Event-free Survival In Patients Research Articles

Indolent Lymphoma and Vitamin D (ILyAD): A Double-Blind, Randomized, Placebo-Controlled Trial to Evaluate the Supplemental Effect of Vitamin D on Event-Free Survival in Patients with Low Tumor Burden Indolent Non-Hodgkin Lymphoma Treated with Rituximab

Indolent Lymphoma and Vitamin D (ILyAD): A Double-Blind, Randomized, Placebo-Controlled Trial to Evaluate the Supplemental Effect of Vitamin D on Event-Free Survival in Patients with Low Tumor Burden Indolent Non-Hodgkin Lymphoma Treated with Rituximab

Real World Outcomes of Patients with Relapsed/Refractory Diffuse Large B Cell Lymphoma Who Are Ineligible for Autologous Stem Cell Transplantation and Receive Commercially-Available Salvage Therapy

Introduction: Salvage immunochemotherapy (IC) followed by high-dose chemotherapy with autologous stem cell transplantation (autoSCT) is standard-of-care second-line therapy (2L) for patients with relapsed or refractory (R/R) diffuse large B cell lymphoma (DLBCL) deemed fit for autoSCT as per the CORAL study (J Clin Oncol. 2010 Sep 20;28(27):4184-90). Optimal therapeutic management of patients with R/R DLBCL who are autoSCT-ineligible is unknown. Here we describe the real-world outcomes of patients with R/R DLBCL who receive palliative intent 2L therapy in community and academic settings and do not receive autoSCT. Methods: This analysis includes de-identified patients from the nationwide Flatiron Health electronic health record-derived database with a histologic diagnosis of DLBCL and R/R disease after frontline IC who do not undergo autoSCT and receive treatment with either bendamustine-based therapy, gemcitabine-based therapy, lenalidomide, or ibrutinib. Patients receiving rituximab/ifosfamide/carboplatin/etoposide (R-ICE) and high-dose cytarabine-containing second-line therapies were excluded. Event free survival (EFS) was defined as the interval between the start of current therapy and start of subsequent therapy if needed, last follow-up on current therapy, or death on therapy. Overall survival (OS) was defined as the time between start of current therapy and death or last follow-up while alive. Results: A total of 250 patients were eligible for inclusion in 2L. Eight patients received autoSCT after gemcitabine therapy and were excluded from this analysis. Clinicopathologic characteristics at time of diagnosis include 56% male, 87% age >60, 55% ECOG performance status >1, 87% stage III-IV disease, 78% IPI >2, 56% germinal center (GCB) of those with cell of origin testing performed, 9% cMYC rearrangement positive when tested, and 29% transformed from indolent disease. A total of 106, 78, 36, and 22 patients received bendamustine, gemcitabine, lenalidomide, and ibrutinib, respectively. For all patients, median EFS was 5.1 months and median OS was 14.3 months in 2L. Median EFS was 7.6, 2.4, 9.1, and 4.2 months, and median OS was 16.0, 9.4, 16.3, and 11 months for bendamustine, gemcitabine, lenalidomide, and ibrutinib in 2L, respectively. Patients receiving bendamustine and lenalidomide demonstrated significantly improved EFS compared to those receiving gemcitabine (p=0.001 and 0.01, respectively), see Figure 1. We observed no difference in EFS (p=0.40) or OS (p=0.89) between lenalidomide and bendamustine in 2L. Univariate analysis demonstrated receipt of gemcitabine, ECOG PS>1, and IPI >2 to have statistically significant increased hazard for treatment failure and ECOG PS>1 to have an increased hazard for death in 2L relative to the reference group. Multivariate analysis demonstrated receipt of gemcitabine (HR 1.57, p=0.03 95% CI: 1.04 - 2.37) and ECOG PS>1 (HR 1.61, p=0.02 95% CI: 1.09-2.38) were associated with an increased hazard for treatment failure in 2L. Median EFS for patients on lenalidomide was 6.7 and 8 months (p=0.26), and median OS was 13.9 and 12.2 months (p =0.48) for patients with nonGCB and GCB cell of origin, respectively. Conclusions: For patients with R/R DLBCL treated with palliative therapy in the 2L, bendamustine- and lenalidomide-based therapies resulted in significantly longer EFS compared to gemcitabine therapy. Although we cannot exclude the possibility that some patients received gemcitabine in 2L with the original intent to proceed with autoSCT, this does not contest our results as this therapy remains inferior to bendamustine and lenalidomide even if given to a potentially more fit patient population. Analysis shows no difference in outcomes by cell of origin if receiving lenalidomide in 2L. These findings may serve as benchmarks for outcomes following receipt of these therapies in the non-investigational setting and suggest both bendamustine and lenalidomide may be considered reasonable standard-of-care therapies for patients unfit for autoSCT in the 2L setting. Figure 1 Disclosures Landsburg: Celgene: Membership on an entity's Board of Directors or advisory committees; Triphase: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Curis, INC: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Curis, INC: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: Speakers Bureau; Seattle Genetics: Speakers Bureau; Triphase: Research Funding; Takeda: Research Funding; Takeda: Research Funding. OffLabel Disclosure: Outcomes with lenalidomide and ibrutinib in patients with relapsed/refractory DLBCL will be discussed.

