High-quality Remission Research Articles

Centralized MRD Assessment at Early Timepoints in Gimema AML1718 Trial, a Phase 2 Open-Label Study of Venetoclax, Fludarabine, Idarubicin and Cytarabine (V-FLAI) in the Induction Therapy of Non Low-Risk AML

Background: New therapeutic strategies are strongly needed to improve the prognosis of high risk Acute Myeloid Leukemia (AML) patients, such as combination of novel agents and conventional chemotherapy. The Italian GIMEMA AML1718 trial (NCT03455504) investigate the safety and efficacy of the BCL-2 inhibitor venetoclax (VEN) in combination with intensive fludarabine-based induction (FLAI) [fludarabine 30 mg/sqm from day 1 to day 5, cytarabine 2000 mg/sqm from day 1 to day 5, and idarubicin 8 mg/sqm on days 1, 3 and 5] as first-line therapy for newly diagnosed non low-risk ELN AML patients. Results from the Planned Interim Analysis of Safety Run-in and Part 1 (early expansion cohorts) were presented at the last 2022 ASH Meeting. Median overall survival (OS) was not reached; probability of 12-month OS was 76%. Median disease-free survival was not reached. With a median follow-up of 10.5 months, 28 patients (49%) received allogeneic stem cell transplantation (HSCT) in first complete remission (CR). Centralized multicolour flow cytometry minimal residual disease (MFC-MRD) assessment was planned during the phase 2, part 2 of the study (confirmatory cohort) where the lower effective dose of VEN (400 mg/day) was administered in association with FLAI. Here we report results from early time-points (TPs) MRD analysis with the aim of identify the most informative TPs for MRD assessment and prognostic correlations. Methods: Erythrocyte-lysed whole bone marrow (BM) samples obtained at diagnosis from patients enrolled in the confirmatory cohort were centralized and analysed with a broad panel of monoclonal antibodies to identify the leukemia-associated phenotype (LAIP) which was used to track residual leukemic cells during follow-up. Eight color flow cytometry analysis was performed at pre-defined TPs (TP1: post-induction I, TP2: post induction II/consolidation I, following TPs: post consolidation/pre-transplantation) (FACSCantoII; BD Facs Diva Software V6.1.3). A positive flow MRD was defined by the presence of no less than 10 clustered leukemic cells/10^4 total events. Enrollment closed on January 2023. Collection and analysis of later TPs is ongoing. Results: Sixty-seven patients from 11 centers were enrolled in the phase 2, part 2. Risk stratification according to ELN 2017 was intermediate in 46% of patients and high risk in 54%. Fifty-eight/67 patients (87%) obtained CR after induction I. In the centralized MRD analysis, 170 samples has been collected and analysed so far (60 baseline samples, 110 MRD samples). Seven patients lacking baseline sample for LAIP identification were excluded from the analysis. TP1 was available in 57/59 patient achieving CR (97%), and TP2 was available in 29 patients, so far. MFC-MRD negativity was obtained in 31/57 (54%) at TP1 (post V-FLAI, Fig. 1). An increase in MFC-MRD negativity rate was observed at TP2 (post Induction II or consolidation I) with 20 MFC-MRD negative patients/29 available samples (69%, Fig. 1). Thirteen/110 follow up samples (8%), albeit resulting MRD negative, were considered inadequate for the analysis due to haemodilution, 9 from TP1 and 4 from TP2 (Fig. 1). TP1 and TP2 MRD assessment were scheduled at day 28 of Induction I and Induction II/consolidation, respectively. However, in most cases, delayed haematological recovery was observed after V-FLAI, thus resulting in suboptimal samples for MRD evaluation. Conclusions: Preliminary results from centralized MRD analysis confirm that the combination therapy is able to induce high-quality remissions with a very high percentage of MFC-MRD negativity in a difficult cohort of patients, with a higher percentage of MFC-MRD-negative after the completion of the second course of therapy. Delayed haematological recovery may impact on reliability of MRD assessment due to hypocellular and regenerative marrow samples, suggesting that in those cases MRD analysis should be postponed. Correlation with survival will be performed as the data collection will be complete.

Clinical and psychological characteristics of alcohol-dependent patients in the formation of high quality therapeutic remission

Objective. To identify clinical and psychological features that contribute to the formation of therapeutic remission in patients with alcohol dependence (PAD).Materials and methods. A comprehensive (clinical, experimental, psychological, statistical) comparative study was conducted of 79 PAD at the stage of therapeutic remission (icnluding 39 people in high-quality remission and 40 in low-quality remission) and 42 practically healthy individuals aged 27 to 55 (40.18 ± 10.2) years.Results. It was found that the condition of patients with high-quality PAD in remission differed from the condition of patients with the threat of relapse and healthy individuals with significantly fewer health complaints (p < 0.05), higher indicators of psychological functioning (p < 0.01) and a high level of activation of the nonspecific adaptive reaction of the body (NARB) (p < 0.001).It was found that the state of PAD in high remission differed from that of patients at risk of relapse and healthy individuals by a significantly lower number of health complaints (p < 0.05), higher indicators of psychological functioning (p < 0.01) and a high level of activation of nonspecific adaptive response of the body (NARB) (p < 0.001).Conclusion. The formation of qualitative and long-term therapeutic remission in PAD requires not only specific changes with a weakening of the manifestations of the disease, but also a high level of NARB, which provides energy support for the process of recovery with integration into a healthy society.

