Improvement In Relapse-free Survival Research Articles

Advances in Immunotherapy of Malignant Melanoma

Development of immunotherapy has dramatically changed poor prognosis of metastatic malignant melanoma (MM). Inhibition of immune checkpoints represents a new effective treatment. Monoclonal antibodies against CTLA-4 ipilimumab and against PD-1 (programme death 1) nivolumab and pembrolizumab prolong progression free survival and overall survival (OS) in patients with advanced metastatic MM. Both achieved significant improvement in relapse-free survival and OS also in adjuvant setting. It looks like the efficacy of the combined immunotherapy of ipilimumab with anti-PD-1 antibodies is superior to the monotherapy, but combined therapy is accompanied by higher toxicity. Management of adverse events of ipilimumab plus nivolumab combination were solved in several clinical trials. New combinations such as immunotherapy with intralesional oncolytic vaccination are explored. In this review, some results of clinical trials presented at ASCO (American Society of Clinical Oncology) 2017 are mentioned. Interesting data were obtained from the evaluation of long-term efficacy of immunotherapy in patients who had to stop the treatment for adverse events. Other trial (CheckMate 172) evaluated the safety and efficiency of nivolumab in MM patients who failed on or after therapy with ipilimumab. Considerable attention has been paid to the efficacy of immunotherapy in the treatment of brain metastases.Key words: malignant melanoma - immunotherapy - ipilimumab - nivolumab - pembrolizumab - talimogene laherparepvec - brain metastases The author declares she no potential conflicts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers.Submitted: 31. 8. 2017Accepted: 24. 10. 2017.

Adjuvant Therapy for Melanoma.

Systemic adjuvant therapy for surgically resected cutaneous melanoma that is at high risk for disease recurrence and death targets residual micrometastatic disease which is the source of future local or distant relapse. Interferon-alfa (IFNα) has been the most extensively studied in regimens that varied by dosage, route of administration, formulation, and duration of therapy. Most regimens have demonstrated improvements in relapse-free survival (RFS), while the regimen administered at high dosage (HDI) showed improvements in overall survival (OS) in two out of three RCTs. HDI benefits as measured by the hazard ratios (HR) in E1684 (vs. observation), E1690 (vs. observation), and E1694 (vs. vaccine) trials were estimated at 0.61, 0.78, and 0.67 (RFS) and 0.67, 1.0, and 0.72 (OS) when first reported with lesser estimates on later updates. Pegylated IFNα (peg-IFN) as studied in the European Organisation for Research and Treatment of Cancer (EORTC) 18991 trial in patients with stage III melanoma significantly reduced the risk of relapse (HR 0.87) with no impact on OS. More recently (EORTC 18071), ipilimumab at the high dose of 10mg/kg was shown to significantly improve RFS (HR 0.76) and OS (HR 0.72) of stage III melanoma patients but at a significant cost in terms of immune-related toxicities. Ongoing adjuvant studies are testing ipilimumab at 3 or 10mg/kg versus HDI (E1609) and the anti-PD-1 antibodies nivolumab (CheckMate 238) and pembrolizumab (KEYNOTE-054 and S1404).

ED08.03 Adjuvant Chemotherapy of Completely Resected

ED08.03 Adjuvant Chemotherapy of Completely Resected

Feasibility of Allogeneic Hematopoietic Cell Transplantation Among High-Risk AML Patients in First Complete Remission: Results of the Transplant Objective from the SWOG (S1203) Randomized Phase III Study of Induction Therapy Using Standard 7+3 Therapy or Idarubicin with High-Dose Cytarabine (IA) Versus IA Plus Vorinostat

