Subsequent Remission Research Articles

AB1147 SCREENED – HIGH REMISSION RATES UNDERLINE THE BENEFIT OF SCREENING CONSULTATION MODELS FOR EARLY RECOGNITION AND TREATMENT OF RHEUMATIC AND MUSCULOSKELETAL DISEASES

Background:Early recognition and treatment of rheumatic and musculoskeletal diseases (RMDs) is of critical importance for the individual outcome. However, nationwide health care structures in Germany do not facilitate early access to initial rheumatologic evaluation. Furthermore, waiting times of several months due to substantial capacity constrains in regional rheumatology care services compromise the prognostically relevant “window of opportunity” for subsequent sustained remission. To promote early detection of RMDs, the Division of Rheumatology at the University hospital Heidelberg, Germany has launched a unique screening consultation model that offers early access to rheumatologic evaluation on regional level.Objectives:The registry-based study SCREENED (“Screen for early diagnosis”) has been initiated to monitor the outcome of patients that were diagnosed with an RMD at the screening clinic and to assess the costs and benefits of this consultation model for the regional quality of care.Methods:The screening consultation model has been launched in two phases: in the first phase (02/2016 - 01/2018), a screening clinic open to all patients without previous rheumatologic evaluation with appointments according to the registration order has been established through rearrangement of available capacities. In contrast to regular appointments, the screening clinic took place in shorter consultation time frames and without additional diagnostic procedures. In the second phase (02/2018 - 01/2020), in order to manage and prioritize access to rheumatologic care at our division more efficiently, prior to appointment allocation (not only) to the screening clinic all new patient registrations became subject to a preselection procedure based on the evaluation of an anamnesis questionnaire, medical reports and laboratory findings by an experienced rheumatologist. Furthermore, SCREENED project has been launched for scientific evaluation of both phases of the consultation model.Results:The screening consultation model achieved a significant reduction in waiting times to few weeks compared to six months for a regular appointment. In the first phase, the screening clinic had a high sensitivity of 94.3% and an improvable specificity of 31.1%. In the retrospective cohort, high remission rates have been observed over all RMD entities (120/206 = 58.3% patients based on physicians’ assessment in the follow-up after screening clinic) and in rheumatoid arthritis (RA) in particular (38/61 = 62.3% and 33/55 = 60% patients with DAS28 score < 2,6 after 12 and 24 months respectively). Remission was usually reached within a year after the first appointment (9.5 ± 6.7 months), however, a trend to higher remission rates in patients with shorter illness duration was obvious. In RA patients, csDMARDs have been initiated in a third of patients immediately at diagnosis in the screening clinic and in another third within six months after the first appointment. After 12 months, > 80% have received csDMARDs, while only 14.2% needed b/tsDMARDs in the follow-up over 24 months.Conclusion:High sensitivity and significant reduction in waiting times for initial rheumatologic evaluation in the screening clinic pave the way for early recognition and treatment of RMDs. Subsequently, high remission rates in the follow-up were reached. In RA, a high proportion of patients only required csDMARDs to achieve sustained remission. A correspondingly small proportion of patients necessitating b/tsDMARD in the follow-up points towards a significant health economic benefit of the early rheumatologic intervention in the screening consultation model.Disclosure of Interests:Karolina Benesova Grant/research support from: Study grants for SCREENED study by Abbvie, Novartis and Rheumaliga Baden-Württemberg, Consultant of: One-time participation in Novartis advisory board., Vivienne Lion Grant/research support from: Grant/research support from: Study grants for SCREENED study by Abbvie, Novartis and Rheumaliga Baden-Württemberg, Oliver Hansen Grant/research support from: Grant/research support from: Study grants for SCREENED study by Abbvie, Novartis and Rheumaliga Baden-Württemberg, Hanns-Martin Lorenz Grant/research support from: Consultancy and/or speaker fees and/or travel reimbursements: Abbvie, MSD, BMS, Pfizer, Celgene, Medac, GSK, Roche, Chugai, Novartis, UCB, Janssen-Cilag, Astra-Zeneca, Lilly. Scientific support and/or educational seminars and/or clinical studies: Abbvie, MSD, BMS, Pfizer, Celgene, Medac, GSK, Roche, Chugai, Novartis, UCB, Janssen-Cilag, Astra-Zeneca, Lilly, Baxter, SOBI, Biogen, Actelion, Bayer Vital, Shire, Octapharm, Sanofi, Hexal, Mundipharm, Thermo Fisher., Consultant of: see above

Hormones as indicator of relapse-free period in breast cancer (BC).

e12550 Background: BC is still one of the main causes of death in women due to the tumor recurrence and/or resistance to anticancer therapy. The criteria to assess the effectiveness of BC treatment are important. The purpose of the study was to analyze blood levels of steroid and pituitary hormones in BC patients after two chemotherapy cycles. Methods: The study included 42 patients with various biological BC subtypes: luminal A, luminal B and triple-negative BC (TNBC). Levels of estradiol, testosterone, progesterone, prolactin, LH, FSH and cortisol were measured by RIA in the blood of all patients before and after two neoadjuvant chemotherapy cycles. Significance of differences was evaluated by the Student’s t-test. Results: Levels of many hormones were high before the treatment in patients with all BC subtypes. After two chemotherapy cycles, unidirectional changes in the values were found in patients with subsequent remission for more than three years. Levels of estradiol decreased in luminal A BC by 1.7 times (p˂0.05), in luminal B BC – by 11.6 times (p˂0.05), cortisol decreased by 2.4 and 1.7 times (p˂0.05) respectively, and prolactin – on average by three times (p˂0.05). LH levels increased in luminal A and luminal B BC by 1.65 times (p˂0.05). In patients with TNBC, levels of estradiol decreased by 1.8 times, and cortisol – by two times (p˂0.05). Patients with subsequent remission regardless of BC subtypes had unchanged levels of testosterone, progesterone and FSH. Patients with luminal B and TNBC subtypes with progression in 6-12 months did not show significant changes in prolactin and cortisol levels after two chemotherapy cycles, compared with the values before treatment. Conclusions: A decrease in blood levels of prolactin and cortisol after two chemotherapy cycles is an indicator of a long-term remission in patients with breast cancer.

