Percent Of Pts Research Articles

657P - Second- and Third-Line Chemotherapy in Advanced Gastric Cancer: a Real-Life Clinical Picture

ABSTRACT Aim: Chemotherapy is the mainstay of palliative treatment for metastatic or unresectable gastric cancer. Nevertheless, almost all patients (pts) will develop progressive disease after 1st-line treatment. The role of subsequent salvage chemotherapy is not well established, especially outside of clinical trials. Methods: We reviewed 223 pts with histologically proven unresectable or metastatic gastric and gastroesophageal junction adenocarcinoma who received 1st-line chemotherapy at our Institution between August 2004 and December 2013. At the time of progression, 105 (47%) pts received 2nd-line chemotherapy. The choice of 2nd-line schedule was primarily driven by performance status and progression free survival during 1st-line treatment (mPFS1). After 2nd-line failure, 37 pts underwent 3rd-line therapy. Data from medical records were retrospectively analyzed. Results: For 2nd-line treatment, median progression free survival (mPFS2), median overall survival (mOS) and response rate (RR) were 2.9 months (mo), 5.5 mo, and 17%, respectively. The table below summarizes efficacy data with the various schedules used. The mPFS and mOS from starting 3rd-line treatment were 2.4 mo and 5.4 mo, whereas the RR achieved was 6%. Discontinuation due to adverse events occurred in 3% of pts during 2nd-line and 8% of those given 3rd-line. No toxic deaths were registered during treatment. However, fifty percent of pts received 2nd-line chemotherapy with dose reduction ab initio. Summary of 2nd-line efficacy data with the various schedules used Schedule pts (n) RR n (%) mPFS1 (mo) mPFS2 (mo) mOS mo Overall 105 17/101 (17) 7.3 2.9 5.5 Platinum-based 17 8/17 (47) 10.3 4.3 12.5 FOLFIRI 29 5/26 (19) 8.3 4.2 7.3 Taxane 43 3/42 (7) 6.2 2.5 4.1 Other 16 1/15 (7) 7.1 2.8 5.1 Conclusions: In line with the limited prospective data available, 2nd-line chemotherapy was safely administered to almost half of pts progressing under 1st-line and appeared to be moderately effective. Pts with longer mPFS1 were likely to receive platinum-based regimen or FOLFIRI as 2nd-line chemotherapy, obtaining interesting outcomes. After 2nd-line progression, only a small subgroup of pts continued to benefit from further treatment. Further investigations are strongly advocated to improve treatment outcomes in this setting. Disclosure: All authors have declared no conflicts of interest.

Hyperthermia and Radiation Therapy for Local Advanced or Recurrent Breast Cancer: Long-Term Outcomes and Adverse Events

To report long-term outcomes and toxicity of combined hyperthermia and radiation therapy (RT) in treatment of breast cancer pts with locally advanced (LA), locally recurrent (LR), or positive resection margins. With IRB approval, records of patients (pts) with LA and LR breast cancer treated with HT and RT from January 1991 to December 2007 were reviewed. Pts with distant metastases were included. Planned radiation doses were > 40 Gy in retreatment pts and > 60 Gy in radiation naïve pts. Each hyperthermia site was planned for 2 sessions/week for > 4 sessions. Superficial or interstitial applicators (MA-120, MA-100, MA-150, MA-201 manufactured by BSD corp.) were used and chosen, based on estimated thickness and target width. Superficial or implanted thermistors measured intra-tumoral temperature. The ultimate temperature goal was > 42.5oC for > 45 minutes. Pt tolerance limited delivered temperature and treatment duration. Thermal equivalent dose (TED), defined by number of minutes at > 42.5°C and > 43°C, and was calculated for each site and for the entire course. Endpoints of analysis were local control and survival. One hundred twenty-seven pts (20% LA and 80% LR) received hyperthermia to 167 sites. Median follow-up was 12 months (mean 27.2 ± 37.8, range 0-182). Median age was 55 years (range 32-106). Fifty-six percent of pts had prior RT. A total of 59.4% of pts had distant metastases. Treated sites were intact breast (21.6%), chest wall/skin (63.5%), and breast/chest wall and nodes (11.4%). Disease volume was microscopic in 11.4%, < 3 cm in 9.6 %, and > 3 cm in 79.0%. Median RT dose was 50 Gy (range 16 - 76.4 Gy). Forty pts (31.5%) received treatment to > 1 hyperthermia site. Number of hyperthermia sites was 1-2, 3-4, and 5-6 in 91.6%, 3.6%, and 4.1% of pts respectively. Local control (LC) at last follow-up was seen in 54.8% of treated sites. Improved LC was seen with increasing RT dose, 37.5%, 51.4%, and 63.8% for 16-39.6 Gy, 40-50 Gy, and > 50 Gy, respectively (p = 0.07). LC improved with more total minutes of adequate hyperthermia - median of 235 and 143 min TED at 42.5°C & 43°C, respectively, in pts with LC, and 180 and 110 min TED at 42.5°C and 43°C, respectively in pts without LC (p = 0.09). All pts treated for microscopic residual disease had LC. The 1-yr, 3-yr, and 5-yr overall survivals were 51.6%, 27.6%, and 20.0%, respectively. Telangiectasia, desquamation, ulceration, fibrosis, and abscess formation were reported in 4.4%, 27.7%, 8.2%, 5.0%, and 1.3% of pts respectively. Hyperthermia and RT is an effective, feasible, and tolerable treatment combination to control locally advanced or recurrent breast cancer. Local control was related to radiation dose and duration of effective hyperthermia dose. Survival in these advanced patients is sufficiently long to warrant aggressive local treatment.

Characteristics, management modalities and outcome in chronic systolic heart failure patients treated in tertiary care centers: results from the EVIdence based TreAtment in Heart Failure (EVITA-HF) registry.

Limited data exist regarding baseline characteristics and management of heart failure with reduced ejection fraction (EF) in tertiary care facilities. EVITA-HF comprises web-based case report data on demography, comorbidities, diagnostic and therapy measures, quality of life, adverse events and 1-year follow-up of patients hospitalized for chronic heart failure and an ejection fraction of less than 40%. Between February 2009 and June 2011, a total of 1,853 consecutive, hospitalized patients (pts) were included in 16 centers in Germany. Mean age was 70 years, 76% were male. Median EF was 30%, and 63% were in NYHA III/IV. Ischemic cardiomyopathy was present in 56%, history of hypertension in 76%, diabetes in 39%, impaired renal function in 33%, thyroid dysfunction in 12%, and malignoma in 7%. Sixty-eight percent of pts had a non-elective admission. Rhythm was sinus/atrial fibrillation or flutter/pacemaker in 64, 28 and 11%, respectively. Median heart rate amounted to 80 bpm, median blood pressure to 122/74 mmHg. LBBB was present in 26% of non-pacemaker pts. Eighteen percent had an ICD or CRT-D. Medication (admission vs. discharge) consisted of ACEI or ARB in 73 vs. 88%, β-blocker in 71 vs. 89%, mineral corticosteroid receptor antagonist (MRA) in 32 vs. 57%, diuretics in 68 vs. 83% (p < 0.001 for each). Forty-two percent of pts received a specific treatment procedure beyond pharmacotherapy, of these 48% revascularization, 39% device therapy, 14% electrical cardioversion, 5% ablation procedures, 9 % valvular procedures, 6% iv inotropes, 1.8% IABP or LVAD implantation. At discharge, 33% of survivors had ICD- or CRT-D implants. One-year mortality amounted to 16.8%, and death or rehospitalization to 56%. NYHA class III/IV was found in 30% (p < 0.001 vs. index admission), general health status was improved in 45% and unchanged in 36% of patients. Eighty-five percent of pts took ACEI or ARB, 86% β-blockers, 47% MRA, and 78% diuretics (p < 0.001 vs. index discharge for all). Patients with chronic heart failure and low ejection fraction represent an elderly and multimorbid population. While hospitalized, they experience a significant optimization of prognosis-relevant medication, revascularization and device therapy. After 1 year, mortality is moderate; drug adherence is high and NYHA status favourable. The EVITA-HF registry is able to reflect coherently the real-world management, efforts and follow-up in heart failure pts managed in tertiary care facilities.