Frequency and Prognostic Impact of IKZF1 and Co-Existed Gene Alterations in Childhood B-ALL in Taiwan

Introduction: IKZF1 deletion was firstly reported to be very frequent in Philadelphia (Ph) positive B-cell acute lymphoblastic leukemia (B-ALL), and continuously found in other B-ALL subtypes. IKZF1plus defined as the presence of any of CDKN2B, CDKN2A,PAX5 or PAR1 in the absence of ERG deletion and was reported to describe a new minimal residual disease (MRD)-dependent poor prognostic profile in B-ALL.1 We aimed to analyze the frequency and prognostic relevance of IKZF1 deletion with or without co-occurring gene alterations in Taiwanese children with B-ALL treated with TPOG-ALL-2002 protocol or MRD-directed TPOG-ALL-2013 protocol. Methods: Bone marrow samples at diagnosis from 561 children excluding Ph+ and infant ALL were analyzed. Detection of gene deletion was carried out with multiplex ligation dependent probe amplification (MLPA) kit (SALSA MLPA P335 and P327) and mutations of RAS pathway genes (NRAS, KRAS, and PTPN11) were assessed by Sanger sequencing. The outcome was analyzed on 259 patients treated with TPOG-ALL-2002 protocol and 158 patients treated with TPOG-ALL-2013 protocol. Results: IKZF1 deletions were present in 11.2% of 561 patients. DEL 4-7, DEL 1-8, and other variants were present in 50.8%, 14.3%, and 34.9%, respectively of 63 IKZF1-deleted patients. Co-existence of additional deletions with IKZF1 deletion was detected in 34.0% for CDKN2B, 37.3% for CDKN2A, 27.7% for PAX5, 2.1% forPAR1, and 8.0% for ERG. IKZF1plus comprised of 4.4% of 546 patients who had all the genes examined. Co-existed mutations of RAS pathway genes were detected in 5.0% for PTPN11, 13.3% for NRAS, and 10.0% for KRASin the IKZF1-deleted patients. The 5-year event-free survival (EFS) of IKZF1-undeleted patients was significantly better compared with IKZF1-deleted patients in TPOG-2002 cohort (82.5 ± 2.6% vs. 56.9 ± 9.1%, P = 0.002) as did TPOG- 2013 cohort (89.4 ± 3.9% vs. 59.1 ± 19.8%, P = 0.012). The 5-year overall survival (OS) of IKZF1-deleted patients was worse than that of patients with undeleted IKZF1 in TPOG-2013 cohort (58.3 ± 19.8% vs. 89.2 ± 4.2%, P = 0.004) but not in TPOG-2002 cohort (90.9 ± 5.0% vs. 86.9 ± 2.3%, P = 0.846). DEL 1-8 patients had an inferior 5-year EFS (33.3 ± 19.2%) compared with DEL 4-7 (63.3 ± 12.0%,) or DEL-others (60.0 ± 18.4 %) in TPOG- 2002 cohort (P = 0.003). No significant difference in OS was observed between patients among different IKZF1-deleted subtypes in TPOG-2002 cohort (P = 0.283) (Fig. 1A) but there was different in TPOG-2013 cohort (P = 0.003) (Fig. 1B). Patients with IKZF1 deletion alone had comparable 5-year EFS and 5-year OS compared with patients with IKZF1plus in TPOG-2002 cohort whereas patients with IKZF1 deletion alone had worse 5-year EFS (33.3 ± 27.2% vs. 80.0 ± 17.9%, P = 0.284) and 5-year OS (33.3 ± 27.2% vs. 80.0 ± 17.9%, P = 0.415) than that of KZF1plus in TPOG-2013 cohort. The prognostic impact of IKZF1 deletion with co-existed gene alterations in TPOG-2002 cohort was further analyzed as follows: IKZF1plus with ≧ 2 co-existed deletions had an inferior 10-year EFS (23.8 ± 20.3%) compared with patients with IKZF1 deletion alone (36.7 ± 17.5%) or IKZF1-undeleted patients (81.5 ± 2.7%) (P = 0.005) (Fig. 1C). Three patients carried both IKZF1 and ERG deletions had a superior 5-year EFS (100%) compared with IKZF1-deleted alone or IKZF1-undeleted patients (P = 0.005) (Fig. 1D). The 10-year EFS of patients with any gene mutation of RAS pathway was worse than that of patients with RAS wild-type genes (66.6% ± 6.4% vs. 83.7% ± 2.6%, P = 0.011). In multivariate analysis, in addition to the initial white blood count > 50 x 109/L and KMT2A-rearranged, IKZF1 deletion (HR=2.609, 95% CI: 1.363-5.034; P = 0.004) and RAS pathway gene mutations (HR=2.360, 95% CI: 1.336-4.168; P = 0.003) were independent genetic predictors for inferior EFS. Co-existence of IKZF1 deletion with RAS pathway mutations had worst 5-year EFS (20.0% ± 12.6%, P < 0.0001, Fig. 1E), and 10-year OS (53.3% ± 17.6%, P = 0.042, Fig. 1F). Conclusions: Our results showed that IKZF1 deletion alone was associated with an inferior OS in MRD-directed TPOG-2013 treated cohort but not in TPOG-2002 cohort in which it became significant when co-existed with RAS pathway mutations. Reference: 1. IKZF1plus defines a new minimal residual disease-dependent very-poor prognostic profile in pediatric B-cell precursor acute lymphoblastic leukemia. J Clin Oncol. 2018, 1240-1249. Figure 1 Disclosures No relevant conflicts of interest to declare.