EXPERIENCE OF PHARMACOGENETIC TESTING IN THE TREATMENT OF ANTIPSYCHOTICS

IntroductionOne of the promising methods for optimizing treatment in order to achieve high-quality remissions is a personalized approach to prescribing therapy in the form of pharmacogenetic testing, the feasibility of which has already been substantiated and proven in a number of clinical guidelines. By the beginning of 2022, several influential regulatory and expert organizations recommend considering the results of genetic testing when prescribing therapy. Thus, personalization of antipsychotic therapy is being introduced in the world practice.ObjectivesTo establish the significance of pharmacogenetic markers that determine the efficacy and safety of antipsychotic therapy in patients with schizophrenia in clinical practice.MethodsThe study included 264 patients (141 men, 123 women; 27.3 ± 4.5 years) from among the first hospitalized in a psychiatric hospital in the period 2018-2020, meeting the inclusion criteria (psychosis within the schizophrenia spectrum disorders; consent to participate in research). Non-inclusion criteria - signs of organic brain damage; alcohol or substance abuse; somatic pathology in the stage of decompensation). The examination took place in three stages - in the first days of hospitalization at the peak of the acute condition and during the formation of remission - after 6 and 12 months. Genetic analysis was performed using high-density biochips from Illumina CoreExome Bead (Illumina Inc, USA). During the follow-up observation, some patients dropped out due to refusal to undergo examination, change of diagnosis or change of place of residence. After 6 and 12 months, it was possible to trace the dynamics of the state of 91 patients (50 men, 41 women; 24.9 ± 4.6 years).ResultsBased on the follow-up results, two types of schizophrenia dynamics were identified - with a relatively favorable and unfavorable course. The formation of a relatively stable remission corresponding to the criteria proposed by the working group was noted in 47 patients (51.6%), carriers of gene polymorphisms: DRD2 rs1799732 (del); COMT rs4680(GG); BDNF rs6265 (CC); ANKK1 rs1800497 (GG); MC4R rs489693 (AA); ABCB1 rs1045642 and ABCC1 rs212090 (GG). An unfavorable course with the ineffectiveness of antipsychotics was found in 48.4% of cases in patients with DRD2 rs1799732 (G/del) carriers; COMT rs4680(AA); BDNF rs6265 (TT); ANKK1 rs1800497 (AA); MC4R rs489693 (GG); ABCB1 rs1045642 and ABCC1 rs212090 (AA).ConclusionsAfter analyzing the results of genetic testing and clinical and dynamic characteristics of the course of schizophrenia, we can talk about the relationship between the establishment of high-quality remission in the presence of polymorphisms in the genotype, whose role has been proven in terms of the effectiveness and safety of antipsychotics.Disclosure of InterestNone Declared

Different trajectories of the first-episode psychosis remission in young adults

IntroductionAnalysis of the first-episode psychosis remission, including post-psychotic affective and primary negative symptoms as well as personality changes, is necessary to personalize therapy and rehabilitation.ObjectivesWe aimed to identify different trajectories of psychosis remission in young adults.MethodsFirst-episode psychosis patients (n=56, mean age 19.8±2.5 years, all males) underwent psychopathological assessment at the stage of remission.ResultsThree trajectories of remission were identified. The thymopathic trajectory (33.93%, 19 patients) was characterized by the gradual increase of subclinical affective symptoms and resulted with a high-quality remission. In 63.61% cases in this group persistent depressed mood was present after a psychotic episode. Some patients (36.84%) became prone to depressive reactions. The pathocharacterological trajectory (39.28%, 22 patients) was characterised by personality changes with increase of existing traits or the development of traits previously not present. Types with an increase of schizoid (14.29%), histrionic (19.64%), and anxiety-hypochondriacal (5.36%) traits were identified. Patients in this group had high- as well as low-quality remission. The destructive trajectory (26.79%, 15 patients) was characterised by residual positive or single negative symptoms. Patients in this subgroup had low-quality remission with poor functioning and signs of treatment resistance.ConclusionsAnalysis of trajectories of the first-episode psychosis remission allowed us to choose the most effective strategy for personalized supportive treatment.DisclosureNo significant relationships.

New goals for depression therapy

The review is devoted to the consideration of the effectiveness of treatment of depression, the ratio of symptomatic and functional remission, factors associated with the achievement of high-quality remission and recovery of patients. Currently, between 29 and 66% of patients do not fully recover from antidepressant therapy and have residual symptoms of depression. Persistent depressive symptoms, neurocognitive deficits predict increased risk of relapse, social disability, impair interpersonal relationships, and represent a barrier to functional recovery. The results of a comparative analysis of antidepressants in terms of their effect on the restoration of the functioning of patients with depression are presented. It has been established that the positive impact on the social functioning of patients should be an important criterion when choosing an antidepressant for supporting therapy. Effective therapeutic approaches that maintain symptomatic remission increase the potential for functional recovery.