Predicting antidepressant response through early improvement of individual symptoms of depression incorporating baseline characteristics of patients: An individual patient data meta-analysis

Overall early improvement in depression after commencement of antidepressant treatment could be associated with subsequent response or remission, but its predictive ability is not adequate. We aimed to investigate whether early improvement of individual depressive symptoms and important baseline characteristics of patients including the number of previous depressive episodes and the duration of index episode, better predicts response or remission. We requested pharmaceutical companies in Japan for individual patient data from randomized placebo-controlled trials focusing on the efficacy of second-generation antidepressants. Primary and secondary outcomes were response and remission at week 6, respectively. We compared models that only included improvement in the overall depression severity at week 2 with models that also included improvement in individual symptoms and baseline characteristics, by conducting an individual patient data meta-analysis. We obtained data from three trials comprising 997 participants. For the response outcome, the model incorporating individual symptoms and baseline characteristics demonstrated better predictive values than those in the model including early improvement in overall depression only. However, the area under the receiver operating characteristic curve, and positive and negative predictive values were 0.65, 0.70, and 0.64, respectively, suggesting that 30% and 36% of the participants still had false-negative and false-positive predictions, respectively. For the remission outcome, the corresponding values in the latter model were 0.72, 0.62, and 0.68, respectively. We suggest that clinical judgement on early discontinuation of antidepressant from non-early improvement at week 2 should be carefully made.

Day 14 Bone Marrow Evaluation During Acute Myeloid Leukemia Induction in a Real-world Canadian Cohort

IntroductionThe 2017 National Comprehensive Cancer Network guidelines for acute myeloid leukemia have recommended performing bone marrow (BM) aspiration and BM trephine biopsy (BMTB) 14 to 21 days after starting induction therapy (commonly referred to as “day 14 [D14] marrow”). Those who do not achieve a hypoplastic marrow, with cellularity < 20% and blasts < 5%, are recommended to undergo 2-cycle induction (2CI). We performed a retrospective analysis to determine the impact of D14 BM characteristics in predicting for remission, association with overall survival (OS), and the effect of 2CI according to the D14 BM results. Patients and MethodsPatients aged 18 to 70 years undergoing induction therapy with standard “7 + 3” regimens were included. D14 cellularity was determined from BMTB samples and the blast percentage was assessed by morphology on BM aspiration and BMTB samples. The outcomes evaluated included the rates of complete remission (CR) and OS. ResultsA total of 486 patients with results from D14 BM evaluation were included in the present study. On multivariate analysis, cytogenetic risk and D14 blasts < 5% were predictive of CR/CR with incomplete count recovery (P < .001). Cytogenetic risk (P < .001), age < 60 years (P = .001), and D14 blasts < 5% (P = .045) predicted for OS. 2CI was performed in 131 patients (27%). Patients with hypocellular D14 BM but residual blasts (n = 106) underwent 2CI in 46% of cases, with improved remission rates (43.9% vs. 72.0%; P = .004) but no difference in OS. ConclusionsThe results from D14 BM evaluations are predictive of subsequent remission and OS. Our findings did not show a survival benefit with D14 BM-driven 2CI.

Association of Changes in Physical Activity and Incidence and Remission of Overall and Abdominal Obesity in 113,950 Adults.

This study examined the dose-response relationship between changes in physical activity (PA) and subsequent incidence or remission of overall and abdominal obesity. A total of 113,950 healthy individuals aged ≥ 18 years participating in the Taiwan MJ Cohort were included. Two-year changes in PA between the first and second examination were linked to subsequent development and remission of overall and abdominal obesity. During a mean 5.6-year follow-up after the second examination, 9,991 and 11,488 individuals developed overall and abdominal obesity, respectively; also, 3,588 and 3,156 participants with obesity lost sufficient weight or reduced their waist circumference to be classified as nonobese. Compared with no changes in PA, the multivariable hazard ratio (95% CI) of overall obesity was 0.95 (0.90-1.00) for a PA increase of 0.01 to 3.74 metabolic equivalent hours (MET-h)perweek and 0.86 (0.80-0.91) for a PA increase of ≥ 3.75 MET-hperweek. Corresponding values for remission of obesity were 1.00 (0.91-1.09) and 1.16 (1.05-1.28). Similar results were observed for the development and remission of abdominal obesity. Any decrease in PA was not associated with the risk of obesity outcomes when compared with a stable pattern (0 MET-h/week). Increasing PA was consistently associated with a progressively lower incidence and higher remission of overall and abdominal obesity.

Outcome of children relapsing after first allogeneic haematopoietic stem cell transplantation for acute myeloid leukaemia: a retrospective I-BFM analysis of 333 children.

Outcome of 333 children with acute myeloid leukaemia relapsing after a first allogeneic haematopoietic stem cell transplantation was analyzed. Four-year probability of overall survival (4y-pOS) was 14%. 4y-pOS for 122 children receiving a second haematopoietic stem cell transplantation was 31% and 3% for those that did not (P=<0·0001). Achievement of a subsequent remission impacted survival (P=<0·0001). For patients receiving a second transplant survival with or without achieving a subsequent remission was comparable. Graft source (bone marrow vs. peripheral blood stem cells, P=0·046) and donor choice (matched family vs. matched unrelated donor, P=0·029) positively impacted survival after relapse. Disease recurrence and non-relapse mortality at fouryears reached 45% and 22%.