24TiP - KEYNOTE-756: A randomized, double-blind, phase III study of pembrolizumab or placebo with neoadjuvant chemotherapy and adjuvant endocrine therapy for high-risk, early-stage, ER+/HER2−breast cancer

24TiP - KEYNOTE-756: A randomized, double-blind, phase III study of pembrolizumab or placebo with neoadjuvant chemotherapy and adjuvant endocrine therapy for high-risk, early-stage, ER+/HER2−breast cancer

P1758The novel small leucin-rich repeat protein podocan is an independent predictor of major adverse cardiac events in patients with angiographically-defined coronary artery disease

Abstract Background Smooth muscle cell (SMC) function determines the clinical course of vascular disease via fibrous cap stability. Podocan is an inhibitor of SMC function and is circulating in peripheral blood rendering it a candidate biomarker to predict MACE in patients with Coronary Artery Disease (CAD). Purpose We designed a prospective cohort study assessing the predictive value of Podocan for cardiovascular outcome (MI, CVA or death) in patients with CAD. Methods 308 patients with angiographic evidence of CAD were enrolled. At index cardiac catheterization Syntax Score was calculated. For patient baseline characteristics see Table. Podocan and CRP-1 were measured using a human Podocan and CRP-1 ELISA. The Kaplan-Meier method was used to construct survival curves, which were compared using the log-rank test. Cox proportional hazard modeling was used for all univariate/multivariate analyses. Statistical analysis was performed using STATA. Results Podocan was detected in 212 patients (69%) with a detection threshold of 0.01 ng/ml. The median Podocan level observed was 1.4±8.2 ng/ml. 96 patients did not have a detectable Podocan level. Mean CRP-1 was 0.117±0.15 mg/ml. Mean Syntax Score was 12±9. Podocan did not correlate with CRP-1. There was also no association between Podocan and Syntax Score, age, BMI, smoking, LDL, and HDL, HgbA1c, LVEF and GFR. At the univariate level, presence of Podocan was associated with an increased rate of MACE (17% Podocan present vs. 7% Podocan absent, p=0.02). Kaplan-Meier survival analysis showed higher event free survival in patients with no detectable Podocan vs. detectable Podocan level (Figure). In a limited multivariate Cox proportional Hazard analysis, Podocan remained an independent predictor of MACE (HR: 2.5; P=0.042) in addition to diabetes, and LV ejection fraction. Baseline Characteristics Total (N=308) Chronic ischemic heart disease (N=273) Acute coronary syndrome (N=35) Age (Year) 66.5±9.5 67±9 61±11 Female (Sex) 106 (33%) 90 (31%) 16 (46%) Hypertension 282 (89%) 244 (89%) 26 (74%) Diabetes 142 (44%) 124 (45%) 11 (31%) Hyperlipidemia 269 (87%) 243 (89%) 26 (74%) CRP (mg/dL) 0.11±0.14 0.10±0.13 0.18±0.19 LVEF (%) 49±10 49±10 48±9.5 CRP, C-reactive protein; LVEF, Left ventricular ejection fraction. Kaplan Meier Survival Curves by Podocan Conclusion Podocan is a novel biomarker independently predicting MACE in secondary prevention of CAD warranting to be further studied in a Multicenter Clinical Trial.

Stratified treatment of non-distant metastatic rhabdomyosarcoma in children: an analysis of its efficacy and prognostic factors

Objective To assess the efficacy of stratified treatment of pediatric non-distant metastatic rhabdomyosarcoma (RMS). Methods A retrospective review was conducted in 129 pediatric patients with non-distant metastatic RMS between January 2005 and December 2016 at Shanghai Children′s Medical Center Affiliated to Shanghai Jiaotong University School of Medicine.According to their pathological types, TNM stages and postoperative pathologic staging, the 129 patients were grouped a low-risk group, an intermediate-risk group and a high-risk group.Multimodality therapies were applied to all patients including chemotherapy, surgery and radiotherapy.The overall survival (OS) and event-free survival (EFS) rates were analyzed by using the Kaplan-Meier method. Results Of 129 patients, 119 cases were included in this study.In 119 patients, the age of onset for the RMS ranged from 7 to 191 months, with the median onset age of 48 months.The median follow-up time was 40 months for event-free patients with RMS, and 36 months for all the 119 patients.The 5-year OS and EFS for all patients were (92.1±2.9)% and (76.5±4.4)%, respectively.While the 5-year EFS for patients in the low-risk group, intermediate-risk group and high-risk group were all above 70%, and the difference among the three groups was not statistically significant (χ2=2.679, P=0.262). A subsequent univariate analysis revealed that the onset age for RMS (≤1 year old or≥10 years old), TNM stage and postoperative pathologic stage were important predictors of EFS with statistical significance (all P 0.05). The 5-year EFS of RMS patients with Forkhead Box Protein O1(FOXO1)-positive was significantly lower than that of FOXO1-negative patients [(56.3%±14.8)% vs.(83.3±15.2)%], and the difference was statistically significant (χ2=4.588, P=0.028). Conclusions It is important that the stratification treatment should be strictly implemented on RMS patients.First, further improvement is necessary for the treatment of patients in the low-risk group due to their poorer prognosis compared to that of their intermediate-risk counterparts, for whom one feasible option is to reduce the dose of chemotherapy drug.Furthermore, FOXO1 can be used as an indicator for poor prognosis, where stratified treatment is necessary for pediatric patients with RMS. Key words: Rhabdomyosarcoma; Stratification treatment; Prognosis; Child

