Not Evaluable Research Articles

Evaluation of Disease Burden and Response to Treatment in Adults with Type 1 Gaucher Disase Using a Validated DS3 Severity Score Index

Evaluation of Disease Burden and Response to Treatment in Adults with Type 1 Gaucher Disase Using a Validated DS3 Severity Score Index

Immunoglobulin Variable Region Family Usage and Outcomes of Patients with Systemic Light Chain Amyloidosis

Introduction: AL amyloidosis is a very heterogeneous disease. Prognosis is a function of organ tropism, extent of organ damage, and ability of tissues to heal, the last of which relates both to hematologic response and intrinsic toxicity of the light chain. Using mass spectroscopy (MS) technology, we are able to distinguish immunoglobulin light chain variable gene family (IGVL) usage on clinical samples. The goal of this study was to evaluate if IGVL usage impacts patient outcomes in patients with light chain amyloidosis (AL).Methods: IGVL usage was determined by mass spectroscopy (MS) of amyloid in clinical tissue specimens of Mayo Clinic patients. Specimens were from fat pad (n=257), bone marrow (n=172), myocardium (n=113), gastrointestinal (n=58), kidney (n=20), lung (n=15), and nerve (n=5). For those cases for which the IGVL could not be identified–not otherwise specified (NOS)—but constant region could be identified as lambda or kappa, we assume that the amyloid consisted primarily of immunoglobulin light chain gene constant regions or variable genes with somatic mutations making them uninterpretable to our matching algorithms. The medical records from these 700 patients were abstracted for relevant clinical and laboratory data.Results: The baseline characteristics of patients are shown in table 1. Three hundred and thirty-two patients have died with a median follow-up of surviving patients of 38 months. The estimated median survival for the entire population is 59 months. Out of 700 patients, 214 (31%) achieved a CR or a VGPR, 432 (62%) were not evaluable (NE) for hematologic or organ response, and 54 (8%) achieved a PR or did not respond (NR).The distribution of IGVL cases is shown in table 2. Overall survival (OS) for the whole group was not different across different IGVLs on univariate analysis, but when corrected for hematologic response, outcomes differed significantly based on IGVL. Patients could be further assembled into two groups, based on risk for death on univariate analyses: an IGVL high risk, which included KV1, LV1, LV2, LV3, and LV6; and low risk, which included all other cases (Figure). In a multivariate model that included level of hematologic response (CR/VGPR versus PR/NR/NE) and IGVL, IGVL family was independently associated with overall survival (RR=1.5 (95% CI 1.2-1.9, p=0.008). The risk ratio for CR/VGPR was 0.28 (95% CI 0.20-0.38, p<0.0001). This effect persisted when either the Mayo 2006 or the 2012 staging system was included in the multivariate.Conclusion: IGVL usage appears to have prognostic significance in patients who have not achieved VGPR or better to initial chemotherapy.Table 1Baseline characteristics of patientsN= 700Age63 (32-94)Male, (%)447 (64%)Biopsy siteSolid organ/Soft tissue271 (39%)Fat pad257 (37%)Bone Marrow172 (25%)Organ involvementCardiac432 (62%)Renal346 (49%)Gastrointestinal168 (24%)Liver56 (8%)Nerve107 (15%)Lung42 (6%)Soft Tissue92 (13%)Organs involved1321 (46%)2228 (33%)≥3151 (22%)Laboratory characteristicsNTBNP, pg/ml2547 (11.3-70000)Troponin, ng/ml0.03 (0.001-0.84)dFLC, mg/dl26 (0.04-2330)Cardiac Stage159 (18%)2125 (38%)3144 (44%)Table 2Variable region family distribution.Light Chain N=700N (%)KV1107 (15%)KV23 (0.4%)KV317 (2%)KV425 (4%)KV61 (0.1%)LV185 (12%)LV264 (9%)LV3118 (17%)LV43 (0.4%)LV697 (14%)LV81 (0.1%)LV91 (0.1%)Kappa NOS134 (4%)Lambda NOS1140 (19%)Heavy chain amyloidosis4 (0.6%)1 No IGVL family could be identified [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Relationship of Bone Marrow Blast (BMBL) Response to Overall Survival (OS) in Patients with Higher-Risk Myelodysplastic Syndrome (HR-MDS) Treated with Rigosertib after Failure of Hypomethylating Agents (HMAs)

▪Background: Patients (pts) withHR-MDS have a median OS of 4 to 6 months (mo) after HMA failure (Prebet et al, J Clin Oncol 2011) and no approved salvage therapy. Development of new therapeutics for this population will benefit from the availability of surrogate endpoints and markers that can predict survival. Gore et al established response to azacitidine (Vidaza®) in first-line therapy for HR-MDS as a reasonable surrogate to predict survival (Gore et al, Haematologica 2013). Rigosertib, a novel dual PI3K/PLK pathway inhibitor, has been shown to reduce bone marrow blasts (BMBL) in these pts (Seetharam et al, Leuk Res 2012). Silverman et al described complete or partial bone marrow (BM) response, or stabilization after 4-8 weeks (wks) of treatment with rigosertib as a potential surrogate for predicting survival in pts with HR-MDS after failure of primary HMA therapy (Silverman et al, Hematol Oncol 2014). We tested this hypothesis in the context of a randomized Phase III trial.Methods:Pts with HR-MDS were randomly assigned 2:1 to rigosertib or best supportive care (BSC) after progressing on, failing to respond to, or relapsing after HMA treatment. BM aspirates were assessed pretreatment, at 4 weeks and at 8-week intervals thereafter. Central slide review was undertaken in a representative population of samples. The BMBL response at each time point was assessed using the following definitions: bone marrow complete response (mCR) = BMBL ≤ 5% and decrease of ≥ 50% from baseline; bone marrow partial response (mPR) = BMBL decrease from baseline of ≥ 50%, but BMBL still > 5%; stable disease (SD) = BMBL decrease or increase from baseline of < 50%; progressive disease (PD) = BMBL increase from baseline of ≥ 50% by an absolute minimum of 5%; Not evaluable (NE).Results:Bone marrow assessment was carried out in 156 patients (pts) on the rigosertib arm and 24 pts on the BSC arm at 4 wks after enrollment, and in 86 and 20 pts, respectively, at 12 wks. The invasive BM procedure was optional on the BSC arm, which accounts for the low number of assessments in this group. BM responses at the 2 time points are presented in Table 1.Since no difference in overall survival was noted between pts who had objective BM response and those who did not progress (ie, stable disease), a landmark analysis was conducted that separated pts who were alive at the 4-wk landmark time into two 4-wk response categories: BM response + SD vs. PD. Results of this analysis in rigosertib-treated patients were statistically significant at p = 0.011, with a hazard ratio (HR) of 0.62 and a median OS (from 4 wks onward) of 9.8 months in the mCR + mPR + SD group vs. 4.6 months in the PD group (Figure 1).Another landmark analysis was conducted at 12-wks. Results of this analysis were also significant (p < 0.001) in rigosertib-treated patients, with an HR of 0.39 and a median OS (from 12 wks onward) of 10.4 months in the mCR + mPR + SD group vs.7.5 months in the PD group (Figure 2).A time-dependent Cox regression of OS by 4-wk BMBL response reinforced the validity of the 4-wk and 12-wk BM assessments as surrogate biomarkers for survival (Table 2).Conclusions: These data suggest that BMBL response at 4 or 12 weeks was correlated with OS in this population of pts with HR-MDS treated with rigosertib after HMA failure and are consistent with previous observations in Phase II studies.Table 14- and 12-week Bone Marrow Blast Response (Intention-to-Treat Population)Number (%) of Patients4-wk BMBL Response12-wk BMBL ResponseRigosertib N = 199BSC N = 100Rigosertib N = 199BSC N = 100Pts with BMBL assessment156 (78)24 (24)*86 (43)20 (20)*BM complete response (mCR)224115BM partial response (mPR)8292Stable disease (SD)779328Progressive disease (PD)499345* Bone marrow assessment was not required on the BSC arm. [Display omitted] [Display omitted] Table 2Time-dependent Cox Regression of Overall Survival by Bone Marrow Blast ResponseAnalysisRigosertibBSCWald P-valueHazard Ratio (95% Confidence Interval)Wald P-valueHazard Ratio (95% Confidence Interval)By 4-wk BMBL response0.0510.72 (0.51 - 1.00)0.560.83 (0.45 - 1.54)By 12-wk BMBL response0.00050.55 (0.39 - 0.77)0.160.68 (0.39 - 1.17)*Stratified by pretreatment BMBL: 5%-19% vs. 20%-30% DisclosuresFenaux:Celgene: Research Funding; Janssen: Research Funding; Novartis: Research Funding. Sekeres:Celgene Corp.: Membership on an entity’s Board of Directors or advisory committees; Amgen: Membership on an entity’s Board of Directors or advisory committees; Boehringer Ingelheim: Membership on an entity’s Board of Directors or advisory committees. Wilhelm:Onconova Therapeutics, Inc: Employment, Equity Ownership. Azarnia:Onconova Therapeutics, Inc: Employment.