Role of Blinatumomab in Minimal Residual Disease and Hematologic Relapsed/Refractory Adult Acute Lymphoblastic Leukemia Patients Treated over 5 Years. a Single Center Experience

Role of Blinatumomab in Minimal Residual Disease and Hematologic Relapsed/Refractory Adult Acute Lymphoblastic Leukemia Patients Treated over 5 Years. a Single Center Experience

AML: Negative Prognostic Impact of Early Blast Persistence Can be Overcome By Subsequent Remission Induction

Introduction: In acute myeloid leukemia [AML] intensive treatment usually includes an interim bone marrow assessment in the context of the first induction chemotherapy cycle. Early blast clearance has been shown to predict for achievement of a complete remission [CR], which makes the interim bone marrow result a widely used additive for further therapy decision making. However, there is an ongoing debate on the prognostic role of early blast clearance (day 14 - 21) and consistent clarification of this issue is still lacking. Here, we provide monocentric data from a large intensively treated AML cohort addressing the prognostic impact of early remission status on long-term survival. Methods: Data of 1008 intensively treated AML patients who were diagnosed between 2000 and 2017 and aged between 18 and 86 years were retrieved from our local AML database. Evaluation of bone marrow aspirates and / or biopsies was conducted by cytologic, flow cytometric and histopathological methods. Remission status was determined in accordance with the European-Leukemia Net [ELN] criteria of 2017. Patients were grouped according to their remission status after induction 1 (day 14 - 21) and prior to further therapy (chemotherapy and / or allogeneic hematopoietic stem cell transplantation [HSCT]). Baseline characteristics of the two groups such as age, cytogenetic / molecular risk according to ELN 2010, performance score according to Eastern Cooperative Oncology Group [ECOG] and Charlson Comorbidity Index [CCI] were compared using chi-square test and Kruskal-Wallis H test followed by post-hoc testing. Overall- and relapse-free-survival [OS, RFS] were analyzed using Kaplan-Meier- and Cox regression models. Results: In 57 % (n = 572) of the entire cohort, complete / incomplete remission [CR / CRi] or at least morphologic leukemia free state [MLFS] were observed after the first cycle of induction therapy. Partial response [PR] was found in 19 % (n = 196) and persistent disease [PD] in 24 % (n = 240) of all patients. The three different groups (CR / CRi / MLFS vs. PR vs. PD) did not significantly differ in age, ECOG-score or CCI, but - as expected - substantially with regard to ELN risk classification. Of the entire cohort, 62 % (n = 626) received a double induction, 61 % (n = 617) consolidation chemotherapy and 47 % (n = 477) allogeneic HSCT as a part of first-line therapy. Prior to HSCT, 85 % (n = 406) of the patients were in first CR / CRi / MLFS. Amongst these 406 patients, 51 % (n = 243) had only achieved PR / PD in early bone marrow puncture on day 14 - 21 of induction therapy. 71 % of these patients (n = 173) were converted into CR / CRi / MLFS prior to HSCT by additional chemotherapy. Within the non-transplanted group, 58 of 130 patients (44 % with initial PR / PD) achieved CR / CRi / MLFS after an additional cycle of induction chemotherapy. Early blast persistence and refractory disease were generally associated with inferior OS as compared with blast clearance (p &amp;lt; 0.001). Interestingly, early PR lost its negative prognostic impact on survival after conversion into CR / CRi / MLFS by additional therapy prior to post-induction therapy. This could particularly be observed in patients undergoing HSCT, but also in non-transplanted patients receiving a second cycle of induction therapy. In patients without allogeneic HSCT, early PR with blast clearance beyond induction 1 resulted in impaired RFS (p = 0.045) but not OS, possibly due to the influence of subsequent salvage therapy. Early PD remained prognostically unfavorable for OS and RFS in both transplanted and non-transplanted patients even after subsequent conversion into CR / CRi / MLFS (p = 0.002 and p = 0.021). Conclusion: Our results show that the achievement of CR / CRi / MLFS prior to post-remission therapy overrides the negative impact of an early partial response on OS, irrespective of the favorable prognostic impact that early blast clearance generally has on OS. With regard to OS, our results suggest a predominant role of the final remission quality after induction therapy. However, the adverse impact of achieving no response at interim bone marrow assessment can apparently not be attenuated by a later remission induction. On the assumption that the final depth of remission after induction therapy is predictive for OS, MRD-guided decision making prior to consolidation treatment might further improve first-line AML therapy, particularly in the intermediate ELN risk group. Disclosures Bullinger: Abbvie: Honoraria; Pfizer: Honoraria; Novartis: Honoraria; Menarini: Honoraria; Janssen: Honoraria; Hexal: Honoraria; Gilead: Honoraria; Daiichi Sankyo: Honoraria; Celgene: Honoraria; Bristol-Myers Squibb: Honoraria; Astellas: Honoraria; Amgen: Honoraria; Bayer: Other: Financing of scientific research; Seattle Genetics: Honoraria; Sanofi: Honoraria; Jazz Pharmaceuticals: Honoraria.

Early Management of CML.

