Median Survival For Pts Research Articles

SU2C-SARC032: A randomized trial of neoadjuvant RT and surgery with or without pembrolizumab for soft tissue sarcoma.

11504 Background: Surgery & radiation therapy (RT) yield high local control rates for soft tissue sarcoma (STS) of the extremity and limb girdle. However, patients (pts) with high-grade stage III STS are at significant risk for developing metastasis. Median survival for pts with metastatic STS is < 2 years. SARC028 (NCT02301039) evaluated the efficacy of pembrolizumab (pembro) for metastatic STS, showing 20% and 8.7% response rates in undifferentiated pleomorphic sarcoma (UPS) and pleomorphic/dedifferentiated liposarcoma (LPS), respectively. We hypothesized that neoadjuvant pembro with concurrent RT followed by surgery and adjuvant pembro for stage III UPS, including myxofibrosarcoma, or LPS would stimulate an anti-tumor immune response to eliminate micrometastatic disease & improve disease-free survival (DFS). SU2C-SARC032 (NCT03092323) is a multi-institutional, international, randomized phase 2 trial evaluating the safety and efficacy of adding pembro to standard of care (SOC) RT & surgery for pts with stage III UPS or LPS. Methods: Pts aged > 12 yo with stage III (FNCLCC grade 2 or 3) UPS or LPS of the extremity and limb girdle were enrolled. Pts were randomized (1:1, stratified by grade) to neoadjuvant RT (50 Gy/25 fx) then surgery (SOC arm) or neoadjuvant pembro and RT then surgery & adjuvant pembro (EXP arm). Pembro was given 200 mg IV Q3 wk for 3 doses (before, during & after RT) & up to 14 adjuvant cycles. The primary endpoint was 2-yr DFS. Secondary endpoints included local recurrence-free survival (LRFS), distant disease-free survival (DDFS), & overall survival (OS). Target enrollment of 126 evaluable patients (max 144 total) provided 80% power (1-sided α = 0.05) to distinguish between a null hypothesis of 50% 2-yr DFS rate & alternative hypothesis of 75% 2-yr DFS rate by log-rank test, with initial analysis at 45 DFS events. Cox models were stratified by grade; primary analysis was a one-sided stratified log-rank test. Results: Between July 2017-November 2023, 143 patients were enrolled, predominantly with UPS (85%) & grade 3 (64%) histology. Median follow-up for alive patients is 24.1 mo. DFS in the EXP arm is significantly higher than the SOC arm (p = 0.023; HR 0.57, 90% CI: 0.35, 0.91). Estimated 2-yr DFS is 53% (90% CI: 43, 66%) for SOC vs 70% (90% CI: 61, 81%) for EXP arm. Currently, there is no statistically significant difference in LRFS (HR 0.55, 95% CI: 0.21, 1.42), DDFS (HR 0.57, 95% CI: 0.32, 1.01), or OS (HR 0.39, 95% CI: 0.14, 1.12). Pts with grade 3 sarcomas had improved DFS with pembro (HR 0.47, 95% CI: 0.25, 0.89), but no difference in DFS was observed in grade 2 tumors (HR 1.21, 95% CI: 0.35, 4.18). The proportion of patients with grade 3+ adverse events was significantly higher in EXP (52%) vs SOC arm (26%) (p = 0.002). Conclusions: Theaddition of neoadjuvant & adjuvant pembro to RT and surgery significantly improves DFS for pts with stage III UPS and LPS of the extremity and limb girdle. Clinical trial information: NCT03092323 .

Lacutamab in Patients with Advanced Sezary Syndrome: Results from an Interim Analysis of the Tellomak Phase 2 Trial

Introduction: Cutaneous T-cell lymphoma (CTCL) is a rare form of non-Hodgkin lymphoma. Sezary syndrome (SS) is a rare and aggressive type of CTCL. It has a unique biology, with high expression of KIR3DL2 reported in more than 85% of patients (pts). SS is characterized by erythroderma, significant blood involvement with malignant SS cells, and lymphadenopathy. These pts suffer from debilitating itching and recurrent skin infections, often affecting quality of life (QoL). SS is distinguished by its poor prognosis, as the median survival of pts is approximately 5 years. To date vorinostat, is the only drug that has been approved by the FDA for the treatment of pts with CTCL with cutaneous manifestations who have received 2 prior systemic therapies. Methods TELLOMAK is an international, open-label, phase 2 trial with multiple cohorts (NCT03902184). Cohort 1, for which preliminary data is reported here, is designed to evaluate safety and efficacy of single agent lacutamab in pts with relapsed/refractory SS after at least 2 prior systemic therapies including mogamulizumab. Pts should have blood stage B2 at screening based on central evaluation by flow cytometry. Pts with evidence of large cell transformation are excluded. lacutamab 750 mg is administered as an intravenous infusion weekly × 5 weeks (w), every 2 w × 10, then every 4 w until progression or unacceptable toxicity. Primary endpoint is Objective Response Rate (ORR) by global response score. Secondary endpoints include additional efficacy endpoints, safety, QoL and translational assessments. Results At the data cut-off of April 29, 2022, 38 pts were enrolled and 37 pts treated with a median follow-up of 10.9 months (m) (range: <1, 34 m). Median age was 69 years (range: 50, 86). At study entry, the median prior lines of systemic therapies was 6 (range: 2, 11), 94.6% (n=35) had stage IVA and 5.4% (n=2) had stage IVB. In the ITT population, Global Confirmed ORR was 21.6% (8/37; 95% CI 11.4, 37.2). Confirmed ORR in skin was 35.1% (13/37; 95% CI 21.8, 51.2). Confirmed ORR in blood was 37.8% (14/37; 95% CI 24.1, 53.9), with 21.6% (8/37) CR as best overall response. Furthermore, 1 of the 28 pts with lymph node involvement at baseline achieved a CR. Grade ≥ 3 Treatment-related (TR) Treatment-Emergent Adverse events (TEAEs) were observed in 6/37 (16.2%) pts, Serious TR TEAEs were observed in 2/37 (5.4%) and 4/37 (10.8%) pts discontinued study drug due to TEAE. Data from additional key endpoints will be presented. Conclusion In this highly refractory SS cohort from the TELLOMAK study, our preliminary data demonstrate that lacutamab shows clinical activity and favourable safety profile. Continued evaluation of this new targeted treatment option for patients with SS is warranted.

Clinical outcomes and healthcare resource utilization (HCRU) in patients (pts) with lower-risk myelodysplastic syndromes (LR-MDS) reinitiating erythropoiesis-stimulating agents (ESAs) following previous ESA treatment.

