Completion Of Induction Treatment Research Articles

INAVO122: A phase III study of maintenance inavolisib or placebo + pertuzumab + trastuzumab following induction with pertuzumab + trastuzumab + a taxane in patients (pts) with PIK3CA-mutated, HER2-positive advanced breast cancer (HER2+ aBC).

TPS1124 Background: The PI3K pathway plays a crucial role in HER2 signaling. Somatic mutations of PIK3CA, the gene that encodes the PI3K p110α subunit, may induce resistance to HER2-targeted therapies and are associated with poorer clinical outcomes (Swain SM, et al. SABCS 2022; P2-11-07). Inavolisib, a potent p110α-selective inhibitor that induces degradation of mutant p110α, has shown antitumor activity in PIK3CA-mutated HER2+ BC and long-term tolerability with early intervention for common on-class toxicities, including hyperglycemia, diarrhea, and stomatitis (Jhaveri KL, et al. SABCS 2023; GS03-13, Bedard P, et al. ASCO 2022; 1052). The current study will assess the efficacy and safety of maintenance inavolisib + fixed-dose combination of pertuzumab + trastuzumab for subcutaneous injection (PH FDC SC) after first-line (1L) induction treatment in pts with PIK3CA-mutated, HER2+ aBC. Methods: INAVO122 (NCT05894239) is a multicenter, randomized, international, double-blind, placebo-controlled study. Pts will be enrolled for: 1L induction treatment if they are receiving/will receive PH + a taxane; or for maintenance treatment if they completed induction treatment per standard of care. In the maintenance phase, pts will be randomized 1:1 to receive inavolisib (9 mg orally once daily; 21-day cycles) + PH FDC SC (every 3 weeks), or placebo + PH FDC SC. Study treatment will continue until disease progression (PD), unacceptable toxicity, death, consent withdrawal, or at the investigator’s (INV) discretion. Enrolled pts must have centrally determined HER2+, PIK3CA-mutated tumors, with documented hormone receptor status per local assessment, and be disease-free for ≥6 months from completion of neoadjuvant/adjuvant HER2-targeted treatment. They must not have received any non-hormonal treatment for aBC prior to induction, and, at screening, fasting glucose must be <126 mg/dL and HbA1c <6.4%. To be randomized, pts must have completed induction therapy without PD and show left ventricular ejection fraction ≥50%. The primary endpoint is INV-assessed progression-free survival. Secondary endpoints are overall survival; INV-assessed objective response rate, duration of response, clinical benefit rate, and time to second disease progression; health-related quality of life; safety; and pharmacokinetics. The primary endpoint analysis will utilize a two-sided stratified log-rank test at a two-sided significance level of 5%. A stratified Cox proportional hazards model will be used to estimate the hazard ratio between the two treatment arms and its 95% confidence intervals. An independent data monitoring committee will be in place for safety. Target randomization is ~230 pts; this study is currently recruiting (15 pts enrolled). Encore from SABCS 2023 (PO2-19-09). Clinical trial information: NCT05894239 .

Treatment Patterns, Acute Healthcare Resource Use, and Costs of Patients with Treatment-Resistant Depression Completing Induction Phase of Esketamine in the United States.

This study aimed to understand treatment patterns, acute healthcare use, and cost patterns among adults with treatment-resistant depression (TRD) who completed induction treatment with esketamine nasal spray in the United States (US). Per label, induction is defined as administration twice a week for 4 weeks, after which maintenance is started on a weekly basis for 4 weeks, and thereafter, patients are treated weekly or bimonthly. Adults with one or more esketamine claim (index date) on or after March 5, 2019 were selected from Optum's de-identified Clinformatics® Data Mart Database (January 2016-June 2022). Before the index date, patients had evidence of TRD and ≥12 months of continuous insurance eligibility (baseline period). Patients with eight or more esketamine treatment sessions were included in the main cohort. A subgroup included patients with one or more baseline mental health (MH)-related inpatient (IP) admission or emergency department (ED) visit (i.e., prior acute healthcare users). Treatment patterns were described during the follow-up period (index date until earliest of end of insurance eligibility or data); acute healthcare (i.e., IP and ED) resource use and costs (2021 US dollars) were reported during the baseline and follow-up periods. Of the 322 patients in the main cohort, 111 comprised the subgroup of prior acute healthcare users. During the follow-up period, mean time from index date to eighth esketamine session was 73.2days in the main cohort and 78.8days in the subgroup (per label, 28days). Further, 75.2% of the main cohort and 73.9% of the subgroup completed four or more esketamine maintenance sessions following induction. In the main cohort, mean all-cause acute healthcare costs per patient per month (PPPM) decreased from baseline ($837) to follow-up ($770). Similar reductions were observed for mean MH-related acute healthcare costs PPPM (baseline $648, follow-up $577). In the subgroup, mean all-cause acute healthcare costs PPPM also decreased (baseline $2323, follow-up $1423), driven by mean MH-related acute healthcare costs PPPM (baseline $1880, follow-up $1139). Mean all-cause acute healthcare use per ten patients per month remained largely stable from baseline to follow-up in the main cohort (IP days: baseline 2.24, follow-up 2.13; ED visits: baseline 1.33, follow-up 1.45) and decreased in the subgroup (IP days: baseline 6.38, follow-up 4.56; ED visits: baseline 2.58, follow-up 2.41). Trends in mean MH-related acute healthcare use were similar. Patients generally required more time than label recommendation to complete esketamine induction treatment, and most went on to have 12 or more esketamine sessions. Completion of induction treatment correlated with reductions in mean all-cause and MH-related acute healthcare costs. Larger reductions were seen in the subgroup of prior acute healthcare users.