Background: Adult acute myeloid leukemia (AML) patients with high-risk cytogenetics have a significantly worse survival compared to similarly treated intermediate- or favorable-risk patients. Although prior studies suggest better outcome in high-risk AML patients in first complete remission (CR1) who undergo allogeneic hematopoietic cell transplantation (HCT) compared with consolidation chemotherapy, only 40% of patients proceed to HCT. The lack of a matched sibling donor (available in about 33%) should not be a barrier to HCT since alternative donors are available for the large majority of high-risk AMLpatients and recent data suggest outcomes after allogeneic HCT from fully matched unrelated donors are similar to those following matched related donor transplantation. We sought to determine if a prospective organized effort could rapidly identify alternative donors to improve the historical 40% allogeneic HCT rate in high-risk CR1 AML patients ≤ age 61. Secondly, we hypothesized that transplanting significantly more adults with high-risk AML in CR1 would lead to an improved outcome compared with the historical relapse-free survival (RFS) of 22%. Patients and Methods: Adult patients between ages 18 and 60 years with untreated AML were randomized to receive induction therapy with standard cytarabine plus daunorubicin (7+3; n=261), idarubicin with high-dose cytarabine (IA; n=261), or IA with vorinostat (IA+V; n=216). Conventional cytogenetics were obtained at time of enrollment and used to determine risk classification by standard criteria. All patients with high-risk cytogenetics underwent expedited HLA-typing. High-risk patientswere encouraged tobe referred for consultation with a transplant team with the goal of conducting an allogeneic HCT in CR1. Results: Of 738 eligible patients (median age, 49 years; range, 18-60), 159 (22%) had high-risk cytogenetics, of whom 60 (38%), 61 (38%), and 38 (24%) received induction with 7+3, IA, or IA+V, respectively. A total of 107 of the 159 high-risk patients achieved CR/CRi (67%). HCT was performed in 317 of all 738 patients (43%) and 68 (64%) of the high-risk patients received a transplant in CR1 (p Conclusions: In newly diagnosed adults with AML age 18-60, early cytogenetic testing with an organized effort to identify a suitable allogeneic HCT donorled to a CR1 transplant rate of 64% in the high-risk group, which in turn led to a significant improvement in RFS over historical controls. Better outcomes in poor prognosis AML patients may be achieved simply by rapidly finding unrelated donors and performing allogeneic HCT in CR1 as soon as possible. Clinical Trials Registry: NCT #0180233; Support: NIH/NCI grants: CA180888, CA180819, CA18020, CA180821, CA180863, CA077202; CCSRI #021039 Disclosures Othus:Glycomimetics: Consultancy; Celgene: Consultancy. Radich:Novartis: Consultancy, Other: laboratory contract; ARIAD: Consultancy; Pfizer: Consultancy; TwinStrand: Consultancy; Bristol-MyersSquibb: Consultancy. Strickland:Alexion Pharmaceuticals: Consultancy; Ambit: Consultancy; Baxalta: Consultancy; Boehringer Ingelheim: Consultancy, Research Funding; CTI Biopharma: Consultancy; Daiichi Sankyo: Consultancy; Sunesis Pharmaceuticals: Consultancy, Research Funding; Abbvie: Research Funding; Astellas Pharma: Research Funding; Celator: Research Funding; Cyclacel: Research Funding; GlaxoSmithKline: Research Funding; Karyopharm Therapeutica: Research Funding; Sanofi: Research Funding. Savoie:AbbVie: Consultancy; Lundbeck: Consultancy; BMS: Consultancy, Honoraria; Velgene: Consultancy; Pfizer: Consultancy; Amgen: Consultancy; Novartis: Consultancy, Honoraria; Jazz: Consultancy. Sekeres:Millenium/Takeda: Membership on an entity9s Board of Directors or advisory committees; Celgene: Membership on an entity9s Board of Directors or advisory committees. Stone:Amgen: Consultancy; Celgene: Consultancy, Membership on an entity9s Board of Directors or advisory committees; Xenetic Biosciences: Consultancy; Jansen: Consultancy; Pfizer: Consultancy; ONO: Consultancy; Juno Therapeutics: Consultancy; Merck: Consultancy; Roche: Consultancy; Seattle Genetics: Consultancy; Sunesis Pharmaceuticals: Consultancy; Abbvie: Consultancy, Membership on an entity9s Board of Directors or advisory committees; Agios: Consultancy; Novartis: Consultancy; Celator: Consultancy; Karyopharm: Consultancy. Erba:Seattle Genetics: Consultancy, Research Funding; Pfizer: Consultancy; Jannsen: Consultancy, Research Funding; Juno: Research Funding; Celator: Research Funding; Ariad: Consultancy; Agios: Research Funding; Amgen: Consultancy, Research Funding; Novartis: Consultancy, Speakers Bureau; Millennium Pharmaceuticals, Inc.: Research Funding; Incyte: Consultancy, DSMB, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Gylcomimetics: Other: DSMB; Sunesis: Consultancy; Daiichi Sankyo: Consultancy; Astellas: Research Funding.

The dose–response of salvage radiotherapy following radical prostatectomy: A systematic review and meta-analysis

Purpose/objectivesTo date neither the optimal radiotherapy dose nor the existence of a dose–response has been established for salvage RT (SRT). Materials/methodsA systematic review from 1996 to 2015 and meta-analysis was performed to identify the pathologic, clinical and treatment factors associated with relapse-free survival (RFS) after SRT (uniformly defined as a PSA>0.2ng/mL or rising above post-SRT nadir). A sigmoidal dose–response curve was objectively fitted and a non-parametric statistical test used to determine significance. Results71 studies (10,034 patients) satisfied the meta-analysis criteria. SRT dose (p=0.0001), PSA prior to SRT (p=0.0009), ECE+ (p=0.039) and SV+ (p=0.046) had significant associations with RFS. Statistical analyses confirmed the independence of SRT dose–response. Omission of series with ADT did not alter results. Dose–response is well fit by a sigmoidal curve (p=0.0001) with a TCD50 of 65.8Gy, with a dose of 70Gy achieving 58.4% RFS vs. 38.5% for 60Gy. A 2.0% [95% CI 1.1–3.2] improvement in RFS is achieved for each Gy. The SRT dose–response remarkably parallels that for definitive RT of localized disease. ConclusionsThis study provides level 2a evidence for dose-escalated SRT>70Gy. The presence of an SRT dose–response for microscopic disease supports the hypothesis that prostate cancer is inherently radio-resistant.

Persistence of minimal residual disease assessed by multiparameter flow cytometry is highly prognostic in younger patients with acute myeloid leukemia.

Predicting outcomes for patients with acute myeloid leukemia (AML) on the basis of pretreatment predictors has been the cornerstone of management. Posttreatment prognostic factors are increasingly being evaluated. Among 280 younger patients who were treated with intermediate-dose cytarabine (total ≥ 5 g/m2 ) and idarubicin-based induction chemotherapy and achieved remission, 186 were assessed for minimal residual disease (MRD) with an 8-color multiparameter flow cytometry panel performed on bone marrow specimens with a sensitivity of 0.1% or higher. One hundred sixty-six patients had samples available 1 to 2 months after induction at the time of complete remission (CR), and 79% became negative for MRD, with an MRD-negative status associated with an improvement in relapse-free survival (RFS; P = .0002) and overall survival (OS; P = .0002). One hundred sixteen were evaluated for their MRD status during consolidation, and 86% were negative, with an MRD-negative status associated with a significant improvement in RFS (P < .0001) and OS (P < .0001). Sixty-nine patients were evaluated for their MRD status after completion of all therapy, and 84% were negative, with an MRD-negative status associated with an improvement in RFS (P < .0001) and OS (P < .0001). In a multivariate analysis including age, cytogenetics, response (CR vs CR with incomplete platelet recovery/incomplete blood count recovery), and MRD, achieving an MRD-negative status was the most important independent predictor of RFS and OS at response (P = .008 and P = .0008, respectively), during consolidation (P < .0001 for both), and at the completion of therapy (P < .0001 and P = .002, respectively). Achieving an MRD-negative status according to multiparameter flow cytometry is associated with a highly significant improvement in the outcomes of younger patients with AML receiving cytosine arabinoside plus idarubicin-based induction and consolidation regimens. Cancer 2017;123:426-435. © 2016 American Cancer Society.