e19067 Background: The median survival for pts with LR-MDS is estimated to be 5–10 years. ESAs are utilized as first-line treatment for anemia in LR-MDS; however, real-world treatment patterns, clinical outcomes, and HCRU for pts with LR-MDS who reinitiated ESAs following previous discontinuation are not well-established. Methods: This was a retrospective study of pts with LR-MDS in a network of US community health systems who initiated ESAs as first-line therapy between January 1, 2016 and June 30, 2019 and were followed through June 30, 2021. Pts were required to have discontinued (had a ≥ 3-week gap between treatment with epoetin alfa, or a ≥ 6-week gap between treatment with darbepoetin alfa) and subsequently reinitiated ESA therapy at least once during follow-up. Outcomes included failure to achieve transfusion independence (TI), progression to acute myeloid leukemia (AML), overall survival (OS), number and type of health system visits, and medication use. TI was defined per IWG 2006 criteria in the subset of pts who had received ≥ 1 transfusion in the 8 weeks prior to ESA initiation. Results: There were 108 pts with confirmed LR-MDS who initiated ESA-based therapy. Pts had a median age of 79 years at diagnosis (interquartile range [IQR] 73–85), were predominantly male (58%), White (97%), and overweight or obese (52%). The median follow-up period was 17.0 months (IQR 7.2–34.7). The most used ESA was darbepoetin alfa (60%), followed by epoetin alfa (38%) and epoetin alfa-epbx (2%). Of the 33 pts who received a baseline transfusion, 52% did not achieve TI; 53% and 43% failed to achieve TI at 6 and 12 months, respectively. The majority of pts were repeatedly treated with ESAs (n = 61, 56%). Among these patients, 2% progressed to AML and 48% died during follow-up; median OS was 45 months. The median number of health system visits per patient-month was 3.2 (IQR 0.6–4.9); 89%, 62%, and 72% of pts had ≥ 1 outpatient, emergency department, or inpatient visit respectively, with median length of hospitalization of 12 days (IQR 4.8–27.8). Most pts (54%) received an antibiotic at least once during follow-up; overall, use of immunosuppressive therapy (2%) or iron chelation (3%) was rare. Conclusions: In this real-world study of community practice in the USA, reinitiation of ESA treatment after prior discontinuation in LR-MDS was prevalent. In these pts, poor clinical outcomes and frequent health system visits were observed. This study highlights the need to consider alternative treatment options for pts with LR-MDS.

Clinical Features and Treatment Outcomes of Large Granular Lymphocytic Leukemia Coexisting with Autoimmune Diseases

Introduction:Large granular lymphocytic leukemia (LGLL) is a rare, indolent malignancy arising from cytotoxic T cells (T-LGLL, ~85%) or NK cells [chronic NK-cell lymphoproliferative disorder (CLPD-NK), ~15%]. When treatment is needed, single-agent immunosuppressive therapeutics are usually used, including low-doses of methotrexate (MTX), cyclophosphamide (Cy), and cyclosporine A (CSA). The coexistence of LGLL with autoimmune diseases (ADs) especially rheumatoid arthritis (RA) and Felty Syndrome (FS) has been reported in some patients (pts), suggesting a role of initial strong antigenic stimuli from autoantigens in the pathogenesis of LGLL. However, it remains unclear whether AD-associated LGLLs have unique clinical features or treatment outcomes. We have recently published the largest retrospective study of 319 LGLL cases (Dong et al. 2021). Here we report the outcomes of the LGLL pts with coexisting ADs.Methods:All patients who presented to Moffitt Cancer Center from 2001 to 2020 with a diagnosis of coexistence of T-LGLL or CLPD-NK and AD were included. Diagnostic criteria, treatment and response evaluation were reported elsewhere (Dong et al. 2021). Comparison of response rates was performed using Fisher's exact test or Chi-square test when appropriate. Median survival was estimated using Kaplan-Meier method and compared with log-rank test. Multivariate analysis was not done due to limitation of sample size. All analyses were done using SAS 9.4.Results:The patient characteristics are listed in Table 1. Among the 83 pts, 77 (92.8%) had T-LGLL and 6 (7.2%) had CLPD-NK. The most common ADs were RA [38 (45.8%)], followed by FS 13 (15.7%), and inflammatory bowel disease, polymyalgia rheumatica and vasculitis [5 (6%) each]. 33 (39.8%) pts needed treatment for LGLL. Three of the 5 pts who underwent NGS testing were positive for STAT3 mutation.In our practice, we favor MTX as the frontline therapy for LGLL with coexisting ADs such as RA. The treatments and responses are presented in Table 2. Among the 29 pts who received MTX, 24 (82.8%) had response, including 6 (20.7%) complete response (CR). Among the 11 pts treated with Cy, 9 (81.8%) had response and 5 (45.5%) had CR. CSA was used in 6 pts and had response in 3 (50.0%) and CR in 2 (33.3%). The response rates were not different between MTX, Cy and CSA, neither were the CR rates, although the statistical testing was limited by sample size. Consistent with our previous findings in LGLL, the response to growth factor (GCSF) was low and only 1 of 4 pts responded. Compared to the 131 LGLL pts without co-existing AD in our series, AD-associated LGLL had higher response rates to MTX, Cy or CSA (61.9% vs 78.3%, respectively, p=0.04).Interestingly, pts with CLPD-NK were less likely to respond to CSA, MTX or Cy compared to pts with T-LGLL [1/5 (20%) vs 35/41 (85.4%), p=0.006]. The type of AD, age, splenomegaly, anemia, neutropenia, thrombocytopenia or STAT3 mutation were not associated with response.With a median follow-up of 5.2 (IQR 2.0-9.5) years, the median survival was 10.9 (95% CI 8.1-not estimable) years. Anemia and thrombocytopenia were associated with worse survival (figures 1 and 2). The median survival for pts with vs without anemia was 8.1 (95% CI 3.9-not estimable) years vs not estimable (95% CI 8.7-not estimable), p=0.01. The median survival for pts with vs without thrombocytopenia was 8.4 (95% CI 3.8-10.1) years vs 13.3 (95% CI 8.1-not estimable) years, p=0.05. The type of LGLL, blood LGL count, splenomegaly, or neutropenia were not associated with survival.Conclusions:The majority (~80 %) of LGLL pts with AD responded to MTX, Cy or CSA, although CR rate was low (20-45%). Interestingly, CLPD-NK pts were less likely to respond compared to T-LGLL which could be attributed to a small sample size and warrants an expanded case study. Anemia and thrombocytopenia were associated with worse survival. Future studies will be of interest to evaluate the hematological responses of LGLL in patients with coexisting ADs treated with FDA-approved biological agents for AD such as TNF inhibitors, IL-6 antagonists and T-Cell co-stimulation blocker. Such studies may provide insights into LGLL treatment as both diseases may share some common pathogenic pathways. [Display omitted] DisclosuresSokol: Kyowa-Kirin: Membership on an entity's Board of Directors or advisory committees; Dren Bio: Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure:Rituximab and alemtuzumab have not been approved by FDA for LGL leukemia.

The Outcome of Treatment-Free Remission after First-Line Nilotinib or Dasatinib in Chronic Phase Chronic Myeloid Leukemia Patients Is Different

The Outcome of Treatment-Free Remission after First-Line Nilotinib or Dasatinib in Chronic Phase Chronic Myeloid Leukemia Patients Is Different

Improvement in Survival for Elderly Pts with AML over the Years: A NCDB Analysis

Objective: There has been significant changes in management of acute myeloid leukemia (AML) over past few years with bunch of new medications approved for AML management. We did a retrospective study to investigate if the recent improvement in AML management options have led to improved survival in elderly AML pts. Subjects and Methods: Patients with AML from 2004-2014 between age from 60-90 years were included in the retrospective study. Chi-square analysis was used to assess the association between treatment and factors investigated. Kaplan-Meier method was used to assess overall survival. Log rank methods were used to determine factors significant for survival. Multivariable Cox regression analysis was used to determine the independent variables. Results: 37,617 patients from the National Cancer Database were eligible for this study. Twenty-seven, thirty-six and thirty-seven percentage of pts were in the age group more than/equal to eighty, between 70-79 years and 60-69 years, respectively. The median survival in months of pts between 60-69 years, 70-79 years and &amp;gt;= 80 years was 9.5, 3.8 and 1.4 respectively. The median survival of pts did improve the years with median survival of 3.3 m, 3.7 m and 5 m in pts who got diagnosed between 2004-2007, 2008-2010 and 2011-2014 respectively. On multivariate analysis, after adjusting for all variable including age, gender, race, treatment received and comorbidity index, the year of AML diagnosis was statistically significant predictor of overall survival. The pts who got diagnosed between 2011-2014 were 19 % less likely to die compared to those diagnosed between 2004-2007. Conclusion: Survival analysis on AML in the National Cancer Database showed that survival in elderly pts with AML has improved over the years with pts who were diagnosed between 2011-2014 were 19 % less likely to die compared to pts diagnosed between 2004-2007. Disclosures No relevant conflicts of interest to declare.