The marked improvement in clinical outcomes for patients with chronic myeloid leukaemia (CML) can be solely attributed to the introduction of targeted therapies against the fusion oncoprotein, BCR-ABL1. However, patient responses, although generally positive, remain heterogenous. Careful drug selection, ensuring the optimal TKI, is chosen for each patient and involves a complex decision process which incorporates consideration of numerous factors. For some patients, with disease characteristics that indicate adverse intrinsic disease biology, more potent BCR-ABL1 inhibition is often appropriate, whereas other patients with major co-morbidities will benefit from a less aggressive approach to avoid life-shortening toxicities. For the vast majority of patients, the long-term goal of therapy will be the achievement of a deep molecular response and subsequent treatment-free remission and this consideration will play a large part in the drug selection process. We explore early management of CML, from the first presentation through to frontline therapy selection.

642 Effects of Ustekinumab Maintenance Therapy on Endoscopic Improvement and Histologic Improvement in the UNIFI Phase 3 Study in Ulcerative Colitis

INTRODUCTION: Ustekinumab (UST) is an effective therapy for moderate-to-severe ulcerative colitis (UC), but its effects on mucosal healing (endoscopic improvement + histologic improvement) during maintenance treatment are unknown. METHODS: We evaluated the effects of maintenance UST on histologic and endoscopic activity in the UNIFI Phase 3 study of UST in moderate-to-severe UC (n = 961). Pts in response 8 weeks after receiving intravenous UST were randomized to receive maintenance treatment with subcutaneous (SC) placebo or UST 90 mg every 8 (q8w) or 12 weeks (q12w). Two colonic biopsies were collected from the distal colon at screening and Weeks 0 and 44 of maintenance. Endoscopic improvement (EI) was defined as a Mayo endoscopy subscore &lt;1; histologic improvement (HI) comprised the following Geboes score-based criteria: absence of erosions or ulcerations, absence of crypt destruction, and &lt;5% of crypts with neutrophil infiltration. To encompass both macro- and microscopic scales, histo-endoscopic mucosal healing (MH) was defined as achieving both EI and HI. RESULTS: At maintenance Week 44, EI was achieved in 28.6%, 43.6%, and 51.1% of pts treated with placebo, UST q12w (P = 0.002 vs placebo), and UST q8w (P &lt; 0.001), respectively. HI was achieved at Week 44 in 32.9%, 54.0%, and 59.3% of pts treated with placebo, UST q12w, and UST q8w, respectively (P &lt; 0.001 for both q12w and q8w). MH was achieved at Week 44 in 24.1%, 38.8%, and 45.9% of pts treated with placebo, UST q12w (P = 0.002), and UST q8w (P 0.001), respectively. HI at Week 44 (irrespective of maintenance treatment) was significantly associated with EI and MH (P &lt; 0.001) and with both lower absolute levels and larger post-treatment changes in total Mayo score, partial Mayo score, and Mayo symptom sub-scores for stool frequency and rectal bleeding at Week 44. Both EI and HI following 8 weeks of UST treatment were associated with clinical remission and steroid-free clinical remission at Week 44 (P &lt; 0.05), as well as remission through Week 44 (i.e., at both Week 8 and Week 44). For example, 26% of pts with induction HI were in clinical remission through Week 44, versus 4% of pts without induction HI. Induction MH was similarly associated with positive outcomes at maintenance Week 44. CONCLUSION: Among pts with moderately-to-severely active UC, those receiving SC UST maintenance had higher rates of EI, HI, and MH than those receiving placebo. Both EI and HI are associated with subsequent clinical remission and steroid-free clinical remission.

831 Serum Biomarkers Are Associated With Endoscopic and Clinical Outcomes in Crohn’s Disease Patients Receiving Vedolizumab Therapy

INTRODUCTION: Vedolizumab is a selective monoclonal antibody directed against a4b7 integrin on lymphocytes and is safe and effective for the induction and maintenance of remission in Crohn’s disease. Serum biomarkers are needed to help guide therapy and predict patient outcomes. This study evaluated biomarker concentrations and patient outcomes during vedolizumab treatment. METHODS: Serum was collected from patients with Crohn’s disease receiving vedolizumab infusions at weeks 0, 2, 6, 14 and ≥26. Biomarkers including soluble(s)-a4b7, s-vascular cell adhesion molecule (VCAM)-1, s-intracellular adhesion molecule (ICAM)-1, and s-mucosal addressin cell adhesion molecule (MAdCAM)-1 were measured and evaluated as surrogate markers associated with clinical and endoscopic outcomes. Statistical analysis was performed using the Mann-Whitney U test for continuous data. RESULTS: Twenty-two patients with Crohn’s disease were included (Table 1). In all patients, s-MAdCAM significantly decreased over time as compared to baseline, and s-a4b7 increased compared to baseline (Figure 1). Overall, s-ICAM1 and s-VCAM1 did not change significantly over time in the entire cohort, however, differentially changed in patients with remission. At week 2, median concentrations of s-ICAM1 were higher in patients with compared to those without clinical remission: 675.1 ng/mL vs. 270.1 ng/mL, respectively (P = 0.046). At week 6, median s-ICAM1 concentrations were higher in patients with compared to without endoscopic remission: 545.7 ng/mL vs. 286.2 ng/mL, respectively (P = 0.027) and clinical remission: 669.1 ng/mL vs. 291 ng/mL, respectively (P = 0.034). At week 6, median s-VCAM1 concentrations were higher in patients with compared to without endoscopic remission: 859.6 vs. 460.31, respectively (P = 0.027) and numerically higher in patients with clinical remission: 859.6 ng/mL vs. 460.6 ng/mL, respectively (P = 0.1). At week 26, there was no difference in median s-VCAM1 or s-ICAM1 concentrations between remitters vs. non-remitters (Table 2). CONCLUSION: Higher concentrations of s-ICAM-1 and s-VCAM-1 early in treatment with vedolizumab may be predictive of subsequent remission in patients with Crohn’s disease. During maintenance, there was no association between serum biomarkers and endoscopic or clinical outcomes. These findings may help predict early patient response to treatment with vedolizumab in Crohn’s disease but will require further validation.

