Efficacy Of Retreatment Research Articles

P517 Re-treatment with filgotinib in patients with Ulcerative Colitis following treatment interruption: Analysis of the SELECTION and SELECTIONLTE studies

Abstract Background Long-term treatment regimens for ulcerative colitis (UC) present challenges for patients who may need to interrupt therapy for various reasons.1 Filgotinib (FIL) is an oral Janus kinase 1 preferential inhibitor. We performed a post hoc analysis of data collected from patients with UC treated with FIL in the phase 2b/3 SELECTION programme to assess the efficacy and safety of re-treatment following treatment interruption. Methods The SELECTION programme comprises two Induction Studies and a Maintenance Study (NCT02914522) and a long-term extension (LTE) study (NCT02914535). Adults aged 18–75 years with moderately to severely active UC, who had clinical remission or Mayo Clinic Score (MCS) response to FIL 200 mg or 100 mg at week 10 of SELECTION were re-randomized 2:1 to continue assigned FIL treatment or placebo (PBO) from week 11 to week 58. Patients with disease worsening (DW) in the Maintenance Study could enter the LTE study to receive open-label FIL 200 mg once daily. We assessed the efficacy of FIL in patients treated with induction FIL 200 mg or 100 mg who were randomized to PBO in the Maintenance Study and were re-treated with open-label FIL in the LTE study. Efficacy endpoints included partial MCS (pMCS) response and remission at LTE baseline and weeks 2, 4, 12 and 24. Non-responder imputation was used to analyse efficacy results. Results This analysis evaluated 50 patients treated with FIL 200 mg and 35 treated with FIL 100 mg in the Induction Study, who were withdrawn and re-treated upon DW. Baseline characteristics were similar among patients in the 200 mg and 100 mg treatment groups, with a median time to DW of 16.9 and 13.3 weeks, respectively. Mean pMCS declined rapidly in both groups from LTE baseline to week 2, reaching pMCS <2 at week 24 (Figure 1). By as early as week 2 of re-treatment, over 60% of patients in both groups had achieved pMCS response (Figure 2). By week 12, 78% of the 200 mg group and 94% of the 100 mg group achieved a pMCS response. Median time to response was 2.4 and 2.1 weeks in the 200 mg and 100 mg groups, respectively. Figure 3 shows that pMCS remission was achieved in 42% of the 200 mg group and 45% of the 100 mg group by week 24. Median time to pMCS remission was 23.6 and 12.1 weeks in the 200 mg and 100 mg groups, respectively. The number of adverse events upon re-treatment in the LTE was consistent with that reported in SELECTION (Table 1). Conclusion The majority of patients re-treated with FIL achieved pMCS response and remission within 12 weeks, with onset as early as week 2. Good disease control was maintained over the course of 24 weeks. Re-treatment was well tolerated, with no new safety signals observed among these patients. Reference 1. Rubin DT. Gastroenterol Hepatol 2019;15:612–5.

Efficacy of Rotary Retreatment Techniques Assisted with Passive Ultrasonic Activation of Resin Solvent in Removal of Gutta-percha with Epoxy Resin and MTA Based Root Canal Sealers: An In-vitro Study

Introduction: Endodontic retreatment is indicated in cases of failed primary endodontic treatment. The main goal of retreatment is to establish conditions that will enable the healing of the periapical tissue. Aim: To evaluate the efficacy of rotary retreatment with the ProTaper Universal Retreatment system supplemented with passive ultrasonic activation of solvent in retreatment of singlerooted mandibular premolar teeth obturated with gutta-percha and two different root canal sealers (AH Plus and MTA Fillapex). Materials and Methods: This in-vitro study was conducted in the Department of Conservative Dentistry and Endodontics at Mahatma Gandhi Mission’s Dental College and Hospital, Navi Mumbai, Maharashtra, India, from January 2019 to April 2019. Total 66 freshly extracted human single rooted mandibular premolars were used in this study. Root canal preparation was done using ProTaper Next rotary files. Teeth were decoronated to get a uniform length of 18 mm and were divided into three retreatment groups based on the technique used for retreatment. Group I included rotary retreatment, Group II involved rotary retreatment with solvent and paper point wicking, and Group III involved rotary retreatment with passive ultrasonic activation of solvent and paper point wicking. Based on the sealer used for obturation, teeth in each group were further divided into two subgroups, subgroup A with AH Plus sealer and subgroup B with MTA Fillapex sealer. Teeth were stored in an incubator for 30 days to allow sealer to set after which sectioning of the specimens was done buccolingually for examination under the stereomicroscope and photographed. Statistical analysis was done by using parametric Analysis of Variance (ANOVA) followed by Post-hoc tests and Unpaired t-test. Results: No statistically significant difference in percentage area of residual root canal filling material noted between the group I and II and when obturated with gutta-percha and AH Plus sealer (subgroup A) as p-value=0.215. Whereas, it revealed a statistically significant difference between the group I, II, and III when obturated with gutta-percha and MTA Fillapex sealer (subgroup B) as p-value<0.001. Conclusion: Passive ultrasonic activation of solvent after guttapercha removal using ProTaper Universal rotary files could improve the quality of endodontic retreatment.