Superior vena cava syndrome caused by a malignant tumor: a retrospective single-center analysis of 124 cases

Superior vena cava syndrome (SVCS) results from compression of the superior vena cava. SVCS is an emergency requiring immediate diagnosis and treatment. We hypothesized that the outcome of patients (pts.) admitted during regular work hours may differ from that of pts. admitted on weekends. From 1992 to 2011, we analyzed all pts. admitted with SVCS due to a malignancy. Clinical outcome was analyzed, focusing on the work-up of pts. hospitalized on a weekend compared with those hospitalized during the week. One hundred and twenty-four pts. with malignant causes of SVCS were analyzed. Causes were as follows: small cell lung cancer (SCLC) 28.2%, non-small cell lung cancer 25%, non-Hodgkin's lymphoma 25%, metastasis of other malignant tumors 19.4% and Hodgkin's disease 2.4%. Sixty-five percent of pts. were admitted during the week and 35% on a weekend. Sixty-one percent received chemotherapy, 24% radiation, 4% radiochemotherapy, 9% palliative treatment and 2% no treatment at all. No difference in choice of treatment between pts. admitted on a weekday versus weekend was seen. Response was as follows: 7 pts. complete remission, 20 pts. partial response, 38 pts. progressive disease, 3 pts. NC and 15 pts. died. Overall response rate was as follows: Hodgkin's disease 100%, non-Hodgkin's lymphoma 29%, SCLC 22.8%, non-small cell lung cancer 9.6% and metastatic cancer 16.6%. Only 2 of the 34 pts. with relapsing carcinoma responded. None of the pts. died due to SVCS. The outcome of pts. with SVCS is not dependent on the day of admission (weekend or weekday) but is related to underlying disease in the setting of a tertiary care center.

Abstract P2-16-09: Retrospective analysis of long-term survivors with HER2+ metastatic breast cancer (MBC) treated with trastuzumab in a community setting

Abstract Background: The median survival for patients (pts) receiving trastuzumab (T) in the metastatic setting is approximately 3 years. There are limited data on real world use and outcomes in T treated pts who live longer than 3 years. The objective of this study was to identify and characterize pts with HER2+ MBC who initiated treatment with T (alone or in combination) in a community setting and to determine their treatment patterns and outcomes, including duration of treatment, overall survival (OS) and time to permanent discontinuation of T. Methods: A retrospective observational study was performed using the IKnowMed electronic medical record (EMR) used by the US Oncology Network with the primary time period of 2007 through Dec. 2012. Eligible pts had at least 2 visits at practice locations with full EMR capability. Pts on T when the EMR was implemented had chart review to determine the dates of diagnosis and start of T treatment. Results: The study population included 1856 women with HER2+ MBC who started T (alone or in combination with chemotherapy or hormonal therapy); 873 presented with MBC and 983 developed recurrence following diagnosis of early-stage disease. The median age was 58, range 23 to 96, 59% had ER+ cancer, 64% were postmenopausal and 35% had multiple sites of disease at presentation. Median OS for the entire group was 40.9 months and the median time to permanent discontinuation of T was slightly less, at 39.9 months. Interestingly, the median OS and duration of T use were similar in the recurrent MBC population and in the population who presented with de novo MBC. The proportion of pts receiving T and OS by year are presented (Table). Thirty-two percent of pts are still alive at 6 years, with 17% continuing to receive T. Outcomes of 1856 Patients Treated with TrastuzumabYear1356Pts still receiving T (%)82%53%27%17%OS (%)84%54%36%32% Ongoing analysis will evaluate whether there are pt and treatment characteristics that may predict for longer term OS. Conclusions: Using an EMR database we identified 1856 women with HER2+ MBC who initiated treatment with T (alone or in combination) with one third still alive at 5 years and 27% still on T. Future research that focuses on understanding the characteristics of this population can potentially improve care for women with HER2+ MBC with T and newer anti-HER2 agents. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P2-16-09.

Abstract OT2-6-08: Phase II, randomized, parallel-cohort study of neoadjuvant buparlisib (BKM120) in combination with trastuzumab and paclitaxel in women with HER2-positive, PIK3CA mutant and PIK3CA wild-type primary breast cancer – NeoPHOEBE

Abstract Background: The PI3K/Akt/mTOR pathway is frequently activated in breast cancer (BC) and is important for the oncogenic function of HER2. Buparlisib is an oral pan-PI3K inhibitor that targets all 4 isoforms of class I PI3K (α, β, γ, Δ). Preliminary clinical activity was observed with buparlisib in patients (pts) with advanced BC as a single agent, and in combination with paclitaxel (Dirix et al. ESMO 2012) or trastuzumab (Pistilli et al. ESMO 2012). Study design: NeoPHOEBE (NCT01816594) is a Phase II, randomized, double-blind, parallel-cohort study of neoadjuvant buparlisib or matched placebo plus trastuzumab and weekly paclitaxel. Upfront stratification of pts into 2 independent cohorts according to PIK3CA mutation status will determine whether pts with PIK3CA-mutant tumors may benefit more from this treatment combination. Adult women with newly diagnosed, HER2-positive, primary non-inflammatory BC who have not previously received systemic therapy for invasive disease are eligible. Other eligibility criteria: tumor size &amp;gt;2 cm; unilateral disease; available tumor tissue for central review of estrogen receptor (ER) and HER2 status, and PIK3CA genotype; known PIK3CA mutation status; and ECOG PS ≤1. Pts in each cohort (PIK3CA mutant or wild-type [wt]) are randomized (1:1) to receive continuous daily buparlisib (100 mg) or placebo and weekly trastuzumab (4 mg/kg loading dose then 2 mg/kg) for 6 weeks, followed by continuous daily buparlisib (80 mg) or placebo with weekly trastuzumab (2 mg/kg) and weekly paclitaxel (80 mg/m2) for 12 weeks. Study treatment is followed by surgery within 4 weeks of last paclitaxel dose. Stratification at randomization is based on PIK3CA (mutant vs wt) and ER (positive vs negative) status. Endpoints: All endpoints will be measured in both PIK3CA-mutant and wt cohorts. The primary endpoint is rate of pathologic complete response (pCR; ypT0) at time of surgery. The key secondary endpoint is objective response rate (ORR) at the end of week 6. Other secondary endpoints include pCR by other definitions, ORR prior to surgery, pCR and objective response by ER status, percent of pts with node-negative disease at surgery, rate of breast conserving surgery, and safety. Exploratory objectives include change in standardized uptake value (SUV) at Day 15 by FDG-PET; and ORR and pCR by PTEN expression, Ki67 level, apoptosis rates, percentage of tumor infiltrating lymphocytes (TIL), and by phenotype of 50% TIL at baseline. Statistical methods: The sample size is based on a minimax 2-stage randomized Phase II design with a prospective control. This design allows for early stopping if the desired efficacy is not observed after stage 1. Both cohorts are powered (80%) to detect a clinically meaningful increase in pCR of 18% at a one-sided significance level (α = 0.15). Target accrual: Planned enrollment for NeoPHOEBE is up to 220 pts at 65 sites in 12 countries across South America, Europe, and Asia-Pacific. Contact: For further study information, contact BIG@bordet.be. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr OT2-6-08.