Haploidentical transplant in adult patients with acute lymphoblastic leukemia in Argentina: a comparison with matched related and unrelated donors.

We aimed at analyzing the outcome of allogeneic stem cell transplant (ASCT) in adult patients with acute lymphoblastic leukemia (ALL), comparing Haploidentical (Haplo) with HLA-matched (sibling and unrelated) donors. Between 2008 and 2017, we collected data from 236 patients (median age 31 years; range 16-64; 90% HCT-CI 0-1) who underwent unmanipulated ASCT in first complete remission and subsequent remissions in 15 Argentinian centers. Donors were HLA-matched (n = 175; 74%) and Haplo (n = 61; 26%). Two-year overall survival (OS) was 55% (95% CI 47-63) for the HLA-matched group and 49% (95% CI 34-62) for the Haplo group (p = 0.351). For OS, crude HR, adjusted HR for covariates (HR 1.24; 95% CI 0.77-1.99; p = 0.363) and HR including a propensity score in the model (HR 1.22; 95% CI 0.71-2.08; p = 0.414) showed no impact of donor category on the OS. No difference was found in terms of nonrelapse mortality, relapse, leukemia-free survival, and grade 3-4 acute graft-versus-host disease (GVHD); 2-year incidence of chronic GVHD was higher in HLA-matched vs Haplo group (p = 0.028). Patients with ALL who underwent ASCT were young subjects with low HCT-CI. In this setting, a Haplo donor represents an alternative widely available in the absence of an HLA-matched donor. Relapse remains a challenge for all donor categories.

Integration of complementary biomarkers in patients with first episode psychosis: research protocol of a prospective follow up study.

In this project, we recruited a sample of 150 patients with first episode of psychosis with schizophrenia features (FEP) and 100 healthy controls. We assessed the differences between these two groups, as well as the changes between the acute phase of illness and subsequent remission among patients over 18-month longitudinal follow-up. The assessments were divided into four work packages (WP): WP1- psychopathological status, neurocognitive functioning and emotional recognition; WP2- stress response measured by saliva cortisol during a stress paradigm; cerebral blood perfusion in the resting state (with single photon emission computed tomography (SPECT) and during activation paradigm (with Transcranial Ultrasonography Doppler (TCD); WP3-post mortem analysis in histologically prepared human cortical tissue of post mortem samples of subjects with schizophrenia in the region that synaptic alteration was suggested by WP1 and WP2; WP4- pharmacogenetic analysis (single gene polymorphisms and genome wide association study (GWAS). We expect that the analysis of these data will identify a set of markers that differentiate healthy controls from patients with FEP, and serve as an additional diagnostic tool in the first episode of psychosis, and prediction tool which can be then used to help tailoring individualized treatment options. In this paper, we describe the project protocol including aims and methods and provide a brief description of planned post mortem studies and pharmacogenetic analysis.

Abstract 1552: A novel PD1-IL2v immunocytokine for preferential cis-activation of IL-2R signaling on PD-1 expressing T cell subsets strongly potentiates anti-tumor T cell activity of PD-1 checkpoint inhibition and IL-2R-beta-gamma agonism

Abstract High-dose IL-2 is approved for patients with metastatic melanoma and renal cell cancer, but is associated with significant toxicity. We have described tumor-targeted CEA-IL2v and FAP-IL2v immunocytokines that are based on an engineered IL2v moiety with abolished binding to IL-2Ra (CD25) to avoid undesired CD25-mediated toxicities and Treg expansion. Their antibodies bind with high affinity to either CEA or FAP, which are broadly expressed in various tumors, and mediate retention/accumulation in malignant lesions. In an effort to further maximize the potency of IL-2R activation of T cells (aka signal 3) without the side effects of wildtype IL-2, we have generated PD1-IL2v that binds to the checkpoint inhibitor PD-1 and delivers IL2v preferentially in cis to PD-1+ T cells substituting binding to CD25. This enables high affinity IL2R signaling selectively in recently primed antigen specific TILs and stem-cell like subsets. Binding/competition experiments demonstrated that PD1-IL2v is 50-fold more potent than FAP-IL2v in inducing p-STAT5 in PD-1 positive T cells, whereas it has equivalent potency on PD-1 negative T cells. Notably, although Tregs can express low constitutive levels of PD-1, PD1-IL2v shows preferential binding to Teff vs. Tregs. Furthermore, PD1-IL2v can overcome Treg suppression of Tconv effector cells to a greater extent than PD-1, FAP-IL2v or their combination. For use in syngeneic mouse models muPD1-IL2v was generated. In an orthotopic pancreatic Panc02-Luciferase model administration of muPD1-IL2v (1 mg/kg IV, qw) resulted in rapid and complete elimination of tumor cells (loss of luciferase signal) and in long term survival (&amp;gt; 140 days) in 7/7 treated animals with protection from tumor cell re-challenge, whereas only 1/7 animals in the muPD-1 + muFAP-IL2v combination group (10 mg/kg + 2.5 mg/kg IV, qw) and none of the animals treated with the respective monotherapies showed long term survival. IHC showed that the improved outcome with muPD1-IL2v was related to a strong intra-tumoral increase of CD3+ CD8+ T cells expressing PD-1 and GrzB. In an immuno-PD study with s.c. Panc02 tumors muPD1-IL2v strongly increased the number of IFNg+ TNFa+ multifunctional and cytotoxic GrzB+ PD-1+ T cells in the tumor accompanied with a 20-fold increase in CD8/CD4 ratio and a strong increase in the CD8+ TEM population resulting in subsequent tumor control or remission in 50% of the animals, respectively. In summary, our data demonstrate that preferential cis-targeting of IL2v to PD-1+ antigen specific T cells with PD1-IL2v results in a strong potentiation of T cell response and anti-tumor efficacy as compared to the combination of PD-1 checkpoint inhibition with FAP-IL2v. These preclinical data establish PD1-IL2v as a promising next generation IL-2 for cancer immunotherapy. Citation Format: Christian Klein, Laura Codarri-Deak, Valeria Nicolini, Stefan Seeber, Laura Lauener, Marine Richard, Esther Bommer, Maria Karagianni, Johannes Sam, Ramona Schlenker, Marisa Mariani, Petra Petra Schwalie, Sylvia Herter, Marina Bacac, Inja Waldhauer, Anne Freimoser-Grundschober, Volker Teichgraeber, Pablo Umana. A novel PD1-IL2v immunocytokine for preferential cis-activation of IL-2R signaling on PD-1 expressing T cell subsets strongly potentiates anti-tumor T cell activity of PD-1 checkpoint inhibition and IL-2R-beta-gamma agonism [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1552.

