Long-term results of sirolimus treatment in lymphangioleiomyomatosis: a single referral centre experience

There are few published data on long-term treatment with sirolimus in lymphangioleiomyomatosis (LAM). The objective of this study was to describe the long-term effect of sirolimus in a series of LAM patients followed up in a referral centre, focusing on pulmonary function. We retrospectively reviewed a series of 48 patients with LAM diagnosed, followed up and treated with sirolimus in a single centre. Response to sirolimus was evaluated at 1 and 5 years. A negative sirolimus response was defined as an FEV1 decline greater than − 75 ml/year. A mixed-effects model was used to estimate the longitudinal changes in FEV1 (average slope), both as absolute (ml/year) and as predicted values (%predicted/year). From a total of 48 patients, 9 patients underwent lung transplantation and 4 died during the study. Mean (95% CI) FEV1 slope over 5 years was − 0.14 (− 26.13 to 25.85) ml/year in the whole LAM group, 42.55 (14.87 to 70.22) ml/year in the responder group, − 54.00 (− 71.60 to − 36.39) ml/year in the partial responder group and − 84.19 (− 113.5 to − 54.0) ml/year in the non-responder group. After 5 years of sirolimus treatment 59% had a positive response, 30% had a partial response and 11% had a negative response. Our study found that sirolimus treatment had a positive long-term effect on most LAM patients.

P141 How effective are high-cost drugs for rheumatoid arthritis beyond the third choice in routine care?

Background/Aims It became apparent at a session at the BSR Annual Conference 2019 that some CCGs restrict the prescription of high cost drugs (HCDs) beyond three drugs for people with rheumatoid arthritis (RA). We were interested to explore the efficacy of HCDs beyond the third choice in our own service. Methods All patients in our service who are being considered for HCDs, are discussed at a multi-disciplinary team meeting comprising of seven consultants and eight nurses. The HCD decision is recorded in the minutes of the meeting which were scrutinised to identify patients who had received four or more HCDs. We began at March 2017, the launch of JAK inhibitors, in the expectation that few people would have had four HCDs before that time. The medical records were reviewed for the order of HCDs given and for evidence of efficacy and toxicity. The response to each drug choice was graded as: responder; partial responder and failure (primary non-responder or toxicity). Results From a database of 2,673 patients with RA, 542 patients were taking HCDs, thirty-two of those had received four or more of these drugs. Eleven of the thirty-two patients had tried four HCDs, seven had received five HCDs, ten patients had six, one patient had seven HCDs, two had tried eight and one patient had received nine HCDs. The response rates for each choice of drug are shown in table 1. Many patients responded to their fourth, fifth and sixth choice of HCD. If there was a restriction of three HCDs in our service, thirty-three prescriptions for drugs that patients have responded to, would not have been made. Conclusion Many patients responded to their fourth or subsequent HCD. Thus, there is no clinical justification in restricting the use of HCDs below at least six choices. Additionally, this data suggests that only small numbers of patients are prescribed more than four HCDs. Therefore lifting this limitation would have little cost implication. P141 Table 1:HCD Response RateHCD Choice*123456>6Responder12 (38%)10 (31%)10 (31%)12 (44%)14 (58%)6 (60%)1 (14%)Partial Responder5 (16%)1 (3%)7 (22%)5 (19%)4 (17%)1 (10%)1 (14%)Failure15 (47%)21 (66%)15 (47%)10 (37%)6 (25%)3 (30%)5 (71%)n =3232322724107*Switches to biosimilars were not regarded as a change. Disclosure D. Walker: Honoraria; Gilead Sciences Ltd, Ely Lilly Pharmaceuticals, Pfizer Pharmaceutical. Grants/research support; Gilead Sciences Ltd. S. Robinson: None. J. Barry: Corporate appointments; Gilead Sciences Ltd. P. Punter: Corporate appointments; Gilead Sciences Ltd. S. Kearns: Corporate appointments; Gilead Sciences Ltd. I. Goff: None.

After Treatment Decrease of Bone Marrow Tregs and Outcome in Younger Patients with Newly Diagnosed Acute Myeloid Leukemia

