Non-durable Response Research Articles

Genicular Artery Embolization for Osteoarthritis Related Knee Pain: A Systematic Review and Qualitative Analysis of Clinical Outcomes.

Objective To systematically review the published literature on genicular artery embolization (GAE) for osteoarthritis (OA) related knee pain. Materials and Methods Using three databases, a systematic review was performed following Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. Outcome measures included the Visual Analog Scale (VAS) and the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC). Results Three single-arm studies were included from an initial search yielding 305 results. One hundred and eighty-sixknees in 133 patients with either mild-to-moderate (174/186, 94%) or severe (12/186, 6%) OA underwent embolization with either imipenem/cilastatin sodium (159/186, 85%) or embozene (27/186, 15%). Technical success was 100%. Average VAS improved from baseline at 1 day, 1 week, 1 month, 3 months, 4 months, 6 months, 1 year and 2 years (66.5 at baseline vs 33.5, 32.7, 33.8, 28.9, 29.0, 22.3, 14.8 and 14.0, respectively). Average WOMAC scores improved from baseline at 1, 3, 4, 6, 12 and 24 months (45.7 at baseline vs 24.0, 31.0, 14.8, 14.6, 8.2 and 6.2). Severe OA in 12 cases showed initially improved VAS, but was not sustained. Minor adverse events such as erythema in the region of embolization (21/186, 11%), puncture-site hematoma (18/186, 10%), paresthesia (2/186, 1%) and fever (1/186, 0.5%) were reported. Conclusion Limited single-arm studies report GAE is promising for treating OA-related pain. Most treatments performed for mild-to-moderate OA demonstrated durable clinical responses from 6months to 4years. Limited data for severe OA suggest a non-durable response. Future studies should be standardized to facilitate comparison and control for placebo effect.

A Critical Review of Second-Generation Anti-EGFR Monoclonal Antibodies in Metastatic Colorectal Cancer.

Anti-EGFR monoclonal antibodies (mAbs) have become a relevant solution for the treatment of patients with metastatic colorectal cancer. Current anti-EGFR monoclonal antibodies face a series of problems, including resistance and non-durable response, and RAS and BRAF mutations serve as exclusion criteria for treatment with anti-EGFR mAbs. Advances in molecular tumor profiling and information on subsequent pathways responsible for disease progression and drug resistance helped develop a new generation of anti-EGFR mAbs. These second-generation mAbs have been developed to overcome existing resistance mechanisms and to limit common side effects. For the moment, existing literature suggests that these novel anti-EGFR mAbs are far from finding their way to clinical practice soon. In this review, we summarize and evaluate current data regarding ongoing research and completed clinical trials for different second-generation anti-EGFR monoclonal antibodies. Anti-EGFR mAbs exhibit efficacy in advanced colorectal cancer, but second-generation mAbs failed to prove their benefit in the treatment of metastatic colorectal cancer. Understanding the biological basis of primary and acquired drug resistance could allow scientists to design better clinical trials and develop improved second-generation mAbs.

Abstract A46: CD73 inhibition enhances the effect of anti-PD-1 therapy on KRAS-mutated pancreatic cancer model

Abstract Background: CD73 catalyzes the extracellular generation of adenosine (ADO) from adenosine monophosphate (AMP). High levels of ADO, found in the tumor microenvironment (TME), have been shown to suppress immune responses and curtail T-cell activation in the presence of anti-PD-1/PD-L1 blocking antibodies. Oncogenic drivers resulting from activating mutations, such as KRAS, BRAF, and EGFR mutations, are commonly treated with tyrosine kinase inhibitors that result in robust but nondurable responses. We show here that KRAS mutations, of which 60% were derived from pancreatic adenocarcinoma (PDAC) samples, significantly upregulated CD73 expression and resulted in worsening prognosis. In a murine model of pancreatic cancer bearing KRASG12C mutation, coadministration of CD73 inhibitor with anti-PD-1 in established tumors resulted in significant tumor growth retardation, comparable to KRAS inhibitor alone. These data support the rationale for the clinical development of CD73 inhibitors in pancreatic cancer. Methods: Linear models were used to evaluate the ability of 299 pan-cancer consensus oncogenic drivers to predict CD73 expression independent of tumor type in the TCGA dataset. Immunohistochemistry (IHC) on formalin-fixed, paraffin-embedded (FFPE) samples was performed using CD73 (Cell Signaling, D7F9A) primary antibody and detected using anti-rabbit HRP. CD73 expressing cells were detected by DAB chromogen and quantified using QuPath Software. CD73 activity in fresh frozen tissues were detected using the Wachstein-Meisel method. C57BL/6J mice bearing established KP4662-G12C tumors (>150 mm3) were treated with A0001421 (CD73i), 30 mg/kg; once a day; s.c. and anti-PD1 (Clone RMP 1-14): 10 mg/kg; twice a week; i.p. Mice were treated for two weeks starting from day 10 post-tumor. Treatment efficacy was monitored using micro-computed tomography (Genisys PET/CT G8 (Sofie Biosciences). All small-molecule inhibitors were synthesized by Arcus Biosciences, Inc. Results: Out of the 299 oncogenes, alterations in KRAS, BRAF, and EGFR were the top 3 oncogenes upregulating CD73 expression. Increase in CD73 expression in KRAS-mutated tumors was further confirmed by IHC. Data extrapolated from Koyama et al. suggest that PD-1 nonresponsive mice express higher levels of adenosine pathway genes, including CD73 and CD39. Coadministration of CD73 inhibitor with anti-PD-1 was superior to anti-PD-1 alone in limiting tumor growth of an aggressive model of pancreatic cancer. Global changes in immune contexture and TME were also observed, consistent with the immune modulatory effects of inhibiting CD73 activity. Conclusion: CD73 is a highly efficient ecto-enzyme that catalyzes the hydrolysis of AMP to immune-suppressive ADO and is associated with worsening prognosis across multiple malignancies. AB680, a potent and selective CD73 inhibitor with excellent safely and pharmacokinetic profile, is currently undergoing clinical evaluation in 1L metastatic PDAC in combination with AB122 and chemotherapy. Citation Format: Thuc M. Le, Akshata Udyavar, Woosuk Kim, Arthur E. Cho, Luyi Li, Daniel DiRenzo, Brandon Rosen, Matthew J. Walters, Joanne B.L. Tan, Caius G. Radu. CD73 inhibition enhances the effect of anti-PD-1 therapy on KRAS-mutated pancreatic cancer model [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2019 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(3 Suppl):Abstract nr A46.

