Interim Response Research Articles

DLBCL Interim Response Evaluation for Customised Therapy

DLBCL Interim Response Evaluation for Customised Therapy

PET-adapted approaches to primary therapy for advanced Hodgkin lymphoma.

Recent results of randomized phase III studies of FDG-PET-adapted therapy for advanced Hodgkin lymphoma (HL) have clearly demonstrated benefit to alteration of treatment according to interim response, in particular regarding reducing toxicity while maintaining efficacy. However, these studies have differences in design including initial chemotherapy regimen, PET response criteria, patient populations enrolled, and inclusion of radiation, and report different results regarding efficacy and toxicities, which makes cross-trial comparisons difficult. Practitioners are presented with deciding which of these approaches will provide the optimum outcome, balancing toxicity and efficacy, and for which patient with advanced-stage HL. This review summarizes the observations reported from these trials and provides context to help guide physicians and patients in treatment decisions for advanced HL.

High Risk Cytogenetic and Immunohistochemistry Findings in Monomorphic Post-Transplant Lymphoproliferative Disorder Following Solid Organ Transplant - a Single Center Experience

Background: Post-transplant lymphoproliferative disorders (PTLD) represent a heterogeneous group of immune-deficiency related lymphoid malignancies occurring after solid organ transplant (SOT) or bone marrow transplant. Monomorphic PTLD (mPTLD) is typically characterized by diffuse large B-cell lymphoma (DLBCL), though other mature B and T-cell lymphomas make up a small contribution. In one of the largest prospective clinical trials in PTLD, Trappe et al described a risk stratified sequential treatment approach using rituximab (R) monotherapy induction followed by either (R) consolidation or chemoimmunotherapy (chemoR) based on interim response. The role of cytogenetic and immunohistochemistry (IHC) risk stratification have not been fully described in mPTLD. In this study, we aim to identify clinical factors which may lead to differences in clinical outcomes in mPTLD. Methods: Pts diagnosed with mPTLD following SOT at the University of North Carolina at Chapel Hill were identified by an IRB approved EMERSE query of the medical record. Histologic classification was determined by pathologist review at the time of diagnosis. DLBCL subtype was determined as either germinal center B-Cell (GCB) type, non-GCB type, or unclassifiable using Hans IHC criteria. Double-Hit lymphoma (DHL) was defined as the presence of a MYC rearrangement in combination with either a BCL2 or BCL6 rearrangement by in-situ hybridization. Double expressor lymphoma (DEL) was defined as the presence of MYC and BCL2 co-expression by IHC. Additional copies of MYC or BCL2 were determined by in-situ hybridization. Clinical responses were determined per Lugano criteria. Cox regression was used to evaluate the association of covariates of interest with overall survival (OS). Results: A total of 29 pts were diagnosed with mPTLD between 2010 and 2019. The median age at diagnosis was 55 years (range, 19-84 years). Transplanted organs included 16 kidney (56%), 5 lung (17%), 4 liver (14%), 3 heart (10%), and 1 kidney/heart (3%). The median time from transplant to diagnosis was 7.1 years (range, 0.2 to 24.5 years). Sub-classification of mPTLD revealed 11 non-GCB type (38%), 10 GCB type (35%), 7 unclassifiable DLBCL (24%), and 1 PTCL (3%). EBV encoded RNA (EBER) in-situ hybridization was positive in 10 pts (35%) and concurrent EBV reactivation was detected in 7 of the 10 pts. Both categorized EBV encoded RNA (EBER) in-situ hybridization, and GCB vs non-GCB type mPTLD did not appear to be significantly associated with OS. mPTLD that was DHL (1 pt), DEL (3 pts), or had extra copies of MYC/BCL2 (3 pts) had significantly shorter OS (p=0.006, Figure 1). The 1 year OS for those with high risk cytogenetics and IHC was 29% [95% CI: 4% to 61%] versus those without at 76% [52% to 89%]. Consistent with prior studies, pts with revised International Prognostic Index (R-IPI) high (3-5) had a significantly shorter OS (p=0.001, Figure 2). The 1 year OS for those with dichotomized R-IPI high was 38% [95% CI: 14% to 63%] versus those with R-IPI low at 87% [95% CI: 56% to 96%]. All pts had a reduction in immunosuppression at diagnosis. Fourteen pts (48%) were treated with front-line (R) monotherapy. Seven of these pts achieved a CR (50%), 3 pts achieved a PR, 3 pts developed progressive disease and 1 pt died during therapy. Eleven pts (38%) were treated with front-line chemoR. Seven of these pts achieved a CR, 3 pts achieved a PR, and 1 pt died during therapy. Pts who achieved a CR or PR with (R) monotherapy induction had a better OS compared to pts who either had no response to (R) or were treated with chemoR (p=0.01, Figure 3). The 1 year OS for (R) CR/PR was 90% [47% to 99%] versus all other pts including those treated with combination chemoR at 47% [23% to 68%]. Of note, pts who achieved a CR with either (R) induction or chemoR in the front-line setting had borderline significantly improved OS (p=0.06). Conclusion: Response to therapy within mPTLD is quite variable. In this study, we reveal a population of mPTLD with particularly poor outcomes (DHL, DEL, and extra copies of MYC/BCL2). To our knowledge, this is the first study to show the dramatic impact of poor risk cytogenetic and IHC findings on clinical outcomes in mPTLD. As seen in other cohorts, high R-IPI score was associated with poor outcomes. Objective response to (R) induction in the front-line setting was associated with improved survival. Disclosures Grover: Seattle Genetics: Consultancy. Dittus:Seattle Genetics: Consultancy.

