Suboptimal Responders Research Articles

S873 EFFICACY OF QUADRUPLET KCRD (CARFILZOMIB, CYCLOPHOSPHAMIDE, LENALIDOMIDE AND DEXAMETHASONE) INDUCTION FOR NEWLY DIAGNOSED MYELOMA PATIENTS: ANALYSIS OF THE MYELOMA XI STUDY BY MOLECULAR RISK

Background:Carfilzomib is a second‐generation irreversible proteasome inhibitor that has shown significant efficacy in phase III studies of relapsed myeloma patients. The UK NCRI Myeloma XI study is the first phase III randomised study that has reported outcomes for the use of carfilzomib as induction therapy in newly diagnosed myeloma patients prior to autologous stem cell transplant (ASCT). The KCRD combination deepened responses and prolonged progression‐free survival compared to response adapted immunomodulatory agent‐based triplet +/‐ proteasome inhibitor‐based triplet therapy (Jackson GH et al, ASH 2018).Aims:In this exploratory analysis we examine the efficacy of KCRD compared to triplet therapy across different molecular subgroups within the Myeloma XI trial.Methods:1056 patients were randomised between KCRD (28 day cycles of carfilzomib (K) 36 mg/m2 IV d1‐2, 8–9, 15–16 (20 mg/m2 #1d1‐2), cyclophosphamide (C) 500 mg PO d1,8, lenalidomide (R) 25 mg PO d1‐21, dexamethasone (D) 40 mg PO d1‐4,8‐9,15‐16) and triplet CTD/CRD prior to ASCT. Patients who received CTD/CRD underwent response‐adapted intensification for suboptimal responders with a randomization to proteasome inhibitor (bortezomib, CVD) containing triplet or no further therapy. A maintenance randomisation at 3 months post ASCT compared lenalidomide to observation. Molecular analysis was available for a representative subset of patients (n = 339). High‐risk (HiR) was classified in the study as the presence of t(4;14), t(14;16), t(14;20), del(17p) or gain(1q) and ultra‐high risk (UHiR) the presence of two or more lesions. Exploratory analyses of outcome by individual molecular risk lesion and by HiR defined without the inclusion of gain(1q) and t(14;20) were also performed. Efficacy analyses included PFS and response.Results:KCRD was associated with a significantly longer PFS than triplet therapy for the whole population, with no significant heterogeneity between risk groups (standard risk (SR) hazard ratio (HR) 0.55, 95%CI 0.33, 0.92, median PFS KCRD NR vs CTD/CRD 36 months), HiR (HR 0.68, 95%CI 0.40, 1.19, median PFS KCRD NR vs CTD/CRD 37 months) and UHiR (HR 0.72, 95%CI 0.26, 2.02, median PFS KCRD 25 vs CTD/CRD 20 months, phet = 0.7841). For patients receiving KCRD there was no difference in response rate at the end of induction 1 by risk group (> = VGPR: SR 86.0%, HiR 87.0% and UHiR 88.2%). However, UHiR disease was associated with significantly shorter PFS than both SR (p = 0.0073) and HiR (p = 0.0180) whilst there was no significant difference in outcome between patients with HiR (only one adverse lesion) and SR (p = 0.7213). Within groups of patients with each HiR lesion there was a benefit for KCRD over CTD/CRD. The lowest hazard ratio was observed in patients with a del(17p), (HR 0.12, 95%CI 0.03, 0.51, median PFS KCRD 38 vs CTD/CRD 17 months). When HiR was defined only by the presence of t(4;14), t(14;16) and/or del(17p) there remained a significant benefit for KCRD over CTD/CRD (HiR: HR 0.38, 95%CI 0.19, 0.77, median PFS KCRD 38 vs CTD/CRD 22 months, SR: HR 0.58, 95%CI 0.39, 0.88, median PFS KCRD NR vs CTD/CRD 38 months) with no heterogeneity of effect identified between risk groups.Summary/Conclusion:KCRD is associated with prolonged PFS compared with response‐adapted triplet therapy across all molecular risk subgroups, however these are defined. Even with the highly effective quadruplet combination KCRD, UHiR patients continue to have significantly worse outcomes than patients with standard risk disease and there remains an unmet need for novel therapeutic approaches for these patients.

S1646 THE COMBINATION OF LOW ADAMTS-13 ACTIVITY AND HIGH ANTI-ADAMTS13 ANTIBODIES AT REMISSION HIGHLY PREDICTS DISEASE RELAPSE IN PATIENTS WITH ACQUIRED TTP: A MULTI-INSTITUTIONAL STUDY