Induction of mucosal healing by intensive granulocyte/monocyte adsorptive apheresis (GMA) without use of corticosteroids in patients with ulcerative colitis: long-term remission maintenance after induction by GMA and efficacy of GMA re-treatment upon relapse.

This study examined the long-term maintenance rate after inducing remission by intensive granulocyte/monocyte adsorptive apheresis (GMA) without use of corticosteroids (CS) and GMA re-treatment efficacy in the same patients upon relapse with ulcerative colitis. Patients who achieved clinical remission and mucosal healing (MH) by first-time intensive GMA (first GMA) without CS were enrolled. The cumulative non-relapse survival rate up to week 156 was calculated. Patients with relapse during the maintenance period underwent second-time intensive GMA (second GMA) without CS. Clinical remission and MH rates following second GMA were compared to those following first GMA in the same patients. Of the 84 patients enrolled, 78 were followed until week 156 and 34 demonstrated relapse. The cumulative non-relapse survival rate by week 156 was 56.4%. Clinical remission and MH rates after second GMA did not differ from those after first GMA in the same patients (week 6: clinical remission, 100% vs 88.4%, p = 0.134; MH, 100% vs 84.8%, p = 0.074). In conclusion, MH induction by intensive GMA without use of CS in ulcerative colitis patients contributes to subsequent long-term clinical remission maintenance. GMA re-treatment efficacy was comparable to that of first GMA in the same patients who had relapse.

Comparison of Obturation Quality between Calcium Silicate-Based Sealers and Resin-Based Sealers for Endodontic Re-treatment.

Background: The objective of this micro-computed tomography (micro-CT)-based study was to compare the filling quality of endodontic treatment and endodontic Re-treatment between two sealers with matched obturation techniques: calcium silicate-based sealer (Endoseal TCS) with a single-cone technique (SCT) and resin-based sealer (AH Plus) with a continuous wave technique (CWT). Methods: Forty maxillary premolars were selected and assigned into four groups, according to the obturation methods of the first endodontic treatment and Re-treatment (n = 10). The AP/AP group was first treated with AH Plus/CWT, then re-treated with AH Plus/CWT. The AP/ET group was first treated with AH Plus/CWT, then re-treated with Endoseal TCS/SCT. The ET/AP group was first treated with Endoseal TCS/SCT, then re-treated with AH Plus/CWT, and the ET/ET group was first treated with Endoseal TCS/SCT, then re-treated with Endoseal TCS/SCT. The specimens were scanned using micro-CT at three time points: after the first endodontic treatment, after gutta-percha (GP) cone removal, and after Re-treatment. The void volume of root canal obturation and the volume of the remaining filling materials were calculated. Data were analyzed using Student’s t-tests and ANOVA. Results: The Endoseal TCS groups (ET/AP and ET/ET) showed a lower percentage of voids than the AH plus groups (AP/AP and AP/ET) on the whole canal and the apical third, after first obturation (p < 0.05). The AH plus group showed significantly fewer remnants than the Endoseal TCS group after GP removal (p < 0.05). Re-treated canals and initially treated canals had similar void volumes (p > 0.05). There was no significant difference in void volume after Re-treatment, regardless of whether the same or different sealers were used for the first treatment and Re-treatment (p < 0.05). Conclusions: Endoseal TCS sealer and AH Plus sealer had a similar Re-treatment efficacy, regardless of which sealer was used in the previous treatment.

The Impact of IL28B Gene Polymorphisms on Drug Responses

The Impact of IL28B Gene Polymorphisms on Drug Responses

ReVenG: A Phase 2 Study of Venetoclax Plus Obinutuzumab Retreatment in Patients with Relapsed Chronic Lymphocytic Leukemia

ReVenG: A Phase 2 Study of Venetoclax Plus Obinutuzumab Retreatment in Patients with Relapsed Chronic Lymphocytic Leukemia

