Lost Response Research Articles

Long-term durability of response to adalimumab in Crohnʼs disease

Adalimumab is an effective treatment for Crohn's disease (CD), but may also be associated with loss of response. Few reports provide insight into the durability of treatment of CD with adalimumab for periods longer than 12 months in clinical practice. To evaluate the long-term durability of adalimumab maintenance treatment and to identify predictive factors associated with loss of response. CD patients who initially responded to adalimumab were evaluated in a historical cohort study. Maintenance of long-term response was estimated using Kaplan-Meier analysis. Cox regression analysis was performed to identify potential predictive factors for loss of efficacy. In all, 380 CD patients were included (mean age, 38 years; 52% female). Of these, 43% had ileocolic CD, 50% inflammatory CD, and 41% perianal CD. Median follow-up with adalimumab was 8 months (range, 4-75 months). The annual risk of loss of response to adalimumab was 18% per patient-year of follow-up. Twenty-eight percent of patients were anti-TNF-naïve and 72% anti-TNF-experienced. The loss of efficacy was 8% per patient-year of follow-up in the anti-TNF-naïve patients and 22% in the anti-TNF-experienced group (P < 0.01). In the multivariate analysis, the presence of extraintestinal manifestations (hazard ratio [HR] = 1.7; 95% confidence interval [CI] = 1.02-2.9) and previous experience with other anti-TNF agents (HR = 2.5,95% CI = 1.2-5.3) were associated with higher risk of loss of efficacy. A relevant proportion of CD patients on long-term adalimumab lost response. The risk of loss of response was higher (more than 2-fold) in anti-TNF-experienced than in anti-TNF-naïve patients (22% vs. 8% per patient-year of treatment). Having extraintestinal manifestations seems to increase the risk of loss of efficacy.

A New Assay for Monitoring Functional Serum Anti-Tumour Necrosis Factor Antibody Level in Crohn's Disease Patients Who Maintained and Those Who Lost Response to Anti-TNF

A New Assay for Monitoring Functional Serum Anti-Tumour Necrosis Factor Antibody Level in Crohn's Disease Patients Who Maintained and Those Who Lost Response to Anti-TNF

Clinical Value of Measuring Trough Levels and Human Anti-Chimeric Antibodies in Patients With Inflammatory Bowel Disease Who Lost Response to Infliximab Therapy

Clinical Value of Measuring Trough Levels and Human Anti-Chimeric Antibodies in Patients With Inflammatory Bowel Disease Who Lost Response to Infliximab Therapy

A tertiary centre experience of vulval crohn's disease

IntroductionCrohn's disease affecting the vulva is rarely described and often difficult to treat. The authors describe their experience of 20 patients with vulval Crohn's disease, which to their knowledge is...

Randomised clinical trial: improvement in health outcomes with certolizumab pegol in patients with active Crohn’s disease with prior loss of response to infliximab

Crohn's disease (CD) is associated with impaired health-related quality of life (HRQoL). Certolizumab pegol, administered either every 2 weeks (q2w) or q4w, maintains efficacy in patients previously failing on the anti-TNF agent infliximab (WELCOME study). To investigate the impact of certolizumab pegol administered q2w and q4w on work productivity and HRQoL in the WELCOME study. Patients with loss of response to infliximab received open-label certolizumab pegol induction and were randomised to receive double-blind maintenance treatment with certolizumab pegol 400 mg either q4w or q2w through week 24, with a final evaluation at week 26. Work productivity and HRQoL were assessed using the Work Productivity and Activity Impairment:CD questionnaire and Inflammatory Bowel Disease Questionnaire respectively. Baseline HRQoL burden was representative of moderately to severely active CD. HRQoL, daily activity and work productivity improved in both treatment groups as early as week 6 and were maintained through week 26. Treatment benefits to HRQoL, daily activity and work productivity were similar between the certolizumab pegol q2w vs. q4w groups. Certolizumab pegol therapy results in meaningful improvements in work productivity, daily activities and HRQoL in patients with active CD who previously responded to but either lost response or could not tolerate infliximab (ClinicalTrials.gov number: NCT00308581).