A Randomized Phase II Trial of Short-Course Androgen Deprivation Therapy With or Without Bevacizumab for Patients With Recurrent Prostate Cancer After Definitive Local Therapy

Patients with recurrent prostate cancer after local treatment make up a heterogeneous population for whom androgen deprivation therapy (ADT) is the usual treatment. The purpose of this randomized phase II trial was to investigate the efficacy and toxicity of short-course ADT with or without bevacizumab in men with hormone-sensitive prostate cancer. Eligible patients had an increasing prostate-specific antigen (PSA) of ≤ 50 ng/mL and PSA doubling time of less than 18 months. Patients had either no metastases or low burden, asymptomatic metastases (lymph nodes < 3 cm and five or fewer bone metastases). Patients were randomly assigned 2:1 to a luteinizing hormone-releasing hormone agonist, bicalutamide and bevacizumab or ADT alone, for 6 months. The primary end point was PSA relapse-free survival (RFS). Relapse was defined as a PSA of more than 0.2 ng/mL for prostatectomy patients or PSA of more than 2.0 ng/mL for primary radiation therapy patients. Sixty-six patients received ADT + bevacizumab and 36 received ADT alone. Patients receiving ADT + bevacizumab had a statistically significant improvement in RFS compared with patients treated with ADT alone (13.3 months for ADT + bevacizumab v 10.2 months for ADT alone; hazard ratio, 0.47; 95% CI, 0.29 to 0.77; log-rank P = .002). Hypertension was the most common adverse event in patients receiving ADT + bevacizumab (36%). ADT combined with bevacizumab resulted in an improved RFS for patients with hormone-sensitive prostate cancer. Long-term follow-up is needed to determine whether some patients have a durable PSA response and are able to remain off ADT for prolonged periods. Our data provide rationale for combining vascular endothelial growth factor-targeting therapy with ADT in hormone-sensitive prostate cancer.

Abstract P4-12-02: Adjuvant trastuzumab improved the prognosis of HER2-positive early breast cancer: Single institutional cohort study from clinical practice

Abstract Background: Trastuzumab-containing regimens for the adjuvant treatment of human epidermal growth factor receptor 2 (HER2)-positive early breast cancer significantly improved the prognosis. However, most data showing the effects of trastuzumab come from clinical trials. Aims: To evaluate the efficacy of the adjuvant trastuzumab in the clinical practice, the prognosis of HER2-positive early breast cancer was investigated according to the adjuvant treatment with or without trastuzumab. Methods: Among 2548 women who underwent surgery for primary breast cancer in our department between 2000 and 2011, 315 patients had HER2-positive tumors. A total of 293 patients aged 75 or younger with invasive HER2-positive breast cancer were included in this study. The associations between clinicopathological characteristics, adjuvant therapy and relapse-free survival (RFS) were examined. The RFS was estimated using the Kaplan-Meier method, and independent predictors were assessed using proportional cox hazard models. Results: 113 (38.5%) patients ware treated with chemotherapy alone (Cohort A), 100 (34.1%) patients were treated with chemotherapy and trastuzumab (Cohort B) and 80 (27.3%) patients received neither chemotherapy nor trastuzumab (Cohort C). The administration of adjuvant trastuzumab significantly increased in 2007. The prognosis of the patients treated in 2007-2011 was significantly better than that of patients treated in 2000-2006 (p=0.0011). The use of adjuvant trastuzumab was significantly associated with longer RFS (p=0.0286). The improvement of RFS by using trastuzumab was significant in node-positive patients. The patients in Cohort C had mainly node negative and small tumors. RFS of the patients treated of Cohort B was significantly more favorable than that of Cohort A. However, RFS of Cohort C was not statistically different from that of Cohort B, probably due to the early stage of Cohort C. In univariate analysis, larger tumor size (T2, 3), lymph node metastasis, lymphovessel invasion and absence of trastuzumab were related to relapse. In multivariate analysis, factors related to relapse were lymph node metastasis and absence of trastuzumab. Univariate and multivariate analysis for relapse-free survivalFactorsUnivariate analysis Multivariate analysis HR95% CIP valueHR95% CIP valueTumor sizeT2, T3 vs. T13.101.69-5.850.00021.820.87-3.950.1131LN meta.positive vs. negative4.372.26-8.84&amp;lt;0.00012.831.26-6.490.0116Histological grade3 vs. 1, 20.770.42-1.440.4199 lypositive vs. negativ3.401.87-6.25&amp;lt;0.00011.430.67-3.100.3538ERpositive vs. negativ0.930.50-1.650.7638 PRpositive vs. negativ0.970.50-1.760.8885 adjuvant chemotherapy 1.570.79-3.490.207 adjuvant trastuzumab 0.410.17-0.880.02070.410.16-0.900.0258LN meta.; lymph node metastasis, ly; lymphovessel invasion ER; estrogen receptor, PgR; progesterone receptor Conclusions: Use of adjuvant trastuzumab improved the prognosis of HER2-positive early breast cancer in clinical practice. Citation Format: Akiyoshi S, Ishida M, Koga C, Nakamura Y, Taguchi K, Ohno S, Tokunaga E. Adjuvant trastuzumab improved the prognosis of HER2-positive early breast cancer: Single institutional cohort study from clinical practice. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P4-12-02.

Long-term results of complete clinical and pathologic regression in patients with breast cancer

The article presents the results of analysis of long-term treatment outcomes of 162 patients who received neoadjuvant chemotherapy for breast cancer based on City Clinical Hospital No. 40 of Ekaterinburg. ER-negative status, triple-negative subtype of tumor and lymph node negative status were found to be significant predictive factors of complete tumor regression. In studying long-term results of the treatment it was showed that negative status of lymph nodes significantly predicts improvement in relapse-free survival, while the surgical treatment does not increase relapse-free survival time in case of complete tumor regression.