THE IMPORTANCE OF CIRCULATING TUMOR DNA IN THE ASSESSMENT OF METASTATIC COLORECTAL CANCER TREATMENT EFFECTIVNE

Challenges in cancer detection, prognosis and management are currently being solved by determining circulating tumor DNA (ctDNA). The assessment of this marker has acquired particular importance in metastatic colorectal cancer (mCRC), the systemic treatment of which depends on the RAS gene status, which has prognostic and predictive value. However, the possibilities of taking samples from the primary or metastatic lesion for pathomorphological and molecular analysis in CRC are often limited. The determination of ctDNA using liquid biopsy has an advantage over standard biopsy due to its low invasiveness and high availability of the method. Analysis of mutations using ctDNA as well as changes in the level of this marker is a criterion for the effectiveness of systemic treatment, as well as a factor that determines the risk of disease progression. Currently, the potential of using ctDNA to monitor effectiveness of first-and second-line chemotherapy, as well as to predict the development of secondary resistance to EGFR inhibitors (cetuximab and panitumumab) in the first-line treatment and assessment of RAS status for returning to therapy with EGFR inhibitors in the third-line treatment of mCRC is being studied. Several pilot studies have provided evidence of the efficacy of EGFR re-treatment. The modern literature data published in leading peer-reviewed journals in Russian and international scientific citation databases, such as Medline, Elibrary, and PubMed were analyzed. Of the 138 analyzed publications, 56 were used to write this review.

S1113 Management of Hepatitis C Genotype 4 Treatment Failure: A Real World Single Center Experience

Introduction: Treatment failure with direct-acting antiviral (DAA) therapy is uncommon but it can be associated with significant worsening of liver disease especially in patients with liver cirrhosis. Retreatment of Hepatitis C (Hep C) patients who failed DAA therapy remains a challenge. Data on retreatment of HCV genotype 4 patients (G4) with DAA failure is limited and these patients are underrepresented in most clinical trials.The purpose of this study is to evaluate the efficacy of retreatment of HCVG4 DAA failure patients using a different DAA class from the currently available first-generation DAA regimens other than the regimen the patient had relapsed to. Methods: Out of 431 HCV G4 patients treated with DAAs in our center, 29 (6.7%) failed to achieve SVR. These patients were retreated by switching to a new DAA class from the first-generation DAA regimens independent of RAS testing. Twenty five out of these 29 patients completed retreatment regimen while 4 patients were lost for follow–up. Results: Among other risk factors, by logistic regression analysis, only older age, high CTP score and high base-line viral load were independent predictors of DAA failure among our cohort. Also, Sofosbuvir/Ribavirin regimen was the most common DAA regimen associated with treatment failure (48.3%). All our DAA failure patients had liver cirrhosis and ∼50% of them had advanced cirrhosis (Child´s class B or C), that made prompt retreatment of them a rescue strategy to halt viral replication and disease progression. After retreatment, 22 (88%) of the 25 patients who completed retreatment achieved SVR12 and the remaining 3 (12%) failed. The 3 patients who failed retreatment were all males, diabetics with advanced cirrhosis (mean CTP=9.33), and 2 of them were retreated by mistake with another drug from the same DAA class they had relapsed to (NS5A). These 3 patients completed a second retreatment, one patient achieved SVR and 2 patients relapsed for the second time (re-relapsers). Conclusion: The overall SVR rate (88%) demonstrated in this real–world study, clearly shows that, the retreatment policy of DAA failure patients by switching to or adding a new drug class independent of RAS testing is a good retreatment option that may be of importance for many areas of the world with no or difficult access to RAS testing or second-generation rescue regimens.

P-209: High response rates with IMiD retreatment post anti-CD38 exposure in patients with Multiple Myeloma