Fluidity of HIV-1-Specific T-Cell Responses during Acute and Early Subtype C HIV-1 Infection and Associations with Early Disease Progression

Deciphering immune events during early stages of human immunodeficiency virus type 1 (HIV-1) infection is critical for understanding the course of disease. We characterized the hierarchy of HIV-1-specific T-cell gamma interferon (IFN-γ) enzyme-linked immunospot (ELISPOT) assay responses during acute subtype C infection in 53 individuals and associated temporal patterns of responses with disease progression in the first 12 months. There was a diverse pattern of T-cell recognition across the proteome, with the recognition of Nef being immunodominant as early as 3 weeks postinfection. Over the first 6 months, we found that there was a 23% chance of an increased response to Nef for every week postinfection (P = 0.0024), followed by a nonsignificant increase to Pol (4.6%) and Gag (3.2%). Responses to Env and regulatory proteins appeared to remain stable. Three temporal patterns of HIV-specific T-cell responses could be distinguished: persistent, lost, or new. The proportion of persistent T-cell responses was significantly lower (P = 0.0037) in individuals defined as rapid progressors than in those progressing slowly and who controlled viremia. Almost 90% of lost T-cell responses were coincidental with autologous viral epitope escape. Regression analysis between the time to fixed viral escape and lost T-cell responses (r = 0.61; P = 0.019) showed a mean delay of 14 weeks after viral escape. Collectively, T-cell epitope recognition is not a static event, and temporal patterns of IFN-γ-based responses exist. This is due partly to viral sequence variation but also to the recognition of invariant viral epitopes that leads to waves of persistent T-cell immunity, which appears to associate with slower disease progression in the first year of infection.

Loss of a cohesin-linked suppressor APRIN (Pds5b) disrupts stem cell programs in embryonal carcinoma: an emerging cohesin role in tumor suppression

Cohesins appear to have critical functions beyond mitotic cohesion. Our data on a cohesin-associated Pds5-paralog, APRIN, indicate a novel cohesin role in stem cell differentiation. APRIN/Pds5B is lost in many cancers and it is a putative tumor suppressor. Its mutations in the germ line, however, generate birth defects. We reasoned that as both cancer and birth defects share disrupted stem cell differentiation, the data suggest an APRIN/Pds5B cohesin function in stem cells. We used an embryonal carcinoma stem cell model and show here that (i) APRIN expression is precisely coordinated with stem cell differentiation; (ii) this coordination involves surface-contact and endocrine pathways; and (iii) APRIN/Pds5b coordination is critical in stem/progenitor exit decisions. APRIN knockdown disrupted Oct4, Nanog and SOX2 patterns, differentiation failed and the resulting immature proliferative cells did not progress beyond proneural progenitor phase. Furthermore, the phenotype-blocked progenitor exit (Mash-1(+)); failed E-cadherin exit (E-Cadh(low+)); incomplete N-cadherin transition (N-Cadh(low+)); retained proliferative capacity (c-myc(+)); irregular stemness (SOX2(late++)) and lost response to contact and hormonal cues-shares similarities with cancer-initiating cells. The data suggest novel APRIN/Pds5B-linked cohesin roles in stem/progenitor programs and a new mechanism in tumor suppression.

PWE-031 Orofacial granulomatosis and anti-tumour necrosis factor therapy: a case series

