Minor Response Research Articles

Host Transcriptional Responses to High- and Low-Virulent Avian Malaria Parasites.

The transcriptional response of hosts to genetically similar pathogens can vary substantially, with important implications for disease severity and host fitness. A low pathogen load can theoretically elicit both high and low host responses, as the outcome depends on both the effectiveness of the host at suppressing the pathogen and the ability of the pathogen to evade the immune system. Here, we investigate the transcriptional response of Eurasian siskins (Spinus spinus) to two closely related lineages of the malaria parasite Plasmodium relictum. Birds were infected with either the high-virulent lineage P. relictum SGS1, the low-virulent sister lineage P. relictum GRW4, or sham-injected (controls). Blood samples for RNA sequencing were collected at four time points during the course of infection, totaling 76 transcriptomes from 19 birds. Hosts infected with SGS1 experienced up to 87% parasitemia and major transcriptome shifts throughout the infection, and multiple genes showed strong correlation with parasitemia. In contrast, GRW4-infected hosts displayed low parasitemia (maximum 0.7%) with a minor transcriptional response. We furthermore demonstrate that the baseline gene expression levels of hosts prior to infection were irrelevant as immunocompetence markers, as they could not predict future pathogen load. This study shows that the magnitude of the host transcriptional response can differ markedly from related parasites with different virulence, and it enables a better understanding of the molecular interactions taking place between hosts and parasites.

A Survey on Illicit Drug Use among University Students by Binary Randomized Response Technique: Crosswise Design

This paper aims to introduce Randomized Response Techniques (RRT’s) and show that how RRT’s are implemented in surveys in which sensitive behaviors are investigated. For this purpose, the most popular designs of the Binary RRT are summarized and an experimental study is conducted on drug use among dormitory students at a public university in Ankara, Turkey. Despite the wide applicability of the drug use studies in Turkey, surprisingly any applications using indirect questioning techniques are not observed in the literature. In this study, for the first time, drug use behavior is investigated with Crosswise design which is the most frequently used indirect questioning technique and indirect questioning method (Crosswise design) is compared with direct questioning method to evaluate the effectiveness of the RRT. Results revealed that when Crosswise design is provided on asking sensitive questions, considerably minor response refusals are happened and significantly higher drug-use estimates are observed.

What is the Prognostic Value of a Discordant Radiologic and Pathologic Response in Patients Undergoing Resection of Colorectal Liver Metastases After Preoperative Chemotherapy?

The clinical significance of discordant radiological and pathological response to preoperative chemotherapy of colorectal liver metastases (CLM) is unknown. From 2011 to 2016, all eligible patients undergoing resection for CLM after preoperative chemotherapy were included at two centres. Patients were categorized according to radiologic response using RECIST as Rad-responders (complete/partial response) or Rad-non responders (stable disease) and according to Blazer et al. pathologic response grade as Path-responders (complete/major response) or Path-non responders (minor response). Survival outcome was analysed according to radiologic and pathologic response. Among 413 patients undergoing resection of CLM, 119 fulfilled the inclusion criteria. Among these, 52 (44%) had discordant radiologic and pathologic response including 27 Rad-non responders/path responders and 25 Rad-responders/Path-non responders. Rad-non responders/path responders and Rad-responders/Path-non responders had similar characteristics except for the proportion receiving more than 6 cycles of preoperative chemotherapy (7/27 vs 16/25; P = 0.017). Median disease-free survival was not different in patients with or without discordant radiologic and pathologic responses (P = 0.195) but the type of discordance had an impact on oncologic outcome as median disease-free survival was 13.9months (95% CI 5.7-22.2months) in Rad-non responders/Path responders and 8.6 (6.2 - 10.9months) in Rad-responders/Path-non responders (P = 0.034). Univariate and multivariate analysis showed that major pathologic response was associated with improved disease-free survival (OR 0.583, 95% CI 0.36-0.95, P = 0.031). A discordant radiologic and pathologic response is common after preoperative chemotherapy for CLM. In these patients, pathologic response drives oncologic outcome.

The structural validity of the Finnish version of the Disabilities of the Arm, Shoulder and Hand: A Rasch model analysis

Introduction The construct validity of the Disabilities of the Arm, Shoulder and Hand questionnaire (DASH) has previously been questioned. The purpose of this study was to evaluate the measurement properties of the Finnish version of the DASH for assessing disability in patients with hand complaints using Rasch Measurement Theory. Methods A cohort of 193 patients with typical hand and wrist complaints were recruited at a surgery outpatient clinic. The DASH scores were analysed using the Rasch model for differential item functioning, unidimensionality, fit statistics, item residual correlation, coverage/targeting and reliability. Results In the original DASH questionnaire, the item response thresholds were disordered for 2 of 30 of the items. The item fit was poor for 9 of 30 of the items. Unidimensionality was not supported. There was substantial residual correlation between 87 pairs of items. Item reduction (chi square 95, degrees of freedom 50, p < 0.001) and constructing two testlets led to unidimensionality (chi square 0.64, degrees of freedom 4, p = 0.96). Person separation index was 0.95. The testlets had good fit with no differential item functioning towards age or gender. Conclusion Unidimensionality of the original Finnish version of the DASH was not supported, meaning the questionnaire seems to gauge traits other than disability alone. Hence, the clinician must be careful when trying to measure change in patients’ scores. Item reduction or the creation of testlets did not lead to good alternatives for the original Finnish DASH. Differential item functioning showed that the original Finnish scale exhibits minor response bias by age in one item. The original Finnish DASH covers different levels of ability well among typical hand surgery patients.