A New Prognostic Index for Overall Survival in Malignant Pleural Mesothelioma

ABSTRACT Aim: Existing prognostic indices for malignant pleural mesothelioma (MPM) do not incorporate recent advances in oncology care and were not based on real-world clinical data. This study aimed to provide a prognostic index for overall survival (OS) in MPM patients receiving chemotherapy with pemetrexed (CTx) or best supportive care (BSC) in a present, real-world setting. Methods: A retrospective cohort study was performed using MPM patients treated in two tertiary hospitals in Japan between 2007 and 2013. The prognostic index was developed using CTx patients, then diagnostic performance of the index was evaluated in both CTx and BSC patients. The primary outcome was OS. The Cox proportional hazards model was used for multivariable analyses to detect prognostic factors. A final model was chosen based on both clinical and statistical significance. Harrell's c index was calculated to examine the discrimination of the model. The bootstrapping technique was used for internal validation. Results: Participants comprised 283 patients (CTx, n=228; BSC, n=55). On multivariate Cox proportional regression analysis, risk factors for poor prognosis of OS for CTx patients included performance status >0, non-epithelial histological type, and stage IV disease. Since hazard ratios of individual risk factors ranged from 1.81 to 2.07, a prognostic index for OS was constructed using a simple count of the number of risk factors (PHS index). Median OS in CTx patients was shortened by each 1-point increase in PHS index: 948 days (95% confidence interval (CI), 884–1012 days) for score 0; 544 days (95%CI, 526–561 days) for 1; 362 days (95%CI, 347–375 days) for 2; and 214 days (95%CI, 186–242 days) for 3. Internal validation showed the model was robust (c index, 0.670; 95%CI, 0.619–0.721). Median OS for each PHS index with BSC was: 573 days (95%CI, not evaluable (NE) - NE) for 0; 402 days (95%CI, 370–434 days) for 1; 94 days (95%CI, 82–105 days) for 2; and 34 days (95%CI, 15–52 days) for 3. Discrimination was consistent in BSC patients (c-index, 0.799; 95%CI, 0.725–0.874). Conclusions: This index will provide clinicians and patients with a better framework for discussing prognosis at the time of diagnosis. Disclosure: All authors have declared no conflicts of interest.

Use of staging and scoring systems in hepatocellular carcinoma (HCC): Lessons from U.S. regional analysis of the GIDEON registry.

323 Background: Because HCC usually occurs in the presence of liver disease, patient (pt) evaluation and treatment are complex and require multidisciplinary care. Tumor staging and liver function scoring systems facilitate HCC research and treatment. However, specialists have varied training in these systems. We evaluated specialty-specific reporting of HCC-related staging/scoring data. Methods: GIDEON is a global, prospective, non-interventional study to evaluate sorafenib (SOR) in HCC under real-life practice conditions. Pts with unresectable HCC who were candidates for systemic therapy and for whom a decision was made to treat with SOR were eligible. Frequency of recorded Child-Pugh (CP); Barcelona Clinic Liver Cancer (BCLC); Cancer of the Liver Italian Program (CLIP); Tumor, Nodes, Metastasis (TNM); and calculated Model for End-stage Liver Disease (MELD) data were analyzed by physician specialty. Results are descriptive. Results: In the safety population (n=563), 299 pts (41%) were enrolled by medical oncology (MO), 228 (40%) by hepatology/gastroenterology (H/G), and 39 (5%) by other (23 by surgeons; 7 by interventional radiologists). 89% were treated by a multidisciplinary team. MO pts were twice as likely as H/G pts to be not evaluable (NE) for CP (table). Unknown international normalized ratio (INR) was the primary reason CP was NE. MO and H/G pts had similar % NE for BCLC stage. H/G pts were more likely to have ECOG performance status (PS) not recorded. MO pts were less likely to have CLIP or MELD data, while H/G pts were less likely to have TNM data. Portal vein thrombosis (PVT) and alpha-fetoprotein (AFP) were unknown in 17% overall. Conclusions: The elements of HCC staging systems represent factors that may influence patient management. Lack of complete data in up to 44% of pts, despite registry enrollment requiring data collection, suggests clinicians may be missing important information and the prevalence of clinicians using comprehensive HCC staging systems is variable. Clinical trial information: NCT00812175. [Table: see text]

Abstract P3-14-21: Neoadjuvant chemotherapy in gynecologic oncology practices in Germany: A real life documentation

Abstract Background: Several clinical studies have confirmed that neoadjuvant chemotherapy (NACT) is equally effective to adjuvant chemotherapy in patients with early breast cancer. The advantages of NACT include potentially improved rates of breast conserving surgery, the possibility of measuring early, in-vivo response to systemic treatment, and potentially improved outcomes for certain subgroups of high-risk breast cancer patients. The German Professional Association of Gynecologic Oncology in Practices (BNGO) is dedicated to quality-assured outpatient treatment of patients with gynecologic tumors. This includes adjuvant and neoadjuvant chemotherapy. In this analysis, we present our data on patients treated with neoadjuvant chemotherapy in BNGO practices. One of our important goals is the standardized documentation of diagnosis and treatment of our patients in order to control and assure the quality in our practices. Methods: From January 2004 to May 2013, 18,319 breast cancer patients have been documented in the BNGO data base registry. 2,059 breast cancer patients (11%) received neoadjuvant chemotherapy. 90 BNGO practices participate in this registry on a regular basis. For documentation, the specialized ODM QuaSi®GYN online documentation system is used. The documentation assesses demographic data of individual patients and practices as well as data regarding diagnosis, treatment and outcome. Results: Patient characteristics: Median age at diagnosis was 52 years (range 21-95 years). Most patients (30%) were 40-49 years old. 47% of patients had a T2 tumor and 81% had no distant metastases. 37% had no lymph node involvement (N0), 35% were classified as N1. 32% of patients had an ER-negative tumor, 37% were PR-negative. 57% had a negative HER-2 status, 25% were HER2-positive. Consequently, 20% of patients received trastuzumab in addition to their neoadjuvant chemotherapy. 82% of the patients were treated with a taxane-containing regimen and 84% received anthracyclines. Efficacy: Most patients (42%) achieved a partial remission (PR) after NACT, 27% had a complete remission (CR), 16% had stable disease (SD), 6% had progressive disease. 40% had breast conserving surgery of one or both breasts after NACT. 38% received other oncoplastic surgery, so a total breast conservation rate of 78% was achieved among the NACT-patients. Only 22% underwent mastecotomy of one or both breasts. ResponseResponse% of patientsCR (Complete Remission)27%PR (Partial Remission)42%SD (Stable Disease)16%PD (Progressive Disease)6%NE (Not Evaluable)9% 52% of patients receiving neoadjuvant chemotherapy developed grade 3-4 leucopenia. The most frequent grade 3-4 non-hematologic toxicity was alopecia (9%). Conclusions: Since 2004, 2,059 breast cancer patients in BNGO-practices received a neoadjuvant chemotherapy for early breast cancer. Most treatment schedules contained an anthracycline and /or a taxane. The objective response rate (PR and CR) was 69%. After NACT, breast conservation surgery was possible in nearly 80% of patients. This real life documentation with non- selected breast cancer patients compares favorably to results achieved in clinical trials with a selected patient population. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P3-14-21.