Impact of Interim FDG-PET (iPET) in the Outcomes of Patients with Aggressive B-Cell Lymphomas Receiving DA-EPOCH-R

Introduction: 2-[18F] fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) remains the standard of care for baseline and end of treatment scans for aggressive non-Hodgkin lymphomas (NHLs). However, the role of interim FDG-PET remains not as well defined across aggressive NHLs, especially in the era of high-intensity chemoimmunotherapy. Interim FDG-PET (iPET) can serve as an early prognostic tool, and prior studies evaluating the utility of iPET-guided treatment strategies primarily focused on diffuse large B-cell lymphomas (DLBCL) and frontline R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone). Classification criteria systems assessing response also differ between studies with no clear consensus between use of Deauville criteria (DC), International Harmonization Project (IHP), and the ΔSUVmax method. Methods: This study evaluates our institutional experience with iPET during treatment with DA-EPOCH ± R (dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin with or without Rituximab) in aggressive NHLs. We retrospectively evaluated 70 patients at Moffitt Cancer Center who started on DA-EPOCH ± R between 1/1/2014 to 12/31/2018 for aggressive NHLs. Response on interim and end-of-treatment (EOT) scans were graded per DC, IHP, and ΔSUVmax methods, and progression free survival (PFS) probability estimates were calculated with chi-square testing and Kaplan Meier method. PFS outcomes were compared between interim negative and positive scans based on each scoring method. Outcomes were also compared between groups based on interim versus EOT positive or negative scans. Results: We identified 70 patients with aggressive NHLs who received DA-EPOCH ± R at our institute. The most common diagnoses were DLBCL (61%) followed by Burkitt's lymphoma (10%), primary mediastinal B-cell lymphoma (9%), plasmablastic lymphoma (7%), gray zone lymphoma (6%), primary cutaneous large B-cell lymphoma (1%), primary effusion lymphoma (1%), and other high-grade NHL not otherwise specified (3%). Of the 43 patients with DLBCL, 21/43 (49%) had double hit lymphoma (DHL) while 7/43 (16%) had triple hit lymphoma (THL), and 3/43 (7%) had MYC-rearranged DLBCL while 2/43 (5%) had double expressor DLBCL. Thirty nine out of 70 (56%) were female, and median age at diagnosis was 58.39 years (range 22.99 - 86.86 years). Most patients had stage IV disease (49/70, 70%), and 43/70 (61%) had more than one extranodal site while 45/70 (64%) had IPI score ≥ 3. Forty-six out of 70 (66%) received central nervous system prophylaxis, most with intrathecal chemotherapy (44/70, 63%). Fifty-five out of 70 (79%) had iPET available while 6/70 (9%) had interim computerized tomography (CT) scans. Fifty-six out of 70 (80%) had EOT PET, and 4/70 (6%) had EOT CT scans. Sustained complete remission occurred in 46/70 (66%) after frontline DA-EPOCH ± R (CR1), and 12/70 (17%) were primary refractory while 5/70 (7%) had relapse after CR1. Four of 70 (6%) died before cycle 3, and 3/70 (4%) did not have long-term follow-up due to transition of care elsewhere. Median follow-up was 15.29 months (range 0.85 - 60.09 months). There was significantly better PFS observed if iPET showed DC 1-3 compared to DC 4-5 (Χ2=5.707, p=0.0169), and PFS was better if iPET was negative by IHP criteria (Χ2=4.254, p=0.0392) or ΔSUVmax method (Χ2=6.411, p=0.0113). Comparing iPET to EOT PET, there was significantly better PFS if iPET was negative with EOT PET negative (iPET-/EOT-) compared to iPET positive with EOT negative (iPET+/EOT-), and iPET+/EOT+ and iPET-/EOT+ had worse PFS after iPET-/EOT- and iPET+/EOT- respectively. This pattern in iPET/EOT PFS probability remained consistent when comparing DC (Χ2=30.041, p<0.0001), IHP (Χ2=49.078, p<0.0001), and ΔSUVmax method (Χ2=9.126, p=0.0104). These findings fit clinical expectations with positive EOT scans indicating primary refractory disease. There was no significant difference in PFS when comparing DLBCL versus non-DLBCL (Χ2=3.461, p=0.0628) or DHL/THL versus non-DHL/THL diagnoses (Χ2=2.850, p=0.0914). Conclusion: Our findings indicate a prognostic role of iPET during treatment with DA-EPOCH ± R for aggressive NHLs. Significant differences in PFS were seen when graded by DC, IHP, and ΔSUVmax methods used in prior studies and when comparing interim versus EOT response. Larger studies are needed to confirm these findings. Disclosures Bello: Celgene: Speakers Bureau. Shah:Novartis: Honoraria; AstraZeneca: Honoraria; Spectrum/Astrotech: Honoraria; Adaptive Biotechnologies: Honoraria; Pharmacyclics: Honoraria; Jazz Pharmaceuticals: Research Funding; Incyte: Research Funding; Kite/Gilead: Honoraria; Celgene/Juno: Honoraria. Sokol:EUSA: Consultancy. Chavez:Janssen Pharmaceuticals, Inc.: Speakers Bureau; Genentech: Speakers Bureau; Kite Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees.