<h3>Background</h3> Anti-CD38 antibodies can alter myeloma pathobiology, and can potentially overcome refractoriness to IMIDs. The aim of the study was to evaluate the efficacy of re-treatment with IMiD-based therapy in patients refractory both to IMiDs and anti-CD38 antibodies. <h3>Patients and Methods</h3> The study included 38 patients who were refractory to anti-CD38-based therapy and to at least one IMiD. Overall, 26 (68%) patients had received lenalidomide, 11 (29%) pomalidomide and 1 (3%) thalidomide before anti-CD38 treatment. <h3>Results</h3> Median number of prior lines before IMiD retreatment was 4 (range 2 to 13). The patient distribution per R-ISS was: R-ISS 1: 8, R-ISS 2: 9, R-ISS 3: 4. Overall, 4 (11%) patients received lenalidomide-, 33 (86.5%) pomalidomide-, and 1 (2.5%) thalidomide-based regimens post anti-CD38. The majority of patients were treated with pomalidomide-cyclophosphamide-dexamethasone (PCD) (n=13) and pomalidomide-dexamethasone (PomD) (n=11). The remaining 14 patients were treated with other IMiD-based triplets. Importantly, 10 (26%) patients received the same IMiD as prior to anti-CD38 exposure (lenalidomide n=2, pomalidomide n=8). Median time from diagnosis to IMiD re-treatment was 61.5 months. Overall, 20 patients (53%) achieved a response during IMiD retreatment, including CR=1, VGPR=5, PR=10 and MR=4; 11 patients achieved SD, whereas 7 patients progressed. The disease control rate (DCR=SD+PR+VGPR+CR) was 82%. Among the patients re-exposed to the same IMiD, 5 responded, 3 progressed and 2 remained stable. Among the responders, 1 achieved VGPR with PCD, 2 PR with PCD and DaraPomDex, whereas 2 showed MR with PCD and PCD with Bortezomib. 79% (22/28) of the patients received pomalidomide following previous exposure to lenalidomide; among them, 15/22 (68%) patients responded (1 CR, 4 VGPR, 8 PR, 2 MR), 3 remained stable and 4 progressed. Interestingly, 10 out of 13 (77%) patients who received PCD responded. Median PFS for all patients was 4 months (range 2.9-4.8). Median time to next treatment (TtNT) for the whole study cohort as well as for those who received the same IMiD pre- and post-exposure to anti-CD38 was 4.2 months as well. Median duration of response (DoR) for the responders was 7 months. Median TtNT for those who received pomalidomide after previous exposure to lenalidomide (n=22) was 3.9 months; median DoR among the responders was 6.6 months. Median OS 5.3 range 0.5-35.5. <h3>Conclusion</h3> IMiD retreatment in patients refractory to both an IMiD and an anti-CD38 antibody can induce significant response rates, even among patients re-exposed to the same IMiD. This indicates that after anti-CD38 therapy a long lasting, probably immunomodulatory effect may be associated with some degree of re-sensitization to IMiDs. The subgroup of patients receiving PCD derived the most benefit. In this context, a prospective study evaluating the role of PCD in this population is currently ongoing.

Management of Hepatitis C Virus Genotype 4 Treatment Failure: A Real-World Single Center Experience

Background: Treatment failure with direct-acting antiviral (DAA) therapy is associated with worsening of liver disease especially in cirrhotic patients. Moreover, data on retreatment of HCV genotype 4 patients (G4) with DAA failure are still very limited, since they are under- represented in most clinical trials.&#x0D; Aims: To evaluate the efficacy of retreatment of Egyptian HCV G4 DAA failure patients based on the use of a new DAA class from currently available first- generation DAA regimens other than the patient had relapsed to.&#x0D; Methods: 29 Egyptian HCV G4 DAA failure patients were retreated by switch to a new DAA class from first- generation DAA regimens than the patient had relapsed to independent of RAS testing. 25 out of these 29 patients completed retreatment and 4 patients were lost for follow–up.&#x0D; Results: Among other risk factors, by logistic regression analysis, only older age, high CTP score and high base-line viral load were independent predictors of DAA failure among our cohort. Also SOF/RBV regimen was the most common prior DAA regimen associated with treatment failure (48.3%).&#x0D; All our DAA failure patients were cirrhotics that made prompt retreatment of them a rescue strategy to halt viral replication and disease progression.&#x0D; After retreatment, 22 (88%) of the 25 patients who completed retreatment achieved SVR12 and the remaining 3 (12%) failed.&#x0D; These 3 patients completed a second retreatment, one achieved SVR and the other 2 relapsed again (re-relapsers)&#x0D; Conclusion: The overall SVR rate (88%) demonstrated in this real –world study, clearly shows that, the retreatment policy of DAA failure patients by switch to – or addition of a new drug class independent of RAS testing is a good retreatment option, that may be of importance for many areas of the world with no or difficult access to RAS testing or second-generation rescue regimens.

Management of Recurrent Endometrial Cancer or Atypical Endometrial Hyperplasia Patients After Primary Fertility-Sparing Therapy.

ObjectiveTo evaluate the efficacy and prognosis of fertility-sparing re-treatment on patients with recurrent endometrial cancer (EC) and atypical endometrial hyperplasia (AEH) who wish to preserve their uterus after complete remission (CR) for primary conservative therapy.MethodsWe performed a retrospective study on recurrent EC or AEH patients who received fertility-sparing re-treatment after achieving CR. Data regarding clinicopathological factors, adverse events, treatment efficacy, tumor prognosis, and reproductive outcome were analyzed.ResultsOf the 98 recurrent patients with a median disease-free interval period of 19 (3–96) months, 18 patients decided to receive hysterectomy directly, and 80 patients received fertility-preserving re-treatment. Seventy-one (88.6%) cases achieved CR, 96.0% in AEH and 75.8% in EC patients, with the 6 (3–16) months’ median CR time. Seven (8.8%) patients failed to achieve CR and then underwent the hysterectomy: one partial response (PR), four stable disease (SD), and two progressive disease (PD). Forty-nine women attempted to get pregnant after CR, 13 (26.5%) became pregnant, seven (14.3%) successfully delivered, and six (12.2%) miscarried. During the follow-up period, 22 (31.0%) women had developed a second relapse with the median recurrence time of 12 (4–90) months, and 10 patients decided to receive the third round of fertility-sparing treatment. Seven (70.0%) patients, 33.3% in EC and 85.7% in AEH, achieved CR again. Hysterectomy was performed in two (20.0%) patients due to SD. After the third-round treatment, six women had the desire to conceive but no one became pregnant successfully.ConclusionFor patients with recurrent EC and AEH after primary conservative treatment, fertility-preserving re-treatment can still achieve a promising response, and patients have possibilities of completing childbirth.