Phase I study of cisplatin (cDDP)/hyperthermia (HT)/lapatinib (Lap) in patients (pts) with recurrent carcinoma of the uterine cervix (rCC) in previously irradiated area (PIA).

e16504 Background: Pts with rCC in PIA might benefit from cDDP plus HT. Lap inhibits the intracellular tyrosine kinase domain of the epidermal growth factor receptor (EGFR) and HER2. Overexpression of EGFR and HER2 is often seen in pts with CC and might be involved in chemotherapy resistance. Besides, preclinical data suggest a synergistic effect of combining cDDP and Lap. Therefore, this phase I dose-escalation study was performed to determine the maximum tolerated dose (MTD) of Lap added to fixed doses of cDDP and HT. Methods: Pts with rCC in PIA, adequate organ function and ECOG performance status 0-1 were scheduled for 6 weekly administrations of 70 mg/m2cDDP plus locoregional HT. Daily Lap was added on days 1-56, starting at a dose-level of 1000 mg. The MTD was defined as the highest dose where ≤1/6 pts experienced dose-limiting toxicity (DLT). Safety, pharmacodynamics (PhD) and response were assessed. Results: Eight pts were treated. The first 4 pts (2 each at dose 1000 mg and 750 mg) experienced DLT. Of the 4 pts treated at dose level -2 (500 mg), only 1 pt was able to complete the treatment as planned, 2 pts experienced a DLT and 1 pt was not evaluable (NE), because of early progressive disease (PD) (see Table). In the evaluable pts 1 PD, 4 stable diseases and 2 partial responses (PR) were observed. One patient with PR had a resection of the local recurrence. Analysis of the resected specimen showed a pathological complete response (pCR). Enumeration of circulating endothelial cells measured at baseline and during therapy did not show consistent results. The same applied for the PhD on Ki-67, p27Kip1and EGFR in pretreatment and on-therapy skin biopsies. Conclusions: It is not feasible to combine Lap with fixed doses of cDDP and HT in pts with rCC in PIA mainly due to increased cDDP-related toxicity. The observed pCR is intriguing and warrants further investigation of combining HER2-blockade and cDDP/HT. Clinical trial information: NL24464.078.08. [Table: see text]

Early Treatment Intensification in Advanced-Stage High-Risk Hodgkin Lymphoma (HL) Patients, with a Positive FDG-PET Scan After Two ABVD Courses – First Interim Analysis of the GITIL/FIL HD0607 Clinical Trial

AbstractAbstract 550 Background:Interim FDG-PET performed after 2 chemotherapy courses (PET-2) is the most powerful predictor of treatment outcome in advanced-stage, ABVD-treated HL (AAHL) patients (pts). Whether early therapy intensification in PET-2 positive HL pts improves overall treatment efficacy for all AAHL pts compared to standard ABVD is still unproven. Patients and study design:In the HD 0607 clinical trial (ClinicalTRial.gov identifier 00795613), AHL (stage IIB-IVB) pts prospectively enrolled by 26 Italian and one Israelian institution are treated with 2 ABVD courses and a PET-2 performed afterwards. PET-2+ pts are randomized to either BEACOPP escalated (Be) plus BEACOPP baseline (Bb) (4+4 courses) or Be+Bb (4+4) and Rituximab (R). PET-2 negative pts are treated with 4 additional ABVD and, upon CR achievement, randomized to either consolidation radiotherapy (Rxt) on the sites of initial bulky disease or no further treatment. Primary endpoint is the efficacy and feasibility of the overall therapeutic strategy. All the non-negative PET-2 (nnPET-2), defined as scans without any residual FDG uptake in any site outside the physiological areas of the tracer concentration, are uploaded in a website for blinded independent central review (BICR) by 6 nuclear medicine experts. Scans are interpreted by visual assessment according to the Deauville 5-point scale (5PS). Results:Starting from 07/2008 till 07/2012, 497 AHL pts were consecutively enrolled and 446 scanned with PET-2. 189/446 (42%) PET-2scans, judged as nnPET-2 by the local PET center, underwent review: 92 were adjudged as positive (62 score 4, 30 score 5) and 97 as negative (score 1–3). Altogether, of 446 pts scanned with a PET-2, 92 (20%) resulted positive and 354 (80%) negative. Age, sex, stage III-IV, bulky, extranodal sites or IPS class where equally distributed among PET-2 positive and negative pts.(p>.05). The median time from PET uploading in the website to review was 45.38 hours, (1–119). The BICR yielded a binary concordance rate among pair of reviewers “very good”, ranging from 0.77 to 0.83 (Cohen’s k coefficient) and a overall concordance rate of 0.77 (Krippendorf’s alpha). In 92 PET-2+ pts, 60 showed a single site of residual uptake in mediastinal (48), laterocervical (4), supraclavear (2), abdominal (3), axillary (1) nodes and in lung (2).In 32 there were ≥ 2 sites of persistent FDG uptake. In 38/40 pts with a positive PET-2 and bulky disease at baseline the residual FDG uptake (singe or multifocal) was seen within the bulky lesion. Overall response to treatment could be assessed in a cohort of 263 pts who had been fully restaged after lymphoma treatment. Forty-one (15%) had a positive and 222 (84%) a negative PET-2 scan. The relative dose intensity (RDI) for Be+Bb ± R and ABVD ± RxT treated pts. was 94.7% and 97.8%, respectively. Among 41 PET-2+ pts CR was achieved in 30 (73%), PR in 1 (2%) Progression or Relapse (Pro/Rel) in 8 (19%) and not evaluable (NE) in 2(5%). Among 222 PET-2- pts. CR was achieved in 212 (95.5%), PR in 2 (1%), Pro/Rel in 6 (3%), NE in 1 (0,5%). Treatment efficacy could be assessed in a cohort of 187 pts. with a complete treatment and a minimum follow-up of 12 months from treatment completion: 27 (15%) with a positive PET-2, treated with Be+Bb ± R and 160 (85%) with a negative PET-2, treated with ABVD ± RxT. The median follow-up from diagnosis was 845 days (101–1345). Among 27 PET-2+ pts, CCR (Continuous CR) was recorded in 22 (81%) Pro/Rel in 5 (18%). Three patients died in CR: 2 for septic shock and one for pneumonia. Among 160 PET-2- pts. CCR was recorded in 146 (91%), Pro/Rel in 9 (5%), Lost of FU (in CR) in 5 (3%). The 1-y PFS was 80.5%, 97.3% and 94.7% for PET-2+, PET-2- p, and for the entire population, respectively. Overall, treatment was well tolerated: 512 Adverse effects were reported: WHO grade 0+1: 453, grade 2: 45. Grade 3 were observed in 12 pts: anemia (2), neutropenia (6), pancytopenia (1), sepsis (1), diverticulitis (1), Vomiting (1). Grade 4 in 2 pts: pneumonia and neutropenia. Conclusions:These preliminary findings suggest that 1) an early switch from ABVD to escalated BEACOPP can be done safely in PET-2 positive pts, with CR achievement in the majority of cases; 2) a centralized online PET scan review system is feasible and allows a real time decision making process, without significant reduction in the RDI administered; 3) 5PS is a reliable interpretation criteria for interim PET scan, with a very good concordance rate among reviewers. Disclosures:No relevant conflicts of interest to declare.

