Major Clinical Response Research Articles

Efficacy and safety of anti-CD20 antibody rituximab for patients with refractory systemic lupus erythematosus.

Objective We examined the efficacy and safety of rituximab in patients with refractory systemic lupus erythematosus (SLE). Methods The study enrolled 63 SLE patients who were treated with rituximab between 2002 and 2015. The participants underwent a battery of tests before treatment and at one year. Treatment ranged from two to four times at 500 or 1000 mg. Results Baseline characteristics were males:females = 6:57, age 33.9 years, and disease duration 87.2 months. The primary endpoint: The rate of major clinical response (MCR) was 60% while the partial clinical response (PCR) was 25%. Thirty of 36 (83%) patients with lupus nephritis (WHO II: 2, III: 5, IV: 22, V: 4, IV+V: 2, not assessed: 1) and 22 of 24 patients (92%) with neuropsychiatric SLE, who could be followed at one year, showed changes from BILAG A or B score to C or D score at one year. Multivariate analysis identified high anti-dsDNA antibody and shorter disease duration as significant determinants of MCR at one year. Repeat examination was conducted at five years. Primary failure was recorded in 8.8% and secondary failure in 32.4% (time to relapse: 24.4 months). Rituximab was well tolerated although 65 adverse events, mostly infections, were recorded within one year. Conclusion Rituximab is potentially efficacious for the treatment of patients with refractory SLE.

Secukinumab in Active Rheumatoid Arthritis after Anti-TNFα Therapy: A Randomized, Double-Blind Placebo-Controlled Phase 3 Study.

Introduction‘REASSURE’ (NCT01377012), a phase 3 study, evaluated the efficacy and safety of secukinumab in patients with active rheumatoid arthritis (RA) who had an inadequate response to, or intolerance of, tumor necrosis factor inhibitors (TNF-inhibitors).MethodsA total of 637 patients were randomized (1:1:1) to receive intravenous secukinumab 10 mg/kg (baseline, weeks 2 and 4) followed by subcutaneous secukinumab 150 mg or 75 mg every 4 weeks (starting from week 8) or placebo at the same dosing schedule. The primary endpoint was the American College of Rheumatology 20% improvement criteria (ACR20) at week 24. Other predefined hierarchical endpoints included Health Assessment Questionnaire-Disability Index, van der Heijde modified total Sharp score (vdH-mTSS) at week 24, and major clinical response (MCR; continuous 6 month period of ACR70 response) at 1 year.ResultsThe primary efficacy endpoint was met with both secukinumab dose groups: ACR20 response rate at week 24 was 35.2% for both secukinumab dose groups (P = 0.0009) vs 19.6% for placebo. The improvements in secondary endpoints were greater in the secukinumab dose groups vs placebo but did not meet statistical significance. The overall safety profile was similar across all treatment groups.ConclusionSecukinumab demonstrated efficacy in reducing disease activity over placebo as measured by ACR20 in patients with active RA who had an inadequate response to TNF-inhibitors. Secukinumab demonstrated a safety profile similar to other biologics currently approved for RA.FundingNovartis Pharma AG.Trial registrationClinicalTrials.gov identifier: NCT01377012.Electronic supplementary materialThe online version of this article (doi:10.1007/s40744-017-0086-y) contains supplementary material, which is available to authorized users.

Effectiveness, safety and drug survival of tumor necrosis factor-α inhibitors in the treatment of spondyloarthritis: A real-life study in Tunisia