Patterns and mechanisms for larval aggregation in carrion beetle Necrodes littoralis (Coleoptera: Silphidae)

Carrion is a patchy, nutrient-rich and frequently bulky resource that hosts a complex community of competing organisms. Several insect species have specialized to use carrion for breeding, revealing a specific suite of behavioural adaptations. Larvae of carrion insects regularly aggregate while feeding, frequently forming spectacular larval masses. Here we analysed patterns and mechanisms of collective feeding by larvae of the communally breeding carrion beetle Necrodes littoralis. Using results of laboratory behavioural assays and findings from previous field experiments using pig carcasses we found that: (1) under field conditions N. littoralis larval aggregations were prevalent on large carcasses, during late decomposition stages; (2) under laboratory conditions larvae of all instars, when present on meat, formed stable aggregations; (3) larvae consistently responded to thermal characteristics of a feeding environment, aggregating in the hottest place and following changes in the heat source location, which suggests thermal cues are important for their aggregation; and (4) ground-deposited chemical cues elicited a minor response by the third-instar larvae, which indicates these cues are less important for the aggregation of larval N. littoralis. These findings highlight the prevalence of communal feeding among necrophagous insect larvae, revealing the interspecific and intraspecific diversity of patterns and mechanisms for larval aggregation on carrion.

Etorphine-Azaperone Immobilisation for Translocation of Free-Ranging Masai Giraffes (Giraffa Camelopardalis Tippelskirchi): A Pilot Study.

Simple SummaryDue to their peculiar anatomy and sensitivity to drugs, giraffes are among the most challenging mammals to immobilise. Masai giraffes have recently been listed as endangered. Hence, their conservation needs actions that require veterinary capture such as translocations. In this study, we evaluated a new protocol of immobilisation for translocation of free-ranging Masai giraffes. The hypothesis is that, by combining a potent opioid with a tranquiliser, it is possible to mitigate the capture stress, which is a major cause of disastrous homeostatic consequences, including capture myopathy and death. The combination produced, in all individuals, smooth and quick inductions and reliable immobilisations. Although hypoxaemia in a few individuals and acidosis were seen, the overall cardiorespiratory function was adequate. Whereas the initial stress to the capture was limited in the individuals, likely due to tourism-related habituation, the opioid-related excitement and resulting increased exertion was responsible for worse immobilisation and physiological derangement. A low dose of an antagonist was used and evaluated and, in the two-week boma follow-up, it proved to be efficient in providing safe recoveries and transport. At the investigated doses, the combination provided partially reversed immobilisation that allowed uneventful translocation in free-ranging Masai giraffes.Etorphine-azaperone immobilisation was evaluated for translocation of Masai giraffes. Nine giraffes were darted with 0.012 ± 0.001 mg/kg etorphine and 0.07 ± 0.01 mg/kg azaperone. Once ataxic, giraffes were roped for recumbency and restrained manually. Naltrexone (3 mg/mg etorphine) was immediately given intravenously to reverse etorphine-related side effects. Protocol evaluation included physiological monitoring, blood-gas analyses, anaesthetic times, and quality scores (1 = excellent, 4 = poor). Sedation onset and recumbency were achieved in 2.6 ± 0.8 and 5.6 ± 1.4 min. Cardio-respiratory function (HR = 70 ± 16, RR = 32 ± 8, MAP = 132 ± 16) and temperature (37.8 ± 0.5) were stable. Arterial gas analysis showed hypoxaemia in some individuals (PaO2 = 67 ± 8 mmHg) and metabolic acidosis (pH = 7.23 ± 0.05, PaCO2 = 34 ± 4 mmHg, HCO3− = 12.9 ± 1.2 mmol/l). Minor startle response occurred, while higher induction-induced excitement correlated to longer inductions, worse restraint, and decreased HCO3−. After 19 ± 3.5 min of restraint, giraffes were allowed to stand and were loaded onto a chariot. Immobilisations were good and scored 2 (1–3). Inductions and recoveries were smooth and scored 1 (1–2). Translocations were uneventful and no complications occurred in 14-days boma follow-up.

Dual dependence on BCL2 and MCL1 in T-cell prolymphocytic leukemia

Key Points Treatment of relapsed refractory T-PLL with venetoclax monotherapy results in only transient and minor clinical responses. In vitro analyses pre- and postvenetoclax indicate dual dependence on BCL2 and MCL1; combined BCL2 and MCL1 inhibition are synergistic.