MON-037 A RARE CASE: FAMILIAL MULTICENTRIC OSTEOLYSIS WITH NEPHROPATHY TREATED WITH TACROLIMUS

Multicentric Carpo-Tarsal Osteolysis is an extremely rare genetic condition with variable inheritance. It is typically associated with progressive osteolysis and bone destruction. Five forms have been described in the literature, with varying nephropathy. We present a case of familial multicentric osteolysis, but with variable inheritance of the nephropathy. The patient (male) originally presented to the hospital aged 16 months with swelling and reduced function of his wrists. Ultrasound showed half of his carpal bones to be missing. His older brother had presented later in childhood with a similar bony phenotype. However, his older brother has none of the nephropathy phenotype. Both parents and his non-identical twin were unaffected. Our patient then presented to the nephrology service aged 3yrs with hypertension; 122/82mmHg (above the 99thcentile for age and height), mild peri-orbital edema, mild hypoalbuminemia (32 g/L) and significant albuminuria (316 mg/mmol). He was initially started on amlodipine to control his hypertension. His blood pressure improved, but his proteinuria persisted, and he was referred for a renal biopsy. His histology showed a complex mixed picture. Light microscopy showed focal segmental glomerulosclerosis (FSGS), with a number of poorly formed/atubular glomeruli. Immunofluorescence showed an immune complex glomerulonephritis. Electron microscopy showed highly abnormal glomerular basement membrane structure. The conclusion was an inherited glomerular basement membrane abnormality with superimposed immune-mediated glomerular disease, resembling membranous nephropathy. All other investigations, including autoimmune screen and renal ultrasound were normal. Following the biopsy, and with ongoing proteinuria, amlodipine was switched to enalapril. During this time, genetic testing demonstrated a pathogenic heterozygous mutation c.176C>Tp. (Pro59Leu) on the MAFB gene. The MAFB gene encodes for a basic leucine zipper transcription factor and is associated with multicentric osteolysis nephropathy and Duane retraction syndrome 3 (with or without deafness). Despite an increasing enalapril dose, his albuminuria persisted, ranging from 74.6 – 170.7 mg/mmol. His creatinine remained normal throughout, ranging from 27 – 38 ummol/L. One previous case described in the literature, used ciclosporin to successfully reduce the proteinuria, so it was decided to add tacrolimus. This reduced albuminuria to 49.3 mg/mmol within a month and increased serum albumin to 39 g/L. Within 6 months his urine dip was negative. Following a successful year of tacrolimus therapy, a trial off treatment was commenced. Within a month his albuminuria had increased to 105.1 mg/mmol, tacrolimus was re-introduced, and subsequent remission quickly achieved. To our knowledge this is only the second case in the literature of a calcineurin inhibitor being used successfully for this indication. We present a rare case of familial multicentric osteolysis which has had variable phenotypic penetrance within the same family. Our patient had a mixed biopsy picture and significant albuminuria which has been successfully treated with tacrolimus.

Novel approach to an early assessment of a patient’s potential for neurological remission after acute spinal cord injury: Analysis of hemoglobin concentration dynamics

Context/objective: Examining hemoglobin (Hb) dynamics with regard to the potential of neurological remission in patients with traumatic spinal cord injury (TSCI). Design: Prospective Clinical Observational Study. Setting: BG Trauma Centre Ludwigshafen, Department of Paraplegiology, Rhineland-Palatinate, Germany. Methods: From 2011 to 2017 a total of 80 patients with acute spinal injury were enrolled and divided into three groups: initial neurological impairment either with (G1; n = 33) or without subsequent neurological remission (G0; n = 35) and vertebral fractures without initial neurological impairment as control group (C; n = 12). Blood samples were taken for 3 months at 11 time-points after injury. Analyses were performed using routine diagnostics. Outcome measures: Multiple logistic regression was used to determine the prognostic value of Hb regarding neurological remission respecting clinical covariates. Results: Data showed elevated mean Hb concentrations in G1 from the third day to 1 month compared to G0, Hb levels were significantly higher in G1 after 3 days (P = 0.03, G1 > G0). The final multiple logistic regression model based on this data predicting the presence of neurological remission resulted in an AUC (area under the curve) of 80.5% (CI: 67.8%–93.2%) in the ROC (receiver operating characteristic) analysis. Conclusion: Elevated Hb concentrations are associated with a higher likelihood of neurological remission. Elevated concentrations of Hb in G1 compared to G0 over time might be linked to both a better initial oxygen supply response and a decreased ECM (extracellular matrix) degradation highlighting the role of Hb as a valuable biomarker for neural regeneration after TSCI.