Clinical Application of Circulating Tumor DNA in Plasma of Patients with Primary Central Nervous System Lymphoma

Introduction Circulating tumor DNA (ctDNA) which is tumor‐specific DNA sequences found in blood, has been considered an important new strategy that will aid in the treatment of non‐Hodgkin's lymphoma (NHL) because ctDNA could be used in various aspects of NHL management such as diagnosis prior to therapy and early prediction of treatment failure as well as disease relapse. High‐throughput DNA sequencing of ctDNA encoding tumor‐specific mutations also could serve as a surrogate for the entire tumor genome and overcome the barrier of spatial and temporal tumor heterogeneity. However, the role of ctDNA in blood is still not determined in primary central nervous system lymphoma (PCNSL) because it is not clear how blood-brain barrier affects the level of ctDNA in blood of patients with PCNSL. Thus, we performed this pilot study to explore clinical relevance of ctDNA in patients who were consecutively diagnosed with PCNSL. Methods The study population was from our prospective cohort study for lymphoma patients (NCT03117036) that has been enrolling patients since January 2017. All patients were enrolled after obtaining written informed consents, and plasma samples for the isolation of ctDNA and targeted sequencing were collected at diagnosis and after the interim and final response evaluation. Additional samples were also collected at the time of relapse. Using DNA samples extracted from plasma, high-depth targeted sequencing consisting of 66 genes was performed. Out of 853 patients enrolled in this cohort, we selected 42 patients who were diagnosed with PCNSL after excluding secondary CNS lymphoma. Results Their median age was 52 years (range, 19-85 years) and, male (n=22) was a slightly more than female (n=20). All patients included in the study were administrated with combination systemic chemotherapy consist of rituximab, high dose methotrexate, vincristine and procarbazine as the first line. By confirming the somatic genetic mutation of tissue samples, we have proven that the detected ctDNA originated from the parent brain tumor. In plasma analysis, targeted sequencing was performed for 41 patients except a patient as a DNA quality control failure. Among 41 patients, the ctDNA amount at the diagnosis was 13.6ng/mL (Range 3.3-121.6). Fifteen patients (36.58%) only carried at least one mutation within the target regions of the panel. BCOR, BTG2 and IDH2 were highly ranked mutated genes in our study, followed by BTG1, DNMT3A, DUSP2, HIST1H1E, PIK3CA, PIK3CD, and PIM. Unlike previously reported studies, we could not observe MYD88 mutation, but more wide range profiles of ctDNA obtained. Compared to ctDNA amount and brain MRI imaging at baseline, we measured the long axis of the largest brain mass and analyzed the association with ctDNA amount. We could figure out the correlation between the amount of ctDNA and brain mass size. The median follow-up duration was 8.9 months (range 1.1-71.2) and median overall survival was 45.8 months (NR). The patients detected ctDNA at the diagnosis did not show any particularly inferior survival outcome than patients without ctDNA (NR vs.45.8months, p-value=0.92). Conclusion In the results of evaluating only the baseline samples, the detection rate in our study was 37% in PCNSL. In addition, the amount of plasma ctDNA showed the possibility of clinical application to predict disease burden at the time of diagnosis. In the future, we would analyze serial ctDNA amount, after then investigate the correlation with chemotherapy response and residual disease monitoring. In conclusion, although more research and time are required for the settlement of ctDNA in clinical practice, it will be possible to realize precision medicine with the advantage of non-invasive procedure. Disclosures Kim: F. Hoffmann-La Roche Ltd: Research Funding; Celltrion: Research Funding; Novartis: Research Funding; Donga: Research Funding; Kyowa-Kirin: Research Funding; Novartis: Research Funding; J + J: Research Funding.

Ibrutinib Maintenance (I-M) Following Frontline Intensive Induction in Mantle Cell Lymphoma (MCL): Interim Safety, Response and Sequential MRD Evaluation

Ibrutinib Maintenance (I-M) Following Frontline Intensive Induction in Mantle Cell Lymphoma (MCL): Interim Safety, Response and Sequential MRD Evaluation

Metabolic Tumor Volume for Early Response Assessment in Early-Stage Unfavorable Hodgkin Lymphoma Treated with Nivolumab in the GHSG Nivahl Phase II Trial