What happens at radiographic disease progression in patients with metastatic cancer receiving immune checkpoint inhibitors? A single institution analysis.

e15157 Background: Immune checkpoint inhibitors (ICIs) are widely adopted for multiple indications across various malignancies. Despite the surge in their use, what occurs at radiographic progression (rPOD) remains poorly characterized. Herein, we describe patients at our institution that experienced rPOD on ICIs. Methods: We retrospectively reviewed charts of patients (pts) with solid tumors that received at least 2 doses of ICI at our institution from 12/01/2010 to 04/25/2017. Patients’ demographic data, medical history, ICI course, and outcomes were recorded. Characteristics at rPOD included change in tumor size by metastatic site, symptoms, and hospital utilization. Additionally, we characterized outcomes of pts who continued ICIs after rPOD. Fisher’s exact test was performed to identify potential clinical predictors of hospitalization at rPOD. Results: Of the 361 evaluable pts, 238 experienced rPOD. In this cohort, the most common primary sites of disease are: genitourinary (24%), thoracic (24%), skin (21%), and hepatobiliary (15%). At rPOD, 71 (30%) patients were hospitalized within 30 days, with infection (27%) and pain (18%) being the most common reasons. Median survival of pts with hospitalization was 2 months (mos; 95% CI: 0-4), compared to 10 months (95% CI: 8-12) for those not hospitalized (p&lt;0.001). Forty-six (19%) pts continued ICI treatment after rPOD (median duration = 2.8 mos), with eleven (5%) pts continuing for at least 6 months (median duration = 8 mos). Conclusions: In our study of real-world cancer pts treated with ICI, a higher than expected proportion was hospitalized within 30 days after rPOD, and this population had a worse overall survival compared to those that were not. A subgroup of pt with rPOD did not experience clinical progression, and thus treatment was continued, although further benefit was limited to a small subset. Further studies are needed to better understand the underlying mechanism to identify those who benefits from treatment beyond rPOD. [Table: see text]

Mutational Patterns and Clonal Architecture of Therapy-Related Acute Myeloid Leukemia

Therapy-related acute myeloid leukemia (t-AML) is a complex disease entity. It results from molecular abnormalities induced by chemotherapy, radiation and immunosuppressive therapies. As a group of diseases, t-AML may represent cases that progressed from therapy-related myelodysplastic syndromes (t-MDS) and "de novo" t-AML. The classification t-AML also includes patients (pts) whose AML is a second primary cancer e.g., due to a genetic predisposition to develop multiple, distinct cancers (those cases would be indistinguishable from the non-therapy-related AML). Origins of the disease may also vary: t-AML may evolve from clonal hematopoiesis of indeterminate potential (CHIP) that preceded the first cancer, as a de novo disease or as a disease which progressed from "de novo" CHIP. Comprehensive genomic analyses involving clonal hierarchy may reveal genetic patterns pointing towards a potential molecular pathogenesis. We applied targeted gene sequencing to analyze a large cohort of pts with AML (n=2696) for the presence of somatic mutations: comparator subtypes include primary AML (pAML, n=2133) and secondary AML (evolving from an antecendent MDS; sAML, n=446) to be compared to t-AML (n=117). These pts have had a history of other primary malignancies for which they received cytotoxic treatments including chemotherapy and/or radiation. t-AML pts were younger than pts with other AML types (median age: 60 years for t-AML vs. 65 and 69 for pAML and sAML). t-AML pts were more likely to have leukopenia compared to pAML (23% vs. 21%, P=0.7) but significantly less likely than pts with sAML (23% vs. 38% P=0.002). Normal cytogenetics were significantly less present in t-AML when compared to pAML (39% vs. 62% P&amp;lt;0.0001), but sAML had similar prevalence as t-AML (both 39%). Focusing on abnormal cytogenetics, t-AML pts had a significantly higher percentage of -5/del(5q) compared to pAML (14% vs. 7% P=0.004) but slightly less than sAML (19%). Similarly, -7/del(7q) and complex karyotyping were significantly more prevalent in t-AML compared to pAML (19 vs. 8% P&amp;lt;.0001) and (25% vs. 11% P&amp;lt;.0001) but similar to sAML (-7/del(7q): 19% vs. 16%; complex karyotype: 25% vs. 25%). In sum, cytogenetic analyses indicated similarities between t-AML and sAML, with both carrying more complex genetic events compared to pAML. While abnormal karyotyping was often more frequent in t-AML, molecular mutations were less frequently noted in t-AML vs. pAML (except for TP53 mutations). Strong predictors of pAML phenotype (e.g., CEPBA, NPM1) were less represented in t-AML vs. pAML (CEBPA, 3% vs. 9% P=0.01; NPM1, 18% vs. 34% P=0.0002). A typical signature of genes (DNMT3A, ASXL1, TET2, TP53) representing a phenotype of CHIP has been associated with t-AML. We observed a lower percentage of mutations in ASXL1 (4% vs. 10% P=0.01), DNMT3A (20% vs. 30% P=0.02), and TET2 (10% vs. 17% P=0.04) in the t-AML population compared to pAML, likely due to the younger age of t-AML pts. TP53 mutations were the only CHIP mutations often enriched in t-AML when compared to pAML (16% vs. 8% P=0.001). On the other hand, when compared to sAML, t-AML had significantly more mutations affecting genes like DNMT3A (21% vs. 13% P= 0.03), FLT3 (30% vs. 9% P&amp;lt;0.0001), NPM1 (18% vs. 5% P&amp;lt;0.0001) and NRAS (16% vs. 9% P=0.04) but significantly fewer lesions in ASXL1 (4% vs. 22% P&amp;lt;0.0001), BCOR (2% vs. 7% P=0.02), RUNX1 (12% vs. 22% P=0.01) and SRSF2 (7% vs. 19% P=0.002). In general, mutation types were most commonly missense and predominantly transversions within t-AML pts. Clonal hierarchy analyses demonstrated that TP53 mutations were acquired before the acquisition of other molecular mutations, as they were often ancestral in t-AML compared to pAML (15% vs. 8% P=0.007). As a consequence, they were the only molecular events carrying a dismal prognosis, as they significantly impacted the median survival of pts with t-AML compared to pAML (6 mo. vs. 17 mo.; P=0.004). On the contrary, when compared to sAML, CBL (5% vs. 1% P=0.03), FLT3 (5% vs. 1% P=0.03) and NRAS (10% vs. 3% P=0.007) were significantly more represented as ancestral lesions in t-AML but did not impact survival outcomes. In sum, cytogenetic and molecular features of t-AML were more similar to those of sAML rather than pAML. TP53 was the most commonly mutated gene and carried a dismal prognosis, possibly representing a selective growth advantage after receiving chemotherapy and/or radiation therapies for primary cancers. Disclosures Nazha: Novartis: Speakers Bureau; Abbvie: Consultancy; Daiichi Sankyo: Consultancy; Incyte: Speakers Bureau; Jazz Pharmacutical: Research Funding; MEI: Other: Data monitoring Committee; Tolero, Karyopharma: Honoraria. Meggendorfer:MLL Munich Leukemia Laboratory: Employment. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Sekeres:Millenium: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Syros: Membership on an entity's Board of Directors or advisory committees. Maciejewski:Alexion: Consultancy; Novartis: Consultancy.

