile neutropenic patients with cancer.

Role of Induction Chemotherapy Prior to Chemoradiation in Head and Neck Squamous Cell Cancer-Systematic Review and Meta-analysis.

The objective of this study was to review and assess the impact of additional induction chemotherapy to concomitant chemoradiation in head and neck squamous cell cancer. We performed a comparative systematic review and meta-analysis of clinical trials of induction chemotherapy + chemoradiation and chemoradiation alone in this setting. We identified trials randomizing 1314 patients (published 2004-2015). A non-statistically significant trend was observed in favor of induction chemotherapy + chemoradiation on overall survival (hazard ratio, 0.88; 95% confidence interval, 0.75-1.04). Disease control was superior in the induction chemotherapy + chemoradiation group (hazard ratio, 0.69; 95% confidence interval, 0.57-0.83). The rate of complete response improved with induction chemotherapy compared with concomitant chemoradiation (relative risk, 1.52; 95% confidence interval, 1.20-1.92). This study showed no benefit of induction chemotherapy + chemoradiation on overall survival. However, improved complete response rate and death certificate-only registrations may imply that selected patients may benefit from induction chemotherapy.

Rituximab maintenance improves overall survival of patients with follicular lymphoma-Individual patient data meta-analysis.

BACKGROUND: Randomised trials of rituximab maintenance (MR) for patients with follicular lymphoma support improved progression-free survival (PFS), but the effect on overall survival has been inconclusive. To evaluate the effect of MR on overall survival according to patient and disease characteristics, and to explore certain adverse events, we performed an individual patient data (IPD) meta-analysis. METHODS: All investigators of randomised controlled trials that compared MR therapy with observation or treatment only at relapse (no MR) for patients with follicular lymphoma were invited to participate in an IPD meta-analysis. We obtained baseline patient and disease characteristics and time to progression and death for each patient. All analyses took into account the trial and original randomised treatment group. We analysed data in two ways: a two-stage analysis and a multivariate model including patient and disease characteristics. FINDINGS: Seven trials including 2315 patients were analysed. Overall survival of patients improved with MR compared with no MR (hazard ratio [HR] 0.79, 95% CI 0.66-0.96). We could not detect any patient or disease characteristics that were associated with a survival benefit with MR. In all of the models, MR had a beneficial effect on overall survival compared with observation for all types of patients, which was not shown in a particular subgroup in which the patient had already received rituximab in the induction phase and received first-line therapy. MR improved PFS compared with observation (HR 0.57, 95% CI 0.51-0.64). The risk of adverse events was higher with MR, specifically infection of any grade and grade 3-4 infections. INTERPRETATION: Based on IPD from randomised controlled trials, MR improves overall survival consistently in all patients, regardless of patient and disease characteristics when compared with observation, and should be prescribed after a successful induction with R-CVP or R-CHOP for patients with follicular lymphoma. It is still uncertain if that holds when the patient has already received rituximab in his/hers first induction. The effect of MR after bendamustine-rituximab induction compared with rituximab at progression should be further explored.

Bendamustine-associated infections-systematic review and meta-analysis of randomized controlled trials.

Data in the literature are lacking regarding the infection-related adverse events of bendamustine-containing regimens. Therefore, we aimed to assess this risk. We conducted a systematic review and meta-analysis of all randomized controlled trials including bendamustine-containing regimens and those administered for any lymphoproliferative disorder or plasma cell dyscrasia compared with any other regimens. A comprehensive search was conducted until December 2015. Two reviewers appraised the quality of trials and extracted data. Primary outcomes were any infections, grade 3 to 4 infections; secondary outcomes were grade 3 to 4 neutropenia and grade 3 to 4 lymphopenia. Relative risks (RRs) with 95% confidence intervals (CIs) were estimated and pooled. A fixed-effect model was used to pool data unless there was significant heterogeneity, in which case a random-effects model was used. Nine trials published between 2006 and 2016 and randomizing 2620 patients were included. There was no statistically significant effect for bendamustine on the rate of any infection (RR 1.09 [95% CI, 0.87-1.36]) or on the rate of grade 3 to 4 infections (RR 1.04 [95% CI, 0.64-1.71]). There was no increase in the rate of grade 3 to 4 neutropenia in the bendamustine arm (RR 0.84 [95% CI, 0.63-1.12]). Our systematic review demonstrates no effect of bendamustine on the rate of infections when compared with either alkylating agents or fludarabine. Thus, bendamustine remains a safe therapeutic option.