Persistence of Minimal Residual Disease Assessed By Multi-Parameter Flow Cytometry Is a Strong Predictor of Outcome in Younger Patients with Acute Myeloid Leukemia

Background - Minimal Residual Disease (MRD) assessed by Multi-parameter Flow Cytometry (MFC) has not been extensively evaluated as a predictor of outcome in younger patients with acute myeloid leukemia (AML) receiving ara-C plus anthracycline inductionMethods - We examined the predictive value of MRD assessment by MFC in mainly younger patients with newly diagnosed AML who were treated with intermediate dose cytarabine (total of ≥ 6 g/m2) and idarubicin based induction chemotherapy. Among 280 patients treated with clofarabine, idarubicin plus ara-C (CIA), fludarabine, idarubicin plus ara-C (FIA), fludarabine, ara-C, GCSF plus idarubicin (FLAG-Ida), cladribine, idarubicin, plus ara-C (CLIA) who achieved complete remission (CR), CR without platelet recovery (CRp), or CR with incomplete count recovery (CRi) 186 had at least one available MRD data and are the subject of this analysis. MRD by MFC was assessed using an 8-color panel containing 19 distinct markers, on bone marrow specimens obtained at the time of achievement of CR/CRi/CRp (approximately 1-2 months post induction), during consolidation (approximately 3-7 months post-induction) and at completion of therapy (≥ 8 months post induction). Residual leukemic blasts were identified based on phenotypic differences from normal myelomonocytic precursors. Sensitivity was estimated at 0.1% in most cases, with maximum achievable sensitivity of 0.01%, depending on the leukemic phenotype.Results - Median age of the patients was 51 years (Range, 17 - 77 years). 6 patients were older than 65 (all with ELN favorable disease). Median WBC at presentation was 4.7 x 109/L (Range, 0.5 - 103 x 109/L). Cytogenetics was favorable risk in 34 (18%), intermediate risk in 115 (62%) and adverse in 27 (15%) and was not available in 10 (5%) Treatment included CIA in 102 (55%), FIA in 34 (18%), FLAG-Ida in 34 (18%) and CLIA in 16 (9%). 166 patients had available samples at 1-2 months post induction and 131 (79%) became MRD negative. Achieving MRD negative status at response was associated with a statistically significant improvement in relapse free survival (RFS) (p= 0.001) and overall survival (OS) (p= 0.003) (Figure 1). 116 patients were evaluated for MRD status during consolidation and 100 (86%) became negative. Achieving a negative MRD status during consolidation was associated with a significant improvement in RFS (p˂0.001) and OS (p˂0.001)(Figure 2). 69 patients were evaluated for MRD status after completion of all therapy and 58 (84%) became negative. Achieving a negative MRD status at completion of therapy was associated with improvement in RFS (P˂0.001) and OS (P˂0.001) (Figure 3). On multivariate analysis including age ˂40 years vs. ≥ 40, WBC at presentation ˂or ≥ 10 x 109/L, cytogenetics (favorable, intermediate, adverse), achieving CR vs. CRp/CRi, and treatment with CIA, FIA, CLIA, or FLAG-Ida, achieving MRD negative status was the only independent predictor of RFS and OS at response (P=0.03 and P=0.005, respectively), during consolidation (p˂0.001 for both), or at completion of therapy (p˂0.001 for both).Conclusion - Achieving MRD negative status by MFC at response, during consolidation therapy and after completion of therapy is associated with a highly significant improvement in the outcome of younger patients with AML receiving ara-C plus idarubicin-based regimens. [Display omitted] [Display omitted] [Display omitted] DisclosuresJabbour:Pfizer: Consultancy, Research Funding. Faderl:Astellas: Research Funding; Celator: Research Funding; JW Pharma: Consultancy; Seattle Genetics, Inc.: Research Funding; Karyopharm: Consultancy, Research Funding; Pfizer: Research Funding; Celgene: Consultancy, Research Funding, Speakers Bureau; Onyx: Speakers Bureau; Ambit: Research Funding; BMS: Research Funding. Pemmaraju:Stemline: Research Funding; Incyte: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; LFB: Consultancy, Honoraria. Konopleva:Novartis: Research Funding; AbbVie: Research Funding; Stemline: Research Funding; Calithera: Research Funding; Threshold: Research Funding. Cortes:BerGenBio AS: Research Funding; Teva: Research Funding; Novartis: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Ariad: Consultancy, Research Funding; Astellas: Consultancy, Research Funding; Ambit: Consultancy, Research Funding; Arog: Research Funding; Celator: Research Funding; Jenssen: Consultancy.

Early Allogeneic Stem Cell Transplantation and Use of Asparaginase during Induction Chemotherapy Appear to Improve Otherwise Poor Outcomes in Adult T-Cell Acute Lymphoblastic Leukemia/Lymphoma (T-ALL/T-LBL) Patients: A Multi-Institutional Review