<h3>Introduction</h3> Anti-tumour necrosis factor (TNF) therapy (infliximab (IFX) or adalimumab (ADA)) has been used as an alternative treatment in patients with Orofacial granulomatosis (OFG) failing conventional therapies, with evidence of promising clinical efficacy. However, concerns regarding safety have been raised and experience is limited. We report on the short and long-term efficacy and safety of anti-TNF therapy for OFG in this case series of 15 patients, the largest reported series to date. <h3>Methods</h3> A retrospective study of all patients who received anti-TNF therapy for OFG±Crohn9s disease (CD) was performed. Diagnoses of OFG and CD were made on conventional clinical and histological grounds. Demographics, clinical details, oral disease activity scores (ODAS) and laboratory results were obtained from patient records. Patients were considered for induction and maintenance anti-TNF therapy after failing other recognised OFG therapies. Clinical response was assessed at 4 months, 1 and 2 years after anti-TNF initiation. Regular monitoring for adverse effects was performed. <h3>Results</h3> Of 207 patients in our OFG clinic database, 15 (9 males) were treated with anti-TNF therapy between 2001 and 2009 (OFG only (n=7), OFG with CD (n=7), OFG with perianal disease (n=1)). Median age at OFG onset and at anti-TNF initiation were 26 years and 36 years. Median time between OFG onset and presentation to clinic was greater for the anti-TNF treated OFG patients than those not requiring anti-TNF (5 vs 2 years, p=0.001). Mean rank ODAS at initial presentation to clinic was higher in anti-TNF treated group than those not requiring anti-TNF (p&lt;0.05). First line anti-TNF therapy was IFX (n=14) and ADA (n=1). Ten patients received concomitant immunosuppression. Median duration of anti-TNF therapy was 12 months (range; 1 dose to 84 months). Short-term response was achieved in 9/15 (60%) patients. Eight of 15 (53%) and 4/13 (31%) patients remained responders at 1 and 2 years follow-up. Two patients failed IFX therapy and were treated with ADA; one remains responsive at 18 months, the other lost response at 12 months. Oral sulcal involvement was the only predictor for response at 1 and 2 years (p&lt;0.05). Concurrent CD did not predict response. The only adverse event leading to cessation of anti-TNF therapy was a patient with an IFX infusion reaction. <h3>Conclusion</h3> Anti TNF therapy has good short and reasonable long-term clinical efficacy (60% and 31%) for patients with OFG failing other therapies. It appears to be safe with a good side effect profile. OFG patients who fail IFX may respond to ADA.

Adalimumab for Crohnʼs disease in clinical practice at Mayo clinic: The first 118 patients

We sought to assess the effectiveness and safety of adalimumab for the treatment of Crohn's disease (CD) in clinical practice. Demographic, clinical, and treatment data were abstracted from the medical record. The primary outcome was clinical response to induction therapy with adalimumab for CD (complete, partial, or nonresponse). In all, 118 patients were prescribed adalimumab for CD between January 2003 and June 2007. All but five subjects (96%) had received prior infliximab and 50 were on systemic corticosteroids at the time of initial adalimumab dose (44%). A complete response was achieved in 53 patients and 20 patients had no response. The cumulative probability of any response (complete or partial) was 81.3% at 1 year. Dose escalation was required in 59 patients (1-year cumulative probability, 54.0%). Among patients with complete response, 18 lost response during follow-up (1-year cumulative probability, 21.4%). Among 50 patients on corticosteroids at baseline the median daily dose was 20 mg, which decreased to a median of 0 mg during treatment. Sixty-four patients (54%) experienced a total of 117 adverse events. Thirteen patients (11%) experienced 15 serious adverse events. Sixteen patients (14%) discontinued adalimumab due to an adverse event. Adalimumab was both effective and well tolerated for the treatment of CD in this tertiary practice with a high prevalence of past infliximab exposure. This experience largely predates FDA approval of adalimumab for CD.

Cost effectiveness of pregabalin in the treatment of fibromyalgia from a UK perspective