CXCR4 mutational status does not impact outcomes in patients with Waldenström macroglobulinemia treated with proteasome inhibitors.

CXCR4 mutational status does not impact outcomes in patients with Waldenström macroglobulinemia treated with proteasome inhibitors.

Acalabrutinib monotherapy in patients with Waldenström macroglobulinemia: a single-arm, multicentre, phase 2 study

Chemoimmunotherapy is typically the standard of care for patients with Waldenström macroglobulinemia; however, infectious and hematologic toxic effects are problematic. Acalabrutinib is a selective, potent Bruton tyrosine-kinase inhibitor. The aim of this trial was to evaluate the activity and safety of acalabrutinib in patients with Waldenström macroglobulinemia. This single-arm, multicentre, phase 2 trial was done in 19 European academic centres in France, Italy, Greece, the Netherlands, and the UK, and eight academic centres in the USA. Eligible patients were 18 years or older and had treatment naive (declined or not eligible for chemoimmunotherapy) or relapsed or refractory (at least one previous therapy) Waldenström macroglobulinemia that required treatment, an Eastern Cooperative Oncology Group performance status of 2 or less, and received no previous Bruton tyrosine-kinase inhibitor therapy. Patients received 100 mg oral acalabrutinib twice per day in 28-day cycles until disease progression or unacceptable toxicity. The primary endpoint was investigator-assessed overall response (at least a minor response) according to the 6th International Workshop for Waldenström Macroglobulinemia (IWWM) and the modified 3rd IWWM workshop criteria. The primary outcome and safety were assessed in all patients who received at least one dose of treatment. This study is registered with ClinicalTrials.gov, number NCT02180724, and is ongoing, but no longer enrolling. Between Sept 8, 2014, and Dec 24, 2015, 122 patients were assessed for eligibility, of which 106 (87%) patients were given acalabrutinib (14 were treatment naive and 92 had relapsed or refractory disease). With a median follow-up of 27·4 months (IQR 26·0-29·7), 13 (93% [95% CI 66-100]) of 14 treatment naive patients achieved an overall response and 86 (93% [86-98]) of 92 relapsed or refractory patients per both the modified 3rd and 6th IWWM criteria. Seven (50%) of 14 treatment naive patients and 23 (25%) of 92 relapsed or refractory patients discontinued treatment on study. Grade 3-4 adverse events occurring in more than 5% of patients were neutropenia (17 [16%] of 106 patients) and pneumonia (7 [7%]). Grade 3-4 atrial fibrillation occurred in one (1%) patient and grade 3-4 bleeding occurred in three (3%) patients. The most common serious adverse events were lower respiratory tract infection (n=7 [7%]), pneumonia (n=7 [7%]), pyrexia (n=4 [4%]), cellulitis (n=3 [3%]), fall (n=3 [3%]), and sepsis (n=3 [3%]). Pneumonia (n=5 [5%]) and lower respiratory tract infection (n=4 [4%]) were considered treatment related. One treatment-related death was reported (intracranial hematoma). This study provides evidence that acalabrutinib is active as single-agent therapy with a manageable safety profile in patients with treatment-naive, or relapse or refractory Waldenström macroglobulinemia. Further studies are needed to establish its efficacy against current standard treatments and to investigate whether outcomes can be improved with combination therapies. Acerta Pharma.

RECIL versus Lugano for Treatment Response Assessment in FDG-Avid Non-Hodgkin Lymphomas: A Head-to-Head Comparison in 54 Patients.

The response evaluation criteria in lymphoma (RECIL) classification for lymphoma treatment response assessment was introduced in 2017, but it has not yet been compared to the established Lugano classification. Also, the value of the provisional “minor response” (MiR) category of RECIL is unclear. In 54 patients with FDG-avid non-Hodgkin lymphomas (41 diffuse large B-cell lymphomas (DLBCL) and 13 follicular lymphomas), [18F]FDG-PET/CT-based response according to RECIL and Lugano was determined at interim and end-of-treatment (EOT) restaging. Rates of agreement and Cohen’s kappa (κ) coefficients were calculated. The relationship between RECIL and Lugano responses and 2-year complete remission (CR) status of DLBCL patients was determined. At interim restaging, MiR was observed in 14.8%, and at EOT, in 5.6% of patients. When MiR was recoded as partial remission, agreement between RECIL and Lugano was 83.3% at interim restaging (κ = 0.69), and 90.7% at EOT (κ = 0.79). 85.4%, of DLBCL patients with responding disease at interim restaging according to both RECIL and Lugano achieved 2-year CR status; whereas, at EOT, 82.9% of patients with responding disease according to Lugano, and 85.4% of patients with responding disease according to RECIL, achieved 2-year CR status. Thus, RECIL and Lugano classifications show comparable performance for treatment response assessment, and a similar association with 2-year CR status in FDG-avid lymphomas.

