Chance Of Response Research Articles

Cytotoxic therapy in acute myeloid leukemia: not quite dead yet.

Given the recent approvals of new agents for acute myeloid leukemia (AML), a clinical trial pipeline stocked with novel therapies, and the rapid integration of imaginative approaches in diseases like acute lymphocytic leukemia and chronic lymphocytic leukemia, it is reasonable to ask whether treatment of AML might finally depart from the classical cytotoxic induction therapy that has been employed since the 1970s. However, for better or worse, in 2018, cytotoxic induction regimens remain the standard of care for most patients. Indeed, the future likely lies in combinations of therapies that act with a spectrum of mechanisms. Using a case-based format, this review will outline current treatment expectations for patients according to karyotypic risk and familiarize readers with the basis for common induction choices. Relapsed/refractory disease may be especially amenable to interventions with novel agents or clinical trials; however, there are still some patients who most benefit from intensive chemotherapy. This review will outline risk systems that help the practitioner identify those with the best chances for response and survival. Finally, clinical tools, including geriatric assessments and comorbidity calculators, may help clinicians recognize patients for whom disease risk and comorbidity tip the balance against classical chemotherapy, a frequent challenge for those who treat this devastating disease.

Azacitidine Response Prediction in MDS Patients with NGS Data Using a Computational Biology Modeling (CBM) Based Clinical Decision Support System

BACKGROUND: Azacitidine (AZA) is currently a drug of choice for most of high-risk MDS patients. However, only 40-50% of MDS patients achieve clinical improvement with AZA. There is a need for a predictive clinical decision support tool that can identify MDS patients with higher or lower likelihood of AZA response. Ideally, patients with no chance of response would be spared of life-threatening toxicities and expense; while patients with high chance for response would receive maximized treatment.AIM: The objective of this study was to predict response to AZA in a cohort of intermediate- and high-risk MDS patients using CBM approach in retrospective blinded manner.METHODS: We analyzed the clinical and genomic (NGS, cytogenetics and FISH) data for a cohort of 48 Int-2 and high risk MDS patients treated with AZA for median of 12 (4-34) cycles. Median age was 70.4 years, M:F ratio 1:1. MDS subtypes: EB-2 (35.4%, N=17), EB-1 (39.6%, N=19), MDS/AML (18.6%, N=9), CMML1/2 (4.2%, N=2), and RARS (2.1%, N=1). Median IPSS-R was 5 (3-10), cytogenetic score was 1. Median BM blasts were 10% (0.88-43.12), Hemoglobin 91g/L (62-145), ANC 1.24x109/mL (0.09-11.64), Platelets 84x109/mL (2-576). Patients were treated by AZA until progression to AML. Median AZA cycles was 14. Median overall survival (OS) on therapy was 24.2 months (4.4-61.6). Median progression free survival (PFS) was 15.9 months (4.0-61.6). Clinical responders were defined by IWG2006 criteria. Overall response rate (ORR) was 60.4% (CR/PR: 18 of 48 patients, stable disease with hematology improvement (SD-HI): 11/48). While 29 of 48 (60.4%) patients progressed to AML following the AZA therapy; 5 patients (10.4%) were primarily AZA-resistant.CBM for each MDS patient was created utilizing genomic data to create a predictive workflow (Cellworks Group) complemented with digital mechanistic model of AZA and other FDA-approved drugs. Drugs were modeled by programming their mechanism of action on pathways and simulated individually and in combination. A disease inhibition score (DIS) characterized the drug impact to which malignant phenotypes was inhibited. For AZA non-responder profiles, unique combinations were selected that reduced DIS.RESULTS: CBM cohort analysis performed on 37 out of 48 patients predicted 20 clinical responders (54.05%) and 17 clinical non-responders (45.95%). CBM accurately predicted the clinical outcomes of 14 out of 20 responders and 17 out of 17 non-responders with overall accuracy 83.78%. Sensitivity of identifying a responder is 70% while non-responders are called with 100% specificity. The CBM identified AZA based combination in 17 patients who did not respond to AZA monotherapy: AZA+Lenalidomide (N=6), AZA+Dasatinib (1), AZA+Ruxolitinib (2), AZA+Sorafenib (1), and AZA+Venetoclax (7). In the patient AZA014 (EB1 with isolated 5q-) who underwent AZA for 17 cycles and responded with mCR (MLD) without HI, the CBM predicted Lenalidomide sensitivity. Following the treatment with Lenalidomide the patient entered a long lasting CR (> 3 years). Digital droplet ddPCR technology during patient follow-up confirmed loss of the clone characterized by TP53(p.Thre377Pro) mutation upon Lenalidomide therapy. In contrast, ddPCR of AZA048 utilized SF3B1 (p.Lys700Glu) mutation tracking during patient follow-up that predicted the relapse by 8 months.CONCLUSION: The CBM prediction of AZA clinical response in newly diagnosed, higher risk MDS patients showed high predictive accuracy of AZA resistant patients. The study validates the approach to a priori predict response and identify the right therapy option for the patient and could be used to establish criteria for precision enrollment in drug development trials. In addition, analysis uncovered possible mechanisms for AZA resistance that could be targeted to induce response. Clonal architecture is trackable using ddPCR technology providing time for additional NGS analysis to target the progressing clone. Ultimately, improving patient selection and mutation tracking may avoid unnecessary chemotherapy toxicity and reduce health care expenses. DisclosuresAbbasi:Cell Works Group Inc.: Employment. Singh:Cellworks Research India Private Limited: Employment. Ullal:Cellworks Research India Private Limited: Employment. Narayanabhatia:Cellworks Research India Private Limited: Employment. Alam:Cellworks Research India Private Limited: Employment. Roy:Cellworks Research India Private Limited: Employment. Choudhary:Cellworks Research India Private Limited: Employment. Vali:Cell Works Group Inc.: Employment. Cogle:Celgene: Other: Steering Committee Member of Connect MDS/AML Registry.