The VIP (Very Immunocompromised Patient) Protocol: Improved Access To Care and Time To Antibiotics

Fever and sepsis in neutropenic or very immunocompromised patients (VIP) can lead to rapid progression of infection and is an oncologic emergency. Many cancer patients (pts) now receive therapy in the outpt setting, including BMT and hematologic malignancy pts. However, outside of normal clinic hours these pts need to have rapid access to medical attention. Methodist Hospital in San Antonio, Texas provides emergency services to a large number of community oncology practices and to the BMT pts of the Texas Transplant Institute. A task force of nurses, Emergency Department (ED) and BMT physicians, and community hematologist/oncologists was formed to develop a protocol to rapidly assess and treat pts with febrile neutropenia. Pts were provided with a kit, education on fever, and ID card that would identify them as a VIP that they could easily present to the triage nurse in the ED. Pts were enrolled through private physician clinics and the BMT unit. A preprinted protocol was agreed upon by the physicians that ordered the necessary lab and cultures and appropriate broad spectrum antibiotic when pts presented with their VIP card and reported fever. Target time lines were set to accomplish each step of the protocol. Education sessions were provided to the ED nurses on the importance of febrile neutropenia and oncology/BMT physicians attended ED physician staff meetings to stress the importance of implementing the protocol. The VIP protocol was implemented in June 2012 and we retrospectively reviewed the first 12 months of data. Pts with fever and history of cancer or BMT presenting to the ED were reviewed. There were 187 pts meeting this criteria in the 12 month period, 96 pts had the VIP protocol initiated at triage in the ED and 91 pts did not. Reasons for not implementing the VIP protocol in eligible pts were lack of familiarity with the protocol, and pts having other chief complaints besides fever, or not reporting that they were cancer or BMT pts. The percent of febrile neutropenic pts who had the VIP protocol initiated increased throughout the study. The median door to antibiotic time decreased from 127 minutes in the first 3 months to 51 minutes in the last 3 months (p=0.03). The percent of pts receiving antibiotics within 60 minutes increased from 10% to 45% over the duration of the study. Obstacles overcome during the year that increased utilization were increasing the number of pts enrolled, providing ED nurse education on febrile neutropenia, and holding discussions with ED physicians to make the VIP protocol a pre-printed order set. In conclusion, the VIP protocol has improved pt care and delivery of antibiotics to febrile neutropenic and BMT pts presenting to the ED. Future efforts will be to implement the VIP protocol at other outlying community EDs, continue to educate and communicate with community hematologists/oncologists and ED staff, and to assess admissions, length of stay and clinical outcomes. Disclosures:Shaughnessy:Sanofi/Genzyme: Honoraria, Research Funding, Speakers Bureau; Millenium: Speakers Bureau. Lyons:Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding; Lilly: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding. [Display omitted]

A Single-Arm, Open-Label, Multi-Center Phase I/II Study Of The Combination Of Panobinostat and Carfilzomib In Patients (pts) With Relapsed Or Relapse/Refractory Multiple Myeloma (MM)

BackgroundProteasome inhibitors (PI) such as bortezomib and carfilzomib (CFZ) have improved the treatment of MM; however, resistance invariably develops and MM remains an incurable disease. Changes in histone modification are commonly found in human cancers including MM, and several histone deacetylase inhibitors (HDACi) are in clinical development. Preclinical studies demonstrate synergistic anti-MM activity of the combination of HDACi with PI through dual inhibition of the proteasome and aggresome pathways. Panobinostat (PAN) is an oral pan-HDACi which has shown synergy with PIs in clinical studies. In this study, we evaluate the safety and efficacy of the PAN/CFZ combination in pts with relapsed and relapsed/refractory MM. Here we present the updated results of this ongoing trial. MethodsPatients with MM who had relapsed after at least one prior treatment were eligible to participate. In the dose escalation portion of the study a standard 3+3 design was used to determine the maximum tolerated dose (MTD) of 4 planned dose levels with the combination of CFZ and PAN. PAN was administered orally three times weekly during weeks 1 and 3 of each cycle (Days 1, 3, 5, 15, 17, 19). CFZ was administered IV over 30 min on Days 1, 2, 8, 9, 15, and 16 of each 28-day cycle. The 4 dose levels tested were DL 1, defined as 20 mg PAN and 20/27 mg/m2 CFZ; DL 2, defined as 20 mg PAN and 20/36 mg/m2 CFZ; DL 3, defined as 20 mg PAN and 20/45 mg/m2 CFZ; and DL 4, defined as 30 mg PAN and 20/45 mg/m2 CFZ. Treatment was continued until PD or intolerable toxicity. The primary efficacy endpoint was the overall response rate (ORR) (≥ PR). Secondary end points were time to progression (TTP), progression-free survival (PFS) and overall survival (OS), calculated using Kaplan-Meier methods. Adverse Events (AEs) were assessed according to CTCAE Version 4 and responses were assessed using IMWG criteria (plus MRs as per the EBMT criteria). The MPD (maximum planned dose) was further explored in the expansion phase. Results10 patients were treated in the dose escalation portion of the study. No DLTs were observed. DL 4 was further explored and 31 patients were enrolled in the expansion phase of the study. As of the data cutoff of 5/31/2013, 44 pts were accrued to the trial, including 34 pts on the eventual expanded DL 4. The median age of pts was 66 (41-83); most patients were ISS stages 2 and 3; 38% of pts had adverse prognostic cytogenetics or FISH, including 23% with del 17p. The median number of prior therapies was 3 (1-6) including 89% with prior bortezomib, 89% with prior immune modulating drugs (IMiDs), 34% with prior stem cell transplants. Thirty six percent of pts were refractory to bortezomib, 30% were refractory to IMiDs, 14% were refractory to both bortezomib and IMiDs, and 43% were refractory to their last treatment regimen. Twenty seven (61%) pts remain on active treatment. Forty five percent of pts experienced ≥ grade 3 hematologic-related AEs, the most common being G3 thrombocytopenia (30%) and neutropenia (20% G3 and 2% G4). Thirty four percent of pts experienced ≥ grade 3 non-hematologic AEs, the most common being fatigue (11% G3) and nausea/vomiting (9% G3). The most salient of all grade AEs were nausea/vomiting (39% G1, 20% G2, 9% G3, 0 G4) and thrombocytopenia (14% G1, 27% G2, 30% G3, 0 G4). Peripheral neuropathy was rare (5% G1, 2% G2, 0 G3/4). In pts treated on DL 4 (30 mg PAN and 20/45 mg/m2 CFZ), late cycle dose reductions for PAN were common (59% of pts) and the median PAN dose delivered was 23.4 mg. CFZ dose reductions were rare (18% of pts) and the median CFZ dose was 40.8 mg/m2. The ORR was 64% with 31% ≥VGPR and 30% PR. In addition, there were 5% MR, 26% SD and 5% PD. The ORR for bortezomib exposed pts, bortezomib refractory pts and dual bortezomib and IMiD refractory pts was 60%, 67% and 66%, respectively. With a median follow up of 6.3 months, the PFS at 6 and 12 months was 63% and 41% respectively. The OS was 83% at both 6 and 12 months and the median TTP was 8.6 months. ConclusionsThe combination of PAN and CFZ is feasible and effective in this relapsed/refractory MM population. Due to dose reductions required for PAN and no MTD reached, 2 further dose levels will be explored with plans to do a parallel dose expansion if tolerated. Disclosures:Off Label Use: Off-label use of the combo Panobinostat and Carfilomib in the treatment of relapsed/refractory Multiple Myeloma.