ACT-14 A FIRST-IN-HUMAN STUDY OF MUTANT IDH1 INHIBITOR DS-1001B IN PATIENTS WITH RECURRENT GLIOMAS

BACKGROUNDWHO grade II/III gliomas frequently harbor isocitrate dehydrogenase 1 (IDH1) mutations, resulting in intratumoral accumulation of oncometabolite D-2-hydroxyglutarate (D-2-HG) and subsequent clonal expansion. DS-1001b is an oral selective inhibitor of mutant IDH1 R132X that was designed to penetrate the blood-brain barrier.METHODSIn this first-in-human, multicenter, phase I study (NCT03030066), eligible patients (pts) with recurrent/progressive IDH1 mutant glioma received DS-1001b twice daily (bid), continuous. A modified continual reassessment method was used for dose escalation. RANO and RANO-LGG criteria were used to assess tumor response. Pts who planned to undergo salvage surgery after developing progressive disease (PD) and who provided informed consent received DS-1001b treatment until surgery. Tumor samples were also obtained from those pts to measure the free form of DS-1001b and D-2-HG levels.RESULTSBetween Jan 2017 and May 2019, DS-1001b (125–1400 mg bid) had administered for 47 pts, and 15 pts were continuing treatment. Maximum tolerated dose (MTD) was not reached. Most AEs were Gr 1–2. Gr 3 AEs were observed in 40% of pts. No Gr 4 or 5 AEs or serious drug-related AEs were reported. One dose limiting toxicity was Gr 3 white blood cell count decreased (1000 mg bid). Of 35 evaluable pts with contrast enhancing gliomas, one, five and 11 achieved complete response, partial response and stable disease (SD), respectively. Of evaluable 12 pts with contrast non-enhancing gliomas, four achieved minor response and eight achieved SD. Peak plasma concentration (Cmax) and area under the curve (AUC) increased dose-dependently.CONCLUSIONSDS-1001b was well tolerated up to 1400 mg bid with favorable brain distribution, and MTD was not reached. Recurrent/progressive IDH1 mutant glioma pts responded to treatment. Investigation is ongoing to determine the recommended Phase II dose. The latest data will be updated. Funding source: This study was funded by Daiichi Sankyo Co., Ltd.

Abstract B143: Establishment of primary tumor models of TNBC and ER+/HER2- breast cancer in humanized mice and validation of pembrolizumab efficacy

Abstract Background: Immunotherapy is an emerging treatment option for different subtypes of breast cancer. Pembrolizumab (Keytruda®) targets PD-1 expressing T cells in tumors and mediates anti-tumor effects. Targeting PD-1 has shown promising results in advanced breast cancer and is being evaluated in clinical trials in triple-negative breast cancer (TNBC) and in estrogen receptor positive, human epidermal growth factor 2 negative (ER+/HER2-) breast cancer patients. Immunotherapy is not yet an established treatment option for early breast cancer. The aim of this study was to establish preclinical primary tumor models for TNBC and ER+/HER2- in humanized mice, and to evaluate efficacy of pembrolizumab in the models. Materials and methods: Immunodeficient CIEA NOG female mice engrafted with human CD34+ hematopoietic stem cells (huNOG mice) were inoculated orthotopically into mammary fat pad with either MDA-MB-231(SA) (TNBC) or MCF-7 (ER+/HER2-) human breast cancer cells. The mice receiving MCF-7 cells were implanted with estradiol (E2) releasing pellets before cancer cell inoculation to support tumor growth. The mice were treated with pembrolizumab (5 mg/kg) or isotype control in a Q5D schedule. The treatments were started 3 or 14 days after cancer cell inoculation in the TNBC and ER+/HER2- models, respectively. Tumor growth was monitored by caliper measurements, and the study was terminated at 3 weeks (TNBC model) or 7 weeks (ER+/HER2- model). Tumors were collected and analyzed immunohistochemically for tumor-infiltrating lymphocytes (TILs), and hematological analysis was performed from the mice in the ER+/HER2- model. Results: Tumors responded to pembrolizumab treatment in the TNBC model. Three out of eight mice responded to the treatment and one of them had a tumor rejection. Pembrolizumab treatment was associated with decrease in CD8+ TILs and granzyme B+ cells in the tumor. In the ER+/HER2- model, E2 supplementation was essential for tumor growth. However, E2 caused a decrease in the clinical condition, including decrease in white and red blood cells, leading to early sacrifices. Only modest responses for pembrolizumab were observed in a few mice and the results did not reach statistical significance. No major changes were observed in TILs due to pembrolizumab treatment. Conclusions: In the established breast cancer models in humanized mice, pembrolizumab decreased tumor growth in the TNBC model but induced only minor tumor responses in the ER+/HER2- model. Estrogen was essential for ER+/HER2- tumor growth but induced severe anemia and had immunomodulatory effects potentially influencing the lack of pembrolizumab efficacy in the model. Citation Format: Tiina E Kähkönen, Mari I Suominen, Jenni HE Mäki-Jouppila, Azusa Tanaka, Philip Dube, Michael Seiler, Jussi M Halleen, Jenni Bernoulli. Establishment of primary tumor models of TNBC and ER+/HER2- breast cancer in humanized mice and validation of pembrolizumab efficacy [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr B143. doi:10.1158/1535-7163.TARG-19-B143