Background: Metabolic tumor volume (MTV) measured by FDG-PET/CT is becoming established as an independent risk factor for treatment failure in Hodgkin lymphoma (HL). Moreover, response to treatment with novel agents including checkpoint inhibitors may be better reflected by a decrease in MTV than by currently used response criteria. Our aim was to evaluate the early response to first-line HL treatment with the PD-1 inhibitor nivolumab using MTV. Methods: The analysis set included 59 patients with newly diagnosed, early-stage unfavorable HL treated within the prospective, multicenter, open label, randomized, phase II NIVAHL trial of the German Hodgkin Study Group (GHSG). Patients in NIVAHL were randomized to receive either four double cycles of nivolumab, doxorubicin, vinblastine, and dacarbazine (4x Nivo-AVD, group A, n=31) or a sequential therapy starting with 4x nivolumab monotherapy followed by 2xNivo-AVD and 2x AVD (group B, n=28). Early response to treatment was assessed at a 1st interim restaging after either 2x Nivo-AVD or 4x nivolumab. All NIVAHL patients who underwent PET at both initial staging and early response assessment, with images available to the central review panel for quantitative analysis before April 30th 2019, were included. MTV was calculated using a fixed SUV threshold of 4 for both staging and restaging. Results: Patient characteristics of the MTV analysis subset presented here did not differ in any relevant way from the overall NIVAHL trial population. Median age of the 59 patients was 27 years (range 18-57) with a female predominance (61%). All patients presented with stage II disease (IIB 27%) and ≥3 involved areas was the most common risk factor (75%) followed by elevated erythrocyte sedimentation rate (51%), extranodal disease (17%) and large mediastinal mass (14%). Mean MTV at initial staging was 124 ml (range 4 - 578 ml) and 177 ml (11 - 581 ml) in groups A and B, respectively. In both groups a marked decrease in MTV was observed at the 1st interim restaging (Figure 1): After 2x Nivo-AVD all patients in group A showed a reduction of MTV >80% (mean percentage change in MTV -99.8%). In group B a reduction of MTV >80% was observed in 26/28 patients (93%), while in 2/28 patients an increase <10% was observed (mean percentage change in MTV -91%; Figure 1). The mean residual MTV at interim restaging after 2x Nivo-AVD was 0.4 ml (range 0 - 8) in group A and 11 ml after 4x nivolumab in group B (range 0 - 176). The reduction of MTV was observed irrespective of initial MTV with a similar mean percentage change in patients above and below the median MTV in both groups. When applying the Deauville score, however, the number of patients presenting with a Deauville score ≥4 was higher in the group with an initial MTV above the median MTV than in the group where initial MTV lay below the median value. Using the Lugano criteria and a Deauville score of 4 or higher as cut-off for PET-positivity, early interim complete remission was observed in 81% of patients after 2xNivo-AVD, as compared to 51% after 4x nivolumab monotherapy. Further analyses regarding MTV and response at the 2nd and end-of-treatment restaging as well as survival data are not yet available due to limited follow-up. These data will be available at the time of presentation and shown at the meeting. Conclusions: Marked reductions of MTV demonstrate an excellent early efficacy for both 2x Nivo-AVD and 4x nivolumab as 1st-line therapy for early-stage unfavorable HL. The unexpectedly and previously unreported high MTV reduction with nivolumab monotherapy indicates a relevant potential of anti-PD1 mono- or debulking-therapy in the 1st-line treatment of early-stage unfavorable HL. Early interim response assessment based on MTV may help to identify HL patients treated with anti-PD1 antibodies in whom a significant reduction or even omission of chemotherapy could be considered. MTV appears to have the potential to accurately measure response to immune checkpoint inhibition. However, correlation of early MTV reduction with response at the end of treatment or with survival data is pending. Disclosures Borchmann: Novartis: Honoraria, Research Funding. Bröckelmann:Bristol-Myers Squibb: Honoraria, Other: Travel Support, Research Funding; Takeda: Consultancy, Honoraria, Other: Travel Support, Research Funding; MSD Sharpe & Dohme: Research Funding.

Coal-Mine Canaries in Clinical Psychology: Getting Better at Identifying Early Signals of Treatment Nonresponse

Sequential, multiple-assignment, randomized trials (SMARTs) have emerged as a preferred design strategy with which to inform dynamic mental-health treatment decisions and adaptive interventions, yet their potential to improve patient outcomes is only as strong as the extent to which selected tailoring variables (i.e., interim response factors that dictate whether treatment shifts course) do indeed predict ultimate response. To date, tailoring variable selection has rarely drawn on adequately powered findings or conceptual links to interim target mechanisms underlying treatment response. Building on early work in this area, we detail a strategy that leverages randomized controlled trial data to simultaneously compare candidate tailoring variables at candidate decision points and their relationships with treatment response. Findings from such efforts can improve the conceptual clarity and efficiency of SMARTs, laying a foundation for modern clinical trials to ask, “Are treatment-related change mechanisms being affected and, if not, what is the most appropriate next treatment strategy?”

PB1798 EFFICACY AND TOLERABILITY OF R‐MINICHOP IMMUNOCHEMOTHERAPY IN ELDERLY PATIENTS WITH HIGH GRADE NON‐HODGKIN LYMPHOMA: REAL WORLD EXPERIENCE AT A RURAL UK HOSPITAL.