An emerging body of evidence demonstrates that defects in antileukemic effector cells in patients with acute myeloid leukemia (AML) can contribute to the development and/or persistence of the disease. In particular, immune suppressive regulatory T cells (Tregs) may contribute to this defective antileukemic immune response, being recruited by bone marrow leukemic cells to evade immune surveillance. We evaluated Tregs (CD4+/CD45RA-/CD25high/CD127low), performing multiparametric flow cytometry on freshly collected bone marrow aspirate (BMA), in addition to the usual molecular and cytogenetic work-up in newly diagnosed AML patients to look for any correlation between Tregs and the overall response rate (ORR). We studied 39 AML younger patients (<65 years), all treated with standard induction chemotherapy. ORR (complete remission (CR)+CR with incomplete hematologic recovery (CRi)) was documented in 21 out of 39 patients (54%); two partial responder patients were also recorded. Apart from the expected impact of the molecular-cytogenetic group ( p = 0.03 ) and the NPM mutation ( p = 0.05 ), diagnostic BMA Tregs did not show any correlation with ORR. However, although BMA Tregs did not differ in the study population after treatment, their counts significantly decreased in responder patients ( p = 0.039 ), while no difference was documented in nonresponder ones. This suggested that the removal of Treg cells is able to evoke and enhance anti-AML immune response. However, the role of BMA Tregs in mediating immune system-AML interactions in the diagnostic and posttreatment phase should be confirmed in a greater number of patients.

A novel multiple-catheter implantation method for advanced head and neck cancer.

6582 Background: We previously developed a super-selective intra-arterial chemotherapy (iaCT) approach for head and neck cancer (HNC), by which, an intra-arterial catheter is retrogradely inserted via either the superficial temporal artery (STA) or occipital artery (OA) and connected to a subcutaneous reservoir. As a result, since this approach overcomes the need for frequent fluoroscopy sessions, the infusion frequency can be increased and the therapeutic effectiveness improved. However, since the anticancer effect is limited to the region supplied by the selected blood vessel, it is often difficult to control an advanced HNC by single-catheter iaCT. Subsequently, a novel multiple-catheter implantation method (MCIM) for super-selective iaCT has been developed using, both, the STA and OA. Methods: A total of 21 patients with stage III or IV HNC were enrolled in this study and treated via MCIM for iaCT between 2009 and 2017. The catheters were super-selectively placed in the tumor-feeding arteries after having entered the STA or OA. The first catheter was introduced into one of the target branches. Next, a second catheter was introduced into another target branch. If a third catheter was required, the procedure was repeated. The extra-arterial portions of the catheters were subcutaneously connected to an implanted juxta-mastoidal infusion reservoir. Results: The response rate was 100%; particularly, 20 cases of complete response and 1 of partial response were confirmed. Although the partial responder underwent salvage surgery and two complete responders ultimately died (due to either delayed recurrence or brain metastases), the other 18 patients have been living cancer-free for 2-9 years. Conclusions: The MCIM method allows to expand the infusion region while maintaining the main advantages of super-selective iaCT. As a consequence, due to the lack of need for patient confinement in the catheter room and for frequent fluoroscopy sessions, patients’ mental and physical distress, medical expenses, and treatment time are all ultimately reduced.

PL3.5 Efficacy and safety of selinexor in recurrent glioblastoma

BACKGROUND New treatment modalities are needed for recurrent glioblastoma (rGBM). Selinexor is a novel, oral selective inhibitor of nuclear export which forces nuclear retention of tumor suppressor proteins including p53 and p27, leading to apoptosis. We previously reported interim results showing tolerability, preliminary efficacy, and blood-brain barrier penetration in a surgical cohort (N=8). We now report updated results following completion of accrual to non-surgical cohorts (N=68). MATERIALS AND METHODS This is an open-label, multicenter, phase 2 study of selinexor monotherapy. Patients (pts) not undergoing surgery for measurable rGBM per response assessment neuro-oncology criteria (RANO) were enrolled in one of 3 arms encompassing different dosing schedules of selinexor (50 mg/m2 [~ 85 mg] BIW, 60 mg BIW, and 80 mg QW). Treatment was continuous, although cycles were defined as 28 days and response was assessed every other cycle by MRI. Prior treatment with radiotherapy and temozolomide was required and prior bevacizumab was exclusionary. The primary endpoint was 6-month progression free survival (6mPFS) rate, calculated by the Kaplan-Meier method. RESULTS 76 pts were enrolled; 24, 14 and 30 pts on doses of ~85 mg BIW, 60 mg BIW, and 80 mg QW, respectively. Median age was 56 years (range 21–78). Median number of prior treatments was 2 (range 1–7) At the end of the 6 cycles, 30.2% pts on 80 mg QW were free from progression. The 6mPFS rate on 80 mg QW was 18.9%. Best RANO-defined responses (assessed locally) among 26 evaluable pts on 80 mg QW included 1 complete response, 2 partial responses, 7 stable disease, and 16 with progressive disease. Complete and partial responses were durable: the complete and a partial responder remain on selinexor for 393 and 1093 days respectively, as of the cut-off date. Median duration of response was 10.8 months. The most common related adverse events (all grades) in pts on ~85 mg BIW/60 mg BIW/80 mg QW were nausea (42%/64%/63%), leukopenia (38%/7%/43%), fatigue (71%/71%/47%), neutropenia (29%/14%/33%), decreased appetite (46%/71%/27%), and thrombocytopenia (67%/29%/23%). CONCLUSION Selinexor demonstrated efficacy, with durable responses and disease stabilization in rGBM. Based on the favorable efficacy and safety profile, selinexor at a dose of 80 mg QW is recommended for further development in rGBM.