Background: Acquired thrombotic thrombocytopenic purpura (aTTP) is an immune-mediated life-threatening thrombotic microangiopathy (TMA). Daily therapeutic plasma exchange (TPE) and the optimized use of rituximab have dramatically improved the overall prognosis, however the rate of disease recurrence remains high. Acute-phase treatment and specific predictors of relapse can be relevant for an optimal patient management. Aims: In a large multicenter cohort of aTTP patients, we aimed to analyze the effect of acute-phase treatment on disease recurrence and to identify predictive variables of relapse. Methods: From 2002 to 2018, 325 TMA were referred to our Centers. A complete ADAMTS13 activity deficiency (<10%) was diagnostic for TTP in 163 patients. An anti-ADAMTS13 Ab titer >15U/L was considered positive and identified aTTP cases. Seventy-four aTTP patients with complete medical records were enrolled into the study and prospectively monitored. Complete response (CR) to treatment was defined as platelets >150x109/L for >2 days and LDH normalization, lasting for 30 days; a suboptimal response included exacerbation (EX) = recurrent disease within 30 days after reaching CR; and refractoriness (REF) = no treatment response by day 30. Results: aTTP patient characteristics at diagnosis are shown in the Table. Sixty-three patients were evaluated for treatment response. Two (3%) early deaths were due to myocardial infarction and diffuse rectal ischemia after 7 and 10 days from diagnosis, respectively. Forty patients (64%) obtained a CR after a median time to response (mTTR) of 10 days and a median number of TPE (mTPE) of 7; 21 (33%) obtained a suboptimal response: 13 EX (mTTR 31 days, mTPE 13), and 8 REF (mTTR 42.5, mTPE 19). Thirteen patients with a suboptimal response to TPE were treated with rituximab, all obtaining CR. TTR to 1st line treatment <13 days significantly correlated with a sustained CR (p = 0.004). At remission, 57% of patients showed normal levels (>50%) of ADAMTS13 activity, while 20% a moderate (21–50%), 10% a severe (10–20%), and 11% a complete (<10%) deficiency. A complete or partial recovery of ADAMTS13 activity was associated to negative Ab levels in 90% of cases. Twenty-one patients (34%) relapsed, 14 of them had multiple relapses. Median follow-up was 7 years. Patients were evaluated for predictive parameters of disease recurrence. By multivariate analysis, the association of ADAMTS13 activity ≤20% with a high anti-ADAMTS-13 titer during remission, and a TTR to 1st line treatment ≥13 days, were independent prognostic factors of relapse (p = 0.003 and p = 0.004, respectively). Furthermore, the use of rituximab in patients with a suboptimal TPE response significantly reduced relapse rate (p = 0.002). By Cox regression analysis, patients with ADAMTS13 activity ≤20% plus anti-ADAMTS13 Ab titer >15U/L at remission had an increased risk of relapse (HR 1.98, CI 95% 1.087–3.614; p < 0.02).Summary/Conclusion: In conclusion, our study shows that the association of a low ADAMTS13 activity with high anti-ADAMTS13 antibodies is highly predictive of disease relapse. Moreover, a shorter time to 1st line CR achievement and the salvage use of rituximab in suboptimal responders to TPE significantly reduces relapse. These observations support the use of new therapeutic strategies able to provide faster responses to 1st line TPE treatment in these patients.

Cumulative live birth rates in low-prognosis women.

STUDY QUESTIONDo cumulative live birth rates (CLBRs) over multiple IVF/ICSI cycles confirm the low prognosis in women stratified according to the POSEIDON criteria?SUMMARY ANSWERThe CLBR of low-prognosis women is ~56% over 18 months of IVF/ICSI treatment and varies between the POSEIDON groups, which is primarily attributable to the impact of female age.WHAT IS KNOWN ALREADYThe POSEIDON group recently proposed a new stratification for low-prognosis women in IVF/ICSI treatment, with the aim to define more homogenous populations for clinical trials and stimulate a patient-tailored therapeutic approach. These new criteria combine qualitative and quantitative parameters to create four groups of low-prognosis women with supposedly similar biologic characteristics.STUDY DESIGN, SIZE, DURATIONThis study analyzed the data of a Dutch multicenter observational cohort study including 551 low-prognosis women, aged <44 years, who initiated IVF/ICSI treatment between 2011 and 2014 and were treated with a fixed FSH dose of 150 IU/day in the first treatment cycle.PARTICIPANTS/MATERIALS, SETTING, METHODSLow-prognosis women were categorized into one of the POSEIDON groups based on their age (younger or older than 35 years), anti-Müllerian hormone (AMH) level (above or below 0.96 ng/ml), and the ovarian response (poor or suboptimal) in their first cycle of standard stimulation. The primary outcome was the CLBR over multiple complete IVF/ICSI cycles, including all subsequent fresh and frozen-thawed embryo transfers, within 18 months of treatment. Cumulative incidence curves were obtained using an optimistic and a conservative analytic approach.MAIN RESULTS AND THE ROLE OF CHANCEThe CLBR of the low-prognosis women was on average ~56% over 18 months of IVF/ICSI treatment. Younger unexpected poor (n = 38) and suboptimal (n = 179) responders had a CLBR of ~65% and ~68%, respectively, and younger expected poor responders (n = 65) had a CLBR of ~59%. The CLBR of older unexpected poor (n = 41) and suboptimal responders (n = 102) was ~42% and ~54%, respectively, and of older expected poor responders (n = 126) ~39%. For comparison, the CLBR of younger (n = 164) and older (n = 78) normal responders with an adequate ovarian reserve was ~72% and ~58% over 18 months of treatment, respectively. No large differences were observed in the number of fresh treatment cycles between the POSEIDON groups, with an average of two fresh cycles per woman within 18 months of follow-up.LIMITATIONS, REASONS FOR CAUTIONSmall numbers in some (sub)groups reduced the precision of the estimates. However, our findings provide the first relevant indication of the CLBR of low-prognosis women in the POSEIDON groups. Small FSH dose adjustments between cycles were allowed, inducing therapeutic disparity. Yet, this is in accordance with current daily practice and increases the generalizability of our findings.WIDER IMPLICATIONS OF THE FINDINGSThe CLBRs vary between the POSEIDON groups. This heterogeneity is primarily determined by a woman’s age, reflecting the importance of oocyte quality. In younger women, current IVF/ICSI treatment reaches relatively high CLBR over multiple complete cycles, despite reduced quantitative parameters. In older women, the CLBR remains relatively low over multiple complete cycles, due to the co-occurring decline in quantitative and qualitative parameters. As no effective interventions exist to counteract this decline, clinical management currently relies on proper counselling.STUDY FUNDING/COMPETING INTEREST(S)No external funds were obtained for this study. J.A.L. is supported by a Research Fellowship grant and received an unrestricted personal grant from Merck BV. S.C.O., T.C.v.T., and H.L.T. received an unrestricted personal grant from Merck BV. C.B.L. received research grants from Merck, Ferring, and Guerbet. K.F. received unrestricted research grants from Merck Serono, Ferring, and GoodLife. She also received fees for lectures and consultancy from Ferring and GoodLife. A.H. declares that the Department of Obstetrics and Gynaecology, University Medical Centre Groningen received an unrestricted research grant from Ferring Pharmaceuticals BV, the Netherlands. J.S.E.L. has received unrestricted research grants from Ferring, Zon-MW, and The Dutch Heart Association. He also received travel grants and consultancy fees from Danone, Euroscreen, Ferring, AnshLabs, and Titus Healthcare. B.W.J.M. is supported by an National Health and Medical Research Council Practitioner Fellowship (GNT1082548) and reports consultancy work for ObsEva, Merck, and Guerbet. He also received a research grant from Merck BV and travel support from Guerbet. F.J.M.B. received monetary compensation as a member of the external advisory board for Merck Serono (the Netherlands) and Ferring Pharmaceuticals BV (the Netherlands) for advisory work for Gedeon Richter (Belgium) and Roche Diagnostics on automated AMH assay development, and for a research cooperation with Ansh Labs (USA). All other authors have nothing to declare.TRIAL REGISTRATION NUMBERNot applicable.