A case for adding fluvoxamine to clozapine

Treatment‐refractory schizophrenia affects at least 30% of all patients with schizophrenia. Clozapine remains the gold standard treatment as the chances of response with another non clozapine medication are very low. However, initiating and then maintaining patients on clozapine can be a challenge due to a complex titration regimen, dose‐related side‐effects and the requirement for regular monitoring. In this article, Dr Sharma describes the successful addition of fluvoxamine to clozapine in a patient to achieve a therapeutic level of clozapine.

Efficacy and safety of enzalutamide, abiraterone and cabazitaxel in post-docetaxel treatment of castration-resistant prostate cancer: meta-analysis data

Background. Castration-resistant prostate cancer (CRPC) is wide-spread severe disease in many regions of the world. Enzalutamide, abiraterone and cabazitaxel have been recently registered for the treatment of this condition. Objective: to perform indirect comparison of enzalutamide, abiraterone and cabazitaxel efficacy and safety in 2nd line “post-docetaxel” treatment of CRPC according to published clinical data. Materials and methods . Indirect comparison was undertaken to extract efficacy and safety parameters of enzalutamide, abiraterone and cabazitaxel from integrated registration pivotal trials and independent retrospective studies. 13 articles were selected: enzalutamide – 2, abiraterone – 7, cabazitaxel – 3 and orteronel 1 article. Results. Enzalutamide had highest chances of prostatic specific antigen response (50 % and more decline from baseline) and highest chances of Response Evaluation Criteria In Solid Tumors (RECIST) soft-tissue objective response. Chances of enzalutamide and abiraterone adverse effects did not have serious difference from control groups in pivotal trials. Cabazitaxel increased adverse effects chances, mostly hematological adverse effects. Conclusion. Treatment with enzalutamide of CRPC in 2nd line “post-docetaxel” provided best parameters of prostatic specific antigen response. Enzalutamide is safer than cabazitaxel and does not have several adverse events typical for abiraterone.

Left ventricular contractile reserve by stress echocardiography as a predictor of response to cardiac resynchronization therapy in heart failure: a systematic review and meta-analysis

BackgroundThe presence of left ventricular contractile reserve (LVCR) during stress echo (SE) may provide favorable response to cardiac resynchronization therapy (CRT) in heart failure patients. The aim of the study was to perform a meta-analysis of available SE data in this set of patients.MethodsFrom a Pubmed and Advance Google Scholar database web based search scan up to December 2016, we initially identified 5906 records. From this initial set, we removed that did not include SE and duplicate studies. We assessed for eligibility 71 full-text articles assessed for eligibility, and 60 of them did not meet the inclusion criteria as follow: 1) heart failure patients with NYHA class III and IV, depressed ejection fraction (EF <35%) and QRS duration ≥120 ms at study entry; 2) SE with assessment of LVCR; 3) Follow-up data. LVCR during SE was identified as reduction in wall motion score index and/or an increase in EF.ResultsEleven studies with 861 patients (mean age 67 ± 9 years, ejection fraction 25 ± 6%) were included in the meta-analysis. The type of stress was either exercise (n = 2) or dobutamine (n = 9), the latter with low-dose (10 mcg) in two, intermediate-dose (20 mcg) in five, and high-dose (40 mcg) protocol in two studies. LVCR was detected in 555 patients (63%) and CRT-response was present in 584 (66%). The overall odds ratio for LVCR to predict a favorable CRT response was 2.06 (95%, CI 1.70–2-43), Z score: 11.055, p < 0.001.ConclusionThe presence of LVCR during SE with either dobutamine or exercise is associated with a greater chance of response to CRT. This parameter is now ready to be tested in a prospective multicenter trial to select patients more likely to benefit from CRT.

Second-line (SL) chemotherapy containing oxaliplatin (OXA) in metastatic pancreatic cancer (PC): Whom should we trust?