Background: AdultT-cell acute lymphoblastic leukemia/lymphoma (T-ALL/T-LBL) is a rare, aggressive bone marrow malignancy with a historically poor prognosis despite use of various chemotherapies.Methods: After institutional review board approval, we compiled a database of all adult T-ALL/T-LBL cases at three large cancer centers between the years 2005-2015, treated at the physician's discretion. Data collected included patient demographics, tumor characteristics (white cell count at diagnosis, blast phenotype, FISH, cytogenetics, bone marrow involvement), treatment regimens and patient outcomes. Relapse-free survival (RFS) and overall survival (OS) were examined looking at medians and interquartile ranges of times to events. Kaplan Meier curves provided a graphical representation of the survival probability. Moreover, we provided estimates of the 50th percentile along with corresponding 95% confidence intervals (CIs). We also used Univariate and Multivariable Cox Regression to estimate unadjusted and adjusted Hazard Ratios (HRs) and their 95% CIs. Stratified analysis was also performed using the Mann-Whitney U-test to compare median survival times, and the Log-rank to compare survival curses for RFS and OS.Results: The final analysis included 95 adult patients. Median age at diagnosis was 32 (range 17-75). 71.6% of patients were male. 49.5% of patients were white, 14.7% were black, 6.3% were Hispanic, 7.4% were Asian and in 22.1% of patients the race was unknown. Multiple frontline treatment regimens were used with 60% of patients treated with Hyper-CVAD, an additional 5.3% of patients received Hyper-CVAD with asparaginase, 24.2% of patients were treated on a pediatric-based protocol, 4.2% on a clinical trial, and 6.3% received other regimens. In total, 40 patients (42.1%) received asparaginase at some point during treatment regimen with 27 patients (28.4%) receiving it in the initial treatment regimen. After induction therapy, 65 patients (68.4%) achieved remission. Twenty-eight patients (29.5%) underwent transplant (8 matched-related donors, 10 matched unrelated donors, 5 mismatched unrelated donor, 2 cord transplants, 2 autologous, and 1 haplo-identical transplant). Ten patients (10.5%) underwent transplant in first complete remission (CR1) while two patients (2.1%) proceeded to transplant with minimal residual disease following induction. Despite therapy, 59 patients (62.1%) had known disease relapse or progressive disease. 16 patients (16.8%) underwent transplant after disease relapse. At time of analysis, 57 patients (60.6%) died. In the entire cohort, median RFS was 12.9 months and median OS was 19 months. In patients with a very high white count (>100 x 103/cmm at presentation) there was a trend toward earlier relapse when compared to patients presenting with white counts in the normal range (HR 2.27, p-value 0.085). Patients who received asparaginase in their initial treatment regimen have statistically improved RFS (HR 2.65, p-value = 0.014) and OS (HR 2.3, p-value=0.017). When adjusting for the presence of the covariates of age, sex, and WBC, patients who received initial asparaginase still had significant improvement in RFS (HR 3.18, p-value 0.033). In overall survival, significant benefit was seen in the addition of asparaginase in patients under 40 (HR 3.4, CI 1.22-9.5), however in patients greater than 40, asparaginase use seemed to decrease survival (HR 0.24, CI 0.03-1), although this did not reach statistical significance. All patients who underwent transplant had an improvement in OS, with median survival in the transplant group of 27 months compared to 18.2 months in the non-transplanted patients (log-rank test p-value = 0.048). Patients who received a transplant in CR1 had a trend towards improvement in RFS of 6.3 months (17.8 months versus 11.5 months in non-transplanted patients; log-rank test p-value = 0.03).Conclusion: Overall, adult T-ALL/T-LBL has a poor prognosis. Our multi-institutional retrospective review showed that OS and RFS may be improved by incorporating asparaginase use in front line therapy and by transplanting patients in first CR. Our data is limited in that actual dosing of asparaginase was not examined and that relatively few patients > 40 yrs old received asparaginase (4 pts) or SCT (5 pts). More prospective studies are needed in older adult T-ALL/LBL patients using these approaches to possibly improve their outcomes. DisclosuresBorate:Gilead: Speakers Bureau; Genoptix: Consultancy; Seattle Genetics: Research Funding; Novartis: Speakers Bureau; Amgen: Speakers Bureau; Alexion: Speakers Bureau. Hathaway:OnQ Health: Research Funding. Kota:Pfizer: Membership on an entity's Board of Directors or advisory committees; Leukemia Lymphoma Society: Research Funding. Shah:DeBartolo Institute for Personlaized Medicine: Research Funding; Rosetta Genomics: Research Funding; Acetylon Pharmaceuticals, INC: Membership on an entity's Board of Directors or advisory committees; Plexus Communications: Honoraria; Pharmacyclics: Speakers Bureau; Spectrum: Speakers Bureau; Bayer: Honoraria; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Speakers Bureau; Seattle Genetics: Research Funding; SWOG: Consultancy; NCCN: Consultancy. Jillella:Leukemia Lymphoma Society: Research Funding. Heffner:Amgen: Consultancy. Erba:Novartis; Incyte; Celgene: Consultancy, Patents & Royalties; GlycoMimetics; Janssen: Other: Data Safety & Monitoring Committees; Seattle Genetics; Amgen: Consultancy, Research Funding; Millennium/Takeda; Celator; Astellas: Research Funding; Sunesis;Pfizer; Daiichi Sankyo; Ariad: Consultancy.

Multi-Center US Intergroup Study of Intensive Chemotherapy Plus Dasatinib Followed By Allogeneic Stem Cell Transplant in Patients with Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia Younger Than 60