The extrahepatic events of Asian patients with primary biliary cholangitis: A 30-year cohort study

The extrahepatic complications of primary biliary cholangitis (PBC) in Asian patients remain elusive. A 30-year cohort study of 150 Taiwanese PBC patients treated with ursodeoxycholic acid (UDCA) was conducted. Patients with alkaline phosphatase levels >1.67 × ULN after 1-year treatment were considered suboptimal responders. At baseline, of 150 patients (mean age: 53.75 years), 128 (85.3%) were females, and 34 (22.8%) had cirrhosis. The cumulative incidences of various incident events were all-cause mortality or liver transplantation: 46.7%; extrahepatic mortality: 24.5%; extrahepatic malignancies: 8.1%; hypertension: 46.2%; dyslipidemia: 44.1%; diabetes: 30.6%; hyperuricemia: 11.2%; acute coronary syndrome: 3.1%; cerebral vascular accident (CVA): 8.9%; autoimmune diseases: 16%; and osteoporosis: 20.9%. The 5- to 20-year cumulative incidences for all-cause mortality or liver transplantation and extrahepatic mortality were 16.2–41.3% and 3.1–11.9%, respectively. Baseline associations were age and alpha-fetoprotein levels with extrahepatic mortality, 80% due to sepsis; age with extrahepatic malignancies and hypertension; gender and hyperuricemia with CVA; and UDCA response with autoimmune disease. Conclusions: Sepsis accounted for most extrahepatic mortality in PBC patients, and the longer the follow-up was, the higher the extrahepatic/all-cause mortality ratio. Baseline age is crucial for incident extrahepatic events and only CVA shows gender-dimorphism; the association between UDCA response and autoimmune disease requires further investigation.

An Observational Retrospective Cohort Trial on 4,828 IVF Cycles Evaluating Different Low Prognosis Patients Following the POSEIDON Criteria.

Objective: To study the actual controlled ovarian stimulation (COS) management in women with suboptimal response, comparing clinical outcomes to the gonadotropins consume, considering potential role of luteinizing hormone (LH) addition to follicle-stimulating hormone (FSH).Design: Monocentric, observational, retrospective, real-world, clinical trial on fresh intra-cytoplasmic sperm injection (ICSI) cycles retrieving from 1 to 9 oocytes, performed at Humanitas Fertility Center from January 1st, 2012 to December 31st, 2015.Methods: COS protocols provided gonadotropin releasing-hormone (GnRH) agonist long, flare-up, short and antagonist. Both recombinant and urinary FSH were used for COS and LH was added according to the clinical practice. ICSI outcomes considered were: gonadotropins dosages; total, mature, injected and frozen oocytes; cumulative, transferred and frozen embryos; implantation rate; pregnancy, delivery and miscarriage rates. Outcomes were compared according to the gonadotropin regimen used during COS.Results: Our cohort showed 20.8% of low responders, defined as 1–3 oocytes retrieved and 79.2% of “suboptimal” responders, defined as 4–9 oocytes retrieved. According to recent POSEIDON stratification, cycles were divided in group 1 (6.9%), 2 (19.8%), 3 (11.7%), and 4 (61.5%). The cohort was divided in 3 groups, according to the gonadotropin's regimen. Women treated with FSH plus LH showed worst prognostic factors, in terms of age, basal FSH, AMH, and AFC. This difference was evident in suboptimal responders, whereas only AMH and AFC were different among treatment groups in low responders. Although a different result, in terms of oocytes and embryos detected, major ICSI outcomes (i.e., pregnancy and delivery rates) were similar among groups of COS treatment. Outcomes were significantly different among Poseidon groups. Implantation, pregnancy and delivery rates were significantly higher in Poseidon group 1 and progressively declined in other POSEIDON groups, reaching the worst percentage in group 4.Conclusions: In clinical practice, women with worst prognosis factors are generally treated with a combination of LH and FSH. Despite low prognosis women showed a reduced number of oocytes retrieved, the final ICSI outcome, in terms of pregnancy, is similarly among treatment group. This result suggests that the LH addition to FSH during COS could improve the quality of oocytes retrieved, balancing those differences that are evident at baseline.Clinical Trial Registration: www.ClinicalTrials.gov, identifier: NCT03290911