CTNI-05. INTRATHECAL PEMETREXED FOR LEPTOMENINGEAL METASTASES FROM SOLID TUMOR: A MULTICENTER, PHASE I/II, OPEN-LABEL STUDY (PMLM, NCT 05289908)

Abstract OBJECTIVES This phase I/II study was to evaluate maximum tolerated dose (MTD) of intrathecal pemetrexed (IP) with vitamin supplementation and antitumor activity for leptomeningeal metastases (LM) from solid tumors. METHODS Phase I study followed the classic 3 + 3 design, with dose escalated from 15 mg. Phase II followed Simon 2-stage design with recommended dose determined in phase I. IP was administered twice per week for 2 weeks (induction therapy), followed by once per week for 4 weeks (consolidation therapy). Vitamin B12 (1000 μg) and folic acid (400 μg, q.d.) were given at the beginning of treatment. Primary end points were MTD in phase I and clinical response rate (CRR) in phase I/II. RESULTS Between Feb 2022 and Jan 2023, 34 patients were enrolled, including non-small cell lung cancer (20), small-cell lung cancer (3), breast cancer (8), others (3). Ten patients were enrolled in phase I. Three of 4 patients receiving IP at 15 mg completed induction and consolidation treatment without dose limiting toxicity (DLT). Two DLT (1 grade 4 hematologic toxicity and 1 grade 5 arachnoiditis) occurred in 6 patients at 20 mg. MTD was determined to be 15 mg. Then 24 patients were enrolled in phase II and given 15 mg of IP. 82.4% (28/34) and 58.8% (20/34) patients completed induction and consolidation therapy, respectively. Adverse events (AEs) rate was 73.5% (25/34). 50% (17/34) patients showed grade ≥ 3 AEs. Overall CRR was 41.2% (14/34), including 10 (29.4%) with improved neurological dysfunction, 11 (32.4%) with CSF cytological response and 4 (11.8%) with neuroimaging improvement. Median survival was 7.6 (range 0.3–13.7) months in phase I, while has not yet been achieved in phase II. CONCLUSION MTD of IP was 15 mg with folic acid and vitamin B12 supplementation. IP is an optimal therapeutic option for LM from solid tumors.

Efficacy and Tolerance of Isatuximab, Cyclophosphamide, Bortezomib, and Dexamethasone (Isa-CBD) Induction Chemotherapy in Newly Diagnosed, Transplant Eligible Multiple Myeloma: Report of the Phase 2 Multi-Centre, Open Label Canadian Myeloma Research Group (CMRG)-008 Prospective Clinical Trial

Background: The previous standard Canadian approach to autologous stem cell transplantation (ASCT) included CyBorD induction and single-agent lenalidomide maintenance until progression (Cote J, et al. ASH 2022: abstract 117). In an effort to improve outcomes, the current Canadian Myeloma Research Group (CMRG)–008 trial aimed to assess the efficacy and tolerance of a regimen of isatuximab-CyBorD (Isa-CyBorD) induction, stem cell mobilization/collection, high-dose melphalan with ASCT, followed by continuous maintenance with isatuximab and lenalidomide in newly diagnosed multiple myeloma (NDMM) patients eligible for transplant. We now report the first planned analysis of Isa-CyBorD induction and stem cell mobilization and collection. Methods: This is a multi-centre phase 2 prospective study conducted in 8 centres in which transplant-eligible NDMM (TE-NDMM) patients received isatuximab added to four cycles of standard induction CyBorD chemotherapy (cyclophosphamide 300 mg/m 2 PO, bortezomib 1.5 mg/m 2 SC, and dexamethasone 40 mg PO, all given on days 1, 8, 15 and 22 of a 28-day cycle along with isatuximab 10 mg/kg IV days 1, 8, 15 and 22 of cycle 1 and days 1 and 15 of cycles 2-4). Isatuximab premedication also included acetaminophen, H2-antagonist (ranitidine) or proton pump inhibitor and montelukast. No thromboprophylaxis required per protocol. After the completion of induction treatment, subjects achieving ≥ stable disease (SD) proceeded to mobilization and collection of hematopoietic stem cells (SCs) per local institutional standards. Eligible patients with successful SC collection then proceeded to high-dose melphalan 200 mg/m 2 followed by ASCT. Maintenance treatment commenced at 100 days (+/- 7 days) post-ASCT and continued until disease progression. Maintenance treatment consisted of 28-day cycles of isatuximab (10 mg/kg IV on days 1, 8, 15 and 22 of cycle 1; days 1 and 15 of cycles 2-3; then day 1 of each subsequent cycle) administered with lenalidomide (10 mg daily on days 1-21). Results: Between December 2022-January 2023, 71 patients with ECOG ≤ 2 were enrolled: 25 females, 46 males; median age 61 years (range: 31-73); 46.5%, 35.2% and 18.3% were ISS stages I, II and III, respectively. High-risk cytogenetics were documented in 20.6% of evaluable patients (13/63). All completed Isa-CyBorD induction therapy. The treatment was well-tolerated with rare grade 3 - 4 adverse events: neutropenia (8.2%), anemia (8.2%) and febrile neutropenia (4.1%). Common side-effects (All grades combined, ≥20%) included nausea (50%), constipation (28%), fatigue (28%), peripheral neuropathy (27% - all ≤ grade 2 with no dose holds for neuropathy), insomnia (24%), diarrhea (22%), infusion-related reaction (22%). Response assessment at the end of induction was available for 57 pts by the data cut-off date (June 1 st, 2023). All patients had clinical improvement with no primary progressive disease. Complete response (CR), very good partial response (VGPR) and partial response (PR) were documented in 7%, 52.6% and 33.3%, respectively. Four patients (7%) had <50% improvement of M-protein (SD). Three patients did not proceed to stem cell transplantation due to patient / physician choices. SC mobilization utilized cyclophosphamide in 10 (15.4%) and plerixafor in 12 (18.5%) patients; mobilization was successful in all 65 patients mobilized so far with 1-3 apheresis (median 2). The median number of CD34+ cells collected was 5.3 x10^6/kg (range: 2.25-7.28). Conclusion: Isa-CyBorD with weekly bortezomib is an effective induction therapy in patients with NDMM (93% ≥ PR with no progression and no mobilization failures). The treatment was well-tolerated with a side-effect profile comparable to our Canadian prior experience with CyBorD alone. All patients who proceeded to mobilization had successful collection of adequate number of SCs. Further follow-up is ongoing to assess long-term outcomes with this approach.