e15719 Background: After the intensification of first-line treatment in metastatic PC the number of patients fit and able to receive a SL treatment is increasing; despite these results, the choice of SL chemotherapy remains a challenging issue. The role of OXA in SL setting has given conflicting results in CONKO-003 and PANCREOX trials; the reasons of this inconsistency are difficult to understand. Methods: In order to detect a possible advantage from the use of oxaliplatin in SL, we pooled together the results of randomized phase II/III studies adding OXA to fluoropyrimidines after a gemcitabine-based first-line. Hazard ratios (HRs) for progression-free (PFS) and overall survival (OS) with 95% confidence intervals (CIs) were extracted, while the number of events was used for RR to determine odds ratio (OR) with corresponding 95%CIs. Fixed-effect and random-effect models were used as appropriate, on the basis of the evidence of a non-significant or significant heterogeneity among trials, respectively. The Review Manager software was used (version 5.3). Results: Three studies were identified; main characteristics and results are summarized in the table. No benefit in overall survival derived from the use of OXA (HR 1.03, 95% CI, 0.64-1.67; p=0.90) but significant heterogeneity was reported (p=0.003); the addition of OXA produced a significant benefit in terms of PFS (HR 0.81, 95% CI 0.68-0.97; p=0.02) with a higher chance of response (OR 1.81, 95% CI 1.01-3.24; P=0.05). Interestingly heterogeneity between trials was less evident in PFS and RR than in OS suggesting that this could be a confounding element in the interpretation of data. Conclusions: The reasons of conflicting results concerning the use of oxaliplatin doublets in SL setting are not clear. Given the recent advances in first-line setting, it would be interesting to identify an optimal sequential strategy, hopefully in a personalized approach. [Table: see text]

Outcomes with Extracorporeal Photopheresis in the Management of Chronic Gvhd: A Multi-Centre Experience

Introduction: Chronic graft-versus-host disease (cGVHD) is a major cause of morbidity and non-relapse mortality in allogeneic haematopoietic stem cell transplant patients (Allo-HSCT). Extracorporeal Photopheresis (ECP) is now an established second-line treatment for steroid-refractory cGVHD. Here we report a large, multi-centre case series of 115 patients treated with ECP for cGVHD. To the best of our knowledge, this is the largest reported series of patients receiving fortnightly ECP for cGVHD.Method:A retrospective case note audit identified 115 consecutive Allo-HSCT patients who commenced fortnightly ECP for cGVHD between 2007 and 2016 at The Christie and Central Manchester NHS Foundation Trusts. cGVHD was classified and graded using the National Institutes of Health (NIH) consensus response criteria.Results: Median age when starting ECP was 49 years (range 18-75). 61% patients were male (n=70) and 39% Female (n=45). Underlying disease groups undergoing Allo-HSCT included Acute Leukaemia/Myelodysplastic Syndrome (n=69; 60%), Lymphoma (10%; n=12), Chronic leukaemia (13%; n=15) Myeloma (14%; n=16) and Aplastic Anaemia (3%; n=3). 24% of patients had myeloablative conditioning (n=27) and 76% had reduced-intensity conditioning (n=88). 61% (n=70) received stem cells from Voluntary Unrelated Donors (VUD) and 39% (n=45) Siblings (Sib). Patients received post Allo-HSCT GvHD prophylaxis with Calcineurin inhibitors, either alone, or in combination with Methotrexate and/or Mycophenolate Mofetil. Median time to stopping Calcineurin inhibitor post Allo-HSCT was 12 months (range 0-88). 14 patients received Donor Lymphocyte Infusions (DLI).Median time to development of GvHD post Allo-HSCT was 5 months (range 0-33). 94% developed cutaneous cGVHD (n=108), 32% oral cGVHD (n=37), 23% gut cGVHD(n=27), 24% liver cGVHD (n=28), 11% lung cGVHD (n=13) and 26% ocular cGVHD (n=30). 49% (n=57) patients had sclerodermoid disease. 37% (n=43) had one, 31% (n=36) two, 21% (n=24) three, 9% (n=10) four and 2% (n=2) five organ involvement. All 115 patients had been previously treated with immunosuppressive drugs - 109 Prednisolone; 73 Calcineurin Inhibitors; 60 Mycophenolate mofetil and other (ATG, n=1; Basiliximab, n=1; Methotrexate, n=6; Rituximab, n=10; and Thalidomide, n=18). Median duration of ECP treatment was 12 months (range 1-27 months).Response to ECP was assessed using NIH Criteria - 29% (n=33) Complete Response (CR), 19% (n=22) Partial Response (PR), 16% (n=18) Stable Disease (SD), 11% (n=13) Progressive Disease (PD), 17% (n=19) Death and 9% (n=10) Other. As a result of ECP treatment 26% (n=30) were able to stop steroid treatment while the remaining 74% were able to reduce their steroid dose. There was no overall difference in response between the two centres. Patients with cutaneous and oral cGVHD were more likely to achieve a PR or better (cutaneous p=0.03; oral p=0.05) but there was no difference with other organ involvement. The chance of response was not influenced by the number of organs involved.Median Overall Survival (OS) from the date of Allo-HSCT was 110 months (range 8-221). OS was not influenced by age, donor type, diagnostic group (Acute Leukaemia/Myelodysplastic Syndrome, Lymphoma, Chronic Leukaemia, Myeloma and Aplastic Anaemia), gender or the number and type of organs involved. The only exception was oral cGVHD which was associated with a lower OS (p=0.03). Patients with cGVHD achieving a CR/PR with ECP treatment, had a significantly better OS (40 months vs. median not reached, p<0.0001).Conclusion: ECP is an effective second line treatment for steroid-refractory and steroid-dependent cGVHD with a 50% response rate. This is not affected by the underlying diagnostic group or pattern of organ involvement, however patients with cutaneous and oral cGVHD seem to respond better. As response to ECP translates into better OS, this most likely reflects the reduction in immunosuppressive related complications. Therefore it is worth considering the use ECP treatment early in the management of cGVHD. DisclosuresRoutledge:Celgene: Honoraria; Jazz Pharmaceuticals: Honoraria; Gilead: Honoraria. Dignan:Jazz: Honoraria; Adienne: Speakers Bureau; Therakos/Mallinckrodt: Honoraria, Research Funding, Speakers Bureau; Gilead: Other: Cl for GvHD Study. Bloor:Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; Gilead: Honoraria; GSK: Consultancy, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees. Tholouli:Johnson and Johnson: Speakers Bureau; MSD: Speakers Bureau; Celgene: Honoraria; Giles: Speakers Bureau; Amgen: Honoraria, Speakers Bureau.