A role for ABCB1 in prognosis, invasion and drug resistance in ependymoma

Three of the hallmarks of poor prognosis in paediatric ependymoma are drug resistance, local invasion and recurrence. We hypothesised that these hallmarks were due to the presence of a sub-population of cancer stem cells expressing the multi-drug efflux transporter ABCB1. ABCB1 gene expression was observed in 4 out of 5 paediatric ependymoma cell lines and increased in stem cell enriched neurospheres. Functional inhibition of ABCB1 using vardenafil or verapamil significantly (p ≤ 0.05–0.001) potentiated the response to three chemotherapeutic drugs (vincristine, etoposide and methotrexate). Both inhibitors were also able to significantly reduce migration (p ≤ 0.001) and invasion (p ≤ 0.001). We demonstrate that ABCB1 positive patients from an infant chemotherapy-led trial (CNS9204) had a shorter mean event free survival (EFS) (2.7 versus 8.6 years; p = 0.007 log-rank analysis) and overall survival (OS) (5.4 versus 12 years; p = 0.009 log-rank analysis). ABCB1 positivity also correlated with reduced event free survival in patients with incompletely resected tumours who received chemotherapy across CNS9204 and CNS9904 (a radiotherapy-led SIOP 1999-04 trial cohort; p = 0.03). ABCB1 is a predictive marker of chemotherapy response in ependymoma patients and vardenafil, currently used to treat paediatric pulmonary hypertension in children, could be repurposed to reduce chemoresistance, migration and invasion in paediatric ependymoma patients at non-toxic concentrations.

Abstract LB-322: Identification of a novel fusion protein SPTAN1-ABL1 in a child with T-cell acute lymphoblastic leukemia: Functional characterization and therapeutic implications

Abstract Precursor T-cell acute lymphoblastic leukemia (T-ALL) is a genetically heterogenous hematologic malignancy resulting from accumulation of molecular lesions in a multistep process. Although survival rates have improved considerably, event free survival for patients with T-ALL are generally inferior compared to B-cell ALL. Genetic alterations are important determinants of responsiveness to therapy and serve as targets for molecularly tailored therapies. More than 75 chimeric fusion genes have been reported in T-ALL, the majority of which encode factors involved in transcriptional regulation, while only a smaller percentage codes for tyrosine kinases. We report a case of relapsed T-ALL, despite low risk stratification at the time of diagnosis, harboring a novel fusion protein SPTAN1-ABL1. Primary bone marrow specimen collected at diagnosis was transplanted in NSG-B2m mice and propagated as a patient-derived xenograft (PDX) line. For transcriptomic characterization, RNA isolated from primary and PDX samples was subjected to error-corrected targeted next-generation sequencing using ArcherDX FusionPlex HemeV2 kit. Bioinformatics analysis identified the novel SPTAN1-ABL1 gene fusion in which exon 2 of SPTAN1 was fused with exon 4 of ABL1. This fusion was confirmed by Sanger sequencing. Translation of the fusion product sequence showed in-frame fusion leading to the generation of a chimeric protein containing N-terminal SPTAN1 and C-terminal ABL1 with intact kinase domain. SPTAN1 encodes non-erythryocytic-1-spectrin-alpha protein, an actin-binding protein, with N-terminal domain possessing oligomerization activity. Because oligomerization of ABL1 promotes its kinase activity, it is possible that SPTAN1-ABL1 possesses constitutive kinase activity. The full-length SPTAN1-ABL1 fusion protein was cloned in a mammalian expression vector and expressed in BaF3 cells. SPTAN1-ABL1 fusion was detected at similar allelic frequencies in primary and PDX samples indicating the concordance between the two. Furthermore, treatment of engrafted mice with dasatinib (Qd10, 5 mg/Kg, p.o.) significantly prolonged survival compared to untreated mice (n=5 each, P<0.005). Taken together, these data suggest the possibility that the presence of SPTAN1-ABL1 fusion gene may confer a higher risk disease thereby leading to early recurrence, similar to the treatment failures observed in B-ALL patients later found to harbor BCR-ABL1 fusion gene. This study also indicates a potential therapeutic role for tyrosine kinase inhibitors in the treatment of T-ALL patients with ABL1 fusion. Citation Format: Anilkumar Gopalakrisnapillai, Erin Crowgey, Demetria Ruhl, Darcy Hamill, Nitin Mahajan, Todd Druley, E. Anders Kolb, Sonali P. Barwe. Identification of a novel fusion protein SPTAN1-ABL1 in a child with T-cell acute lymphoblastic leukemia: Functional characterization and therapeutic implications [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-322.

Significance of the microRNA‑17‑92 gene cluster expressed in B‑cell non‑Hodgkin's lymphoma.

To evaluate the prognostic value of the microRNA (miR)‑17‑92 gene cluster, the expression of miR‑17‑92 in B‑cell non‑Hodgkin's lymphoma (B‑NHL) was examined. Patients with B‑NHL, who received therapy in the Department of Hematology, Harbin Medical University Cancer Hospital between January 2012 and October 2014, were enrolled in the study. The expression of the miR‑17‑92 cluster in tumor tissue samples was detected by reverse transcription‑quantitative polymerase chain reaction analysis. The overall survival (OS) and event‑free survival (EFS) times were also investigated by the Kaplan‑Meier method and comparisons between groups were estimated using a log‑rank test. Three types of lymphoid cancer cells with wild‑type (WT), knockout of miR‑17‑92 (KO), and overexpression of miR‑17‑92 (TG), were utilized to establish a tumor xenograft model, and a reactive hyperplasia lymph cell was used as a control. The tumor incubation times and weights were examined. A total of 71patients with B‑NHL were registered. No significant correlations were identified between the expression of miR‑17‑92 and clinical factors (P>0.05). Members of the miR‑17‑92 cluster exhibited various expression in the subtypes of B‑NHL, and the difference between follicular lymphoma (FL) and germinal center B‑cell like (GBC) was most marked. The overexpression of miR‑18, miR‑19a, and miR‑92a induced a marked reduction in the OS of patients with B‑NHL, and high‑levels of miR‑19a and miR‑92a led to a decline in EFS. The overexpression of miR‑17‑92 shortened the duration of incubation required for visualization of the xenograft tumor, whereas knockout led to inhibition of tumor formation. The expression of miR‑17‑92 in FL differed significantly from that in GBC, and miR‑19a may have a crucial effect on the OS and EFS of patients with B‑NHL.

