Liver failure after treatment with inotuzumab and polychemotherapy including PEG-asparaginase in a patient with relapsed Philadelphia chromosome-negative acute lymphoblastic leukemia.

We present the case of a 58-year-old female patient who presented with an extramedullary B-ALL relapse after prior allogenic HSCT and blinatumomab therapy. The patient died from complications of a drug-induced acute liver failure after a salvage therapy combining inotuzumab ozogamicin (InO)-based induction followed by consolidation with high dose MTX and pegaspargase based on the GMALL protocol for older ALL patients. After a diagnosis of the extramedullary relapse in the form of a retro vesical chloroma, the patient received an individualized multi-agent chemotherapy based on induction chemotherapy for older patients in combination with InO. After four administrations of InO, in combination with vincristine, dexamethasone, cytarabine, and cyclophosphamide, CT-imaging showed a reduction in volume of the chloroma and response to therapy. Consolidation with high-dose methotrexate and pegaspargase was administered. The patient developed toxic liver damage manifested by hyperbilirubinemia and progressive hepatic encephalopathy. The diagnostic criteria for VOD were met, and therapy with defibrotide was initiated. Liver biopsy revealed no histological signs of VOD but instead steatohepatitis indicative of drug-induced toxicity. The patient ultimately died of hemorrhagic shock through postinterventional hemorrhage after liver biopsy. In conclusion, although InO shows promising results in the therapy of r/r ALL with and without additional chemotherapy, the combination with MTX and pegaspargase in an intensively pretreated patient with relapse after HCST may impart an increased risk for liver-related toxicity. Special caution is required when assessing fitness for further liver toxic regimens. A key takeaway is also the reminder that InO can cause liver damage not only in the form of VOD but also through direct hepatocellular toxicity.

Cell-resistant wavelength-shifting molecular beacons made of L-DNA and a clickable L-configured uridine.

Wavelength-shifting molecular beacons were prepared from L-DNA. The clickable anchor for the two dyes, Cy3 and Cy5, was 2'-O-propargyl-L-uridine and was synthesized from L-ribose. Four clickable molecular beacons were prepared and double-modified with the azide dyes by a combination of click chemistry on a solid support for Cy3 during DNA synthesis and postsynthetic click chemistry for Cy5 in solution. Cy3 and Cy5 successfully formed a FRET pair in the beacons, and the closed form (red fluorescence) and the open form (green fluorescence) can be distinguished by the two-color fluorescence readout. Two molecular beacons were identified to show the greatest fluorescence contrast in temperature-dependent fluorescence measurements. The stability of the L-configured molecular beacons was demonstrated after several heating and cooling cycles as well as in the cell lysate. In comparison, D-configured molecular beacons showed a rapid decrease of fluorescence contrast in the cell lysate, which is caused by the opening of the beacons, probably due to degradation. This was confirmed in cell experiments using confocal microscopy. The L-configured molecular beacons are potential intracellular thermometers for future applications.

Enantio- and Diastereomerically Pure Titanocenes by Dynamic Conformational Locking.

The synthesis of enantiomerically pure titanocenes is limited to cases with enantiomerically pure substituents at the cyclopentadienyl ligands and to ansa-titanocenes. For the latter complexes, the use of achiral ligands requires a resolution of enantiomers and frequently also a separation of the diastereoisomers obtained after metalation. Here, we introduce a new synthetic method that relies on the use of enantiomerically pure camphorsulfonate (CSA) ligands as control elements for the absolute and relative configuration of titanocene complexes. Starting from the conformationally flexible (RC5 H4 )2 TiCl2 , the desired conformationally locked and hence enantio- and diastereomerically pure complexes (RC5 H4 )2 Ti(CSA)2 are obtained in just two steps. According to X-ray crystallography the (RC5 H4 )2 Ti fragment is essentially C2 -symmetric and nuclear magnetic resonance displays overall C2 -symmetry. We applied density functional theory methods to unravel the dynamics of the complexes and the mechanisms and selectivities of their formation.

Treatment with midostaurin and other FLT3 targeting inhibitors is associated with an increased risk of cardiovascular adverse events in patients who underwent allogeneic hematopoietic stem cell transplantation with FLT3-mutated AML.

The addition of midostaurin to standard chemotherapy has improved survival in patients with FLT3-mutated AML. However, the impact of midostaurin and other FLT3 inhibitors (FLT3i) on cardiovascular adverse events (CAEs) has not been studied in patients who underwent allogeneic hematopoietic stem cell transplantation in a real-world setting. We reviewed 132 patients with AML who were treated with intensive induction therapy and consecutive allogeneic stem cell transplantation at our institution (42 FLT3-mutated AML and 90 with FLT3 wildtype). We identified treatment with midostaurin and/or FLT3i as an independent risk factor for CAEs not resulting in higher non-relapse mortality (NRM) or impaired overall survival (OS). Hence, close monitoring for CAEs is warranted for these patients.