OS09.6.A A MULTICENTER, PHASE I/II, OPEN-LABEL STUDY OF INTRATHECAL PEMETREXED FOR LEPTOMENINGEAL METASTASES FROM SOLID TUMOR (PMLM, NCT 05289908)

Abstract BACKGROUND There has never been a dose-escalation study on intrathecal pemetrexed (IP) with vitamin supplementation. This phase I/II study was to evaluate the maximum-tolerated dosage (MTD) of IP with vitamin supplementation and the antitumor activity for leptomeningeal metastases (LM) from solid tumors. MATERIAL AND METHODS Phase I study followed the classic 3 + 3 design, with the dose of IP escalated from 15 mg. Phase II followed the Simon 2-stage design with the recommended dose determined in phase I. IP was administered twice per week for 2 weeks (induction therapy), followed by once per week for 4 weeks (consolidation therapy). Clinically stable or improved patients continued IP once a month (maintenance therapy). Vitamin B12 (1000 μg) and folic acid (400 μg, q.d.) were given at the beginning of treatment. Primary end points were MTD in phase I and clinical response rate (CRR) in phase I/II. All patients were assessed to investigate safety, CRR and overall survival (OS). RESULTS Between Feb 2022 and Jan 2023, 34 patients (male: 16; female: 18; age: 45-68 years; median: 56 years) were enrolled, including non-small lung cancer (20), small-cell lung cancer (3), breast cancer (8), others (3). Thirty-three patients had a confirmed LM diagnosis (positive CSF cytology). Remaining one had probable diagnosis (positive neuroimaging with typical clinical signs). Ten patients were enrolled in phase I. Three of 4 patients receiving IP at 15 mg completed induction and consolidation treatment without dose limiting toxicity (DLT). The dose was escalated to 20 mg. Two DLT (1 grade 4 hematologic toxicity and 1 grade 5 arachnoiditis) occurred in 6 patients at 20 mg. The MTD was determined to be 15 mg. Then 24 patients were enrolled in phase II and given 15 mg of IP. 82.4% (28/34) and 58.8% (20/34) patients completed induction and consolidation therapy, respectively. 41.2% (14/34) patients received maintenance therapy. Adverse events (AEs) rate was 73.5% (25/34). 50% (17/34) patients showed grade ≥ 3 AEs, including myelosuppression (11), elevation of hepatic aminotransferases (EHA) (5), elevation of blood bilirubin (EBB) (1), arachnoiditis (1), radiculitis (1), fatigue (1) and nausea (1). The overall CRR was 41.2% (14/34) by neuro-oncology proposal criteria, including 10 (29.4%) with improved neurological dysfunction, 11 (32.4%) with CSF cytological response and 4 (11.8%) with neuroimaging improvement. In a total of 28 patients receiving IP at 15 mg, 50% (14/28) patients showed grade ≥ 3 AEs, including myelosuppression (9), EHA (10), fatigue (1) and nausea (1). The CRR was 46.4% (13/28) in patients at 15 mg IP. Median survival was 7.6 (range 0.3-13.7) months in phase I, while has not yet been achieved in phase II until March 15, 2023. CONCLUSION MTD of IP was 15 mg with folic acid and vitamin B12 supplementation. IP is an optimal therapeutic option for LM from solid tumors.

Remote symptom-monitoring of patients with advanced lung cancer: A Danish national randomized controlled trial—The ProWide study.

1508 Background: Symptom-monitoring of patients with lung cancer has previously been shown to improve clinical outcomes. We conducted a national randomized controlled trial to evaluate the effects of remote symptom-monitoring of patients with advanced lung cancer completing induction treatment in a Danish setting. Methods: Patients with stage III-IV lung cancer treated with palliative intention, ECOG performance status ≤2, internet access and non-progressive disease after completed induction treatment were eligible. Patients were randomized 1:1 to remote symptom-monitoring (intervention arm) added to standard of care or standard of care alone (control arm). Maintenance therapy was allowed. Patients in the intervention arm weekly completed an electronic questionnaire from home covering 13 common symptoms related to lung cancer. A severity-threshold was applied to each question. When a threshold was exceeded, a notification was sent to a clinical nurse. The nurse was instructed to contact the patient and offer best supportive care. If disease progression was suspected, a computerized tomography (CT) scan was performed. Primary outcome was overall survival. Secondary endpoints included Health-related Quality of Life (HRQoL) measured by the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire EORTC QLQ-C30/LC13 and Hospital Anxiety and Depression Scale (HADS) scales. Results: Of 494 randomized patients, recruited from 8 departments, 239 were assigned to the intervention and 254 to standard of care (inclusion rate 75%). Weekly compliance to symptom-monitoring during the first year was 82% in the intention-to-monitor population. At a median follow-up of 2.6 years, no significant improvement in overall survival (OS) was found in the intervention arm compared to the control arm (hazard ratio (HR) 0.93, 95% confidence interval (CI); 0.75 to 1.16; p = 0.54). Sub-group analyses indicated improved OS for patients treated with carboplatin/vinorelbine (HR 0.65, CI 95%; 0.44-0.96, p = 0.03) and for patients treated in a department with prior implementation and use of patient-reported outcomes in clinical decision-making (HR 0.68, CI 95%; 0.46-1.01, p = 0.054). For prespecified scales in the HRQoL-analyses, no clinically meaningful effects were found. For physical functioning, mean overall change from baseline was 3.1 points (95% CI 0.1 to 6.2, p = 0.043), for pain, -3.9 points (95% CI; -8.4 to 0.7, p = 0.096) and for HADS-anxiety, -0.5 points (95% CI; -1.0 to 0.0, p = 0.070). Conclusions: Remote symptom-monitoring did not significantly improve clinical outcomes for patients with advanced lung cancer in a Danish population. The results indicated benefits for a sub-group of patients not receiving maintenance therapy and that prior organizational experiences may be a prerequisite for improving outcomes of symptom-monitoring. Clinical trial information: NCT03608410 .

Factors affecting central macular thickness of diabetic macular oedema patients after an induction treatment of intravitreal ranibizumab.