Allogeneic hematopoietic cell transplantation for patients with a history of multiple relapses of acute myeloid leukemia.

The prognosis of patients with acute myeloid leukemia (AML) is dismal after experiencing multiple relapses. This study retrospectively analyzed outcomes of allogeneic hematopoietic cell transplantation (HCT) for 192 adults with AML in third or subsequent complete remission (CR3+), 300 in second relapse (REL2), and 50 in third or subsequent relapse (REL3+) who were enrolled in a Japanese nationwide transplantation registry. The study population included patients undergoing umbilical cord blood transplantation, but not those undergoing haploidentical HCT. Patients transplanted in CR3+ had better survival than those transplanted in REL2 and REL3+ (48%, 21%, and 12% at 4years; P < 0.001), and this was due to a reduction in post-transplant relapse (23%, 57%, and 52%; P < 0.001). The corresponding cumulative incidence of non-relapse mortality was 33%, 26%, and 36% (P = 0.022). Multivariate analysis revealed significantly lower relapse and overall mortality for those in CR3+ and significantly lower non-relapse mortality for those in REL2. Hazard ratios (95% confidence intervals) for overall mortality were 2.02 (1.56-2.64) for REL2+ versus CR3+ (P < 0.001) and 2.12 (1.40-3.19) for REL3+ versus CR3+ (P < 0.001). Our analysis demonstrates the curative potential of allogeneic HCT for patients with a history of multiple AML relapses and suggests the potential benefits and risks of reinduction attempt before transplantation, highlighting the need for an individualized approach in determining whether to give reinduction therapy in this setting.

OUTCOME OF PATIENTS WITH AGGRESSIVE B‐CELL LYMPHOMA WHO FAILED TO PROCEED TO OR RELAPSED AFTER HIGH DOSE CHEMOTHERAPY AND AUTOLOGOUS HEMATOPOIETIC CELL TRANSPLANTATION

Background: Patients with high-risk or relapsed aggressive lymphoma are usually treated with high dose chemotherapy (HDT) and autologous hematopoietic cell transplantation (auto-HCT). Aim: We evaluated patients who were referred to auto-HCT and who failed to proceed to or relapsed after auto-HCT. Methods: We evaluated data from 101 consecutive patients with aggressive B-cell lymphoma: DLBCL (n= 86) and PMBL (n=15), who were planned for HDT and auto-HCT at our institution between 2012 and 2017 including 45 female and 56 male, median age (range) of 49 (20-69), clinical stage III/IV in 85 (85%) pts. Results: After first-line treatment, CR and PR was achieved in 51 (50%) and 43 (43%), respectively. Twenty three patients (23%) were not eligible for transplant: 7 pts failed stem cell mobilization, and 16 patients progressed before transplantation. 78 pts underwent HDT and auto-HCT: 21 pts in the first remission, and 57 pts after a median of 2 (2-4) lines of treatment. At transplant, 46 (60%) and 31 (40%) patients were in CR, and PR, respectively. Relapse after transplant occurred in 30 (38%) patients including 6 pts in first remission and 24 pts in subsequent remission (p=0.24), and 12 (26%) pts in CR and 18 (58%) in PR (56%) (p=0.003). The HR for progression in pts with response less than CR was 2.89 (95%CI: 1.51, 6.66) compared to pts with CR at transplant. With a median (range) PFS of 20 months (0-79), 1-year PFS was 66% (95%CI: 56%, 76%). Median (range) PFS for patients who relapsed post-transplant was 3 (0-40) months. With a median (range) follow up of 21 (0-79) months, 1- year OS for all transplanted patients was 69% (95%CI: 59%, 79%). Median (range) OS for pts who relapsed after auto-HCT was 6 (0-40) months.Conclusion: Around 20% of patients with high-risk or relapsed aggressive B-cell lymphoma were not able to proceed to HDT/auto-HCT, and around 40% of those who did, progressed after transplantation. Non-CR at transplant increased the risk of progression after transplantation. Taken together, 60% of patients with aggressive B-cell lymphoma referred to HDT/auto-HCT at our institution might be candidates for novel therapies. Keywords: diffuse large B-cell lymphoma (DLBCL); high-dose therapy (HDT). Disclosures: Romejko-Jarosinska, J: Honoraria: Roche, Takeda; Other Remuneration: Travel grant- Takeda, Servier. Paszkiewicz-Kozik, E: Honoraria: Roche, Takeda; Other Remuneration: Travel grant- Roche. Popławska, L: Other Remuneration: Travel grant- Roche. Targonski, L: Other Remuneration: Travel grant- Roche, Celgena. Szymanski, M: Other Remuneration: Travel grant- Roche. Walewski, J: Consultant Advisory Role: Roche, Celgene, Takeda, Janssen-Cilag, Servier, Amgen, Incyte Abbvie; Honoraria: Roche, Takeda, Celgene Janssen Cilag, Servier; Research Funding: Roche, GSK/Novartis, Takeda Janssen Cilag; Other Remuneration: Travel grant- Roche.