Background:Fibromyalgia is a chronic condition associated with widespread pain, sleep disturbance and disability. Disease related costs are high and effective treatment options few.Objectives:To evaluate the cost effectiveness of pregabalin in the treatment of fibromyalgia.Methods:A decision-analytic model was developed comparing pregabalin 300 mg or 450 mg against placebo, duloxetine 60 mg or 120 mg, gabapentin, tramadol and amitriptyline. After a 12 week treatment phase patients who responded to treatment entered an ongoing treatment phase using a Markov model in which patients maintained response, lost response or dropped out. The base case considered patients with severe fibromyalgia defined as a Fibromyalgia Impact Questionnaire score of ≥59 and a pain score of ≥6.5 at baseline. Response rates for pregabalin and placebo were taken from three randomised trials, and a 1 year open-label extension study was used for long-term parameters. Response was defined as a ≥30% improvement over baseline in pain score and a patient global impression of change rating of much improved or very much improved. Relative rates of response for other comparators over placebo were extracted from a systematic review of published randomised controlled studies. The primary effectiveness endpoint was Quality Adjusted Life Years (QALYs). Utilities gained over baseline were estimated by applying the SF-6D utility algorithm to SF-36 data collected in the pregabalin trials. Resource use associated with fibromyalgia management was estimated from published studies and costs were estimated from the UK NHS perspective at 2008 prices. Costs and QALYs were discounted at 3.5%. Non-parametric bootstrapping analysis was used to generate confidence intervals.Results:In the base case, pregabalin 300 mg and 450 mg increased cost per patient by £601 (95% CI: 532, 669) and £653 (587, 727) and improved QALYs per patient by 0.03 (−0.03, 0.06) and 0.03 (−0.04, 0.08) respectively compared to placebo. The cost per QALY gained (CQG) was £23,166 and £22,533. In the base case population CQG for pregabalin 450 mg against duloxetine 60 mg and 120 mg was £19,224 and £14,096, against gabapentin £35,737, against tramadol £98,072, and was dominated by amitriptyline. Sensitivity analysis found the cost effectiveness of pregabalin to be most sensitive to drug price and response rates. Limitations of the analysis include different definitions of response used and lack of subgroup data reported in the published studies synthesised, and limited data on long-term effect of therapies in fibromyalgia. Although the analysis was based on the best available evidence, the comparisons against amitriptyline and tramadol rely on old studies that were not designed to meet current quality criteria.Conclusion:This model found pregabalin 300 mg and 450 mg to be cost effective compared with placebo and, within the limits of available evidence, against duloxetine using standard UK criteria in patients with fibromyalgia experiencing severe pain.

Systematic review: the short‐term and long‐term efficacy of adalimumab following discontinuation of infliximab

Therapy with adalimumab has been shown to be effective in Crohn's disease (CD) patients who have lost response or are intolerant to infliximab. To determine the efficacy of adalimumab in CD patients who discontinued infliximab through a systematic review. Electronic searches of EMBASE and MEDLINE databases up to May 1, 2009, as well as abstracts from the AGA (2006-2008), ACG (2006-2007), UEGW (2006-2008) and CDDW (2006-2009) identified randomized-controlled trials (RCT) or open-labelled cohorts (OLC) evaluating the short-term and/or long-term efficacy of adalimumab in infliximab failures. The response rates for short-term (clinical response and remission at 4 weeks) and long-term (remission at 6 and 12 months) efficacy were considered. A total of 1810 CD patients were identified among the 15 studies (2 RCT and 13 OLC). The majority of studies evaluated CD patients who either lost response or were intolerable to infliximab, although five OLCs permitted patients refractory to infliximab. Short-term clinical response (n = 9 articles) ranged from 41% to 83%. Long-term clinical remission at 12 months (n = 8 articles) ranged from 19% to 68%. The occurrence of severe adverse events ranged from 0% to 19% and four patients died. Current RCT and OLC evidence suggest that adalimumab is an efficacious therapy for CD patients who discontinue infliximab.

Adalimumab for Patients with Ulcerative Colitis Who have Lost Response or are Intolerant of Infliximab: Initial Response Rates are High, But the Response May Not be Durable

