Improvement In Event-free Survival Research Articles

Abstract P1-10-10: Tumor infiltrating lymphocytes (TILS) among high risk for recurrence breast cancer patients treated with tetrathimolybdate (TM)

Abstract Background: Tumor infiltrating lymphocytes (TILs) evaluated in the primary tumor biopsy or surgical resection have been well established as having prognostic significance in patients with triple negative breast cancer (TNBC) and HER2+ breast cancer treated with adjuvant chemotherapy (Savas et. al, Nat Rev Clin Oncol 2016). In TNBC, stromal TILs behave as a continuous variable with every 10% increase in TIL resulting in a decrease in risk of recurrence and death. The definition of lymphocyte-predominant breast cancer (LPBC) has been used for tumors that contain 50%–60% TILs and usually have a particularly good outcome (Salgado et al, Ann Oncol 2015). Our group recently demonstrated in a phase II single arm study that tetrathimolybdate (TM), a copper-depleting agent, resulted in improved event free survival (EFS) for TNBC patients compared to historical controls. The 2-year event-free survival (EFS) for stage 2-3 and stage 4 NED was 91% and 67%, respectively. In this analysis, our goal was to explore whether the encouraging results we observed were influenced by enrolling TNBC patients with better prognostic factors at initial diagnosis, namely higher stromal TIL score, in our copper depletion trial. Methods: Archived primary breast tissue was available from 67 of the 75 patients enrolled in the phase II TM trial. The phase II study included patients with stage II TNBC or stage III or IV NED breast cancer patients, who were treated with TM for 2 years or until relapse. Here we focused on the 30 patients with TNBC. The demographic data for the patients is included in the following table. Patient DemographicsAge at diagnosisStage at study entryPrior Adjuvant or Neoadjuvant therapyNumber of prior chemotherapy regimens in metastatic setting%Tumor Infiltrating Lymphocytes504Adjuvant110543AAdjuvantn/a30563AAdjuvantn/a20513CNeoadjuvantn/a<5454Adjuvant230514Neoadjuvant210363CAdjuvantn/a20592BAdjuvantn/a60453CAdjuvantn/a<5544Adjuvant130443CNeoadjuvantn/a20474Adjuvant020563CNeoadjuvantn/a10512AAdjuvantn/a10583AAdjuvantn/a20654None25513CNeoadjuvantn/a50503CNeoadjuvantn/a30543CNeoadjuvantn/a10542AAdjuvantn/a20403CNeoadjuvantn/a40604Adjuvant160564None160554Adjuvant010633CNeoadjuvantn/a5424Adjuvant050454Adjuvant110463AAduvantn/a10523CNeoadjuvantn/a10514Adjuvant1<5 The number of TILs in each sample was calculated by an experienced pathologist using published criteria (Salgado et al, Ann Oncol 2015). We used TILs >50% to define LPBC. Results: Overall, we found that only 3/30 (10%) of TNBC patients had TILs >50%. In addition, 14/30 (46.7%) of TNBC patients had tumors with <10% TILs. The 2-year EFS for the patients with TILs >10% v. <10% was 76.9% v. 69.8%, respectively. (P=0.65) Conclusions: Only 10% of TNBC patients enrolled in the study had LPBC at diagnosis thus indicating that this cohort was not enriched for patients with immunogenic tumors. When stratified by TILs >10% or <10%, there was no statistically significant difference in EFS. Although the analysis is limited due to the small sample size, it does suggest that the amount of TILs present at initial diagnosis did not influence the overall outcome for patients treated with TM. Citation Format: Rybstein MD, Nackos E, Kornhauser N, Cigler T, Andreopoulou E, Moore A, Cobham M, Fitzpatrick V, Demaria S, Vahdat LT. Tumor infiltrating lymphocytes (TILS) among high risk for recurrence breast cancer patients treated with tetrathimolybdate (TM) [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P1-10-10.

736P - Randomized phase 2 trial of peri- or post-operative chemotherapy in resectable pancreatic adenocarcinoma

Background: Pancreatic ductal adenocarcinoma (PDAC) has a remarkable trend to metastasize early. Accordingly, there is a strong rational to investigate preoperative chemotherapy in patients with resectable disease. We conducted a multicenter randomized phase 2 trial (PACT-15; NCT01150630) to assess the role of combination chemotherapy in perioperative setting. Methods: Treatment-naïve patients with 18-75 yr, KPS>60 and pathologically confirmed stage 1-2 resectable PDAC were randomized to surgery followed by 6 cycles of adjuvant gemcitabine 1000 mg/m21,8,15q4w (arm A), or PEXG (cisplatin 30 mg/m2, epirubicin 30 mg/m2, and gemcitabine 800 mg/m2 1,15q4w and capecitabine 1250 mg/m2/day 1-28) (arm B), or to 3 cycles of PEXG before and 3 after surgery (arm C). The primary endpoint was 1-year event-free survival (EFS); the secondary endpoints were EFS, overall survival (OS), and the difference in pathological findings between arm A+B and arm C. With 24 eligible patients in each group (H0 20%, H1 40%, α 10%, β 20%), ≤16 events of 24 would support further evaluation of experimental therapy. Results: Between September 2010 and April 2015, 88 eligible patients were randomized in 9 Italian centers (arm A: 26, B: 30, C: 32). Basal patients and tumor characteristics were well balanced across arms. One-year EFS (A, B, C) was 6/26 (23%), 15/30 (50%), 23/32 (72%). Median EFS was 4.8, 12.4, 18.9 months (A vs C p=0.002). Three-year OS (A,B,C) was 35%, 42%, 55%. Median OS (A,B,C) was 20.4, 25.1, not reached at 33 months (A vs C p = 0.022). Pathological results are summarized in the table. Treatment safety profile was good.Table736P Pathological findingsA+BCEnrolled5632T resection49 (88%)27 (84%)Intraoperative metasteses7/56 (13%)2/32 (6%)Postoperative metastases10/56 (18%)3/32 (9%)Grade 329/49 (59%)6/27 (22%)T12/49 (4%)4/27 (15%)No13/49 (27%)13/27 (48%)Ro16/49 (33%)15/27 (56%)Median size2.5 cm2.0 cm Open table in a new tab Conclusions: Patients receiving perioperative chemotherapy had significant improvement of EFS and OS as compared to those receiving adjuvant treatment. This trial provides the strongest piece of evidence currently available in favor of preoperative chemotherapy in resectable PDAC. Clinical trial identification: NCT01150630 Legal entity responsible for the study: IRCCS San Raffaele Scientific Institute, Milan, Italy Funding: IRCCS San Raffaele Scientific Institute, Milan, Italy Disclosure: M. Reni: Funding from Celgene, Baxalta, Helsinn, and Merck-Serono; consultant or advisor for Celgene, Baxalta, Merck Serono, Boheringer, Lilly, Pfizer, AstraZeneca, Novocure, Genentech, Halozyme, Novartis. G. Balzano: Advisory role for Celgene. M. Falconi: Research funding to institution from Novartis. L. Gianni: Consulting/advisory role for Roche, Pfizer, GlaxoSmithKline, Synthon, Taiho Pharmaceutical, AstraZeneca, Genomic Health, Merck Sharp & Dohme, Boehringer Ingelheim, Tiziana Pharma, Synaffix, Celgene; patents/royalties/intellectual property with Roche. All other authors have declared no conflicts of interest.