▪Background- Introduction of tyrosine kinase inhibitors in the treatment of patients with Philadelphia (Ph) chromosome positive (Ph+) acute lymphoblastic leukemia (ALL) has led to a significant improvement in the long term outcome of patients, in particular those who are unsuitable to undergo allogeneic stem cell transplant (alloSCT) in first complete remission (CR1).Design- This multicenter, phase II, clinical trial was conducted in 37 centers across the US to determine whether the addition of dasatinib to chemotherapy followed by an alloSCT in the eligible patients would lead to a significant improvement in relapse-free survival. The study also examined the duration of CR in patients unable to receive an alloSCT and the potential value of detection of minimal residual disease (MRD) using quantitative PCR for BCR-ABL fusion transcripts at defined intervals. Patients ≥ 18 and ≤ 60 years of age with newly diagnosed Ph+ ALL with an ECOG performance status of 0-2 and adequate organ function were enrolled to receive 8 cycles of alternating hyperCVAD and high dose cytarabine and methotrexate chemotherapy in addition to dasatinib 100 mg daily for the first 14 days of each cycle. Later the protocol was amended and patients received dasatinib 70 mg daily continuously from cycle 2 onwards. Central nervous system prophylaxis was in the form of alternating doses of cytarabine and methotrexate administered intrathecally twice per cycle for 8 doses. Patients who had received one cycle of induction therapy before the Ph abnormality was identified were allowed to participate in the study. All patients with an available matched sibling or unrelated donor were encouraged to undergo an alloSCT in CR1. Others received maintenance therapy with continuous dasatinib 100 mg daily as well as monthly vincristine and prednisone for 2 years and followed by dasatinib indefinitely. Patients receiving alloSCT would receive dasatinib 100 mg daily starting from day 100 for up to 5 years, with dose adjustments as necessary.Results- The study has accrued 97 patients, 94 of whom were eligible and evaluable. Their median age is 44 years (range, 20-60 years) and median WBC at presentation 10 x 109/L (range, 1 - 410 x 109/L). Among 93 patients with available data, 82 (88%) achieved CR or CR with incomplete count recovery (CRi). 34 patients were enrolled having received prior therapy, 16 in CR/CRi, 7 with unknown response status (5 achieved CR on the study), and 11 with refractory disease after 1 course of prior therapy (9 achieved CR on the study). Among the 60 untreated patients, 51 achieved CR, 2 achieved CRi, 2 had unconfirmed CR, 2 died early, 2 were refractory and 1 had missing data. 41 patients underwent study-related alloSCT in CR1 including 35 with TBI-based regimens and 4 with busulfan-based regimens; 2 had missing data. 8 patients had non-prescribed alloSCT off study. Median follow-up among all patients known to be alive is 26 months (range 9 - 57 months). For the overall population, overall survival (OS), event-free survival (EFS), and relapse-free survival (RFS) at 12 months were 88%, 74%, and 85%, respectively (Figure 1). The 12-month RFS and OS after transplant were 71% and 87%, respectively. Landmark analysis at 131 days from the time of CR/CRi (time to alloSCT in 75% of transplanted patients), showed a statistically superior advantage for RFS (p=0.03) but no difference in survival (p=0.07) for the transplanted patients (Figures 2a and 2b, respectively). MRD status at CR1 is available in 19 patients, 13 were positive (MRD+) and 6 were negative (MRD-). There is no difference in RFS by the MRD status at CR (p=0.52).Conclusion- The addition of dasatinib to the treatment in younger patients with Ph+ ALL significantly improves the 12-month RFS for those who undergo alloSCT in CR1 and is associated with an improved OS compared to historical data prior to the introduction of TKIs.Acknowledgments: Dr. Meir Wetzler is posthumously recognized for his important contributions to this study. Support from NIH/NCI/NCTN grants CA180888, CA180819, CA180821, CA180820; and in part by Bristol-Myers Squibb Company. Dasatinib was distributed by the NCI/DCTD/CTEP. [Display omitted] [Display omitted] DisclosuresUy:Novartis: Research Funding. Borate:Genoptix: Consultancy; Gilead: Speakers Bureau; Seattle Genetics: Research Funding; Novartis: Speakers Bureau; Alexion: Speakers Bureau; Amgen: Speakers Bureau. Erba:Seattle Genetics: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Celator: Research Funding; Astellas: Research Funding; Celator: Research Funding; Amgen: Consultancy, Research Funding; Incyte: Consultancy, Speakers Bureau; Pfizer: Consultancy; Sunesis: Consultancy; Novartis: Consultancy, Speakers Bureau; Ariad: Consultancy; Celgene: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Millennium/Takeda: Research Funding; Millennium/Takeda: Research Funding; Jannsen (J&J): Other: Data Safety and Monitoring Committees ; Seattle Genetics: Consultancy, Research Funding; Celgene: Consultancy, Speakers Bureau; Incyte: Consultancy, Speakers Bureau; Astellas: Research Funding; Daiichi Sankyo: Consultancy; Ariad: Consultancy; Sunesis: Consultancy; GlycoMimetics: Other: Data Safety and Monitoring Committees ; Pfizer: Consultancy; Jannsen (J&J): Other: Data Safety and Monitoring Committees ; Daiichi Sankyo: Consultancy; GlycoMimetics: Other: Data Safety and Monitoring Committees.

Differential Responses to Hormone Therapy Among ER+/PR+/HER2‐ Breast Cancers That Differentially Express the Estrogen Response Signature

ER+/PR+/HER2‐ breast cancers are frequently associated with good outcomes, but some patients experience disease progression/recurrence. We examined responses to hormone therapy (HT) in 182 ER+/PR+/HER2‐ breast cancers (with known molecular subtype) that differentially express a 583‐gene estrogen response signature (ERS). Overall, 13/33 (39%) patients treated with HT relapsed versus 77/149 (52%) untreated patients. 142 ER+/PR+/HER2‐ breast cancers are ERS+ (27% relapse with HT, 48% untreated relapse), and 40 ER+/PR+/HER2‐ breast cancers are ERS‐ (100% relapse with HT, 62% untreated relapse). Kaplan‐Meier analysis revealed a significant improvement in relapse‐free survival among ERS+ ER+/PR+/HER2‐ breast cancers that received HT versus untreated (P=0.0489). ERS+ ER+/PR+/HER2‐ Luminal A breast cancers benefit from HT – 5/19 (26%) treated relapsed versus 36/75 (48%) untreated relapsed. ERS+ ER+/PR+/HER2‐ Luminal B (LumB) breast cancers show less benefit from HT – 1/3 (33%) treated relapse versus 12/29 (41%) untreated relapse. Any HT benefit observed is lost among ERS‐ ER+/PR+/HER2‐ LumB breast cancers – 5/5 (100%) treated relapse versus 10/17 (59%) untreated relapse. ER+/PR+/HER2‐ HER2‐enriched breast cancers do not benefit from HT – Over 50% relapse irrespective of ERS or HT status. Despite small numbers, ERS+ ER+/PR+/HER2‐ Basal‐like and Claudin‐low breast cancers appear to show benefit from HT – 0/3 (0%) treated relapse versus 4/6 (67%) untreated relapse. Most molecular subtypes of ERS+ ER+/PR+/HER2‐ breast cancer benefit from HT.