Results of Gamma Knife anterior capsulotomy for refractory obsessive-compulsive disorder: results in a series of 10 consecutive patients

OBJECTIVEObsessive-compulsive disorder (OCD) is a severe psychiatric condition. The authors present their experience with Gamma Knife radiosurgery (GKRS) in the treatment of patients with OCD resistant to any medical therapy.METHODSPatients with severe OCD resistant to all pharmacological and psychiatric treatments who were treated with anterior GKRS capsulotomy were retrospectively reviewed. These patients were submitted to a physical, neurological, and neuropsychological examination together with structural and functional MRI before and after GKRS treatment. Strict study inclusion criteria were applied. Radiosurgical capsulotomy was performed using two 4-mm isocenters targeted at the midputaminal point of the anterior limb of the capsule. A maximal dose of 120 Gy was prescribed for each side. Clinical global changes were assessed using the Clinical Global Impression (CGI) scale, Global Assessment of Functioning (GAF) scale, EQ-5D, Beck Depression Inventory (BDI), and State-Trait Anxiety Inventory (STAI). OCD symptoms were determined by the Yale–Brown Obsessive Compulsive Scale (Y-BOCS).RESULTSTen patients with medically refractory OCD (5 women and 5 men) treated between 2006 and 2015 were included in this study. Median age at diagnosis was 22 years, median duration of illness at the time of radiosurgery was 14.5 years, and median age at treatment was 38.8 years. Before GKRS, the median Y-BOCS score was 34.5 with a median obsession score of 18 and compulsion score of 17. Seven (70%) of 10 patients achieved a full response at their last follow-up, 2 patients were nonresponders, and 1 patient was a partial responder. Evaluation of the Y-BOCS, BDI, STAI-Trait, STAI-State, GAF, and EQ-5D showed statistically significant improvement at the last follow-up after GKRS. Neurological examinations were normal in all patients at each visit. At last follow-up, none of the patients had experienced any significant adverse neuropsychological effects or personality changes.CONCLUSIONSGKRS anterior capsulotomy is effective and well tolerated with a maximal dose of 120 Gy. It reduces both obsessions and compulsions, improves quality of life, and diminishes depression and anxiety.

Plasma Biomarker Association with Response in Acute GVHD Subjects Treated with the Combination of Itacitinib and Corticosteroids in a Phase 1 Clinical Trial

BACKGROUND: Acute Graft versus Host Disease (aGVHD) represents a serious and sometimes life-threatening condition associated with patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT). Development of aGVHD is characterized by increased levels of inflammatory mediators and activated T cells in circulation, leading to tissue and organ damage. Corticosteroids are primarily utilized as first line treatment for aGVHD; however, this approach does not provide therapeutic benefit for a significant portion of aGVHD subjects. The combination of itacitinib, a JAK1-selective inhibitor, with corticosteroids was evaluated in a parallel-cohort phase 1 trial (NCT02614612) and resulted in improved overall responses for both steroid naïve and refractory aGVHD subjects. Previous studies have demonstrated that a panel measuring the plasma levels of ST2, REG3A, and TNFR1 can be utilized to distinguish steroid treated subjects with an increased risk of progressive aGVHD; however, it is unknown if these biomarkers are predictive of response to the combination of corticosteroids and itacitinib. In this study, we compared the plasma levels of ST2, REG3A, TNFR1, and Trappin-2/Elafin in order to distinguish response to combination treatment. Additionally, we conducted a broad proteomic analysis to identify potential prognostic biomarkers of response to the combination treatment. METHODS: Plasma samples were collected from 31 subjects enrolled in the Phase 1 clinical trial prior to and at designated times following treatment. Levels of REG3A, ST2, TNFR1, and Trappin-2/Elafin were measured using SimplePlex multiplex platform based on manufacturer instructions. Broad proteomic analysis was additionally conducted by OLINK Proteomics using a proximity extension assay. Statistical differences were identified using unpaired T tests and significance conferred when p<0.05. All subjects provided written consent prior to enrollment. RESULTS: Subjects were separated into responders (10- Complete Responder, 1-Very Good Partial Responder, 8-Partial Responder) and non-responders (2-Mixed Responder, 10-Progressive Disease/Death) based on CIBMTR response criteria at day 28. Levels of ST2 and TNFR1 were significantly elevated at baseline in non-responders (p<0.05 for both ST2 and TNFR1) when compared with responders (Table 1). Additionally, baseline levels of ST2 and TNFR1 significantly correlated (p<0.0001 for both ST2 and TNFR1) with the Minnesota and CIBMTR response criteria for aGVHD. There were no significant differences in the levels of REG3A and Trappin-2/Elafin between responders and non-responders. Novel biomarkers were identified and associated with therapeutic response by comparing the levels of approximately 1000 proteins in the CR and PD/Death cohorts specifically. The initial analysis identified 44 proteins significantly upregulated (p<0.05; fold change > 1.5) and 61 proteins significantly down-regulated (p<0.05; fold change < -1.5) in the CR cohort at baseline compared with the PD/Death cohort. Further analysis of the CR cohort identified 23 proteins significantly modulated (Fold Change > |1.5|, p<0.05) between baseline and day 28 samples which may serve as additional biomarkers of therapeutic response. CONCLUSION: Proteomic analysis of clinical samples confirmed the value of ST2 and TNFR1 in predicting response to treatment with itacitinib and steroids and also identified a number of novel plasma biomarkers that may have utility in selecting and/or monitoring aGVHD subjects when treated with a combination of corticosteroids and itacitinib. Disclosures Pratta: Incyte Research Institute: Employment, Equity Ownership. Liu:Incyte Research Institute: Employment, Equity Ownership. Arbushites:Incyte Corporation: Employment, Equity Ownership. Newton:Incyte Research Institute: Employment, Equity Ownership. Howell:Incyte Research Institute: Employment, Equity Ownership.