SAR245409 Monotherapy In Relapsed/Refractory Follicular Lymphoma: Preliminary Results From The Phase II ARD12130 Study

SAR245409 Monotherapy In Relapsed/Refractory Follicular Lymphoma: Preliminary Results From The Phase II ARD12130 Study

Phase II, Open Label, Randomized Comparative Trial Of Ondansetron Alone Versus The Combination Of Ondansetron Plus Aprepitant For The Prevention Of Nausea and Vomiting In Patients (Pts) With Hematological Malignancies Receiving Regimens Containing High Dose Cytarabine

▪ BackgroundChemotherapy induced nausea and vomiting can be a significant problem for pts with acute myeloid leukemia (AML) receiving induction chemotherapy causing deterioration in quality of life. Cytarabine-containing regimens are the cornerstone for the management of AML and cytarabine is a moderate emetic risk chemotherapy agent. Combination of cytarabine with other chemotherapeutic agent can substantially worsen nausea and vomiting. Ondansetron has been used for nausea control in pts receiving chemotherapy. Aprepitant is a P/neurokinin-1 (NK1)-receptor antagonist approved for use in combination with a 5-HT3-receptor antagonist and dexamethasone for the prevention of acute and delayed chemotherapy-induced nausea and vomiting. We explored whether the combination of two drugs with different mechanisms of action may improve the control of nausea in pts with AML receiving cytarabine-based induction. MethodsPts with AML, high-risk MDS or CML blast phase receiving induction chemotherapy with cytarabine at a dose of ≥1 g/m2/day for at least 3 days were randomized to: Arm 1) Ondansetron 8mg IV 30 minutes before high dose cytarabine followed by ondansetron 24mg IV continuous infusion daily until 6-12 hours after the end of last chemotherapy infusion. Arm 2) Aprepitant 125mg PO plus ondansetron 8mg IV 30 minutes before high dose cytarabine followed by ondansetron 24mg IV continuous infusion daily until 6-12 hours after the end of last chemotherapy, plus aprepitant 80 mg PO daily and to continue for 1 day after last dose of chemotherapy. Pts were followed for 72 hrs post chemotherapy. A diary was used by the pts to record daily number of episodes of nausea and /or vomiting experienced during the study, as well as to record any need of extra medications for escape nausea. Complete response was defined as no emesis episodes and no use of rescue medication during the study period. Partial response was defined as ≤ 1 episode of emesis during the entire study period, no use of rescue medication during the study period, and no more than moderate nausea (NCI grade 2). ResultsForty nine pts were enrolled in each arm. Fifty seven percent were men in arm 1 and 55% men in arm 2. The median age was 53yrs (ranges, 30-68) in arm 1 and 49yrs (ranges, 21-70) arm 2. Caucasians were 83% in arm 1 and 76% in arm 2. African American and Hispanics were 10 % and 6% respectively in arm 1 and 8% and 12% in arm 2. Among the population studied 96% were diagnosed with AML in each arm. MDS 2% in arm 1 and 4% in arm 2. Fourteen percent received Idarubicin with cytarabine (Ara-C) in each arm. Twenty percent in ondansetron (OND) arm and 16% in ondansetron plus aprepitant (OND+APREP) arm receive Ara-C combined with Fludarabin. Ara-C in combination with anthracycline plus nucleoside analogues was given to 49% of pts in each arm. Ten percent in arm 1 received Ara-C with anthracycline and targeted therapy, 8% in arm 2 receive similar combination. Forty two pts on OND arm and 41 pts in the OND+APREP arm were evaluable for efficacy. Patient in the OND+APREP arms achieved higher overall response rates (complete plus partial responses) as shown in Figure 1, but the difference was not statistically significant (OND 67%, OND+APREP 80%; P= 0.11). More than 75% of pts overall were free of nausea on Days 1 and 2. On days 6 and 7 higher proportion of pts in OND+APREP arm were free from nausea than OND arm. Overall 36% of pts required rescue medications, 38% in OND arm and 34% in OND+APREP arm. Among them 14% of pts required rescue more than once; 19% in the OND arm and 10% in OND+APREP arm, as shown in Figure 2. Requirement of rescue medications on Days 2 and 3 were fewer in OND+APREP arm 7% and 5% respectively compare to 21% and 16% in the ondansetron arm (P = 0.06 and P=0.07).Most common adverse events were headache and diarrhea. Twenty percent of pts in OND arm and 19% in OND+APREP arm reported to have NCI grade 2 headache (P= 0.56). Five percent of pts in ondansetron arm and 12% in ondansetron plus aprepitant arm had grade 2 diarrhea (P=0.19). ConclusionsThe daily assessment of emesis and nausea did not show statistically significant differences between the study arms but there was a clear trend towards better responses in ondansetron plus aprepitant arm with more overall response rates and lower use of rescue medications. Further larger studies are warranted to further define the benefits of this combination of antiemetic drugs. [Display omitted] [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Bone Marrow May Be More Informative Than Peripheral Blood To Evaluate Minimal Residual Disease During 1st and 2nd Year Follow Up After First-Line Fludarabine, Cyclophosphamide, and Rituximab For Chronic Lymphocytic Leukemia

BackgroundMinimal Residual Disease (MRD) status at end of first-line chemoimmunotherapy is an independent prognostic factor for patients (pts) with chronic lymphocytic leukemia (CLL). In the CLL8 trial of the German CLL Study Group, peripheral blood (PB) was monitored for MRD during follow up. Because the microenvironment is important for CLL cell growth and survival and typically it is the last site to eliminate residual disease with chemoimmunotherapy, bone marrow (BM) might be a more reliable site to monitor MRD. MethodsTwo-hundred thirty-seven pts with CLL and an indication for therapy (IWCLL-WG 2008) received first-line fludarabine, cyclophosphamide, and rituximab (FCR) on protocol between 09/2008 and 09/2012. MRD was prospectively assessed in BM and/or PB by flow cytometry using the highly sensitive international standardized approach, 2 months after the last course of treatment (final response assessment) and every 3-6 months thereafter. Kaplan-Meier estimates were compared using the log-rank test. ResultsSixty-one percent of pts were male, 21% were >65 years old, 40% had Rai stage III-IV, 41% had beta2-microglobulin (B2M) ≥4 mg/L, 61% had unmutated IGHV, and 21% had FISH analysis positive for deletion 11q and 7% for deletion 17p. Seventy-five percent of pts received ≥3 total courses of FCR. The complete remission (CR) and overall response (OR) rates were 65 and 97%, respectively. BM MRD negativity was achieved in 59% of pts at final response assessment.For monitoring, BM MRD was assessed in 121 pts during the 1st year and in 30 pts during the 2nd year after completion of treatment with FCR; all samples were serial. PB MRD was assessed in 106 pts during the 1st year and in 57 during the 2nd year of follow up; again all samples were serial. BM MRD negativity was observed in 63 (52%) pts during the 1st year of follow up and in 15 (50%) pts during the 2nd year. PB MRD negativity was observed at the same staging times in 81 (76%) and 29 (51%) pts, respectively. Concurrent BM and PB samples were taken during the 1st year in 51 pts, and in 6 pts during the 2nd year of follow up. We evaluated the association between MRD negativity during the 1st and 2nd year of follow-up and progression-free survival (PFS). BM MRD positive status was associated with shorter PFS when assessed during both the 1st and 2nd year of follow up (p<0.001 and p=0.001, respectively; Figure). In contrast, PB MRD positive status did not correlate with PFS for either time (p=0.15 and p=0.79, respectively; Figure). [Display omitted] ConclusionsAfter first-line FCR for pts with CLL, positive BM MRD may identify pts at higher risk for progression. Based on this finding, BM may be preferred to assess MRD status and pts with positive BM MRD could be considered for maintenance or consolidation strategies. Additional studies confirming these findings are warranted. Disclosures:No relevant conflicts of interest to declare.