Aim of the workThe aim of the present study was to evaluate effectiveness of anti-tumor necrosis factor-α (anti-TNFα) in the treatment of spondyloarthritis (SpA) and to assess their safety and drug survival. Patients and methodsForty-two SpA patients (33 men, 9 women) were retrospectively studied. The disease was progressive in all patients. Response was assessed after 6 months using Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) and Functional Index (BASFI) scores and other clinical parameters. A major clinical response was defined as 50% improvement of the initial BASDAI. Patients were grouped into those with ankylosing spondylitis (AS) (24 patients) or psoriatic arthritis (PsA) and enteropathic arthritis (EA) (18 patients) and the response to anti-TNF was compared. ResultsThe mean age of the patients was 41.3 ± 9.7 years and disease duration 14.6 ± 8.2 years. After 6 months, 74% of patients were BASDAI 50 responders. The mean BASDAI and BASFI scores varied from 56 ± 20 and 61.8 ± 26 to 19 ± 19 and 24 ± 25 respectively (p < .001). The two SpA groups had the same effectiveness profile. The comparison between them showed a greater reduction of morning stiffness duration and erythrocyte sedimentation rate in patients with PsA or EA (p = .04). At least, one adverse event developed by 48% of patients and it was severe in 12%. Bronchopulmonary infections were the most frequent (8 patients). Drug survival rate was estimated at 86% after 1 year of treatment. ConclusionAnti-TNFα therapy has a good response rate in SpA patients and an acceptable safety profile which explains the high drug survival rates.

Sirukumab for rheumatoid arthritis: the phase III SIRROUND-D study

ObjectivesInterleukin-6 (IL-6) is implicated in rheumatoid arthritis (RA) pathophysiology. Unlike IL-6 receptor inhibitors, sirukumab is a human monoclonal antibody that selectively binds to the IL-6 cytokine. The phase III, multicentre,...

Rectal sparing approach after preoperative radio- and/or chemotherapy (RESARCH) in patients with rectal cancer: a multicentre observational study.

Rectum-sparing approaches appear to be appropriate in rectal cancer patients with a major (mCR) or complete clinical response (cCR) after neoadjuvant therapy. The aim of the present study is to evaluate the effectiveness of rectum-sparing approaches at 2years after the completion of neoadjuvant treatment. Patients with rectal adenocarcinoma eligible to receive neoadjuvant therapy will be prospectively enrolled. Patients will be restaged 7-8weeks after the completion of neoadjuvant therapy and those with mCR (defined as absence of mass, small mucosal irregularity no more than 2cm in diameter at endoscopy and no metastatic nodes at MRI) or cCR will be enrolled in the trial. Patients with mCR will undergo local excision, while patients with cCR will either undergo local excision or watch and wait policy. The main end point of the study is to determine the percentage of rectum preservation at 2years in the enrolled patients. This protocol is the first prospective trial that investigates the role of both local excision and watch and wait approaches in patients treated with neoadjuvant therapy for rectal cancer. The trial is registered at clinicaltrials.gov (NCT02710812).

Predicting and managing primary and secondary non-response to rituximab using B-cell biomarkers in systemic lupus erythematosus

ObjectiveTo assess factors associated with primary and secondary non-response to rituximab in systemic lupus erythematosus (SLE) and evaluate management of secondary non-depletion non-response (2NDNR).Methods125 patients with SLE treated with rituximab...

Transanal endoscopic microsurgery after neoadjuvant radiochemotherapy for locally advanced extraperitoneal rectal cancer

PurposeThe aim of this study is to provide a prospective analysis of post-operative and oncological outcomes in patients affected by locally advanced rectal cancer (LARC), who obtained a major/complete clinical response after pre-operative radio-chemotherapy (RCT) and were treated with local excision (LE) by trans-anal endoscopic microsurgery (TEM) to confirm a pathological complete response (pCR) after to neo-adjuvant RCT. MethodsAll patients with LARC treated by pre-operative RCT and full-thickness LE by TEM (2000–2014) were included in the study. If the pathological analysis confirmed near complete or pCR, intensive follow up was proposed. If the pathological response was incomplete, a radical resection with TME was proposed. Post-operative (according to Clavien's classification), functional and long-term oncological outcome were analyzed. Results36 patients were treated by TEM. The median post-operative hospital stay was 5 days. The post-operative morbidity was 41.6% (no grade ≥3). At pathological analysis, 23 specimens were ypT0 TRG1, and 4 were ypT1 TRG2. In 9 cases (ypT>1 and/or TRG>2), radical surgery with TME was proposed but 3 refused it. Median follow-up was 68 months. One local recurrence and 4 distant metastases occurred. The 5-yr actuarial local control, overall survival and disease-free survival were 96.0%, 92.0% and 82.8%. ConclusionsIn case of major or complete clinical response of LARC after pre-operative RCT, LE by TEM can be used to confirm the pathological response. This avoids the necessity of radical surgery and, in our experience, this approach seems to guarantee oncological safety with the functional advantages of an organ-sparing procedure.