Efficacy of PD-1 inhibitors in patients with metastatic non-small cell lung cancer (NSCLC) with KRAS or EGFR T790M mutations.

e20513 Background: Immune checkpoint blockade(ICB) has revolutionized the treatment of progressive NSCLC with its durable benefit when compared to cytotoxic agents. In the era of personalized medicine, there is a need to identify effective predictive biomarkers to detect exceptional responders to ICB. Immune modulating interventions with cytotoxic or biologic agents can maximize clinical responses from ICB in poorly immunogenic tumors. KRAS mutations are a negative prognostic factor for survival and generally lack targeted therapies. The T790M mutation in EGFR is the most common cause of acquired resistance to first line TKIs. As a group, patients with EGFR mutations generally do not derive clinical benefit from ICB versus cytotoxic chemotherapy. Preclinical data suggests that mutations like T790 m are associated with higher immunogenicity leading to avid stimulation of antigen specific T-cells (Ofuzi et al, 2014) and better response to ICB (Yamada, 2013). However, the efficacy of ICB by specific molecular mutations remains poorly defined. Methods: We reviewed data for 83 pts with recurrent or progressive metastatic lung cancer treated with nivolumab from June 2015-Dec 2016. All pts were treated with ICB as a second or subsequent line of treatment. The patients were assessed for pathology, mutational status and overall survival. Mutational status was checked on either tissue biopsy or serum samples submitted for proteomic veristrat/genestrat (Biodesix Inc., Boulder, CO, USA) assay. Results: Of the 83 patients treated with nivolumab, 65 patients were found to have NSCLC. Eleven pts were found to have KRAS mutation which was further subdivided as: 6 pts with KRAS G12C, 4 with KRAS G12V, 1 with KRAS G12D. Two pts were found to have T790M mutation. 81%(9/11) pts with KRAS mutation died. Median survival in pts with KRAS G12C mutation was 10 weeks and KRAS G12V was 12 weeks (p = 0.17). Median survival was not reached for patients with T790M mutation. Conclusions: KRAS mutations tend to have a shorter overall survival with ICB as compared to patients with EGFR T790M mutations. Further studies are necessary to isolate poorly immunogenic subtypes of NSCLC and develop novel treatment approaches to optimize outcomes.

Causes of Discontinuation and Long-Term Outcomes of Patients with CLL after Discontinuing Ibrutinib

Introduction: Ibrutinib is approved for treatment of patients (pts) with treatment-naïve or relapsed CLL. We previously reported poor outcomes for pts discontinuing ibrutinib; however, long-term outcomes were not reported.Methods: We present the outcomes for 90 pts who discontinued ibrutinib from a total of 320 pts treated with ibrutinib-based regimens on clinical studies from 2010-15 at M.D. Anderson Cancer Center.Results: Ninety (28%) pts discontinued ibrutinib. Forty pts (44%) were alive at the time of last follow up; 50 (56%) have died. Among the 90 pts, 47 received ibrutinib monotherapy, 31 ibrutinib plus rituximab and 12 ibrutinib with bendamustine and rituximab; 80 pts were relapsed/refractory (r/r) and 10 were treatment-naive. The median time to discontinuation for the 90 pts was 15 months (range 1.2-54), 19 months (5-47) for the untreated and 14.5 months (1.2-54) for r/r pts. Overall, causes and median time for discontinuation were: disease transformation [n=9, 10%; 13.2 mo.]; progressive CLL [n=19, 21%; 22.3 mo], intolerance/toxicity [n=29, 32%;16 mo]; transition to commercial supply (n=5;26 mo.); miscellaneous [n=28, 31%; 10.4 mo] (9 stem cell transplantation, 8 other cancers, 2 sudden death, 6 sepsis and previous comorbidities, 3 unknown). Reasons for discontinuation after first-line ibrutinib were - disease transformation [n=2]; intolerance [n=6; 3 atrial fibrillation and arrhythmias, 2 bleeding and 1 pneumonia]; transition to commercial supply (n=1) and death due to unknown cause (n=1). In r/r pts, reasons for discontinuation were: disease transformation [n=7]; intolerance [n=24; 3 atrial fibrillation, 2 bleeding and 1 pneumonia]; progression [n=19], 27 miscellaneous reasons and 4 for commercial supply. Characteristics of pts who discontinued due to intolerance and progression/transformation are summarized in Table-1. Median time to discontinuation was 16 months (1.2-49 months) for intolerance and 19 months (2-54 months) for progression/transformation. Survival of pts according to the cause of discontinuation is shown in Figure-1A. Median survival of pts was: 33 months for intolerance,16 months in progressive disease and 2 months in disease transformation. Survival of pts according to prior treatment status is shown in Figure-1B. We then assessed response to subsequent therapies among the 19 pts who developed progressive CLL on ibrutinib. Eight of 19 pts (42%) responded to subsequent therapy:5/8 (62%) achieved PR on venetoclax-based therapies (3/5 also failed idelalisib prior to commencing venetoclax); 2/8 (25%), responded to ofatumumab monotherapy;1/10 patients treated with idelalisib or duvelisib-based therapy responded.Conclusions: Ibrutinib discontinuation is common. Subsequent survival correlates with reason for discontinuation; disease transformation has very poor outcome, while patients who develop progressive CLL have a median survival of 16 months. Development of effective salvage strategies for patients with progression/ transformation on ibrutinib therapy is of critical importance. Ideally, these strategies should be guided by the knowledge of the molecular mechanisms of resistance in each patient. Of note, response rates to venetoclax-based therapy were relatively favorable. Despite having superior outcomes to those patients who progress, those who develop treatment-limiting toxicity have a median survival of 33 months and development of guidelines for managing toxicity to allow continued therapy is of importance, as is developing successful salvage options for those unable to continue.# at baseline [Display omitted] [Display omitted] DisclosuresThompson:Pharmacyclics: Consultancy, Honoraria. Jain:Incyte: Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Celgene: Research Funding; Servier: Consultancy, Honoraria; Abbvie: Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding; BMS: Research Funding; Novimmune: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Genentech: Research Funding; Seattle Genetics: Research Funding; ADC Therapeutics: Consultancy, Honoraria, Research Funding; Infinity: Research Funding. Burger:Roche: Other: Travel, Accommodations, Expenses; Janssen: Consultancy, Other: Travel, Accommodations, Expenses; Gilead: Research Funding; Portola: Consultancy; Pharmacyclics, LLC, an AbbVie Company: Research Funding. O'Brien:Pharmacyclics, LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria. Wierda:Novartis: Research Funding; Acerta: Research Funding; Gilead: Research Funding; Genentech: Research Funding; Abbvie: Research Funding.