Early Ofatumumab Treatment For High-Risk, Treatment-Naive Patients With Chronic Lymphocytic Leukemia

Background Ofatumumab is a human IgG1-kappa monoclonal antibody that binds to CD20 on normal B cells and on B chronic lymphocytic leukemia cells, resulting in B cell lysis. Ofatumumab has single-agent activity in patients (pts) with refractory CLL (Wierda, JCO 2010). Pts with CLL who have early stage disease (Rai 0-II) but have high-risk prognostic markers such as deletion 17p or deletion 11q have an increased risk of disease progression. Currently, these pts are offered watch-and-wait approach. The objective of this Phase II study is to evaluate the efficacy of ofatumumab in treating these pts with the goal to delay time to first chemoimmunotherapy treatment. Methods Pts with CLL/SLL were eligible provided they had high-risk for progression based on the presence of at least one of the following features: Rai stage II, serum beta-2 microglobulin (β2M) ≥3 mg/L, absolute lymphocyte count ≥25,000/µL, unmutated (≤2%) IGHV gene or mutated IGHV3-21, ZAP70 positive, CD38 positive (≥ 30%), or 11q or 17p deletion by FISH. Pts having a 2008 IWCLL/NCI-WG indication for CLL treatment were not eligible. Pts with Rai stage III-IV CLL were not eligible. Ofatumumab 300 mg dose 1, then 1000 mg weekly for 7 additional weeks (8 doses) was administered. Response assessment, including bone marrow evaluation, was done at least 2 months after last dose of ofatumumab and pts were followed for progression-free survival and time to first chemoimmunotherapy. Results Twenty-five pts (9 women, 16 men) were enrolled so far. The median age was 59 yrs (range, 40-81). The baseline characteristics are listed in the Table. Fifty percent of pts had unmutated IGHV gene. Thirty-four percent of pts had high-risk cytogenetic by FISH analysis. The median follow-up on the study is 4.7 months (range, 0.5-26). Grade 3-4 adverse events included infusion reaction in 6 pts. Autoimmune hepatitis with grade 4 ALT, grade 4 AST, and grade 4 alkaline phosphatase elevations was seen in 1 pt. Other grade 3-4 toxicities included rash (1 pt), shingles (1 pt), and tumor lysis (1 pt). Tumor lysis was seen in the pt with the WBC count of 207 K/µL. Eighteen pts (7 too early) are evaluable for response. Responses are as follows: 6 CR, 3 nPR, 3 PR, and 6 with stable disease. Three pts have progressed at 18.8, 14.1 and 3.2 months after starting the study treatment; 2 pts had unmutated IGHV gene (FISH negative) and one pt had trisomy 12 (IGHV mutation status unknown). None of the pts with deletion 17p or deletion 11q have progressed. All pts are alive at this time. The median overall follow up time is 7.6 months (range, 1-28). Conclusions Ofatumumab is well tolerated in pts with early stage CLL and may delay time to first chemoimmunotherapy. Disclosures: Ferrajoli: GlaxoSmithKline: Research Funding.

Spliceosome Mutations Are Frequent In Patients With Myelodysplastic Syndromes Who Failed Hypomethylating Therapy: Possible Implications Of Spliceosome Inhibitors As Alternative Treatments

Myelodysplastic syndromes (MDS) are a heterogeneous group of blood cancers characterized by bone marrow (BM) failure, peripheral blood cytopenias, dysplasia, chromosomal abnormalities and an increased risk for transformation to acute myeloid leukemia (AML). Patients (pts) with higher risk disease are primarily treated with pharmacologic treatments like hypomethylating therapy (HMT) (5-azacytidine and decitabine). 5-azacytidine (AZA) and decitabine (DAC) can result in overall response rates of 36% with a median duration of response of 15 months and 17-21% with a median duration of response of 10 months, respectively. Pts refractory to HMT have poor outcomes with a median overall survival of ∼4 months. Spliceosome gene mutations are frequently found in certain subtypes of MDS specifically SF3B1 (∼28%), U2AF1 (6-12%) and SRSF2 (6-12%). The prognostic value of spliceosome mutations in different MDS subtypes has been largely investigated while the impact of these mutations on treatment response is still unknown. We aim to investigate the frequency of three commonly mutated spliceosome genes (SF3B1, U2AF1, and SRSF2) in pts who failed HMT in order to define mutational frequency and evaluate the feasibility of targeted therapy with next generation spliceosome inhibitors. We screened a cohort of 120 pts (MDS, 70; MDS/MPN, 33; MDS/sAML, 17; median age: 69; male/female: 85/35) that underwent HMT (AZA: 58; DAC: 21; AZA/DAC: 7; AZA/REV: 25; DAC/REV: 4; AZA/DAC/REV: 5). Forty-eight percent of pts failed HMT therapy as refractory or relapse. We performed Sanger sequencing on BM/peripheral blood DNA for known pathways involved in MDS pathogenesis including methylation (TET2, DNMT3A, IDH1/2), histone (ASXL1, UTX, EZH2), signaling (CBL, N/KRAS), transcription (RUNX1, TP53, JAK2), and RNA splicing (SF3B1, U2AF1, SRSF2). Data analysis was available for 90 pts. We detected a total of 131 mutations in different pathways. In total, spliceosome mutations were observed in 28/90 (31%) of pts. When we analyzed the presence of the mutations in relation to the rate of response, we found that pts who failed HMT have frequent spliceosome mutations: 17/58 (29%). We have reported that molecular mutations in TET2 and DNMT3A can predict response to treatment to HMT (Traina F, Blood (ASH Annual Meeting Abstracts), Nov 2011; 118: 461). Indeed, the frequency of mutations in methylation genes was lower in the group of pts who failed HMT (11/58; 18.9%) compared to pts who achieved hematological response (11/32; 34%). Spliceosome inhibitors have been proposed for targetted therapy in MDS. The presence of spliceosome mutations in pts who failed HMT can open a new era of investigation leading to the possibility of using spliceosome inhibitors in pts who fail conventional therapy. We performed RNA-sequencing analysis on BM cells of pts who failed HMT compared to pts who achieved hematological response (n=2 vs 2) in order to define any specific gene signature explaining the differences in response to HMT. We performed differential gene expression testing on 11,459 expressed genes. In total, 158 genes were differentially expressed at FDR < .2 in responders compared to not responders. We identified several interesting genes involved in tumorigenesis and epigenetic regulation such as YPEL3, and ST14, which were up-regulated in responders vs not responders (FC: 4 and 7.5; P<.00001). In sum, spliceosome mutations are frequent in pts who failed HMT and may affect downstream pathways most probably in the epigenetic network leading to differences in susceptibility to HMT and can open the possibility of treatment with spliceosome inhibitors. Disclosures:No relevant conflicts of interest to declare.

Bendamustine, Bortezomib and Dexamethasone (BBD) As First-Line Treatment Of Patients (Pts) With Multiple Myeloma Who Are Not Candidates For High Dose Chemotherapy

