Impact of surgery versus other treatment options in recurrent glioblastoma. Analysis of the Spanish Group of Neurooncology Research (GEINO) RETSINE database.

e14047 Background: Glioblastoma (GBM) is the most common brain primary tumor. Almost all patients have recurrent disease after initial treatment with surgery, radiotherapy and chemotherapy. After disease recurrence, there is no standardized treatment and reoperation is common but there is no proven benefit in randomized trials. Here we retrospectively review the Spanish national database to identify the frequency of reoperations in recurrent GBM and to analyze the impact of surgery on survival in this setting. Methods: We retrospectively reviewed relapsed GBM patients from the Spanish national database RETSINE (Registro Nacional Español de Tumores del Sistema Nervioso Central) supported by the GEINO group. Kaplan-Meier curves and log rank test were used to compare survival. Results: The number of patients with recurrent GBM analyzed was 538, 40% were women and 60% were men. The MGMT status was: methylated 30.9%, unmethylated 33.8%, unknown 35.3%. A total of 89.9% of the patients received radiotherapy and 88.7% received chemotherapy after initial surgery. The median progression-free survival until first recurrence was 7.63 months (IC95% 6.97-8.29). Median overall survival (OS) from GBM diagnosis was 11.96 months (IC95% 10.69- 23.23). At the time of the first progression, surgery was performed in 75 patients, (13.9%), 18 cases were treated with a second radiotherapy (3.3%), second line CT was administered in 268 patients (49.6%), 221 cases received only chemotherapy (40.9%), 47 cases were treated with both surgery and chemotherapy (8.7%); 28 were treated with surgery without chemotherapy (5.2%), 19 cases had a surgery procedure but we have no data about CT, 223 cases did nor receive CT nor surgery (41%). Median overall survival after relapse was 4.06 months (IC95% 3.25-4.87). For those patients without surgery, median OS after relapse was 3.1 m (IC95% 2.84-3.71) and for patients reoperated, median OS was 12.2 m (IC95% 10.8-13.52) p=0.00 Median overall survival after relapse was 1.7 months (IC95% (IC 1.31-2.08) for patients that did not had CT and 7.03 for those with CT(IC95%5.9-8.16) p=0.00 We also compared the results from different treatment options: median OS was 1.6 m (IC95% 1.11-2.08), for patients without treatment; 6.33 m (IC95% 5.34-7.32) for patients treated with chemotherapy; 12.2 m (IC95%11.05-13.34) for patients treated with surgery and CT;12.1 m(IC95% 4.64-19.55) for patients with surgery. Conclusions: Recurrent glioblastoma is a very aggressive disease. In this retrospective study, patients treated with surgery and surgery and CT could have a clinical benefit in terms of survivalin comparison with those not treated with reoperation. Randomized prospective trials are needed to clarify the role of surgery in recurrent GBM.

Prognostic Clinical and Biologic Features for Overall Survival after Relapse in Childhood Medulloblastoma

Given the very poor prognosis for children with recurrent medulloblastoma, we aimed to identify prognostic factors for survival post-relapse in children with childhood medulloblastoma. We retrospectively collected clinico-biological data at diagnosis and main clinical characteristics at relapse of children newly diagnosed with a medulloblastoma between 2007 and 2017 at Gustave Roussy and Necker Hospital. At a median follow-up of 6.6 years (range, 0.4–12.3 years), relapse occurred in 48 out 155 patients (31%). The median time from diagnosis to relapse was 14.3 months (range, 1.2–87.2 months). Relapse was local in 9, metastatic in 22 and combined (local and metastatic) in 17 patients. Second-line treatment consisted of chemotherapy in 31 cases, radiotherapy in 9, SHH-inhibitor in four and no treatment in the remaining four. The 1-year overall survival rate post-relapse was 44.8% (CI 95%, 31.5% to 59.0%). While molecular subgrouping at diagnosis was significantly associated with survival post-relapse, the use of radiotherapy at relapse and time to first relapse (>12 months) might also have a potential impact on post-relapse survival.