ESCAlate – Ein adaptiver Behandlungsansatz für Jugendliche und Erwachsene mit ADHS

Zusammenfassung. In der Behandlung der adulten ADHS haben sich sowohl pharmakologische Interventionen als auch psychosoziale Behandlungen als wirksam erwiesen. In der täglichen klinischen Routine wird die Behandlung jedoch weniger von den Ergebnissen klinischer Studien als von Behandlungsrichtlinien und Anforderungen nationaler Institutionen (Gemeinsamer Bundesausschuss) beeinflusst. Der Hauptaspekt dieser Vorschriften ist die Anforderung, dass ein stufenweiser Behandlungsansatz, beginnend mit niederschwelligen Interventionen, am sinnvollsten für die Behandlung bei adulten ADHS-Patienten ist. Leider gibt es bis heute fast ausschließlich klinische Studien, welche die Auswirkungen einzelner Therapiestrategien erforschen. Das gestufte Versorgungsmodell scheint noch nicht ausreichend validiert. Genau hier möchte die im Folgenden beschriebene ESCAlate-Studie ansetzen. Bei ESCAlate handelt es sich um eine randomisierte, kontrollierte Studie. Es sollen 279 Patienten im Alter zwischen 16.00 und 45.11 Jahren in das Behandlungsprogramm, welches sich in mehrere Abschnitte gliedert, aufgenommen werden. In einem ersten Behandlungsabschnitt werden die Patienten nach dem Zufallsverfahren in drei Gruppen eingeteilt: Psychoedukation im Einzelsetting (PE), Telefonassistierte Selbsthilfe (TASH) oder Wartekontrollgruppe. Alle Patienten der Wartegruppe erhalten nach dreimonatiger Wartezeit eine Behandlung mit TASH. Im zweiten Behandlungsabschnitt werden die Patienten entsprechend der Schwere ihrer persistierenden Symptome in die drei Gruppen Full-Responder, Partial-Responder und Non-Responder eingeteilt. Patienten, welche als Full-Responder eingestuft wurden erhalten ein verhaltenstherapeutisch orientiertes Coaching. Partial-Responder erhalten ebenfalls dieses Coaching, wobei in dieser Gruppe der Zufall entscheidet, ob die Patienten zusätzlich ein Neurofeedbacktraining (NF) erhalten. Non-Responder erhalten eine pharmakologische Behandlung mit Methylphenidat. Hier entscheidet ebenfalls der Zufall, ob die Patienten zusätzlich ein Neurofeedbacktraining erhalten. ESCAlate zeichnet sich durch eine relativ naturalistische Stichprobenzusammensetzung aus, da auf hochspezifische Ein- und Ausschlusskriterien verzichtet wurde, um eine Patientenstichprobe zu erhalten, die die Patienten der alltäglichen klinischen Routine in den Praxen widerspiegelt. Die Wirksamkeit einer evidenzbasierten Intervention mit gestufter Behandlung wird durch primäre (Verringerung des Schweregrads der ADHS-Symptome) und sekundäre Ergebnisse (funktionelle Ergebnisse; z.B. Lebensqualität, Ärger-Management, Steigerung des psychosozialen Wohlbefindens) untersucht. Prädiktoren für therapeutisches Ansprechen bzw. Nicht-Ansprechen werden bei jedem Schritt der Intervention evaluiert. Darüber hinaus können eventuelle geschlechtsspezifische Unterschiede untersucht werden.