Abstract 2710: Model evolution technique as a novel concept for characterization of tumor heterogeneity in dynamic contrast enhanced MRI studies

Abstract Introduction: Many studies have shown that tumor vascular network and the assortment of tumorous cells inside and on the periphery of solid tumors are spatially heterogeneous. Variation in cell packing density (VCPD), hypoxia, acidosis, and elevated interstitial fluid pressure (IFP) are main characteristic features of solid tumors. Elevated IFP and VCPD in solid tumors can be generally relevant to the pathological structures at the cellular level that is fundamental to understanding the chance of response to treatment and recurrence. Therefore, non-invasive quantification of tumor heterogeneity for the same types of tumors can play an important role in diagnosis and treatment planning. Hypothesis: In this pilot study, using Nested Model (NM) selection technique, Model Evolution (ME) concept is framed and introduced to quantify the evolutions of 3 different physiologically NM that are derived from standard Tofts model, throughout the course of Dynamic Contrast Enhanced (DCE) Magnetic Resonance Imaging (MRI) experiment. Using ME technique for pharmacokinetic (PK) modeling and DCE-MRI data analysis, a heterogeneity measure is formulated and introduced based on the evolutionary profile of the estimated extra-cellular extra-vascular (ve) volume. We hypothesized that the ME profiles in the course of DCE-MRI experiment, highly depend on the inward diffusion and outward convection of contrast agent concentration and contain abundant information for describing the compartmentalization and heterogeneity levels of solid tumors. Material and Methods: 24 athymic Nude rats with U251n rat tumor model of cerebral tumor were studied. Look-Locker T1 mapping and DCE-MRI experiments (Dual Gradient Echo, 150 image sets at 4.0 sec intervals over 10 min: matrix = 128×64, five 2.0 mm slices, NE = 2, NA = 1, TE/TE/TR = 2.0/4.0/40ms with bolus intravenous injection of the Magnevist at 0.25 mmol/kg) acquired at 7T field strengths. In each animal, in-vivo measurement of tumor IFP was done right after the DCE-MRI experiment using a wick-in-needle technique. The ME technique was applied on DCE-MR data of 24 U251n rat tumors to characterize the heterogeneity of each tumor and then the results were compared to their known in vivo measure of IFPs. Results and Conclusions: Results of this pilot study clearly attest that the evolutionary profile of ve can be used to characterize the heterogeneity level of solid tumors. The ME results imply that as the slop of the evolutionary profile increases, the IFP of tumor increases. Also, the latency of the profile during the course of MR experiment can reliably explain the tumor compartmentalization and their elevated IFP. This pilot study confirms that the ME concept can make a paradigm shift in non-invasive quantification of tumor heterogeneity from DCE-MRI studies Citation Format: Hassan Bagher-Ebadian, Azimeh NV Dehkordi, Rasha Alamgharibi, David Nathanson, Hamid Soltanian-Zadeh, Arbab S. Ali, Stephen Brown, Meser M. Ali, Tom Mikkelsen, James R. Ewing. Model evolution technique as a novel concept for characterization of tumor heterogeneity in dynamic contrast enhanced MRI studies. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2710.

Immunomodulation and immune thrombocytopenia: some unmet needs, questions, and outlook

During the last two decades, new therapeutic strategies have been developed, particularly anti-CD20 agents and thrombopoietin-receptor (TPO-r) mimetics, for immune thrombocytopenia (ITP). However, although the new efficient drugs have deeply modified the therapeutic strategy and the disease prognosis, there are still unmet needs and challenges. Concerning rituximab, reassuring data concerning its safety have recently been reported. The main limitation of the treatment is its modest long-term efficacy, with frequent disease relapse. Maintenance treatment or association with other immunomodulatory drugs such as dexamethasone may achieve better long-term response. With failure of one of the available TPO-r agonists (ie, romiplostim and eltrombopag), another can be used. Switching may be beneficial, with more than 50% chance of response, and could limit the risk of platelet fluctuation occasionally observed with these treatments. According to the mechanism of action of TPO-r agonists, a rapid relapse of thrombocytopenia should be observed after they are stopped. Several recent observational studies suggested sustained responses in patients achieving complete response with TPO-r agonists and who stopped the treatments. Prospective studies to confirm these unexpected data are needed. Thrombosis in ITP is a concern, particularly with TPO-r agonists, even though the pivotal studies of eltrombopag and romiplostim did not report a higher incidence of thrombosis events with TPO-r agonists than placebo. Despite these reassuring data, the risk of thrombosis with TPO-r agonists remains unanswered, particularly with secondary ITP or in older adults.