Abstract LB-048: Impact of KIR/KIR ligand genotype for neuroblastoma patients in a Phase 3 COG immunotherapy trial

Abstract Introduction: High-risk neuroblastoma (NBL) patients (pts) enrolled in a COG Phase 3 clinical trial (ANBL0032) were randomized to isotretinoin (RA) alone or Immunotherapy: dinutuximab (anti-GD2 mAb) + IL2 + GMCSF + RA (Yu et al., NEJM, 2010). Dinutuximab acts via antibody-dependent cell-mediated cytotoxicity by innate immune cells, including NK cells. NK cells express Killer Immunoglobulin-like Receptors (KIRs); most of the inhibitory KIRs have KIR-ligands that belong to the HLA class I family. Specifically, KIR2DL1 is a receptor for HLA-C2, KIR2DL2 and KIR2DL3 are receptors for HLA-C1, and KIR3DL1 is a receptor for HLA-Bw4. Some prior studies of anti-GD2 mAb immunotherapies have shown associations with outcome based on the genotypes of these inhibitory KIR/KIR ligand relationships. We investigated whether certain KIR/KIR-ligand genotypes were associated with event-free survival (EFS) and overall survival (OS) in this trial. Methods: Of the 226 pts randomized, 174 pts had DNA allowing evaluation of genotype correlations with outcome (RA: n=86; Immunotherapy: n=88; >5yr follow-up if no event). We looked for associations of inhibitory KIRs with their respective KIR-ligands and clinical outcome. Log-rank tests and Cox proportional hazards regression models were used to compare EFS/OS by genotype group; adjustment was made for non-proportional hazards as needed using time-dependent covariates. Results: We found that certain, hypothesis-identified, inhibitory KIR/KIR-ligand combinations were associated with improved clinical outcome. Namely, pts that were both KIR2DL2+/HLA-C1+ and KIR3DL1+/HLA-Bw4+ had improved EFS and OS if treated with Immunotherapy (n=23) vs. RA (n=26) (5-yr EFS: 61% vs. 27%, p=0.02; 5-yr OS: 91% vs. 34%, p=0.007). Conversely, for pts that were not both KIR2DL2+/HLA-C1+ and KIR3DL1+/HLA-Bw4+, we found insufficient evidence to support an improvement in EFS or OS with Immunotherapy (n=65) vs. RA (n=60) (5-yr EFS: 57% vs. 53%, p=0.76; 5-yr OS: 68% vs. 68%, p=0.66). Conclusions: Our data suggest that KIR/KIR-ligand genotype may be predictive of benefit from Immunotherapy. The impact of immunotherapy appears different for pts that were both KIR2DL2+/HLA-C1+ and KIR3DL1+/HLA-Bw4+ vs. those that were not both KIR2DL2+/HLA-C1+ and KIR3DL1+/HLA-Bw4+. Validation of these KIR/KIR-ligand associations in similarly treated high-risk NBL patients would be required prior to proposing their prospective use in the aid of clinical treatment decisions. Further investigation of KIR/KIR-ligand genotypes may also clarify their role and the role of NK cells in the activity of this form of cancer immunotherapy. Citation Format: Amy K. Erbe, Wei Wang, Lakeesha Carmichael, KyungMann Kim, Patrick K. Reville, Wendy B. London, Jacquelyn A. Hank, Mitchell B. Diccianni, Arlene Naranjo, Michael Hogarty, Julie R. Park, Alice L. Yu, Paul M. Sondel. Impact of KIR/KIR ligand genotype for neuroblastoma patients in a Phase 3 COG immunotherapy trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-048. doi:10.1158/1538-7445.AM2017-LB-048

Abstract ES9-3: ES9-3 (Neo)adjuvant systemic therapy of TNBC: How much is enough?

Abstract The use of neoadjuvant chemotherapy in ER-negative cancers has become quite popular in patients with stage II and III breast cancers, since it gives us important information on long-term prognosis, based on the amount of residual disease burden at the time of definitive surgical resection. Two relatively large phase II randomized neoadjuvant clinical trials have explored the addition of carboplatin to an anthracycline/taxane based chemotherapy regimen for patients with stage II or III triple-negative breast cancers (TNBC): GeparSixto, in Europe, and CALGB40603, in the US. Despite significant differences in chemotherapy backbone, and frequency and duration of carbo administration, both trials showed that the addition of carboplatin significantly increased the rate of pCR from ∼ 40% to 54%. Both trials also reported a significant amount of added toxicity for the carboplatin arms, with a significant amount of patient not being able to complete their planned treatment. However, whereas the GeparSixto trial reported an improvement in 3-year disease-free survival (DFS), the CALGB40603 did not. Since neither of these studies was powered to address disease-free or overall survival benefit from the addition of carboplatin to neoadjuvant systemic chemotherapy, lack of precision from small sample sizes are likely responsible for the difference seen in DFS between these two trials. Additionally, there's not yet a confirmed correlation between increases in frequency of pCR and event-free survival (EFS). A recently pooled analysis by Cortazar et al. could not validate pCR as a surrogate endpoint for improved EFS and overall survival (OS): as some patients who achieve a pCR go on to relapse and many with residual disease never experience a recurrence, small differences in pCR may never translate to improvements in EFS. Long term effects of the added toxicity of carboplatin are also not known. At present, upon completion of neoadjuvant therapy, the standard of care for patients with TNBC (who have no clinical evidence of metastatic disease after surgical excision of the cancer regardless of burden of residual disease) is observation. But recently, preliminary data from a Japanese phase III trial (CREATE-X) that randomized patients with HER2-negative breast cancer with lack of pCR post-neoadjuvant chemotherapy to observation or capecitabine x 8 cycles showed that the addition of capecitabine provided a statistically significantly higher 5-year DFS and OS in the TNBC group. EA1131, an ongoing adjuvant randomized phase III clinical trial seeks to address if patients with basal-like TNBC, with high risk of recurrence due to residual disease post completion of neoadjuvant chemotherapy, have a higher DFS benefit from a platinum agent than from capecitabine. The results of this trial will ultimately help avoid exposing upfront unselected patients, many of whom will never relapse, to toxic therapy in the absence of long-term known benefit. In summary, the addition of a platinum agent routinely in the neoadjuvant setting in TNBC is still an individualized decision and not yet standard of care for all patients. The decision to use capecitabine in patients with residual disease post-neoadjuvant chemo may still be slightly premature, confirmatory results of EA1131 are eagerly awaited. Citation Format: Mayer IA. ES9-3 (Neo)adjuvant systemic therapy of TNBC: How much is enough? [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr ES9-3.

Surgical Management of Wild-Type Gastrointestinal Stromal Tumors: A Report From the National Institutes of Health Pediatric and Wildtype GIST Clinic.