Achievement of remission after first-episode psychosis in youth

IntroductionDynamic assessment of remission achievement after first-episode psychosis (FEP) is necessary for early detection of post-psychotic depression, negative symptoms and changes in personality traits. The latter allows to decrease suicide risk and optimize treatment and social rehabilitation.ObjectivesWe aimed to analyze achievement of remission after FEP in youth and to define prognostic criteria for psychosis outcome.MethodsFifty-six patients (16-25 y.o., mean age 19,8 ±2,5 y.o.) after FEP have been receiving follow-up outpatient visits for 3 years. PANSS was applied to assess psychotic symptoms. Depressive symptoms were assessed with HAMD-21.ResultsRemission achievement after FEP is a three-stage process. The stage of reduction and modification of psychotic symptoms is characterized by diminishing personality deterioration and decrease of leading positive symptoms. The second stage, stabilization, is defined through the presence of depressive symptoms with positive (HAMD-21 17,49 ± 7,49) and negative affectivity (HAMD-21 23,68 ± 9,24) with preponderance of emotional, volitional, and cognitive deficits as well as high suicide risk. The third stage, reintegration, is characterized by the combination of negative symptoms with preserved personality resources. There are three reintegration trajectories, with predominant affective or negative symptoms or personality deficits. Mean decrease of PANSS scores was 54,88 ± 6,17 during the overall remission. In the majority of cases (62,5%) the stage of reintegration was finished with the achievement of high-quality remission, coinciding with international remission criteria. The study was supported by RFBR grant 18-013-01214ConclusionsOur approach to remission assessment allowed us to decrease suicide risk and to provide optimal treatment.DisclosureNo significant relationships.

Depression during the COVID-19 pandemic (analysis of clinical cases)

Currently, in various world regions, the prevalence of depressive and anxiety disorders due to the impact of coronavirus infection is repeatedly increased compared to that in previous years. Among the predictors of their development during the pandemic, there are COVID-19 symptoms, a history of mental disorders, as well as restrictive measures, and financial losses.The paper describes three clinical cases of depressive disorders during the COVID-19 pandemic, with the depiction of the anamnesis, somatic and mental status, the patholopsychogical qualification of the condition, and the justification of a therapy regimen. The multifactorial stressor effect of the COVID-19 pandemic has provoked an exacerbation of depression in a male patient with a history of affective disorder; the development of a nosogenic depressive reaction of demoralization in a female patient with coronavirus pneumonia; the worsening of somatization dysthymia in a female patient of involutional age. The timely recognition of depression and its treatment with currently available antidepressants have contributed to the achievement of high-quality remission, the increase of stress resistance, and the improvement of quality of life in the patients.

A real-world study of 176 cases with aplastic anemia treated in outpatient

目的探索真实世界门诊治疗再生障碍性贫血（AA）患者的诊断流程、治疗及疗效。方法评估2018年1月至2019年12月门诊治疗176例AA患者的诊断流程、治疗方案及疗效。结果患者出现症状至首次就诊中位时间7（5～120）个月，就诊原因包括出血（52.3%）、贫血（51.7%）、感染（6.8%）。诊断流程中168例（95.5%）患者完成髂骨骨髓穿刺（骨穿），仅22例（17.1%）完善了多部位骨穿（胸骨分类）；骨髓活检完成率85.1%（143/168）；只有59.5%（100/168）和58.9%（99/168）完成了骨髓流式免疫分型及染色体核型分析；86例（48.5%）完成阵发性睡眠性血红蛋白尿（PNH）克隆筛查；造血祖细胞培养检查完成率最低，仅45例（26.8%）。环孢素A（CsA）联合雄激素及左旋咪唑为最常见治疗方案，总计77例（43.8%），其次为CsA联合雄激素45例（25.6%），单用CsA者24例（13.6%），单用雄激素者16例（9.1%），14例（7.9%）患者确诊后选择中药或未治疗。根据门诊复诊频率将176例患者分为复诊规律组（每年≥4次）130例（73.9%）和复诊欠规律组（每年<4次）46例（26.1%）。复诊规律组6个月有效率较高（52.5%对28.0%，P＝0.005），12个月高质量缓解率更好（40.7%对16.7%，P＝0.027），24个月复发率更低（4.4%对36.4%，P＝0.001）。结论真实世界治疗的AA患者诊断流程需重视多部位骨穿检查并完成PNH克隆筛查、流式免疫分型、染色体核型分析及造血祖细胞培养检查；门诊规律复诊患者可获得高质量缓解，复发率低，推荐每年至少复诊4次。