Economic burden of not testing for FLT3 to treat acute myeloid leukemia.

e13652 Background: Acute myeloid leukemia (AML) is a hematologic neoplasm with poor 5-year survival (33%; US 2016), a median survival of only 4 months for relapsed/refractory cases, and in 2016, a US incidence of 19,950 cases and 10,340 deaths. With the largest patient cohort over 65, AML treatment costs in the first year are > $25,000 per patient per month (PPPM); the initial month’s cost is $82,328. Mutations in the FMS-like tyrosine kinase 3 ( FLT3+) pathway confer resistance to standard chemotherapy and reduce the likelihood of survival after relapse. In 2017 and 2018, the FDA approved midostaurin and gilteritinib, two current FLT3+ precision medicines for AML. Here, we determine the economic burden of not testing for FLT3+. Methods: AML healthcare costs were assessed and modelled for the following settings: hospital, outpatient, emergency, and primary care. Pharmaceutical activity and cost data were extracted from the Centers for Medicare and Medicaid Services (CMS) database, employing Diaceutics’ proprietary Global Diagnostic Index. Our model forecasts the economic impact of precision testing to guide FLT3+ precision medicines in 2017 through 2019. Our algorithm calculates the number of AML patients with FLT3+ based on AML Medicare patients in the Healthcare Cost and Utilization Project database and FLT3+ prevalence and switching data. Results: Total US 2016 AML costs were $1.574 billion (bn), consisting of (i) hospital care $1 bn (including $229 million (mn) for bone marrow transplantation and $20.5 mn for pharmaceuticals); (ii) outpatient care $9.8 mn; (iii) emergency care $553.9 mn; (iv) primary care $6.6 mn. Analysis of CMS data revealed a paucity of FLT3+ testing to guide therapy. We estimate that after testing, 2,164 FLT3+ Medicare patients could benefit from precision medicine interventions, generating 2,965 quality-adjusted life years (QALYs) or 2,783 QALYs when administering midostaurin or gilteritinib respectively. Conclusions: This study is the most detailed analysis of the economic burden of AML among US Medicare patients to date and is the only AML cost-of-illness study to incorporate data concerning patients’ QALYs lost by failure to employ precision medicine. This study not only illustrates the minimal FLT3 testing conducted, but also the lack of precision medicines administered.

Targeted Treatment and Survival Following Relapse after Allogeneic Hematopoietic Cell Transplantation for Acute Leukemia and MDS in the Contemporary Era