Induction of apoptosis in CD4(+) T-cells is linked with optimal treatment response in patients with relapsing-remitting multiple sclerosis treated with Glatiramer acetate

BackgroundInduction of T-cell apoptosis constitutes a mechanism of action for Glatiramer Acetate (GA). We investigated whether activation of apoptotic T-cell death may be indicative of optimal treatment response in patients with relapsing-remitting Multiple Sclerosis (RRMS), with respect to radiological activity. MethodsWe studied apoptotic markers on blood T-cells of forty patients with RRMS, 19 patients under GA and 21 patients under interferon-β (IFNβ), by flow cytometry. Patients were relapse-free and were further classified into optimal and sub-optimal responders based on radiological activity. Eighteen patients (8 patients under GA and 10 patients under IFNβ were additionally evaluated at a 12-month follow-up and were relapse- and radiological activity-free. For these patients, apoptosis was also evaluated by molecular techniques. ResultsAt inclusion, optimal responders to GA exhibited increased (23.6 ± 1.976) relative % frequency of CD4(+)AnnexinV(+)7AAD(−) T-cells, compared to sub-optimal responders (14.478 ± 1.204, p = 0.001). Similarly, relative % frequency of caspase-3(+) T-cells was 1.517 ± 0.436 versus 0.45 ± 0.149 (p = 0.041), respectively. Anti-apoptotic molecule bcl-2 showed an inverse pattern 4.532 ± 1.321 versus 13.094 ± 3.987, p = 0.044, respectively. These differences were not evident for IFNβ-treated patients. ConclusionsT-cell apoptotic markers may be applied as a biomarker useful in evaluating optimal treatment response under GA, thus allowing for personalized treatment decisions.

Cumulative live birth rates following a 'freeze-all' strategy: a population-based study.

STUDY QUESTIONWhat is the cumulative live birth rate following a ‘freeze-all’ strategy compared with a ‘fresh-transfer’ strategy?SUMMARY ANSWERThe ‘freeze-all’ strategy resulted in a similar cumulative live birth rate as the ‘fresh-transfer’ strategy among high responders (>15 oocytes retrieved) but did not benefit normal (10–15 oocytes) and suboptimal responders (<10 oocytes).WHAT IS KNOWN ALREADYFrozen-thawed embryo transfer is associated with a decreased risk of adverse obstetric and perinatal outcomes compared with fresh embryo transfer. It is unclear whether the ‘freeze-all’ strategy should be offered to all women undergoing ART treatment.STUDY DESIGN, SIZE, DURATIONA population-based retrospective cohort study using data collected by the Victorian Assisted Reproductive Treatment Authority. This study included 14 331 women undergoing their first stimulated ART cycle with at least one oocyte fertilised between 1 July 2009 and 30 June 2014 in Victoria, Australia. Demographic characteristics, type of ART procedures and resulting pregnancy and birth outcomes were recorded for the stimulated cycle and associated thaw cycles until 30 June 2016, or until a live birth was achieved, or until all embryos from the stimulated cycle had been used.PARTICIPANTS/MATERIALS, SETTING, METHODSWomen were grouped by whether they had undergone the ‘freeze-all’ strategy (n = 1028) where all embryos were cryopreserved for future transfer, or the ‘fresh-transfer’ strategy (n = 13 303) where selected embryo(s) were transferred in the stimulated cycle, and remaining embryo(s) were cryopreserved for future use. A discrete-time survival model was used to evaluate the cumulative live birth rate following ‘freeze-all’ and ‘fresh-transfer’ strategy.MAIN RESULTS AND THE ROLE OF CHANCEA total of 1028 women undergoing ‘freeze-all’ strategy and 13 303 women undergoing ‘fresh-transfer’ strategy had 1788 and 22 334 embryo transfer cycles resulting in 452 and 5126 live births, respectively. Most women (61.3%) in the ‘freeze-all’ group had more than 15 oocytes retrieved in the stimulated cycle compared with 18.1% of women in the ‘fresh-transfer’ group (P < 0.001). For high responders (>15 oocytes), the cumulative live birth rate in the ‘freeze-all’ group was similar to the ‘fresh-transfer’ group (56.8% vs. 56.2%, adjusted hazard ratio (AHR) 0.90, 95% CI 0.77–1.04). However, the likelihood of a live birth was lower in the ‘freeze-all’ group compared with the ‘fresh-transfer’ group among normal responders (10–15 oocytes) (33.2% vs. 46.3%, AHR 0.62, 95% CI 0.46–0.83) and suboptimal responders (<10 oocytes) (14.6% vs. 28.0%, AHR 0.67, 95% CI 0.14–1.01). During the minimum follow-up time of 2 years, 34.1%, 24.4% and 8.4% of suboptimal, normal and high responders, respectively, in the ‘freeze-all’ group did not return for any embryo transfer after the stimulated cycle, whereas all women in the ‘fresh-transfer’ group had at least one embryo transferred in the stimulated cycle.LIMITATIONS REASONS FOR CAUTIONA limitation of this population-based study is the lack of information available on clinic-specific protocols for the ‘freeze-all’ strategy and the potential impact of these on outcomes. Data were not available on whether the ‘freeze-all’ strategy was used to prevent ovarian hyperstimulation syndrome (OHSS).WIDER IMPLICATIONS OF THE FINDINGSThis study presents population-based evidence on clinical efficacy associated with a ‘freeze-all’ and ‘fresh-transfer’ strategy. The ‘freeze-all’ strategy may benefit some subgroups of patients, including women who are high responders and those who are at risk of OHSS, but should not be offered universally. Clinicians should consider the potential impact of electively deferring embryo transfer on treatment discontinuation in choosing the optimal embryo transfer strategy for couples undergoing ART treatment.STUDY FUNDING/COMPETING INTEREST(S)No specific funding was received to undertake this study. There is no conflict of interest, except that M.B. is a shareholder in Genea Ltd.