Clinical Relevance of- Limit of Detection (LOD) - Limit of Quantification (LOQ) - Based Flow Cytometry Approach for Measurable Residual Disease (MRD) Assessment in Acute Myeloid Leukemia (AML)

Background: In Acute Myeloid Leukemia (AML), identification of measurable residual disease (MRD) thresholds with clinical significance is still a matter of debate. For this purpose, multiparametric flow cytometry (MFC) is extensively employed for MRD quantification, due to high sensitivity (down to 1:10-3/10-5 cells) and wide applicability (up to 90% of cases). The identification of 20 clustered residual leukemic cells seems sufficient for the recognition of MRD presence (lower limit of detection [LOD]), whereas a cluster of 50 events may be the minimum threshold for the quantification of a cell population (lower limit of quantitation [LOQ]), provided a sufficient denominator of relevant events (500'000-1'000'000) is acquired. Methods: Using a MFC assay, we assessed the predictive power of a threshold calculated applying the criteria of LOD and LOQ on 261 intensively treated AML patients enrolled in the GIMEMA AML1310 prospective trial.According to the protocol design, patients with a bone marrow residual leukemic cells count (RLCc) equal or above 0.035% of the total no. of mononuclear (MNC) cells qualified as MRDpos,, whileusing LOD and LOQ, we selected the following categories of patients: 1) LODneg if RLCc was below LOD (20x100/total no. of events); 2) LODpos-LOQneg if RLCc was between LOD and LOQ; and 3) LOQpos if RLCc was above LOQ (50x100/total no. of events). Results: The ELN target of 500'000 events was reached in 182/261 (69.6%) patients. Overall, using the predefined AML1310 protocol MRD threshold, 154 (59%) and 107 (41%) were MRDneg and MRDpos, respectively, whereas 74 (28.4%), 43 (16.5%) and 144 (54.4%) patients were classified as LODneg, LODpos-LOQneg and LOQpos, respectively. Two-year overall survival (OS) was 75.4% vs. 79.8% vs. 66.4% for LODneg, LODpos-LOQneg and LODpos, respectively (p=0.1197), and 74.5% vs. 66.4% according to AML1310 protocol 0.035% threshold for MRDneg and MRDpos patients, respectively (p=0.3521). Due to superimposable outcome, LOD-LOQneg and LODpos-LOQneg categories were combined. Accordingly, LODneg/LODpos-LOQneg and LOQpos groups clearly differed in terms of OS (77% vs. 66.4%, p=0.0437) [FIGURE 1A]. Such a figure was challenged in multivariate analysis (p=0.048, HR 0.628, 95% CI 0.396-0.997) that confirmed the independent role of LOD-LOQ approach in influencing OS. To enhance the predictivity of LOD-LOQ estimate, we then focused on samples acquisition of which passed the 500'000 events, according to ELN guidelines. Among 182/261 (69.7%) cases with &amp;gt; 500'000 MNC events as denominator, LODneg/LODpos-LOQneg and LOQpos subgroups were clearly distinct in terms of OS (2-years OS of 83.5% vs. 69.4%, p=0.009). [FIGURE 1B] Similarly, also when selecting those patients (158/261 [60.5%]) whose acquisition passed 500'000 CD45+ events, LODneg/LODpos-LOQneg and LOQpos showed a different behavior with 2-years OS of 86.7% vs. 69.0%, respectively (p=0.004). [FIGURE 1C] Finally, when considering the interaction of the 3 LOD-LOQ categories with possible post-remissional strategies, LODneg/LODpos-LOQneg patients submitted to autologous stem cell transplant showed the best 2-years OS (88.9%) as compared to all the other categories (allogeneic stem cells transplant and no graft-based treatments) (p=0.026). Summary/Conclusion: In conclusion, the use of LOD-LOQ method results in a more sensitive detection of MRD that, in turn, translates in a more accurate recognition of patients with different prognosis. Actually, such an approach allowed to dissect even further the category of patients called MRDneg according to the AML1310 protocol definition, since MRDneg subjects who belonged to a "true negative" LOD-LOQ sub-group [LODneg/LODpos-LOQneg] had a better outcome than the other MRDneg ones. This MRD approach could serve as a useful tool to personalize post-remission strategy in intensively treated AML patients, through selection of high-quality remission patients who may benefit from less intensive post-consolidation therapies. Disclosures Voso: Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Venditti:Novartis: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Pfizer: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Speakers Bureau; Amgen: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Jazz: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); AbbVie: Consultancy, Honoraria, Other: TRAVEL, ACCOMODATIONS, EXPENSES (paid by any for-profit health care company); Janssen: Consultancy, Honoraria, Other: TRAVEL, ACCOMODATIONS, EXPENSES (paid by any for-profit health care company).