First-line single-agent chemotherapy for patients with recurrent or metastatic gastric cancer with poor performance status

Combination chemotherapy is a standard treatment approach in advanced gastric cancer. However, combination chemotherapy for advanced gastric cancer is often associated with severe treatment-related toxicities and most oncologists are reluctant to perform combination chemotherapy in patients with a poor clinical condition. We retrospectively investigated the efficacy and tolerability of single-agent chemotherapy in patients with recurrent or metastatic gastric cancer with poor performance status (PS). We reviewed advanced gastric adenocarcinoma patients who received first-line single-agent palliative chemotherapy due to poor PS between June 2006 and December 2010. A total of 125 patients with Eastern Cooperative Oncology Group (ECOG) PS 2–3, whose general condition did not allow combination chemotherapy, were enrolled. Four single agents were used: TS-1 (n=63), paclitaxel (n=42), irinotecan (n=15) and capecitabine (n=5). The median age was 66 years, with a range of 25–81 years. The percent response rate and rate of stable disease (SD) were 19.2 and 35.2%, respectively, giving a disease control rate of 54.4%. The median progression-free survival (PFS) was 3.9 months (95% CI, 2.73–5.06). The median overall survival (OS) was 9.1 months (95% CI, 7.70–10.56) with a 1-year survival rate of 31.2%. Multivariate analysis demonstrated that the independent prognostic factors for OS were chemotherapy regimen (capecitabine) [reference: TS-1, hazard ratio (HR), 5.00; 95% CI, 1.81–13.81; P=0.002], no second-line chemotherapy (HR, 2.3; 95% CI, 1.48–3.57; P=0.001), bone metastasis (HR, 2.73; 95% CI, 1.22–6.09; P=0.014), ECOG PS 3 (HR, 38.10; 95% CI, 13.72–105.78; P=0.001), Glasgow prognostic score (GPS) ≥1 (HR, 1.88; 95% CI, 1.24–2.85; P=0.003) and chemotherapy response [SD + progressive disease (PD) + not evaluable (NE); HR, 2.37; 95% CI, 1.39–4.05; P=0.002)]. First-line single-agent palliative chemotherapy demonstrated a relatively good clinical efficacy for recurrent or metastatic gastric cancer patients with poor PS.

MK-0646 (MK), insulin growth factor 1 receptor (IGF-1R) antibody combined with pemetrexed (P) and cisplatin (C) in stage IIIb or IV metastatic nonsquamous lung cancer (NSQL).

e13551 Background: IGF-1R regulates cell growth, proliferation and apoptosis. Adenocarcinoma and never smokers have higher expression of IGF-1R and it is associated with worse survival. MK is a humanized monoclonal antibody that targets IGF-1R. P has higher activity in NSQL. We initiated a randomized phase II trial to evaluate the combination of P and C +/- MK in NSQL. Methods: Eligibility criteria: untreated NSQL stage IIIB or IV, ECOG 0 or 1, measurable disease, adequate organ function and no other intercurrent illness. Standard B12 and folic acid were given. P at 500mg/m2 and C at 75mg/m2 IV were given every 3 weeks. MK was given at the dose of 10mg/kg IV weekly on days 1, 8 and 15 of every 3 week cycle in the experimental group. The patients had radiographic assessment after every 2 cycles and treated for a maximum of 6 cycles if there was either response or stable disease. The primary objective of the study was to estimate the individual response rate of standard and experimental arm. IRB reviewed and approved the study at participating institutions. Results: From 1/2009 to 2/2011, the study accrued 26 patients, 16 male, 10 female, median age 59 yo. 14 patients were treated with PC and 12 patients were treated with PC +MK. In the PC arm we observed 2 partial responses (PR), 7 stable disease (SD), 3 had progression (PD) and 2 were not evaluable (NE). In the MK arm there were 3 PRs, 4 SD, 4 PD and 1 NE. In both arms, hematologic adverse events(AE) observed were: grade 3 neutropenia(5), hemoglobin (3), febrile neutropenia (2), platelet (2) leukopenia (1), lymphopenia (1); grade 4 platelet (2), hemoglobin (1); Grade 3 non-hematological AE were: hyperglycemia (4) and 1 occurrence each of hearing deficit, pain in extremity, hyponatremia, urinary tract infection, fatigue, dyspnea, laboratory, hypokalemia, esophageal stenosis, hypoxia, dysphagia and muscle weakness; Grade 4 hypoxia and hyperglycemia. The study was closed due to termination of funding. Conclusions: PC with MK had a similar response rate to PC. There was a higher rate of hyperglycemia in the MK group. Identification of a response predictive marker would be critical in order to continue the study of this agent.

Mismatches in Ethnicity Between Donor and Recipient Affects Overall Survival In Umbilical Cord Blood Transplantation,

Abstract 4159Limited data is available on the role of ethnicity on outcomes after umbilical cord blood transplants (UCBT). This study retrospectively analyses the role of donor and recipient ethnicity on clinical outcomes after UCBT. All patients (pts) had UCBT at the Texas Transplant Institute in San Antonio where Hispanics make up a large proportion of pts undergoing UCBT. Pts had UCBT between 2001 and 2010. CIBMTR and hospital records supplied the data and included 260 pts who were: White (76), Hispanic (141), Black (19) and Asian (6). Blacks and Asians were excluded from analysis due to small numbers. Characteristics of Whites and Hispanics are described in table. Age, cell dose, myeloablative and non-myeloablative conditioning regimens, and single (s) and double (d) UCBTs were similar between the two ethnicities. More Whites (88%) had UCBT for malignant disease than Hispanics (68%) (p<0.001).Incidence of graft-versus-host disease (GVHD) was similar between Whites (acute GVHD grades II-IV: 44%, grades III-IV: 15%, limited chronic GVHD: 9% and extensive chronic GVHD: 11%) and Hispanics (acute GVHD grades II-IV: 34%, grades III-IV: 22%, limited chronic GVHD: 28% and extensive chronic GVHD: 15%) and regardless of whether they had malignant or non-malignant disease, standard (CR1, CR2 and CML-CP) or high (all others) risk hematologic malignant disease, s or d UCBT, and age. Disease and non-disease related mortalities (DRM and NDRM) were similar between Whites (DRM: 20% and NDRM: 23%) and Hispanics (DRM: 16% and NDRM: 24%) and regardless of whether they had malignant or non-malignant disease, high or standard-risk malignant disease, s or d UCBT, and age.Overall survival (OS) was similar between Hispanics (73.7 months) and Whites (70.2 months) and regardless of whether they had malignant or non-malignant disease, high or standard-risk malignant disease, s or d UCBT, and age. Hispanics had a longer OS (88.7 months) than Whites (68.5 months) when each received an ethnically matched s UCB product (p=0.030) and a shorter OS (43.3 months) than Whites (OS=not evaluable (NE), all patients alive) when each received an ethnically mismatched s UCB product (p=0.004). Hispanics with an ethnically mismatched s UCB product and malignant disease had a shorter OS (47.4 months) than Whites (NE, all patients alive) (p=0.016). Whites and Hispanics with ethnically matched and mismatched s UCB products had similar numbers of patients with malignant and high-risk malignant disease. Only 6 of the 163 Whites and Hispanics who had s UCBT were adults (≥18 years).Improvement in OS in Hispanics with ethnically matched s UCB products was related to an increase in OS from NDRM while worse OS in Hispanics with ethnically mismatched s UCB products was related to decreases in OS from both DRM and NDRM. There was a trend to longer OS among all pts with ethnically matched (82.3 months) versus mismatched (68.5 months) s UCB products (p=0.154). OS was shorter among all Hispanics with mismatched (43.3 months) versus matched (88.7 months) s UCB products (p=0.001). Cell dose, degree of HLA-matching, and percent with malignant and non-malignant disease were similar for all pts and between Whites and Hispanics with ethnically matched and mismatched s UCB products.In conclusion, ethnic mismatches between donor and recipient appear to affect survival in pediatric s UCBT. The effect of ethnic mismatches was more pronounced in Hispanics than Whites.Table:CHARACTERISTICS AND OUTCOMESWhiteHispanicNumber of patients76141Median age at transplant, years (range)9.0 (0.1–79.2)8.0 (0.1–61.7)Age category, years<1861 (82%)116 (82%)≥1813 (17%)21 (15%)Median weight, kg (range)25 (4–111)26.3 (4–160)Recipient sexmale43 (57%)90 (65%)female31 (41%)50 (35%)Transplant typesingle57 (76%)107 (76%)double18 (24%)34 (24%)Recipient CMV statuspositive24 (32%)61 (43%)negative27 (36%)41 (29%)*Malignant disease66 (88%)96 (68%)Donor/Recipient ethnicity match, s UCBmatched39 (70%)57 (53%)mismatched10 (18%)28 (26%)HLA-matching, s UCBT6/614 (25%)9 (8%)5/628 (56%)50 (47%)4/613 (23%)44 (41%)Median cell dose x 10'37 TNC/kg (range)5.7 (1.5–28.5)5.6 (1.5–45.5)Median days ANC >500/μL21 (10–50)20 (10–100)Median days platelets >20K/μL51 (24–165)47 (21–167)Median days platelets >50K/μL60 (29–137)49 (24–224)Overall survival, months70.273.7Median follow-up, months (range)28 (.25–121)25 (.25–69)*p-value < 0.05 Disclosures:Shaughnessy:Otsuka: Honoraria, Speakers Bureau; Millenium: Honoraria, Speakers Bureau; Genzyme: Honoraria, Speakers Bureau.