IA33 Mechanisms of Small-Cell Lineage Transformation in Resistance to Targeted Therapies

EGFR tyrosine kinase inhibitors (TKIs) are highly effective for tumors with EGFR mutations. However, resistance to these compounds remains a major issue, with the most frequent mechanism including the acquisition of a secondary mutation in EGFR (T790M) (1), followed by amplification of the hepatocyte growth factor receptor (MET) gene (2) and mutations in BRAF and PIK3CA genes (3,4). Epithelial–mesenchymal transition (EMT) and lineage transformation are less frequent but also prevalent, with up to 15% of cases with acquired resistance to first- and second-generation EGFR TKIs demonstrating histologic change from lung adenocarcinoma (LUAD) to small-cell lung cancer (SCLC) (4). Histologic plasticity as a mechanism of resistance is becoming increasingly prominent as other resistant mechanisms can now be successfully targeted (5). Currently, as with de novo SCLC, conventional platinum doublet chemotherapy is the standard of care for patients with treatment-induced SCLC. Unfortunately, this treatment often produces an incomplete and nondurable response followed by inevitable relapse within months, leading to poor patient outcomes (6). Thus, this mechanism of resistance will represent a major barrier towards the success of third-generation TKIs, and new strategies to prevent this lineage shift or to treat SCLC transformed tumors are urgently needed. Despite the increasing clinical importance, the biologic pathways regulating LUAD to SCLC transformation are poorly understood. Assessment of clinical samples has revealed that EGFR-mutant tumors universally lose EGFR protein expression upon SCLC transformation, despite still harboring EGFR mutation (7). Furthermore, the mutation spectrum of these transformed cases includes inactivation of the tumor suppressors RB and p53 in nearly all cases, mirroring de novo SCLC (7). However, accumulating experimental evidence has demonstrated that while necessary, dual inactivation of RB and p53 is not sufficient to cause SCLC lineage transformation in EGFR-mutated LUAD, suggesting that additional factors are required (7). MYC amplification and PIK3CA mutation have been proposed to potentially cooperate with RB/p53 loss to facilitate transformation (8), and specific epigenetic regulators may also provide the appropriate context for lineage reprogramming to occur. Despite this, no in vitro or in vivo models of SCLC transformation in EGFR TKI resistance have been developed, making it difficult to comprehensively explore the molecular events driving this lineage shift. Interestingly, there are clear differences between LUAD and SCLC regarding EGFR expression and gene alterations in MAPK pathway including EGFR/KRAS mutations: EGFR is usually not expressed (9) and EGFR/KRAS mutations are extremely rare in SCLC (10); in contrast, EGFR/KRAS play crucial roles in LUAD biology, including regulating differentiation in addition to proliferation (11). To date, however, no clear explanation has been given for these differences. We have recently shown that activation of MAPK signaling in SCLC leads to suppression of the neuroendocrine phenotype—including downregulation of the transcription factors NEUROD1, INSM1, BRN2, and ASCL1—and transformation to an NSCLC-like state (12). Using this model system, we have begun to elucidate the key transcription factors and epigenetic changes that drive SCLC to NSCLC transformation in the hope that the same processes will also be involved in the clinically relevant scenario: SCLC transformation from EGFR mutant LUAD during TKI resistance. We suggest that only EGFR-mutant LUADs that do not reactivate MAPK signaling through secondary EGFR mutations or alterations in parallel kinase pathways (i.e., MET) during development of TKI resistance will be able to undergo SCLC lineage transformation, and that RB/p53 loss and epigenetic plasticity provide the permissive context in which this transformation can occur. Greater understanding of lineage transformation in LUAD will provide important insights in terms of managing outcomes of patients undergoing targeted therapy and offer new avenues towards treatment of TKI resistant tumors.