Vorinostat Does Not Improve Outcome in Patients with Acute Myeloid Leukemia and High Risk Myelodysplasia Treated with Azacitidine: Results of the UK Trials Acceleration Programme Ravva Trial

Introduction:Azacitidine (AZA) represents a significant advance in the treatment of adults with acute myeloid leukaemia (AML) (Dombret et al Blood 2016 126:291-9) and myelodysplasia (MDS) (Fenaux et al Lancet Oncol 2009) 10:223-32) ineligible for intensive chemotherapy. However complete response (CR) rates remain modest and disease progression is almost inevitable. Consequently, additional agents which improve the clinical activity of AZA and other hypomethylating agents are urgently required. Pre-clinical and Phase II studies have identified the potential of co-administration of histone deacteylase inhibitors, notably vorinostat (VOR), with AZA as a strategy to improve its clinical activity. We have therefore compared outcomes after AZA monotherapy or combined AZA and VOR in a prospective randomized trial in adults with high risk AML and MDS.Patients and Methods: 259adults with AML or high risk MDS deemed ineligible for intensive chemotherapy were randomized to receive either AZA (75 mg/m2) x 7 days every 28 days or AZA in combination with VOR 300 mg bd days 3-9 po for a minimum of 6 cycles. Patients were assessed for response, using modified Cheson criteria, after 3 and 6 cycles of therapy. Patients who achieved a major clinical response (CR, CRi or PR) were eligible to receive continued treatment until loss of response, toxicity or death. Major response after 6 cycles and overall survival (OS) were co-primary endpoints. 219 patients had AML (newly diagnosed n= 108) and 44 had MDS (newly diagnosed n= 30).Results: Co-administration of VOR did not increase either the major response rate at 6 months compared with AZA monotherapy (33% AZA v 37% AZA+VOR, OR (95% CI)=1.2 (0.7,2.0), p=0.55) or improve OS (1 year OS AZA 43% versus AZA/VOR 44%, HR (95% CI)=1.06 (0.8, 1.4), p=0.68). No benefit of addition of VOR was observed in any patient subgroup. In multivariate analysis of the study population, a low presentation white blood count (p=0.029) and a diagnosis of MDS vs AML (p=0.0048) was associated with significantly improved survival, whilst disease status (CR v advanced disease) (p=0.023) and low presentation white blood count (p=0.034) significantly improved major response rates. Presentation karyotype was not predictive of either survival or response. Both adverse events (AE) and serious adverse events (SAE) were balanced between treatment arms with 64 and 89 patients in the AZA arm experiencing AE and SAEs respectively versus 75 and 97 in the combination arm respectively.Discussion: To our knowledge this is the largest randomized study of epigenetic therapy in AML and MDS. We conclude that the addition ofVOR to AZA therapy does not increase either major response rates or overall survival in patients with AML and high risk MDS. Alternative therapeutic strategies with the potential to increase response to AZA are required in this patient population. DisclosuresFerguson:Celgene: Consultancy. Raghavan:Celgene: Consultancy. Quek:Celgene: Research Funding. Cavenagh:Celgene: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau. McMullin:Novartis: Honoraria, Speakers Bureau. Pillai:Celgene: Honoraria. Vyas:Celgene: Honoraria, Research Funding.