Aminophthalimide as a mimetic of purines and a fluorescent RNA base surrogate for RNA imaging.

Aminophthalimide and N,N-dimethylaminophthalimide are used as fluorescent mimetics of purines due to their similar size and their possibility for hydrogen bonding. Their C-nucleotides were synthetically incorporated into RNA by means of phosphoramidite chemistry, behave as nonspecific fluorescent base analogs with flexible hydrogen bonding capabilities, and show solvatochromic fluorescence that is suitable for RNA imaging in live cells.

Asciminib in Chronic Myeloid Leukemia after ABL Kinase Inhibitor Failure.

BACKGROUND: Asciminib is an allosteric inhibitor that binds a myristoyl site of the BCR-ABL1 protein, locking BCR-ABL1 into an inactive conformation through a mechanism distinct from those for all other ABL kinase inhibitors. Asciminib targets both native and mutated BCR-ABL1, including the gatekeeper T315I mutant. The safety and antileukemic activity of asciminib in patients with Philadelphia chromosome-positive leukemia are unknown. METHODS: In this phase 1, dose-escalation study, we enrolled 141 patients with chronic-phase and 9 with accelerated-phase chronic myeloid leukemia (CML) who had resistance to or unacceptable side effects from at least two previous ATP-competitive tyrosine kinase inhibitors (TKIs). The primary objective was to determine the maximum tolerated dose or the recommended dose (or both) of asciminib. Asciminib was administered once or twice daily (at doses of 10 to 200 mg). The median follow-up was 14 months. RESULTS: Patients were heavily pretreated; 70% (105 of 150 patients) had received at least three TKIs. The maximum tolerated dose of asciminib was not reached. Among patients with chronic-phase CML, 34 (92%) with a hematologic relapse had a complete hematologic response; 31 (54%) without a complete cytogenetic response at baseline had a complete cytogenetic response. A major molecular response was achieved or maintained by 12 months in 48% of patients who could be evaluated, including 8 of 14 (57%) deemed to have resistance to or unacceptable side effects from ponatinib. A major molecular response was achieved or maintained by 12 months in 5 patients (28%) with a T315I mutation at baseline. Clinical responses were durable; a major molecular response was maintained in 40 of 44 patients. Dose-limiting toxic effects included asymptomatic elevations in the lipase level and clinical pancreatitis. Common adverse events included fatigue, headache, arthralgia, hypertension, and thrombocytopenia. CONCLUSIONS: Asciminib was active in heavily pretreated patients with CML who had resistance to or unacceptable side effects from TKIs, including patients in whom ponatinib had failed and those with a T315I mutation. (Funded by Novartis Pharmaceuticals; ClinicalTrials.gov number, NCT02081378.).

Genomic CDKN2A/2B deletions in adult Ph+ ALL are adverse despite allogeneic stem cell transplantation.

We investigated the role of copy number alterations to refine risk stratification in adult Philadelphia chromosome positive (Ph)+ acute lymphoblastic leukemia (ALL) treated with tyrosine kinase inhibitors (TKIs) and allogeneic stem cell transplantation (aSCT). Ninety-seven Ph+ ALL patients (median age 41 years; range 18-64 years) within the prospective multicenter German Multicenter ALL Study Group studies 06/99 (n = 8) and 07/2003 (n = 89) were analyzed. All patients received TKI and aSCT in first complete remission (CR1). Copy number analysis was performed with single nucleotide polymorphism arrays and validated by multiplex ligation-dependent probe amplification. The frequencies of recurrently deleted genes were: IKZF1, 76%; CDKN2A/2B, 45%; PAX5, 43%; BTG1, 18%; EBF1, 13%; ETV6, 5%; RB, 14%. In univariate analyses, the presence of CDKN2A/2B deletions had a negative impact on all endpoints: overall survival (P = .023), disease-free survival (P = .012), and remission duration (P = .036). The negative predictive value of CDKN2A/2B deletions was retained in multivariable analysis along with other factors such as timing of TKI therapy, intensity of conditioning, achieving remission after induction phase 1 and BTG1 deletions. We therefore conclude that acquired genomic CDKN2A/2B deletions identify a subgroup of Ph+ ALL patients, who have an inferior prognosis despite aSCT in CR1. Their poor outcome was attributable primarily to a high relapse rate after aSCT.