Abstract 2535: Enhanced gene expression of replication fork and other E2F targets genes is associated with sensitivity and, paradoxically, also with acquired drug resistance, to the Chk1 inhibitor prexasertib

Abstract Many cancers are under replicative stress (RS) arising from the combined influence of oncogenic drivers (i.e. Cyclin E, E2F, Myc), genomic instability and/or deficiencies in DNA Damage Repair (DDR). Tumors survive RS by upregulating checkpoints such as those driven by the ATR/CHK1 pathway. Dependence of tumors under high RS on the Chk1 pathway is currently being explored in the clinic with the Chk1 kinase inhibitor prexasertib. Preclinical and clinical studies have demonstrated evidence of efficacy in various cancers supporting the notion that this drug has the potential to improve the standard of care for patients with these malignancies. Two pivotal steps to ultimately fulfill the promise of a novel therapeutic in the clinic are, 1) to enable a patient selection strategy via predictive biomarkers of drug response or de novo resistance; 2) to gain insight into mechanisms underlying the development of acquired resistance, a common phenomenon of cancer therapeutics that contributes to non-durable response. Two experimental objectives to address these challenges for prexasertib were set, 1) to profile a large pan-cancer tumor cell line panel for prexasertib response and explore the association between drug response and baseline molecular profile via transcriptomic profiling, (2) to establish an in vitro tumor line with acquired resistance to prexasertib and characterize it via transcriptomic and targeted proteomic profiling to probe the mechanism of acquired resistance to prexasertib. Key observations from this study: A) pathways corresponding to E2F targets, G2M checkpoint and the Spindle Assembly Checkpoint (SAC), with a distinct enrichment for replication fork genes emerged across three different studies, (a) across a pan-cancer tumor line panel associated with prexasertib sensitivity, (b) associated with resistance in a tumor cell line with acquired resistance to prexasertib and (c) as top hits in an unbiased functional shRNA screen aimed at identifying genes that upon knockdown sensitize the resistant tumor cell line to prexasertib. B)knockdown of specific replication fork components in the drug-resistant tumor line was associated with marked sensitization to prexasertib and concomitant evidence of RS and DNA damage.To explain these paradoxical observations, we postulate that tumors may upregulate the expression of E2F target/G2M/SAC genes to resist oncogene-induced RS and that they may rely on similar genes to survive prexasertib-induced RS. Based on this data, transcriptomic profiling may prove of utility in the identification of patient tailoring biomarkers for prexasertib and as tool to unravel mechanisms of acquired resistance. Citation Format: Wayne D. Blosser, Jack A. Dempsey, Ann M. McNulty, Wenjuan Wu, Philip J. Ebert, Jason C. Ting, Yue W. Webster, Trent R. Stewart, Xueqian Gong, Farhana F. Merzoug, Sean Buchanan, Ricardo Martinez. Enhanced gene expression of replication fork and other E2F targets genes is associated with sensitivity and, paradoxically, also with acquired drug resistance, to the Chk1 inhibitor prexasertib [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2535.

Oral melphalan for the treatment of relapsed canine lymphoma.

Oral melphalan has been included in multi-agent rescue protocols for canine lymphoma but its activity as a single-agent for this purpose has not been established. Inexpensive cost, ease of administration and tolerability make oral melphalan an attractive candidate for single-agent rescue therapy of canine lymphoma. Retrospective evaluation of 19 cases of relapsed canine lymphoma treated with oral melphalan was performed. Melphalan was primarily administered (n = 16) via a high dose protocol (HDM) with a median dosage of 19.4 mg m-2 . Fifteen dogs (78.9%) were treated concurrently with corticosteroids. Response evaluation was possible for all dogs with a calculated overall clinical benefit (partial response [PR] + stable disease [SD]) of 31.6% (PR 3/19; SD 3/19). Times to progression following melphalan (TTP-M) were 14, 24 and 34 days for responders and 20, 28 and 103 days for dogs experiencing SD. Twelve of 17 dogs evaluable for toxicity experienced an adverse event (AE) with only 3 dogs experiencing a grade III or higher AE. Haematologic toxicity was common (11/17) while gastrointestinal toxicity was rare (1/17). Although treatment resulted in limited clinical benefit and non-durable responses, oral melphalan was well-tolerated and may be a reasonable rescue option in cases where minimal effective agents remain.