Introduction: Relapse is the most frequent cause of treatment failure after allogeneic hematopoietic cell transplantation (alloHCT). While transplant-related mortality has decreased substantially over the last few decades, little progress has been made in outcomes and no standard of care exists for patients (pts) with post-alloHCT relapse. In the recent era, several new therapies, including targeted agents, have been approved for ALL, AML, and MDS. We conducted a study to evaluate outcomes of pts with these diseases who relapse after alloHCT in the contemporary period with routine availability of these newer therapeutic agents. Methods: We performed a single-institution retrospective cohort study to review treatment strategies and outcomes of relapse post-alloHCT. We identified 420 adult pts who received their first alloHCT in 2010-2018 using any conditioning regimen or donor source. Overall, 115 (27%) pts experienced relapse (ALL=17/64 [27%], AML=67/242 [28%], MDS=31/114 [27%]) and were included in the analysis. Results: Myeloablative (54%) matched-unrelated donor grafts (50%) were the most common types of HCTs. Peripheral blood stem cell graft (49%) and bone marrow graft (48%) were used the most. Median time from alloHCT to relapse was 5 (range 1-65) months, and 83% of relapses occurred within the first year. Only 24% and 11% of pts experienced grade II-IV acute and any chronic GVHD prior to relapse, respectively. Seven of 17 pts had Philadelphia chromosome positive ALL. Mutation panel was tested in 56% of AML and MDS. Median follow-up period after relapse was 19 (range 6-80) months. The estimated survival after relapse for all diseases was 32% (95% CI 24-41%) at 6 months, 21% (14-28%) at 12 months, and 14% (8-21%) at 24 months (Fig 1). Excluding pts treated with supportive care only, the majority received a combination of different treatments; pts with ALL received median 3 (range 1-5), pts with AML received median 2 (1-4), and pts with MDS received median 1 (1-3) agent. Targeted therapies used for ALL pts included blinatumomab (n=5) and BCR-ABL targeting tyrosine kinase inhibitors with (n=2) or without (n=4) chemotherapy. Among AML pts, targeted agents were used in 15 pts (sorafenib [n=7], 2 each with enasidenib, gemtuzumab ozagamicin, and ivosidenib, and 1 each with venetoclax and SEL24 [a dual pan-PIM/FLT3 inhibitor]). One pt each was treated with enasidenib, gemtuzumab ozagamicin, and PTC299 (an inhibitor of VEGFA mRNA translation) followed by SEL24 for MDS. Second alloHCTs (n=5) were performed median 5 (range 1-16) months after first HCT and median 1 month (range 0-5 months) after relapse. Two pts received no bridging therapy, while 3 pts received chemotherapy (n=2) or donor lymphocyte infusions (DLI [n=1]) prior to the second transplant. DLI without second transplant was used in 25 pts at a median of 20 (range 3-18) months after ALL relapse, median 2 (range 0-13) months after AML relapse, and median 3 (range 1-5) months after MDS relapse. Following DLI, 53% pts developed GVHD. Targeted therapy was associated with a trend towards better survival compared to other therapies (Fig 2, HR 0.65, 95% CI 0.41-1.03, p=0.06). Based on multivariable analysis, matched unrelated (vs. matched sibling, HR 1.70, p=0.027) or haploidentical donor grafts (HR 2.69, p=0.003), presence of grade II-IV acute GVHD before relapse (HR 2.46, p<0.001), and less than 12 months from HCT to relapse (<6 vs. >12 months, HR 6.34, p<0.001; 6-12 vs. >12 months, HR 3.16, p=0.005) were adverse prognostic features with survival after relapse post-alloHCT (Table 1). Conclusion: Outcomes of pts with ALL, AML, and MDS who relapse following alloHCT remain poor in the contemporary era when several newer therapies, including targeted agents, are available for their treatment. Targeted agents were used only in a minority of post-alloHCT relapses likely due to the combination of pt status, absence of the target mutation, the agents' availability, and other factors. Pts who developed grade II-IV acute GVHD and had shorter "disease-free" duration from unrelated or haploidentical donor grafts had the significantly shorter survival following relapse. More innovative treatment strategies to prevent and treat relapse post-alloHCT are needed. Disclosures Hill: Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celegene: Consultancy, Honoraria, Research Funding; Amgen: Research Funding; TG therapeutics: Research Funding; Genentech: Consultancy, Research Funding; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Kite: Consultancy, Honoraria; Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Takeda: Research Funding. Anwer:In-Cyte: Speakers Bureau; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees. Majhail:Atara Bio: Consultancy; Anthem, Inc.: Consultancy; Nkarta: Consultancy; Mallinckrodt: Honoraria; Incyte: Consultancy.

Increasing Lengths of First Complete Remission with 7+3 Induction Chemotherapy for Acute Myeloid Leukemia over the Past Four Decades: Analysis of SWOG Trial Data