Background:The increasing incidence of high grade Non‐Hodgkin Lymphoma in aging populations places a significant burden on healthcare systems. Co‐morbidity, frailty, and reduced organ and physiological reserve contribute to treatment‐related complications. R‐miniCHOP is emerging as the standard of care for these patient with good efficacy and tolerability in clinical trial settings. We reviewed our single centre experience of delivering R‐miniCHOP therapy to elderly patients with high grade lymphoma over a 5 year period in a rural British hospital.Aims:We sought to assess the clinical efficacy and tolerability of attenuated immunochemotherapy (R‐miniCHOP) in elderly patients with high grade lymphoma in a ‘real‐world’ setting with medium term follow up of up to 7 years.Methods:We conducted a retrospective case review of patients who presented to our haematology service with aggressive non‐Hodgkin lymphoma and received R‐miniCHOP attenuated immunochemotherapy as outpatient therapy between 2012 and 2017. Patients received rituximab (375 mg/m2), cyclophosphamide (400 mg/m2), doxorubicin (25 mg/m2) and vincristine (1 mg/m2) on day 1 of each cycle, and prednisolone (40 mg/m2) on days 1‐5. We examined baseline patient characteristics, ECOG performance status, Ann Arbor stage, serum lactate dehydrogenase (LDH) concentration and International Prognostic Index (IPI) at diagnosis. Furthermore, we undertook a review of interim or post chemo disease response by PET/CT imaging and determined renal, cardiac, hepatic and bone marrow toxicities in all patients with follow up until January 2019. A route cause analysis was undertaken for all patients who had died during the follow‐up period.Results:We identified 23 patients treated with R‐miniCHOP between 2012 and 2017. Median age at diagnosis was 82 years (range 74‐88) and 52% were female. Diffuse large B‐cell lymphoma (DLBL) was the most common diagnosis (74%). Mean serum [LDH] at diagnosis was 320U/L (range 162‐1202U/L). Ann Arbor staging and IPI are detailed in Table 1 but patients of all IPI stage were represented in our cohort. The mean number of immunochemotherapy cycles administered was 4 (range 1‐8) and only 3 patients required dose/regimen modifications. Fatigue (52%), peripheral neuropathy (26%), and alopecia (22%) were the most commonly identified toxicities. Two patients (9%) experienced significant cardiotoxicity with echocardiographic evidence of reduced left ventricular ejection fraction. There were no intensive care admissions or deaths related to neutropenic sepsis. Overall, 30% of patients experienced a partial treatment response and a further 39% were in clinical remission at the time of reporting. Ten patients (43%) died over the follow up period, with 5 deaths attributable to disease progression, 1 died of GI bleeding which may have been associated with chemotherapy and the other 4 died of alternative unrelated causes.Summary/Conclusion:In our single centre experience at a small rural general hospital, attenuated immunochemotherapy proves an efficacious and generally well‐tolerated treatment regimen for elderly patients with high grade non‐Hodgkin lymphoma and can provide lasting remissions for a substantial number of patients in this age group. These data are broadly in line with a previous phase 2 study of R‐miniCHOP in patients aged over 80 years with DLBL and support the continued use of this regimen in elderly patients with high grade NHL receiving treatment in a variety of settings. (Peyrade et al., Lancet Oncology 2013).image

PROGNOSTIC VALUE OF BASELINE FDG PET PARAMETERS IN HIGH RISK DIFFUSE LARGE B‐CELL LYMPHOMA PATIENTS

Introduction: In treatment of diffuse large cell lymphoma (DLBCL) PET/CT is currently used as interim risk stratification and response evaluation. Here, a high risk cohort of patients included in a Nordic multi-centre study was analysed to evaluate possible associations between baseline FDG-PET parameters and patient outcome. Methods: Patients with available baseline PET/CT were included for study. Patients were treated with dose-dense chemo-immunotherapy, and data on overall survival (OS) and progression-free survival (PFS) were available for all patients. The following PET parameters were derived for each lesion: Standardized uptake value (SUV) max, metabolic tumour volume (MTV) and total lesion glycolysis (TLG). Total MTV and TLG values (tMTV and tTLG) were evaluated as possible predictors of outcome. Each variable was divided at the median and high vs. low values were entered into Cox regression. Analyses were adjusted for age and international prognostic index (IPI) score. Results: Fifty-one patients were included for study. Median age was 52 years and 29 % were female. Median follow-up time was 42 months (5-66). During follow-up, nine patients died, and ten patients relapsed. Median baseline values (range) for tMTV, SUVmax and tTLG were 567.0 (3.1 – 13505.9), 20.5 (5.1-79.0) and 4615.3 (15.3– 46393.3), respectively. In adjusted analyses, tMTVwas significantly associated with both increased mortality (HR 5.2, 1.1-11.3-, p=0.037) and relapse or death (HR 4.7, 1.0-10.4, p=0.046). No significant associations were seen for SUVmax or tTLG. Conclusion: Baseline tMTV could be a promising marker for risk stratification at baseline. However, this is a small study sample of high risk DLBCL patients, and results must be interpreted with caution. A larger study of baseline parameters and outcome seems warranted. Keywords: B-cell lymphoma; positron emission tomography (PET); prognostic indices.

PS1371 ELOTUZUMAB IN COMBINATION WITH CARFILZOMIB, LENALIDOMIDE, AND DEXAMETHASONE (KRD) IN PATIENTS WITH NEWLY DIAGNOSED MULTIPLE MYELOMA (NDMM): A PHASE 2 MMRC TRIAL