Contrast-Enhanced Ultrasound for Early Prediction of Response of Breast Cancer to Neoadjuvant Chemotherapy

Abstract Purpose To evaluate the time-intensity curve (TIC) parameters on contrast-enhanced ultrasound (CEUS) for early prediction of the response of breast cancer to neoadjuvant chemotherapy (NAC). Materials and Methods This prospective study included 41 patients with breast cancer. CEUS was performed before and after the first cycle of NAC. TIC parameters were analyzed for different regions of interest (ROIs). ROI 1 targeted the hotspot area of greatest enhancement, ROI 2 delineated the area of hyperenhancement, ROI 3 included the entire tumor on grayscale ultrasound, and ROI 4 encircled the normal parenchyma. The TIC perfusion values for ROI 1, 2, and 3 were divided by the ROI 4 value. Results 11 (26.8 %) of the 41 patients showed a good response (Miller-Payne score 4 or 5) and 30 (73.2 %) showed a minor response (Miller-Payne score 1, 2, or 3). There were significant differences in the wash-out area under the curve, the wash-in and wash-out areas under the curve on ROI 1/4 after the first cycle of NAC, pre-NAC mean transit time local (mTTl) on ROI 2/4, and pre-NAC mTTl on ROI 3/4 between good and minor responders (area under the receiver-operating characteristic curve > 0.70, p < 0.05). Conclusion Some TIC parameters obtained by CEUS may allow prediction of the response of breast cancer to NAC at a very early time point.

A multi-omics approach reveals mechanisms of nanomaterial toxicity and structure–activity relationships in alveolar macrophages

In respect to the high number of released nanomaterials and their highly variable properties, novel grouping approaches are required based on the effects of nanomaterials. Proper grouping calls for a combination of an experimental setup with a higher number of structurally similar nanomaterials and for employing integrated omics approaches to identify the mode of action. Here, we analyzed the effects of seven well-characterized NMs comprising different chemical compositions, sizes and chemical surface modifications on the rat alveolar macrophage cell line NR8383. The NMs were investigated at three doses ranging from 2.5 to 10 µg/cm2 after 24 h incubation using an integrated multi-omics approach involving untargeted proteomics, targeted metabolomics, and src homology 2 (SH2) profiling. By using Weighted Gene Correlation Network Analysis (WGCNA) for the integrative data, we identified correlations of molecular pathways with physico-chemical properties and toxicological endpoints. The three investigated SiO2 variants induced strong alterations in all three omics approaches and were, therefore, be classified as “active.” Two organic phthalocyanines showed minor responses and Mn2O3 induced a different molecular response pattern than the other NMs. WGCNA revealed that agglomerate size and surface area as well as LDH release are among the most important parameters correlating with nanotoxicology. Moreover, we identified key drivers that can serve as representative biomarker candidates, supporting the value of multi-omics approaches to establish integrated approaches to testing and assessment (IATAs).

Churning races in Canada: Visible minority response change between 2006 and 2011

Why do most people have stable responses to census race questions, while some do not? Using linked Canadian data, we examine personal, social, and economic characteristics that predict response stability as White or as one of six large visible minority groups, versus a change in response to/from White or to/from another visible minority group. Response change rates in Canada are generally comparable to those in the US, UK, and New Zealand. Likely reflecting the centuries-old hegemony of Whites in these countries, White is the most stable response group in Canada as well as the US, UK, and New Zealand. Multiple-race response groups are among the newest and least stable response groups. Social statuses and experiences (mixed ethnic heritage, immigration status, and exposure to own-group members) are generally more predictive of race response stability and change than economic (income level and change in income) or personal statuses (education, age). This highlights the socially-constructed nature of race group boundaries. Joining and leaving a group are often predicted by the same status/characteristic and in the same direction, hinting that the status/characteristic adds complexity to the race-related experiences of constituents.

Randomized Comparison of Rituximab Versus Bortezomib Plus Cyclophosphamide and Dexamethasone in Newly Diagnosed Waldenstrom Macroglobulinemia Patients