Background: We have previously shown that the survival of patients with AML who fail to achieve complete remission (CR) with 7+3 has improved since the 1980s. However, although CR rates with 7+3 have improved over the last four decades, we have not previously evaluated how outcomes for patients who achieve a CR1 with 7+3 has changed over time. Here we evaluate if either length of first CR (CR1) after 7+3 or of survival after relapse from CR1 has changed over the last four decades. Patients and Methods:We analyzed 1247 patients randomized to 7+3 arms from 5 SWOG studies and restricted to patients age 65 or younger: S8600 (n=530), S9031 (n=98), S9333 (n=57), S0106 (n=301), S1203 (n=261). S8600 enrolled patients in the 1980s, S9031 and S9333 in the 1990s, S0106 in the 2000s, and S1203 in the 2010s. S9031 and S9333 were analyzed together. All 5 protocols gave 7+3 per existing standard, which changed over time. In S8600, S9031, and S9033 the ara-C and daunorubicin doses were 200mg/m2and 45mg/m2, in S0106 100mg/m2and 60mg/m2, and in S1203 200mg/m2and 90mg/m2. CR was defined morphologically. To account for censoring in the dataset, we used landmark analyses. To evaluate patterns in length of CR1, among patients achieving CR1 and alive at 2 and 3 years, we calculated the proportion of 2 (or 3) years spent in CR1. To evaluate survival after relapse, among patients who achieved CR1 but who relapsed in next 2 (or 3) years we calculated the proportion of patients alive at least 1 year after relapse. To account for changing patient characteristics over time, multivariate linear and logistic regression models were fit. Results:Overall survival has improved dramatically over the last 4 decades (Figure 1). Additionally, among patients who achieved CR1 and were alive 2 years later, the proportion of those 2 years spent in CR1 has significantly improved over the last 4 decades (Figure 2) from a median of 58% to a median of 96% (p&lt;0.001). This trend was maintained in multivariable modeling (Table 1) and similar trends were observed using a 3-year landmark time. Survival after relapse also improved over the 4 decades. Among patients who relapsed in the first 2 years after CR1, the proportion alive at least one year after relapse has significantly increased from 32% to 52% (Table 2, p&lt;0.0001). This pattern was maintained in multivariable modeling adjusting for patient prognostic factors (Table 3) and similar trends were observed using a 3-year landmark time. Conclusion:Both length of CR1 and survival after relapse have increased over the last four decades in patients age 65 or younger even after accounting for differences in patient characteristics. Possible explanations for the longer survival after relapse include higher 2ndCR rates, more frequent use of hematopoietic cell transplant in CR, or better supportive care. Regardless, the longer survival after relapse suggests analyses of event-free survival should complement those of overall survival when evaluating new treatments in AML. Acknowledgement:The authors wish to gratefully acknowledge the important contributions of the late Dr. Stephen H. Petersdorf to SWOG and to study S0106. Disclosures Othus: Glycomimetics: Other: Data Safety and Monitoring Committee; Celgene: Other: Data Safety and Monitoring Committee. Garcia-Manero:Helsinn: Research Funding; Novartis: Research Funding; AbbVie: Research Funding; Celgene: Consultancy, Research Funding; Astex: Consultancy, Research Funding; Onconova: Research Funding; H3 Biomedicine: Research Funding; Merck: Research Funding; Amphivena: Consultancy, Research Funding. Erba:Agios, Amgen, Astellas Pharma, Daiichi Sankyo, ImmunoGen, Janssen, Jazz Pharmaceuticals, Juno, Millennium, Seattle Genetics: Research Funding; Amgen, Celgene, Daiichi Sankyo, ImmunoGen, Incyte, Jazz Pharmaceuticals, Millennium, Novartis, Ono, Pfizer, Seattle Genetics, Sunesis: Consultancy; Celgene, Incyte, Novartis: Speakers Bureau.

P14.99 Clinical and biologic features predictive of survival after relapse of childhood medulloblastoma