Ponatinib in the Treatment of Chronic Myeloid Leukemia and Philadelphia Chromosome-Positive Acute Leukemia: Recommendations of a German Expert Consensus Panel with Focus on Cardiovascular Management.

Treatment of chronic myeloid leukemia (CML) and Philadelphia chromosome-positive acute leukemia (Ph+ ALL) has been revolutionized with the advent of tyrosine kinase inhibitors (TKIs). Most patients with CML achieve long-term survival similar to individuals without CML due to treatment with TKIs not only in frontline but also in further lines of therapy. The third-generation TKI ponatinib has demonstrated efficacy in patients with refractory CML and Ph+ ALL. Ponatinib is currently the most potent TKI in this setting demonstrating activity against T315I mutant clones. However, ponatinib's safety data revealed a dose-dependent, increased risk of serious cardiovascular (CV) events. Guidance is needed to evaluate the benefit-risk profile of TKIs, such as ponatinib, and safety measures to prevent treatment-associated CV events. An expert panel of German hematologists and cardiologists summarize current evidence regarding ponatinib's efficacy and CV safety profile. We propose CV management strategies for patients who are candidates for ponatinib.

A longitudinal approach to biological psychiatric research: The PsyCourse study.

In current diagnostic systems, schizophrenia and bipolar disorder are still conceptualized as distinct categorical entities. Recently, both clinical and genomic evidence have challenged this Kraepelinian dichotomy. There are only few longitudinal studies addressing potential overlaps between these conditions. Here, we present design and first results of the PsyCourse study (N = 891 individuals at baseline), an ongoing transdiagnostic study of the affective-to-psychotic continuum that combines longitudinal deep phenotyping and dimensional assessment of psychopathology with an extensive collection of biomaterial. To provide an initial characterization of the PsyCourse study sample, we compare two broad diagnostic groups defined by the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) classification system, that is, predominantly affective (n = 367 individuals) versus predominantly psychotic disorders (n = 524 individuals). Depressive, manic, and psychotic symptoms as well as global functioning over time were contrasted using linear mixed models. Furthermore, we explored the effects of polygenic risk scores for schizophrenia on diagnostic group membership and addressed their effects on nonparticipation in follow-up visits. While phenotypic results confirmed expected differences in current psychotic symptoms and global functioning, both manic and depressive symptoms did not vary between both groups after correction for multiple testing. Polygenic risk scores for schizophrenia significantly explained part of the variability of diagnostic group. The PsyCourse study presents a unique resource to research the complex relationships of psychopathology and biology in severe mental disorders not confined to traditional diagnostic boundaries and is open for collaborations.

Psychosis Is Mutable over Time: A Longitudinal Psychopathology Study.

BACKGROUND: A neurobiologically informed, system-specific psychopathological approach has been suggested for use in schizophrenia. However, to our knowledge, such an approach has not been used to prospectively describe the course of schizophrenia. SAMPLING AND METHODS: We assessed psychopathology in a well-described sample of 100 patients with schizophrenia or schizoaffective disorder with the Bern Psychopathology Scale (BPS) at 6-month intervals for up to 18 months. The BPS groups symptoms into the 3 domains language, affectivity and motor behaviour; each domain is rated as being normal, inhibited or disinhibited. In addition, we collected qualitative psychopathological data in the form of case reports. RESULTS: Forty-eight patients completed at least 2 assessments over the course of at least 1 year. Of these, 16 patients (33.3%) showed a bipolar course pattern (i.e., a switch from inhibited to disinhibited or vice versa) in 1 domain and 6 patients (12.5%) in more than 1 domain. Shifts from 1 dominant domain to another were seen frequently (n = 20, 41.7%), but shifts between 1 dominant domain and a combination of dominant domains were more common (n = 33, 68.8%). CONCLUSIONS: The course of schizophrenia is heterogeneous and shows frequent changes in psychopathology. This should be taken into account in the communication with patients and in the research on underlying illness mechanisms and treatment. A major limitation of this study is the small sample size.

Severe clinical events in 100 patients with schizophrenia: a retrospective clinical description using a system-specific psychopathological approach.