Background:Waldenstrom's macroglobulinemia (WM) is one type of lymphoma that had the characteristic of both lymphocytes and plasma cells. Rituximab-based or bortezomib-based regiments are commonly used treatment approaches in routine practice in previously untreated patients with LPL/WM. However, which regiment is better still unknown. The purpose of this study is to compare the efficacy of RCD (Rituximab,cyclophosphamide and dexamethasone) and BCD (Bortezomib, cyclophosphamide and dexamethasone)in newly diagnosed WM patients. Methods:30 newly diagnosed WM patients were randomly assigned to BCD or RCD group for introduction chemotherapy. Chemotherapeutic response was evaluated after 3 cycles. If a minor response (MR) or better response achieves, addition 3 cycles will be given. If not, patients will be crossed to control group for another 3 cycles. If a MR or better response comes out, addition 3 cycles will be given, otherwise, the patients will quit this study. Results: Finally, 15 patients were assigned to each treatment group. The basic characteristics of the two groups were similar. The median time to response in RCD and BCD group were 4 months and 3 months, respectively. The CR rate in RCD and BCD group was 20% and 26.7% respectively, with VGPR rate 26.7% and 6.7%, PR rate 46.7% and 40% in each group respectively. Additional 20% minor response was observed in BCD group. The overall response was 86.7% in both groups. However, RCD group had higher good response rate (≥VGPR) compared to BCD ( 46.7% vs 33.4%, p=0.05). The rate of major response (≥PR) in RCD group was higher than that in BCD group (86.7% vs 66.7%, p=0.195). The median follow-up time was 29 months. The median duration of response in RCD and BCD group was 35 months and 30 months, respectively. The 3-year progression-free rate of RCD group was significantly higher than that of the BCD group (87.5% vs 39.2%,p=0.045). The 3-year overall survival rate was 100% with RCD group versus 70% with BCD group (100% vs 70%, p=0.127)The most common adverse events of any grade with RCD and BCD were hematological toxicity. 3 patients in the RCD group had grade 3 or higher granulocytopenia.4 patients in the BCD group occurred grade 3 or higher hypocytosis. Other adverse event in the RCD group included pneumonia (40%), non-infectious fever (26.7%), hyperglycemia (13.3%) and rash (6.7%).The most common non-hematological adverse event in BCD group were peripheral neuropathy (40%), pneumonia (26.7%), herpes zoster (13.3%) and ventosity(6.7%). Events of non-infectious fever occurred more frequently in the RCD group (26.7% vs 0%, p=0.032). However, peripheral neuropathy was more common in the BCD group (40% vs 6.7%, p=0.031). There was no serious non-hematological grade 3 or higher adverse events occurred in the both groups. Conclusion: The RCD and BCD regimens have similar overall response in newly diagnosed WM. RCD regimen has higher good response rate and longer PFS time compared to BCD regimen. Both regimens have good tolerance. Disclosures No relevant conflicts of interest to declare.

Hematological Response to Eculizumab in Paroxysmal Nocturnal Hemoglobinuria: Application of a Novel Classification to Identify Unmet Clinical Needs and Future Clinical Goals

Hematological Response to Eculizumab in Paroxysmal Nocturnal Hemoglobinuria: Application of a Novel Classification to Identify Unmet Clinical Needs and Future Clinical Goals

A Multicenter Phase II Single Arm Trial of Isatuximab in Patients with High Risk Smoldering Multiple Myeloma (HRSMM)