Improved Outcome in Unrelated Donor Recipients After Allogeneic Hematopoietic Stem Cell Transplantation for Patients with Advanced Relapse / Refractory Chronic Lymphocytic Leukemia

Abstract 4474Chronic lymphocytic leukemia (CLL) remains incurable with standard therapies and a large number of patients become refractory to treatment or develop toxicities that prevent further treatment and contribute to their mortality. Allogeneic hematopoietic stem cell transplantation (Allo-HSCT) is the only known curative treatment for CLL. However, management and prevention of toxicities as well as patient / donor selection remain as the most significant challenges that limit the success of this treatment.In this observational study we evaluated the efficacy and tolerability of Allo-HSCT in relapse / refractory patients with CLL and correlated the clinical outcome with prognostic markers as well as the donor type.All patients were enrolled at the University of California, San Diego - Moores Cancer Center between November 1998 and July 2009. Eighteen patients with progressive relapse / refractory CLL were included (9 males [8 Caucasian, 1 Hispanic], 9 females [8 Caucasian, 1 Hispanic]), nine patients received stem cells from related donors and the other nine from unrelated donors. The median age was 50 years (age range, 26–71), median interval between diagnosis and Allo-HSCT was 83 months, and the median number of regimens prior to transplant was 5.3 (range, 2–11).Five out of eighteen patients were fludarabine-refractory and one was not evaluable (NE). All patients had a high-risk disease at the time of transplantation, with advanced stages according to Rai classification, and high prevalence of IgVH unmutated state, as well a high expression of CD38 and ZAP-70. Six patients had cytogenetic abnormalities, ten were normal and two were not evaluated. The most common pre-transplantation cytogenetic alteration was deletion 17p (33.3%), followed by deletion 13q (22.2%) and deletion 11q (22.2%). Prior to Allo-HSCT, three were in CR, ten patients were in PR and five had PD. CMV serologic reactivity was present in 67% of patients. Seventeen patients received non-myeloablative conditioning regimens and one patient was treated with a myeloablative regimen.Disease status was assessed 30 and 100 days, 1, 2 and 3 years post Allo-HSCT. 13 out of 18 patients showed response to Allo-HSCT (6 PR and 7 CR) with the remaining patients having PD. Two patients had acute GVHD and 3 patients had extensive chronic GVHD. We observed no differences in the rate of GVHD in unrelated vs. related donor recipients (p=0.1). Five patients died, three due to progression of the disease, one due to post-transplant organ failure and one for acute GVHD. Survival analysis showed a median OS of 60.1 ± 3.9 months. We observed a significant difference in terms of OS in patients who had unrelated vs. related transplants (HR=3.1 [95% CI 1.5–18.7]). We observed no difference in survival of patients discriminated by the IgVH mutational status (HR =1.8 [95% CI 0.2–17.5]) or ZAP-70 expression (HR =1.0 [95% CI 0.9–1.1]). The median progression free survival was 56 months.Five of the 18 patients were retreated with donor lymphocyte infusions or a second Allo-HSCT after relapse or lost of chimerism. Three of these patients died of PD while the other two are still alive.In conclusion, Allo-HSCT induces long-term remission and survival in high-risk relapse / refractory CLL patients including patients with multiple previous treatments and progressive disease status at the time of transplantation. The response to Allo-HSCT is independent of prognostic markers such as IgVH and ZAP-70 expression. Patients that received stem cells from unrelated donors have a better clinical outcome including OS with no evidence of increased GVHD. Disclosures:No relevant conflicts of interest to declare.

Safety and Tolerability of Plerixafor in Combination with Cytarabine and Daunorubicin in Patients with Newly Diagnosed Acute Myeloid Leukemia- Preliminary Results From a Phase I Study