Purpose Wild-type gastrointestinal stromal tumors (WT-GISTs) that lack KIT or PDGFRA mutations represent a unique subtype of GIST that predominantly affects children. We sought to determine the effect on event-free survival (EFS) of staging variables, extent of resection, and repeat resection of tumors. Methods In 2008, a WT-GIST clinic was established at the National Cancer Institute, allowing the development of a large clinical database. We included participants who underwent resection of WT-GIST. Associations with EFS (ie, freedom from disease progression or recurrence) were evaluated using the Kaplan-Meier method and Cox proportional hazards modeling. Results Among 76 participants with WT-GISTs, the median follow-up was 4.1 years. Overall EFS (± SE) was 72.6 ± 5.4% at 1 year, 57.6 ± 6.2% at 2 years, 23.7 ± 6.0% at 5 years, and 16.3 ± 5.5% at 10 years postoperatively. Hazard of disease progression or recurrence was significantly increased for patients with metastatic disease (adjusted hazard ratio [AHR], 2.3; 95% CI, 1.0 to 5.1; P = .04) and > 5 mitoses per 50 high-power fields (AHR, 2.5; 95% CI, 1.1 to 6.0; P = .03), whereas there was no significant effect of negative microscopic resection margins (AHR, 0.9; 95% CI, 0.4 to 2.2; P = 0.86). There was no association between type of gastric resection (ie, anatomic v partial/wedge) and EFS ( P = .67). Repeated resection after the initial resection was significantly associated with decreasing postoperative EFS ( P < .01). Five patients (6%) died after initial enrollment in 2008. Conclusion WT-GIST is an indolent disease, and most patients survive with disease progression. We found no improvement in EFS with more extensive or serial resections. Disease progression or recurrence may be more closely related to tumor biology than surgical management. These data suggest that resections for WT-GISTs be restricted to the initial procedure and that subsequent resections be performed only to address symptoms such as obstruction or bleeding.

Myeloablative versus reduced intensity allogeneic stem cell transplantation for relapsed/refractory Hodgkin's lymphoma in recent years: a retrospective analysis of the Lymphoma Working Party of the European Group for Blood and Marrow Transplantation

To evaluate long-term outcome of myeloablative allogeneic stem cell transplantation (allo-SCT) (MAC) versus reduced-intensity allo-SCT (RIC) in patients with relapsed/refractory Hodgkin's lymphoma (HL) in recent years. A total of 312 patients (63 MAC and 249 RIC) with relapsed/refractory HL who received allo-SCT between 2006 and 2010 and were reported to the EBMT Database were included in the study. With a median follow-up for alive patients of 56 (26-73) months, there were no significant differences in non-relapse mortality (NRM) between MAC and RIC. Relapse rate (RR) was somewhat lower in the MAC group (41% versus 52% at 24 months, P = 0.16). This lower RR translated into a marginal improvement in event-free survival (EFS) for the MAC group (48% versus 36% at 24 months, P = 0.09) with no significant differences in overall survival (73% for MAC and 62% for RIC at 24 months, P = 0.13). Multivariate analysis after adjusting for disease status at the time of allo-SCT showed that the use of MAC was of borderline statistical significance for predicting a lower RR and EFS [HR 0.7, 95% CI (0.5-1.0), P = 0.1] and [HR 0.7, 95% CI (0.5-1.0), P = 0.07], respectively, after allo-SCT. With modern transplant practices, the NRM associated with MAC for HL has strongly decreased, resulting into non-significant improvement of EFS because of a somewhat better disease control compared with RIC transplants. The intensity of conditioning regimens should be considered when designing individual allo-SCT strategies or clinical trials in patients with relapsed/refractory HL.

Orteronel Switch Maintenance Therapy in Metastatic Castration Resistant Prostate Cancer After First-Line Docetaxel: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial (SAKK 08/11).

We tested whether a switch maintenance treatment with orteronel, an oral inhibitor of androgen biosynthesis, prolongs disease control in men with metastatic castration-resistant prostate cancer (mCRPC) after documented disease stabilization with docetaxel. Men with mCRPC and non-progressive disease after a cumulative dose of ≥300 mg/m2 docetaxel for first line treatment were randomized 1:1 to receive orteronel 300 mg twice daily or placebo. The primary endpoint was event-free survival (EFS) defined as the time from randomization to death or the combination of at least two of radiographic, clinical, or PSA progression. Ninety-six patients per arm were planned to demonstrate an improvement of median EFS from 4 months on placebo to 6.7 months on orteronel (hazard ratio (HR) 0.6; type I error 5% and power 90%). Forty-seven patients (23 orteronel, 24 placebo) were randomized before premature closure of the trial because of discontinuation of clinical development of orteronel. Median EFS was 8.5 months with orteronel and 2.9 months with placebo (P = 0.001; HR 0.32; 95%CI 0.15-0.65). Median radiographic progression-free survival (rPFS) was 8.5 and 2.8 months (P = 0.02; HR 0.42; 95%CI 0.20-0.91) in the orteronel and placebo arm, respectively. PSA decline ≥50% was seen in 57% on orteronel and 4% on placebo. Toxicity was mainly mild, one patient on orteronel developed transient grade 3 adrenal insufficiency and one grade 4 pneumonitis. Orteronel significantly prolongs EFS in men with mCRPC who achieve disease stabilization with docetaxel. The concept of switch maintenance therapy in mCRPC warrants further research. Prostate 76:1519-1527, 2016. © 2016 Wiley Periodicals, Inc.

Association of Pathologic Complete Response to Neoadjuvant Therapy in HER2-Positive Breast Cancer With Long-Term Outcomes: A Meta-Analysis.

The expense and lengthy follow-up periods for randomized clinical trials (RCTs) of adjuvant systemic therapy in breast cancer make them impractical and even impossible to conduct. Randomized clinical trials of neoadjuvant systemic therapy for breast cancer may help resolve this dilemma. To assess the utility of pathologic complete response (pCR) for neoadjuvant drug development in human epidermal growth factor receptor 2 (HER2 [also referred to as ERBB2])-positive breast cancer. We searched MEDLINE (Ovid), Embase (Ovid), CENTRAL (Wiley), and Northern Light Life Sciences Conference Abstracts (Ovid) in December 2014. Searches combined terms for "breast cancer" and "neoadjuvant therapy," with no limit on publication date. Cohort studies and RCTs were selected that met following criteria: stages I to III HER2-positive breast cancer, neoadjuvant therapy, and reports of both pCR and an event-free survival (EFS)-type outcome. The initial search identified 2614 publications, of which 38 studies met the selection criteria. Two authors independently screened each study for inclusion and extracted the data. Data were analyzed using Bayesian hierarchical models. Event-free survival and overall survival (OS) hazard ratios (HRs) for pCR vs non-pCR. For RCTs, main outcome measures were treatment benefits in pCR and the corresponding treatment HRs for EFS and OS. A total of 36 studies with EFS by pCR status representing 5768 patients with HER2-positive breast cancer were included in the patient-level analysis. Overall, the improvement in EFS for pCR vs non-pCR was substantial: HR, 0.37 (95% probability interval [PI], 0.32-0.43). This association was greater for patients with hormone receptor-negative disease (HR, 0.29 [95% PI, 0.24-0.36]) than hormone receptor-positive disease (HR, 0.52 [95% PI, 0.40-0.66]). In RCTs, the R2 correlations between odds ratios for pCR and HRs were 0.63 for EFS and 0.29 for OS. Based on absolute treatment improvements in pCR rate, predicted HRs for EFS for RCTs were concordant with observed HRs. Pathologic complete response in HER2-positive breast cancer is associated with substantially longer times to recurrence and death. This relationship is maintained in RCTs. For any particular new therapy the relationship between pCR and survival may differ. Quantifying the importance of pCR is necessary for designing efficient clinical trials, which should adapt to the relationship between pCR and survival for the therapy under investigation.

Neoadjuvant Imatinib in Locally Advanced Gastrointestinal stromal Tumours, Will Kit Mutation Analysis Be a Pathfinder?