Intravitreal ranibizumab is one of the anti-vascular endothelial growth factors used for the treatment of diabetic macular oedema, not always successfully. We aimed to identify the factors affecting the changes of central macular thickness after induction treatment with intravitreal ranibizumab, to predict the treatment effect and facilitate early treatment decisions. Cross-sectional study involving a retrospective record review of diabetic macular oedema patients who received an induction treatment of three monthly 0.5mg intravitreal ranibizumab injections between 2016 and 2019. Central macular thickness was measured at baseline and 3months post-treatment. Linear regression was applied to identify the factors associated with the changes of central macular thickness. A total of 153 diabetic macular oedema patients were involved in this study. Their mean age was 57.5± 7.7 years, 54.9% were female. The mean change of central macular thickness from baseline to 3months after completed induction treatment of intravitreal ranibizumab was 155.5± 137.8μm. Factors significantly associated with changes of central macular thickness were baseline central macular thickness [b=0.73; 95% (CI): 0.63, 0.84; p= <0.001] and presence of subretinal fluid [b=35.43; 95% CI: 3.70, 67.16; p= 0.029]. Thicker baseline central macular thickness and presence of subretinal fluid were the factors significantly associated with greater changes of central macular thickness in diabetic macular oedema patients after receiving three injections of intravitreal ranibizumab.

P354 Application of the clinical decision support tool to predict treatment outcomes in Crohn’s Disease patients treated with vedolizumab subcutaneous formulation

Abstract Background There is a need to identify Crohn’s Disease (CD) patients who will obtain most clinical benefit from treatment with vedolizumab (VDZ), an anti-α4β7 integrin inhibitor for the treatment of ulcerative colitis and Crohn’s Disease (CD). Previously, a clinical decision support tool (CDST) has been developed and validated to guide treatment decisions in CD patients (pts) treated with intravenous VDZ.1 In this study, we aimed to test the ability of the CDST to predict clinical outcomes in CD pts receiving maintenance treatment with the subcutaneous (SC) formulation of VDZ. Methods Pts with moderate to severe CD receiving maintenance treatment with VDZ SC in the VISIBLE 2 study were categorized using the CDST into low (≤13 points), intermediate (&amp;gt;13 and ≤19 points) and high response probability groups (&amp;gt;19 points) based on the scoring system detailed in Table 1. Clinical outcomes evaluated included clinical remission: CD Activity Index (CDAI) ≤ 150 at Week 6, 14, 30, and 52, and enhanced clinical response: decrease from baseline in CDAI score ≥ 100 points at Week 52. All outcomes were evaluated as observed. Results There were 275 pts who completed induction treatment with VDZ 300 mg IV and continued into maintenance treatment with VDZ 108 mg SC until Week 52. Using the CDST, at baseline, 14 pts (5.1%) had a low, 98 (35.6%) had an intermediate, and 163 (59.3%) had a high probability of treatment response with VDZ. Due to the low number of pts in the low probability group, the low and intermediate groups were combined. At Week 6, 99 pts (61.1%) in the high probability group had achieved clinical remission vs 38 pts (33.9%) in the low/intermediate probability group (Fig 1). Rates of clinical remission in the high probability group continued to exceed those of the low/intermediate group through until Week 52 when 89 pts (86.4%) in the high probability group were in clinical remission vs 43 pts (79.6%) in the low/intermediate probability group (Fig 1). In the high probability group, 97 pts (94.2%) had an enhanced clinical response at Week 52 compared with 46 pts (85.2%) in the low/intermediate group. Conclusion Compared with the low/intermediate group, pts categorized by the CDST as having the highest probability of treatment response to VDZ achieved clinical remission sooner, as early as Week 6. These findings provide further confirmation of the CDST as a means of identifying pts with CD likely to benefit from treatment with VDZ in either IV or SC formulations.

High-Dose Chemotherapy and Autologous Stem Cell Transplant in Elderly and Fit Primary CNS Lymphoma Patients - a Multicenter Study By the Cooperative PCNSL Study Group (MARTA study)

Introduction: High-dose methotrexate (HD-MTX) based induction chemo-immunotherapy followed by high-dose chemotherapy and autologous stem cell transplantation (HCT-ASCT) has been shown to be feasible and effective in younger and in selected elderly PCNSL patients. We aimed to investigate this treatment approach in patients > 65 years with newly diagnosed PCNSL in a multicentre study. Methods: This open-label, multicentre, single arm phase II study was conducted at 15 German centres (DRKS 00011932). Main eligibility criteria included newly diagnosed PCNSL, immunocompetence, age > 65 years, Eastern Cooperative Oncology Group Performance Status (ECOG PS) ≤ 2, and adequate organ function. Induction treatment consisted of two 21-day cycles of HD-MTX 3.5 g/m² (day 1), cytarabine 2 g/m² twice daily (days 2, 3) and rituximab 375 mg/m² before and after each chemotherapy with stem cell harvest after the 1st cycle. Patients not suffering disease progression subsequently received consolidation treatment with HCT-ASCT with rituximab 375 mg/m² (day -8), busulfan 3.2 mg/kg (days -7, -6), thiotepa 5 mg/kg/d (days -5, -4) and reinfusion of stem cells (day 0). Primary endpoint was progression-free survival (PFS) at 1 year by intention-to-treat (ITT). Secondary endpoints included overall survival (OS), treatment response and toxicities. Results: Between Nov 2017 and Sept 2020, we registered 57 patients. Five patients were excluded because of systemic lymphoma manifestation, absence of measurable radiologic lesion(s), inadequate renal function, ECOG PS >2 and deterioration before the start of study treatment. Finally, 52 eligible patients were included in the ITT population. Mean age was 72 years (range 65-80 years), 27/52 (51.9%) patients initially presented with an ECOG PS > 1. All patients started induction chemo-immunotherapy, 45 of 52 (86.5%) patients completed induction treatment. Thirty-seven of 52 (71.2%) patients proceeded to HCT-ASCT. Most common serious adverse events were infections, renal failure and (cerebro)vascular events, which mainly occurred during induction treatment. Overall, 22 (42.3%) patients died, 12 of whom (23.1%) without evidence of disease progression or relapse. Three (5.8%) patients died because of treatment-related complications, all of them during induction treatment. An additional patient died within 30 days after HCT-ASCT due to fatal viral pneumonia, main other non treatment-related causes of deaths were late infections and (cerebro)vascular events. Forty-one of 52 (78.8%) patients responded to induction treatment; 23 (44.2%) patients achieved a (unconfirmed) complete response and 11 (21.2%) patients a partial response 30 days after HCT-ASCT. After an estimated median follow-up of 23 months, PFS at 12 and 24 months was 57.7% (95% CI 43.2-69.7%) and 54.8% (40-67.4%), respectively; median PFS was 41.1 months (95% CI 6.7 to not calculable). Overall survival at 12 and 24 months was 63.1% (95% CI 48.4-74.7%) and 60.5% (95% CI 45.5-72.5%), respectively; median OS was 41.1 months (95% CI 10.3 to not calculable). Of those 37 patients undergoing HCT-ASCT, 2-year PFS and OS rates were 71.7% (95% CI 53.4-83.8%) and 80.8% (95% CI 63.8-90.3%), respectively. Conclusions: Feasibility and efficacy of HCT-ASCT in selected elderly patients with newly diagnosed PCNSL are confirmed in a multicenter setting with survival rates comparable to those of younger cohorts. Nevertheless, non-relapse mortality remains a major challenge in this vulnerable patient population emphasizing that standardized assessment of eligibility for intensive treatment is of utmost importance. This will be addressed in the upcoming randomized phase III PRIMA-CNS trial (DRKS00022768). Final data analysis is currently ongoing and will be presented in detail at the meeting.