Purpose: Adalimumab (ADA), a human antibody to tumor necrosis factor (TNF), is an effective treatment for patients with Crohn's disease but data are scarce about its effectiveness in ulcerative colitis (UC) patients. Our aim was to assess the efficacy of ADA in a series of patients with moderate to severe UC who either lost response or were intolerant to infliximab (IFX). Methods: We searched the database of the Colitis and Crohn's Disease Center at the University of California San Francisco to identify all patients with a history of UC who were treated with ADA. The following data were collected: demographics, clinical history, adverse events on ADA and clinical response. Response to ADA therapy was measured using the partial Mayo Score. Clinical remission was defined as partial Mayo score ≤2 points with no individual score >1 point and partial response was defined as decrease in partial Mayo score > 30% from baseline and a decrease of ≥2 more points. Results: Seventeen patients (8 men and 9 women) received ADA for moderate to severe UC. All of these patients had received IFX previously. Twelve patients (71%) had stopped IFX because of a lost response while 2 (12%) had developed severe infusion reactions and 3 patients had stopped because of an inadequate response, drug induced lupus and a diagnosis of breast cancer. Patients had received ADA for a median of 7 months (range 1-24 months). Eight patients (47%) required dose escalation of ADA to weekly administration. Initial response was achieved in 13 of 17 (76%) patients, with 6 patients (35%) achieving complete remission, and, 7 patients (41%) having a partial response. However, a durable response occurred in few patients only. Of the 13 initial responders, 8 patients (62%) went on to colectomy or were referred for colectomy within 2 years of being on ADA. ADA was well tolerated in all but 3 patients— one developed drug induced lupus and 2 patients reported severe myalgia and fatigue leading to discontinuation of the drug. Conclusion: Among UC patients with moderately severe disease, who were initially treated with IFX but then switched to ADA, ADA is well tolerated and a majority of patients respond initially to the change in therapy. One third patients are able to achieve clinical remission. The response, however, may not be durable and many patients undergo colectomy within two years of starting ADA. Larger prospective studies are needed to confirm our findings as well as to determine efficacy of ADA as the initial biologic agent for treatment of UC. Disclosure: Dr Mahadevan: Consultant for Abbott and has received honoraria payment from Abbott for talks Dr Terdiman: Consultant for Abbott and has received honoraria payment from Abbott for talks.

A pilot study comparing hydrocortisone premedication to concomitant azathioprine treatment in preventing loss of response to infliximab

Antibodies to infliximab may lead to loss of response to infliximab (IFX) in Crohn's disease. Azathioprine (AZA) coadministration prevents the formation, whereas hydrocortisone (HC) premedication reduces the levels of antibodies to IFX. This pilot study aims at assessing the efficacy of these strategies to prevent loss of response to IFX. Eligible patients had active steroid-dependent luminal Crohn's disease and received IFX (5 mg/kg at weeks 0, 2, and 6 for induction and then scheduled q8 week for remission maintenance). Patients were stratified in a 1 : 1 ratio to oral AZA (2-2.5 mg/kg/day, stratum A) or HC premedication (250 mg intravenously, stratum B). Stratum A included only patients naive to AZA; stratum B included both AZA naive and intolerant patients. Steroids were tapered within 6-8 weeks. Patients were followed up with monthly clinical assessments, laboratory tests, Crohn's Disease Activity Index calculations, adverse-events check up, and adherence to treatment. Overall, 23 patients received IFX/HC and 23 IFX/AZA. There were no differences at baseline in any patient-related or disease-related parameters. Seventeen (74%) patients on IFX/AZA completed the study; six patients were withdrawn for primary nonresponse (one patient), lost response to IFX (two patients), or AZA-related adverse events. Eighteen (78%) patients on IFX/HC completed the study; five patients were withdrawn for primary nonresponse (one patient), loss of response (two patients), or infusion reactions to IFX. No significant differences emerged between strata in clinical remission rates or lost response to IFX. This prospective 2-year pilot study has not confirmed superiority of any available strategy to maintain the efficacy of IFX.

14 - Clinical course and cost of care in ulcerative colitis: Markov chain analysis of a European prospective population-based cohort

14 - Clinical course and cost of care in ulcerative colitis: Markov chain analysis of a European prospective population-based cohort

P069 - The CARE trial: adalimumab improves work productivity and quality of life in patients with Crohn's disease