BACKGROUND Salvage therapy for recurrent medulloblastoma (MB) is not standardized. Factors associated with survival after recurrence have not been reported. MATERIAL AND METHODS Medical records were reviewed for 155 consecutive patients with newly diagnosed MB between 2007 and 2017, treated at Gustave Roussy and Hospital Necker. The following variables were collected for all patients: age at diagnosis, stage, histology (central review according to WHO 2016 classification), molecular subgrouping (DNA methylation), first-line treatment modalities, time to relapse, pattern of recurrence and current status. RESULTS A disease recurrence was observed in 47 patients (30%) at a median time of 15 months (range, 1–88 months). The 1-year survival after recurrence was 44% (CI 95%,29.6 to 58.8). The pattern of recurrence was local in 9 patients, metastatic in 21 and combined local and metastatic in 17 patients. The time to first recurrence, less or more than 12 months from diagnosis, was a predictor of post-recurrence overall survival (p < 0.0001) after adjustment for age, treatment, MYC amplification and molecular subgroups. Twenty-seven patients (57%) experiencing recurrent or progressive disease more than 12 months after diagnosis, had an estimated 1-year survival after recurrence of 100% (CI 95%, 100.0 to 100.0) vs 30% (CI 95%, 12.2 to 50.1) with an earlier recurrence. Early relapse was more frequent in children younger than 5 years of age at diagnosis (75% vs 37%, p =0.009), anaplastic/large cell MB (30% vs 3.7%, p=0.046) and Group 3 tumours (76.5% vs 20.8%, p=0.003). Other factors influencing post-relapse survival were metastatic disease and treatment modalities at diagnosis. Multivariable analyses will be presented. CONCLUSION The overall prognosis after relapse remains poor. Time to relapse is a significant prognostic factor for postrelapse survival and may help in the design of clinical trials evaluating new agents.

Prognostic factors for survival after relapsed acute lymphoblastic leukemia (ALL): A Children’s Oncology Group (COG) study.

10008 Background: Survival of pediatric ALL patients (pts) now approaches 90%, but is historically poor for those who relapse. Methods: In the largest cohort assembled to date we analyzed overall survival (OS) rate post relapse, defined as duration between date of relapse and death, among pts diagnosed from 1996-2014 treated on 10 contemporary COG frontline trials. Comparisons of post-relapse OS were based on logrank tests, with two-sided p values reported. Results: Of 15,874 pts enrolled on frontline trials, 1,967(12%) relapsed. Relapse rates ranged from 35% in infant ALL to 9.7% in pts with NCI standard risk B-ALL. Rates were similar for T and B-ALL, 11% vs. 12%. Relapse patterns differed by phenotype: almost half of non-infant B-ALL relapses occurred late (≥36 mos), and at all time periods bone marrow (BM) relapse predominated. Conversely 65% of T-ALL relapses were early ( < 18 mos) with similar number of isolated CNS (iCNS) and isolated BM (iBM) relapses. Median time to relapse was shorter for infant ALL and T-ALL (both 13.8 mos) compared to B-ALL (34.4 mos). The 5yr OS rates (±SE) after relapse for B, T, and infant ALL were 52±1%, 33±3% and 19±4%, respectively, with greater variability in OS by site in T vs. B-ALL. 5yr OS rates for pts with early BM relapse was similar for both B and T-ALL (28%), but pts with B-ALL who relapsed between 18-36 mos fared better than pts with T-ALL (OS 50±2% vs 34±8%, p = 0.014). The 5yr OS rates for pts with late relapses were 65±2% for B-ALL and 50±12% for T-ALL. In multivariable analysis, time to relapse, site of relapse, age < 1 or > 10 yrs at diagnosis, initial WBC > 100K, and T-cell phenotype were associated with worse outcomes post relapse (all p < 0.01). Sex, CNS status at diagnosis, or prior therapy on POG versus CCG/COG backbone did not influence OS. Compared to pts treated from 1988-2002 (Nguyen et al. Leukemia 2008), 5yr OS rate post relapse has improved over time for B-ALL from 37±2% to 52±1% (p < 0.001) and T-ALL from 23±4% to 33±3% (p < 0.05). 5-yr OS rates improved significantly for pts with iBM from 24±2% to 45±2% (p < 0.001) and marginally for pts with iCNS from 59±3% to 65±3% (p = 0.15). Conclusions: In the modern era there are fewer relapses for B and T-ALL, however sites of recurrence and outcomes differ by phenotype. Infants continue to do poorly. Compared to prior analyses, survival after relapse is significantly improved.