BackgroundDespite significant advances, multiple myeloma is an incurable plasma cell disorder with an eventual fatal outcome. In newly diagnosed MM, combinations of bortezomib, steroids and alkylating agents, such as melphalan and prednisone, have achieved response rates in excess of 70% and have been established as a standard of care in pts who are ineligible for high dose chemotherapy. Outcomes are more attenuated in pts > 75 yrs old. Bendamustine is a bi-functional alkylating agent with a purine-like benzimidazole ring effective as a single agent and in various combinations for the treatment of relapsed/refractory MM (Poenisch et al, 2007, Fenk et al, 2007). In this study, the combination of bendamustine, bortezomib and dexamethasone (BBD) was evaluated as a first-line therapy for pts with MM. Here we present the updated results of this ongoing trial. MethodsPts with newly diagnosed active MM who were not candidates for high-dose chemotherapy and met standard eligibility criteria with regards to renal, hepatic and hematologic function were enrolled. The original treatment schema consisted of: bendamustine 80 mg/m2 IV on days 1, 4; bortezomib 1.3 mg/m2 IV on days 1, 4, 8, 11; and dexamethasone 40 mg on days 1, 2, 3, 4 with cycles repeating every 28 days. Pts had the option to continue treatment up to 8 cycles or 2 cycles beyond confirmed CR. An interim analysis found this combination to be efficacious but relatively toxic. As a result, the treatment schema was amended to the following: bendamustine 80 mg/m2 IV on days 1, 2; bortezomib 1.3 mg/m2 IV on days 1, 8, 15; and dexamethasone 20 mg on days 1, 2, 8, 9, 15, 16 every 28 days for a total of 8 cycles or 2 cycles beyond documented CR, whichever occurred first. Pts achieving at least SD continued on to maintenance bortezomib 1.3 mg/m2 IV/SQ every 2 weeks for 2 years. Acyclovir or equivalent viral prophylaxis was originally recommended and became required on the modified schema. Responses were assessed using the IMWG criteria. The overall response rate (ORR) was defined as ≥ PR. Adverse Events (AEs) were assessed using the CTCAE Version 4.0. Overall survival (OS) and progression-free survival (PFS) were calculated using the Kaplan-Meier method. ResultsAs of 5/31/2013, 43 pts have been enrolled (18 on the original schema, 25 on the modified schema). The median age was 75 (45-89) and 39% of pts were > 75 (48% in the modified schema). Forty two percent of pts were ISS II and 32% were ISS III. Fifteen (35%) pts remain on treatment, all on the modified schema. Treatment-related Grade 3 hematologic AEs were seen in 30% of pts. Only 1 treatment-related Grade 4 hematologic AE of neutropenia was observed. Treatment-related Grade 3 non-hematologic AEs were seen in 21% of pts. The most common non-hematologic Grade 3 AE was neuropathy, seen in 12% of pts (all but 1 on the original schema). There was 1 treatment-related Grade 4 non-hematologic AE of atrial fibrillation and 1 treatment related death (congestive heart failure). Herpes Zoster was seen in 19% of the pts, all from the original treatment schema. A total of 40 pts were evaluable for response. The ORR was 83% (55% ≥VGPR, 28% PR) plus 17% SD and 0 PD. Of the 23 evaluable pts on the modified treatment schema, the ORR was 83% (52% ≥VGPR and 31% PR). For the 15 pts > 75, the ORR was 93% (60% ≥VGPR and 33% PR). At a median FU of 13.1 months, the 1-year PFS is 79% (0.53-0.92) and the 1-year OS is 83% (0.54-0.95). ConclusionThe combination of bendamustine, bortezomib and dexamethasone is feasible and efficacious in this elderly pt population with a large number of pts over the age of 75 years. The modified schema is better tolerated allowing pts to proceed to maintenance treatment which may eventually translate to improved results. Enrollment is ongoing. Disclosures:Off Label Use: Off-label use of Bendamustine in the Treatment of Multiple Myeloma. Chu:Teva: Research Funding; Millennium: Research Funding. Boccia:Teva: Research Funding; Millennium: Research Funding. Flinn:Teva: Research Funding; Millennium: Research Funding.

Evaluation Of Allogeneic Hematopoietic Cell Transplantation (HCT) Outcomes Of One Hundred Thirty-Two Patients With Myelodysplastic Syndrome (MDS) Or Chronic Myelomonocytic Leukemia (CMML) Up To Age Seventy-Five and The Effect Of Pre-Transplant 5-Azacitidine

HCT is the only known curative treatment for MDS. Treatment with the DNA methyltransferase inhibitor 5-azacitidine (aza) can slow leukemic progression and has been utilized prior to HCT for both tumor debulking and to provide stabilization of the disease during the pre-allograft period. To discern the impact of pretransplant aza treatment on HCT outcomes, we retrospectively analyzed 132 patients (pts) according to pretransplant aza exposure. Patients included those who had a diagnosis of MDS or CMML at any time point in the course of their disease who subsequently received a HCT from a HLA-compatible donor. Eligible patients proceeded to transplant if they had adverse disease features such as elevated IPSS risk, treatment related MDS, progression of disease or refractory disease.Consecutive patients referred for HCT between July 2004 and July 2009 were evaluated. Seventy percent of pts with an identified donor proceeded to HCT. All received a myeloablative HCT using fludarabine and IV-busulfan [targeted to a specific AUC of 3500, 5300, 6000 or 7500]. Graft versus host disease prophylaxis was with tacrolimus plus methotrexate or sirolimus or mycophenolate mofetil. Only those with mismatched donors received antithymocyte globulin.The median age of the 64 allograft pts not receiving preHCT aza (No AZA group) was 56.8 (24.8 –73.5) years (yrs). Thirty-seven (58%) pts were older than 55 yrs. At diagnosis, IPSS risk was Low (n=4), Int-1 (n=23), Int-2 (n=13), High (n=5), not evaluable (n=4) (NE), AML (n=16) and CMML (n=9). Seventeen had treatment related MDS (tMDS) and 18 had AML at one time. Donors included 24 sibling donors (MRD), 29 matched unrelated donors (MUD) and 11 mismatched unrelated donors (mMUD). Median follow-up is 66.2 months (29.7 – 105.7 months).Sixty-eight pts received a median of four (1-12) cycles of aza prior to HCT (YES AZA group). The median age was 57.3 (25.6 – 73.8) yrs. Thirty-nine pts (57%) were older than 55 yrs. At diagnosis, IPSS risk was Low (n=3), Int-1 (n=21), Int-2 (n=21), High (n=12), NE (n=2), AML (n=2) and CMML (n=7). Eighteen had tMDS and 10 had AML at one point. Donors included MRD (n=32), MUD (n=31) and mMUD (n=5). Median follow-up is 53.8 months (24.1 – 103.2 months).Prior to transplant the number of marrow blasts in the No-AZA vs Yes-AZA was: <5% (n=37 vs 36), 5-10% (n=12 vs 14), 11 – 20% (n=9 vs 9), >20% (n=2 vs 3) and CMML (n=4 vs 6). All patients engrafted with no difference in engraftment rates or toxicities between the two groups. Additionally, cumulative incidence of non-relapse mortality and relapse rates at 1 yr/ 3 yrs were similar [NRM: No AZA 20.5/ 37.4% vs Yes AZA 20.7/ 23.9 %; REL: 34.2/ 37.5% vs 26.4/ 32.4%]. At 3 years, the RFS and OS suggest improvement with pretransplant AZA but do not reach statistical significance [RFS: No AZA 26% vs Yes AZA 44.1%; p = 0.14; OS: 30.9% vs 51.4%; p=0.15].Utilization of pre-HCT 5-azaciticidine is a feasible strategy and doesn't appear to have any negative impact on HCT outcomes. Given the disease control facilitated by aza it should be offered to patients with high risk MDS coming to transplant. Disclosures:Field:Celgene: Research Funding. Alsina:Millennium: Membership on an entity's Board of Directors or advisory committees, Research Funding. Lancet:Celgene: Research Funding. List:Celgene: Research Funding. Komrokji:Celgene: Research Funding, Speakers Bureau.

Rituximab Combined With Three Cycles Of High Dose Dexamethasone Provides a Long Term Response Rate Similar To That Of Splenectomy In Patients With Immune Thrombocytopenia (ITP) Of Duration Less Than 2 Years

Rituximab Combined With Three Cycles Of High Dose Dexamethasone Provides a Long Term Response Rate Similar To That Of Splenectomy In Patients With Immune Thrombocytopenia (ITP) Of Duration Less Than 2 Years

Differences In Perceptions Of Disease and Treatment Effectiveness and Adherence Between Physicians and Patients With Myelodysplastic Syndromes (MDS)