Background High risk smoldering multiple myeloma (HRSMM), defined as having immunoparesis and at least 95% abnormal plasma cells/all plasma cells by advanced flow cytometry, has a risk of progression to multiple myeloma of about 75% after 5 years of diagnosis. These patient have no symptoms and current standard is to follow them without treatment. Isatuximab is an IgG1 monoclonal antibody that binds to CD38 highly expressed in myeloma cells. Isatuximab has activity as monotherapy (overall response rate (ORR) 35%), with lenalidomide/dexamethasone (ORR 56%) and pomalidomide/dexamethasone (ORR 62%) in relapsed MM. We designed a phase II study to test the efficacy of isatuximab in high risk smoldering myeloma. Our study is registered in clinicaltrials.gov as NCT02960555. Methods The primary endpoint of the study is the ORR of isatuximab 20 mg/kg IV days 1, 8, 15, 22 cycle 1; days 1, 15 cycles 2-6 and day 1 cycles 7-30 in high risk smoldering myeloma. 24 patients were accrued in the first stage (of maximum 61 patients). Secondary endpoints are PFS, OS, clinical benefit rate (CBR). Exploratory endpoints are quality of life analysis (QoL), MRD, molecular/immune characterization using DNA/RNA sequencing of myeloma cells and the microenvironment before and after treatment. Results 24 patients with HRSMM were accrued from 02/08/2017 until 12/21/2018 (Table 1). All patients are evaluable for response. Best responses: ORR (≥PR) 15(62.5%), CR MRD- flow at 10-5 1 (5%), VGPR 4 (17%), PR 10 (42%), minor response (MR) 4 (18%), stable disease 5 (21%); CBR (≥MR) 79%. Median number of cycles received were 11.5 (range 6-30). Five patients have stopped treatment (one has completed the study, one with heavy history of smoking was diagnosed with squamous cell cancer of the tongue, one could no longer travel to treatments due to relocation, two progressed to active multiple myeloma after 16 and 6 cycles of treatment, respectively). There have been no deaths. DNA/RNA seq is ongoing for biomarkers of response. There were 5 grade 3 severe treatment-related adverse events (RAE) which resolved to baseline: dyspnea -related to infusion reaction (n=2), headache (n=1), ANC decrease (n=1), urinary tract infection (n=1). Most common grade 1-2 related adverse events (n): nausea (7), vomit (5), WBC decrease (3), diarrhea (3), fatigue (6), headache (4), mucositis (4), myalgia (4) and infusion reaction (3). In patients with available QoL functional scores (n=9 at baseline and n=7 after 6 months of therapy), isatuximab was effective in reducing their anxiety and worry of progression to multiple myeloma. Isatuximab also improved general QoL scores by the end of cycle 6 of treatment which were now comparable to those in the general population (Figure 1). Conclusion Isatuximab is very well tolerated, results in high response rates in HRSMM and has the potential to change the natural history of this disease. In ongoing QoL analysis, initial data shows improvement in QoL and decreased cancer worry after isatuximab treatment. Immune-genomic analysis is ongoing and may identify patients that benefit the most from treatment. Disclosures Manasanch: celgene: Honoraria; merck: Research Funding; quest diagnostics: Research Funding; sanofi: Research Funding; BMS: Honoraria; Sanofi: Honoraria. Jagannath:Multiple Myeloma Research Foundation: Speakers Bureau; BMS: Consultancy; Celgene: Consultancy; Novartis: Consultancy; Medicom: Speakers Bureau; Merck: Consultancy. Lee:Daiichi Sankyo: Research Funding; Celgene: Consultancy, Research Funding; GlaxoSmithKline plc: Research Funding; Sanofi: Consultancy; Takeda: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Janssen: Consultancy, Research Funding. Patel:Poseida Therapeutics, Cellectis, Abbvie: Research Funding; Oncopeptides, Nektar, Precision Biosciences, BMS: Consultancy; Takeda, Celgene, Janssen: Consultancy, Research Funding. Kaufman:Janssen: Other: travel/lodging, Research Funding. Thomas:Xencor: Research Funding; BMS: Research Funding; Celgene: Research Funding; Amgen: Research Funding. Mailankody:Takeda Oncology: Research Funding; Juno: Research Funding; Celgene: Research Funding; Janssen: Research Funding; CME activity by Physician Education Resource: Honoraria. Lendvai:Janssen: Employment. Neelapu:Acerta: Research Funding; Celgene: Consultancy, Research Funding; BMS: Research Funding; Kite, a Gilead Company: Consultancy, Research Funding; Incyte: Consultancy; Merck: Consultancy, Research Funding; Allogene: Consultancy; Cellectis: Research Funding; Poseida: Research Funding; Karus: Research Funding; Pfizer: Consultancy; Unum Therapeutics: Consultancy, Research Funding; Novartis: Consultancy; Precision Biosciences: Consultancy; Cell Medica: Consultancy. Orlowski:Poseida Therapeutics, Inc.: Research Funding. Landgren:Sanofi: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Adaptive: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Theradex: Other: IDMC; Abbvie: Membership on an entity's Board of Directors or advisory committees; Merck: Other: IDMC. OffLabel Disclosure: Isatuximab for the treatment of smoldering myeloma

Hypercoagulability Biomarkers in a New Score Linked to Treatment Resistance for Multiple Myeloma Patients. the Roadmap-MM Study

Background: Research has focused on the implications of platelet, endothelial cell and blood coagulation activation in the risk of venous thromboembolism (VTE) in patients with multiple myeloma (MM). The reciprocal interaction between cancer cells and blood coagulation renders biomarkers of hypercoagulability as potential candidates for the evaluation of resistance to treatment in patients with newly diagnosed multiple myeloma (NDMM). Aims: The aim of the current analysis of the ROADMAP-MM study was to identify among a large number of hypercoagulability biomarkers in NDMM patients the most clinically relevant for the inclusion in treatment-resistance assessment tools. Methods: The ROADMAP-MM-CAT study (NCT03405571) was an investigator initiated, prospective, non-interventional trial. Newly diagnosed, treatment naïve symptomatic patients with multiple myeloma (based on 2014 IMWG Criteria) (n=144) were enrolled prior to treatment initiation and response to treatment was assessed at 3 months. Selected biomarkers , such as STA-Procoag-PPL®, factor VIIa factor V, antithrombin, fibrin monomers, thrombomodulin, free TFPI, D-Dimers, P-selectin, heparanase and thrombin generation (Calibrated Automated Thrombogram® and PPP-Reagent®) were measured. Results: At inclusion no patient had received any anti-myeloma treatment or thromboprophylaxis. Median age was 66.0±11.6 (36-86) years and 53% of the population was male. Regarding ISS disease stage: 32% were ISS-I, 23% ISS-II and 45% ISS-III. High risk cytogenetics [defined as presence of any of t(4;14), t(14;16) or del17p by FISH] were detected in 27% of the patients. In 32% of patients the treatment was immunomodulatory drug (IMiD) (90% lenalidomide and 10% thalidomide) and in 64% proteasome inhibitor (PI) based whereas 4% of patients received other regimens. Before any treatment administration - patients showed significantly increased levels of TFa, FVIIa, D-Dimers and FM and significantly shorter Procoag-PPL® as compared to the group of healthy individuals. Levels of P-selectin and TM were significantly lower in patients as compared to healthy individuals. Overall, thrombin generation was attenuated in patients compared to healthy individuals. Lag-time and ttPeak were significantly increased and Peak, MRI and ETP were significantly lower as compared to the group of healthy individuals At 3 months from treatment initiation, 23% (n=33) of the patients showed poor response or resistance to the anti-myeloma treatment. Among them, 7.6% (n=11) had progressive disease, 9.7% (n=14) had stable disease and 5.7% (n=8) had minor response. Among responders (n=111) 42.3 % (n=61) achieved PR and 34.7% (n=50) had VGPR. Multivariate logistic regression analysis for demonstrated that Procoag-PPL®≥41.7 versus <41.7 sec (OR=4.06, 95% CI: 1.59-10.38, p=0.003), D-Dimers ≥1.44 versus <1.44 μg/ml (OR=2.52, 95% CI: 1.06-6.01, p=0.037) and thrombin peak ≥181.66 versus <181.66 nM (OR=3.29, 95% CI: 1.17-9.26, p=0.024), were independently associated with poor response or resistance to anti-myeloma treatment Poor response/treatment resistance was associated with longer Procoag-PPL, higher D-dimer levels and higher thrombin's Peak. The new score had 84% sensitivity and 59% specificity to identify patients who showed treatment resistance at 3 months from treatment initiation. The AUC of the ROC analysis for the model was 0.75. Conclusions: Based on the evaluation of Procoag-PPL®, D-Dimers and Peak of thrombin generation, the prospective ROADMAP-MM-CAT study led to the derivation of an original risk assessment model for the identification of NDMM patients with poor response or resistance to the anti-myeloma treatment.. The identified biomarkers of hypercoagulability need to be correlated in future studies with established clinical prognostic parameters in multiple myeloma patients and then validated clinically within the context of prospective clinical trials in order to assess their role in clinical practice and in anti-myeloma treatment optimization. Disclosures Dimopoulos: Sanofi Oncology: Research Funding. Mohty:Jazz Pharmaceuticals: Honoraria, Research Funding.