Application of vaginoscopy in the diagnosis and treatment of occult vaginal high-grade squamous intraepithelial lesions

Objective: To investigate the application value of vaginoscopy in the diagnosis and treatment of vaginal squamous intraepithelial lesions post hysterectomy. Methods: From May 2017 to June 2020, patients with high-risk (HR)-HPV infection and (or) cytological abnormalities after hysterectomy in Obstetrics and Gynecology Hospital Affiliated to Fudan University were examined by colposcopy, and those who were not satisfied with exposure under colposcopy were further examined by vaginoscopy. The role of vaginoscopy in the detection and treatment of occult vaginal squamous intraepithelial lesions was analyzed. Results: A total of 153 patients with HR-HPV infection and (or) cytological abnormalities, and inadequate colposcopy were enrolled in this study. The average age was (49.8±8.1) years. All cases were successfully performed vaginoscopy with no vaginal perforation, no bladder and intestinal injury. During vaginoscopy, 11 (7.2%, 11/153) cases with unclear high-grade squamous intraepithelial lesion (HSIL) boundary under colposcopy were found with clear HSIL boundary, and new HSIL was found in 23 (15.0%, 23/153) cases. According to colposcopy, there were 89 cases of normal or inflammation, 45 cases of vaginal low-grade squamous intraepithelial lesion (LSIL) and 19 cases of vaginal HSIL. According to vaginoscopy, there were 56 cases of normal or chronic inflammation, 55 cases of vaginal LSIL, 40 cases of vaginal HSIL (including 2 cases of vaginal HSIL could not exclude cancer) and 2 cases of vaginal carcinoma. There were significant difference between colposcopy and vaginoscopy (P<0.01). The missed diagnosis rate of vaginal apex blind curettage under colposcopy was 54.8%. For the 40 cases with vaginal HSIL under vaginoscopy, 15 cases were completely curettaged with vaginal endoscopic claw forceps, and 22 cases were vaporized by Versapoint. Among the 37 cases of vaginal HSIL treated by vaginoscopy, 34 cases were followed up for 6 months with 31 cases of vaginal HSIL cured. The cure rate was 91.2% (31/34), the positive rate of HR-HPV decreased from 100.0% (34/34) to 79.4% (27/34). Conclusion: For patients with inadequate exposure of vaginal apex during colposcopy posthysterectomy, vaginoscopy is helpful to detect the occult lesions in the vaginal apex, and it could also be used for the treatment of vaginal squamous intraepithelial lesions.

Retreatment of Irinotecan in Later Lines of Therapy for Metastatic Colorectal Cancer: A Retrospective Study

Background: Due to few efficacious options in later lines of therapy in metastatic colorectal cancer (mCRC), there has been considerable interest in the possibility of retreatment with previously administered agents. This study investigated the efficacy and safety of irinotecan retreatment (IRI2) in patients with refractory mCRC. Methods: We performed a retrospective analysis of patients with mCRC who were retreated with irinotecan-based regimens. The retreatment regimens with anti-epidermal growth factor receptor therapies were excluded. Results: A total of 64 patients were included. Patients had a median age of 56 years and were offered mainly in the setting of third- or fourth-line therapy with IRI2. The disease control rate was 78.2% including an objective response of 23.5%. Median progression-free survival and overall survival were 5.5 and 19.3 months, respectively. The most frequent grade 3 or higher toxicities were nausea/vomiting (27.9%) and neutropenia (25%). Conclusion: IRI2 might be a reasonable option for heavily pretreated patients with mCRC who achieved disease control with prior irinotecan therapy.

27454 Efficacy and safety of long-term risankizumab re-treatment following drug withdrawal: IMMhance trial

Introduction: Risankizumab, a humanized IgG1 monoclonal antibody approved to treat plaque psoriasis, selectively inhibits IL-23 by binding its p19 subunit. The IMMhance trial evaluated the efficacy of risankizumab re-treatment following drug withdrawal in patients with moderate-to-severe plaque psoriasis.