First line treatment with newer tyrosine kinase inhibitors in chronic myeloid leukemia associated with deep and durable molecular response - systematic review and meta-analysis.

BACKGROUND: The choice of a specific tyrosine kinase inhibitor (TKI) as first line treatment in chronic myeloid leukemia (CML) is complex and influenced by multiple factors. We published a meta-analysis examining the role of newer TKIs as first line treatment in chronic phase CML. In view of the recently published data, we decided to update it. METHODS: We conducted a systematic review and meta-analysis of randomized controlled trials comparing first line treatment with imatinib to the newer TKIs (nilotinib, dasatinib, bosutinib and ponatinib). We searched MEDLINE, conference proceedings and databases of ongoing trials up to August 2015. RESULTS: Our search yielded eight trials including 3554 patients. Treatment with the newer TKIs significantly improved major molecular response (MMR) at all time points and increased the rate of complete molecular response (CMR) at 12 and 24 months [relative risk (RR) 2.58, 95% CI 1.98-3.37, six trials and RR 2.05, 95% CI 1.63-2.58, three trials, respectively]. Early molecular response at three months was better with the newer TKIs (RR 1.33, 95% CI 1.26-1.40, six trials). Importantly, progression rate to accelerated or blastic phase was significantly lower with the newer TKIs at 12, 24 months and 5 years. Yet, there was no difference in all-cause mortality. The risk of adverse events requiring treatment discontinuation increased with the newer TKIs. CONCLUSIONS: With a longer follow-up, the newer TKIs remain more potent than imatinib, yet with no significant effect on survival. As CMR is a prerequisite for treatment discontinuation and cure, the newer TKIs favor treatment cessation.

Chlorambucil for the treatment of patients with chronic lymphocytic leukemia (CLL) - a systematic review and meta-analysis of randomized trials.

Randomized clinical trials that compared chlorambucil to different regimens, for patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) do not support an overall survival (OS) benefit. To assess the efficacy and safety of chlorambucil as frontline treatment, we conducted a systematic review and meta-analysis of randomized controlled trials. OS was the primary outcome. Meta-analysis of 18 trials that compared purine analogs, alkylators, alemtuzumab and ibrutinib to chlorambucil demonstrated no OS benefit for therapy without chlorambucil over chlorambucil (pooled HR 0.99, 95% CI 0.91-1.08; 4133 patients). PFS was longer with purine analogs compared with chlorambucil with an increased risk of infection. The risk of secondary malignancies was not increased with chlorambucil. In conclusion, our study showed that chlorambucil is an acceptable chemotherapy backbone for unfit patients with CLL. Purine analogs should be preferred in fit younger patients because of longer PFS. Future trials should focus on unfit patients who are underrepresented in clinical trials.

Infections associated with bendamustine containing regimens in hematological patients: a retrospective multi-center study.

A multi-center retrospective analysis of a cohort of patients in Israel treated with any bendamustine containing regimen between 2010-2014 was performed in order to determine the incidence and predictors for infection. The Kaplan Meier Model, employing log rank analysis, was used to assess time-to-infection. The Cox Proportional Hazards model was used to analyze multivariate effects of risk and 234 patients were included in the analysis. One hundred and nine (46.6%) developed at least one infection and 33.76% had severe infections. Seventy-six (41.5%) developed bacterial infection, nine (3.8%) fungal infection and 26 (11.5%) had viral infections. Factors significantly associated with time to infection on multivariable analysis were: bendamustine-combinations [hazard ratio (HR) = 0.589 (95% CI = 0.374-0.926), p = 0.022], Hb level [HR = 0.791 (95% CI = 0.716-0.875), p < 0.0001] and ischemic heart disease [HR = 1.828 (95% CI = 1.165-2.868), p = 0.009]. Infections were associated with a higher mortality and hospitalization rate.

CHOP-like-14 compared to CHOP-like-21 for patients with aggressive lymphoma--a meta-analysis of randomized controlled trials.