Catatonic states and numerous other severe clinical events can complicate the course of schizophrenia. Whether these severe courses are associated with particular system-specific symptom dimensions remain unclear. Aim is to assess the frequency of severe clinical events in a clinical population and to investigate the association of these events with sociodemographic data and system-specific psychopathology, combining qualitative and quantitative data. We performed a comprehensive retrospective description of a well-described and geographically stable sample of 100 patients with schizophrenia or schizoaffective disorder and linked severe clinical events with sociodemographic data at inclusion into the study (as indicators of social functioning) and symptoms at first admission, classified with the Bern Psychopathology Scale (BPS). We found 12 mentions of catatonic stupor or excitement, 45 of suicide attempts, 26 of suicidality, 18 of deliberate self-harm, 18 of self-threatening behaviour other than deliberate self-harm, 34 of violence against other persons, 18 of violence against objects and six of sexual harassment. Disinhibited language on first admission seemed to be a protective factor against suicidality and disinhibited motor behaviour seemed to predict self-threatening and violent behaviour. Catatonia and violence in particular seemed to be socially disabling. This exploratory study showed that the BPS is a promising instrument and might represent a system-specific approach in identifying patients at risk for severe sequelae of schizophrenia. This will have to be tested in future prospective studies.

[Are Depressed People Aggressive People? Differences Between General Population and Depressive Patients]. / Sind depressive Menschen aggressive Menschen? Unterschiede zwischen Allgemeinbevölkerung und depressiven Patienten.

IntroductionThe study aimed to investigate the relationship between depression and aggression. Material and Methods681 depressive and non-depressive subjects of the general population as well as 132 depressive patients completed the Beck Depression Inventory Revised (BDI-II) as well as the Short Questionnaire for Gathering Factors of Aggressiveness (K-FAF). ResultsDepressive patients and depressive subjects of the general population did not merely report the highest levels of self-aggressiveness but also reached the highest scores on the scales of reactive and proactive aggression, indicating a high level of externalizing aggressiveness. DiscussionThe results support the neurobiological approach of the etiology of depressive disorders. Conclusions For future research of depressive disorders and aggression the investigation of the mediating roles of a low serotonin-level is recommended.

Psychopathological Symptoms Assessed by a System-Specific Approach Are Related to Global Functioning in Schizophrenic Disorders.

BACKGROUND: By mostly using a positive-negative approach, several studies have identified factors that influence day-to-day functioning. We applied a different, system-specific approach to expand the knowledge of this issue. SAMPLING AND METHODS: We recruited a sample of 100 inpatients with a DSM-IV diagnosis of schizophrenia or schizoaffective disorder. Psychopathological characteristics were assessed with the Bern Psychopathology Scale (BPS) and functional characteristics with the Global Assessment of Functioning (GAF) scale. Linear regression analyses were performed with the GAF score as the dependent variable and the global values of the BPS subscores as independent variables. The model was controlled for confounding variables. Spearman rank correlation analyses were used to identify associations between the relevant BPS subdomains and global functioning. RESULTS: Higher absolute global values of the BPS domains language (px2009; = x2009;0.038) and motor behavior (px2009; = x2009;0.049) were significantly associated with lower GAF scores. These findings remained stable after adjusting for potential confounding variables. A statistically significant negative correlation was found between both qualitative symptoms (rx2009; = x2009;-0.273, px2009; = x2009;0.006) and indirect signs (rx2009; = x2009;-0.269, px2009; = x2009;0.007) of the language domain and GAF scores. Also, quantitative (rx2009; = x2009;-0.211, px2009; = x2009;0.035) and qualitative symptoms (rx2009; = x2009;-0.214, px2009; = x2009;0.033) in the motor behavior domain were associated with poorer functioning. CONCLUSIONS: A system-specific approach can describe subgroups of patients with poor functioning. Identifying such subgroups could help to utilize targeted treatment opinions in a timely manner. Another goal of future research is to clarify the underlying neurobiological deficits.

Psychopathological Course Typology in Schizophrenia Spectrum Disorders: A Heuristic Approach in a Sample of 100 Patients.

BACKGROUND: Despite several previous attempts at subtyping schizophrenia, a typology that reflects neurobiological knowledge and reliably predicts course and outcome is lacking. We applied the system-specific concept of the Bern Psychopathology Scale (BPS) to generate a course typology based on three domains: language, affectivity, and motor behaviour. SAMPLING AND METHODS: A cohort of 100 patients with schizophrenia or schizoaffective disorders according to DSM-IV criteria underwent psychopathological assessment, and all their available medical records were retrospectively analysed on the basis of the BPS. RESULTS: Overall, 39% of the patients showed dominant abnormalities in only one domain, 37% in two domains, and 24% in all three domains. The motor domain was affected in the majority of patients (76%), followed by affectivity (63%) and language (46%). Eighty-six percent of patients showed a bipolar course pattern in at least one domain. CONCLUSIONS: In a retrospective analysis of 100 patient records we described system-specific course patterns of schizophrenia by using a neurobiologically informed psychopathological assessment. The results showed a surprisingly high proportion of bipolar courses and a pattern of pure and mixed subtypes, which speaks for an overlap of domains with regards to psychopathological symptoms. A limitation of this heuristic and retrospective approach is that it was largely based on clinical judgement. Prospective studies with more rigorous threshold definitions are needed to clarify the neurobiological and clinical implications of the proposed reorganization of psychotic disorders.