Development of a Functional Biomarker for Use in Cell-Based Therapy Studies in Seropositive Rheumatoid Arthritis.

Cell-based therapy has potential therapeutic value in autoimmune diseases such as rheumatoid arthritis (RA). In RA, reduction of disease activity has been associated with improvement in the function of regulatory T cells (Treg) and attenuated responses of proinflammatory effector T cells (Teff). Mesenchymal stem cells (MSCs) and related multipotent adult progenitor cells (MAPC) have strong anti-inflammatory and immunomodulatory properties and may be able to "reset" the immune system to a pre-RA state. MAPC are MSC-like cells that are slightly earlier in lineage, have greater expansion capacity, and can be used as "off-the-shelf" therapy. Assessment of cell-based therapy to treat arthritis and related diseases is limited by the lack of available biological correlates that can be measured early on and indicate treatment response. We set out to develop a functional measure that could be used ex vivo as a biomarker of response. We were able to demonstrate that MAPC products could inhibit Teff responses from patients with active RA and that Treg from RA patients suppressed Teff. This assay used ex vivo can be used with MAPC or Treg alone or in combination and reflects the overall level of Teff suppression. Use of a novel functional biomarker as an exploratory endpoint in trials of cell-based therapy should be of value to detect biological outcomes at a point prior to the time that clinical response might be observed. Therapy with mesenchymal stem cells and related multipotent adult progenitor cells is immune modifying in a variety of diseases. There is interest in using cell-based therapy in rheumatoid arthritis (RA) to induce tolerance and "reset" the immune system to its pre-RA state. In a clinical trial, it should be known as soon as possible if there is a chance of response. A biomarker has been developed that permits measurement of the effects of cell-based therapy on effector T cell function.

Are antidepressants effective? A debate on their efficacy for the treatment of major depression in adults

ABSTRACTRecently, the efficacy of antidepressants, a treatment used by 11% of US American adults, has been debated. Thousands of randomized controlled trials (RCTs) have been used to study antidepressants, with the majority demonstrating at least moderate superiority over placebo. In contrast, studies have found antidepressant effects to be unspecific and mainly resulting from placebo. The effects of antidepressants may also be overestimated due to selective publishing and selection of patients who have a high chance of response in RCTs. Studies have also shown the drugs do not reduce suicidal events when compared to placebo, and efficacy differences to placebo are often too small to prove clinical relevance. Here, we review the claims for and against antidepressant efficacy.

Dynamic Changes of Molecular Markers during Natural History in Metastatic Melanoma: Ethical Issues and Lessons to Learn

Objective: Malignant melanoma with brain metastases is associated with a higher risk of death. No specific treatments were demonstrated to be useful in a such situation. Drugs as temozolomide orally or new targeted treatments showed significant objective response rates, even complete regression. Such responses could be obtained using new strategies based on dynamic changes over time of some molecular markers. Elements of ethics should be taken into account in order to adapt treatment and avoid resistance. Methods: The case of a 59-year old male with a primary cutaneous melanoma of the trunk, treated at Cancer Institute “Ion Chiricuta” from August 2001 is presented. After multiple loco-regional relapses, the patient developed brain metastases and started temozolomide 150 mg once daily, five days, every 4 weeks, 6 cycles with concurrent whole brain external radiotherapy. Comparative immunostaining including proliferation and pro-apoptotic molecular markers between the initial diagnosis (2001), before (2005) and after (2008) temozolomide treatment was performed. Result: Nine months after the start of temozolomide treatment, complete response was confirmed by magnetic resonance imaging. Overall cancer specific survival was 41 months. Ki-67, cyclin E, HMB-45 expression and Bax/ Bcl-2 ratio increased during almost 10 years of treatment and follow-up. Bcl-2 staining was absent at the last analysis. Only p53 and Bax expression doesn't changed during treatment. Conclusion: It seems that metastatic melanoma cells lost some of pro-apoptotic markers and overexpressed markers of proliferation. Predictive markers of response and resistance were actively identified; their combination and dynamic over time could help the oncologist to select those metastatic patients with highest chances of response. Dynamic changes of these molecular markers would guide treatment and the overall core strategy. Serial biopsies and tissue analyses become a challenging ethical issue. Empiric treatments based on a unique tumor signature should be modified using an adaptive approach.

Personalized biological treatment for rheumatoid arthritis: a systematic review with a focus on clinical applicability.

To review studies that address prediction of response to biologic treatment in RA and to explore the clinical utility of the studied (bio)markers. A search for relevant articles was performed in PubMed, Embase and Cochrane databases. Studies that presented predictive values or in which these could be calculated were selected. The added value was determined by the added value on prior probability for each (bio)marker. Only an increase/decrease in chance of response ⩾15% was considered clinically relevant, whereas in oncology values >25% are common. Of the 57 eligible studies, 14 (bio)markers were studied in more than one cohort and an overview of the added predictive value of each marker is presented. Of the replicated predictors, none consistently showed an increase/decrease in probability of response ⩾15%. However, positivity of RF and ACPA in case of rituximab and the presence of the TNF-α promoter 308 GG genotype for TNF inhibitor therapy were consistently predictive, yet low in added predictive value. Besides these, 65 (bio)markers studied once showed remarkably high (but not validated) predictive values. We were unable to address clinically useful baseline (bio)markers for use in individually tailored treatment. Some predictors are consistently predictive, yet low in added predictive value, while several others are promising but await replication. The challenge now is to design studies to validate all explored and promising findings individually and in combination to make these (bio)markers relevant to clinical practice.