Targeting IRAK1/IRAK4 Signaling in Waldenstrom's Macroglobulinemia

Background: MYD88 L265P somatic mutations are highly prevalent in Waldenström's macroglobulinemia (WM) (NEJM 367(9):826-33). MYD88 L265P activates multiple downstream signaling pathways including BTK and IRAK1/IRAK4 that support malignant cell growth and survival (Nature 470(7332):115-9; Blood 122(7):1222-32). Ibrutinib targets BTK, and shows high overall and major clinical response rates, though no complete responses are observed indicating alternative survival signaling.Methodology: Phospho-flow analysis of IRAK1, IRAK4, and BTK was performed in primary WM cells taken from untreated WM patients, and those on ibrutinib therapy. IRAK1 or IRAK4 knockdown experiments were performed using lentiviral shRNA transduction. Immunoprecipitation, western blot and phospho-flow studies were used to detect protein expression and phosphorylation in WM cells. Cell survival following IRAK4 or IRAK1 knockdown, ibrutinib and/or IRAK4/IRAK1 inhibitor (EMD Millipore) treatment was assessed by Annexin V staining, AlamarBlue® Cell Viability Assay or CellTiter-Glo® Luminescent Cell Viability Assays.Results: Phospho-flow analysis of bone marrow lymphoplasmacytic cells taken from WM patients following > 6 months of continued ibrutinib treatment demonstrated highly active IRAK1 and IRAK4, but not BTK. These findings prompted us to dissect the relative impact of IRAK1 and IRAK4 in supporting WM cell survival. Using lentiviral transduction, we identified shRNAs that produced similar levels of protein reduction by western blot analysis for both IRAK1 and IRAK4. Compared to scrambled control vector, knockdown of IRAK1 or IRAK4 both produced decreased tumor cell survival in MYD88 mutated BCWM.1 and MWCL-1 cells. More pronounced apoptosis, as well as sustained reduction in tumor cell growth occurred following knockdown of IRAK1 versus IRAK4. Treatment of primary WM cells taken from untreated patients, patients on ibrutinib therapy, as well as MYD88 mutated WM cells lines with ibrutinib and a toolbox IRAK4/IRAK1 inhibitor resulted in more robust reductions in NFkB signaling, and at least additive tumor cell killing versus either agent alone.Conclusions: MYD88 L265P mutated WM cells show greater dependence on IRAK1 versus IRAK4 directed signaling. IRAK1/IRAK4 signaling may contribute to persistent WM cell survival following ibrutinib treatment. Combined BTK and IRAK inhibition leads to augmented blockade of NFKB signaling and enhanced WM cell killing. The studies provide a framework for the development and investigation of IRAK inhibitors, alone and in combination with ibrutinib in WM patients. DisclosuresNo relevant conflicts of interest to declare.

Association between the major histocompatibility complex and clinical response to infliximab therapy in patients with Behçet uveitis.

Our aim was to investigate whether major histocompatibility complex (MHC) polymorphisms are associated with response to infliximab therapy in Japanese patients with Behçet uveitis (BU). We retrospectively reviewed 24 patients (17 men and seven women) treated with infliximab for BU. Of them, ten patients were genotyped as HLA A*2601, and nine as HLA B*5101. Therapeutic response levels in the two groups were compared based on ocular attacks and the Behçet disease ocular attack score 24 (BOS24) over 24months of treatment. Mean frequencies of ocular attacks at 13-18 and 19-24months after the start of treatment were significantly higher in the HLA A*2601 group (P=0.0392 and 0.0177, respectively). Mean BOS24-6M values for months 1-6, 7-12, 13-18, and 19-24 were also significantly higher in the HLA A*2601 group (P=0.0459, 0.0150, 0.0394, and 0.0178, respectively). Shortening of the infusion interval was required in eight patients in the HLA A*2601 group but in one only in the HLA B*5101 group. Behçet-disease-related adverse events occurred in eight patients in the HLA A*2601 group and two in the HLA B*5101 group. Nonocular adverse events occurred in four patients in the HLA A*2601 group and none in the HLA B*5101 group. Although mean change from baseline in the number of ocular attack scores in the HLA A26 and HLA B51 groups seemed to be similar, the HLA-A26 group had a more severe disease course under infliximab therapy for ocular/extraocular involvement. These data suggest that response to infliximab therapy in Japanese patients with BU is partly due to genetic determinants in the HLA complex.

SAT0361 Short Term Efficacy of Tumor Necrosis Factor Inhibitors in Patients with Non–Radiographic Axial Spondylarthritis and Ankylosing Spondylitis; Results from TURKBIO Registry

BackgroundAxial spondylarthritis (AxSpA) has been proposed as an umbrella term for ankylosing spondylitis (AS) and non-radiographic (nr) AxSpA. This new concept makes diagnosis of AS possible at an early stage...