Longer duration of neoadjuvant (NA) imatinib(IM) used for locally advanced (LA) gastrointestinal stromal tumours (GIST) is not based on biology of the tumour reflected by kit mutation analysis. LA or locally recurrent (LR) GIST treated with NA IM from May 2008 to March 2015 from a prospective database were included inthe analysis. Archived formalin-fixed paraffin-embedded tissues (FFPE) were used for testing KIT exons 9, 11, 13 and 17 by PCR. One hundred twenty-five patients with LA or LR GIST were treated with NA IM. Forty-five patients (36%) had undergone c-kit mutation testing. Exon 11 was seen in 25 patients (55.5%), 3 with exon 9 (6.7%) and 2 with exon 13 (4.4%). Twelve were wild type (26.6%) and 3 (6.7 %) were declared uninterpretable. Response rate (RR) for the exon 11 mutants was higher than the non-exon 11 mutant group (84 vs. 40%, p = 0.01). Disease stabilization rate (DSR) rates were also higher in the exon 11 subgroup than non-exon 11 group (92 vs. 75%). Eighty-four per cent exon 11 and 75% non-exon 11 mutants were surgical candidates. Patients undergoing surgery had significantly improved event free survival (EFS) (p < 0.001) compared to patients not undergoing surgery, with the same trend seen in OS (p = 0.021). Patients with a SD on response to NA IM had a lower EFS (p = 0.076) and OS compared to patients achieving CR/PR. There were no differences between the various exon variants in terms of outcomes and responses CONCLUSION: Upfront evaluation of kit mutation status may help us in delineating separate treatment strategies for potentially biologically different tumours and assessing the correct timing of surgery for this subset of GIST.

Patterns of care and outcomes for second-line targeted therapy in metastatic renal cell carcinomas: A registry based analysis.

Patterns of care for metastatic renal cell carcinomas (mRCC) have seen tremendous reform in the last decade. Here, we present our pattern of care in second-line targeted therapy for mRCC. Patients with mRCC treated with second-line therapy were included from a prospective database. Demographics, risk stratification, and treatment details were noted. Event-free survival (EFS) and overall survival (OS) was calculated using Kaplan-Meier method. Log-rank test was used to identify factors affecting EFS and OS. Multivariate analysis was performed using cox regression. Nearly 21.7% (46/212) of patients received second-line targeted treatment. Heng score for risk stratification showed 21.7% of patients in low risk, 36.9% in intermediate, and 34.8% in high risk group. Everolimus followed by pazopanib were the most common second-line therapies used in 65.2% and 13% of patients, respectively. The estimated median EFS was 3.5 months (95% confidence interval [CI] 2.7-4.26 months) and estimated median OS from the start of second-line therapy was 6.2 months (95% CI 3.4-9.0 months) with a median follow-up of 4.3 months. On univariate log-rank analysis, EFS of more than 6 months with first-line therapy was associated with improvement in EFS with second-line therapy (9.5 vs. 2.0 months; hazard ratio (HR) 0.364; P = 0.002). There was no factor independently associated with EFS or OS on multivariate analysis. Patterns of care for second line targeted therapy tend to vary with setting. A longer EFS with first-line therapy predicts improved outcomes with second-line treatment.

TARC Predicts PET-Normalization and Event Free Surival in Relapsed/Refractory Hodgkin Lymphoma Patients Treated with Brentuximab Vedotin

Background/methods: Hodgkin lymphoma (HL) is characterized by elevations in serum cytokines and chemokines, produced by HL Reed-Sternberg cells and surrounding inflammatory cells, several which have been found to be prognostic and/or predictive for response to therapy. We previously reported the results of our phase II study evaluating PET-adapted salvage therapy with single-agent brentuximab vedotin (BV) followed by augmented ICE for patients with relapsed or refractory (rel/ref) HL (Lancet Oncology 2015). In this study, patients who failed 1 line of therapy for HL were treated with 2 cycles of BV, 1.2mg/Kg, administered weekly, 3 weeks on and 1 week off. Those who acheived PET-normalization proceeded directly to consolidation with autologous stem cell transplantation (ASCT). Those with persistent abnormalities on PET received augmented ICE prior to consideration for ASCT. Patients with localized, nodal-based disease that had not previously been radiated received involved field radiation prior to ASCT. Interleukin-6 (IL-6), interleukin-10 (IL-10), tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ), and cysteine-cysteine thymus and activation related chemokine (TARC) were measured at baseline and after 2 cycles of BV by multiplex enzyme-linked immunosorbent assay (ELISA) array. We aimed to evaluate the prognostic and predictive significance of these cytokines and chemokines in this uniformly treated patient population.Results: Of the 45 patients enrolled onto this protocol 37 (82%) had serum samples available both at baseline and after 2 cycles of BV for analysis. Table 1 displays the median values and ranges at baseline and after treatment with BV. Baseline levels of IL-6, IL-10, TNF-α, IFN-γ, and TARC were abnormal in 32%, 8%, 78%, 97%, and 97%, respectively. Elevated baseline IFN-γ and IL-10 correlated with presence of extranodal sites of disease (p=0.003 and 0.049 respectively) whereas elevated IL-10 and TNF-α correlated with the presence of B-symptoms (p=0.019 and 0.019 respectively). With regard to response to treatment, percent change in TARC (TARC%) from baseline to post-BV predicted for PET-normalization following BV (OR 5.82, 95% C.I 1.18-43.74). Furthermore, lower post-BV TARC was significantly associated with improved event free survival (EFS) (2 year EFS 94% vs 67%, p=0.033) (Figure 1). No other factors correlated with response to therapy, event free survival, or overall survival.Conclusions: To date, this is the largest series evaluating the prognostic and predictive significance of TARC in rel/ref HL patients treated with BV. Our analysis confirms the role of TARC as a biomarker of response to BV and PET-normalization. In line with its correlation with PET-normalization, post-BV TARC level was also predictive of EFS. Continued incorporation of TARC evaluation in prospective clinical trials for HL is warranted to better define its role in predicting PET-normalization and prognosis.Table 1Cytokine/chemokinePre-brentuximab vedotin (pg/ml)Post-brentuximab vedotin (pg/ml)medianrangemedianrangeIL-62.270.10-154.441.410.09-34.00IL-100.380.09-112.290.450.14-17.53TNF-α2.550.55-15.152.250.58-22.31IFN-γ8.661.45-1553.679.012.62-112.83TARC8250.00236.10-220773.001026.70241.70-34453.00 [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Does the Achievement of MR4.5 Improve the Outcome of Patients with Chronic Phase Chronic Myeloid Leukemia (CP-CML) Treated with Front Line Tyrosine Kinase Inhibitors (TKI)?