Abstract 82 Introduction:Plerixafor is thought to enhance chemotherapy mediated myeloid leukemia cell death by promoting mobilization from the protective bone marrow niche and disrupting CXCL12-mediated survival signals. We conducted a Phase 1, open-label, multi-center, dose escalation study in patients (pts) with newly diagnosed AML to determine the maximum tolerated dose (MTD) and safety of plerixafor when combined with cytarabine and daunorubicin. Methods:Adult pts ≤70 years old with newly diagnosed AML were eligible to participate in this ongoing study. Pts with M3 AML and those <50 years old with core binding factor leukemias were excluded. Pts received IV cytarabine 100 mg/m2/day by continuous infusion on days 1–7 and IV daunorubicin 90 mg/m2/day on days 1–3 (7+3 regimen). Plerixafor was given as a 30-min IV infusion, 4–5 hours before daunorubicin beginning on day 2, and repeated at the same time on days 3–7, starting at 0.24 mg/kg, proceeding to dose levels of 0.32, 0.40, and 0.48 mg/kg. Three to 12 evaluable pts were enrolled in each cohort in a modified 3+3 design. Pts were observed for dose-limiting toxicities (DLT) from the first plerixafor dose through day 49. Responses were assessed using IWG response criteria. Serial peripheral blood (PB) samples were analyzed before and after the first and last plerixafor doses for circulating CD34+/CD117+ leukemia cells. Results:Twenty-three pts (median age 57 years) have been enrolled in 4 cohorts. Baseline characteristics are included in Table 1. [Display omitted] Plerixafor infusion on day 2 caused a rise in PB AML blasts (mean 3.01-fold increase) peaking at 2–4 hours after administration. On day 7, there was a mean 1.51-fold increase in PB AML blasts but far fewer total cells were detected.Eighteen (86%) pts experienced adverse events (AEs) that were reported as at least possibly related to plerixafor. The majority were Grade 1/2 in severity and mainly included gastrointestinal disorders. Four (19%) pts experienced Grade 3 plerixafor-related AEs including febrile neutropenia (n=3), neutropenia (n=1), nausea (n=1), infections (n=2) and decreased appetite (n=1) commonly observed with 7+3 regimen. One (5%) pt (0.48 mg/kg cohort) experienced Grade 4 related AEs of thrombocytopenia and asymptomatic pulmonary embolism (while receiving medroxyprogesterone); the latter was the only possibly-related SAE reported. The median time to neutrophil (≥ 0.5 × 109/L) and platelet (≥100 × 109/L) recovery for responders was 19.5 (range 13–35) and 21 (range 17–37) days, respectively. There were 4 (17%) plerixafor unrelated deaths (0.24mg/kg): 1 within 30 days post induction due to an AE of acute respiratory distress syndrome and 3 due to disease progression > 3 months post induction. No DLTs have been reported.Of 21 pts with available data, 14 (67%) had complete response (CR), 2 had CR with incomplete count recovery (CRi), 2 had residual leukemia (RL), 2 had treatment failure (TF) due to resistant disease and 1 was not evaluable (NE) due to early death. Conclusions:The toxicity or hematopoietic recovery expected with the 7+3 regimen was not significantly altered by the addition of plerixafor. Transient mobilization of AML blasts into PB was observed immediately following plerixafor treatment. Sixteen of 21 patients, majority of who had intermediate or poor risk cytogenetics, achieved a CR or CRi, with responses observed across all plerixafor doses. Twice daily plerixafor dosing and addition of G-CSF to augment mobilization are being currently explored. Disclosures:Uy:Sanofi Oncology: Consultancy, Speakers Bureau. Off Label Use: Plerixafor (Mozobil®), a hematopoietic stem cell mobilizer, is approved by the US FDA in combination with granulocyte-colony stimulating factor (G-CSF) to mobilize hematopoietic stem cells to the peripheral blood for collection and subsequent autologous transplantation in patients with non-Hodgkin’s lymphoma and multiple myeloma. Avigan:Sanofi Oncology: Membership on an entity’s Board of Directors or advisory committees, Research Funding. Cortes:Ariad: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Pfizer: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Chemgenex: Membership on an entity’s Board of Directors or advisory committees, Research Funding. Becker:Millenium: Research Funding; Glycomimetics: Research Funding; Sanofi Oncology: Research Funding; Amgen: Consultancy, Research Funding; Pfizer: Consultancy. Hewes:Sanofi Oncology: Employment. Johns:Sanofi Oncology: Employment. Erba:Ambit: Research Funding; Ascenta: Research Funding; Celgene: Speakers Bureau; Chroma: Research Funding; Eli Lilly: Research Funding.

A Phase I Study of the Combination of Azacitidine, Cyclophosphamide, Vincristine, and Rituximab in Relapsed and Refractory Lymphoma

Abstract 1624Tumor suppressor gene silencing via mechanisms including DNA hypermethylation is a recognized event in lymphomagenesis and lymphoma recurrence and transformation. DNA methyltransferase inhibitor, azacitidine, reduces epigenetic methylation in lymphoma and numerous other tumor models. Given the poor outcome of patients with transformed or refractory lymphoma, there is an immediate need to find novel therapies.We report the first results of an ongoing Phase I trial evaluating the maximal tolerated dose (MTD) of azacitidine given in a schedule intended to sensitize lymphoma to a regimen of oral cyclophosphamide, intravenous vincristine, and rituximab (for those patients whose lymphoma expresses CD20) for patients with recurrent or refractory lymphoma. Participants receive azacitidine (days 1–5, starting with 25 mg/m2) followed by oral cyclophosphamide (days 6–9, 300 mg/m2), vincristine (day 8, 1.4 mg/m2, maximum of 2 mg), and rituximab (day 8, 375 mg/m2). All patients receive pegfilgrastim (day 10, 6 mg) with each cycle. Cycles are repeated every 21 days for up to eight cycles if participants continue to benefit from therapy.To determine the MTD, a “3+3” design was employed. Dose limiting toxicity (DLT) is assessed during cycle 1. DLT is defined as the following: grade 3 or 4 non-hematologic toxicity (excluding emesis or isolated elevation of alkaline phosphatase); grade 4 neutropenia or thrombocytopenia of ≥7 days duration; increased serum creatinine > 2.0 times upper limit of normal; inability to receive all doses of azacitidine or cyclophosphamide within the first cycle or inability to initiate cycle 2 within two weeks of completing cycle 1 due to drug-related toxicity.Of the first 10 patients enrolled (8 patients in 25 mg/m2 azacitidine cohort, and 2 patients in 50 mg/m2 cohort), median age was 56 years (range 39–73). Median number of prior lines of therapy was 3 (range 2–4). Lymphoma subtypes included diffuse large B cell lymphoma (DLBCL; n=4), follicular lymphoma (FL; n=3), Hodgkins lymphoma (HL; n=1), small lymphocytic lymphoma (SLL; n=1), and cutaneous T-cell lymphoma (CTCL; n=1).A median of 2 cycles (range 1–6) have been received. The MTD has not yet been reached. One patient experienced thrombocytopenia as a DLT. The DLT criteria were subsequently revised to allow grade 4 thrombocytopenia of < 7 days after initially noting that some patients experienced asymptomatic grade 4 thrombocytopenia lasting only a short duration. An additional three patients were accrued to the first dose level after this adjustment to the current DLT, with no additional patients experiencing a DLT. Grade 3–4 toxicities during any cycle of therapy were as follows: neutropenia (n=5); thrombocytopenia (n=4); anemia (n=2); and abscess, anorexia, bacteremia, hypoalbuminemia, and nausea (n=1 each). Additionally, grade 3 cardiac ischemia and deep venous thrombosis each occurred in one patient but were considered unrelated to treatment by the investigator. Of the 8 patients who have completed treatment, 1 patient with FL achieved a complete response (CR), 1 patient with FL achieved a partial response (PR), 2 had stable disease (SD), 2 experienced progressive disease (PD), and 2 were not evaluable (NE) for response. Interestingly, the CR was maintained for 7 months and the PR has been ongoing for 6 months since completion of therapy. These preliminary data suggest the therapeutic potential of this novel combination and enrollment remains ongoing to define the MTD. Additional correlative assessments of tumor and peripheral blood mononuclear cells are also underway. Disclosures:Off Label Use: Azacitidine is the test article in this study and is not FDA approved for the treatment of lymphoma. Hayslip:Celgene: Research Funding.

Final results of phase I/II study of decitabine (DAC) combined with temozolomide (TMZ) in metastatic melanoma (MM).