Exploring sub-optimal response to tumour necrosis factor inhibitors in axial spondyloarthritis.

ObjectivesThe aim was to define sub-optimal response to TNF inhibitors (TNFi), compare long-term drug survival rates and identify predictors of sub-optimal response in axial spondyloarthritis (axSpA) patients in a UK cohort.MethodsAll axSpA patients attending two centres who commenced TNFi between 2002 and 2016 were included. Routinely recorded patient data were reviewed retrospectively. Patients with paired BASDAI at baseline, 3 and/or 6 months were included for analysis. Sub-optimal response was defined as achieving a ≥ 2-point reduction in BASDAI but not BASDAI50, post-treatment BASDAI remaining at ≥4, and in the opinion of the treating physician these patients demonstrated a meaningful clinical response.ResultsFour hundred and ninety-nine patients were included: 82 (16.4%) patients were classified as having a sub-optimal response; 64 (78%) males, 78 (95.1%) AS and 55/67 (82.1%) HLA-B27 positive. Results are reported as the mean (s.d.). Time to diagnosis was 10 (8.6) years, age at diagnosis was 37 (11.7) years, and age at initiating index TNFi was 48 (11.1) years. Individual index TNFi were Humira (adalimumab, n = 41, 50%), Enbrel (etanercept, n = 27, 32.9%), Remicade (infliximab, n = 5, 6.1%), Simponi (golimumab, n = 3, 3.7%) and Cimzia (certolizumab pegol, n = 6, 7.3%). The rate of attrition was greater among sub-optimal responders at 2 and 5 years (P < 0.05), but not at 10 years (P = 0.06), compared with responders. Older age at initiation of TNFi was a predictor of sub-optimal response (odds ratio 1.04, 95% CI 1.01, 1.09, P < 0.05).ConclusionA significant proportion of patients continued TNFi despite demonstrated sub-optimal response. Further research needs to be undertaken in order to understand this group.

A Quadruplet Regimen Comprising Carfilzomib, Cyclophosphamide, Lenalidomide, Dexamethasone (KCRD) Vs an Immunomodulatory Agent Containing Triplet (CTD/CRD) Induction Therapy Prior to Autologous Stem Cell Transplant: Results of the Myeloma XI Study

A Quadruplet Regimen Comprising Carfilzomib, Cyclophosphamide, Lenalidomide, Dexamethasone (KCRD) Vs an Immunomodulatory Agent Containing Triplet (CTD/CRD) Induction Therapy Prior to Autologous Stem Cell Transplant: Results of the Myeloma XI Study

Enrichment of gut-derived Fusobacterium is associated with suboptimal immune recovery in HIV-infected individuals

We explored the gut microbiota profile among HIV-infected individuals with diverse immune recovery profiles following long-term suppressive ART and investigated the relationship between the altered bacteria with markers of immune dysfunction. The microbiota profile of rectal swabs from 26 HIV-infected individuals and 20 HIV-uninfected controls were examined. Patients were classified as suboptimal responders, sIR (n = 10, CD4 T-cell <350 cells/ul) and optimal responders, oIR (n = 16, CD4 T-cell >500 cells/ul) after a minimum of 2 years on suppressive ART. Canonical correlation analysis(CCA) and multiple regression modelling were used to explore the association between fecal bacterial taxa abundance and immunological profiles in optimal and suboptimal responders. We found Fusobacterium was significantly enriched among the HIV-infected and the sIR group. CCA results showed that Fusobacterium abundance was negatively correlated with CD4 T-cell counts, but positively correlated with CD4 T-cell activation and CD4 Tregs. Multiple linear regression analysis adjusted for age, baseline CD4 T-cell count, antibiotic exposure and MSM status indicated that higher Fusobacterium relative abundance was independently associated with poorer CD4 T-cell recovery following ART. Enrichment of Fusobacterium was associated with reduced immune recovery and persistent immune dysfunction following ART. Modulating the abundance of this bacterial taxa in the gut may be a viable intervention to improve immune reconstitution in our setting.

The Effect of Dose Adjustments in a Subsequent Cycle of Women With Suboptimal Response Following Conventional Ovarian Stimulation.

Several infertile patients, who may even represent around 40% of the infertile cohort, may respond “suboptimally” (4–9 oocytes retrieved) following IVF, despite being predicted as normal responders. The aim of our longitudinal study was to evaluate the ovarian response of suboptimal responders in terms of the number of oocytes retrieved, following their second IVF cycle, evaluating exclusively patients who had the same stimulation protocol and used the same or higher initial dose of the same type of gonadotropin compared to their previous failed IVF attempt. Overall, our analysis included 160 patients treated with a fixed antagonist protocol in their second cycle with the same [53 (33.1%)] or higher [107 (66.9%)] starting dose of rFSH. The number of oocytes retrieved was significantly higher in the second IVF cycle [6 (5–8) vs. 9 (6–12), p < 0.001]. According to our results, a dose increment of rFSH remained the only significant predictor of the number of oocytes retrieved in the subsequent IVF cycle (coefficient 0.02, p-value = 0.007) after conducting GEE multivariate regression, while adjusting for relevant confounders. A regression coefficient of 0.02 for the starting dose implies that an increase of 50 IU of the initial rFSH dose would lead to 1 more oocyte.