Background: Aside from the possibility of treatment discontinuation, the prognostic significance of deep molecular responses regarding survival endpoints in pts with CP-CML treated with TKI remains controversial. Achievement of complete cytogenetic response (CCyR) correlates with improved overall survival (OS). Among pts with CCyR, achievement of major molecular response (MMR) correlates with improved event-free survival (EFS). We have previously shown that among pts in sustained CCyR, those who achieve deeper molecular responses at 18 or 24 months may have longer EFS and failure-free survival (FFS) but not transformation-free survival (TFS) or OS. In this analysis, we sought to determine whether the achievement of a MR4.5 might correlate with improved long-term outcome in CP-CML pts who achieve CCyR after frontline TKI therapy.Methods: Pts with CP-CML treated with front line TKI, including imatinib 400 mg daily (IM400), imatinib 800 mg daily (IM800), nilotinib (NILO), or dasatinib (DASA), were included in the analysis. Landmark analyses were conducted at various time points to identify the association between achieving MR4.5 and various survival outcomes. Since the benefit of achieving CCyR is well established, only pts who were in CCyR were considered at each time point. The probabilities of OS, EFS, FFS and TFS were estimated using the Kaplan-Meier method and Cox proportional hazards regression models were fit to assess the association between OS, EFS, FFS, TFS and response. All outcomes were measured from the date treatment was started. OS was measured until death from any cause; TFS until death or transformation to accelerated (AP) or blast phase (BP) during study; EFS until loss of complete hematologic response or major cytogenetic response, transformation to AP or BP, or death from any cause; FFS until any event (as per EFS definition), failure (as defined by the ELN criteria), loss of CCyR, discontinuation or change of therapy for any reason.Results: The study population consisted of 478 pts. 59% of them were males and 9% had high Sokal score at diagnosis. 71 pts received IM400, 204 IM800, 105 NILO, and 98 DASA. Median follow-up is 106 (4-177) months (163 for IM400, 133 for IM800, 61 for NILO and 71 for DASA). The overall cumulative rate of CCyR was 92% (85% for IM400, 90% for IM800, 99% for NILO, and 97% for DASA). The overall cumulative rate of MR4.5 was 73% (56%, 74%, 80% and 78%, respectively for the 4 treatment cohorts). Among pts with CCyR, corresponding rates of MR4.5 were 79% overall and 66%, 81%, 83% and 80%, respectively, for the 4 treatment cohorts. For the entire population, the 5-year OS was 92.7%, TFS 86.0%, EFS 80.7%, and FFS 69.1%. In pts who were in CCyR at 12, 18, 24, 30, 36 or 48 months after initiation of TKI therapy there was no significant difference in terms of EFS, FFS, TFS or OS between pts who achieved a MR4.5 and those who did not (Table).Conclusion: Our analysis suggests that the achievement of MR4.5 does not provide a meaningful improvement in EFS, FFS, TFS, or OS for CP-CML pts who have achieved CCyR after being treated with frontline TKI. While obtaining a MR4.5 may enable the option of TKI discontinuation, our results suggest that failure to do so should not be considered failure or suboptimal response and thus should not prompt a change in TKI in pts who are in CCyR. Change of therapy to achieve MR4.5 with the goal of treatment discontinuation should be considered only within clinical trials.Table 1Cox proportional hazards models for EFS, FFS, TFS, and OS at various time points.Time pointEFSFFSTFSOSHR95% CIp-valueHR95% CIp-valueHR95% CIp-valueHR95% CIp-value12 months0.820.42-1.610.570.940.58-1.530.810.990.46-2.120.981.060.47-2.390.8918 months0.960.51-1.820.90.750.45-1.250.271.340.69-2.810.361.410.68-2.940.3524 months0.850.44-1.650.630.80.49-1.330.390.90.41-2.010.80.990.43-2.250.9730 months0.750.35-1.620.470.640.36-1.150.140.820.34-1.960.650.980.40-2.390.9736 months0.980.46-2.090.960.550.30-1.020.061.110.47-2.650.811.240.52-2.950.6348 months0.860.35-2.100.730.70.35-1.400.310.840.29-2.430.750.860.30-2.480.78 DisclosuresPemmaraju:Stemline: Research Funding; Incyte: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; LFB: Consultancy, Honoraria. Cortes:Pfizer: Consultancy, Research Funding; ARIAD Pharmaceuticals Inc.: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Teva: Consultancy, Research Funding.

Optimization of Rituximab for Treatment of DLBCL in Young, High-Risk Patients-Results of the Dense-R-CHOEP Trial of the German High-Grade Lymphoma Study Group

Background. The German High-Grade Non-Hodgkin Lymphoma Study Group published several studies performed in order to optimize the use of Rituximab (R) in conjunction with CHOP chemotherapy in older patients (pts) with diffuse large B-cell lymphoma (DLBCL) (Pfreundschuh et al., J Clin Oncol 2014, 32, 4127; Murawski et al., Ann Oncol 2014, 25, 1800). The prospective, randomized R-MegaCHOEP study reported 3-yr-PFS and -OS rates of 74 and 85%, respectively, in young, high-risk pts (aaIPI 2, 3) treated with 6 x R and 8 x CHOEP-14 (Schmitz et al., Lancet Oncol. 2012,13,1250). We wanted to further improve treatment results in young, high-risk pts. by doubling the number of R infusions from 6 to 12.Methods. Pts. with aggressive B-NHL (90% DLBCL), age 18-60 yrs., aaIPI 2 or 3, received treatment with 8 x CHOEP-14. In contrast to the randomized study reported previously, where R (375 mg/ m2) had been administered only six times (days 0, 15, 29, 43, 71 and 99) R was administered twelve times (days 0, 1, 4, 8, 15, 22, 29, 43, 57, 71, 85 and 99) after an amendment. Event-free survival (EFS) (primary endpoint) and overall survival (OS) achieved with 12 x R vs. 6 x R were compared.Results. Between 10/ 2010 and 02/ 2014 seventy-nine pts (median age 47 yrs., 53% males) were registered, 78 pts were analyzed. Sixty-six pts (85 %) presented with aaIPI 2 and 11 pts. presented with aaIPI 3. Feasibility (86 % of pts. received all study treatment) and safety (TRM 0%) of this intense regimen was excellent. CR/ CRu rate was 77 %, 2-yr-EFS 69% (95% CI:59-80%), 2-yr-PFS 76% (95% CI: 66-86%) and 2-yr OS 82% (95% CI: 73-92%). After a median observation time of 24 months 12 patients have died, 8 patients from lymphoma, 2 pts. from toxicity of salvage therapy, and 2 from other causes. Comparing these results to those achieved in 130 pts. treated with 6 x R and 8 x CHOEP-14 2-yr-EFS (71% (95% CI: 63-79%), p=0.766), 2-yr-PFS (75% (95% CI: 67-83%), p=0.871) and 2-yr-OS (85% (95% CI: 78-91%), p=0.843) did not significantly differ. These results could be confirmed in multivariate analyses adjusted for factors of aaIPI, bulk and gender. Interestingly, in pts. with aaIPI 3 12 x R + 8 x CHOEP-14 resulted in 2-yr-EFS and -OS rates of 72% (95% CI: 44-99%) and 91% (95% CI: 74-100%), respectively. These remarkable results, however, were not significantly different from those achieved with 6 x R + 8 x CHOEP-14 because only 11 pts. with aaIPI 3 had received 12 x R. Conclusions. In contrast to the significant improvements of EFS and OS achieved with the SMARTE-R- CHOP-14 regimen (Pfreundschuh et al. 2014) but in agreement with the results of the DENSE-R-CHOP-14 trial (Murawski et al, 2014) in older pts. (60-80 years) with high-risk disease (IPI 3-5) increasing the number of R infusions from 6 to 12 in young, high-risk pts. did not result in a significant improvement of EFS and OS in pts. with aaIPI 2 and overall. This may reflect the necessity of longer R exposure of tumor cells in order to achieve optimal results. EFS and OS in pts. with aaIPI 3 were surprisingly good but improvement was not statistically significant because only 11 pts. with aaIPI 3 had been enrolled; more pts. with aaIPI 3 need to be investigated. Among other possible explanations for the lack of further improvement by doubling the number of R infusions, the more aggressive chemotherapy (CHOEP vs. CHOP), the different timing of R in pts. receiving 6 and 12 R infusions, and differences in pharmacokinetics between younger and older patients may be responsible. DisclosuresSchmitz:Roche, Celgene, Takeda, Riemser, Ctilifescience: Honoraria, Research Funding. Off Label Use: different rituximab schedule. Viardot:Gilead: Consultancy; Pfizer: Honoraria; Amgen: Consultancy, Honoraria; Roche: Honoraria; Janssen: Consultancy, Honoraria; CTI: Consultancy. Borchmann:Millennium: Research Funding. Pfreundschuh:Roche, Janssen, Celgene: Honoraria, Research Funding. Glass:Roche, MSD, Takeda, Riemser, Ctilifesciences: Honoraria, Research Funding.