OP0028 Effects of Sarilumab plus MTX on Clinical, Radiographic, and Functional Endpoints in Patients with Moderate-To-Severe Rheumatoid Arthritis: Results of A Phase 3, Randomized, Double-Blind, Placebo-Controlled, International Study

BackgroundSarilumab, a fully human mAb directed against IL-6R, demonstrated efficacy in phase 2 of SARIL-RA-MOBILITY in rheumatoid arthritis (RA) patients (pts) with inadequate response to methotrexate (MTX) and was generally...

FRI0039 Modulation of the ACPA Fine Specificity in Patients with RA Treated with Either Abatacept or Adalimumab in the AMPLE Study

BackgroundAnti-citrullinated protein antibodies (ACPAs) are markers of RA and emerging evidence suggests they may play a role in disease progression. Analysis of biomarkers from AMPLE provides a unique opportunity to...

Genetics of canine anal furunculosis in the German shepherd dog

Canine anal furunculosis (AF) is characterised by ulceration and fistulation of perianal tissue and is a disease that particularly affects German shepherd dogs (GSDs). There are some similarities between AF and perianal Crohn's disease (CD) in man. An immune-mediated aetiopathogenesis for AF has been suggested due to tissue pathology, a major histocompatibility complex (MHC) association and clinical response to ciclosporin. Genome-wide association studies (GWAS) can be conducted in dogs with fewer markers and individuals than would be required in a human study. A discovery GWAS was performed on 21 affected and 25 control GSDs from the UK. No SNPs reached genome-wide significance levels at this stage. However, 127 nominally associated SNPs were genotyped in further 76 cases and 191 controls from the UK and Finland. Sequencing of these regions was undertaken to discover novel genetic variation. Association testing of these variants in the UK and Finnish cohorts revealed nine significantly associated SNPs, six of which cause non-synonymous changes in protein sequence. The ADAMTS16 and CTNND2 gene regions were most significantly associated with disease. Members of the butyrophilin protein family, important in intestinal inflammatory regulation, were also associated with disease, but their independence from the MHC region remains to be established. The CTNND2 gene region is also interesting as this locus was implicated in human ulcerative colitis and CD, albeit at a different candidate gene: DAP. We suggest that this represents a common association between inflammatory bowel disease-related conditions in both species and believe that future studies will strengthen this link.

Umbilical cord mesenchymal stem cell transplantation in active and refractory systemic lupus erythematosus: a multicenter clinical study

IntroductionIn our present single-center pilot study, umbilical cord (UC)–derived mesenchymal stem cells (MSCs) had a good safety profile and therapeutic effect in severe and refractory systemic lupus erythematosus (SLE). The present multicenter clinical trial was undertaken to assess the safety and efficacy of allogeneic UC MSC transplantation (MSCT) in patients with active and refractory SLE.MethodsForty patients with active SLE were recruited from four clinical centers in China. Allogeneic UC MSCs were infused intravenously on days 0 and 7. The primary endpoints were safety profiles. The secondary endpoints included major clinical response (MCR), partial clinical response (PCR) and relapse. Clinical indices, including Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) score, British Isles Lupus Assessment Group (BILAG) score and renal functional indices, were also taken into account.ResultsThe overall survival rate was 92.5% (37 of 40 patients). UC-MSCT was well tolerated, and no transplantation-related adverse events were observed. Thirteen and eleven patients achieved MCR (13 of 40, 32.5%) and PCR (11 of 40, 27.5%), respectively, during 12 months of follow up. Three and four patients experienced disease relapse at 9 months (12.5%) and 12 months (16.7%) of follow-up, respectively, after a prior clinical response. SLEDAI scores significantly decreased at 3, 6, 9 and 12 months follow-up. Total BILAG scores markedly decreased at 3 months and continued to decrease at subsequent follow-up visits. BILAG scores for renal, hematopoietic and cutaneous systems significantly improved. Among those patients with lupus nephritis, 24-hour proteinuria declined after transplantation, with statistically differences at 9 and 12 months. Serum creatinine and urea nitrogen decreased to the lowest level at 6 months, but these values slightly increased at 9 and 12 months in seven relapse cases. In addition, serum levels of albumin and complement 3 increased after MSCT, peaked at 6 months and then slightly declined by the 9- and 12-month follow-up examinations. Serum antinuclear antibody and anti-double-stranded DNA antibody decreased after MSCT, with statistically significant differences at 3-month follow-up examinations.ConclusionUC-MSCT results in satisfactory clinical response in SLE patients. However, in our present study, several patients experienced disease relapse after 6 months, indicating the necessity to repeat MSCT after 6 months.Trial registryClinicalTrials.gov identifier: NCT01741857. Registered 26 September 2012.