Neoadjuvant Platinum-based Chemotherapy Followed by Radical Hysterectomy for Stage Ib2-IIb Adenocarcinoma of the Uterine Cervix - An Italian Multicenter Retrospective Study.

To assess the patterns of recurrence and clinical outcomes of patients with cervical adenocarcinoma who underwent neoadjuvant platinum-based chemotherapy (NACT) followed by radical hysterectomy. Data were retrospectively analyzed for 82 patients with International Federation of Gynecology and Obstetrics stage Ib2-IIb cervical adenocarcinoma who underwent this chemo-surgical treatment. The median follow-up of survivors was 89 months (range=5-208 months). Pathological complete response, optimal response and suboptimal response with intra-cervical residual disease were obtained in five (6%), 10 (12%) and 36 (44%) patients, respectively. Adjuvant external-beam radiotherapy with or without concurrent chemotherapy was administered to 47 patients. Nineteen (23%) out of the 82 patients experienced recurrence after a median of 12 months (range=5.3-86.8 months). Recurrent disease was pelvic in 12 (63%) patients, extra-pelvic in five (26%), and both pelvic and extra-pelvic in two (10%). According to pathological response, tumor relapsed in 10% of optimal responders, 14% of sub-optimal responders with intra-cervical residual disease, and 36% of sub-optimal responders with extra-cervical residual disease or non-responders. Five-year recurrence-free and overall survival were 77% and 84%, respectively. Patients who achieved an optimal response or sub-optimal response with intra-cervical residual disease had better 5-year recurrence-free (87% vs. 64%, p=0.017) and overall (92% vs. 74%, p=0.012) survival than those who had sub-optimal response with extra-cervical residual disease or no response. The latter had a 1.441-fold higher risk of recurrence and a 1.652-fold higher risk of death than those who obtained an optimal response or a sub-optimal response with intra-cervical residual disease. NACT followed by radical hysterectomy may be an option for patients with stage Ib2-IIb adenocarcinoma of the uterine cervix.

CR1 gene polymorphisms in Chinese patients with paroxysmal nocturnal hemoglobinuria

Patients with paroxysmal nocturnal hemoglobinuria (PNH) who have minor allele of the complement receptor 1 (CR1) gene, displayed more sub-optimal responder to eculizumab compared with major allele. To investigate polymorphism of the CR1 gene in Chinese patients with PNH and its correlation with clinical features and the potential impact on eculizumab efficiency, we genotyped CR1 rs2274567, rs3811381 and the intron 27 Hind III restriction fragment length polymorphism in 95patients with PNH and 96 controls. The results indicated that the genotypes of CR1 rs2274567, rs3811381 and the intron 27 Hind III in PNH patients and controls both consist with Hardy-Weinberg equilibrium. The minor allele frequency (MAF) of rs2274567 and rs3811381 in PNH patients and normal controls were lower compared with data from the dbSNP database. Further analysis showed that the MAF of Chinese patients was significantly lower than that of Caucasians (P < 0.0001, P = 0.0006 and P < 0.0001, respectively). The minor allele of CR1 rs2274567, rs3811381 and the intron 27 Hind III was associated with decreased of hemoglobin level (P = 0.007, P = 0.022,and P = 0.022, respectively) in our patients. However, there was no significantly difference found in other clinical parameters. In conclusion, the results demonstrated the minor alleles of CR1 polymorphisms were lower in Chinese patients than in Caucasians, with a decrease in hemoglobin level. These findings may indicate less sub-optimal responders to eculizumab in Chinese patients.

Fingolimod reduces the clinical expression of active demyelinating lesions in MS

BackgroundFingolimod is a modulator of Central and peripheral sphingosine pathways, which is currently approved for treatment of Multiple Sclerosis (MS). In animal models it reduces inflammation, but it is also able to potentiate glutamatergic transmission and synaptic plasticity. We aimed to explore whether Fingolimod is able to modify the clinical expression of new demyelinating lesions with respect to IFNβ−1a in relapsing remitting MS (RRMS) patients suboptimal responders to IFNβ−1a. Methods103 patients with RRMS switching for inefficacy from IFNβ−1a to Fingolimod and treated for at least 12 months were included. Annualised Relapse Rate (ARR), EDSS and the number of new brain and spinal gadolinium enhancing (Gd +) and T2 lesions were retrospectively assessed in the whole group during each treatment period. The likelihood of co-occurrence of new Gd + lesions and clinical relapses during IFNβ−1a and Fingolimod treatment was analysed. ResultsThe mean duration of treatment with IFNβ−1a and Fingolimod was 3.14 (SD 1.6) and 3.22 years (SD 1.1) respectively. Significant reduction of ARR (p < .001), total number of Gd + and T2 lesions (p < .001) was found switching from IFNβ−1a to Fingolimod. Gd + lesions occurring during treatment with Fingolimod were more likely to be asymptomatic compared with IFNβ−1a (88% vs 30.9%, p = < .025). ConclusionFingolimod reduces clinical and radiological inflammation in MS. Additionally, it limits the clinical expression of new Gd + lesions, possibly reducing local inflammatory processes and improving brain network plasticity in patients with suboptimal response to IFNβ−1a.