A real-world experience: Outcomes among relapsed/refractory diffuse large B cell lymphoma patients with CD20 loss.

e19570 Background: Despite novel therapies for relapsed/refractory (R/R) DLBCL, outcomes among this cohort remain poor. A prior study indicated that patients who lost CD20 expression after treatment have earlier disease progression, but whether this translates to inferior outcomes remains unknown. We hypothesized that R/R DLBCL patients who lost CD20 expression upon disease relapse would have worse survival and response rates compared to those who retained expression. Methods: We performed a retrospective cohort study of R/R DLBCL patients seen at the University of Michigan between 2007-2021. Inclusion criteria were patients ≥ 18 years old, diagnosis of CD20 positive (+) DLBCL (de novo or transformed), relapsed/refractory disease, and CD20 status available at relapse on flow cytometry/immunohistochemistry. Overall survival (OS) was defined as time from first relapse to death and relapse-free survival (RFS) was time from first relapse to death or next treatment; both of which were estimated with Kaplan Meier analysis. Overall response rate (ORR) was complete response or partial response after first salvage therapy. Descriptive statistics with univariate and multivariate analyses were also performed. Results: 98 patients were included (65% male) with median age at diagnosis of 62 years. Majority of patients had stage III/IV disease at diagnosis (85%), 45% with GCB subtype and 7% with high-grade lymphoma. At diagnosis, all patients had CD20+ disease. Median time from diagnosis to first relapse was 7 months and median time from completion of induction treatment to first relapse was 2.4 months. Among the 98 patients, 84 were CD20+ at first relapse, 12 were CD20 negative and the remaining 2 patients were indeterminate and excluded from survival analyses. The estimated OS in the CD20+ group was 17.9 months (95% CI 14.0, 41.8) compared to 10.6 months in the CD20 negative group (95% CI 6.9, Not Reached). Although median OS in the CD20+ group was longer, a two-sample log-rank test failed to identify a significant difference in OS between the two groups (p = 0.085). The estimated RFS in the CD20+ group was 3.5 months (95% CI 3.3, 3.9) compared to 4.4 months in the CD20 negative group (95% CI 2.6, Not Reached, p = 0.739). ORR among CD20+ and CD20 negative patients was 64% and 50%, respectively. Of patients who became CD20 negative at relapse, 100% received anti-CD20 directed therapy thereafter, as part of salvage or with conditioning prior to transplant. Conclusions: Patients with DLBCL who relapse and maintain CD20 positivity seem to have a trend towards longer OS, though this was not statistically significant in our analysis. Our study was limited given the retrospective data collection and small sample size which may have limited our ability to detect a statistical significance in outcomes. In the future, we will plan to expand our study to involve other academic institutions and reassess outcomes among these cohorts.

P385 Tailoring induction treatment for children with Crohn’s disease

Abstract Background Multiple clinical studies in children with Crohn’s disease (CD) have demonstrated the high efficacy of nutritional therapy with exclusive enteral nutrition (EEN) to induce remission and even to promote mucosal healing. However, EEN as inductive treatment may be not tolerated or inefficient and we are well aware of the paramount importance of a well conducted induction treatment for paediatric CD with the goal of an individualized induction treatment to improve the prognosis and the quality of life of inflammatory bowel disease (IBD) children. Methods A retrospective multicentre study including newly diagnosed children with CD treated with EEN as induction therapy was designed. The primary aim of the study was to study predictive factors of non- adherence to treatment. The secondary endpoint were predictive factors of clinical non-remission at the end of induction treatment. Those data together were analysed with the ultimate goal of trying to define an individualized induction treatment for children with CD. Results 376 CD children from, 14 IBD paediatric referral centres were enrolled in the study. The rate of EEN adherence was, 89 %. Colonic involvement and FC &amp;gt;, 600 μg/g at diagnosis were found associated with a reduced EEN adherence in univariate and multivariate analysis. The remission rate of those who completed induction treatment was, 67%. A multivariate analysis showed that factor determining lower remission rate were age &amp;gt;, 15 years and PCDAI &amp;gt;, 50. With those results we were able to create a decisional algorithm which is provided in figure 1. Conclusion EEN administered for, 8 weeks is effective for inducing clinical remission. The rate of adherence is high but there is a group of patients (colonic involvement + hight FC) which are at risk of non-adherence and thus may be candidate for alternative dietary induction regimens. Moreover, older patients with moderate to severe active disease (PCDAI&amp;gt;40), are at higher risk of failing clinical remission achievement after EEN and may benefit from an early anti-TNF alpha treatment. Personalized treatment strategies should be proposed weighing the benefits and risks based on each patient’s disease location, phenotype and disease activity with the overall aim of obtaining rapid control of inflammation to reduce long-term bowel damage.

Resection rate of locally advanced pancreatic cancer in gemcitabine plus nab-paclitaxel versus FOLFIRINOX.