Background:Several recent studies have showed improved results with addition of antibodies to anti‐myeloma regimens. The KRd combination is highly active in NDMM. We hypothesized that addition of elotuzumab (ELO) to KRd (E‐KRd combination) would improve efficacy as compared to KRd.Aims:We report interim response data at key landmark timepoints of the studyMethods:The study has enrolled newly diagnosed patients (pts) requiring treatment as per IMWG criteria, regardless of transplantation eligibility. Per protocol, pts receive 12–24 cycles of E‐KRd, with adaptive design of the duration of E‐KRd treatment based on sustained MRD‐negativity by next gene sequencing (NGS) clonoSEQ (Adaptive Biotechnologies), followed by E‐Rd maintenance. ELO is given at 10 mg/kg QW for Cycles 1–2, Q2W for Cycles 3+, and Q4W during E‐Rd maintenance. Carfilzomib (K) is administered on Days 1, 8 and 15 of each 28‐day cycle, 20 mg/m2 on C1D1, then escalated up to 56 mg/m2 or 70 mg/m2 based on tolerability. Lenalidomide 25 mg is given on Days 1–21 and dexamethasone 20–40 mg per week. Per protocol, transplant candidates undergo stem cell collection after C4 using G‐CSF plus plerixafor, and then resume E‐KRd treatment. Pts who choose to discontinue treatment to receive autologous stem cell transplant (ASCT) are censored from the analysis at the time of their last cycle of treatment. Landmark evaluations are performed after 4, 8, 12, 18, and 24 cycles and include MRD evaluation using multi‐color flow cytometry (MCF) with 10–5 sensitivity and by NGS with 10–5–10–6 sensitivity, and by Mass Spectrometry (MassSpec) for sCR confirmation. A total of 40, transplant ineligible and/or transplant eligible pts who agree to defer ASCT will be enrolled as well as an additional 15 pts who plan to proceed to ASCT. The primary end‐point of the study is sCR/MRD(‐) rate after 8 cycles of E‐KRd therapy for the transplant ineligible/deferred pts and sCR/MRD(‐) rate at the end of 4 cycles for all enrolled pts.Results:Twenty‐four pts (median [range] age 61, [46–81]) were enrolled, of which 11 pts (46%) had IMWG high‐risk cytogenetics, including 5 pts (21%) with del p53. At the cut‐off date Feb 21, 2019, pts received a median of 4 (1–20) treatment cycles. Per protocol criteria, 10 pts escalated carfilzomib dose to 70 mg/m2. Median (range) duration of follow‐up was 9.7 (1–19) months. Four (17%) pts discontinued treatment (1 adverse event [cardio‐pulmonary toxicity]; 1 elective ASCT and 2 progressive disease). In intent‐to‐treat (ITT), ORR was 100% (50% CR/sCR, 95% at ≥VGPR (N = 22, 2 of 24 pts are too early to assess, <1 cycle); all pts achieved at least PR after C1 with CR/sCR rates 36% and 60% at the end of 4 and 8 cycles, respectively. For the ITT population, MRD(‐) rates were 70% by MFC at the end of 4 cycles (N = 20) and 70% by MFC (N = 10) and 56% by NGS (N = 9) at the end of 8 cycles. The most common non‐hematological AEs (all grades) were fatigue (63%), fever (33%), dyspnea (33%), upper respiratory infection (29%), constipation (25%), diarrhea (25%), and rash (25%). Serious AEs occurred in 9 pts (38%) and 41% pts experiences TEAE. The most common grade 3/4 TEAEs (>10%) were pneumonia (17%) and lymphopenia (13%). No grade 5 TEAE was reported. Updated results, including pending MassSpec analyses and MRD analyses by NGS will be presented at the meeting.Summary/Conclusion:The addition of ELO to KRd demonstrated manageable toxicity profile and promising activity suggestive of possible benefit of adding this agent to KRd, with high rates of deep responses including MRD‐negativity

Evolution of United States Legislation to Facilitate Bystander Response to Opioid Overdose

Introduction:Opioid overdose deaths in the United States are increasing. Time to restoration of ventilation is critical. Rapid bystander administration of opioid antidote (naloxone) is an effective interim response but is historically constrained by legal restrictions.Aim:To review and contextualize development of legislation facilitating layperson administration of naloxone across the United States.Methods:Publicly accessible databases (1,2) were searched for legislation relevant to naloxone administration between January 2001 and July 2017.Results:All 51 jurisdictions implemented naloxone access laws between 2001 and 2017; 45 of these between 2012 and 2017. Nationwide mortality from opioid overdose increased from 3.3 per 100,000 population in 2001 to 13.3 in 2016, 42, and 35 jurisdictions enacted laws giving prescribers immunity from criminal prosecution, civil liability, and professional sanctions, respectively. 36, 41, and 35 jurisdictions implemented laws allowing dispensers immunity in the same domains. 38 and 46 jurisdictions gave laypeople administering naloxone immunity from criminal and civil liability. Forty-seven jurisdictions implemented laws allowing prescription of naloxone to third parties. All jurisdictions except Nebraska allowed pharmacists to dispense naloxone without a patient-specific prescription. Fifteen jurisdictions removed criminal liability for possession of non-prescribed naloxone. The 10 states with highest average rates of opioid overdose-related mortality had not legislated in a higher number of domains compared to the 10 lowest states and the average of all jurisdictions (3.4 vs 2.9 vs 2.7, respectively).Discussion:Effective involvement of bystanders in early recognition and reversal of opioid overdose requires removal of legal deterrents to prescription, dispensing, distribution, and administration of naloxone. Jurisdictions have varied in degree and speed of creating this legal environment. Understanding the integration of legislation into epidemic response may inform the response to this and future public health crises.

Prognostic Value of 18F-FDG PET/CT-Metabolic Parameters at Baseline and Interim Assessment in Pediatric Anaplastic Large Cell Lymphoma.

The event-free survival in pediatric anaplastic large cell lymphoma (ALCL) remains at 70% irrespective of the diverse chemotherapy regimens used. There is lack of valid prognostic factors identifying high-risk patients. We investigated the prognostic value of baseline metabolic parameters and interim response on F-FDG PET/CT in pediatric ALCL patients. We retrospectively reviewed 40 pediatric ALCL patients with paired F-FDG PET/CT and treated uniformly on vinblastine-based institution protocol. The SUVmax, SUVmean, metabolic tumor volume (MTV), and total lesion glycolysis of the lymphomatous lesion were measured. Continuous PET parameters were stratified by their median values. Deauville scoring system was used to assess response to chemotherapy in the interim scan. Prognostic factors for overall survival (OS) and disease-free survival (DFS) were estimated using the Kaplan-Meier method, log-rank test, and Cox proportional hazards model. At median follow-up of 52 months, 13 patients died and 13 had recurrence. On univariate analysis, higher whole-body MTV (WBMTV) and partial response on interim scan were statistically associated with OS. High-risk features, WBMTV, and partial response were statistically associated with DFS. On multivariate analysis combining baseline characteristics and interim response, interim response (hazard ratio, 3.56; P = 0.034) was statistically significant for OS. Multivariate analysis for DFS using only baseline characteristics revealed WBMTV as statistically significant (hazard ratio, 4.08; P = 0.035), but none of the parameters was statistically significant when baseline characteristics and interim response were evaluated together. Whole-body tumor burden assessment with MTV and interim response may help to identify high-risk patients who might get benefitted from intensive therapy.