Early Response to Intravitreal Dexamethasone Implant Therapy in Diabetic Macular Edema May Predict Visual Outcome

To determine whether early visual acuity response to intravitreal dexamethasone implant therapy in diabetic macular edema (DME) is associated with long-term outcome. Retrospective case series. Multicenter (8 sites) retrospective review of medical records of eyes with DME treated with 0.7mg intravitreal dexamethasone implant and minimum 18-month follow-up. One hundred and two eyes were included. Eyes with vitreoretinal interface abnormalities or that had undergone vitrectomy were excluded. Eyes were categorized into 3 groups based on change in best-corrected visual acuity (BCVA) at 3months (logMAR equivalence of <5-letter, 5-9-letter, or ≥10-letter gain). Visual acuity outcomes were determined for each early response group. The relationship between early (3-month) and overall change in BCVA was assessed using regression analysis. In the study population (102 eyes), <5-letter, 5- to 9-letter, and ≥10-letter BCVA improvements were seen in 44.1%, 18.6%, and 37.3% of eyes, respectively, at 3months. Among suboptimal (<5-letter) responders at 3months, 6.7% showed ≥10-letter gains at study conclusion compared to 29% in the robust (≥10-letter) early response group (P=.009). Change in BCVA at 3months showed significant positive correlation with overall change in BCVA (coefficient= 0.44, P= .002). A similar proportion of eyes demonstrated suboptimal (<5-letter) and robust (≥10-letter) early response to treatment at 3months. Eyes with a robust early response demonstrated ≥10-letter long-term gain in BCVA at a significantly higher rate compared to those with poor early response. Early treatment response directly correlated with overall change in BCVA.

Characterization of a suboptimal IVF population and clinical outcome after two IVF cycles

The number of oocytes retrieved in in vitro fertilization (IVF) cycles is an independent factor influencing pregnancy rate (PR), and optimal number of oocytes would be between 10 and 15. This has led to the hypothesis that the identification of a suboptimal group of responders beforehand (4–9 oocytes retrieved) would allow physicians to optimize their PR. A retrospective observational study counting on 735 women doing an IVF treatment in our center was performed. Multivariable logistic regression was used to analyze the relationship between anti-Mullerian hormone (AMH) and antral follicle count (AFC), within suboptimal and optimal responders. We also analyzed the outcome of those patients with an estimated high probability of having an optimal response and the second cycles of those who did not get pregnant in the first cycle to observe the main significant traits that made them change from one group of responders to the other. Main results are that suboptimal responders account for almost half of our patients. Ovarian reserve markers (AMH and AFC) are significantly different in optimal and suboptimal responders, even when adjusted by age. There is a significant difference in the cumulative PR between both groups. Interestingly, 18.9% shifted from suboptimal to optimal response, and 36.9% from optimal to suboptimal.

Characteristics of antimuscarinic responders versus suboptimal responders in a randomized clinical trial of patients with overactive bladder symptoms

Objective: To assess the characteristics of tolterodine extended-release (ER) 4 mg responders and suboptimal responders (≤50% decrease in UUI episodes/24 h) among patients with overactive bladder (OAB), including urgency urinary incontinence (UUI), and identify predictors of a >50% UUI response with fesoterodine 8 mg in tolterodine suboptimal responders.Methods: Adult patients with OAB symptoms for ≥6 months and ≥8 micturitions, and ≥2 and <15 UUI episodes/24 h at week −2 received open-label tolterodine ER 4 mg during a 2 week run-in. Suboptimal responders after tolterodine treatment (week 0) were randomized to fesoterodine (4 mg for 1 week, 8 mg for weeks 2–12) or placebo once daily. Post-hoc analyses compared the percentage change from week −2 to week 0 in UUI episodes/24 h in tolterodine responders versus suboptimal responders and identified significant predictors of a UUI response at week 12 with fesoterodine 8 mg among tolterodine suboptimal responders.Results: Of 897 patients, 610 (68%) were UUI suboptimal responders during the run-in period. UUI episodes/24 h at week −2 were similar in tolterodine responders and suboptimal responders (4.2 vs. 4.3), but responders showed a significantly greater median percentage decrease in UUI episodes/24 h after tolterodine treatment at week 0 (80.0% versus 15.3%; p < .0001). During double-blind treatment, the percentage of patients with a UUI response at week 12 was significantly greater with fesoterodine (69.9%) than placebo (57.0%; p = .0027). Fesoterodine (vs. placebo), no previous antimuscarinic use before tolterodine run-in, and less UUI severity at baseline were significant predictors of a UUI response.Conclusions: For patients with OAB, including UUI, who were treated initially with tolterodine and showed a suboptimal UUI response, nearly 70% demonstrated a UUI response with second-line fesoterodine 8 mg. No antimuscarinic use before tolterodine and fewer baseline UUI episodes were significant predictors of a UUI response with fesoterodine.

Anti-VEGF treatment of diabetic macular edema in clinical practice: effectiveness and patterns of use (ECHO Study Report 1).