Relapse-free survival (RFS) after surgical resection to predict survival after relapse (SAR) and overall survival (OS) in patients with pancreatic ductal adenocarcinoma (PDA).

e15735 Background: We aimed to evaluate the clinical relevance of RFS after local PDA resection as a prognostic factor in terms of SAR and OS. Methods: Patients diagnosed with local PDA who had undergone surgical resection in 4 hospitals from Spain were identified. Disease location, demographic, pathologic, treatment during recurrence and mortality information was retrospectively collected. RFS was measured from date of surgery until recurrence and censored at death or last follow-up. SAR was measured from relapse, until death or last follow-up. We defined patients presenting an RFS value of 6 months or more, or less than 6 months as High-RFS and Low-RFS respectively. Results: Of 93 patients with resected PDA, 51 (54.8%) were male and 42 (45.2%) female. The median age was 65.2 years. 62 (66.7%) tumors were localized in the head. There were 5 (5.4%), 17 (18.3%) and 69 (74.1%) stage I, II and III respectively. 53 (57%) patients had undergone cephalic (Whipple), 20 (21.5%) distal and 20 (21,5%) total pancreatectomy. 48 (51.6%) patients received radiotherapy and 86 (92.5%) received chemotherapy in the neoadjuvant and/or adjuvant setting. Median RFS was 12.3 months. In the metastatic setting, the most frequent chemotherapy combination was gemcitabine plus nab-paclitaxel. 43(46,2%) of patients received second line chemotherapy. Median OS and median SAR were 25,9 and 10,1 months respectively. Kaplan-Meier survival analysis showed that PDA cancer patients with Low-RFS have a poorer clinical outcome than those with High-RFS (median OS 48.26 months, CI 95% 39,3-57,1 for High-RFS; 19.2 months CI 95% 15.7-22-8 for Low-RFS; p = 0.0001). On multivariate Cox regression analysis, age, initial stage I-II, adjuvant chemotherapy utilization and High-RFS were independent prognostic factors for OS and SAR rate. Conclusions: RFS was strongly correlated and discriminated PDA patients with better SAR and OS from the poorer prognosis patients in the ulterior metastatic setting. Prospective studies are needed to confirm this finding.

PS02.020: ADENOCARCINOMA OF THE ESOPHAGOGASTRIC JUNCTION (SIEWERT I AND II): DOES TRANSHIATAL APPROACH SUFFICIENT FOR A STANDAND LYMPHADENECTOMY? A MULTIVARIABLE STUDY ANALYSIS

Background The surgical treatment of adenocarcinoma of the esophagogastric junction surgical treatment (AGEJ) is still controversial, particularly concerning to survival and postoperative complications. To compare thoracoscopic esophagectomy (group A) with transhiatal esophagectomy (group B) in patients with AGEJ in relation to the occurrence of complications and mortality; number of ressected lymph nodes, the positive and the ratio between the ressected and positive; overall and disease free survival; and survival after relapse. Methods There was a selection of 147 patients from 2000 to 2017. Epidemiological data were analyzed and compared between the groups. Postoperative complications were evaluated. The anatomopathological staging was evaluated, analyzing the resected lymph nodes. Analysis of overall survival, disease free survival and survival after relapse were made, besides multivariate analysis of survival related factors. Results In relation to the complications, group A presented greater occurrence of hoarseness and surgical infections. In relation to mortality, group A presented 2 cases (3.7%) and group B presented 4 (4.3%), without statistical difference. In group A, the average number of ressected lymph nodes was 31.88 and in group B was 20.73 (P < 0.001), however the average number of affected lymph nodes was 3.96 in group A and 4.25 in group B. The general overall survival was 42.3%, in group A was 38.9% and in group B was 47.6% (P = 0.298). In the multivariate analysis of overall survival only lymphatic invasion (P = 0.005), diabetes mellitus (P = 0.038) and surgical infection (p-0.001) were significant. However, in tumors with stage until 2B, group A overall survival was 80.4% and group B was 38.5% (P = 0.001). Conclusion Both methods are safe with similar morbidity and mortality rates. Transthoracic thoracoscopic esophagectomy allows a larger ressection in the number of lymph nodes. Overall survival and disease free survival are similar, however until stage 2B thoracoscopic esophagectomy improves overall survival. Diabetes and lymphatic invasion interfere in overall and disease free survival. Disclosure All authors have declared no conflicts of interest.