Characteristics and Outcomes of Older Patients with Secondary AML According to Treatment Approach

BACKGROUND: Advanced age, AML arising from an antecedent hematologic disorder (AHD), and therapy-related AML (t-AML) are well established risk factors associated with poor outcome in AML. This subgroup of AML has been associated with lower rates of complete remission (CR) and shorter disease-free survival compared with de novo AML in younger patients (pts), when using standard therapy. Developing newer strategies to improve outcomes in this subgroup of pts is therefore a critical unmet need. Establishing baseline metrics from which to evaluate newer approaches is important. We sought to review our own experience with pts treated with different therapies at our institution to establish this baseline.METHODS: We retrospectively reviewed pts aged 60-75 years with newly diagnosed AML treated at our institution from 1990-2015 with one or more of the following characteristics: history of prior MDS, CMML, MPN, or aplastic anemia, the diagnosis of t-AML, or AML with karyotypic abnormalities characteristic of MDS as defined by the WHO. The pts were grouped into 5 study cohorts based on their treatment regimen: 1) High-dose Ara-C based intensive chemotherapy (HiDAC), 2) Hypomethylating agents (HMA)/HMA combinations, 3) Low-dose Ara-C combinations (LDAC), 4) Liposomal Ara-C:Daunorubicin (CPX-351), and 5) Other investigational agents (INV). Pts’ karyotypes were divided into 4 categories: adverse karyotype (complex: defined by >2 chromosomal abnormalities, Del 5/5q, Del 7/7q, 11q, 3q abnormality); diploid karyotype, intermediate karyotype (karyotype other than adverse or diploid); and unknown/not available. Endpoints included complete response (CR) rate/CR with low platelets (CRp) and 8-week mortality rates. Both univariate and multivariate analyses were performed to examine the relationships between disease characteristics and outcomes (CR, Overall survival).RESULTS: We evaluated a total of 931 pts with newly diagnosed AML meeting these criteria of age and secondary AML (s-AML). The baseline characteristics of pts in each group are summarized in table 1. The median age was 68 (60-75) years. Most pt characteristics were well balanced across the 5 treatment groups. Karyotyping was performed in 89% of the pts: 57.5% belonged to adverse risk profile and 31% belonged to intermediate risk profile (excluding diploid). The overall CR/CRp rates for the entire group was 39.5%. CR/CRp rates were lower in the HMA (36%) and INV (16%) groups compared to HiDAC (46%), CPX (45%) and LDAC (43%). Eight week mortality rate for the entire group was 20%: HiDAC (23%), HMA (12%), CPX (10%), LDAC (19%), and INV (27%). The median OS for the entire group was 6 months and by each treatment regimen is shown in Figure 1. There was a significant difference in OS between the 5 treatment groups. Pts receiving less intensive regimens [HMA + LDAC] had a superior median OS compared to those receiving HiDAC-based regimens (6.9 vs. 5.4; P=0.002, Figure 2). There was no difference in median survival in pts treated with CPX compared with conventional lower-intensity approaches (HMA + LDAC) (p=0.75). In the multivariate analysis, age >70yrs, adverse karyotype, and prior treatment for AHD were associated with a decreased OS. Similarly, use of HMA/INV treatment, adverse/intermediate risk karyotype, history of prior treatment for AHD were associated with lower CR rates.CONCLUSIONS: The outcomes of older pts with newly diagnosed s-AML are poor and reflective of their advanced age and poor-risk karyotype. Various treatment approaches have been attempted to improve outcomes. Lower-intensity approaches such as HMA and LDAC-based regimens have response rates similar to HiDAC regimens, but are associated with lower early mortality and improved overall survival. While the investigational liposomal formulation CPX-351was associated with favorable CR rates and low early mortality, the median OS was similar to pts treated with low intensity therapy. The unsatisfactory outcomes using other investigational agents in the INV group underscores the need for more effective therapies for these patients. [Display omitted] [Display omitted] [Display omitted] DisclosuresKantarjian:BMS, Pfizer, Amgen, Novartis: Research Funding. Konopleva:Reata Pharmaceuticals: Equity Ownership; Abbvie: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Stemline: Consultancy, Research Funding; Eli Lilly: Research Funding; Cellectis: Research Funding; Calithera: Research Funding. DiNardo:Celgene: Research Funding; Abbvie: Research Funding; Novartis: Other: advisory board, Research Funding; Daiichi Sankyo: Other: advisory board, Research Funding; Agios: Other: advisory board, Research Funding. Jain:Celgene: Research Funding; Infinity: Research Funding; ADC Therapeutics: Consultancy, Honoraria, Research Funding; Novimmune: Consultancy, Honoraria; Incyte: Research Funding; Abbvie: Research Funding; Novartis: Consultancy, Honoraria; Servier: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria, Research Funding; Genentech: Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding; BMS: Research Funding; Seattle Genetics: Research Funding. Wierda:Acerta: Research Funding; Novartis: Research Funding; Gilead: Research Funding; Abbvie: Research Funding; Genentech: Research Funding. Cortes:ARIAD: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Teva: Research Funding.

Predictors of long-term survival with metastatic pancreatic cancer (mPC) in the gemcitabine era: The Fox Chase Cancer Center experience.

253 Background: Although median survival (OS) for patients (pts) with mPC was ~6 months (m) in the gem era, a subset of pts lived significantly longer as long term survivors (LTS). We compared the patterns of care and outcomes of pts living &lt; 12 m (Gp 1) and ≥ 12 m (Gp 2) to identify predictors for LTS. Methods: With IRB approval, we retrospectively analyzed medical charts of mPC pts treated at our center between 2000 and 2010. Gp 1 and Gp 2 were compared with respect to pt, tumor and treatment characteristics. Fisher’s exact and Mann-Whitney tests were used, respectively, to compare categorical and continuous variables, and the log-rank test to compare OS. All tests were two-sided and a Type I Error of 5% was used to determine statistical significance. Results: 579 mPC pts (median age 64 y, 56% males) were identified, 476 pts in Gp1 and 103 in Gp 2 (OS 4m vs 18 m, respectively). There was no significant difference in the age, site of pancreatic primary, comorbidities, tobacco use or stage at diagnosis between the two. 341 (72%) pts in Gp1 and 86 (83%) in Gp 2 had an initial PS &lt;2 (p 0.06). Alcohol use was more prevalent in LTS [170 (36%) in Gp1 vs 50 (49%) in Gp2 (OR 1.8, p 0.008)]. 170 (36%) pts in Gp 1 and 55 (52%) in Gp 2 had serum albumin (alb) &gt; 3.5 gm/dl (p&lt; 0.001) and this predicted survival (OS 4m if Alb &lt; 3.5 and 7m if Alb &gt; 3.5, p &lt;0.001). Use of chemotherapy in the metastatic setting (66% in Gp1 vs 93% in Gp 2) and number of agents used also predicted survival with 202 (42%) pts in Gp 1 and 79 (87%) in Gp 2 having received &gt; one agent in the metastatic setting (p &lt; 0.001). Liver metastases were more common as an initial site in Gp1 vs Gp2 [329 (70%) vs 48 (47%) respectively, p &lt; 0.001]. In contrast, lung metastases were more common in Gp 2 [42 (9%) Gp 1 vs 20 (19%) in Gp 2, p&lt; 0.001]. The median survival for pts with liver as initial metastatic site was worse than those with lung metastases (5m vs 7m, p &lt; 0.001). Conclusions: Use of chemotherapy and increasing number of agents are associated with better survival in mPC, in line with the current practice of using combination chemotherapy. The site of initial metastasis and serum albumin also predict for survival. Clinical trial designs should consider the latter as stratification factors.