Early metabolic response to chemoradiotherapy by interim FDG PET/CT is associated with better overall survival and histological response in esophageal cancers

BackgroundEarly assessment of response to neoadjuvant chemoradiotherapy (CRT) is crucial in determining the most suitable treatment strategy in locally advanced oesophageal cancer (LAEC). AimsWe evaluated the impact of early metabolic response during CRT on overall survival (OS) and histological response. MethodsPatients with biopsy-proven oesophageal carcinoma underwent FDG PET/CT with evaluation of the standardized uptake value (SUV) before any treatment and during CRT after 20 Gy. Results116 patients (Male: 66.4%, Median age: 63; squamous cell carcinomas (SCC): 70%) met inclusion criteria. Median OS was 21.7 months. There was a significant positive correlation between interim metabolic response and OS. In multivariate analysis, only metabolic response using the 50% cut-off value remained significantly associated with OS (IC95% = 0.28–0.73; p = 0.001). In this statistical analysis, surgery (p = 0.007) and T stage (p = 0.023) were also correlated with OS. There was a significant correlation between early metabolic response and local recurrence (Chi-squared test p = 0.0001). ConclusionsEarly metabolic response using FDG PET/CT is associated with better OS, disease-free survival, local control and pathological response in patients treated by CRT for LAEC.

Phase I/II Study of CHOEP Plus Lenalidomide As Initial Therapy for Patients with Stage II-IV Peripheral T-Cell Lymphoma: Phase II Results

Phase I/II Study of CHOEP Plus Lenalidomide As Initial Therapy for Patients with Stage II-IV Peripheral T-Cell Lymphoma: Phase II Results

Phase I Trial of Carfilzomib + R-CHOP (CarR-CHOP) for Frontline Treatment of Patients with Diffuse Large B-Cell Lymphoma (DLBCL)

Phase I Trial of Carfilzomib + R-CHOP (CarR-CHOP) for Frontline Treatment of Patients with Diffuse Large B-Cell Lymphoma (DLBCL)

Interim PET/CT Predicts Response in Pediatric Lymphoma Patients - Report of an IAEA Multicenter Prospective Study

Background: PET/CT is well established as method for prognostic stratification in adult Hodgkin (HL) and Non-Hodgkin lymphoma (NHL). In pediatric lymphoma, there is no uniform system of prognostic stratification. This study evaluates the prognosis of interim FDG-PET/CT in HL and NHL pediatric patients in a large multicenter population from low-middle, upper-middle and high income countries. Methods: Eleven worldwide centers prospectively performed FDG-PET/CT studies on pediatric patients for staging and interim response evaluation. Clinical and PET/CT findings, events, and mortality data were collected. Expert panel performed central review of baseline and interim FDG-PET/CT examinations visually with Lugano classification (LC) and semi-quantitatively (including SUVmax and Delta SUVmax). LC scores of 1, 2, 3 and X were considered negative (LC-); LC scores 4 and 5 were considered positive (LC ). Prognostic analysis compared the 2-y event-free survival (EFS) rate to the PET2 results, and clinical data. Findings: Whole-body FDG-PET/CT acquisitions were performed in 250 patients (183 males; mean age = 10 ± 4 years; 70% with Hodgkin lymphoma) with clinical stage I-IV represented. There were 9 deaths and 46 events during follow-up and 194 (78%) patients with LC- interim studies. LC studies were significantly and independently associated with increased overall mortality (HR=8.96; p 0.002) and more events (HR 5.80; p<0.001). At multivariate analysis neither Delta SUV nor SUVmax were predictor of events. LC studies were associated with more events in children with HL (HR=9.77; p<0.001) than in NHL (HR 2.41; p=0.10). Interpretation: LC FDG-PET/CT scan at interim evaluation is an independent predictor of OS and EFS in pediatric lymphoma patients. LC studies are able to independently predict decreased EFS in patients with HL but not patients with NHL. Funding Statement: IAEA provided funding to investigator institutions from developing countries (Brazil, South Africa, India, Israel, Uruguay, Bangladesh, Pakistan, Philippines) for support of study data management. This research/study/project was funded by IAEA and supported by researchers at the National Institute for Health Research University College London Hospitals Biomedical Research Centre. Declaration of Interests: No potential conflicts of interest relevant to this article exist. Ethics Approval Statement: Each center obtained research ethics approval for the study protocol and patient information from local Ethics Review Board. Full informed consent was obtained for all patients with the signed consent forms kept by each institution. To ensure confidentiality while sharing data internationally, all cases were anonymized.