Abstract 3812: JAK2 and PTPN11 mutations as potential biomarkers for BCL-xL inhibition as monotherapy and in combination therapy for acute myeloid leukemia

Abstract Acute Myeloid Leukemia (AML) is a heterogeneous disease where many distinct functional mutations have been identified. While mutations in FLT3, NRAS, NPM1, and IDH genes have been well characterized in de novo AML, a subset of AML associated with leukemic transformation of chronic myeloproliferative neoplasms (MPNs) are enriched in mutated JAK2 and PTPN11. MPNs are a set of disorders characterized by the chronic and abnormal overproduction of blood cells which can ultimately progress to AML. Targeted therapy against mutated JAK2 and PTPN11 with small molecule inhibitors against the JAK-STAT and RAS-ERK pathways, respectively, are being actively investigated in AML. However, acquired resistance and non-durable responses are already being demonstrated in monotherapy treatment. Thus, AML that has arisen from leukemic transformation of MPNs remains an area of unmet medical need. This need is underscored by the fact that these patients suffer from poor outcomes and low response rates to standard chemotherapy. Together, these results indicate the need for rational combinations in this population. In this study, we sought to better define the dependencies of AML cells on BCL-2 family members by screening AML cell lines with selective small molecule inhibitors to the BCL-2 family members. The screen revealed that the majority of AML cell lines depend on BCL-2, or BCL-2 together with MCL1 for survival. Intriguingly, a subset of AML cell lines is exquisitely sensitive to BCL-xL inhibition. Treating these cell lines with BCL-xL-selective inhibitor or with navitoclax, a dual BCL2/BCL-xL inhibitor induces apoptosis. These BCL-xL inhibitor-sensitive cell lines express high levels of BCL-xL, but not BCL-2 and MCL1. Genomic analysis of BCL-xL inhibitor-sensitive AML cell lines revealed that this subset is also enriched in JAK2V16F and PTPN11 mutations. We further demonstrate positive combination effect between BCL-xL inhibitor or navitoclax with JAK inhibitor (ruxolitinb) and two MEK inhibitors (trametinib and AZD6244) in cell lines with JAK2V16F and PTPN11 mutations, respectively. Together, these results demonstrate the potential utility of a BCL-xL inhibition as a combination partner in JAK2 and PTPN11 mutated cancers. Importantly, JAK2 and PTPN11 mutations in addition to expression of BCL-xL, BCL-2, and MCL1 could also be further tested as potential biomarkers for the utility of BCL-xL inhibition based treatments for patients with these mutations. Citation Format: Richard J. Bellin, Valerie Hilgenberg, Relja Popovic, Tamar Uziel, Lloyd T. Lam. JAK2 and PTPN11 mutations as potential biomarkers for BCL-xL inhibition as monotherapy and in combination therapy for acute myeloid leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3812. doi:10.1158/1538-7445.AM2017-3812

Clinical validation of chemotherapy predictors developed on global microRNA expression in the NCI60 cell line panel tested in ovarian cancer.

ObjectiveOvarian cancer is the leading cause of death among gynecologic malignancies. This is partly due to a non-durable response to chemotherapy. Prediction of resistance to chemotherapy could be a key role in more personalized treatment. In the current study we aimed to examine if microRNA based predictors could predict resistance to chemotherapy in ovarian cancer, and to investigate if the predictors could be prognostic factors for progression free and overall survival.MethodsPredictors of chemotherapy-resistance were developed based on correlation between miRNA expression and differences in measured growth inhibition in a variety of human cancer cell lines in the presence of Carboplatin, Paclitaxel and Docetaxel. These predictors were then, retrospectively, blindly validated in a cohort of 170 epithelial ovarian cancer patients treated with Carboplatin and Paclitaxel or Docetaxel as first line treatment.ResultsIn a multivariate cox proportional analysis the predictors of chemotherapy-resistance were not able to predict time to progression after end of chemotherapy (hazard ratio: 0.64, 95% CI: 0.36–1.12, P = 0.117). However, in a multivariate logistic analysis, where time to progression was considered as either more or less than 6 months, the predictors match clinical observed chemotherapy-resistance (odds ratio: 0.19, 95% CI: 0.05–0.73, P = 0.015). Neither univariate nor multivariate, time-dependent, cox analysis for progression free survival (PFS) or overall survival (OS) in all 170 patients showed to match predicted resistance to chemotherapy (PFS: hazard ratio: 0.69, 95% CI: 0.40–1.19, P = 0.183, OS: hazard ratio: 0.76, 95% CI: 0.42–1.40, P = 0.386).ConclusionIn the current study, microRNA based predictors of chemotherapy-resistance did not demonstrate any convincing correlation to clinical observed chemotherapy-resistance, progression free survival, or overall survival, in patients with epithelial ovarian cancer. However the predictors did reflect relapse more or less than 6 months.

Donor Lymphocyte Infusions Used to Treat Mixed Chimerism in Relapsed and Non-Relapsed Patient Populations after Allogeneic Transplant for Hematologic Malignancies Are Associated with High 5-Year Survival If Persistent Full Donor Chimerism Is Obtained