Inhibitory killer cell immunoglobulin-like receptor (iKIR) mismatches improve survival after T-cell-repleted haploidentical transplantation.

Alloreactivity triggered by interaction between killer cell immunoglobulin-like receptors (KIRs) and natural killer (NK) cells plays a role in the graft-versus-tumor effect after hematopoietic stem cell transplantation (SCT). Our aim in this study was to evaluate this role in the setting of T-cell-repleted haploidentical SCT with postinfusion high-dose cyclophosphamide (PT-Cy). We included 33 patients. Among patient-donor pairs with at least 1 inhibitory KIR (iKIR) gene mismatch, event-free survival (EFS) and cumulative incidence of relapse 1year after transplant were significantly better (85% vs. 37% [P=0.008] and 18% vs. 46% [P=0.041], respectively). A subanalysis in 12 patients with Hodgkin's lymphoma (HL) showed an improvement in EFS 1year after transplant in those patients with KIR ligand mismatch (100% vs. 25%, P=0.012), although overall survival (OS) was not affected (85% vs. 80%, P=0.2). Eight of 12 patient-donors pairs presented iKIR mismatches. Of note, this outcome was better in the small subgroup, both for EFS (100% vs. 25%, P=0.012) and for OS (100% vs. 37%, P=0.004). Our data suggest that in the setting of T-cell-repleted haploidentical SCT with PT-Cy, iKIR mismatch is associated with improved survival, with particularly good results for both iKIR and KIR ligand mismatches in patients with HL.

Abstract P4-15-05: Effects on outcome of concomitant neoadjuvant chemotherapy-trastuzumab compared with sequential neoadjuvant chemotherapy followed by post-operative trastuzumab

Abstract Background: Neoadjuvant chemotherapy delivered with trastuzumab (NCT) has been shown to increase the rates of pathological complete response (pCR) compared to neoadjuvant chemotherapy (NC) alone in women with HER2 positive breast cancer (BC). pCR in this setting has been associated with improved event free survival (EFS). However, no study has yet investigated the effect on outcomes of NCT compared to NC followed by adjuvant trastuzumab initiated postoperatively (NCAT). This study sought to investigate the impact on breast cancer outcomes of concomitant (NCT) versus sequential (NCAT) treatment in HER2 positive early breast cancer. Methods: Women with HER2 positive invasive breast cancers treated with neoadjuvant chemotherapy between 2006-2010 were identified at each of 7 European institutions and the case notes reviewed. Preoperative clinical, radiological and pathological details, treatment details and pathology results following breast surgery were reviewed. To be defined as NCT at least one dose of trastuzumab needed to be given preoperatively. pCR was defined as absence of invasive disease in breast and lymph nodes. Multivariable Cox regression and logistic regression were used to Survival outcomes for event-free survival (EFS) were calculated by log rank analysis model the influence of a number of factors on event-free survival (EFS) and pCR respectively. Results: 236 patients were identified; 138 (58%) received NCAT &amp; 98 (42%) received NCT. The median follow up for the whole group was 53.7 months (IQR 41.7-68.8), 61.5 months (IQR 50.3-78.5) for NCAT group and 44.8 months (range 37-53.9) for NCT group. The 5-year EFS for NCAT vs NCT was 59.3% (95% CI: 49.8-67.6) and 69.6% (95% CI: 51.5-82.0) respectively. The unadjusted hazard ratio (HR) for EFS with NCT compared with the NCAT was 0.63 (95% CI 0.37–1.08; p=0.091). NCT significantly increased the odds of having pCR relative to NC (OR: 4.39 (2.18-8.86); p&amp;lt;0.001), and pCR was associated with a significantly improved EFS, with an unadjusted HR of 0.23 (95% CI 0.08–0.64; p=0.002). Multivariable analysis revealed that treatment group, tumour size and ER status were significantly associated with EFS. NCT was associated with a reduced risk of relapse relative to NCAT (HR 0.48, 95% CI 0.26-0.89). In ER negative tumours NCT was significantly associated with a reduced risk of an event relative to NCAT (HR:0.25; 95% CI, 0.10-0.62), this was not observed for ER positive tumours (HR: 1.07; 95% CI, 0.46-2.52). Conclusion Concomitant as compared to sequential trastuzumab is associated with improved outcomes in the neoadjvuant setting for women with ER negative tumours. These data further support the need for the early introduction of targeted combination therapy in women with ER negative/HER2 positive BC. Citation Format: Carlo Palmieri, Iain RJ Macpherson, Kelvin Yan, Felipe Ades Moraes, Pippa Riddle, Riz Ahmed, Waheeda Owadally, Barabara Stanley, Deep Shah, Ondrej Gojis, Adam Januszewski, Conrad Lewanski, Rebecca Asher, Daniel Lythgoe, Evandro De Azambuja, Mark Beresford, Sacha J Howell. Effects on outcome of concomitant neoadjuvant chemotherapy-trastuzumab compared with sequential neoadjuvant chemotherapy followed by post-operative trastuzumab [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P4-15-05.

Gemtuzumab Ozogamicin (GO) in Infants with Acute Myeloid Leukemia (AML) – Combined Results from the Children’s Oncology Group (COG) Trials, AAML03P1 and AAML0531