Phase II results of mitoxantrone in combination with clofarabine in children with relapsed/refractory acute leukemia.

7036 Background: Despite improved outcomes in pediatric acute leukemia, those who relapse or are refractory do poorly. Mitoxantrone and clofarabine as single agents have proven efficacy in pediatric leukemia. Our previously reported phase I results demonstrated the MTD of this combination to be clofarabine 35 mg/m2 x 5 days and mitoxantrone 12 mg/m2 x 4 days. Here, we present our phase II data utilizing the RP2D. Methods: Prospective, open label safety and efficacy study (NCT01842672). Patients 0-30.99 yr old with ALL or AML with relapse OR induction failure were given 1 to 3 cycles of clofarabine (RP2D 35 mg/m2/day) Day 1-5, in combination with mitoxantrone 12 mg/m2/day on Day 3-6. Dexrazoxane was given prior to mitoxantrone. CNS prophylaxis was achieved with intrathecal liposomal cytarabine. MRD was defined by flow cytometry (≥ 0.01%). Results: Total 21 patients have enrolled at the RP2D clofarabine. Median age 8 yrs (0.5-22 yrs). Patient characteristics include 13 ALL (8=Induction Failure, 4=Relapse 1, 1=Relapse 2) and 8 AML (4=Induction Failure, 4=Relapse 1). Overall regimen was well tolerated. One patient with grade IV prolonged myelosuppression. Median time to neutrophil recovery was 24 days. Eighteen of 21 (85.7%) patients achieved an MRD negative CR. Three patients died of progressive disease. All 18 patients achieving CR went on to receive an allogeneic HSCT with no documented transplant associated toxicities attributed to prior MITCL therapy. One patient developed MRD (2.6%) at Day +270 post HSCT and underwent subsequent therapy. The remaining 17 patients continue to demonstrate MRD negativity. Two patients died of transplant associated complications. The overall and event free survival for patients who responded to therapy are 89% (CI95 0.64-0.98) and 83% (CI95 0.58-0.96), respectively at a median follow up time of 24 months (range 2-58). Conclusions: The combination of clofarabine and mitoxantrone reinduction therapy for relapsed or refractory acute leukemia has been demonstrated to be safe and well tolerated at a RP2D of 35 mg/m2 clofarabine in children with poor risk acute leukemias. Phase II data is encouraging with 85.7% MRD negative CR rate in leukemic patients allowing patients to safely proceed to AlloHSCT with a 2 year survival rate of 89%. Longer follow up and a larger cohort is planned and ongoing. Clinical trial information: NCT01842672.

KEYNOTE-756: Randomized, double-blind, phase 3 study of pembrolizumab vs placebo combined with neoadjuvant chemotherapy and adjuvant endocrine therapy for high-risk, early-stage estrogen receptor–positive, human epidermal growth factor receptor 2–negative (ER+/HER2−) breast cancer.

TPS601 Background: Although ER+/HER2− breast cancer (BC) has better overall prognosis than other subtypes, a high-risk subpopulation is characterized by high-grade tumors, decreased sensitivity to endocrine therapy (ET), higher responsiveness to chemotherapy (CT), and worse prognosis. Based on prior studies, increased pathological complete response (pCR) rates after neoadjuvant CT may have a substantial impact for patients with high-risk, early-stage HR+/HER2− BC. KEYNOTE-756 (ClinicalTrials.gov, NCT03725059) is a global, randomized, double-blind, phase 3 study of pembrolizumab (vs placebo) + CT as neoadjuvant treatment followed by pembrolizumab (vs placebo) + ET as adjuvant treatment for patients with high-risk, early-stage ER+/HER2− BC. Methods: Patients with T1c-2 cN1-2 (tumor size ≥2 cm) or T3-4 cN0-2 grade 3, invasive, ductal ER+/HER2− BC will be stratified by lymph node involvement (positive vs negative), tumor PD-L1 status (positive [CPS≥1] vs negative [CPS < 1]), ER positivity (ER+ ≥10% vs ER+ < 10%), and anthracycline dosing schedule (every 3 weeks [Q3W] vs Q2W), then randomized 1:1 to neoadjuvant treatment with pembrolizumab 200 mg Q3W or placebo combined with paclitaxel (80 mg/m2 Q1W) for 4 cycles followed by doxorubicin (60 mg/m2) or epirubicin (100 mg/m2), each with cyclophosphamide (600 mg/m2) Q2/3W for 4 cycles. After definitive surgery (± radiation therapy, as indicated), patients will receive adjuvant treatment of pembrolizumab (200 mg Q3W) or placebo for 9 more administrations combined with ET, which can be given for up to 10 years. There will be no crossover between treatment arms when moving from neoadjuvant to adjuvant treatment. Dual primary endpoints are pCR rate (ypT0/Tis ypN0) and event-free survival (EFS). Secondary endpoints include ypT0/Tis and ypT0 ypN0 pCR rates in all patients and all 3 pCR definitions in those with PD-L1+ tumors, EFS in patients with PD-L1+ tumors, overall survival, safety, and health-related quality of life. Interim analyses are planned. Enrollment is currently ongoing. Clinical trial information: NCT03725059.