381 Background: There is no established treatment for locally advanced pancreatic cancer (LAPC), but by utilizing the regimens approved for metastatic pancreatic cancer, hope remains for rendering tumors resectable with chemotherapy. In this context, we looked at the resection rate in patients receiving gemcitabine plus nab-paclitaxel (Gem-Nab) in a prospective trial of patients with LAPC. Methods: TIGeR-PaC is an ongoing phase III clinical trial, studying the role of intra-arterial Gemcitabine (IA-Gem) in LAPC. The trial is designed with an induction phase where patients receive 3 cycles of Gem-Nab and a cycle of radiation after which they are randomized to IA-Gem or continuing with 4 cycles of Gem-Nab. We studied the resection rate in patients receiving Gem-Nab during induction who had subsequently continued receiving Gem-Nab post-randomization. Results: As of July 2020, 80 patients have been enrolled in the study. From this report, 30 patients were excluded because they had not completed induction and/or active treatment or were randomized to IA-Gem at the time of analysis. From the remaining 50 patients, 5 underwent resection for an overall resection rate of 10%. The median age for the total cohort was 67 years (range 47-83). Most of the resections were performed on the younger cohort of patients under 65 years (median age 60, range 47-65) in whom the resection rate was 4 out of 22 (18.2%). Conclusions: In the younger cohort of patients, TIGeR-PaC results are in line with the 15% resection rate in the LAPACT trial of patients with median age of 65 years, as reported by Phillip et al., 2020. In the TIGeR-PaC study the resection rate for LAPC treated with Gem-Nab was 10% overall, and 18.2% for younger patient population. These resection rates are comparable to the other reports for Gem-Nab and are similar to retrospective reports for the younger patients undergoing resection after treatment with FOLFIRINOX. Clinical trial information: NCT03257033.

Depth of Response to Isatuximab, Carfilzomib, Lenalidomide and Dexamethasone (Isa-KRd) in Front-Line Treatment of High-Risk Multiple Myeloma: Interim Analysis of the GMMG-CONCEPT Trial

Depth of Response to Isatuximab, Carfilzomib, Lenalidomide and Dexamethasone (Isa-KRd) in Front-Line Treatment of High-Risk Multiple Myeloma: Interim Analysis of the GMMG-CONCEPT Trial

Evaluation of Whole-Body MRI (WB-MRI) in Smoldering Multiple Myeloma (SMM)

Introduction Whole-body magnetic resonance imaging (WB-MRI), including multiplanar multisequence technique with diffusion weighted images, is a novel imaging technique being evaluated for patients with multiple myeloma (MM). WB-MRI is ideal for this population due to its high sensitivity for bone marrow signal changes and full anatomic coverage from vertex to mid-thighs. It is well established that patients with unequivocal focal lesions on MRI have worse outcomes. Currently the IMWG recommends that all patients with smoldering multiple myeloma (SMM) undergo WB-MRI (or whole spine MRI if WB-MRI is not available) to rule out two or more focal lesions which would classify the patient as having symptomatic myeloma requiring treatment. There is a clear benefit of using MRI for the detection of early focal myeloma lesions however less is known about findings in the SMM population. Detection of subtle findings such as one small focal lesion or heterogeneous bone marrow in WB-MRI has unknown clinical significance that needs to be further evaluated. This study aimed to evaluate the sensitivity of WB-MRI compared to other highly sensitive functional imaging modalities in patients with SMM both at baseline and after treatment. Methods Imaging of patients with WB-MRI performed at the National Institutes of Health Clinical Center Myeloma Program were reviewed and compared to whole spine MRI and 18F-FDG PET/CT completed at the same timepoint. The majority of patients were being evaluated for enrollment on clinical trials. Patients had undergone a WB-MRI with a 3-Tesla system either as a baseline study, after completion of induction treatment, or during follow up determined by the time DWI became available at our institution. The imaging protocol included sagittalT1 weighted (W) and Short tau inversion recovery (STIR) for spine and coronal, axial T1W and axial T2 TSE pulse sequences. The functional component included diffusion weighted imaging in the axial plane (b=0 and 900sec/mm2). Radiological interpretation was performed by two readers using myeloma response assessment and diagnosis system (My-RADS) {Messiou, 2019 #340}. WB-MRIs were categorized as positive if focal lesions or diffuse/heterogenous pattern of bone marrow infiltration were present. Similarly, 18F-FDG PET/CTs and whole spine MRIs were classified as positive if focal lesions or diffuse/heterogenous pattern of bone marrow were present. Results A total of 34 patients with SMM and 5 patients with relapsed refractory multiple myeloma (RRMM) had sequential WB-MRI and 18F-FDG PET/CT. Figure 1 summarizes the radiological data of the SMM population. Eleven of these patients had PET/CT, whole spine MRI, and WB-MRI at baseline. Twenty-five patients had PET/CT and WB-MRI completed after at least 8 cycles of treatment. Thirteen patients had consistently negative imaging at baseline, 7 of which also had negative imaging after treatment, while 2 patients were found to have new lesions seen on WB-MRI after treatment. Six patients had resolution of positive imaging seen at baseline after treatment. Among the 17 patients with a positive WB-MRI, 12 (71%; 95% CI 47% - 87%) had a negative correlating PET/CT. Among 5 patients with positive PET/CT at the same time point as a WB-MRI, only 1 (20%; 95% CI 2% - 64%) correlated to a negative WB-MRI. Figure 2 depicts findings from patients with RRMM for comparison. All imaging modalities showed multiple focal findings in all 5 patients. Conclusions This study depicts the high sensitivity of WB-MRI in the SMM population. Such a high sensitivity is especially needed in SMM and early myeloma when disease burden is lower and the decision for treatment is being considered. In comparison to the RRMM population where all three imaging modalities easily detect multiple focal lesions, WB-MRI tends to identify myeloma involvement in the SMM patients more than the other imaging techniques. This suggests the importance of utilizing WB-MRI when diagnosing SMM. In the SMM population, the prognostic significance of lesions that are discrepant between MRI and FDG PET/CT is not yet known. Further follow up is needed to evaluate any difference in hard endpoints such as progression free survival between patients with positive findings described by WB-MRI. Disclosures No relevant conflicts of interest to declare.

Depth of response to isatuximab, carfilzomib, lenalidomide, and dexamethasone (Isa-KRd) in front-line treatment of high-risk multiple myeloma: Interim analysis of the GMMG-CONCEPT trial.