BackgroundMixed chimerism, a persistent or increasing number of host cells, after allogeneic hematopoietic stem cell transplant (allo-HSCT) is a predictor of disease relapse. Donor lymphocyte infusion (DLI) has the potential to enhance the graft vs. malignancy effect and reduce the risk of relapse in patients with mixed chimerism (MC) and in patients at high-risk (HR) for relapse. Hence, there is a motivation to utilize DLI for patients with hematologic malignancies while in complete remission (CR) after transplant to prevent disease relapse. To assess the safety and efficacy of DLI after allo-HSCT, in both the relapsed and non-relapsed settings, records of 88 patients receiving DLI between 2003 and 2015 at a single institution were retrospectively reviewed.Patients & MethodsMedian age at time of transplant was 53 (range, 18-68 years). Fifty-four patients received allo-HSCT from related donors (RD) and 34 patients received allo-HSCT from matched unrelated donors (MUD). Reasons for DLI were relapsed/residual disease (n=52, 59%), MC with no evidence of disease (n=29, 33%), and HR with no evidence of disease (n=7, 8%). 44 of 52 relapsed/residual disease patients received treatment before DLI (41 chemotherapy, 4 other, 7 no treatment). 17/52 patients (33%) were treated within 6 months of transplant, the rest after 6 months.DLI was administered according to a dose-escalating protocol in 4-8 week intervals. Starting dose varied based on donor and disease status: 1.0x107 CD3+ cells/kg for relapse/residual RD, 3.0x106 CD3+ cells/kg for relapse/residual MUD, 3.0x106 CD3+ cells/kg for MC/HR RD and 1.0x106 CD3+ cells/kg for MC/HR MUD. Endpoints to discontinue DLI included: full donor chimerism (FDC), remission, GvHD development, disease progression, or lack of further donor cells.ResultsMedian interval from transplant to DLI was 195 days (range, 50-2026 days) and median number of DLI infusions was 2 (range, 1-7 infusions). From first DLI, 1 year overall survival (OS) rates were 52%, 83%, and 86% for relapse/residual, MC, and HR populations respectively. 5 year OS rates were 27%, 70%, and 71%, respectively. Cumulative incidence of acute GvHD grade III-IV and extensive chronic GvHD was 33% (29/88 patients). Six patients died of GvHD-related toxicities (7%).In the relapsed setting, 31/52 patients (60%) responded to DLI with disease control, of whom 12/52 (23%) had durable remissions/disease control while 19/52 (36.5%) eventually relapsed or had disease progression. Thirty-four patients had MC at the time of relapse, and 20/34 patients (59%) returned to FDC after DLI. All 14 patients who did not re-establish FDC after DLI relapsed or had disease progression. Relapse/disease progression remained the most frequent cause of death in the relapsed/residual population, 56%. The 1-year OS was 29% for those who relapsed within 6 months of transplant, 64% for those who relapsed beyond 6 months. The 5 year OS was 18% for those relapsed within 6 months, 33% for those who relapsed beyond 6 months.DLI induced FDC in 27/29 patients (93%) in the MC population, with durable FDC and ongoing CR in 22/29 patients (76%). Seven MC patients (24%) relapsed after DLI. In the HR population, DLI was protective against relapse in 5 patients while 2 patients (29%) relapsed after DLI.ConclusionsNinety three percent of MC patients in the non-relapsed setting achieved FDC after DLI, with a 24% relapse rate over five years. Further, pre-emptive DLI in patients with MC or HR is associated with a 70% 5 year OS. These results suggest a clinically meaningful effect of pre-emptive and prophylactic DLI in MC and HR patient populations. For patients with MC, both relapsed and non-relapsed, achieving FDC after DLI is essential for disease control. All 17 patients in both populations that did not achieve FDC had non-durable responses or no responses to DLI with subsequent disease progression. Fifteen of the 17 patients who did not achieve FDC after DLI died due to disease progression, while the remaining 2 underwent a second allo-HSCT. DLI for HR was associated with significant rates of acute >grade II and extensive chronic GvHD. In this population, development of GvHD may not be the optimal endpoint, in order to limit GvHD-attributable mortality. [Display omitted] DisclosuresAkard:Ariad, BMS, Celgene, Gilead, Novartis, Takeda: Speakers Bureau.

Genetic Markers Predict Primary Non-Response and Durable Response To Anti-TNF Biologic Therapies in Crohn's Disease.

One-fifth of patients with Crohn's disease (CD) are primary non-responders to anti-tumor necrosis factor (anti-TNF) therapy, and an estimated 10-15% will fail therapy annually. Little is known about the genetics of response to anti-TNF therapy. The aim of our study was to identify genetic factors associated with primary non-response (PNR) and loss of response to anti-TNFs in CD. From a prospective registry, we characterized the response of 427 CD patients to their first anti-TNF therapy. Patients were designated as achieving primary response, durable response, and non-durable response based on clinical, endoscopic, and radiologic criteria. Genotyping was performed on the Illumina Immunochip. Separate genetic scores based on presence of predictive genetic alleles were calculated for PNR and durable response and performance of clinical and genetics models were compared. From 359 patients, 36 were adjudged to have PNR (10%), 200 had durable response, and 74 had non-durable response. PNRs had longer disease duration and were more likely to be smokers. Fifteen risk alleles were associated with PNR. Patients with PNR had a significantly higher genetic risk score (GRS) (P =8 × 10-12). A combined clinical-genetic model more accurately predicted PNR when compared with a clinical only model (0.93 vs. 0.70, P <0.001). Sixteen distinct single nucleotide polymorphisms predicted durable response with a higher GRS (P =7 × 10-13). The GRSs for PNR and durable response were not mutually correlated, suggesting distinct mechanisms. Genetic risk alleles can predict primary non-response and durable response to anti-TNF therapy in CD.