Abstract P3-06-34: Platelet predominant breast cancer is a new predictor for pathological complete response to neoadjuvant chemotherapy

Abstract Background and Objective: Platelets, the smallest anucleate hematopoietic cells, are increasingly recognized as the key regulator of tumor progression and metastasis in breast cancer. They contribute significantly to hematogenous metastasis, which increases tumor invasiveness, by protecting tumor cells from shear stress or immune surveillance and facilitating their extravasation to distant sites. Additionally, recent studies have demonstrated direct signaling between platelets and tumor cells during epithelial–mesenchymal transition (EMT) in the blood stream. However, the existence of platelets in primary breast cancer and its relationship with clinicopathological factors and pathological response to chemotherapy remain poorly understood. This study aimed to investigate (1) the presence of platelet infiltration in tumor tissue, (2) relationships between platelets and clinicopathological features, and (3) the association of platelets with pathological complete response (pCR) to neoadjuvant chemotherapy and EMT markers in primary breast cancer. Methods: We retrospectively analyzed the pre-chemotherapeutic biopsy specimens from 100 breast cancer patients who underwent surgical resection after anthracycline/taxane-based neoadjuvant chemotherapy at Kanazawa University Hospital. Platelet subsets (glycoprotein Ib [CD42b]) and the expression of EMT markers (E-cadherin, vimentin, and β-catenin) were evaluated by immunohistochemistry and correlated with pCR after neoadjuvant chemotherapy. Platelet-predominant breast cancer (PPBC) was defined as the presence of ≥10% of anucleate cells positively stained for CD42b in direct contact with tumor cells. pCR was defined as the absence of residual invasive tumor cells in breast and lymph nodes (ypT0/is, ypN0). Results: PPBC was observed in 48 patients (48%). The prevalence of PPBC was significantly higher in human epidermal growth factor receptor 2 (HER2)-negative patients (HER2 [+] vs. HER2 [-]; 65% vs. 90%, p = 0.008). There was no significant association between CD42b expression and stage, nuclear grade, histology, and estrogen receptor status. PPBC patients had a significantly decreased pCR rate (6/48, 12.5%) compared to non-PPBC patients (33/51, 64.7%; p &amp;lt; 0.001). Tumor cells surrounded by platelets exhibited EMT-like morphological changes, EMT marker expression, nuclear-staining of β-catenin, loss of E-cadherin expression, and expression of vimentin. Conclusions: Our results suggested the presence of tumor-associated platelets in breast cancer as a new predictor of response to neoadjuvant chemotherapy. Platelets might facilitate EMT at the primary site by potentiating tumor cell adhesion. Platelet-tumor interaction might be a new therapeutic strategy for breast cancer. If our finding is validated in further investigations, it might serve as the basis for novel therapeutic approaches of combining conventional chemotherapy with antiplatelet therapy. Our data also identified new predictive parameters to stratify patients with an increased chance of response to anthracycline/taxane-based neoadjuvant chemotherapy. Citation Format: Satoko Ishikawa, Masafumi Inokuchi, Hironori Hayashi, Katsunobu Oyama, Hisatoshi Nakagawara, Tomoharu Miyashita, Hidehiro Tajima, Hiroyuki Takamura, Itasu Ninomiya, Hirohisa Kitagawa, Sachio Fushida, Takashi Fujimura, Tetsuo Ohta. Platelet predominant breast cancer is a new predictor for pathological complete response to neoadjuvant chemotherapy [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P3-06-34.

15 HLA-MATCHED ALLOGENEIC STEM CELL TRANSPLANTATION IMPROVES OVERALL SURVIVAL OF HIGHER RISK MYELODYSPLASTIC SYNDROME

sotatercept (ACE-011), a novel first-in-class activin type IIA receptor fusion protein, in anemic patients with IPSS Low/Intermediate-1risk MDS or non-proliferative CMML. ClinicalTrials.gov identifier: NCT01736683. Methods: The primary endpoint of this study is erythroid hematological improvement (HI-E; defined by modified IWG 2006 criteria). Secondary endpoints include rate of RBC-transfusion independence (RBC-TI) ≥8 weeks and safety. Eligible patients have lower-risk MDS or non-proliferative CMML and anemia, with no response, loss of response, or low chance of response to ESAs. Patients receive subcutaneous sotatercept at 0.1, 0.3, 0.5, or 1.0 mg/kg every 3 weeks. Results: As of May 22, 2014, 54 MDS patients were enrolled: 7, 6, 21, and 20 in the sotatercept 0.1, 0.3, 0.5, and 1.0 mg/kg groups, respectively. Median age 71 years, median time from diagnosis 4 years, and 70% of patients were male. Patients received a median 6 RBC units (range 0–16) in the 8 weeks before starting treatment; 46 received ≥4 RBC units (high transfusion burden; HTB) and 8 received. Of 53 patients evaluable for efficacy, 24 achieved HI-E: 0, 4, 8, and 12 patients in the sotatercept 0.1, 0.3, 0.5, and 1.0 mg/kg groups, respectively. Five of 46 (11%) HTB patients achieved RBCTI ≥8 weeks; duration of response ranged from 59–345+ days. Five of 8 (63%) LTB patients achieved RBC-TI ≥8 weeks with a mean hemoglobin increase of ≥1.5 g/dL sustained for ≥8 weeks; duration ranged from 76–233+ days. Sotatercept was generally well tolerated. Twenty (37%) patients reported ≥1 suspected treatment-related adverse event. The most common were: fatigue/asthenia (13%), headache (9%), decreased appetite (7%), and nausea (7%). Three patients discontinued due to suspected treatment-related adverse events: 1 each with grade 2 hemolytic anemia, grade 3 hypertension, and grade 2 muscular weakness in the sotatercept 0.3, 0.5, and 1.0 mg/kg groups, respectively. Conclusions: Sotatercept was well tolerated, with promising evidence of clinical activity in this cohort of anemic, lower-risk MDS patients. Further exploration of sotatercept treatment is ongoing. PF and AFL contributed equally to this abstract as senior coauthors.