8530 Background: TMZ is widely used in MM despite low response rates (7-13%) and no improvement in median overall survival (OS) 7.7 months (m) when compared to dacarbazine in Phase III trials. The DNA repair protein, O6-methylguanine-DNA-methyltransferase (MGMT), is implicated in melanoma resistance to TMZ and can be depleted with extended schedule TMZ. DNA mismatch repair (MMR) deficiency is another mechanism of resistance that can be reversed with DNA hypomethylators such as DAC. We sought to determine the recommended phase II Dose (RP2D), safety, and efficacy of DAC in combination with extended schedule TMZ in MM. Methods: In the Phase I portion, pts were treated with 2 dose levels (DL) of DAC: 0.075 mg/kg IV QD and 0.15 mg/kg IV QD. DAC was administered qd x 5 d/wk for 2 wks, and TMZ was administered PO at 75 mg/m2 qd for 4 wks, starting on wk 2 of each 6-wk cycle. A Simon 2-stage Phase II design with success defined as ≥5 Objective Responses (OR) in 34 evaluable patients gave µ=0.10 and 85% power. PK sampling was performed on Days 1 and 8; PBMC and tumor tissues were studied on Days 1, 8, 15 and 29 of cycle 1. Results: The RP2D is DAC 0.15 mg/kg and TMZ 75 mg/m2. 35 patients were accrued to the Phase II portion of the study, the majority with M1c disease (88%); brain metastases were present in 42%. 2/35 were not evaluable (NE) for efficacy. For the remaining 33 patients, the best RECIST responses were 1CR, 4 PR, 13 SD, and 15 PD, for an OR rate of 15% and a clinical benefit rate (CR+PR+SD) of 54%. The median PFS was 2.8 m, median OS was 15.2 m (compared to 7.7 m), and 1-year OS rate was 62% (compared to 25%). Grade 3/4 neutropenia was observed in 68% of pts but reversible, lasting >7 d in only 5 pts (DLT rate 15%). Only 2 patients discontinued therapy for hematologic toxicity. PK studies revealed no effect of DAC on the PK profile of TMZ. Conclusions: The combination of DAC and TMZ is safe and results in improved median OS from historic reference of 7.7 m to 15.2 m, and 1-year OS rate from 25% to 62%. The addition of DAC appears to improve the clinical activity of TMZ, possibly through dual modulation of DNA repair (depletion of MGMT and re-expression of MMR), and warrants further evaluation in a randomized setting.

Prospective Trial of Pre-Transplant 5-Azacitidine on Hematopoietic Cell Transplantation Outcomes for Myelodysplastic Syndrome and CMML

AbstractAbstract 1333In a prior retrospective analysis, we reported no adverse effects of pre-transplant 5-azacitidine on subsequent allogeneic hematopoietic cell transplantation (HCT) outcomes. We now report the results of a prospective observational clinical trial with the objective of evaluating HCT outcomes following pre-HCT therapy with 5-azacitidine. Twenty-three patients seen in consultation for HCT and medically eligible for a donor search were enrolled and received 5-azacitidine [75mg/m2 for 7 days every 4 weeks] until a suitable donor was identified. Four did not proceed to transplant for the following reasons: failure to obtain insurance approval due to patient age, failure of the pre-HCT organ evaluation although a donor was identified, CNS hemorrhage in setting of chronic anti-coagulation five days prior to HCT admission and one (62 years) declined HCT as only a HLA-A mismatched donor was available. Nineteen patients received a HCT following a myeloablative targeted busulfan fludarabine regimen. Median age at HCT was 57 years (25 – 67), 18 patients were older than 45 years, 7 older than 60 years. Disease at diagnosis was RCMD (3), RAEB2 (11), RAEB1 (3), CMML1 (1) and AMLM6 (1). IPSS at diagnosis was Int-1 (2), Int2 (9) and high (5), CMML1 (1), AMLM6 (1) and not evaluable (NE) (1). Cytogenetic risk was good (7), intermediate (5) and poor (7). Three patients had therapy related MDS. Patients received a median of 4 (1-6) cycles of 5-azacitidine. Median time from diagnosis (or time of progression and start of therapy in 2 patients) to HCT infusion was 195 days (107 – 350). Response to 5-azacitidine prior to HCT by the International Working Group 2006 criteria included partial response (8), stable disease (9) and 2 progressed. Two received leukemic induction chemotherapy prior to HCT. Disease status prior to HCT was RCMD (8), RAEB2 (2), RAEB1 (6), CMML1 (2) and AMLM6 (1). IPSS score prior to HCT was Low (1) Int-1 (6), Int2 (9) and poor (1) and CMML1 (2). Source of donor cells was peripheral blood siblings (7), matched unrelated donors (10) and mismatch unrelated donors (2). Median follow-up from HCT is 440 days (83-696). There are 3 patients who did not achieve remission (1) or relapsed (2) and 1 of the three remains alive with active disease. There are 3 non-relapse deaths, 2 due to infection and 1 due to GVHD. All deaths occurred between days 180 – 262. At one year OS is 69% (SE 0.12) and DFS is 63% (SE 0.12). In conclusion, pre-HCT 5-azacitidine was well tolerated, provided control of disease as a bridge to HCT and did not impose additional toxicity after allogeneic HCT with a promising 1 year progression-free survival. Controlled trials are needed to determine whether post-transplant relapse and survival are improved by pre-transplant 5-azacitidine. Disclosures:Field:Celgene: Research Funding. Perkins:Celgene: Research Funding. Komrokji:Celgene: Research Funding, Speakers Bureau. Lancet:Celgene: Research Funding. Alsina:Celgene: Research Funding. List:Celgene: Research Funding. Anasetti:Celgene: Research Funding.

Hematopoietic Stem Cell Transplantation for Myelodysplastic Syndrome and Chronic Myelomonocytic Leukemia In Patients up to Age 75: Comparison of Survival In Patients with An Available Donor Compared to Patients without a Donor

AbstractAbstract 2381Allogeneic hematopoietic cell transplantation (HCT) remains the only curative treatment strategy for patients with Myelodysplastic Syndrome (MDS) or Chronic Myelomonocytic Leukemia (CMML). Recent reduction of the transplant related toxicity has permitted the expansion of empiric age limitations for HCT up to 75 years. There has been limited comparative data on HCT focusing on donor availability in patients with MDS/CMML. Between January 2004 and September 2009, a total of 255 new patients (NP) with a diagnosis of MDS or CMML were evaluated for HCT at Moffitt Cancer Center. This report describes the outcomes of these patients with emphasis on donor availability. Donor Search Results: Of the 255 NP, 58 did not undergo a donor search. Reasons for not proceeding were as follows: Medicare declined coverage due to age >65 (18), waiting as have low risk disease (15), patient declined (6), patient seen as second opinion only (7) and patient was not eligible for HCT (12). These patients were not included in the survival analysis. Of the 197 patients who had a donor search initiated, a sibling (SIB) matched unrelated (MUD) or single HLA antigen/allele mismatch (mMUD) unrelated adult donor was found in 173 patients. A suitable adult donor was not identified in the remaining 24 patients. To mitigate bias due to factors giving a survival advantage to patients who were stable enough to survive the donor and proceed to HCT, the survival analysis included only those patients alive 90 days after the donor search was initiated. We have been able to identify donors within this time frame for 99% of the patients who ever found one, although time to transplant is longer. At the 90 days landmark, there were 164 patient in the Donor cohort, and 19 patients in the No Donor cohort. Donor Cohort: The median age was 56.6 yrs (18.5 – 73.5). Ninety-seven patients (59%) were older than 55 yrs and 26 (16%) were above 65 yrs. At the time of the transplant consult, IPSS risk was Low (10), Int-1 (44), Int-2 (48), High (25), AML (21), CMML (13), or not evaluable (NE) (3). Donors included SIB (60), MUD (75) and mMUD (29). Median follow-up of surviving patients is 27.7months (7.2 – 70.7). No Donor Cohort: Median age was 57.4 yrs (32.6 – 68.1) with 12 patients (63%) older than 55 yrs and 3 (16%) patients older than 65 years of age. IPSS at initiation of the donor search was Int-1 (5), Int-2 (6), High (5), AML (1) and CMML (2). Median follow-up is 9.2 months (1.4 – 61.5). Of the 19 patients with no donor, 3 patients received an umbilical cord blood HCT elsewhere and were analyzed by intent to treat. Outcomes: Patients with a donor had significantly improved overall survival from time of donor search vs. patients with no donor (P=0.007) with 2 year OS of 48% vs. 23%, respectively. Median survival for the donor group was 22.2 months [95% CI 14.7 – 35.7] vs. 10.1 months for those without a donor [95% CI 2.3 – 14.7]. Transplant: Of the 164 patients with a donor, 121 (74%) patients received the planned allogenic transplants. The 2-year overall survival (OS) after transplantation is similar for SIB (51%), MUD (39%) or mMUD (68%) transplant recipients (P=0.4), and also similar by age below or above 55 years (P=0.7). These data demonstrate that most patients with MDS or CMML can have a suitable donor identified and proceed to HCT. Overall survival is significantly improved for those patients who have a suitable sibling or unrelated donor. Disclosures:Lancet: Eisai: Consultancy; Celgene: Honoraria. Alsina: Millenium: Consultancy, Research Funding; Celgene: Research Funding; Novartis: Consultancy. List: Celgene: Research Funding.