Background and MethodsMDS are complex conditions, described with sometimes confusing terminology (e.g., “refractory anemia”), and contemporary drug therapies (tx) for MDS require repeated administration cycles to achieve clinical effect. Lack of disease understanding or premature tx discontinuation may result in poorer outcomes for patients (pts). To better understand physician (MD) and pt perceptions about MDS and tx decisions, we conducted two online surveys: one for pts with MDS and one for healthcare providers (HCP) registered with the non-profit Aplastic Anemia & MDS International Foundation. The protocol and consent were approved by a central Institutional Review Board. Pt and HCP surveys consisted of 57 and 49 questions, respectively, and assessed understanding of MDS, perceptions of specific tx, barriers to tx adherence, and overall tx experience. Data were analyzed using proportions, means, and medians; groups were compared using a Chi-squared test. ResultsOf 4,039 pts invited to participate via e-mail, 477 (12%) complete responses were received from 42 US States. Of responders, 247 (52%) were men; 63% were ≥age 60; pts were diagnosed with MDS a median of 5 years prior to the survey (range, 0-32 years). Of 4,594 HCPs invited to participate, 120 (3%) complete responses were received. Due to low participation among other HCP groups, only MD responses were examined. Of the 61 MDs (from 23 US states), 35 (57%) practice in an academic setting and 26 (43%) in the community setting. Survey responses from self-designated academic and community MDs did not differ significantly. Among MDs, 48% reported they see 5-19 new MDS pts per year. Only 10% of pts reported MDS was described to them as “cancer”, compared to how 59% of MDs stated they described it (p<.001). Only 29% of pts reported that MDS is “curable”, compared to 52% of MDs (p<.001). Forty-two percent of pts had received at least one disease-modifying tx: azacitidine (AZA, 58%), decitabine (DAC, 27%), lenalidomide (LEN, 35%) or hematopoetic stem cell transplant (HSCT, 26%) (total >100% due to multiple answers).MD and pt perceptions of active tx were significantly different, with MDs overestimating quality of life (QOL) benefits and underestimating the burden of tx on pt activities. [Table 1]MDs interpreted the benefit of active tx significantly higher than pts, however pts perceived the actual tx experience more positively than MDs. [Table 2]Most pts (81%) reported that MDs had the most influence on their tx decisions. Sixty-nine percent of MDs reported recommending stopping tx prior to the completion of tx regimen. Reported reasons diverged between pts and MDs, including burden of tx exceeding the benefit to the pt, as well as perceptions that the impact on the pt and family was too great. [Table 3]Table 1Active Tx – MD & Pt PerceptionsAZADACLENStatementsMDs n=55Pts n=115P-valueMDs n=23Pts n=54P-valueMDs n=40Pts n=69P-valueCan improve QOL89%63%P=.00185%65%NS80%56%P=.023Makes patients (me) feel better while taking it62%29%P<.00162%46%NS63%35%P=.009Has no side effects7%24%P=.0145%28%P=.0125%24%P=.019Makes regular activities difficult on tx days27%45%P=.03826%41%NS30%25%NSMade regular activities difficult for days following tx25%43%P=.04631%44%NS60%21%P<.001Table 2Tx for MDS – MD & Pt PerceptionsMD StatementsMDs N=61Pts n=200P-valuePt StatementsMy patients' lives are better because I prescribed tx95%79%P=.007My life is better because I received txMy patients are glad they have received tx93%82%P=.049I'm glad I had the txThe tx cured my patients' MDS44%25%P=.005The tx cured my MDSTx is uneventful16%34%P=.016Tx was uneventfulGetting tx is easy21%51%P<.001Getting tx was easyTable 3Barriers to Adherence – MD & Pt PerceptionsStatements (pt)MDs n=42Patients n=116p-valueBurden of tx outweighed benefit to pt (me)69%35%P<.001Burden of tx was too great on the family/caregiver50%23%P=.002Patient fatigue was too great to continue60%33%P=.004Tx made the patient (me) feel too sick to continue79%33%P<.001Tx side effects interfered with the pt's (my) regular activities74%35%P<.001 ConclusionPhysicians and pts with MDS have distinct views of the value of tx for MDS, with MDs underestimating the impact of tx on pt QOL while overestimating it as justification for stopping tx. Improved communication may improve understanding of disease and impact of active treatment and achieve better tx adeherence and responses. Disclosures:No relevant conflicts of interest to declare.

Comparison Of Epigenetic Versus Intensive Chemotherapy For Newly Diagnosed Acute Myeloid Leukemia Patients ≥60 Years Old: The Roswell Park Experience

Abstract Background Epigenetic therapy (Epi) with the hypomethylating agents, azacitidine (Aza) and decitabine (Dec), is increasingly being utilized for induction treatment of older AML patients (pts) based on studies demonstrating both tolerability and prolonged survival. By contrast, standard “7+3” intensive chemotherapy (IC) effectively induces remission in many individuals but is associated with significant toxicity and higher mortality. We compared our institute's experience with Epi vs. IC for the upfront treatment of newly diagnosed AML pts ≥60 years old. Methods We performed a retrospective chart review of 164 pts ≥ 60 yrs old with newly diagnosed AML who underwent initial therapy at our center between 3/2008-2/2013. Half (n=84; 51%) received IC with regimens containing cytarabine 100 mg/m2 IV for 7 days and daunorubicin 60 mg/m2 IV for 3 days. Half were treated with Epi (n=82; 49%) regimens containing either Dec (20 mg/m2 IV daily for 5 or 10 days) or Aza (75 mg/m2 sq daily for 7 days). Kaplan Meier method, log rank test, and univariate cox proportional hazard models were used to assess overall survival (OS) and correlation with covariates of interest. Results Baseline pt characteristics demonstrated a difference in the median age of pts in each group (IC 67 vs. Epi 75 yrs; p &lt;0.01). All other factors were comparable: ECOG status 0-2 (96% vs. 96%, p=1.0), WBC (12.0 x 109/dL vs. 4.5 x 109/dL; p=0.08), hemoglobin (9.2g/dL vs. 9.4g/dL; p=0.39), platelets (69 x 109/dL vs. 54 x109/dL; p=0.99), marrow blasts (53% vs. 45%; p=0.10), peripheral blasts (21% vs. 9%; p=0.14), poor-risk cytogenetics (56% vs. 66%; p=0.21). At our center, older AML pts receiving IC had superior complete response at any time point (CRatp)(43% vs. 21%; p&lt; 0.01) and higher overall response rates (ORR=CR+CRp) (50% vs. 28%; p&lt;0.01) versus Epi-treated pts. IC also resulted in a longer median OS as compared to Epi (10.6 vs. 7.9 mos; p=0.01). Thirty-day mortality and leukemia-free survival (LFS) were similar across the two groups (IC 10% vs. Epi 11%; p=0.8; 11.2 vs. 9.3 mos; p=0.47 respectively). Interestingly, in pts with AML characterized by poor-risk cytogenetics (n=77; 46%), the choice of induction (IC vs. Epi) did not impact outcome and yielded similar CRatp (39% vs. 27%; p= 0.4) and OS (10.3 vs. 7.8 months; p=0.4). Choice of Epi drug (Aza vs. Dec) did not impact results. Thirty-three percent of pts (n=55; IC 38% vs. Epi 28%) had refractory or relapsed disease (RR-AML) after induction, requiring ≥1 salvage treatment. We found that selection of either IC or Epi as prior treatment had no effect on CR or ORR in RR-AML pts receiving salvage. In multivariate Cox regression analysis, older age, higher ECOG score, increased peripheral blasts, and poor-risk cytogenetics were independently associated with inferior survival. By comparison, marrow blast percentage, hemoglobin, and choice of induction therapy did not impact OS (IC vs. Epi: HR 0.79; CI 0.508-1.237, p= 0.31). Conclusions Our results suggest that IC and Epi represent clinically equivalent approaches for the upfront treatment of older AML pts. In spite of significantly higher CR and ORR in the IC group, our finding of improved OS following IC vs. Epi was not substantiated in multivariate analysis, suggesting that this difference may be explained by the comparatively younger age of pts in the IC group. Leukemia-free survival and 30-day mortality were the same for IC vs. Epi-treated pts, as were all response and survival outcomes in the poor-risk cytogenetics subgroup. These data highlight the growing need for prospective clinical trials to conclusively determine the respective roles of IC vs. Epi therapy in older AML pts. Disclosures: No relevant conflicts of interest to declare.