EGFR activating mutations and their association with response to platinum-doublet chemotherapy in Brazilian non-small cell lung cancer patients.

The aim of the study was to analyze the frequency of epidermal growth factor receptor (EGFR) mutations in Brazilian non-small cell lung cancer patients and to correlate these mutations with response to benefit of platinum-based chemotherapy in non-small cell lung cancer (NSCLC). Our cohort consisted of prospective patients with NSCLCs who received chemotherapy (platinum derivates plus paclitaxel) at the [UNICAMP], Brazil. EGFR exons 18-21 were analyzed in tumor-derived DNA. Fifty patients were included in the study (25 with adenocarcinoma). EGFR mutations were identified in 6/50 (12%) NSCLCs and in 6/25 (24%) adenocarcinomas; representing the frequency of EGFR mutations in a mostly self-reported White (82.0%) southeastern Brazilian population of NSCLCs. Patients with NSCLCs harboring EGFR exon 19 deletions or the exon 21 L858R mutation were found to have a higher chance of response to platinum-paclitaxel (OR 9.67 [95% CI 1.03-90.41], p = 0.047). We report the frequency of EGFR activating mutations in a typical southeastern Brazilian population with NSCLC, which are similar to that of other countries with Western European ethnicity. EGFR mutations seem to be predictive of a response to platinum-paclitaxel, and additional studies are needed to confirm or refute this relationship.

Dose Modification In MDS Pts Receiving Lenalidomide As a Means To Improve Patient Persistence

BackgroundLenalidomide (LEN) has been studied in transfusion-dependent MDS patients (pts) with IPSS Low/Int-1 risk del5q disease with 55%-70% of pts becoming transfusion-independent (TI) (List, JCO, 2006). A review of Medicare claims showed MDS pts' response rates were higher when receiving >3 cycles of LEN therapy (Zeidan, Cancer 2013, in print). Interestingly, cytopenias and other cytotoxic effects of LEN can challenge physicians and pts to remain on treatment despite the finding that in del5q pts effects may indicate an expected TI Response under study conditions (Sekeres, JCO, 2008). For example, 80% of pts with del5q MDS on the Phase II MDS-003 study required dose modification (DM) due to an adverse event (AE) in achieving excellent response rates, yet less than a third had an AE leading to discontinuation of drug, suggesting that AEs can be managed through DM without discontinuation (Celgene, data on File). AimThis study examined DM and discontinuation in MDS real world pts treated with LEN in the US; results were compared with those seen in the MDS-004 clinical trial. MethodsCommercial and Medicare Advantage MDS pts newly initiating therapy with LEN were identified between 01/07 and 12/12 in a US claims database. Both pharmacy and medical benefits and ≥1 fill for LEN indicating a 10 mg/day dose were required; index date was the first LEN claim date. Pts were 18+ years old and continuously enrolled in the health plan 6 months prior to the index date (baseline period) and ≥6 months after the index date (follow-up). At least 1 claim with MDS diagnosis (ICD-9-CM 238.72-238.75) was required during study period. Pts with evidence of LEN during the baseline period were excluded.Pts with a 60+ day gap in LEN fills were considered to have discontinued LEN. Pts with an initial LEN fill of 10 mg/day dose who were subsequently prescribed 5 mg/day dose during the follow-up (prior to discontinuation) were considered to have had dose reduction. LEN fills prior to discontinuation was captured.The clinical study report summarizing the clinical trial data from MDS-004 was examined to identify the proportion of pts who dose modified and/or discontinued during trial.Real world use of LEN was then modeled using clinical trial results from MDS-004 to identify pts who may have benefitted from DM vs. discontinuation of drug. ResultsTable 1 summarizes use patterns in the MDS-004 clinical trial and real world claims database and estimates impact on real world use of LEN if DM strategy was applied based on MDS-004. In the real world dataset, 168 MDS pts were identified as initiating LEN therapy at 10mg/day. 26% (44 pts) had evidence of DM from 10 mgs to 5 mgs/day in the real world compared to 55% (38 pts) with DM in the MDS-004 study, where LEN dose reductions were required due to AEs. Similarly, 32% (54 pts) discontinued therapy in the real world, compared to 6(9%) pts in the clinical study. Pts who dose reduced in the real world had a higher average persistence of 10.8 LEN fills prior to discontinuation vs. an average of 4.25 LEN fills for pts without of dose reduction.Table 1DM, Discontinuation, and Persistence on Therapy of ‘Real-World' vs. Clinical DataA) MDS-004 Data for del5q pts starting at 10mg QD n (%) n= 69B) Real World Data MDS pts n (%) n=168C) Real World Data modeled after MDS-004 del5q pts n (%) n=168D) B and C DifferentialReceived DM38 (55%)44 (26%)92 (55%)48 (29%) Additional Real World pts who would have received DM in Clinical TrialDiscontinued6 (9%)54 (32%)15 (9%)39 (23%) Additional Real World pts who would have continued on study in Clinical Trial ConclusionsAnalysis of real world practices examined shows a small proportion of pts dose reduced LEN compared to rates in the clinical trial. LEN's overall impact may be unrealized as studies of prescribing patterns from US claims data suggest that many pt treatment courses are shortened or discontinued after a single course. Additonally, pts who DM were associated with longer persistence on LEN compared to those who did not. Further studies are warranted to assess the clinical factors association with more early discontinuation of LEN vs compared to DM, but we suspect this was in part due to expected and common side effects that were managed more commonly under study conditions. Modeling dosing patterns used in clinical trials of LEN suggests that there are likely pts that can stay on drug longer through DMs, which can be done safely and chances for response would be increased under such care. Disclosures:No relevant conflicts of interest to declare.