Background: Infants <1 year of age with AML are at high risk of early death during induction, pulmonary and infectious toxicities, and treatment related mortality (TRM). Compared with older children, infants are more likely to have higher risk clinical and cytogenetic features. Targeted therapy is needed to improve the outcomes for infants with AML while minimizing toxicities.Objective: To determine if the addition of gemtuzumab ozogamicin (GO) to standard chemotherapy is safe, tolerable, and improves event free survival (EFS) in infants <1 year of age with AML.Methods: Infants >/= 1 month to <1 year of age with de novo AML or <1 month of age with progressive AML were eligible for enrollment on the COG trials AAML03P1 and AAML0531. Infants with acute promyelocytic leukemia, juvenile myelomonocytic leukemia, bone marrow failure syndromes, or Down syndrome were not eligible. The 5-course chemotherapy backbone was identical in both trials. GO 3 mg/m2/dose (0.1 mg/kg for patients with a body surface area <0.6 m2) was given on day 6 of Induction (Ind) I and day 7 of Intensification (Int) II to all patients on AAML03P1 and to randomized patients on the experimental arm of AAML0531. Patients on the control arm of AAML0531 were treated with standard therapy without GO (noGO). Stem cell transplant (SCT) was given following IntI to patients on AAML03P1 with a matched family donor (MFD) and to patients on AAML0531 with high risk (HR) disease or with intermediate risk (IR) disease and a MFD. SCT recipients only received one dose of GO. Patients were removed from protocol if the bone marrow had >/= 20% blasts after IndI on AAML03P1 or >/= 5% blasts after IndII on both studies. Early death (ED) was defined as death during IndI.Results: AAML03P1 enrolled 39 infants from 2003-2005 and AAML0531 enrolled 103 infants from 2006-2010 (Table 1). Median follow up was 5.02 years. The demographics and disease characteristics of infants enrolled on both studies were similar. Compared with enrolled children >/= 1 year of age, infants had higher frequencies of hepatomegaly (p<0.001), splenomegaly (p<0.001), hyperleukocytosis (WBC>100x103/µL, p=0.003) and French-American-British (FAB) M5 (p<0.001), and M7 (p<0.001) AML. Infants had less FAB M1 (p<0.001), M2 (p<0.001), and M4 (p=0.029) AML. There was no difference in CNS disease by age. The frequency of 11q23/MLL rearrangement was highest in infants 0-179 days of age (44%) and significantly decreased with increasing age (p<0.001). Favorable cytogenetics were rare in infants: t(8;21) was not found and inv(16)/t(16;16) was only found in 4 patients. FLT3-ITD HAR was absent in infants. The majority of infants (89%) fell into the IR group and infants were less likely to have had high (HR) or low risk (LR) disease when compared with children >/= 1 year. [Display omitted] The ED rate was higher in younger infants (7 ED, infants 0-179d) when compared with older infants (1 ED, infants 180-364d) (p=0.013). EDs were not increased in infants who received GO vs. noGO (5 vs. 3 ED, p=0.730). The complete remission (CR) rate for infants was 68% at the end of IndII. The 5 year EFS was lower in infants than children >/= 1 year (42 vs. 50%, p=0.001). The 5 year OS for infants was 62%, relapse risk (RR) was 44%, and TRM was 10%. Infants who received GO had improved OS, EFS, and RR, though the differences were not statistically significant (Table 2). [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Final Analysis of the Australasian Leukaemia and Lymphoma Group (ALLG) APML4 Trial: All-Trans Retinoic Acid (ATRA), Intravenous Arsenic Trioxide (ATO) and Idarubicin (IDA) As Initial Therapy for Acute Promyelocytic Leukemia (APL)

▪BACKGROUNDThe combination of ATRA and anthracycline-based chemotherapy has traditionally been regarded as the gold standard for induction and consolidation in previously untreated APL patients (pts), with ATO usually reserved for relapse. Recent data in Sanz low-risk (LR) and intermediate-risk (IR) APL indicate ATRA + ATO is superior to ATRA + chemotherapy (N Engl J Med 2013), but the optimal therapy for high-risk (HiR) pts remains unclear. In an attempt to improve anti-leukemic efficacy whilst limiting reliance on anthracyclines for all risk categories of APL, the ALLG incorporated ATO into an ATRA + reduced chemotherapy backbone, and the results of an interim analysis with a median follow-up of 2 years (yr) have been published (Blood 120:1570, 2012). Herein, we report results of the protocol-specified final analysis, conducted when all surviving pts had been followed for at least 2 yr after completion of consolidation.METHODS As published, APML4 protocol treatment comprised: (i) induction with ATRA (45 mg/m2 d1-36), IDA (12 mg/m2 d2,4,6,8), ATO (0.15 mg/kg d9-36), prophylactic prednisone (1 mg/kg d1-10) and aggressive hemostatic support; (ii) consolidation with ATRA and ATO (continuous in cycle 1, intermittent in cycle 2); (iii) 2 yr oral maintenance with ATRA, 6-mercaptopurine and methotrexate. Between 2004-2009, 124 evaluable pts were accrued, and median follow-up by the censor-reversing Kaplan-Meier method in this final analysis is 4.2 yr.RESULTS Median age was 44 (3-78) yr, median white cell count was 2.4 x 109/L (0.1-85.8), and median platelet count 22 x 109/L (2-173). Risk groups were 33 LR, 67 IR, 23 HiR, 1 unknown. FLT3 mutations were present in 44%, and 11% had ≥ 2 additional cytogenetic abnormalities (2+ACA). There were 4 (3.2%) deaths during induction (myocardial infarction d1, cerebral hemorrhage d3 and d7, cerebral edema and seizures d30). Grade 3-4 non-hematological adverse events included differentiation syndrome in 14%, and frequent but reversible biochemical hepatic and gastrointestinal toxicity. Q-Tc prolongation > 500 msec occurred in 14%, but there were no cases of ventricular arrhythmias or torsades de pointe. Significant neurological and cutaneous toxicity were infrequent.After induction, 118 pts (95%) achieved hematological complete remission; 112 commenced consolidation, and all were in molecular remission after cycle 2. A total of 5 relapses and 3 deaths have occurred post-induction, but none of the deaths were attributable to protocol therapy. Severe adverse events were less common during the chemotherapy-free consolidation cycles, especially cycle 2. The frequency of grade 3-4 neutropenia was 62% in cycle 1 and 27% in cycle 2, but there was no grade 3-4 thrombocytopenia.The following table lists event-free survival (EFS), disease-free survival (DFS), overall survival (OS) and cumulative incidence of relapse (CIR):TableAll ptsLRIRHiR2 yr5 yr2 yr5 yr2 yr5 yr2 yr5 yrEFS92%90%97%97%93%89%83%83%DFS97%95%100%100%97%93%95%95%OS94%94%97%97%96%96%87%87%CIR3%5%0%0%3%7%5%5%In univariate analysis, 2+ACA predicted for inferior DFS (P = .04), whereas age > 70 was associated with increased risk of early death (ED, P = .02), inferior EFS (P = .0002), and inferior OS (P = .001). Neither Sanz risk category nor FLT3 mutation status was significantly correlated with these outcome endpoints (all P > .05). In multivariate analysis, the significant associations of 2+ACA (P = .04 for DFS) and age > 70 (P = .0002 for EFS, P = .005 for OS) were retained. In addition, Sanz risk category was correlated with EFS (P[trend] = .003) and OS (P[trend] = .02).When compared with our previous ALLG APML3 trial (ATRA + IDA for induction and consolidation without ATO; Haematologica 2012), treatment with APML4 was associated with substantial and statistically significant improvements (see Figure) in EFS (P = .002), DFS (P = .001) and OS (P = .02). The significance of trial assignment was retained in multivariate analysis when APML3 and APML4 data were combined.CONCLUSIONS APML4 is a potent anti-leukemic regimen with manageable toxicity and a low ED rate. EFS and OS remain impressive with mature follow-up, and were influenced primarily by advanced age and Sanz risk category. The CIR was 5%, and was only associated with 2+ACA. Our results support the inclusion of ATO in induction and consolidation as front-line therapy for APL whilst simultaneously limiting cumulative anthracycline exposure. [Display omitted] DisclosuresOff Label Use: Arsenic trioxide is currently only registered in the US, Europe and Australia for the treatment of relapsed APL. This report includes its use in the initial treatment of APL.

Management and functional outcome of intramedullary spinal cord tumors: A prospective clinical study.