P.(L576P) -KIT mutation in GIST: Favorable prognosis and sensitive to imatinib?

ABSTRACTExon 11 KIT mutations are found in a majority of gastrointestinal stromal tumors (GIST) and are usually predictive of response to imatinib, a KIT, PDGFRA and ABL inhibitor. Exon 11 mutations with poor sensitivity to imatinib and poor outcome can be observed on rare occasions, including p.(L576P). In silico and in vitro studies suggested a decreased binding affinity for imatinib in p.(L576P) KIT mutations, thereby offering an explanation for their poor outcome and poor response to standard therapy. These observations were further corroborated with anecdotal case reports of refractoriness or non-durable response to imatinib therapy. However, we describe the favorable response to imatinib and outcome in 5 p.(L576P)-KIT mutant GIST patients treated at a tertiary sarcoma referral center. The sensitivity of p.(L576P)-KIT mutations to imatinib, and the prognostic impact of this mutation need to be further evaluated in a larger cohort. Based on our observations, p.(L576P) mutated GISTs should be treated with standard first line imatinib therapy.

Prostate-specific antigen doubling time subsequent to radical prostatectomy is a predictor of outcome following salvage external beam radiation therapy: A single-centre experience

Objective. The aim of this study was to review the impact of salvage external beam radiotherapy (EBRT) of postprostatectomy patients with long-term follow-up on biochemical-free recurrence (BFR) and metastatic-free survival, and to describe pathological and clinical predictors of outcome. Materials and methods. In the period 1987–2010, 76 postprostatectomy patients with biochemical and clinical recurrence received salvage EBRT. Patients were treated with conformal EBRT and 68 (90%) received a dose of 70 Gy; eight patients (10%) received a dose of 60–64 Gy. No patients received adjuvant or neoadjuvant androgen deprivation therapy in conjunction with salvage EBRT. Results. The median follow-up time after salvage EBRT was 82 months (range 5–192 months). Seventeen patients (22%) developed biochemical recurrence subsequent to postprostatectomy salvage EBRT during the observation time, and the overall 50 and 75 month actuarial BFR rates after salvage EBRT were 84% and 79%, respectively. Seven patients (9%) developed metastatic disease and two patients died of prostate cancer. Independent predictors of biochemical recurrence were seminal vesicle invasion (SVI) in the prostatectomy specimen (p < 0.05) and prostate-specific antigen doubling time (PSADT) of 6 months or less (p = 0.041) before salvage EBRT. Conclusions. Salvage EBRT provides effective long-term BFR and metastatic-free survival in a selected group of patients with detectable, rising prostate-specific antigen values following radical prostatectomy. SVI and PSADT are prognostic variables for a non-durable response to salvage EBRT and thus predictors of high-risk prostate cancer in patients in whom neoadjuvant and adjuvant androgen deprivation therapy should be considered.

Polynesian Variant Of Idiopathic Multicentric Castleman Disease

Multicentric Castleman Disease (MCD) is an uncommon non-clonal lymphoproliferative disease that traditionally has high morbidity and carries a poor prognosis, with median survival of 26-30 months. There has been growing interest in using interleukin-6 (IL-6) as a therapeutic target due to its role in the pathogenesis of MCD. In our practice, we noted a high number of Polynesian patients with idiopathic MCD (iMCD) and their prognosis appeared good. We therefore carried out a retrospective review. Via email survey, laboratory audit and our local database we identified 13 patients with MCD. Twelve patients were HIV and HHV8 negative hence classified as having iMCD; one patient was positive for HIV and HHV8.Of the twelve patients with iMCD (five females, seven males), the median age at diagnosis was 53 (41 - 70). Eleven patients had plasma cell variant; one patient's MCD subtype was not available. 83.3% (10 of 12 patients) were of Polynesian decent: New Zealand Maori (4), Samoan (3), and Niuean (3). Polynesian subjects had fewer general symptoms compared to literature: weight loss 40%, fever 20%; Skin lesions were observed in 60%, 60% had splenomegaly and 40% had polyarthrialgia related to MCD. There is a recognized association between autoimmune disease and MCD. In our series, 6 of the 12 patients had some form of autoantibodies, including antinuclear antibodies, extractable nuclear antibodies and anti-cardiolipin antibodies; however only 2 patients had confirmed autoimmune diseases, with Grave's disease in one and concurrent autoimmune haemolytic anaemia and coeliac disease in another patient. The median baseline gammaglobulin (IgG) was 61g/L (12- 96), C-reactive protein (CRP) was 105mg/L (39 - 219) and hemoglobin (Hb) was 89g/L (50 - 118), excluding one Polynesian patient who was an outlier with a CRP of 1 and Hb of 140. We traced pre-diagnosis electronic records of biochemical markers, such as total protein and total globulin levels, an indirect marker for hypergammaglobulinaemia. We could not find a normal value amongst the Polynesian patient group prior to the diagnosis, abnormalities were noted up to 6 years pre-diagnosis. Despite the biochemical derangement of most patients, performance status was high and 80% of the Polynesian patients remained at work. The mean duration of disease after tissue diagnosis was 5.3 years whereas the mean duration of biochemical evidence of disease presence was 9.2 years.Various therapies including corticosteroid (dexamethasone or prednisone), Rituximab and chemotherapeutic agents were used with mixed but mostly non-durable response until 2009 when those needing treatment were given targeted treatment to block IL-6 with Tocilizumab (6) or Siltuximab (2 in a randomized double-blind placebo controlled study; results will be presented separately). Tocilizumab was administered as an intravenous infusion (at 8mg/kg) in a 3-4 weekly cycle. We used CRP as a measure of the response to treatment. By aiming for a low CRP (i.e. less than 20mg/L) rather than a normal CRP value, at the end of each cycle, we were able to increase the time interval between treatment cycles and therefore rationalize treatment frequency. The median duration of therapy was 19 months during which we saw normalization of Hb in 6/6 of patients, their median hemoglobins increasing from 87g/L (69 - 140) to 133g/L (118 - 157). There were significant improvement of IgG from 65g/L (42 - 96) to 32g/L (17 - 59); CRP from 86mg/L (39 - 160) to 4mg/L (1 - 23). Treatment was stopped in 2/6 patients with subsequent relapse, and response to tocilizumab retreatment. There were three deaths in the entire patient group, only 1/10 Polynesian, and all three patients died before IL-6 specific therapy became available.Because most patients had high levels of IgG, we reviewed all patients tested at North Shore Hospital in the past 3 years with a polyclonal increase of IgG>35g/l and identified 3 further patients, all Polynesian, with blood test consistent with iMCD. Clinical follow-up on these patients was not available.Our review demonstrates a disproportionately large group of Polynesians with iMCD, with distinctively favourable disease outcome. iMCD shows promising response to IL-6 targeted therapy. Based on the chronicity of the IgG elevation and the genetic association, we speculate that the up-regulation of IL-6 could be related to a defect in IL-6 regulation. Similar clinical cases have also been described in Japan. Disclosures:No relevant conflicts of interest to declare.