Clinical and Dynamic Characteristics оf Therapeutic Remissions after Acute Paranoid Psychoses in Schizophrenic Patients Treated with Antipsychotics of Various Generations

Background: the comparative aspect of the clinical-diagnostic and prognostic evaluation of long-term remissions treated with antipsychotics of various generations in patients with shift-like schizophrenia remains poorly studied and retains scientific and practical actuality. The purpose of the study: a comparative study of the therapeutic effect of antipsychotics of different generations on clinical-psychopathological peculiarities and the dynamics of 2-year remissions after acute paranoid states in patients with shift-like schizophrenia. Patients and methods: 34 female patients (average age made up 26.9 years old) were diagnosed in shift-like schizophrenia with a clinical picture of the attack as acute paranoid syndrome (F20.02 according to ICD-10). 16 patients received treatment with typical neuroleptics (TN), other 18 patients received atypical neuroleptics (ATN). The study was conducted as an open prospective, using clinical-psychopathological, clinical-catamnestic and clinical-psychometric methods. The mental state of patients was assessed four times: upon admission to the hospital in acute psychosis (1 point), when entering remission (2 points), after 1 and 2 years of remission (3 and 4 points). In psychometric assessment was used calculated for 1 patient indices of the main total score of all signs (MTS) and main score of 1 sign (MS) of the PANSS scale and its subscales of positive (P), negative (N) and general psychopathological (G) syndromes. Results: at the end of the active treatment with both types of antipsychotics at the 2 point of assessment, was reduced MS of positive symptoms P+G subscales from 3.3 to 1.7 scores on TN and from 3.8 to 2.2 scores on ATN, with a remission and stabilization of the achieved improvement with reduction of MS at 4 points up to 1.5. MS of negative symptoms by the 2 nd year of remission on ATN decreased from 2.7 to 2.0 in parallel with the reduction of positive signs by P + G; on TN there was an increase in MS indices of subscale N from 2.3 to 2.7 scores. The assessment of negative disorders is discussed as “secondary” negative due to the phenomenologically is assumed with the symptoms of the positive syndrome and the effects of neurolepsy. Conclusion: TN and ATN exhibit a similar “antipsychotic” effect in the treatment of acute paranoid psychoses in shift-like schizophrenia patients with the formation of long-term high quality remissions, stabilization of degrees of reducted productive psychopathological symptoms and with the absence of the progredience disease. To optimize the therapeutic effect of both types of antipsychotics, it is recommended correction of the regime and the term in transition from active to maintenance therapy and prescription of neurolepsy correctors to reduce severity in the picture of “secondary” negative symptoms.

Parallel Evolution of Multiple PSMB5 mutations in a Myeloma Patient Treated with Bortezomib

Introduction:Proteasome inhibition is the backbone of various Multiple Myeloma (MM) treatment regimens, leading to durable responses and high quality remissions. However, under prolonged therapy patients eventually develop drug resistance and the underlying mechanisms have been poorly understood. Proteasome inhibitor resistant cell lines were generated by continuous exposure to proteasome inhibiting drugs. In these cell line models a number of variants within the PSMB5 gene were observed. This includes single point mutations, leading to conformational changes of the _5 subunit within the 20S proteolytic core of the proteasome, impairing its chymotryptic catalytic function and the binding of inhibitory drugs. However, no PSMB5 mutations could, so far, be identified in human disease, leaving the functional relevance of such mutations to be determined.Methods:We applied the MM Mutation Panel (M3P) and used the Personal Genome Machine (Life Technologies) to sequence CD138+ purified bone marrow plasma cells and peripheral blood germ line control from a MM patient in third relapse that had been previously treated by various proteasome inhibitor containing therapies (VTD-PACE, VCD, PAD-Rev). This patient was subsequently treated with a pomalidomide, bortezomib, adriamycin and dexamethasone combination therapy (Pom-PAD) and achieved a partial remission after 4 cycles of therapy. When being exposed to VCD at earlier relapse a complete remission was induced within 6 cycles of therapy, demonstrating excellent response to proteasome inhibition at this earlier disease stage.Results:We identified clonal missense mutations in this patient at known NRAS hotspot location (p.Gln61Arg) and in MAX (p.Arg35His). Most notably we found and validated four subclonal single point mutations in PSMB5, each of them in subclonal frequencies with variant reads (VR) ranging from 1.9%- 5.9% (average read depth 750X). All PSMB5 mutations occurred in a highly conserved region in exon 2 of the gene (p.Cys122Tyr, p.Met104Ile, p.Ala86Pro, p.Ala79Thr), with three of them being located within the proteasome inhibitor drug binding site. Our 400bp amplicon design allowed us to observe that each mutation identified in PSMB5 is exclusively present on a different sequencing read and no reads are shared between the mutations. This implies that the mutations are present on different subclones of the tumor, which means that, despite low VR frequencies of the single mutation, in sum more than a quarter of the whole tumor might be affected by mutated PSMB5. At a disease stage when the patient was well responsive to proteasome inhibitor treatment (at diagnosis and at first relapse), of note, none of the mutations in PSMB5 is detectable.Conclusion:Here we report the first in human PSMB5 mutation in a MM patient. These mutations evolved in parallel within different subclones of the disease under the selective pressure of bortezomib- containing treatment regimens, representing branching evolution. It is to speculate whether previous investigations negating the existence of PSMB5 mutations in proteasome inhibitor treated patients might not have sequenced deep enough or did set up a sensitivity cut-off too rigid to detect such subclonal mutations. Our finding suggests that the mutations identified may contribute to the development of proteasome inhibitor resistance, emphasizing the need for more detailed genomic characterization of tumors, including minor subclonal mutation detection. Functional analysis of the mutations is ongoing and results will be presented at the meeting. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Combined Antirelapse Therapy in Patients with Schizoaffective Disorder: A Prospective Cohort Study