Insulin resistance: a predictor for response to interferon-based therapy in Egyptian patients with chronic HCV genotype 4

Egypt has the highest worldwide hepatitis C virus infection (HCV), it estimated about 13.8 %. Interferon alpha is considered the backbone for any effective treatment. These therapies are not without adverse effects nor are they always cost effective. Accordingly, it is important to identify patients with a considerable chance of response before initiation of therapy. Rapid virological response (RVR) is important for identification of non-responders permitting therapy discontinuation and avoiding adverse effects and costs. Evaluate the reliability of homeostasis model assessment (HOMA) method in prediction of HCV treatment response among Egyptian patients with chronic HCV genotype 4 infections. Our study included 80 participants; 50 non-cirrhotic non-diabetic patients with chronic HCV genotype 4 (group I), and 30 age- and sex-matched patients negative for HCV RNA and consequently they did not receive hepatitis treatment at the time of sampling (group II) were included. According to HOMA score, group I was further divided into group Ia with insulin resistance (IR) >2.5 (36 %) and group Ib with IR <2.5 (64 %). HOMA-IR was significantly associated with high RVR, progressive fibrosis stages, high pretreatment ALT levels, and body mass index. Our data suggests that IR strongly affects VR. HOMA-IR would appear to be useful in predicting RVR and should be evaluated at baseline in all chronic HCV patients before initiating interferon therapy to reduce unnecessary and ineffective treatments and enhance cost effectiveness of treatment.

Are immunosuppressive medications associated with decreased responses to routine immunizations? A systematic review

Long-term immunosuppressive medications are being used more commonly for a variety of medical conditions, including immune-mediated diseases and organ transplantation. While these medications are often necessary, they are associated with an increased risk of serious infections. Vaccination may be a way to prevent a variety of infections but vaccine responses among patients receiving immunosuppressive therapies have been variable. To systematically review the literature describing immune responses among patients on immunosuppressive therapies to vaccinations including influenza, pneumococcal, meningococcal, hepatitis A and B, tetanus toxoid, pertussis, varicella, and zoster. English language citations in the MEDLINE and EMBASE databases from 1985 to 2010. Two reviewers independently screened titles and abstracts to identify prospective, controlled studies reporting pre- and post-vaccination titers of recommended vaccines in patients receiving long-term immunosuppressive therapies for full-text review. Three reviewers independently assessed study characteristics including treatment regimens and pre- and post-vaccination titers. Of the 972 identified titles, fifteen met inclusion criteria. Ten studies assessed the effects of immunosuppressive medications on responses to influenza vaccine, four studies investigated responses following pneumococcal vaccination, and one study assessed both influenza and pneumococcal vaccination. Five of the studies that evaluated influenza vaccination showed partially diminished responses among individuals receiving immunosuppressive therapies, while one of the pneumococcal vaccine studies showed significantly decreased responses following vaccination. Patients treated with more than one immunosuppressive medication were the least likely to respond to vaccination. The heterogeneity of reported outcomes limits generalizeability. Immunosuppressive therapy, particularly combination regimens, may blunt response to influenza and pneumococcal vaccinations. To ensure the best chance of response, immunizations should be administered prior to initiation of immunosuppressive medications whenever possible.

Therapy for Aplastic Anemia

A 24-year-old man from Ecuador presents to your clinic with dyspnea on exertion, bruising, and petechiae. He is noted to be pancytopenic with ANC 430, hemoglobin 7.4 g/dL (reticulocyte count 0.9%), and platelets 18 000. His BM biopsy is hypocellular for age. Ultimately, he is diagnosed with severe aplastic anemia. He is the only child of 2 South American parents without any matches in the unrelated donor registry, including cord blood. He is red cell- and platelet transfusion-dependent. He has been recommended therapy with antithymocyte globulin and cyclosporine but declined it. He seeks recommendations about new alternatives to this regimen to improve his chance of response.