Update On The Safety and Efficacy Of The Pan Class I PI3K Inhibitor SAR245408 (XL147) In Chronic Lymphocytic Leukemia and Non-Hodgkin's Lymphoma Patients

BackgroundConstitutive activation of phosphatidylinositol 3-kinase (PI3K)/ mammalian target of rapamycin (mTOR) pathway by various mechanisms has been implicated in the pathogenesis of chronic lymphocytic leukemia (CLL) and non-Hodgkin's lymphoma (NHL). There is mounting evidence suggesting that along with PI3Kγ, PI3Kα may be involved in CLL/NHL. SAR245408 is a potent and selective inhibitor of all α, γ and δ class I PI3K isoforms. It has been shown to inhibit PI3K signaling and impact tumor growth in preclinical tumor models. The impact of SAR245408 on safety, tolerability, pharmacokinetics, pharmacodynamics and anti-tumor effect was evaluated in patients with relapsed/refractory CLL and NHL from the Sanofi sponsored phase 1 single-agent study (NCT00486135) [Brown et al. ASH Annual Meeting Abstracts 2011. 118 (21): 2683]. MethodsSAR245408 was administered orally, once daily, with continuous dosing in monthly cycles. A total of 25 patients were enrolled at the maximum tolerated dose identified in solid tumor patients as part of the expansion cohort in relapsed/refractory lymphoproliferative malignancies. Plasma cytokines and chemokines were evaluated using the Myriad RBM Human Discovery MAP250+ panel (> 250 analytes) and ELISA assays. ResultsAmong the 25 patients (pts), 40% (n=10) had refractory CLL and 60% (n=15) had various relapsed/refractory lymphomas (R/RL), including follicular lymphoma (FL) (n=5), diffuse large B-cell lymphoma (DLBCL) (n=4), Waldenstrom's macroglobulinemia (WM) (n=3), Hodgkin lymphoma (n=2) and B-cell prolymphocytic leukemia (n=1). The median age was 65 years (range 28–83), and 56% were female. Eighty percent of pts had stage III-IV disease and 48% had bulky disease. Five pts were categorized as having refractory disease and the median number of prior regimens was 1 (range 1-7) for CLL pts and 3 (range 0-9) for R/RL pts. For all 25 patients, the median starting absolute lymphocyte count was 1.15 x 103/μL (range 0.3–37.2), the median starting hemoglobin was 11.4 g/dL (range 9.1–15) and the median platelet count was 162 x 103/μL (range 60–431). The median number of cycles administered in CLL pts was 10 (range 5-24) and 5 (range 1-26) in R/RL pts. Six CLL pts experienced an increase in absolute lymphocyte counts within 2-4 weeks of treatment, as has been seen with other PI3K inhibitors. According to modified International Workshop on Chronic Lymphocytic Leukemia (IWCLL) response criteria, 4 CLL pts had partial response (PR), 1 had nodal PR with increased lymphocytosis, and 5 had stable disease (SD); the progression free survival (PFS) in the responding pts was 22, 21.2, 15.6 and 15.4 months while in the SD pts was 12.5, 9.2, 7.4, 5.6, 4.6 and 3.6 months. According to the modified International Working Group response criteria, 3 PRs were reported in R/RL pts [1 WM, 1 DLBCL (transformed) and one FL with PFS of 23.7, 18.4 and PFS 4.8 months respectively]. One hundred percent of CLL and 80% of R/RL pts reported grade 3 or higher AEs, with the most common (≥ 10% of patients) including neutropenia, diarrhea, anemia and hypotension. SAR245408 induced a reduction in levels of chemokines involved in lymphocyte trafficking in CLL subjects (n=8), including CXCL13, CCL3, CCL22 and CCL19 (64, 58, 52 and 54% reduction, respectively, p<0.05) similar to what was reported with PI3K δ specific inhibitors. In addition, a reduction of tumor necrosis factor receptor 2 (TNFR2) and interleukin-2 receptor alpha (IL-2Rα) levels was observed (63% reduction each, p<0.01). ConclusionsThe recommended phase 2 dose of SAR245408 in solid tumor patients was confirmed as safe and tolerable in patients with CLL and R/RL. Single agent SAR245408 demonstrates clinical activity in patients with relapsed or refractory CLL and promising pharmacodynamic effects on chemokine levels involved in lymphocyte trafficking. Disclosures:Brown:Emergent: Consultancy; Onyx: Consultancy; Sanofi Aventis: Consultancy; Vertex: Consultancy; Novartis: Consultancy; Genzyme: Research Funding; Avila: Consultancy; Celgene: Consultancy, Research Funding; Genentech: Consultancy; Pharmacyclics: Consultancy. Off Label Use: The abstract shows scientific information on SAR245408 which is an investigational product developed by Sanofi. This investigational product is not approved by any health authority for any indication. Egile:Sanofi: Employment. Ruiz-Soto:Sanofi: Employment. Awan:Lymphoma Research Foundation: Research Funding; Spectrum Pharmaceuticals Inc.: Speakers Bureau.

Long-term Follow-up Study of Fecal Microbiota Transplantation (FMT) for Inflammatory Bowel Disease (IBD)

Purpose: The role of intestinal dysbiosis in the pathogenesis of IBD is being increasingly appreciated. FMT restores fecal microbiome diversity in patients (pts) with C. difficile infection (CDI), and has resulted in impressive cure rates. It is possible that FMT can have a similar therapeutic benefit in IBD. Methods: A long-term follow-up study of the efficacy of FMT for refractory IBD. Sixteen of 21 pts who had FMT at Montefiore Medical Center between 2010-2012 for the treatment of refractory IBD were successfully contacted and completed a questionnaire soliciting pre- and post-FMT data. Results: Fifty-six percent of pts were men (average age: 39 years [yrs]; range: 20-75 yrs). Follow-up period between FMT and data collection ranged from 4.5 to 30 months (mos) (avg: 14 mos). Pts had a diagnosis of IBD for an avg of 7.5 yrs (range: 1-33 yrs) before FMT. Fourteen (87%) had ulcerative colitis (UC), and two (13%) had Crohn's disease (CD). Initial FMT was by colonoscopy (n=15) or nasojejunal infusion (n=1), followed by self-administered fecal enemas (SAFE) in a tapered, and then maintenance, schedule. After FMT, 10 of 16 pts (63%) noted improved frequency of disease flares. Three of these 10 pts did not have a flare during the follow-up period (avg: 21 mos; range 8-30 mos), while seven pts had a reduction in the number of flares (pre FMT: 10.1 flares/yr; post-FMT: 2.8 flares/yr). No pt noted an increased number of flares after FMT. Nine pts (56%; 8 UC, 1 CD) reported decreased diarrhea (avg pre-FMT BMs/day: 8.2; avg post-FMT BMs/day: 3.6), while the remaining seven pts (44%) had no change. Of 14 pts who had rectal bleeding (13 UC, 1 CD), resolution, decrease, or no change in bleeding was reported in four (29%), six (43%), and three (21%) pts post-FMT, respectively; one pt (7%) noted increased bleeding post-FMT. Of 11 pts (69%) who reported abdominal pain, resolution, improvement, or no change was seen in five (46%), four (36%), and two (18%) pts post-FMT, respectively. Twelve pts (75%) reported weight loss prior to FMT, and weight was maintained (n=8, 67%) or increased (n=4, 33%) in all after FMT. Of the 10 pts (63%) who were on oral steroids at the time of FMT, steroids were no longer required or required at decreased doses in four (40%) and three (30%) pts, respectively. TNF-α inhibitors were discontinued in one of four pts after FMT. Concomitant CDI was present in four UC pts who had the most improvement after FMT, and all were able to discontinue maintenance medications (steroids, n=3 and 6-MP, n=1). The only adverse event experienced after FMT was a transient worsening of abdominal distension in three pts (19%). Conclusion: In this group of 16 pts with refractory IBD, FMT followed by SAFE resulted in improved symptoms and decreased medication requirements, especially in those with concomitant CDI.