Background: In most studies, patients with schizoaffective disorder (SAD) are often combined into one group along with schizophrenia patients or less commonly with those suffering from affective disorders, which makes it difficult to obtain data about the peculiarities of SAD treatment. Articles dedicated to SAD treatment in the interictal period are rare. Methods and Results: The prospective cohort study was conducted from 2011 to 2015. The study involved 86 patients diagnosed with SAD according to ICD-10. Patients received neuroleptics (NLs) as antirelapse therapy for 2 years (NL therapy); then mood stabilizers (MSs) were added to the antirelapse treatment (NL+MS therapy). The results of this combined therapy with MSs were evaluated after 2 years of treatment. Our results suggest that the use of combination therapy that includes antipsychotics and MSs leads to maintenance of a higher quality remission. Remission becomes more prolonged and affective swings less pronounced, resulting in improved quality of life in SAD patients. Improving the quality of remission can be attributed to the following characteristics of the combined therapy: a) the use of lower doses of neuroleptics; b) a reduction in the frequency and severity of mood swings; and c) an increase in patient compliance. Conclusion: The use of combined pharmacotherapy including antipsychotics and MSs produces a longer, high-quality remission. The inclusion of MSs in the scheme of treatment increases the patient adherence to a medication regimen. The use of MSs in combination therapy reduces affective fluctuations, thereby increasing the probability of maintaining remission with complete symptom relief. (Int J Biomed. 2016;6(2):119-123.).

Src family kinase inhibitor PP2 enhances differentiation of acute promyelocytic leukemia cell line induced by combination of all-trans-retinoic acid and arsenic trioxide

An all-trans-retinoic acid (ATRA) and arsenic trioxide (ATO) combination yields high-quality remission and survival in newly-diagnosed acute promyelocytic leukemia (APL). For subsequent similar data, NCCN guidelines indicate that ATRA plus ATO is one of the recommended regimens for the treatment of patients with APL. We demonstrated SFK (Src family kinase) inhibitor PP2-enhanced APL cell differentiation when combined with either ATRA or ATO with difference in activation of RA-induced genes. In this study, we investigated whether SFK inhibitor PP2 could enhance the differentiation of NB4 APL cells when combined with ATRA and ATO and the changes in the expression of intercellular adhesion molecule-1 (ICAM-1) derived from the retinoic acid receptor (RAR) target gene.Treatment of NB4 cells with 1μM of ATRA, 0.5μM of ATO, or 10μM of PP2 for 72h induced expression of CD11b-positive cells by 13.01%, 11.53% or 13.28%, respectively. However, the combination of ATRA and ATO and the combination of three agents (ATRA, ATO, and PP2) led to a significantly higher expression of CD11b-positive cells (30.96% and 63.17%, respectively). The synergistic effect of the combination of three agents was more significant than the combination of ATRA and ATO. These results were confirmed with NBT staining. These effects were not related to apoptosis. Annexin-V-fluorescein staining revealed that a combination of ATRA and ATO and combination of the three agents did not induce apoptosis in NB4 cells. The expression of ICAM-1 markedly increased in cells treated with the combination of the three agents.These findings suggest that the SFK inhibitor can enhance differentiation of APL cells combined with ATRA and ATO. FDA approved SFK inhibitors, such as dasatinib and bosutinib, may be beneficial for the treatment of APL with a combination of ATRA and ATO.

Src Family Kinase Inhibitor PP2 Enhances Differentiation Of Acute Promyelocytic Leukemia Cell Line Induced By Combination Of ATRA and Arsenic Trioxide