Densely Connected Discriminative Correlation Filters for Visual Tracking

Discriminative Correlation Filters (DCFs)-based approaches have recently achieved competitive performance in visual tracking. However, such conventional DCF-based trackers often lack the discriminative ability due to the shallow architecture. As a result, they can hardly tackle drastic appearance variations and easily drift when the target suffers heavy occlusions. To address this issue, a novel densely connected DCFs framework is proposed for visual tracking. We incorporate multiple nested DCFs into the deep learning architecture, and then train the compact network with the data-specific target. Specifically, feature maps and interim response maps are shared and reused throughout the whole network. By doing so, the implicit information carried out by each DCF is fully exploited to enhance the model representation ability during the tracking process. Moreover, a multiscale estimation scheme is developed to account for scale variations. Experimental results on the benchmarks demonstrate that the proposed approach achieves outstanding performance compared to the existing state-of-the-art trackers.

Whole-body MRI for staging and interim response monitoring in paediatric and adolescent Hodgkin\u2019s lymphoma: a comparison with multi-modality reference standard including 18F-FDG-PET-CT

ObjectivesTo prospectively investigate concordance between whole-body MRI (WB-MRI) and a composite reference standard for initial staging and interim response evaluation in paediatric and adolescent Hodgkin’s lymphoma.MethodsFifty patients (32 male, age range 6–19 years) underwent WB-MRI and standard investigations, including 18F-FDG-PET-CT at diagnosis and following 2–3 chemotherapy cycles. Two radiologists in consensus interpreted WB-MRI using prespecified definitions of disease positivity. A third radiologist reviewed a subset of staging WB-MRIs (n = 38) separately to test for interobserver agreement. A multidisciplinary team derived a primary reference standard using all available imaging/clinical investigations. Subsequently, a second multidisciplinary panel rereviewed all imaging with long-term follow-up data to derive an enhanced reference standard. Interobserver agreement for WB-MRI reads was tested using kappa statistics. Concordance for correct classification of all disease sites, true positive rate (TPR), false positive rate (FPR) and kappa for staging/response agreement were calculated for WB-MRI.ResultsThere was discordance for full stage in 74% (95% CI 61.9–83.9%) and 44% (32.0–56.6%) of patients against the primary and enhanced reference standards, respectively. Against the enhanced reference standard, the WB-MRI TPR, FPR and kappa were 91%, 1% and 0.93 (0.90–0.96) for nodal disease and 79%, < 1% and 0.86 (0.77–0.95) for extra-nodal disease. WB-MRI response classification was correct in 25/38 evaluable patients (66%), underestimating response in 26% (kappa 0.30, 95% CI 0.04–0.57). There was a good agreement for nodal (kappa 0.78, 95% CI 0.73–0.84) and extra-nodal staging (kappa 0.60, 95% CI 0.41–0.78) between WB-MRI readsConclusionsWB-MRI has reasonable accuracy for nodal and extra-nodal staging but is discordant with standard imaging in a substantial minority of patients, and tends to underestimate disease response.Key Points• This prospective single-centre study showed discordance for full patient staging of 44% between WB-MRI and a multi-modality reference standard in paediatric and adolescent Hodgkin’s lymphoma.• WB-MRI underestimates interim disease response in paediatric and adolescent Hodgkin’s lymphoma.• WB-MRI shows promise in paediatric and adolescent Hodgkin’s lymphoma but currently cannot replace conventional staging pathways including18F-FDG-PET-CT.

Positron emission mammography in the evaluation of interim response to neoadjuvant chemotherapy in patients with locally advanced breast cancer

Neoadjuvant chemotherapy (NAC) has an important role in patients with locally advanced cancers, treating distant micrometastases, downstaging tumors, improving operability, and sometimes allowing breast-conserving surgery to take place. We studied the association between two Positron Emission Mammography with 18F-FDG (18F-FDG-PEM) semi-quantitative parameters in 108 patients and correlated with pathologic response in each of the following breast cancer subtype: Triple negative breast cancer (TPN), HER2-positive, and ER-positive/HER2-negative cancers. AimExamine the association between two Positron Emission Mammography (PEM) semi-quantitative parameters: PUVmax (maximum uptake value) and LTB (lesion to background) baseline and the end of NAC with pathologic response in each breast cancer subtype. Methods108 patients, 71 with invasive ductal carcinoma and 37 with infiltrating lobular carcinoma were evaluate with 18F-FDG-PEM scans baseline and after end of NAC. We assessed the impact of 2 PEM semi-quantitative parameters for molecular subtype correlated with pathologic response according Miller-Payne grade (MPG). ResultsAfter NAC, an overall reduction of 2 PEM semi-quantitative parameters was found. Neither breast cancer subtypes nor Ki67 modified chemotherapy responses. Compared to PUVmax, an overall increase of LTB was found in baseline condition, independent of the expressed immunophenotype. Post-treatment values of PUVmax revealed a significant reduction compared to baseline values (4.8 ± 0.26 vs. 1.9 ± 0.18; p < 0.001) and LTB exhibited a significant decay after the first course of NACT (15.8 ± 1.36 vs. 5.5 ± 0.49; p < 0.001). Using the Kruskal–Wallis H test which showed no correlation between the different molecular subtypes and the MPG and PUVmax and LTB (p = 0.52), but if a correlation was found between the response rate by MPG and both semiquantitative parameters (p = 0.05). Conclusion2 PEM semi-quantitative parameters demonstrated a statically significant correlation and equivalence across the different breast cancer subtypes correlated with pathologic response according to MPG. PEM did not allow for prediction of NAC response in terms of breast cancer biomarkers, it is not discarded that this technology might be helpful for individual treatment stratification in breast cancer.