Treatment Results In Acute Myeloid Leukemia Over a Time Period Of 20 Years: Analysis Of The German-Austrian Acute Myeloid Leukemia Study Group (AMLSG)

▪ BackgroundOverall survival (OS) in acute myeloid leukemia (AML) treated with intensive chemotherapy has improved over the last 20 year especially in younger adults (18-60 years) but still remains poor in older patients (>60 years) (Döhner et al. Blood 2010). The German-Austrian AMLSG performed controlled prospective treatment trials since 1993 starting with a risk-adapted approach (phase I, 1993-1997), followed by randomized and risk-adapted treatment strategies based on cytogenetic risk groups (phase II, 1997-2002); since 2003 addition of differentiating agents and HiDAC inhibitors to intensive induction therapy was evaluated (phase III, 2003-2007). Of note, until 2007 younger and older patients (> 60 years) were treated in separate protocols with significantly lower dosages of chemotherapy in older patients. Starting from 2008, risk-adapted therapies were replaced successively by a genotype-adapted approach and the artificial age cut-off at 60 years was abandoned (phase IV, 2008-2012). AimsTo evaluate the outcome of adult AML patients within the different time periods. MethodsThe study included 4705 intensively treated adults (younger, n=3546; older, n=1159) with newly diagnosed AML enrolled on 11 AMLSG treatment trials between 1993 and 2012. Patients with acute promyelocytic leukemia were excluded. All patients received intensive induction and consolidation therapy. Analyzed outcome variables were first complete remission rates (CR1), relapse-free survival (RFS), survival after relapse (SAR) and OS. Analyses were performed according to age groups (18-60 vs. >60 yrs). In younger patients comparisons were performed for the 4 treatment phases (I-IV), whereas for older patients analyses were restricted to phase II-IV. ResultsIn younger patients CR rates did not improve over time (1993-2013) and varied between 72% and 77% (p=0.12), whereas early and hypoplastic (ED/HD) death rates significantly declined from 10% to 5% (p=0.0001). In older patients CR rates significantly improved over time from 44% to 50% between 1998 and 2007 to 67% after 2008 (p<0.0001); ED/HD rates gradually declined from 12% to 8%, but the difference was not statistically significant (p=0.17).The proportion of younger patients receiving an allogeneic hematopoietic stem cell transplantation (alloHSCT) increased from 30% (15% in CR1) in phase I to 58% (29% in CR1) in phase III and remained there in phase IV with 53% (26% CR1), whereas the proportion of patients receiving an autologous HSCT constantly decreased from maximally 16% (15% in CR1) in phase II to 0.4% (0.2% in CR1) in phase IV; the proportion of older patients receiving an alloHSCT steadily increased from 4% (2% CR1) in phase II to 21% (12% CR1) in phase IV; autoHSCT was rarely performed. OS at 4 years in both age groups significantly improved (p<0.0001, each) from 41% to 56% and from 10% to 23% in younger and older patients, respectively. This beneficial effect on OS over time in younger patients was due to a better RFS (p=0.01) and SAR (p<0.0001), whereas in older patients no improvement in RFS (p=0.20) and only in trend for SAR (p=0.07) was noted. In cytogenetically high-risk patients, OS in younger (p=0.001) and in older (p=0.007) patients got better; in older patients mainly driven by increase in CR rates (p=0.001) and in younger patients by an improvement in RFS (p=0.02) and SAR (p=0.05). Nearly the same pattern was identified for cytogenetically intermediate risk patients with a better OS in younger (p<0.0001) and older patients (p=0.01) due to higher CR rates in older patients (p<0.0001), no improvement in RFS in both age groups and a significantly better SAR in younger patients (p=0.0002). In contrast, in low risk patients improvement in OS was only present in older patients (p=0.02), due to a better RFS in older patients (p=0.02) but without any progress in younger patients. Furthermore we performed two subgroup analyses in intermediate risk patients. In the subgroup of patients characterized by the genotype NPM1-mut/FLT3-ITDneg a significant better OS was present only in younger patients (p=0.03); in FLT3-ITD positive AML a better OS was seen in younger patients (p<0.0001) due to a better RFS (p=0.05) and SAR (p=0.01). ConclusionsBased on the German-Austrian AMLSG experience the prognosis in younger and older AML patients has improved over time. In older patients this is mainly a result of higher CR rates and in younger patients of better RFS and SAR. Disclosures:Schlenk:Celgene: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Chugai: Research Funding; Amgen: Research Funding; Novartis: Research Funding; Ambit: Honoraria. Off Label Use: Pomalidomide in Myelofibrosis. Greil:Novartis: Honoraria, Research Funding.

Phase II Randomized Trial Comparing High-Dose IFN-α2b with Temozolomide Plus Cisplatin as Systemic Adjuvant Therapy for Resected Mucosal Melanoma

Mucosal melanoma is rare and associated with extremely poor prognosis. However, standard adjuvant therapy for mucosal melanoma has not been established. We conducted a randomized phase II clinical trial in patients with resected mucosal melanoma to compare the efficacy and safety of high-dose IFN-α2b (HDI) and temozolomide-based chemotherapy as adjuvant therapy. Patients with mucosal melanoma in stage II/III after surgery were randomized into three groups: observation group (group A, surgery alone), HDI group (group B, treated with 15 × 10(6) U/m(2)/d IFN-α2b, followed by 9 × 10(6) U IFN-α2b), and temozolomide (200 mg/m(2)/d) plus cisplatin (75 mg/m(2)) group (group C). The endpoints were relapse-free survival (RFS), overall survival (OS), and toxicities. One hundred and eighty-nine patients were enrolled and finally analyzed. With a median follow-up of 26.8 months, the median RFS was 5.4, 9.4, and 20.8 months for group A, B, and C, respectively. Estimated median OS for group A, B, and C was 21.2, 40.4, and 48.7 months, respectively. Patients treated with temozolomide plus cisplatin showed significant improvements in RFS (P < 0.001) and OS (P < 0.01) than those treated with either HDI or surgery alone. Toxicities were generally mild to moderate. Both temozolomide-based chemotherapy and HDI are effective and safe as adjuvant therapies for resected mucosal melanoma as compared with observation alone. However, HDI tends to be less effective than temozolomide-based chemotherapy for patients with resected mucosal melanoma in respect to RFS. The temozolomide plus cisplatin regimen might be a better choice for patients with resected mucosal melanoma.