All-trans-retinoic acid (ATRA) and arsenic trioxide (ATO) combination yields a high quality remission and survival in newly diagnosed acute promyelocytic leukemia. For subsequent similar data, NCCN guidelines indicate that ATRA plus ATO is an alternative for patients who cannot tolerate anthracycline therapy. We demonstrated that SFK (Src Family Kinase) inhibitor PP2 enhanced acute promyelocytic leukemia (APL) cell differentiation when combined with either ATRA or ATO with difference in activation of RA-induced genes. In this study, we investigated SFK inhibitor PP2 could enhances the differentiation of NB4 APL cells when combined with ATRA and ATO and the changes in the expression of intercellular adhesion molecule-1 (ICAM-1) derived from the retinoic acid receptor (RAR) target gene.Treatment of NB4 cells with 1 nM of ATRA, 0.5 uM of ATO, or 10 uM of PP2 for 72 hours induced expression of CD11b-positive cells by 13.01%, 11.53% or 13.28%, respectively. However, the combination of ATRA and ATO and the combination of three agents (ATRA, ATO, and PP2) led to a significant higher expression of CD11b-positive cells (30.96% and 63.17%, respectively). The synergistic effect of the combination of three agents was more significant than the combination of ATRA and ATO. These results were confirmed by NBT staining. These effects were not related with apoptosis. Annexin-V-fluorescene staining revealed that combination of ATRA and ATO and combination of three agents did not induced apoptosis in NB4 cells. The expression of ICAM-1 was markedly increased in cells treated with the combination of three agents.These findings suggest that the SFK inhibitor can enhances differentiation of APL cells combined with ATRA and ATO. FDA approved SFK inhibitors, such as dasatinib and bosutinib, may be beneficial for the treatment of APL in combination with ATRA and ATO. Disclosures:No relevant conflicts of interest to declare.

P03-155 Clinical content of schizotypal personality disorder

Background and aim:«Schizotypal personality disorder» occupies a special position in the classification of mental disorders. It is not enough investigated, what kind of disorders they are like, their characteristics are, and how they differ from schizoid personality disorder and continuous sluggish schizophrenia. with the aim to define the clinical features of schizotypal personality disorder 58 patients were examined.Results:•Schizotypal personality disorder is similar to deficit states, observed at schizophrenia, clinically limited to personality sphere, without the signs of flow of endogenous process and psychotic disorders.•Schizotypal personality disorder on the clinical content reminds schizoid, but insignificant ideatory disorders are typical. Dymamic of psychopathy - disposition to decompensation - is never observed.•Schizotypal personality disorder can be diagnosed as latent schizophrenia, because the clinical picture is similar. the special value acquires a dynamic aspect typical of the endogenous process.•High quality remission of schizophrenia limited of specific personality changes, as a variant of «acquired psychopathy» can be considered as clinically identical to «schizotypal personality disorder».Conclusion:A content of Schizotypal personality disorder includes a group of disorders of schizophrenia spectrum, different originally, from shizofreniform personality disorders without the signs of dynamics to the different states of development of schizophrenia - initial (latent schizophrenia), and final (high quality remission of schizophrenia as practical completion of schizophrenia process with the formation of certain features of personality). It can explain the special place of «Schizotypal personality disorder» in the classification of psychic disorders.

Addressing circadian rhythm disturbances in depressed patients

Desynchronisation of normal circadian rhythms, including the sleep-wake rhythm, is common in major depressive disorder (MDD). The association between sleep disturbances and depression has long been recognised. Disturbed sleep is a diagnostic criterion for MDD, and insomnia commonly precedes the onset of symptomatic mood disorders. Disruptions of the sleep-wake cycle (sleep architecture and timing) are residual symptoms that may prevent the attainment of high-quality remission and delay recovery from MDD. Therefore, early recognition and treatment of sleep disturbances may be important for the treatment and prevention of recurrent depression. Evidence suggests that melatonergic (MT(1) and MT(2)) and the 5-HT(2C) serotonergic receptor subtypes are important modulators of circadian rhythmicity. Agomelatine is the first melatonergic antidepressant; an agonist of melatonin MT(1) and MT(2) receptors, with additional antagonist properties at the 5-HT(2C) receptors. Agomelatine combines antidepressant efficacy including quality and efficiency of sleep, with a more favourable side-effect profile than current antidepressant treatments, including neutral effects on sexual function, bodyweight and the absence of discontinuation symptoms. These positive features provide a novel approach to the treatment of depression and the attainment of high-quality remission in MDD.

ThaDD-V Treatment for Patients with Relapsed/Refractory Multiple Myeloma: A Feasibility/Activity Study.