8508 Background: High-risk (HR) multiple myeloma (MM) still has a significant impaired prognostic outcome. Addition of CD38 monoclonal antibodies to standard-of-care regimens significantly improved response rates and depth of response in newly diagnosed (ND) and relapsed/refractory MM patients (pts). Here, we report the prespecified end of induction interim analysis (IA) of the investigator-initiated GMMG-CONCEPT trial (NCT03104842), evaluating the quadruplet regimen isatuximab plus carfilzomib, lenalidomide and dexamethasone (Isa-KRd) in HR NDMM pts. Methods: 153 pts with HR NDMM are planned to be included into the trial. HR MM is defined by the presence of del17p or t(4;14) or t(14;16) or &gt; 3 copies 1q21 and ISS 2 or 3 stage disease. Pts receive 6 cycles of Isa-KRd induction, 4 cycles of Isa-KRd consolidation and Isa-KR maintenance. Transplant eligible pts (arm A) undergo high-dose therapy. Transplant ineligible pts (arm B) receive 2 additional cycles of Isa-KRd induction. The primary endpoint is MRD negativity measured by next-generation flow after consolidation. This IA reports on overall response rates (ORR) after induction. Additional MRD analysis will be presented. Results: 50 pts (46 arm A, 4 arm B) were included in the IA population for ORR. HR MM was defined by del17p in 52%, t(4;14) in 38%, t(14;16) in 12% and &gt; 3 copies 1q21 in 42%. 39/46 pts in arm A and 4/4 pts in arm B completed induction treatment. ORR was 100%, with 5 pts (10.0%) showing partial response (PR), 22 (44.0%; including 4 in arm B) very good partial response (VGPR) and 23 (46.0 %) complete response (CR). Median stem cell yield was 6.6 × 106CD34+ cells/kg. Grade 3/4 treatment-emergent adverse events (≥ 10%) with Isa-KRd included neutropenia (34.0%), leukopenia (26.0%) and thrombocytopenia (14.0%). Main non-hematologic toxicities grade 3/4 were hypertension (12.0%) and infection (8.0%). Conclusions: To the best of our knowledge, we report for the first time on a trial investigating solely HR NDMM and Isa-KRd quadruplet treatment. Isa-KRd induction induces deep responses in HR MM pts. The overall safety profile of Isa-KRd is expected and consistent with previous reports. The study is ongoing, with pts continuing to be included. Clinical trial information: 03104842 .

Nab-paclitaxel plus gemcitabine in patients with locally advanced pancreatic cancer (LAPACT): a multicentre, open-label phase 2 study

Treatment options for patients with unresectable locally advanced pancreatic cancer are scarce. Results from a subanalysis of the phase 3 MPACT trial in metastatic pancreatic cancer suggested potential activity of nab-paclitaxel plus gemcitabine against locally advanced pancreatic cancer. The objective of this phase 2 trial was to evaluate safety and efficacy of nab-paclitaxel plus gemcitabine in previously untreated locally advanced pancreatic cancer. This international, open-label, multicentre, phase 2 trial (LAPACT) took place at 35 sites in five countries (USA, France, Spain, Canada, and Italy). Patients with Eastern Cooperative Oncology Group performance status of up to 1 underwent six cycles of induction with nab-paclitaxel 125 mg/m2 plus gemcitabine 1000 mg/m2 (days 1, 8, and 15 of each 28-day cycle). After induction, patients without progressive disease or unacceptable adverse events were eligible to receive continued therapy per investigator's choice: continued nab-paclitaxel plus gemcitabine, chemoradiation, or surgery. The primary endpoint was time to treatment failure; secondary endpoints were disease control rate, overall response rate, progression-free survival, overall survival, safety, and quality of life. The reported efficacy outcomes were analysed in the intention-to-treat population, and safety outcomes were analysed in the treated population. This trial is registered with ClinicalTrials.gov, NCT02301143, and EudraCT, 2014-001408-23 and is complete. Between April 21, 2015, and April 26, 2018, 107 patients were enrolled in the study. 106 received the study treatment; one patient enrolled but did not receive treatment. 44 (41%) of 107 enrolled patients discontinued induction; the most common reason for discontinuing induction was adverse events (22 [21%] patients). 62 (58%) of 107 enrolled patients completed induction treatment and 47 (44%) patients subsequently received continued treatment per investigator's choice: 12 (11%) continued nab-paclitaxel plus gemcitabine, 18 (17%) received chemoradiation, and 17 (16%) underwent surgery (seven had R0 resection status, nine had R1). 15 (14%) patients completed induction treatment but did not receive continued treatment. Median time to treatment failure was 9·0 months (90% CI 7·3-10·1); median progression-free survival was 10·9 months (90% CI 9·3-11·6), and median overall survival was 18·8 months (90% CI 15·0-24·0). During induction, 83 patients achieved disease control and the disease control rate was 77·6% (90% CI 70·3-83·5). 36 patients had a best response of partial response; the overall response rate during induction was 33·6% (90% CI 26·6-41·5). The most common treatment-emergent adverse events that were grade 3 or higher in the treated population during induction were neutropenia (35 [33%] of 106 patients), anaemia (12 [11%]), and fatigue (11 [10%]). The most common treatment-emergent serious adverse events during induction were pneumonia (five [5%] patients), pyrexia (five [5%]), and febrile neutropenia (three [3%]). No deaths were caused by treatment-related adverse events during the induction phase, and global quality of life was maintained in most patients. The data from this trial support the tolerability and activity of nab-paclitaxel plus gemcitabine for locally advanced pancreatic cancer, and a potential to convert unresectable, locally advanced disease to surgically resectable disease. The safety profile was generally consistent with previous findings. Celgene.