Inotuzumab Ozogamicin in Combination with Low-Intensity Chemotherapy (mini-hyper-CVD) As Salvage Therapy for Adult Patients with Refractory/Relapse (R/R) Acute Lymphoblastic Leukemia (ALL)

Background: Outcome of pts with R/R ALL is poor. Addition of IO to effective low-intensity chemotherapy might improve outcome. CD22 expression occurs in >90% of pts with ALL. Inotuzumab ozogamicin (IO) is a CD22 monoclonal antibody bound to a toxin, calecheamicin, and has shown single-agent activity in relapsed/refractory ALL with a response rate of 58% and median survival of 6.3 months. The addition of targeted non-myelosuppressive therapy to effective low-intensity chemotherapy might further improve outcome.Methods: Pts ≥18 years with R/R ALL were eligible. The chemotherapy was lower intensity than conventional hyper-CVAD and referred to as mini-hyper-CVD (cyclophosphamide and dexamethasone at 50% dose reduction, no anthracycline, methotrexate at 75% dose reduction, cytarabine at 0.5 g/m2 x 4 doses). Rituximab and intrathecal chemotherapy were given for first 4 courses. IO was given on Day 3 of each of the first 4 courses. Pts received IO at 1.8 mg/m2 for cycle 1 followed by 1.3 mg/m2 for subsequent cycles.Results: Thirty-five pts (14 men, 21 women) have been treated so far. Pts characteristics and outcome are summarized in Table 1. Median age is 35 yrs (range 9-87). Median follow-up is 10 months (mos). The overall response rate was 71%: 18 (51%) CR, 6 (17%) CRp, and 1 (3%) marrow CR. Four (11%) pts were refractory and early death was reported in 6 (17%) pts. Grade 3-4 non-hematological toxicities included infections, mucositis, increased LFTs, and VOD (1 on study who had prior allogeneic stem cell transplantation, 3 were post transplantation following IO therapy). Four (11%) pts were switched early to maintenance therapy due to poor functional status (n=1), infectious complications (n=2), and prolonged myelosuppression (n=1). Twelve (34%) pts proceeded to receive allogeneic stem cell transplantation; of the rest, 6 (17%) relapsed within 3 mos (range, 1 to 7). At the last follow-up, 17 pts (49%) are alive, 18 (51%) died: 6 early death (3 hemorrhage, 2 sepsis, and 1 unknown cause); 8 were responders (5 died post relapse after subsequent salvage, 2 died post transplantation VOD in 1, and 1 died due to sepsis and multiple organ failure), 4 were refractory and died of disease progression. The 6-month PFS and OS rates were 79% and 58%, respectively. Median survival for pts with CR/CRp/marrow CR was 14 mos versus less than 1 mo in pts with refractory disease. Furthermore, median survival was not reached in pts with S1, 4 mos in pts with S2 and 5 mos in pts with S3+.Conclusions: The combination of IO with low-intensity mini-hyper-CVD chemotherapy is effective and shows encouraging results (71% ORR) in pts with R/R ALL. Pts with previous liver damage and transplant candidate should be considered carefully for this treatment to minimize the risk of VOD.Table 1Patient characteristics and outcomeParameterCategoryN (%)/Median [Range]Follow-up (mos)10 [1-14]Age (yrs)35 [9-87]Performance Status (ECOG)0-130 (86)Salvage StatusS119 (54)S1, primary refractory4 (12)S1, CRD1 <12 mos8 (23)S1, CRD1 ≥12 mos7 (20)S28 (23)≥ S38 (23)KaryotypeDiploid8 (23)T(4;11)5 (14)Miscellaneous16 (46)Insufficient metaphases6 (17)CD2296 [29-100]CD20≥ 20%5 (14)CR18 (35)CRp6 (17)Marrow CR1 (3)No response4 (11)ORR25 (71)Early death6 (17)6-months PFS %79Median (months)Not reached6-month OS %58Median (months)7 DisclosuresKadia:GSK: Research Funding; ARIA: Honoraria. Kantarjian:ARIAD: Research Funding; Pfizer: Research Funding; Amgen: Research Funding.

Outcome and Prognostic Factors of 17p Deleted Multiple Myeloma Patients

Introduction: During the last decade, the outcome of patients (pts) with symptomatic multiple myeloma (MM) has markedly improved. However, there is still a significant proportion of pts who do not achieve a longtime control of their disease. In particular, pts presenting with a deletion 17p (del17p) still have dismal prognosis. In order to better stratify this important group of MM pts we sought to investigate the prognostic impact of the following parameters in a larger cohort of del17p pts: del17p clone size, concomitant genetic abnormalities, treatment modalities and the incorporation of the novel agents lenalidomide and bortezomib.Methods: We identified 54 MM pts diagnosed between 1998 – 2012 who had a del17p at diagnosis and were treated at the University Hospital of Ulm. The patients were screened for additional chromosomal aberrations by fluorescence in situ hybridization (FISH) performed on purified bone marrow plasma cells.Results: The median age at MM diagnosis was 59 years and the proportion of male pts was 52%. At presentation the median del17p clone size was 83% (range: 28%-98%). In the vast majority of cases (83%) the presence of a del17p was associated with the presence of a del13q14. Other concomitant genetic abnormalities detected by FISH were t(4;14) in 17%, t(11;14) in 30% and gain at 1q21 (+1q21) in 31% of cases (figure 1). The median overall survival (OS) was poor (18.9 months) and did not change substantially over time (similar median survival in pts diagnosed before 2006 versus pts diagnosed thereafter). The del17p clone size had no impact on OS, neither the presence of a t(4;14) or a t(11;14). In patients with an additional +1q21 OS was significantly shorter (15.2 versus (v) 32.4 months; p=0,032). The incorporation of one of the novel agents into first-line treatment did not change the outcome significantly. In contrast, pts receiving at least one autologous transplantation showed a significantly longer OS (33.1 v 12.7 months; figure 2). On univariate analysis there was an improved median OS for pts undergoing an allogeneic transplantation (n=15; 32.4 v 14.4 months; p=0.025). In multivariate analysis ISS stage and the implementation of an autologous transplantation remained significant prognostic factors for OS.Conclusions: The outcome of MM pts with a del17p remains poor, even after the introduction of lenalidomide and bortezomib into clinical practice. The development of novel therapeutic strategies therefore is urgently warranted. [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Long Term Follow up of the AML97-Study for Patients with AML Older Than 60 Years: A Study of the East German Hematology and Oncology Study Group (OSHO)

The incidence of acute myeloid leukemia (AML) is age-dependent with the majority of patients (pts) being older than 60 years at diagnosis. Treatment of these pts needs to be well balanced between sufficient efficacy and tolerable toxicity. Here, we report long term follow-up of the OSHO AML97 study. Pts with AML older than 60 years were registered after informed consent and received age-adapted intensive chemotherapy treatment (curative arm; induction therapy with AraC 2 g/m2 iv day 1, 3, 5, 7 and mitoxantrone 10 mg/m2 iv day 1 to 3 to induce complete remission (CR), followed by 2 consolidation courses with AraC 240 mg/m2 iv day 1 to 5 and mitoxantrone 10 mg/m2 iv day 1 to 2), low dose chemotherapy (palliative arm; idarubicin 10 mg po day 1 and either thioguanine 40 mg po day 1-5, or AraC 80 mg sc day 1-5 or etoposide 100mg po day 1-5) or supportive therapy (best supportive care including transfusions). A total of 618 pts were enrolled (curative arm n=471, palliative treatment n=115 and supportive therapy n=32 pts). In the curative arm, CR was obtained in 66.8% of pts. Treatment related mortality (TRM) was 11.2% after induction and 4.5% after consolidation I, respectively. Median overall survival for all pts in the curative arm was 12 months, event free survival (EFS) at 12 years was 0.11±0.02%. In multivariate analysis, cytogenetics at diagnosis was the most important prognostic factor for CR (p=0.001). With a median follow up of 10 years (range 0.1 - 11.8) probability of overall survival (OS) at 5 years was 0.48±0.11; 0.13±0.03; 0.10±0.04 and 0.08±0.03 for pts with favorable, normal, other and unfavorable cytogenetics. Median survival for pts treated with palliative chemotherapy was 54 days.In conclusion treatment of older AML pts with an intense dose of AraC in the induction therapy is feasible and able to induce high rates of CR. Nevertheless, despite the high CR rate in this setting OS and EFS are still low. However, importantly, this does not apply for patients with favorable cytogenetics. This result also confirms the need for cytogenetic analysis to be performed in all pts older than 60 years potentially eligible for intensive induction therapy. The treatment results with palliative chemotherapy are disappointing. These results reported here need to be set in relation with the new therapeutic modalities for AML including epigenetic and molecular therapies. DisclosuresAl-Ali:Novartis: Consultancy, Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Wolf:Bayer: Honoraria; Geo Pharma: Honoraria.