PurposeTo evaluate the efficacy, safety, and injection frequency of vascular endothelial growth factor (VEGF) inhibitors as used in clinical practice for the treatment of diabetic macular edema.MethodsMulticenter (10 sites), retrospective chart review in patients (n=156) who received ≥3 anti-VEGF injections. Data collected for ≥6 months after the first injection included Snellen best-corrected visual acuity (BCVA) and central retinal thickness (CRT) by time-domain or spectral-domain optical coherence tomography (TD-OCT or SD-OCT).ResultsMean number of anti-VEGF injections (627 bevacizumab, 594 ranibizumab, 1 aflibercept) was 5.8 (year 1), 5.0 (year 2), and 3.4 (year 3). Percentage of patients with BCVA of 20/40 or better and CRT ≤250 μm on TD-OCT or ≤300 μm on SD-OCT at the same visit (primary endpoint) ranged from 16.4% to 38.9% after the first 10 injections; 51.9%–62.3% achieved ≥20/40 BCVA and 26.2%–48.0% met CRT criteria. Therapy was well tolerated with 19 treatment-related adverse events (all ocular) reported.ConclusionAnti-VEGF injections were administered less frequently and were less effective than those in the ranibizumab registration trials. After each of the first 9 injections, <25% of patients achieved both BCVA of 20/40 or better and a dry macula. A substantial proportion of patients are suboptimal responders to anti-VEGF therapy; these patients may be candidates for other therapies, including intravitreal corticosteroid and laser therapy.

Efficacy and safety of adjunctive bitopertin versus placebo in patients with suboptimally controlled symptoms of schizophrenia treated with antipsychotics: results from three phase 3, randomised, double-blind, parallel-group, placebo-controlled, multicentre studies in the SearchLyte clinical trial programme

Many patients with schizophrenia require high doses of medication for their ongoing psychotic symptoms. Glutamate theories and findings from studies showing efficacy of sarcosine, an endogenous, non-selective glycine-reuptake inhibitor mediated by GlyT1, offer an alternative approach. We undertook the SearchLyte trial programme to examine the efficacy of bitopertin, a selective GlyT1-mediated glycine-reuptake inhibitor, as an adjunctive treatment to ongoing antipsychotic treatment. SearchLyte consisted of three phase 3, randomised, double-blind, parallel-group, placebo-controlled, multicentre studies done in outpatient clinics in Asia, Europe, and North and South America (TwiLyte done at 109 sites, NightLyte at 84, and MoonLyte at 87). Participants were male and female outpatients, aged at least 18 years, meeting DSM-IV criteria for schizophrenia with suboptimally controlled positive symptoms despite treatment with antipsychotics. Inclusion criteria included a Positive and Negative Syndrome Scale (PANSS) total score of at least 70 and antipsychotic treatment stability for the past 12 weeks before randomisation. Key exclusion criteria included meeting criteria for symptomatic remission or previous treatment with a GlyT1 inhibitor or any other investigational drug. After a screening or 4-week prospective stabilisation period, we randomly assigned participants (1:1:1) to a 12-week, double-blind treatment of either placebo or one of two fixed doses of oral, once-daily bitopertin (10 or 20 mg in TwiLyte and NightLyte; 5 or 10 mg in MoonLyte) added to their current antipsychotic medicine. After completion of 12 weeks' treatment, the study design allowed for additional double-blind treatment for 40 weeks to assess maintenance of the effect, followed by a randomised 4-week washout period to assess withdrawal effects. Subsequently, all patients were offered the opportunity to receive bitopertin treatment in a 3-year follow-up. The primary efficacy endpoint was the mean change from baseline in the PANSS Positive Symptom Factor Score (PSFS) at week 12, analysed in the modified intention-to-treat population. The trials were registered at ClinicalTrials.gov (numbers NCT01235520 [TwiLyte], NCT01235585 [MoonLyte], and NCT01235559 [NightLyte]). Between Nov 19, 2010, and Dec 12, 2014, we randomly assigned 1794 patients to treatment, of whom 1772 were treated and analysed. MoonLyte was discontinued in September, 2014, on the basis of results from futility analyses. Across studies and treatment arms, most patients completed 12 weeks of treatment (505 in TwiLyte, 517 in NightLyte, and 506 in MoonLyte). Only one study, NightLyte, met the primary endpoint where the PANSS PSFS significantly differed from placebo at week 12, and only in the 10-mg arm: mean difference in score -1·37, 95% CI -2·27 to -0·47; p=0·0028. Improvements from baseline for the bitopertin 20-mg arm in Nightlyte were not significant compared with placebo: -3·77, 95% CI -4·40 to -3·14; p=0·3142. Results from the other two studies also did not differ from placebo (TwiLyte 0·58, 95% CI -0·34 to 1·50, p=0·22 for 10 mg and 0·43, -0·49 to 1·36, p=0·36 for 20 mg; MoonLyte 0·06, 95% CI -0·79 to 0·92, p=0·88 for 5 mg and 0·44, -0·41 to 1·28, p=0·31 for 10 mg). Placebo responses varied across studies and might have contributed to the differences in efficacy between studies. Four deaths occurred during the 12-week treatment period, three in NightLyte (upper gastrointestinal haemorrhage, alcohol poisoning and related head injury, and a completed suicide) and one in MoonLyte (myocardial infarction in a patient with pre-existing risk factors). Only the death by suicide was deemed related to the study drug. The incidence of serious adverse events was low across treatment groups in all three studies; psychiatric disorders were the most frequently reported serious adverse events and the most frequent cause of adverse events leading to discontinuation. Only one of six active treatment arms across the three studies offered an advantage of adjunctive bitopertin over placebo for the treatment of suboptimally controlled symptoms of schizophrenia. The small improvement associated with bitopertin together with the varying placebo response suggests that adjunctive bitopertin treatment might offer only modest benefit to suboptimal responders to antipsychotics, if any. F Hoffmann-La Roche.

Managing Sub-Optimal Responders through Combination Therapy

Managing Sub-Optimal Responders through Combination Therapy