ThaDD regimen has provided significant results in recurrent/relapsed multiple myeloma (MM) patients (Offidani et al, 2006). In order to further improve those results without significantly increasing toxicity, we decided to include Velcade, synergic as per activity but not toxicity with the other drugs of ThaDD regimen. ThaDD-V was scheduled as follows: Thalidomide 100 mg/day, pegylated liposomal Doxorubicin 30 mg/sm iv days 4; Dexamethasone 20 mg days 1–2, 4–5, 8–9, 11–12 and Velcade 1.3 mg/sm iv days 1, 4, 8, 11 every 28 days (induction therapy). Patients received bortezomib for alternate cycles as following: 1 mg/sm day 1, 8, 15 and dexamethasone 20 mg days 1–2, 8–9, 15–16 and thalidomide 100 mg/day and dexamethasone 40 mg/day for 4 days monthly for a total of six cycles as consolidation therapy. Then patients received thalidomide 100 mg/day until relapse (maintenance therapy). Actually 20 patients (7 M, 13 F; median age 62.5 yrs, range 31–75) are assessable for response and toxicity. Five pts (25%) showed WHO performance status (PS) > 1, 9 pts (45%) presented refractory disease, 8 pts (40%) were priorily administered ≥ 2 lines of a treatment and 14 patients (70%) were submitted to one previous autologous stem cell procedure. Seven patients (35%) had extramedullary disease and 7 had unfavourable cytogenetics. Twelve patients scored an ISS ≥ 2 and 11 (55%) were in first remission for ≤ 12 months median duration. No patients were previously treated with Velcade, whereas six patients had received short-term Thalidomide treatment. Response was assessed according to IMVG uniform response criteria. Seventeen of 20 patients responded after at least one chemotherapy cycle reporting 5 (25%) sCR, 3 CR (15%), 8 VGPR (40%) and 1 stable disease. Three patients (15%) had extramedullary progressive disease. In a median follow-up of 12 months, 2 (10%) patients progressed and 1 (5%) died from cardiac infarction. Time to progression and overall survival were 73% and 95% at 12 months. We observed 4 grade 3 thrombocytopenia, 2 grade 3 DVT, 1 grade 3 diarrhoea, 1 grade 3 asthenia, 1 grade 4 infection and 1 grade 3 dermatological toxicity. Six patients developed grade 2 peripheral neuropathy and other three grade 3. In conclusion, ThaDD-V is extremely active in advanced MM patients as demonstrated by the elevated precentage of high quality remission. Nevertheless, patients are at substantial risk of developing neurotoxicity so the protocol was amended as per Velcade dose intensity and Thalidomide dose.

C.12.04 A high quality remission: benefits for depressed patients

C.12.04 A high quality remission: benefits for depressed patients

High-quality remission: potential benefits of the melatonergic approach for patients with major depressive disorder

Full remission of symptoms is the goal for the acute treatment of depression, because incomplete remission is associated with poor outcomes including higher risk of relapse and chronicity. The current definitions for remission (e.g. a score of </=7 on the Hamilton Depression Rating Scale), however, allow for the presence of residual symptoms of depression even if remission is attained. The focus now is on the quality of remission, that is, ensuring a minimum of such residual symptoms, because the consequences of low-quality remission also include impairment in psychosocial functioning. The most common residual symptoms are sleep disturbances, fatigue, and disinterest. Sleep-associated residual symptoms are particularly common, and are a major concern because most current treatments fail to adequately address sleep disturbances and may even aggravate them. Other side effects of current treatments, such as weight gain and sexual dysfunction, may also reduce the quality of remission. A novel approach to the treatment of depression with agomelatine, a melatonergic MT1 and MT2 receptor agonist and 5-HT2C receptor antagonist, may be an effective treatment that improves the quality of remission, as it combines good efficacy with positive effects on sleep, neutral effects on sexual function, and a favorable side effect profile.

Biology and treatment of chronic lymphocytic leukemia.

Major advances have occurred in our understanding of the biology, immunology, and opportunities for treatment of chronic lymphocytic leukemia (CLL) in recent times. Surface antigen analysis has helped us define classical CLL and differentiate it from variants such as marginal zone leukemia, mantle cell leukemia, and prolymphocytic leukemia. An important observation has been that the B-cells in indolent types of CLL, which do not require therapy, have undergone somatic hypermutation and function as memory B-lymphocytes whereas those more likely to progress have not undergone this process. Section I by Dr. Nicholas Chiorazzi encompasses emerging elements of the new biology of CLL and will address the types of somatic hypermutation that occur in CLL cells and their correlation with other parameters such as telomere length and ZAP70 status. In addition he addresses the concept of which cells are proliferating in CLL and how we can quantitate the proliferative thrust using novel methods. The interaction between these parameters is also explored. Section II by Dr. Thomas Kipps focuses on immune biology and immunotherapy of CLL and discusses new animal models in CLL, which can be exploited to increase understanding of the disease and create new opportunities for testing the interaction of the CLL cells with a variety of elements of the immune system. It is obvious that immunotherapy is emerging as a major therapeutic modality in chronic lymphocytic leukemia. Dr. Kipps addresses the present understanding of the immune status of CLL and the role of passive immunotherapy with monoclonal antibodies such as rituximab, alemtuzumab, and emerging new antibodies. In addition the interaction between the CLL cells and the immune system, which has been exploited in gene therapy with transfection of CLL cells by CD40 ligand, is discussed. In Section III, Dr. Michael Keating examines the question "Do we have the tools to cure CLL?" and focuses on the fact that we now have three distinct modalities, which are able to achieve high quality remissions with polymerase chain reaction (PCR) negativity for the immunoglobulin heavy chain in CLL. These modalities include initial chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab, the use of alemtuzumab for marrow cytoreduction in minimal residual disease and allogeneic bone marrow transplants. The emergence of non-ablative marrow transplants in CLL has led to the broadening of the range of opportunities to treat older patients. The addition of rituximab to the chemotherapy preparative regimens appears to be a significant advance. The combination of our increased understanding of the biology, immune status, and therapy of CLL provides for the first time the opportunity for curative strategies.