Clinical Outcome of Advanced Non-Small Cell Lung Cancer Patients (Ansclc Pts) on Phase I Trials in the Drug Development Unit (Ddu) at the Royal Marsden Hospital (Rmh)

ABSTRACT Aim: Relapse to licensed antitumor therapies in ANSCLC is almost inevitable. Novel agents in phase I trials may benefit such pts. Methods: Retrospective study of ANSCLC pts allocated to phase I trials in the DDU at RMH (1/2005-12/2013). Results: 132 ANSCLC pts were allocated to ≥ 1 phase I clinical trials (152 total allocations). ANSCLC subtypes were adenocarcinoma 84 (63%), squamous cell 42 (32%) and other NSCLC 6 (5%). Mutation status was known in 34 (26%) ANSCLC pts, of which actionable KRAS and EGFR mutation were found in 11 (8%) and 2 (1.5%) pts, respectively. Median prior therapies 3 (range 1-6). 88 (67%) ANSCLC pts started ≥ 1 phase I trials (total 103); 34 pts (26%) did not start due to progressive disease (PD) and 10 (7%) for other reasons. Pts received targeted therapy (TT)-chemotherapy combos (n= 21 [24%]), HDAC-inhibitors (n = 14 [16%]), TT-TT combos (n = 12 [13%]), PI3K pathway inhibitors (n = 9 [10%]), novel chemotherapies (n= 8 [9%]), IGFR -1R inhibitors (n= 7 [8%]) and other TTs (n = 17 [20%]) such as PARP and angiogenesis inhibitors. Of 72 evaluable pts, there were 8 (11%) RECIST partial responses (PR) and 42 (58%) stable disease (SD) > 4 months (m). Most common toxicities were ≤ grade 2 rash and gastrointestinal (rash n = 23 [26%]; nausea-vomiting n = 29 [33%]; diarrhoea: n = 18 [20%]; mucositis n = 17 [19%]). Grade ≥ 3 toxicities were in 19 pts (21%), mainly diarrhoea (n = 6 [7%]), rash (n = 5 [6%] and drug reaction (n = 3 [3%]). Factors associated with pts who started trial versus (v) who did not due to progression were platinum sensitivity (p = 0.016), better RMH Prognostic Score (0-1 vs 2-3; p = 0.016), higher haemoglobin (p = 0.011) and albumin (p = 0.006). Median survival for pts who started trial v those who did not start because of PD was 241 days v 154 (p = 0.0045). Pts who started trial had a median time to progression of 131 days, 61% of these pts were alive at 6 ms v 36 % who did not start trial. Conclusions: Phase I trial therapies provided benefit in ANSCLC pts with PR comparable to standard therapies. These data suggest that with the emergence of promising novel agents, phase I trials should be considered earlier in ANSCLC treatment with mutational testing to guide therapy. Disclosure: All authors have declared no conflicts of interest.

Survival patterns following brain metastases for patients with melanoma in the targeted therapy era.

9064 Background: Survival from metastatic melanoma (MM) has been significantly prolonged with the introduction of molecularly targeted therapy, including BRAF inhibitors (BRAFi) for patients (pts) with the V600E mutation. Here, we present the first data describing patterns of survival after diagnosis of brain metastases (BM) in a large cohort of these pts with long follow-up. Methods: A retrospective review of 191 MM pts accrued on multiple prospective trials between 2008–2012 was conducted. These trials assessed novel immunologic and targeted therapies in pts with both BRAF mutant (n=70) and wild type/unknown (n=121) tumors. We evaluated pt characteristics and the impact of systemic and BM-directed treatments. Results: Of 98 pts who developed BM, median follow-up after first BM was 7.7 months (15.5 months for the 25 living pts), and 33 were treated with BRAFi. Median duration of BRAFi use was 5.9 months (range 0.7–27.1), which preceded BM in 30%, was concurrent with first BM in 18%, and followed first BM in 52%. Ipilimumab or anti–PD-1/PD-L1 immunotherapy was given to 58% of pts who received a BRAFi and 95% of those who did not. Limited intracranial disease on initial BM presentation (defined as ≤3 lesions) occurred in 70% of BRAFi-treated pts and 74% of non-BRAFi pts, and 70% of BRAFi pts received at least one focal BM treatment (stereotactic radiosurgery or resection) compared to 75% of non-BRAFi pts. As shown in the Table, actuarial survival after BM diagnosis was prolonged among pts treated with a BRAFi. This is due primarily to the nearly 2-year median survival of pts for whom a BRAFi was initiated after BM were diagnosed. Conclusions: Survival for pts with BM from BRAF mutant MM can significantly exceed the often anticipated 4–6 months, particularly if a BRAFi is initiated after BM arise. This supports BRAFi activity in intracranial disease, and helps to inform trials currently under way testing BRAFi use among MM pts with previously diagnosed BM. [Table: see text]

Should all patients (pts) with advanced biliary cancers receive first-line treatment with cisplatin and gemcitabine (GC)?

244 Background: GC is considered the standard of care for pts with advanced biliary tract cancer (BTC), providing median survival of nearly one year. (Valle J et al. NEJM 2010) Nevertheless, many pts experience poor outcomes, leading to a growing interest to identify pts who might benefit from such treatment. Here we aimed to investigate clinical and laboratory factors associated with poor survival among BTC pts treated with GC. Methods: We retrospectively evaluated all consecutive pts with advanced/metastatic BTC who received first line GC at the Instituto do Cancer do Estado de Sao Paulo, Brazil, in a 2 year-period. Clinical and laboratory variables that could influence pts’ outcomes were gathered from medical charts. Cox regression proportional hazard model was used to investigate the following prognostic factors for death: pre-treatment biliary deobstruction, baseline Ca 19.9, any GC interruptions or dose reductions, baseline ECOG status, Charlson Comorbidity Index (CCI) and age. P values &lt; 0.05 in multivariable analysis were considered significant. Results: From January/2009 to July/2011, 72 pts were identified. The median age was 60 years (range 30-80 years), 45 pts (62.5%) were female and 50 (69.4%) presented baseline ECOG 0-1. The median number of cycles of CG was 4 (range 1-9). Grade 3 /4 neutropenia and thrombocytopenia occurred in 16.6% and 12.5% of pts, respectively. Median survival of the whole cohort was 9.53 months (95% CI: 6.2 - 11.4). Median survival in pts with ECOG 0/1 was 13.5 months (95% CI: 9,5 – NR) and among pts with ECOG 2/3 3,5 months (95% CI: 1-7). In the Cox multivariable model, ECOG 2 /3 versus 0/1 (HR: 8.4, 95% CI: 3.4 to 20.7; p&lt;0.001) and CCI score ≥ 2 (HR: 9.5 95% CI: 1.6 to 55.3; p= 0.012) significantly predicted for poor survival. There was a trend for improved survival among pts who had biliary drainage before starting GC (HR: 2.3 95% CI: 1.0 - 5.3; p= 0.051). Conclusions: In this retrospective cohort of unselected pts with advanced BTC treated with first line GC, poor performance status and multiple comorbid illnesses were associated with dismal prognosis. Treatment with GC should be carefully discussed before being offered to these pts.