Preliminary Results from a Phase I Study of SHC014748M in Patients with Relapsed or Refractory Indolent B-Cell Lymphomas

Introduction: The phosphatidylinositol-3-kinase (PI3K) pathway plays an important role in multiple cellular functions, including proliferation, differentiation, and trafficking, and deregulation of PI3K is a hallmark of many malignancies. The preferential expression of the PI3Kδ isoform on leukocytes provides an attractive target for hematologic malignancies. SHC014748M is a novel, potent, and highly selective PI3Kδ inhibitor. This study is a phase I, first-in-human study to assess the safety, tolerability and pharmacokinetics of SHC014748M in patients with relapsed or refractory indolent B-cell lymphomas (NCT03588598). Methods: Dose escalation was performed in a 3+3 design in sequential cohorts at doses of 50-250 mg QD, and then dose expansion was conducted at the selected cohorts to find recommended Phase II dose (RP2D). Eligible patients were those with relapsed or refractory indolent B-cell lymphomas, having at least 1 measurable lesion, and with ECOG performance status 0-2. Patients received a single dose on day 1, and then after 3 days washout multiple dosing once daily was initiated until disease progression or unacceptable toxicity. Primary endpoints included safety, tolerability and pharmacokinetics. Secondary endpoints included overall response rate (ORR), lymph node response (LNR), time to response (TTR), progression-free survival (PFS) and duration of response (DOR). Results: As of Jul 16, 2019, 38 patients with relapsed or refractory indolent B-cell lymphomas were enrolled in the study, including 23 with follicular lymphoma (FL), 11 with chronic lymphocytic leukemia/Small lymphocytic lymphoma (CLL/SLL), 1 with marginal zone lymphoma (MZL) and 3 with Waldenstrom's macroglobulinemia (WM). 15 patients were treated in the dose escalation phase and 23 were treated in the dose expansion phase (12 in 150 mg cohort, 11 in 200 mg cohort). The average number of prior therapies was 2.2 (range 1-8), and 84 percent of patients had received rituximab before. No dose-limiting toxicities occurred. The most common adverse reactions were neutropenia (39.5%), fatigue (21.1%), thrombocytopenia (18.4%), diarrhea (13.2%), pneumonia (13.2%), cough (13.2%), lymphopenia (13.2%), anemia (13.2%) and rash (13.2%). Grade ≥ 3 adverse reactions were neutropenia (23.7%), pneumonia (13.2%), rash (7.9%) and diarrhea (5.3%). Among 14 FL patients who were available for efficacy evaluation, ORR was 57.1% (8 PR, 5 SD, 1 PD). Of 9 CLL/SLL evaluable patients, 5 (55.6%) had partial response, 3 (33.3%) had partial response with lymphocytosis, and 1 had stable disease. Of 3 WM patients, 1 had partial response and 2 had minor response. Conclusion: SHC014748M was well tolerated and demonstrated promising clinical activity in patients with relapsed or refractory indolent B-cell lymphomas. Disclosures Wang: Nanjing Sanhome Pharmaceutical Co., Ltd.: Employment.