Dupuytren Contracture Recurrence Following Treatment with Collagenase Clostridium Histolyticum (CORDLESS Study): 3-Year Data

To evaluate long-term efficacy and safety of collagenase clostridium histolyticum (CCH) after the third year of a 5-year nontreatment follow-up study, Collagenase Option for Reduction of Dupuytren Long-Term Evaluation of Safety Study. This study enrolled Dupuytren contracture patients from 5 previous clinical studies. Beginning 2 years after their first CCH injection, we re-evaluated patients annually for joint contracture and safety. Recurrence in a previously successfully treated joint (success = 0° to 5° contracture after CCH administration) was defined as 20° or greater worsening in contracture in the presence of a palpable cord or medical/surgical intervention to correct new or worsening contracture. We assessed partially corrected joints (joints reduced 20° or more from baseline contracture but not to 0° to 5°) for nondurable response, also defined as 20° or greater worsening of contracture or medical/surgical intervention. Of 1,080 CCH-treated joints (648 metacarpophalangeal [MCP]; 432 proximal interphalangeal [PIP]; n = 643 patients), 623 (451 MCP, 172 PIP) had achieved 0° to 5° contracture in the original study. Of these joints, 35% (217 of 623) recurred (MCP 27%; PIP 56%). Of these recurrences, an intervention was performed in 7%. Of the 1,080 CCH-treated joints, 301 were partially corrected in the original study. Of these, 50% (150 of 301; MCP: 38% [57 of 152]; PIP: 62% [93 of 149]) had nondurable response. We identified no new long-term or serious adverse events attributed to CCH during follow-up. Anti-clostridial type I collagenase and/or anti-clostridial type II collagenase antibodies were reported for 96% or more of patients who received 2 or more CCH injections and 82% who received 1 injection. The recurrence rate, which is comparable to other standard treatments, and the absence of long-term adverse events 3 years after initial treatment indicate that CCH is an effective and safe treatment for Dupuytren contracture. Most successfully treated joints had a contracture well below the threshold for surgical intervention 3 years after treatment. Recurrence rates among successfully treated joints were lower than nondurable response rates among partially corrected joints. Therapeutic IV.

Intracerebellar Granulocytic Sarcoma Presenting as a First Manifestation of Relapse in Chronic Myelogenous Leukemia (CML) During Imatinib Mesylate Therapy: A Case Report and Literature Review.