Biomarkers ER, PR, HER-2 En Topoisomerase II alpha in Correlation with Response to Neoadjuvant Chemotherapy for Primary Breast Cancer.

Abstract Background: Neoadjuvant chemotherapy (CT) is widely accepted for patients with primary breast cancer (BC) not eligible for breast conservative surgery (BCS). Docetaxel, when used in combination with or when sequentially added to an anthracycline-based regimen, is active in the adjuvant setting. The objectives of this trial were to assess the activity of sequential anthracycline-docetaxel chemotherapy in the neo-adjuvant setting and to evaluate these markers as predictors of response.Patients and methods: Patients with unilateral BC &amp;gt; 2 cm (with or without positive sentinel lymph node (LN)), adequate liver, kidney and bone marrow function and no evidence of distant metastasis were eligible for enrolment. Patients with stage T4d or inflammatory BC were excluded. Treatment prior to surgery consisted of 4 cycles of Adriamycin (60 mg/m²) plus cyclophosphamide (600 mg/m²) (AC) administered intravenously every 3 weeks (q3wk), followed by 4 cycles of docetaxel (D) (100mg/m²) q3wk. Patients were clinically evaluated after 4 cycles of AC and again after 4 cycles of D. Pathological evaluation was performed after definitive surgery. Hormonal receptor, HER2 and topoisomerase II alpha (topoII) status and tumor grade were evaluated for their ability to predict response to treatment.Results: Fifty-three patients with a mean age of 49 years (range 31-69), were included in this analysis. Mean largest tumor diameter before treatment was 49.1 mm (range 25-90 mm). There were 12 grade 2 and 30 grade 3 tumours representing 46 ductal carcinomas, 5 lobular carcinomas and 2 mixed tumors. Eleven tumors (21%) were not evaluable (NE). LNs were positive in 62% of patients. Forty patients were evaluable for HER-2 and topoII. Thirteen patients (33%) were HER2-positive by immunohistochemistry (IHC) and 11 of these 13 were also HER2-positive by fluorescence in situ hybridization (FISH), 4 patients were topoII positive by FISH. The mean topoII level for FISH-positive patients was 1.83 (CI, 95%, 1.49 to 2.16). There was no increase in the topoII level without HER2 amplification by FISH. Forty-three percent of patients were oestrogen (E) and progesterone (P) receptor (R) positive, 28% were ER and PR negative, and 15% of patients were triple negative. After 4 cycles of AC, a complete reponse (CR) was seen in 17% of patients, partial response (PR) in 53% stable disease (SD) in 26%, and progressive disease (PD) in 4%. After 4 cycles of D the corresponding figures were 30%, 45%, 11% and 2% respectively. Eleven percent of patients were NE. Forty patients (75.5%) had BCS and 13 (24.5%) underwent mastectomy. A correlation was found between HER2 amplification by FISH and topoII amplification: r=0.576 (95% CI, 0.290 to 0.767). ER, PR, tumor grade, HER2 and topoII failed to predict response.Conclusions: Sequential AC followed by D is a highly effective neoadjuvant treatment and permits BCS in more than 75% of patients. There is a significant correlation between HER2 amplification by FISH and topoII levels. Tumor grade, ER, PR, HER2 or topoII were no predictors of response to AC nor D. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 2045.

Factors associated with clinical benefit from epidermal growth factor receptor inhibitors in recurrent and metastatic squamous cell carcinoma of the head and neck

Single agent epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) have demonstrated reproducible response rates of 5-15% in treatment of squamous cell carcinomas of the head and neck (SCCHN). The subset of patients that benefits most from these agents remains unknown. We reviewed individual patient data from five clinical trials of erlotinib, lapatinib, or gefitinib to determine if there are clinical characteristics that are associated with clinical benefit defined as complete response (CR), partial response (PR), and stable disease (SD) >4months. Secondary endpoints included progression-free survival (PFS) and overall survival (OS). Three-hundred and nineteen subjects were included. Observed responses were: 1% CR, 6% PR, 24% SD >4months, 18% SD <4months, 45% progressive disease (PD), 7% not evaluable (NE). The median OS was 6.4months and the median PFS was 2.7months. The most common toxicities observed were rash (grade 1 in 37%, grade 2 in 33%, grade 3+ in 6%) and diarrhea (grade 1 in 30%, grade 2 in 10%, grade 3+ in 5%). Performance status (PS) (p=0.04), older age (p=0.02), and development of rash (p<0.01), diarrhea (p=0.03), or oral side effects (p=0.02) were independently associated with clinical benefit. Older age, better PS, and development of rash were associated with longer PFS and OS. Clinical parameters that appear to predict response to EGFR TKI include PS and age. EGFR mechanistic toxicities that develop during therapy are also highly associated with benefit and suggest a relationship between drug exposure and outcome.

A randomized multi-center phase II trial of capecitabine (X) versus S-1 (S) as first-line treatment in elderly patients with metastatic or recurrent unresectable gastric cancer

4546 Background: Although the combination chemotherapy is the standard of care for young patients (pts) with advanced gastric cancer (AGC), single agent chemotherapy may be a good alternative for elderly pts. Recent introduction of two new generation oral fluoropyrimidines, capecitabine and S-1, prompted us to investigate the activity and safety of these agents in elderly pts with AGC in a randomized multi-center phase II design. ( NCT00278863 ) Methods: Elderly chemo-naïve pts (= 65 years) with measurable metastatic or recurrent gastric cancer were randomly assigned to receive capecitabine (1,250 mg/m2 bid, D1–14 every 3 weeks, arm X) or S-1 (40∼60 mg bid according to BSA, D1–28 every 6 weeks, arm S). The primary endpoint was the response rate (RR). Results: From Oct 2004 to Apr 2006, 96 pts were enrolled. Excluding 5 pts who did not fit inclusion criteria, 91 pts were randomized to arm X (N=46) or arm S (N=45). Median age was 70.5 years for arm S and 71.0 years for arm X. Other clinical and tumor characteristics were well balanced across the two treatment arms. Among 44 assessable pts in arm X, 13 attained partial response (PR, 29.5%), 17 stable disease (SD, 38.6%) and 10 progressive disease (PD); 4 pts were not evaluable (NE). The corresponding disease responses in the 45 assessable pts in arm S were: 1 complete response (2.2%), 12 PR (26.7%), 18 SD (40.0%), 10 PD, and 4 NE. The incidence of grade 3–4 granulocytopenia was 6.8% in arm X and 4.8% in arm S. One episode of febrile neutropenia was observed in arm X. Grade 3–4 non-hematologic toxicities were as follows (arm X vs. S): asthenia (0% vs. 7.2%), anorexia (6.8% vs. 9.5%), diarrhea (2.3% vs. 0%), and HFS (6.8% vs. 0%). With a median follow up of 13.5 months (mo) for survivors (range, 8.1∼21.9), median time to progression and time to treatment failure were 4.8 mo (95% CI, 3.0–6.5) and 4.4 mo (3.6–5.3) for arm X and 4.2 mo (1.5–6.9) and 3.0 mo (1.5–4.5) for arm S. Median overall survival was 10.0 mo (8.0–12.0) for arm X and 7.9 mo (4.1–11.7) for arm S. Conclusions: Both treatments were active and tolerable as a 1st line treatment for elderly pts with AGC. No significant financial relationships to disclose.