Introduction:Work Productivity and Activity Impairment (WPAI) questionnaire is a validated, self-administered tool that assesses the impact of disease on productivity. The Short Inflammatory Bowel Disease Questionnaire (SIBDQ) is a simple, validated, 10-item instrument that assesses health-related quality of life (HRQOL) in patients with inflammatory bowel disease. In the Crohn’s Patients Treated With Adalimumab: Results of a Safety and Efficacy Study (CARE), the efficacy and safety of adalimumab in a large population of patients whose treatment approximated usual clinical practice were evaluated. In this analysis, we investigated the impact of adalimumab treatment on work productivity and HRQOL in CARE. Methods: A total of 945 patients with Harvey Bradshaw Index score >7 enrolled in this multicenter, open-label, European, Phase IIIb trial. The study population included patients naive to biotherapy and patients who had failed infliximab therapy (primary nonresponders [PNR] to infliximab, lost response to infliximab, intolerant of infliximab, and other infliximab failures). Patients received induction therapy of 160-mg/80-mg adalimumab at Weeks 0/2, followed by adalimumab 40mg every-other-week maintenance therapy through at least Week 20 (patients with flares/nonresponse could receive 40mg weekly at/after Week 12). In this analysis, patients’ work productivity, as measured by WPAI, and HRQOL, as measured by SIBDQ, were analyzed. The WPAI tool, as adapted for CD, measures the percentage of overall impairment in work productivity (including absenteeism and presenteeism) and daily activity due to CD (0%=no impairment, 100%=total loss of work productivity/activity). An absolute change of 7% in WPAI score is the minimum clinically important difference (MCID). SIBDQ total scores range from 10 70, with greater scores indicating better HRQOL. A 9-point change in SIBDQ is correlated with a 100-point change in CDAI score. Both measures were assessed at baseline and Weeks 4, 8, 12, and 20, and changes from baseline were analyzed using paired Student t-tests. Results: Mean age of patients was 35.3 years, and 60% were female. Mean baseline total daily activity impairment (TAI) was 57% (n = 907). For employed patients, total work productivity impairment score (TWPI) was 51% (n = 442) at baseline, indicating severe impairment. Baseline quality of life of patients was substantially impaired (SIBDQ mean = 37±10). Mean changes in WPAI components and SIBDQ are summarized by reason for infliximab failure (table). Overall, at Week 20, 57% (518/910), 62% (559/907), and 47% (208/442) of patients achieved improvement of SIBDQ of 9 points (correlated with 100-point change in CDAI), TAI of at least 7 points (MCID), and TWPI of 7 points (MCID) (NRI). Conclusions: Adalimumab therapy significantly improved work productivity and quality of life for patients with moderately to severely active CD, including those naive to anti-TNF therapy and those who had failed infliximab therapy. These improvements were observed as early as Week 4 and maintained throughout the study. Mean absolute change in SIBDQ and two WPAI subscores with adalimumab therapy at Weeks 4 and 20 in CARE by prior use of infliximab (observed)

Adalimumab for Crohn’s disease with intolerance or lost response to infliximab: a 3‐year single‐centre experience

Adalimumab is effective in inducing clinical remission in patients with Crohn's disease who lost response or became intolerant to infliximab. To evaluate long-term efficacy and safety of adalimumab as a second line therapy in luminal and fistulizing Crohn's disease. We report our single-centre experience in 53 patients. We evaluated maintenance of clinical response defined as the absence of adverse events leading to drug withdrawal, no major abdominal surgery and no loss of clinical response in initial responders. Major abdominal surgery, steroid sparing, complete fistula closure and safety were also assessed. The probability of maintaining clinical response was 77.2%, 67.8% and 50.8% at 26, 52 and 130 weeks respectively. The probability of remaining major abdominal surgery-free was 82.3% at 26, 52 and 130 weeks. Complete fistula closure occurred in six of 10 patients, and eight of 10 patients were able to taper steroid therapy. Adverse events occurred in 31 patients (58.5%) leading to adalimumab withdrawal in nine patients (17%). Adalimumab therapy may be effective in the long term in both luminal and fistulizing Crohn's disease in infliximab-failure patients, half of patients maintaining clinical response and potentially avoiding major abdominal surgery in 80% of cases.