S1619 BLINATUMOMAB FOR MINIMAL RESIDUAL DISEASE (MRD) IN ADULTS WITH BCELL PRECURSOR ACUTE LYMPHOBLASTIC LEUKEMIA (BCPALL): MEDIAN OVERALL SURVIVAL (OS) NOT REACHED AT 5 YEARS FOR COMPLETE MRD RESPONDERS

Background: MRD is the strongest predictor of relapse in BCP-ALL. Blinatumomab is a bispecific immunotherapy that redirects T cells to kill CD19+ target cells. In a single-arm study (BLAST; NCT01207388) in adults with BCP-ALL and MRD, we previously reported that 78% (88/113) of patients achieved a complete MRD response after cycle 1 of blinatumomab. Patient incidences of grade 3 or 4 adverse events, including neurologic events (13%) or cytokine release syndrome (2%), were consistent with previous blinatumomab studies. Aims: This report describes the final analysis of OS for adults with BCP-ALL and MRD in the BLAST study, with a minimum patient follow-up of 5 years after blinatumomab treatment. Methods: The BLAST study enrolled adults with BCP-ALL in first (CR1) or subsequent (CR2+) hematologic complete remission after ≥3 intensive chemotherapy blocks, with MRD (≥10−3) at least 2 weeks after the last chemotherapy. All patients received blinatumomab 15 μg/m2per day for up to 4 cycles. Each cycle was 4 weeks of continuous infusion and 2 weeks off. Complete MRD response was defined as no target amplification, with a minimum sensitivity of 10−4. After MRD response assessment (end of cycle 1), patients could undergo allogeneic hematopoietic stem cell transplantation (HSCT) at any time. Kaplan-Meier estimates of OS were determined after long-term follow-up (5 years). A conditional landmark of 45 days (the end of cycle 1) was used for subgroup analyses by complete MRD response. Results: Of 116 patients with MRD who received blinatumomab, OS was evaluated for 110 patients with Philadelphia chromosome–negative (Ph−) BCP-ALL and < 5% blasts at enrollment, including 74 who received HSCT in continuous complete remission (CCR) after blinatumomab. With a median follow-up of 59.8 months, median OS was 36.5 months (95% CI: 22.0-not estimable [NE]). At 5 years, outcomes with vs without HSCT in CCR were as follows: alive without relapse, 40.5% vs 19.4%; relapse, 23.0% vs 72.2%; and death without relapse, 36.5% vs 8.3%. Analyses of OS by complete MRD response in cycle 1 (n = 107) excluded patients with no central MRD assay (n = 1) or inadequate MRD test sensitivity (n = 2). Median OS was not reached (95% CI: 29.5 months-NE) for complete MRD responders (n = 84) and 14.4 months (95% CI: 3.8–32.3) for MRD nonresponders (n = 23; log-rank p = 0.002; Figure 1). Estimated 5-year survival was 43% overall (95% CI: 34%>52%) and 50% for complete MRD responders (95% CI: 39%>60%). Among HSCT recipients in CCR, median OS from HSCT was not reached (95% CI: 25.7 months-NE) for complete MRD responders (n = 61) and 16.5 months (95% CI: 1.1-NE) for MRD nonresponders (n = 10; log-rank p = 0.065). Among patients with MRD in CR1, median OS was not reached (95% CI: 29.5 months-NE) for complete MRD responders (n = 60) and 10.6 months (95% CI: 2.7–39.7) for MRD nonresponders (n = 13; p = 0.008).Summary/Conclusion: In the final, 5-year follow-up analysis of a multinational study of adults with BCP-ALL in hematologic complete remission with MRD, median OS was 36.5 months after blinatumomab treatment. Median OS was not reached among patients with a complete MRD response in cycle 1 of blinatumomab treatment. These results provide further support for long-term OS benefits associated with blinatumomab treatment in adults with BCP-ALL and MRD.

HAP1 loss confers l-asparaginase resistance in ALL by downregulating the calpain-1-Bid-caspase-3/12 pathway

Abstractl-Asparaginase (l-ASNase) is a strategic component of treatment protocols for acute lymphoblastic leukemia (ALL). It causes asparagine deficit, resulting in protein synthesis inhibition and subsequent leukemic cell death and ALL remission. However, patients often relapse because of the development of resistance, but the underlying mechanism of ALL cell resistance to l-asparaginase remains unknown. Through unbiased genome-wide RNA interference screening, we identified huntingtin associated protein 1 (HAP1) as an ALL biomarker for l-asparaginase resistance. Knocking down HAP1 induces l-asparaginase resistance. HAP1 interacts with huntingtin and the intracellular Ca2+ channel, inositol 1,4,5-triphosphate receptor to form a ternary complex that mediates endoplasmic reticulum (ER) Ca2+ release upon stimulation with inositol 1,4,5-triphosphate3. Loss of HAP1 prevents the formation of the ternary complex and thus l-asparaginase-mediated ER Ca2+ release. HAP1 loss also inhibits external Ca2+ entry, blocking an excessive rise in [Ca2+]i, and reduces activation of the Ca2+-dependent calpain-1, Bid, and caspase-3 and caspase-12, leading to reduced number of apoptotic cells. These findings indicate that HAP1 loss prevents l-asparaginase–induced apoptosis through downregulation of the Ca2+-mediated calpain-1-Bid-caspase-3/12 apoptotic pathway. Treatment with BAPTA-AM [1,2-bis(2-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid tetrakis(acetoxymethyl ester)] reverses the l-asparaginase apoptotic effect in control cells, supporting a link between l-asparaginase-induced [Ca2+]i increase and apoptotic cell death. Consistent with these findings, ALL patient leukemic cells with lower HAP1 levels showed resistance to l-asparaginase, indicating the clinical relevance of HAP1 loss in the development of l-asparaginase resistance, and pointing to HAP1 as a functional l-asparaginase resistance biomarker that may be used for the design of effective treatment of l-asparaginase-resistant ALL.