Bortezomib-Dexamethasone Re-Treatment at Biochemical Relapse Vs Observation in Relapsed/Refractory Multiple Myeloma Patients: Results of a Phase II Multi-Center, Randomized Study

Bortezomib-Dexamethasone Re-Treatment at Biochemical Relapse Vs Observation in Relapsed/Refractory Multiple Myeloma Patients: Results of a Phase II Multi-Center, Randomized Study

Intensification of Lymphodepletion Optimizes CAR Re-Treatment Efficacy

▪Background: Post chimeric antigen receptor (CAR) therapy relapse has generally occurred via two mechanisms; emergence of antigen-negative leukemia, or via loss of CAR T cells. Anecdotally, CAR re-treatment has had limited success, potentially due to immune-mediated rejection of CAR T cells, or from immunogenicity of epitopes on murine constructs-which may be less applicable to humanized constructs. After several re-infusion attempts on our phase I dose-escalation study of CD22 CAR, in an effort to improve response, we incorporated use of an intensified lymphodepletion regimen prior to CAR re-infusion and report on our findings. Furthermore, preclinical models suggest that modulation of antigen expression, despite persistent positivity, may also impact the CAR response. Therefore, in this re-treatment analysis, we also explore the role of antigen expression on treatment response.Design: Children and young adults with relapsed/refractory CD22+ acute lymphoblastic leukemia (ALL) enrolled on our phase I dose escalation anti-CD22 CAR therapy protocol (NCT02315612) who met eligibility criteria for a second infusion were evaluated. All patients had bone marrow evaluations by morphology and flow cytometry prior to second infusion to demonstrate persistent CD22+ ALL and loss of CD22 CAR T cells, and subsequently had restaging at day 28 (+/- 4 days) post second CAR infusion. Additionally, lymphodepleting chemotherapy, either with the original dosing schema (Fludarabine 25 mg/m2 x 3 days and Cyclophosphamide 900 mg/m2 x 1 day) or at intensified dosing (Fludarabine 30 mg/m2 x 4 days and Cyclophosphamide 600 mg/m2 x 2 days) was utilized at the discretion of the treating team. All patients were re-infused with their original cell dose; 3 x 105 CAR T cells/kg (n=1), 1 X 106 CAR T cells/kg (n=4), or 3 X 106 CAR T cells/kg (n=1). Flow cytometry was utilized to assess CD22 antigen-binding capacity (ABC) of leukemia cells pre and post infusion. Patients were analyzed for response and expansion of CAR T cells.Results: From June 2015 to July 2017, 6 patients with ALL were eligible for a second infusion of CD22 CAR T cells. This included 4 patients who relapsed with CD22+ disease after attaining a complete remission and 2 patients who had stable disease with limited CAR expansion and evidence of clinical benefit following the first infusion. The median time to relapse after a first infusion was 5 months (range: 3-11 months) with a median time to re-infusion of 4 months (range: 2-11 months) from the first infusion. Prior to re-infusion, all patients had <5% circulating CAR T cells, and all had significant disease burden, > M2 marrow (>5% blasts). Our initial re-infusion experience with 4 subjects, which utilized the identical lymphodepletion regimen as with the first infusion, demonstrated CAR expansion in only 2 patients. Following this, the pre-infusion lymphodepleting chemotherapy was intensified, with 2/2 patients having CAR expansion-including one patient who had a minimal expansion with the initial infusion, but robust expansion following the intensified lymphodepletion prior to second infusion. Both patients tolerated the intensified regimen well without any significant chemotherapy related toxicities. Following re-infusion, 4/6 patients had complete clearance of CD22+ leukemia. Notably, in this cohort, 4/6 patients were found to have a drop in their CD22 ABC, between the time from first to second infusion, with a median drop in site density of 3,141 sites/cell (range: 703-6460) with 2 of the re-infusion non-responders having approximately 50% decrease in the ABC from the CAR pre-treatment value.Conclusion: Our preliminary experience with CAR re-infusions demonstrates that in the presence of preserved antigen expression, re-infusions can be effective, and that an intensified lymphodepletion regimen may optimize re-treatment response, both in patients with limited CAR expansion following a first infusion or with post-CAR relapse. Despite antigen positivity, decreased antigen density post-relapse may be one potential mechanism contributing to lack of CAR efficacy with second infusions, and higher level of antigen density may be needed to optimize anti-tumor response. Future directions will include incorporating an intensified lymphodepletion regimen for all second infusions and exploring methods to enhance antigen expression at the time of re-infusion. DisclosuresNo relevant conflicts of interest to declare.