EXPERIENCE OF TOFACITINIB USING IN THERAPY OF ULCERATIVE COLITIS IN REAL CLINICAL PRACTICE

AIM: to demonstrate the first Russian experience with the use of tofaciminib (TOFA) for the treatment of moderate and severe UC in real clinical practice.PATIENTS AND METHODS: eighty-five patients with UC (aged 41.38±14.69 years, average disease duration 9.55±5.27 years, mild UC – 3.5%, moderate UC – 41.2%, severe – 52.9%, acute severe UC – 2.6%), resistant to corticosteroid therapy (36.5%) and biological agents (61.2%), were prescribed with TOFA at an induction dose of 10 mg 2 times a day, followed by a decrease in the dose to a maintenance dose (5 mg 2 times a day). Early clinical response, clinical and endoscopic remission, prevalence and dynamic of extraintestinal manifestations were assessed at 8 and 12 weeks of treatment, as well as safety and tolerability.RESULTS: Sixty-eight (80.0%) patients completed induction treatment with TOFA for 8 weeks, other patients continue to receive TOFA. A quick response within one week was detected in 41 (50.6%) patients, on average, on the 5th day of therapy. At the end of induction, 52 (76.5%) patients achieved clinical remission, 3 (4.4%) achieved a clinical response, 13 (19.1%) patients showed no positive changes. Of the 53 patients observed over 12 weeks, 41 (77.4%) had clinical remission, 6 (11.3%) had clinical improvement, and 6 (11.3%) patients had no response to the treatment. The changes of extraintestinal manifestations were positive: 55.2% of patients at week 8 and 77.8% of patients at week 12 showed clinical improvement, mainly in relation to the joint syndrome. One episode of herpes zoster infection, one case of anemia, were identified dur-ing 12 weeks of follow-up.CONCLUSION: TOFA in UC is effective in achieving a rapid clinical response, clinical remission and mucosal healing in patients who do not adequately respond to therapy with basic as well as biological drugs. Tofacitinib is an effective and safe therapeutic option for this challenging patient population.

Efficacy and Safety of Ixazomib-Dexamethasone, Ixazomib-Cyclophosphamide-Dexamethasone, Ixazomib-Thalidomide-Dexamethasone and Ixazomib-Bendamustine-Dexamethasone for Elderly Newly Diagnosed Multiple Myeloma (NDMM) Patients: Analysis of the Phase II Randomized Unito-EMN10 Study

Efficacy and Safety of Ixazomib-Dexamethasone, Ixazomib-Cyclophosphamide-Dexamethasone, Ixazomib-Thalidomide-Dexamethasone and Ixazomib-Bendamustine-Dexamethasone for Elderly Newly Diagnosed Multiple Myeloma (NDMM) Patients: Analysis of the Phase II Randomized Unito-EMN10 Study

Immune Priming with Single-Agent Nivolumab Followed By Combined Nivolumab & Rituximab Is Safe and Efficacious for First-Line Treatment of Follicular Lymphoma; Interim Analysis of the ‘1st FLOR’ Study

Background: The effectiveness of anti-tumour T and NK cells in malignancy is mitigated by the engagement of the immune check point pathway with PD-1/PDL-1 interaction.1,2 Immune manipulation with PD-1 inhibition, in combination with rituximab, can increase T cell anti-tumour effect and enhance NK cell antibody dependent cell cytotoxicity (ADCC), with this combination proving efficacious in rituximab-refractory follicular lymphoma (FL).3 The concept of 'priming' the immune system with nivolumab, a PD-1 inhibitor, prior to tumour-directed therapy has rationale and evidence, but the safety of this approach in previously untreated FL is not described.4 We are conducting a phase II Simon's two stage study to assess the feasibility and safety of combination nivolumab and rituximab in these patients and present the pre-planned interim analysis results. Methods: The 1st FLOR study (NCT03245021) is an ongoing open-label, multi-centre, phase 2 study of nivolumab and rituximab in patients with previously untreated stage III-IV grade 1-3A FL requiring systemic therapy. Eligible patients are ECOG ≤ 2 and do not require urgent debulking therapy. All patients receive induction nivolumab 240mg intravenously (IV) every 2 weeks for 4 cycles. Patients achieving complete response (CR) based on PET/CT Lugano criteria receive a further 4 cycles of 240mg IV nivolumab monotherapy then maintenance nivolumab 480mg IV every 4 weeks for 12 cycles. Patients achieving less than CR received 240mg nivolumab plus 375mg/m2 IV rituximab every 2 weeks for 4 cycles. Those achieving a response at the end of 8 cycles of nivolumab and rituximab continue maintenance nivolumab 480mg IV every 4 weeks for 12 cycles PLUS rituximab 375mg/m2 every 12 weeks for 8 cycles. PET/CT assessment is performed at baseline, after 4 cycles of nivolumab, after 8 cycles of nivolumab +/-rituximab and prior to maintenance cycle 6. The primary end point is safety, with a pre-planned analysis after the first 19 patients completed induction treatment with 8 cycles of nivolumab +/- rituximab. Secondary endpoints included response rates and time to treatment failure (TTF). The planned total study population is 39 patients, with a Simon's two-stage design. We report the results of the pre-planned interim analysis. Results: Baseline characteristics are summarised in Table 1. Treatment-related adverse events (AEs) were predominantly grade 1-2 with fatigue (74%), infection (59%), nausea/vomiting (36%) and abdominal pain (36%) being the most common (Table 2). Immune-related (IR) AEs were reported in 79% of all patients. Grade 3-4 IRAEs were uncommon and included; pancreatitis plus hepatitis (1 patient); transaminitis (n=1), hyperglycaemia (n=2) and asymptomatic lipase increase (n=2) (Table 3). Median follow-up was 17 months. The overall response rate (ORR) was 84% (16/19) with 47% (9/19) achieving CR, 37% (7/19) partial response (PR), 5% (1/19) stable disease and 11% (2/19) progressive disease (PD) as best response (Figure 1A and 1B). Median time to CR was 5 months. Median TTF was 3.4 months. Three pts (16%) discontinued study treatment; 2 due to early disease progression (1 with suspicion of transformation in cycle 2) and 1 due to development of constitutional symptoms with stable disease. Conclusion: In this planned interim analysis, the combination of nivolumab and rituximab in treatment naive follicular lymphoma is associated with a favourable toxicity profile and high overall and complete response rates potentially providing patients an alternative to traditional chemotherapy. Acknowledgements: Bristol-myers Squibb provided funding and nivolumab for this study.

Efficacy and Tolerability of Ixazomib, Daratumumab and Low Dose Dexamethasone (Ixa Dara dex) in Unfit and Frail Newly Diagnosed Multiple Myeloma (NDMM) Patients; Results of the Interim Efficacy Analysis of the Phase II HOVON 143 Study

Efficacy and Tolerability of Ixazomib, Daratumumab and Low Dose Dexamethasone (Ixa Dara dex) in Unfit and Frail Newly Diagnosed Multiple Myeloma (NDMM) Patients; Results of the Interim Efficacy Analysis of the Phase II HOVON 143 Study