77 - Event-free survival in patients after open partial nephrectomy for RCC in a solitary kidney

77 - Event-free survival in patients after open partial nephrectomy for RCC in a solitary kidney

Can pretreatment 18F-FDG PET tumor texture features predict the outcomes of osteosarcoma treated by neoadjuvant chemotherapy?

To investigate whether tumor texture features derived from pretreatment with 18F-fluorodeoxyglucose positron emission tomography (FDG PET) can predict histological response or event-free survival (EFS) in patients with localized osteosarcoma of the extremities treated by neoadjuvant chemotherapy (NAC). We retrospectively reviewed 35 patients with American Joint Committee on Cancer stage II extremity osteosarcoma treated with NAC and surgery. Primary tumor traditional parameters and texture features were measured for all 18F-FDG PET images prior to treatment. After surgery, histological responses to NAC were evaluated on the postsurgical specimens. A receiver operating characteristic curve (ROC) was constructed to evaluate the optimal predictive performance among the various indices. EFS was calculated using the Kaplan-Meier method and prognostic significance was assessed by Cox proportional hazards analysis. Pathologic examination revealed 16 (45.71%) good responders and 19 (54.29%) poor responders. Although both the texture features (least axis, dependence nonuniformity, run length nonuniformity, and size zone nonuniformity) and metabolic tumor volume (MTV) can predict tumor response of osteosarcoma to NAC, the traditional indicator MTV has the best performance according to ROC curve analysis (area under the curve = 0.918, p < 0.0001). In multivariate analysis, MTV (p < 0.0001), histological response (p = 0.0003), and texture feature of coarsenessNGTDM (neighboring gray tone difference matrix) (p = 0.005) were independently associated with EFS. Intratumoral heterogeneity of baseline 18F-FDG uptake measured by PET texture analysis can predict tumor response and EFS of patients with extremity osteosarcoma treated by NAC, but the conventional parameter MTV provides better predictive power and is a strong independent prognostic factor. • The baseline 18 F-FDG PET tumor texture features can predict tumor NAC response for patients with osteosarcoma. • Coarseness NGTDM is a new and independent prognostic factor for osteosarcoma. • MTV provides the best predictive power and is a strong independent prognostic factor for patients with osteosarcoma.

Outcome and factors affecting survival of childhood myelodysplastic syndrome; single centre experience

Abstract Introduction Although many therapeutic options have been attempted for pediatric myelodysplastic syndrome (MDS), still hematopoietic stem cell transplant (HSCT) is the only curative therapy. We described the outcome of these patients and the factors affecting the overall survival (OS) and event free survival (EFS). Methods This is a retrospective descriptive study included 44 patients with MDS who presented to Children Cancer Hospital Egypt (CCHE-57357), between July 2007 and December 2015. HSCT was offered to patients who had HLA matched family donors. Results Eighteen patients (40.9%) had refractory cytopenia of childhood (RCC), 19 (43.2%) had refractory anemia with excess blasts (RAEB), and 7 (15.9%) had refractory anemia with excess blasts in transformation/myelodysplastic related acute myeloid leukemia (RAEB-T/MDR-AML). Cytogenetic abnormalities were observed in 54.8% of evaluable patients, in which monosomy 7 was the commonest abnormality observed (26.1%). Allogeneic HSCT from HLA matched donors was performed in 9/44 patients. The Average CD34 + count was 3.57 × 106/Kg recipient weight. The 2-year OS and EFS for the whole cohort were 43.3% and 33.8%, respectively, and for the transplanted patients were 75% and 60%, respectively. Univariate analysis showed improved 2 years-OS and EFS in patients who underwent HSCT as compared to those who didn't (75% versus 35.4% for OS, P = 0.088 and 60% versus 27.5%, for EFS, P = 0.074). Conclusion Allografts from either matched related or unrelated or even haplo-identical donors should be offered for pediatric MDS patients, as HSCT is the only curative option for those patients. Further collaborative efforts, a more precise molecular diagnosis, as well as large-scale prospective therapeutic trials are required to develop standard diagnostic and therapeutic guidelines for such rare disease.

Outcome and factors affecting survival of childhood myelodysplastic syndrome; single centre experience

IntroductionAlthough many therapeutic options have been attempted for pediatric myelodysplastic syndrome (MDS), still hematopoietic stem cell transplant (HSCT) is the only curative therapy. We described the outcome of these patients and the factors affecting the overall survival (OS) and event free survival (EFS). MethodsThis is a retrospective descriptive study included 44 patients with MDS who presented to Children Cancer Hospital Egypt (CCHE-57357), between July 2007 and December 2015. HSCT was offered to patients who had HLA matched family donors. ResultsEighteen patients (40.9%) had refractory cytopenia of childhood (RCC), 19 (43.2%) had refractory anemia with excess blasts (RAEB), and 7 (15.9%) had refractory anemia with excess blasts in transformation/myelodysplastic related acute myeloid leukemia (RAEB-T/MDR-AML). Cytogenetic abnormalities were observed in 54.8% of evaluable patients, in which monosomy 7 was the commonest abnormality observed (26.1%). Allogeneic HSCT from HLA matched donors was performed in 9/44 patients. The Average CD34 + count was 3.57 × 106/Kg recipient weight. The 2-year OS and EFS for the whole cohort were 43.3% and 33.8%, respectively, and for the transplanted patients were 75% and 60%, respectively. Univariate analysis showed improved 2 years-OS and EFS in patients who underwent HSCT as compared to those who didn't (75% versus 35.4% for OS, P = 0.088 and 60% versus 27.5%, for EFS, P = 0.074). ConclusionAllografts from either matched related or unrelated or even haplo-identical donors should be offered for pediatric MDS patients, as HSCT is the only curative option for those patients. Further collaborative efforts, a more precise molecular diagnosis, as well as large-scale prospective therapeutic trials are required to develop standard diagnostic and therapeutic guidelines for such rare disease.