Aim:Intramedullary spinal cord tumors (IMSCT) are rare neoplasms of central nervous system but require proper evaluation and management to ensure a good outcome. This study was carried out to evaluate the functional outcome of IMSCT following surgery and to decipher the factors affecting optimal outcome of these cases.Materials and Methods:A prospective clinical study was carried out at a tertiary care center from 2003 to 2012. Forty three patients with intramedullary tumors diagnosed on magnetic resonance imaging were included. Their clinical details, neurological findings and demographic data were recorded. The patients were then subjected to surgery and adjuvant radiotherapy. The patients were followedup clinically and radiologically, and all parameters examined and recorded.Results:Sensory and motor impairment was present preoperatively in majority of patients (n = 39 and n = 38, 90.7% and 88.4%, respectively). Gross total excision was performed in 30 cases (69.76%). The most common histological diagnosis was ependymoma (n = 21, 48.8%). Postoperatively 32 patients (74.4%) were in McCormick functional Grade I or II improving from 13 cases (30.2%) in Grade I or II preoperatively. Fifteen of 17 patients in Medical Research Council (MRC) Grade III and 10 out of 12 patients in Grade MRC IV improved. No mortality was recorded during the entire period of follow-up (mean: 22, range: 3-96 months). Eight patients (18.6%) had recurrence till the last follow-up visit.Conclusions:Preoperative neurological grade was the most important predictor of functional outcome. Gross tumor excision was the best surgical modality to improve event free survival. High-grade tumors had higher rates of recurrence but no effect on functional outcome.

Abstract 984: Alteration of the p53 pathway is associated with subclonal tumor progression in glioblastoma

Abstract To evaluate evolutionary patterns in progression and therapy-resistance of GBM, we analyzed the genomic profiles of 252 GBM samples from The Cancer Genome Atlas (TCGA)1, including 48 multi-sector and recurrent tumor biopsies taken from 17 pairs of pre- and post-treatment GBMs, to understand 1) the intratumoral heterogeneity of GBM and 2) how GBM responds to therapeutic intervention. We integrated variant allele fraction, DNA copy number and genotype information to determine clonality of all mutations and found that 69.5% of mutations (median across samples 70.1% ± 19.6%) were classified as clonal and 30.5% as subclonal. To verify our classification approach, we classified mutations detected in two non-overlapping biopsies from 11 tumors into clonal and subclonal categories. Of mutations detected in both tumor sectors 86.2% were classified as clonal and 45.2% of sample-private mutations were categorized as clonal, which was a strongly significant difference (P = 1.8×10-87). Separating patients into discrete age groups by an interval of 10 years, we found a significant linear correlation between clonal mutations and age (P &amp;lt; 0.001). This observation supports the notion that clonal mutations predominantly accumulated over the life span of the cell population that gave rise to the cell of origin before neoplastic onset2. No correlation with age was found for subclonal mutations. In contrast, the frequency of subclonal mutations was strongly correlated with the presence of alterations related to the p53 pathway (P &amp;lt; 0.001), particularly TP53 point mutation or amplification of MDM2. This observation raises the possibility that p53 pathway alterations stimulate subclonal evolution, possibly by providing greater tolerance to DNA damage and/or suppression of apoptosis3. To evaluate the effects of clonal heterogeneity on disease recurrence, we analyzed matched pairs of primary and recurrent GBM, including five pairs with mutated TP53 and nine pairs with wildtype TP53. Recurrent TP53 mutant GBM showed a further and significant increase in the subclonal mutation frequency. In contrast, TP53 wildtype tumors showed an increase in the frequency of clonal mutations compared to their matched primary tumor. These data suggest that TP53 mutant GBM became increasingly clonally complex at time of recurrence, whereas TP53 wildtype GBM showed a reduced level of intratumoral heterogeneity. We observed an ultramutator phenotype in three recurrent tumors, associated with temozolomide treatment. Our results suggest that mutations in the p53 pathway affect the response to therapy by supporting greater intratumoral heterogeneity. Paradoxically we observe a trend towards improved event free survival in samples with high subclonal mutation frequency. Further research is needed to assess whether the level of intratumoral heterogeneity is a reflection of the molecular portrait of GBM progression. Citation Format: Hoon Kim, Siyuan Zheng, Seyed S. Amini, Selene M. Virk, Tom Mikkelsen, Daniel J. Brat, Jonna Grimsby, Carrie Sougnez, Andrew E. Sloan, Mark L. Cohen, Erwin G. Van Meir, Lisa Scarpace, The Cancer Genome Research Network, Peter W. Laird, John N. Weinstein, Eric Lander, Stacey Gabriel, Gad Getz, Matthew Meyerson, Lynda Chin, Jill S. Barnholtz-Sloan, Roel G.w. Verhaak. Alteration of the p53 pathway is associated with subclonal tumor progression in glioblastoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 984. doi:10.1158/1538-7445.AM2014-984

Final Results of the Sakk 16/00 Trial: a Randomized Phase III Trial Comparing Neoadjuvant Chemoradiation to Chemotherapy Alone in Stage Iiia/N2 Non-Small Cell Lung Cancer (Nsclc)

ABSTRACT Aim: One standard option in the treatment of stage IIIA/N2 NSCLC is neoadjuvant chemotherapy followed by surgery. We investigated in a randomized trial whether the addition of neoadjuvant radiotherapy would improve the outcome. Here we present the final results of this study. Methods: Patients (pts.) with pathologically proven, resectable stage IIIA/N2 NSCLC, performance status 0-1, and adequate organ function were randomized 1:1 to chemoradiation (CRT) with 3 cycles of neoadjuvant chemotherapy (cisplatin 100 mg/m2 and docetaxel 85 mg/m2 d1, q3weeks) followed by accelerated concomitant boost radiotherapy (RT) with 44 Gy in 22 fractions in 3 weeks, or neoadjuvant chemotherapy alone (CT), with subsequent surgery for all pts. The primary endpoint was event-free survival (EFS). Results: 232 pts. were randomized in 23 centers, the median follow-up was 53 months. Two thirds were men, median age was 60 years (range 37-76). Histology was squamous cell in 33%, adenocarcinoma in 43%. Response rate to CRT was 61% vs. 44% with CT. 85% of all pts. underwent surgery, 30-day postoperative mortality was 1%. The rate of complete resection was 91% (CRT) vs. 81% (CT) and the pathological complete remission (pCR) rate was 16% vs. 12%. The median EFS was 13.1 months (95% CI 9.9 - 23.5) for the CRT group vs. 11.8 months (95% CI 8.4 – 15.2) in the CT arm (p 0.665). The median overall survival (OS) with CRT was 37.1 months (95% CI 22.6 -50), with CT 26.1 months ( 95% CI 26.1 – 52.1, p 0.938). The local failure rate was 23% in both arms. In the CT arm 12 pts. were given postoperative radiotherapy (PORT) for R1 resection, 6 pts. received PORT in violation of the protocol. Pts. with a pCR, mediastinal downstaging to ypN0/1 and complete resection had a better outcome. Toxicity of chemotherapy was substantial, especially febrile neutropenia was common, whereas RT was well tolerated. Conclusions: This is the first completed phase III trial to evaluate the role of induction chemoradiotherapy and surgery, in comparison to neoadjuvant CT alone followed by surgery. RT was active, it increased response, complete resection and pCR rates. However, this failed to translate into an improvement of local control, EFS or OS. Notably, surgery after induction treatment was safe, including pneumonectomy. The overall survival rates of our neoadjuvant regimen are very encouraging, especially for a multicenter setting. Disclosure: M. Pless: Advisory Board for Sanofi; R. Cathomas: Advisory Board Sanofi D.C. Betticher: Advisory Board Sanofi. All other authors have declared no conflicts of interest.