Abstract 4289 IntroductionGranulocytic sarcoma (GS) is an unusual solid tumor of extramedullary localization consisting of immature granulocytic precursors. It is mostly encountered in the course of acute myelogenous leukemia (AML), myelodysplastic or myeloproliferative disorders, with an estimated incidence of 7.9% in CML (Terjanian et al). GS can occur before, concomitantly, or after the overt development of these hematologic disorders. Most common localizations are lymph nodes, bones, skin and soft tissues, but there is paucity of published data of isolated intracranial GS manifesting as relapse in CML. Case reportA 34-year-old male with Philadelphia chromosome-positive (Ph+) CML diagnosed in August 2005 in the chronic phase of the disease. After initiation of imatinib therapy at doses of 400 mg/d he achieved complete hematologic, cytogenetic and molecular responses. He remained in clinical remission for 3 years when he presented with bifrontal headache and dizziness. Physical exam revealed no abnormalities. Peripheral blood count showed WBC 9,200/mm3 with normal differential and no immature forms, platelet 180,000/mm3, and hemoglobin 14.4 g/dl. Magnetic resonance imaging of the brain revealed a 3.8 cm enhancing mass lesion within the left cerebellar hemisphere. He underwent posterior fossa exploration with resection of the solid tumor. Microscopic examination of the cerebellar mass demonstrated a diffuse cellular infiltrate of atypical mononuclear cells with high nuclear to cytoplasmic ratios and fine, immature chromatin, consistent with blasts. Flow cytometric analysis confirmed that the majority of the cells in the specimen were composed of blasts which coexpressed the CD33 and CD4 markers. Fluorescence in situ hybridization analysis on the cerebellar tissue detected the presence of BCR/ABL rearrangement in 60% of nuclei. Taken together, the morphologic, immunophenotypic, and molecular features are diagnostic of a myeloid sarcoma representing transformation of chronic myeloid leukemia. DiscussionA literature search was performed to identify all cases of intracranial GS in patients with diagnosis of CML reported in medical literature. Only 3 cases were identified in the literature to date. This case appears to be the first described in the imatinib mesylate era. Table 1 summarizes the clinical data of these previously recorded cases and the present case.Table 1Case no.ReferenceAge / sexGS locationCML Status (systemic)No. years since DxPrior therapiesOutcome1Simpson et al, 198951 FLeft parietal lobeRelapse2.5-Hydroxyurea, busulfan, α-interferonAlive 4 months after cranial RT with no evidence of blastic transformation2Mahendra et al, 199440 MRight frontal lobeRelapse8.5-Busulfan, hydroxyurea -Allogeneic SCTDied 3.8 months after his allograft3Grondin et al, 199631 MMultiple brain nodulesRelapse1.5-HydroxyureaAlive immediately after whole brain RT with near complete resolution of brain lesions4Present case report34 MLeft cerebellar hemisphereRemission3.3-Imatinib mesylateDied 7 months after dx of intracranial relapse. Subsequent to tumor resection and posterior fossa RT, patient achieved a non-durable response, ultimately developing cerebellar and leptomeningeal relapsesAbbreviations: CML: chronic myelogenous leukemia, Dx: diagnoses, GS: granulocytic sarcoma, RT radiotherapy, SCT: stem cell transplantPharmacokinetic analyses (Pfeifer et al, Leis at al, Wolff et al) have demonstrated that imatinib poorly penetrates the blood–brain barrier, with resultant CNS drug levels significantly lower than corresponding plasma levels. Measured CSF levels were below the concentration required for 50% inhibition of the BCR–ABL tyrosine kinase activity, suggesting that Ph+ leukemic patients treated with this selective tyrosine kinase inhibitor are at high risk of CNS relapse even in the setting of complete remission of systemic disease.This case illustrates an unusual site of recurrence of CML. To our knowledge, this is the first case of a granulocytic sarcoma presenting as a solitary parenchymal brain tumor in a patient receiving imatinib for CML. Noticeably, CNS relapse occurred despite lack of systemic evidence of disease. As described in human and animal model studies this may be the result of effective systemic antileukemic activity of imatinib therapy, but with limited activity in the CNS. Poor penetration of imatinib into the cerebrospinal fluid may allow the CNS to become a sanctuary reservoir for relapse of Ph+ CML. Disclosures:No relevant conflicts of interest to declare.

Radioimmunoscintigraphy with In-111-labeled capromab pendetide predicts prostate cancer response to salvage radiotherapy after failed radical prostatectomy.

We investigated the ability of In-111-capromab pendetide to separate patients who have failed radical prostatectomy into categories of those who would versus those who would not respond to salvage radiotherapy. Prostate-specific antigen (PSA) levels in 32 men with prostate cancer who had failed radical prostatectomy and had undergone a whole-body In-111-capromab pendetide scan were followed-up for 13 months (median) after salvage radiotherapy to the pelvis. A logistic regression model was used to determine whether the scan findings, as well as other clinical variables, were associated with a durable complete response (DCR), a nondurable response (NDR), or no response (NR). Sixteen of 23 (70%) men with a normal scan outside the prostatic fossa achieved a DCR after salvage radiotherapy versus two of nine (22%) who had a positive scan outside the prostate fossa and pelvis (P = .0225, Fisher's exact test). Predicted probability (95% confidence interval [CI]) that a DCR would be obtained with a normal scan was 0.88 (0.55 to 0.98); for men with a positive scan limited to the prostatic fossa it was 0.62 (0.42 to 0.79); and for men with a positive scan outside the pelvis it was 0.27 (0.09 to 0.58). No other variables before radiotherapy showed a significant association with the DCR rate. Salvage radiotherapy is statistically more likely to lead to a durable complete PSA response in men with prostate cancer who have failed radical prostatectomy and have a negative In-111-capromab pendetide scan outside the pelvis as compared with those who have a positive scan.