The relation of radiological tumor volume response to histological response and outcome in patients with localized Ewing Sarcoma.

BackgroundMagnetic resonance imaging (MRI) is the modality of choice for local staging and response evaluation of Ewing sarcoma (EwS). Aim of this study was to determine the relevance of tumor volume response (TVR) in relation to histological response (HisRes) and survival, in order to evaluate if early modification of chemotherapy might be indicated in patients with inadequate TVR.MethodsThree dimensional (3D)‐tumor volume data at diagnosis, during early induction phase (1‐3 courses of chemotherapy; n = 195) and/or late induction phase (4‐6 courses; n = 175) from 241 localized patients were retrospectively analyzed. A distinction was made between adequate response (reduction ≥67%) and inadequate response (reduction <67% or progression). Correlations between TVR, HisRes, event free survival (EFS), and overall survival (OS) were analyzed using chi‐square tests, log‐rank tests, and the Cox‐regression model.ResultsEarly adequate TVR, noted in 41% of patients, did not correlate with EFS (P = 0.92) or OS (P = 0.38). During late induction phase 62% of patients showed an adequate TVR. EFS for patients with late adequate TVR was better (78%) than for those with inadequate late TVR (61%) (P = 0.01); OS was 80% and 69% (P = 0.26), respectively. No correlation was found between TVR and HisRes. Multivariate analysis showed that poor HisRes, pelvic location and late inadequate TVR were associated with poor outcome.ConclusionsEarly inadequate TVR does not predict adverse outcome; therefore, changing the treatment to second line chemotherapy is not indicated in case of inadequate early TVR. Late adequate TVR and good HisRes correlate with better EFS; patients with late inadequate TVR might benefit from augmented therapy.

Baseline and interim functional imaging with PET effectively risk stratifies patients with peripheral T-cell lymphoma

AbstractThe prognosis of peripheral T-cell lymphoma (PTCL) is heterogenous. Baseline or interim imaging characteristics may inform risk-adapted treatment paradigms. We identified 112 patients with PTCL who were consecutively treated with cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP)/CHOP-like regimens with the intent to consolidate with an autologous transplant. Baseline (n = 93) and interim (after 4 cycles, n = 99) positron emission tomography (PET) images were reevaluated, and we calculated baseline total metabolic tumor volume (TMTV). Interim PET (iPET) responses were graded visually by 5-point score (i5PS) and by percentage change of standardized uptake value. By univariate analysis, predictors of event-free survival (EFS) included Prognostic Index for Peripheral TCL (PIT) higher than 1 (hazard ratio [HR], 1.83; P = .021), International Prognostic Index (IPI) higher than 3 (HR, 2.01; P = .021), high TMTV (>125 cm3; HR, 3.92; P = .003), and positive iPET (HR, 3.57; P < .001). By multivariate analysis, high baseline TMTV predicted worse overall survival (OS; HR, 6.025; P = .022) and EFS (HR, 3.861; P = .005). Patients with i5PS of 1 to 3 had a longer median OS and EFS (104 months, 64 months) than those with i5PS of 4 to 5 (19 months, 11 months; P < .001). Four-year OS and EFS for patients with i5PS of 1 to 3 and PIT of 1 or less were 85% and 62%, respectively. However, 4-year OS and EFS for those with i5PS of 4 to 5 and PIT higher than 1 were both 0% (P < .001). In multivariate analysis, after controlling for IPI and PIT, i5PS was independently prognostic for EFS (HR, 3.400 95% confidence interval, 1.750-6.750; P < .001) and OS (HR, 10.243; 95% confidence interval, 4.052-25.891; P < .001). In conjunction with clinical parameters, iPET helps risk stratify patients with PTCL and could inform risk-adapted treatment strategies. Prospective studies are needed to confirm these findings.

Hepatoblastoma

Summary: Hepatoblastoma is an uncommon tumour of infancy and childhood. Hepatoblastoma in past had very poor outcomes, which presently has changed with introduction of chemotherapy and protocol based treatment described as SIOPEL. We would hereby like to submit the surgical video of this procedure. Case: A 13 month male child presented with abdominal distension and decreased oral intake, upon evaluation patient was found to have a heterogenous mass in segments 5,6,7 and 8(PRETEXT-II). Ultrasound guided fine needle aspiration suggested hepatoblastoma- fetal type. Child received 2 chemotherapy cycles of SIOPEL -3 protocol. Repeat Computed tomography revealed regression of tumour size. Patient underwent right hepatectomy. Intra and immediate post-operative period was uneventful. Patient had uneventful recovery and was discharged on post-operative day 6. Pre-operative AFP was 28,594 ng/ml. Post-op AFP- 147.9 ng/ml. At follow up period of 8 months patient is alive and having an event free survival. Conclusion: Multidisciplinary approach has steered to a great extent in improving overall and event free survival in patients with hepatoblastoma. Pre-operative chemotherapy makes surgical resection possible which is the definitive therapy for hepatoblastoma.