Efficacy of Dasatinib in Patients (pts) with Previously Untreated Chronic Myelogenous Leukemia (CML) in Early Chronic Phase (CML-CP)

Background: Dasatinib (BMS-354825) is a multi-targeted kinase inhibitor of BCRABL and SRC with significant activity in pts with CML-CP resistant to or intolerant of imatinib (IM). We initiated a phase II trial to study efficacy and safety of dasatinib in pts with previously untreated CML-CP.Aims: To investigate the efficacy and safety of dasatinib as initial therapy for patients with CML-CP.Methods: The primary objective was to estimate the proportion of pts attaining major molecular response (MMR) at 12 months (mo). Pts with previously untreated CML-CP were eligible and received dasatinib 100 mg/day, randomized to either 50 mg-twice-daily (BID) or a 100 mg-once-daily (QD).Results: Fifty pts have been enrolled (25 on the QD schedule, 25 BID). Median age was 45 years (yrs) (range 18–76 yrs); 75% are Sokal low risk. Median follow-up is 24 months (mo). Overall, 44/45 (98%) evaluable patients achieved complete cytogenetic response [CCyR]. The CCyR rate at 3, 6 and 12 mo compares favorably to that observed in historical controls treated with imatinib 400mg or 800 mg daily:Percent with CCyR (No. evaluable)Mo on therapyDasatinibImatinib 400mgImatinib 800mgP value378 (45)37 (49)62 (202)0.0003693 (41)54 (48)82 (199)<0.00011297 (35)65 (48)86 (197)0.00011888 (33)68 (38)89 (179)0.0042480 (25)70 (40)88 (173)0.006MMR was achieved in 12/35 (34%) at 12 mo and 12/25 (48%) at 18 mo. One of 46 (2%) evaluable pts have achieved confirmed complete molecular response, and 1 other unconfirmed (ie, only achieved on their last assessment). Grade 3–4 non-hematologic toxicity (regardless of causality) included pruritus (13%), fatigue (6%), neuropathy (4%), and memory impairment (4%). Pleural effusion occurred in 21% evaluable pts (grade 3–4 in 2%). Grade 3–4 hematologic toxicity (transient) was thrombocytopenia in 11%, neutropenia in 21%, and anemia in 9%. Twenty-seven (54%) pts required transient treatment interruption. The actual median daily dose for all pts was 100mg. There is no significant difference in grade 3–4 toxicity by treatment schedule. Four pts came off study: 1 pts choice after 1 dose, 1 for toxicity (pleural effusion, QD schedule), and 2 lost response after multiple treatment interruptions (1 myelosuppression, 1 pleural effusion, both BID schedule). Two other pts have lost response because of non-compliance. 24 month EFS (event = loss of CHR, loss of MCyR, AP/BP, death, or off because of toxicity) is 81%.Conclusion: Rapid CCyR occurs in most patients with previously untreated CML-CP treated with dasatinib frontline therapy with a favorable toxicity profile. Accrual to this trial continues.

Long‐term outcome of adalimumab therapy for ulcerative colitis with intolerance or lost response to infliximab: a single‐centre experience

Adalimumab may be effective in inducing remission in patients with mild-to-moderate ulcerative colitis who had secondary failure to infliximab. To evaluate long-term efficacy and safety of adalimumab in patients with ulcerative colitis who previously responded to infliximab, and then lost response or became intolerant. We report our single-centre experience in 13 patients. The patients received a loading dose of 160 mg of adalimumab subcutaneously in week 0, followed by 80 mg at week 2 and then 40 mg every other week starting at week 4. The primary efficacy measure was the proportion of patients on adalimumab therapy during the study. Median duration of follow-up was 42 weeks (range, 10-100). The mean number of adalimumab infusions was 21 (range, 5-50). The probability of maintaining adalimumab was 92.3%, 84.6%, 60.6% and 32.5% at 1, 3, 6 and 23 months respectively. Six of 13 patients (46.2%) underwent colectomy during the study. No serious toxicities occurred in the study. Adalimumab is well-tolerated and may be effective in maintaining clinical remission in a subgroup of patients with ulcerative colitis and lost response or intolerance to infliximab, potentially avoiding colectomy in about half of the patients.