BACKGROUND: R-CHOP-21 has remained the standard chemotherapy for aggressive non-Hodgkin's lymphoma. It was suggested that decreasing the treatment interval from three weeks (CHOP-21) to two weeks (CHOP-14) may improve survival and disease control of patients with aggressive lymphoma. PURPOSE: To evaluate the effect of CHOP-like-14 (with or without rituximab) compared to standard CHOP-like -21 on overall survival (OS), disease control and toxicity of patients with aggressive non-Hodgkin lymphoma. METHODS: Systematic review and meta-analysis of RCTs. In October 2014 we searched The Cochrane Library, MEDLINE, LILACS, conference proceedings, and databases of ongoing trials. Authors were contacted for complementary data. The primary outcome was OS. RESULTS: We identified seven trials (4073 patients), conducted between the years 1999 and 2008. Trials were at low or unclear risk for selection bias, and at low or unclear risk of attrition bias. CHOP-like-14 improved OS of patients with aggressive lymphoma compared to the same regimen given every 21 days (all trials): HR of death 0.86, 95% confidence interval (CI) 0.77-0.97. There was no OS difference between rituximab-CHOP-like 14 to rituximab-CHOP-like-21 (3 trials): HR 0.93 95% CI 0.78-1.10. The rates of progression or death, complete response, treatment-related mortality, grade 3-4 infection, and discontinuation were similar between groups. CONCLUSION: R-CHOP-21 remains the standard of care for patient with aggressive B-cell lymphoma. CHOP-14 can be considered as in case rituximab is omitted.

Predicting the emergence of anemia--A large cohort study.

BACKGROUND AND OBJECTIVES: We aimed to find predictors for development of anemia in a large cohort of adults. PATIENTS AND METHODS: Cohort study of a large health database from a screening center at the Rabin Medical Center in Israel, between the years 2000-2013. We asked which variables, known at the first visit, would predict anemia at the last visit. Multivariable analysis was conducted using stepwise logistic regression analysis. Odds ratios (ORs) for anemia with 95% confidence intervals (CIs) were calculated. RESULTS: Our cohort included 10,577 people. At baseline 4.4% were diagnosed with anemia and excluded. Therefore, 10,093 subjects, with a mean age of 42.3 ± 9 years comprised our study sample. At the end of follow-up of 4.7 ± 3.1 years, 307 developed anemia (3%). In men, independent predictors for development of anemia were diabetes mellitus (OR 3.00, 95% CI 1.41-6.39), age (OR 1.03, 95% CI 1.03-1.05, for 1 year increment), low MCV (OR 0.92, 95% CI 0.89-0.96, for every 1 fL unit increment) and elevated platelet count (OR 1.004, 95% CI 1.00-1.01 for 1000/µL unit increment). For women, high total serum protein level was a strong predictor for anemia (OR 3.44, 95% CI 2.33-5.08 for 1mg/dL increment) as well as low triglycerides (OR 0.996, 95% CI 0.993-1.000 for 1mg/dL increment). CONCLUSIONS: Subgroups who are prone to develop anemia include men with diabetes, and women with an elevated serum protein level and low triglycerides.

Higher infection rate after 7- compared with 5-day cycle of azacitidine in patients with higher-risk myelodysplastic syndrome.

INTRODUCTION: Azacitidine (AZA) dose reduction is a common practice in cytopenic patients. However, a correlation between AZA dose and infection complications has never been studied. PATIENTS AND METHODS: Higher-risk patients with myelodysplastic syndrome or acute myeloid leukemia treated with AZA in 18 Israeli hospitals between the years 2008 and 2011 were included in a former national survey. To reveal the effect of AZA dosage on infection risk we limited our analysis to the infection rate after the first AZA dose alone. We excluded subsequent cycles of AZA from the analysis, because infectious events during these cycles might be related to other cofactors such as disease response to AZA therapy. RESULTS: After the first AZA cycle, infectious events were more frequent after doses of 75 mg/m(2) for 7 days than 75 mg/m(2) for 5 days (36/106 [34%] and 10/67 [14.9%], respectively; P = .008), regardless of the patient's age. Of the 46 recorded infectious events, the causative pathogen was identified as bacterial in 25 (54.3%) and as viral or fungal in 2 (4.3%) and 2 (4.3%) cases, respectively. No pathogen was identified in 17 (37%) cases. Infections were significantly more prevalent among patients who presented with platelet counts < 20,000 (43.6% vs. 23.6%; P = .012) and poor risk cytogenetics (40.7% vs. 19.8%; P = .008). CONCLUSION: Reduction of AZA dose might decrease infection rate and therefore should be considered in patients with high infection risk.