Lens Dose-Response Prediction Modeling and Cataract Incidence in Patients With Retinoblastoma After Lens-Sparing or Whole-Eye Radiation Therapy

We retrospectively assessed the incidence of cataracts in patients with retinoblastoma (Rb) treated with either lens-sparing radiation therapy (LSRT) or whole-eye radiation therapy (WERT). A secondary aim of this study was to model the dose-response risk of cataract. We reviewed 65 patients with Rb treated with radiation therapy (RT) at Children's Hospital, Los Angeles from 1997 to 2015. Eyes that were enucleated before RT or lacked follow-up eye examinations were excluded. All patients underwent computed tomography simulation, and mean lens dose data were collected. Follow-up ophthalmologic examinations and intraocular lens implant history were reviewed for cataracts. The primary event-free survival (EFS) outcome was cataract development. Eyes without cataracts were censored on the last date of eye examination or post-RT enucleation, if applicable. Kaplan-Meier estimates were used to compare EFS outcomes, and dose response was projected with Cox regression and logistic regression models. Sixty-one patients (94 eyes) were analyzed with a median follow-up of 51.8months. For eyes treated with WERT, cataracts developed in 71.7% versus 35.3% for LSRT. Median EFS for WERT and LSRT were 20.8 and 67.9months, respectively. Compared with WERT, a significant EFS benefit was demonstrated for LSRT (P<.001). Mean lens dose had a significant effect on cataracts in both Cox regression and logistic regression models (P<.01). The mean lens dose of 7Gy was projected to have a 5-year cataract incidence of 20% and 25% with the logistic and Cox regression models, respectively. We report the first clinical data demonstrating significantly improved EFS in patients with Rb treated with LSRT. Through lens dose-response modeling, we validate a mean lens dose threshold of 7Gy to keep cataract risk below 25%. Although RT is used less often for Rb owing to advances in chemotherapy delivery options, these findings are relevant for refining lens dose constraints, particularly in children who have received radiation dose near the orbit.

Comparison of Cure Rates between Gemtuzumab Ozogamicin Plus Standard of Care Chemotherapy Vs Standard of Care Alone in Patients with Newly Diagnosed Acute Myeloid Leukemia

Introduction: Gemtuzumab ozogamicin (GO; MylotargTM) was approved by the US Food and Drug Administration in 2017 and the European Medicines Agency in 2018 in combination with standard of care (SOC) chemotherapy (daunorubicin/cytarabine) for the treatment of de novo acute myeloid leukemia (AML). Although initial remission rates for de novo AML are high, overall survival (OS) is low; however, a proportion of patients experience long-term remission (>5 years) and can be considered cured. Statistically cured populations can be estimated by fitting mixture cure models (MCMs) to survival data, a method that takes into account background survival rates. The objective of this research was to assess and compare the statistical cure rates with GO plus SOC vs SOC alone among adult patients with de novo AML.Methods: MCMs (Weibull, lognormal, and gamma) were fitted to patient-level data from the phase 3 ALFA-0701 trial on event-free survival (EFS) and OS of patients with remission (GO plus SOC: n=100; SOC alone: n=96), and OS of all patients (with remission and refractory; GO plus SOC: n=135; SOC alone: n=136). As refractory patients do not experience remission, this methodology would not provide clinically meaningful results since they are unlikely to experience a cure. Analyses for the subgroup excluding patients with adverse cytogenetics were also explored. For the GO plus SOC arm, P values <0.05 deemed a statistically significant difference in cure rates between treatment arms. The analyses were implemented in STATA (version 13) statistical package, which accounts for general population mortality in the MCM parametrization.Results: The statistical cure rates of MCMs on EFS for patients with remission for the GO plus SOC and SOC alone arms varied (depending on the distribution) from 34% (P=0.018) to 38% (P=0.018) and from 17% (P=0.008) to 21% (P<0.001), respectively. For the subgroup excluding patients with adverse cytogenetics, EFS cure rates varied from 36% (P=0.007) to 41% (P=0.007) for patients treated with GO plus SOC and from 14% (P=0.113) to 20% (P<0.001) for patients on SOC alone. For OS of patients in remission and patients in remission/refractory states, the GO plus SOC arm demonstrated a trend towards higher statistical cure rates compared to SOC alone. (Table)Conclusions: In both subgroups explored, patients in remission treated with GO plus SOC chemotherapy demonstrated improved cure rates in EFS of newly diagnosed patients with de novo AML compared to patients treated with SOC alone. For OS of patients with remission, GO plus SOC displayed numerically higher (but not statistically significant) cure rates compared with SOC patients. Findings were similar in the overall population that included remission and refractory patients and for the subgroup excluding patients with adverse cytogeneticsThese analyses are limited by the relatively small number of patients in the context of a randomized trial, making it difficult to ascertain if there are sufficient data to accurately estimate cure fractions. Nevertheless, expert validation of cure rates, long-term survival projections, and relative differences between treatment arms suggest the results are reliable. Although a novel survival modeling method, MCMs provided a good visual fit to the EFS and OS in remission data from the ALFA-0701 trial, in part because MCMs account separately for the proportion of cured and uncured patients who experience long-term survival. [Display omitted] DisclosuresMuresan:Ingress-health Nederland BV: Employment. Mamolo:Pfizer: Employment, Equity Ownership. Cappelleri:Pfizer: Employment, Equity Ownership. Mokgokong:Pfizer Inc: Equity Ownership. Palaka:Pfizer Inc: Employment, Equity Ownership. Hills:Daiichi Sankyo: Consultancy, Honoraria. Latimer:Astra Zeneca: Consultancy; Merck: Consultancy; Pfizer: Consultancy; BMS: Consultancy; Janssen: Consultancy; Bluebirdbio: Consultancy. Heeg:Ingress-health Nederland BV: Employment, Equity Ownership, Research Funding.