Review: Efficacy and safety of adalimumab in Crohn's disease

Adalimumab (ADA) is a subcutaneously (SC) self-administered fully human Ig G1 monoclonal antibody directed against tumor necrosis factor alpha (TNFce). In the CLASSIC dose-ranging trial, ADA was superior to placebo for inducing remission in patients with moderate-to-severe Crohn's disease (CD) naive to TNFa inhibitor therapy. In CLASSIC II, patients in remission following CLASSIC I maintained remission for up to 56 weeks while on ADA. In CHARM, approximately 40% of the 499 patients with moderate-to-severe CD who responded to ADA, maintained remission at 26 and 52 weeks, thus confirming long-term efficacy. ADA demonstrated steroid-sparing properties, beneficial effects in patients with perianal fistulas, and decreases in rates of hospitalization and surgery. Sub-group analyses demonstrated similar remission rates irrespective of concomitant immunosuppressive use or previous exposure to other TNFa inhibitor therapy. In the GAIN trial, 325 patients who had either lost response or become intolerant to infliximab (IFX) were randomized to recieve ADA induction therapy or placebo. In this difficult-to-treat patient population, 21% achieved remission and half demonstrated clinical benefit from ADA induction therapy. Injection site reactions may occur with SC ADA (2-5% of patients), which are generally less dramatic in nature than infusion reactions experienced with intravenous IFX. Immunogenicity occurs with all monoclonal antibodies; however, in the CD development program anti-ADA antibodies were detected at low rates (0.7 and 2.6% of patients in the CLASSIC I and CLASSIC II studies, respectively). Based on robust short- and long-term efficacy data from large randomized controlled trials and a favorable safety signal, ADA has become a key addition to the therapeutic armamentarium in the treatment of moderate-to-severe CD.

W1243 Concomitant Use of Immunosuppressive Therapy in An Outpatient IBD Subspecialty Clinic Results in Rates of Response Higher Than Those Seen in the Infliximab Randomized Controlled Trials

(Background: for bold) Infliximab has confirmed efficacy from RCTs for the induction and maintenance of remission of active luminal and fistulizing Crohn's disease (CD). What have been less clearly described are the long-term outcomes of maintenance infliximab therapy outside of the rigors of a clinical trial setting and in actual clinical practice. (Aims: for bold) The objective of this cohort study was to examine, in an outpatient IBD specialty clinic, the induction and maintenance responses to infliximab in patients with moderately severe active CD. (Methods: for bold) A retrospective chart review was conducted of all Crohn's disease patients treated at a large, urban university hospital that serves as a quaternary IBD referral center. All patients treated with induction and maintenance dosing of infliximab were identified and their records reviewed for patient demographics, and clinical responses. Clinical response was defined by physician global assessment and off corticosteroids. (Results: for bold) 151 patients were identified of whom 133 had sufficient records to be entered into the analysis. The study population was 53% female; 98% Caucasian; mean age at initiation of therapy was 36.5 yrs; mean duration of disease from diagnosis to infliximab treatment was 11.5 yrs. Anatomic distribution of CD was 36% ileal, 32% colonic and 32% ileo-colonic. 117/133 (89%) of patients had a clinical response to induction and continued with maintenance infliximab therapy. 105/117 (90%) patients were on concomitant immunomodulatory therapy: azathioprine/6-MP 81/105 (69%); methotrexate 24/105 (21%). The mean duration of clinical response was 94.0 wks (95% CI 78.8-109.2). The proportion of patients with an ongoing clinical response at week 30 was 83.2%, at week 54 was 63.6% and at week 104 was 44.9%. In all, 36 (30.8%) patients lost response (LR) defined as worsening of symptoms, initiation of new CD therapy, or need for surgery. The mean time to LR was 63.8 weeks (95% CI 49.4-78.2). 15/117 (12.8%) patients experienced an adverse event (AE), resulting in the discontinuation of infliximab in 7 (6.0%) patients. AE's included 9 infusion reactions, 4 serum sickness-like reactions, 1 rash of unknown significance and 1 serious infection (osteomyelitis of the jaw). There were no cases of malignancy or death. (Conclusions: for bold) Patients starting infliximab in an IBD outpatient specialty clinic were demographically similar to those in the RCTs. Nevertheless, a higher number were using concomitant immunosuppressive therapy and demonstrated higher induction and maintenance of response rates.