Local Excision After Preoperative Chemoradiotherapy for Rectal Cancer

Transanal local excision has been suggested as an attractive approach for patients with rectal cancer who show a major clinical response after preoperative chemoradiotherapy. To evaluate the impact of transanal local excision on the local recurrence of rectal cancer in patients who had a major clinical response after preoperative chemoradiotherapy. Sequential 2-stage phase II study for early efficacy. Multicenter study. Patients with clinical T3 or low-lying T2 rectal adenocarcinoma that showed a major clinical response after a preoperative chemoradiotherapy. Eligible patients underwent a full-thickness transanal local excision. According to their histopathology, the patients staged as ypT0-1 were observed, while the remaining patients were recommended to undergo a subsequent total mesorectal excision. A local recurrence rate of ≤5% was set as a successful rate for stopping the trial early after the first stage. The study group included 63 patients. Before chemoradiotherapy, patients were staged as clinical T3 (n = 42) and T2 (n = 21). After the local excision, 43 patients fulfilled the criteria to be observed with no further treatment. Nine of the remaining 20 patients for whom a subsequent total mesorectal excision was recommended refused surgery. Two of these patients who refused surgery had intraluminal local recurrence; both had a ypT2 tumor and underwent salvage surgery. The estimated cumulative 3-year overall survival, disease-free survival and local disease-free survival were 91.5% (95% CI: 75.9-97.2), 91.0% (95% CI: 77.0-96.6) and 96.9% (95% CI: 80.3-99.5), respectively. The time of follow-up is still short and the sample size is limited. Our data suggest that local excision is a good option for patients with a major clinical response after chemoradiotherapy. A longer period of follow-up is required to confirm these findings.

Identification of a Novel ComplexBRAFMutation Associated With Major Clinical Response to Vemurafenib in a Patient With Metastatic Melanoma

There is an increasing interest in BRAF V600 mutations in melanomas and their associated sensitivity to vemurafenib, a BRAF inhibitor. However, physicians cannot find information in the literature about vemurafenib response for rare and/or atypical BRAF mutations. We describe the identification of a novel complex BRAF mutation associated with major clinical response to vemurafenib in a patient with metastatic melanoma. Using a pyrosequencing method, we determined that the tumor positive for mutated BRAF, uncovering a novel c.1799_1803delinsAT; p.V600-K601>D variant. We uncovered this atypical BRAF mutation with 2 different sequencing methods, both in the primary lesion and in 1 metastasis. The patient was immediately treated with vemurafenib as monotherapy and achieved a prolonged (5.5-month) positive response. We analyzed the consequences of the BRAF V600-K601>D mutation in terms of amino acids. We referred to the published data and databases to screen chemical properties of well-known BRAF V600 mutations and other complex BRAF mutations to find common features of activated BRAF mutations. Importantly, we highlighted that both the site of the mutation and the involved amino acids are important to predict vemurafenib response. Our conclusion is that complex BRAF mutation surrounding codon 600 could also be sensitive to BRAF inhibitors.

SAT0189 Comparative analysis of alternative outcome measures for use in lupus nephritis trials

BackgroundRecent lupus nephritis (LN) trials have used various primary endpoints, but it is not yet known which endpoint is most sensitive to detecting differences between groups. We recently compared the...

AB0054 A rapid and marked reduction of serum vegf via blocking il-6 signal was associated with early clinical responses to tocilizumab and infliximab in patients with rheumatoid arthritis.

BackgroundAccumulating evidence now suggests that major clinical response at three months after a given treatment may be one of the potential predictors for clinical remission at one year of treatment,...

THU0281 Efficacy of etanercept therapy with an every other week regimen in patients with ankylosing spondylitis

BackgroundEfficacy and safety of etanercept 25 mg twice weekly was comparable to 50 mg once weekly in adult patients with ankylosing spondylitis (AS). We know that AS patient who were...