Combination of Sorafenib and 5-Azacytidine Has Significant Activity in Patients with Relapsed/Refractory or Untreated Acute Myeloid Leukemia and FLT3-ITD mutation

Abstract 1519▪▪This icon denotes a clinically relevant abstract Background:The outcome of patients (pts) with acute myeloid leukemia (AML) and FLT3-ITD mutation is poor, particularly in the relapse setting. Sorafenib is a potent inhibitor of FLT3 kinase with reported clinical activity as a single agent (Metzelder S, Blood, 2009), and in combination with chemotherapy (Ravandi F, JCO, 2010). A potential mechanism of resistance to FLT3 kinase inhibitors is high levels of FLT3 ligand (FL) as seen after myelosuppressive chemotherapy. We hypothesized that combining sorafenib with a less myelosuppressive agent, such as 5-azacytidine (AZA), may lead to higher and more durable responses than cytotoxic chemotherapy. Furthermore, both drugs have demonstrated a potential for inducing differentiation in AML cells, thereby providing further rationale for the combination. Methods:Pts were eligible if they had relapsed or refractory AML, were 18 years of age or older, and had adequate performance status (ECOG ≤ 2) and organ function. Older pts without prior therapy were also eligible, if they were deemed unsuitable to receive chemotherapy. Presence of FLT3-ITD was not a requirement but these pts were targeted for enrollment. Treatment regimen included AZA 75 mg/m2 daily for 7 days together with sorafenib 400 mg twice daily for 28 days; cycles were repeated in approximately 4 to 5-week intervals. Overall responses were assessed after the completion of at least one cycle of therapy and at the time of the best peripheral blood and bone marrow response. Plasma samples were collected on approximately Day 1 and Day 10 of each cycle. To assess the degree of FLT3 inhibition, the plasma inhibitory activity (PIA) assay was performed using the Molm-14 cell line (Levis M, Blood, 2006). Plasma FL concentrations were measured using an ELISA kit (R&D Systems). Results:43 pts with AML with a median age of 64 years (range, 24–87) were enrolled. They included 19 (44%) pts with diploid cytogenetics, 11 (26%) with chromosome 5/7 or complex cytogenetic abnormalities, and 13 (30%) with miscellaneous abnormalities. Prior to the initiation of treatment, FLT3-ITD was detected in 40/43 (93%) pts with a median allelic ratio of 0.28 (range, 0 – 0.93). They had received a median of 2 prior treatments (range, 0–7). 16 (37%) pts had received ≥3 prior regimens and 9 had failed therapy with FLT3 kinase inhibitors (5 with AC220, 1 with PKC412, and 6 with sorafenib, either as monotherapy or with chemotherapy or plerixafor); 3 had failed 2 prior FLT3 inhibitors. 6 pts were inevaluable as they discontinued therapy before response assessment at one month and 3 are too early for response assessment. The overall CR/CRi/PR rate among the 34 evaluable pts is 44%, including 10 (29%) with CRi and 4 (12%) with CR and 1 (3%) with PR (in this pt, bone marrow blast declined from 51% to 6% with normalization of blood counts). Overall, pts have received a median of 3 (range, 1–9) treatment cycles with the median number of cycles to response among the responders being 2 (range, 1 – 4) and the median time to achieving response, 2.1 months (range, 0.9 – 4.6 months). The median duration of CR/CRi Is 2.3 months (range, 1 – 12.2+ months). Six pts have proceeded to allogeneic stem cell transplant. The most common study drug-related adverse events were rash and fatigue with no deaths attributable to study medications. One pt developed grade 3 cardiomyopathy suspected to be related to the study regimen. Of the 34 pts included in the clinical analysis, there were 22 pts from whom plasma samples spanning at least one cycle of therapy were available. Among them, 64% achieved FLT3 inhibition to a targeted level of less than 15% of baseline during their first cycle of therapy. Median survival in pts who achieved this degree of inhibition was 238 days, while median survival in pts who did not reach this level was 154 days (p=0.13). Mean FL levels at cycle 1, day 1 and cycle 1, day 10 were 9 pg/mL and 17 pg/mL, respectively. Mean FL levels at cycle 2, day 0 and cycle 2, day 10 were 27 pg/mL and 54 pg/mL, respectively. Conclusions:Combination of AZA and Sorafenib is effective for the treatment of older pts and pts with relapsed and refractory AML and FLT3-ITD mutation. While not statistically significant, there was a trend toward improved survival in pts with adequate FLT3 inhibition during cycle 1. FL levels did not rise to the levels seen in pts receiving cytotoxic chemotherapy. Disclosures:Ravandi:Bayer/Onyx: Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Off Label Use: Off-label use of sorafenib and 5-azacytidine in patients with acute myeloid leukemia. Levis:Astellas Pharma: Consultancy; Plexxikon: Consultancy; Symphogen: Consultancy. Garcia-Manero:Celgene: Research Funding. Andreeff:Hoffmann-La Roche: Research Funding; Karyopharm Therapeutics: Unrestricted gift, Unrestricted gift Other. Cortes:Celgene: Research Funding.

Incidence and Outcomes of a Rare Translocation t(3,5) in Patients (pts) with Acute Myeloid Leukemia (AML) and Myelodysplastic Syndrome (MDS)

AbstractAbstract 1456 Background:Cytogenetic analysis of large pt cohorts allows us to evaluate the prognostic impact of rare and unique translocations. Little is known about the clinical outcomes of pts with t(3,5), which generally results in fusion of NPM and MLF1 in pts with MDS and AML. Methods:We retrospectively reviewed the charts of 8,215 pts with a diagnosis of MDS or AML evaluated at our institution from 1985–2011. Results:A total of 17 pts with a t(3,5) either at diagnosis or post-treatment were identified (10 pts, as the sole cytogenetic abnormality, and 7 pts, as part of other/complex karyotype). Among evaluable cases (15/17), frequently occurring breakpoints included q25;q34 (n=4), p21;q15 (n=2), and p21;q13 (n=2).10 pts had MDS with IPSS of Int-1(n=5) and Int-2(n=5), and 7 pts had AML. Four pts had therapy-related MDS (3 pts with prior lymphoma, 1 pt small cell lung cancer) and one pt with MDS had PNH. Median age was 56 years (range, 20–78) at diagnosis. Four pts (24%) had a FLT3-ITD mutation (3 with AML and 1 with MDS), 1 of these FLT3-mutated pts had additional mutations in c-KIT and NRAS mutation, 9 pts were tested and negative for molecular abnormalities, and 4 pts did not have molecular analysis available. Therapies were diverse, with two most common: cytarabine-based regimens (n=6) and hypomethylating agent-based therapy (n=6). Overall, median number of therapies for all pts was 1 (range, 0–5), including 2 pts treated with upfront stem cell transplant (SCT) and 1 pt treated with only growth factors/supportive care. Six pts (35%) (MDS 3 pts, AML 3 pts) underwent SCT during their course of therapy (including 1 cord blood, 1 SCT with NK cells, and 4 allogeneic MUD SCT). Overall median survival for pts with MDS was 8.1 months (range, 1–57) and for pts with AML, 21 months (range, 2–53). CR was achieved overall in 12 pts (71%) with median CR duration of 3.2 months (range, 1–60 months). Three (18%) pts were refractory to all chemotherapy and one pt died during induction chemotherapy (infection and diffuse alveolar hemorrhage). One pt never received treatment. Conclusions:Survival is particularly poor among patients with MDS and t(3;5) while those with AML have survival comparable to normal karyotype (NK) AML. Further investigation with novel treatment approaches is warranted in this subpopulation of MDS/AML pts. Disclosures:No relevant conflicts of interest to declare.