Survival Benefit of Adding Chemotherapy to Intensity Modulated Radiation in Patients with Locoregionally Advanced Nasopharyngeal Carcinoma

BackgroundTo evaluate the contribution of chemotherapy for patients with locoregionally advanced nasopharyngeal carcinoma (NPC) treated by intensity modulated radiotherapy (IMRT) and to identify the optimal combination treatment strategy.Patients and MethodsBetween 2006 and 2010, 276 patients with stage II-IVb NPC were treated by IMRT alone or IMRT plus chemotherapy. Cisplatin-based chemotherapy included neoadjuvant or concurrent, or neoadjuvant plus concurrent protocols. The IMRT alone and chemoradiotherapy groups were well-matched for prognostic factors, except N stage, with more advanced NPC in the chemoradiotherapy arm.ResultsWith a mean follow-up of 33.8 months, the 3-year actuarial rates of overall survival (OS), metastasis-free survival (MFS), relapse-free survival (RFS), and disease-free survival (DFS) were 90.3%, 84.2%, 80.3%, and 69.2% for all of the patients, respectively. Compared with the IMRT alone arm, patients treated by concurrent chemoradiotherapy had a significantly better DFS (HR = 2.64; 95% CI, 1.12−6.22; P = 0.03), patients with neoadjuvant-concurrent chemoradiotherapy had a significant improvement in RFS and DFS (HR = 4.03; 95% CI, 1.35−12.05; P = 0.01 and HR = 2.43; 95% CI, 1.09−5.44; P = 0.03), neoadjuvant chemoradiotherapy provided no significant benefit in OS, MFS, RFS, and DFS. Stage group and alcohol consumption were prognostic factors for OS and N stage was a significant predictor for DFS.ConclusionsAddition of concurrent or neoadjuvant-concurrent chemotherapy to IMRT is available to prolong RFS or DFS for locoregionally advanced NPC. Such work could be helpful to guide effective individualized therapy.

Advances in Adjuvant Therapy for the Treatment of High-risk Melanoma

The global incidence of melanoma is increasing, and the prognosis for patients remains poor. High-dose interferon-alpha (HD-IFN-a) and pegylated IFN are the only US Food and Drug Administration (FDA)-approved agents for adjuvant therapy for high-risk melanoma, and an improvement in relapse-free survival (RFS) has been observed consistently across nearly all published studies and meta-analyses. Some studies and meta-analyses have also supported an overall survival (OS) benefit. However, despite a number of adjuvant studies, controversy remains regarding the role of this treatment. As the benefits in OS are modest with IFN treatment, there is therefore a need for new therapeutic targets, new drugs, and optimum patient selection. Current research is investigating new adjuvant agents, either individually or in combination, which may advance the standard of care beyond HD-IFN. Additionally, identifying biomarkers of patients with greater likelihood of response may allow patient-specific therapeutic approaches. Following the recent FDA approval of ipilimumab, vemurafenib, dabrafenib, and trametenib for metastatic melanoma, ongoing adjuvant trials are now underway.

How Much of a Good Thing? What Duration for Interferon Alfa-2b Adjuvant Therapy?

How Much of a Good Thing? What Duration for Interferon Alfa-2b Adjuvant Therapy?

Early‐stage squamous cell carcinoma of the lip: The Australian experience and the benefits of radiotherapy in improving outcome in high‐risk patients after resection

The purpose of this study was to analyze the outcome of Australian patients treated for early lip cancer. Data on 217 patients with T1 to T2 squamous cell carcinoma (SCC) of the lip and treated with radical intent were analyzed. The addition of local adjuvant radiotherapy in patients with a close/positive margin was associated with a significant improvement in relapse-free survival (RFS; p = .008). Tumor thickness (≤4 mm vs >4 mm) was also significantly associated with RFS (p = .01). The 5-year RFS was 51% after surgery, 87% after radiotherapy, and 92% after adjuvant radiotherapy. Patients with a tumor thickness >4 mm experienced an increased risk of recurrence, especially nodal. Compared with patients having any radiotherapy, those undergoing surgery experienced a higher rate of locoregional recurrence. The addition of adjuvant radiotherapy in patients with inadequate excision significantly decreased the risk of recurrence.

The Timing of Salvage Radiotherapy After Radical Prostatectomy: A Systematic Review

Salvage radiotherapy (SRT) after radical prostatectomy can potentially eradicate residual microscopic disease. Defining the optimal patient and treatment factors is essential and is particularly relevant within the context of adjuvant vs early vs delayed postoperative radiotherapy (RT). A systematic review of all published SRT studies was performed to identify the pathologic, clinical, and treatment factors associated with relapse-free survival (RFS) after SRT. A total of 41 studies encompassing 5597 patients satisfied the study entry criteria. Radiobiologic interpretation of biochemical tumor control was used to provide the framework for the observed relationships. Prostate-specific antigen (PSA) level before SRT (P<.0001) and RT dose (P=.0052) had a significant and independent association with RFS. There was an average 2.6% loss of RFS for each incremental 0.1 ng/mL PSA at the time of SRT (95% CI, ∼2.2-3.1). With a PSA level of 0.2 ng/mL or less before SRT, the RFS approached 64%. The dose for salvage RT in the range of 60-70 Gy seemed to be on the steep part of the sigmoidal dose-response curve, with a dose of 70 Gy achieving 54% RFS compared with only 34% for 60 Gy. There was a 2% improvement in RFS for each additional Gy (95% CI, ∼0.9-3.2). The observed dose-response was less robust on sensitivity analysis. This study provides Level 2a evidence for initiating SRT at the lowest possible PSA. Dose escalation is also suggested by the data. Progressively better tumor control rates with SRT after radical prostatectomy are achieved with a lower PSA at initiation and with a higher RT dose. Early salvage RT may be an equivalent strategy to adjuvant RT.