Linkage of resistance-associated substitutions in GT1 sofosbuvir + NS5A inhibitor failures treated with glecaprevir/pibrentasvir

Retreatment with glecaprevir/pibrentasvir (G/P) resulted in a rate of sustained virologic response 12 weeks after treatment completion (SVR12) of >90% in HCV genotype 1 (GT1) patients who previously failed a regimen of sofosbuvir plus an NS5A inhibitor (NS5Ai). This study investigated the prevalence and impact of baseline NS3 and NS5A resistance-associated substitutions (RASs) on the efficacy of G/P in prior GT1 sofosbuvir+NS5Ai failures and the persistence of treatment-emergent RASs. Longitudinal samples from 177 patients enrolled in a phase IIIb, randomized pragmatic clinical trial were analyzed. Patients without cirrhosis were randomized to 12 or 16 weeks of G/P, and patients with compensated cirrhosis were randomized to G/P and ribavirin for 12 weeks or G/P for 16 weeks. Linkage of RAS was identified using Primer-ID next-generation sequencing at a 15% cut-off. Of 177 patients, 169 (95.5%) were PI-naïve. All 33 GT1b-infected patients achieved SVR12. In GT1a-infected patients, baseline NS5A RASs were prevalent (74.5%, 105/141) but NS3 RASs were uncommon. Baseline NS3 RASs had no impact on G/P efficacy and patients with baseline NS5A RASs showed a numerically but not statistically significantly lower SVR12 rate compared to those without NS5A RASs (89% vs. 97%). SVR12 was achieved in 34 of 35 (97%) patients without NS5A baseline substitution, and 53 of 57 (93%), 35 of 40 (88%), 5 of 8 (63%) with single, double-linked, and triple-linked NS5A substitutions, respectively. Among 13 patients with virologic failure, 4 acquired treatment-emergent NS3 RASs and 10 acquired NS5A RASs. Baseline NS5A RASs were highly prevalent. The presence of an increasing number of linked NS5A RASs in GT1a showed a trend in decreasing SVR12 rates, although no specific NS5A RASs or their linkage pattern were associated with lower SVR12 rates. Direct-acting antivirals have revolutionized the treatment of chronic hepatitis C infection, but treatment failure occurs in some patients. Retreatment of patients who previously failed a regimen consisting of sofosbuvir and an NS5A inhibitor with a regimen of glecaprevir and pibrentasvir (G/P) is >90% effective. Herein, we analyzed samples from these patients and showed that retreatment efficacy with G/P is lower in patients with double- or triple-linked NS5A resistance mutations than in patients with single or no NS5A resistance mutations. NCT03092375.

Efficacy and Safety of Tofacitinib Re-treatment for Ulcerative Colitis After Treatment Interruption: Results from the OCTAVE Clinical Trials.

Background and AimsTofacitinib is an oral, small molecule Janus kinase inhibitor for the treatment of ulcerative colitis. Here, we evaluate the efficacy and safety of tofacitinib re-treatment following treatment interruption in patients with ulcerative colitis.MethodsHere, patients with clinical response to tofacitinib 10 mg b.d. induction therapy were randomised to receive placebo in OCTAVE Sustain. Those experiencing treatment failure after Week 8 of OCTAVE Sustain entered OCTAVE Open and re-initiated tofacitinib 10 mg b.d. [re-treatment subpopulation]; efficacy and safety data are presented up to Month 36 of OCTAVE Open.ResultsMedian time to treatment failure following interruption was 169 (95% confidence interval [CI], 94.0–179.0) and 123 [95% CI, 91.0–168.0] days for induction remitters, and induction responders but non-remitters, respectively. Following re-treatment with tofacitinib, rates (non-responder imputation after a patient discontinued; latest observation carried forward imputation after a patient advanced to a subsequent study [NRI-LOCF]) of clinical response, remission, and endoscopic improvement were 74.0%, 39.0%, and 55.0% at Month 2, and 48.5%, 37.4%, and 42.4% at Month 36, respectively. Among induction remitters and induction responders but non-remitters, clinical response rates at Month 36 were 60.6% and 42.4% [NRI-LOCF], respectively. Efficacy was recaptured regardless of prior tumour necrosis factor inhibitor failure status. The safety profile of tofacitinib 10 mg b.d. re-treatment was consistent with the overall cohort and demonstrated no new safety risks associated with exposure of ≤36 months.ConclusionsMedian time to treatment failure was numerically higher in induction remitters versus induction responders but non-remitters. Following treatment interruption, efficacy was safely and successfully recaptured with tofacitinib 10 mg b.d. re-treatment in a substantial proportion of patients [ClinicalTrials.gov:NCT01458574;NCT01470612].

Infliximab discontinuation in patients with ulcerative colitis

Biologics have a central role in the treatment of moderate-to-severe ulcerative colitis. However, the question of the optimal clinical scenario and timing for therapy discontinuation has become very relevant. Therapy withdrawal would minimise potential infectious and neoplastic adverse events, and save costs and patients' time. 1 Lichtenstein GR Feagan BG Cohen RD et al. Serious infection and mortality in patients with Crohn's disease: more than 5 years of follow-up in the TREAT registry. Am J Gastroenterol. 2012; 107: 1409-1422 Crossref PubMed Scopus (545) Google Scholar , 2 Lemaitre M Kirchgesner J Rudnichi A et al. Association between use of thiopurines or tumor necrosis factor antagonists alone or in combination and risk of lymphoma in patients with inflammatory bowel disease. JAMA. 2017; 318: 1679-1686 Crossref PubMed Scopus (285) Google Scholar Nevertheless, previous research has shown that episodic, intermittent therapy with anti-tumour necrosis factor (anti-TNF) agents increases the risk of immunogenicity and therapy failure. 3 Rutgeerts P Diamond RH Bala M et al. Scheduled maintenance treatment with infliximab is superior to episodic treatment for the healing of mucosal ulceration associated with Crohn's disease. Gastrointest Endosc. 2006; 63: 433-442 Summary Full Text Full Text PDF PubMed Scopus (512) Google Scholar Discontinuation of infliximab in patients with ulcerative colitis in remission (HAYABUSA): a multicentre, open-label, randomised controlled trialMaintenance of remission was significantly more common in patients who continued infliximab than in those who discontinued. Discontinuing infliximab should therefore be discussed with caution, taking both risk of relapse and efficacy of re-treatment into account. Full-Text PDF

Discontinuation of infliximab in patients with ulcerative colitis in remission (HAYABUSA): a multicentre, open-label, randomised controlled trial

Anti-tumour necrosis factor (TNF) agents are the mainstay of long-term treatment for refractory ulcerative colitis. However, long-term use of anti-TNF therapy might lead to an increased risk of malignancy or infection. To date, no randomised controlled trial has evaluated whether anti-TNF agents can be safely discontinued in patients with ulcerative colitis in remission. We therefore aimed to compare outcomes in these patients who continued infliximab with those who discontinued infliximab. We did a multicentre, open-label randomised controlled trial at 24 specialist centres in Japan. We enrolled patients with ulcerative colitis who were in remission, had been treated with intravenous infliximab (5 mg/kg) every 8 weeks, and had started infliximab at least 14 weeks before study enrolment. No restrictions regarding age and comorbidities were used to exclude participation. Patients who were confirmed to be in remission for more than 6 months, to be corticosteroid-free, and to have a Mayo Endoscopic Subscore (MES) of 0 or 1 were centrally randomised. An independent organisation randomly assigned patients (1:1) into either the infliximab-continued group or infliximab-discontinued group, using a computer-generated stratified randomisation procedure. The stratified factors were the use of immunomodulators (yes or no) and MES (0 or 1). Neither patients nor health-care providers were masked to the randomisation. The primary endpoint was the remission rate at week 48 in the full analysis set, which was based on the intention-to-treat principle and excluded participants with no efficacy data after randomisation. This study was registered with the University Hospital Medical Information Network Center Trials registry, UMIN000012092. Between June 16, 2014, and July 28, 2017, 122 patients were eligible for screening and a total of 95 patients were randomly assigned to the infliximab-continued group (n=48) or the infliximab-discontinued group (n=47). 92 patients (n=46 for both groups) were included in the full analysis set. 37 (80·4% [95% CI 66·1-90·6]) of 46 patients in the infliximab-continued group and 25 (54·3% [39·0-69·1]) of 46 patients in the infliximab-discontinued group were in remission at week 48. The between-group difference was 26·1% (95% CI 7·7-44·5; p=0·0076) before adjustment and 27·3% (95% CI 8·0-44·1; p=0·0059) after adjustment for stratification factors. Eight (17%) of 48 patients in the infliximab-continued group and six (13%) of 47 in the infliximab-discontinued group developed adverse events (between-group difference 3·9% [95% CI -10·3 to 18·1]; p=0·59). In the infliximab-continued group, one patient had an infusion reaction and two patients had psoriatic skin lesions. Eight (66·7%, 95% CI 34·9-90·1) of the 12 patients in the infliximab-discontinuation group who were re-treated with infliximab after relapsing were in remission within 8 weeks of re-treatment; none had infusion reactions. Maintenance of remission was significantly more common in patients who continued infliximab than in those who discontinued. Discontinuing infliximab should therefore be discussed with caution, taking both risk of relapse and efficacy of re-treatment into account. Mitsubishi Tanabe Pharma Corporation and the Intractable Disease Project of the Ministry of Health, Labour and Welfare of Japan. For the Japanese translation of the abstract see Supplementary Materials section.