A Multicentre, Randomized Trial in Adults with de novo Philadelphia Chromosome-Positive Acute Lymphoblastic Leukaemia to Assess the Efficacy of Ponatinib versus Imatinib in Combination with Low-Intensity Chemotherapy, to Compare End of Therapy with Indication for Stem Cell Transplantation versus Tyrosine Kinase Inhibitor, Blinatumomab, and Chemotherapy in Optimal Responders, and to Evaluate Blinatumomab in Suboptimal Responders (GMALL-EVOLVE).

INTRODUCTION: Philadelphia chromosome-positive acute lymphoblastic leukaemia (Ph+ALL) is treated as standard of care (SoC) by imatinib-based treatment combined with induction and consolidation chemotherapy followed by allogeneic stem cell transplantation (SCT) in first remission. The German Multicenter ALL Study Group for Adult ALL (GMALL) reports about a trial to evaluate the impact of ponatinib-based therapy, blinatumomab treatment for suboptimal responders, and the possibility of omission of SoC Allo SCT in optimal responders entitled GMALL-EVOLVE. METHODS: Herein, imatinib is randomized versus ponatinib as frontline treatment combined with chemotherapy, optimal responders also get randomized between SCT and chemo-immunotherapy, and suboptimal responders receive immunotherapy before SCT. The trial is registered under the EudraCT number 2022-000760-21. CONCLUSION: This trial will answer several major questions in the treatment of Ph+ALL.

Asciminib monotherapy in patients with chronic-phase chronic myeloid leukemia with the T315I mutation after ≥1 prior tyrosine kinase inhibitor: 2-year follow-up results.

Asciminib targets the BCR::ABL1 myristoyl pocket, maintaining activity against BCR::ABL1T315I, which is resistant to most approved adenosine triphosphate-competitive tyrosine kinase inhibitors. We report updated phase I results (NCT02081378) assessing safety/tolerability and antileukemic activity of asciminib monotherapy 200 mg twice daily in 48 heavily pretreated patients with T315I-mutated chronic-phase chronic myeloid leukemia (CML-CP; data cutoff: January 6, 2021). With 2 years' median exposure, 56.3% of patients continued receiving asciminib. Overall, 62.2% of evaluable patients achieved BCR::ABL1 ≤1% on the International Scale (IS); 47.6% and 81.3% of ponatinib-pretreated and -naive patients, respectively, achieved BCR::ABL1IS ≤1%. Of 45 evaluable patients, 48.9% achieved a major molecular response (MMR, BCR::ABL1IS ≤0.1%), including 34.6% and 68.4% of ponatinib-pretreated and -naive patients, respectively. MMR was maintained until data cutoff in 19 of 22 patients who achieved it. The most common grade ≥3 adverse events (AEs) included increased lipase level (18.8%) and thrombocytopenia (14.6%). Five (10.4%) patients experienced AEs leading to discontinuation, including 2 who discontinued asciminib and died due to COVID-19; these were the only deaths reported. These results show asciminib's effectiveness, including in almost 50% of ponatinib pretreated patients, and confirm its risk-benefit profile, supporting its use as a treatment option for T315I-mutated CML-CP.

T-bet+ B cells are activated by and control endogenous retroviruses through TLR-dependent mechanisms.

Endogenous retroviruses (ERVs) are an integral part of the mammalian genome. The role of immune control of ERVs in general is poorly defined as is their function as anti-cancer immune targets or drivers of autoimmune disease. Here, we generate mouse-strains where Moloney-Murine Leukemia Virus tagged with GFP (ERV-GFP) infected the mouse germline. This enables us to analyze the role of genetic, epigenetic and cell intrinsic restriction factors in ERV activation and control. We identify an autoreactive B cell response against the neo-self/ERV antigen GFP as a key mechanism of ERV control. Hallmarks of this response are spontaneous ERV-GFP+ germinal center formation, elevated serum IFN-γ levels and a dependency on Age-associated B cells (ABCs) a subclass of T-bet+ memory B cells. Impairment of IgM B cell receptor-signal in nucleic-acid sensing TLR-deficient mice contributes to defective ERV control. Although ERVs are a part of the genome they break immune tolerance, induce immune surveillance against ERV-derived self-antigens and shape the host immune response.

Remission induction versus immediate allogeneic haematopoietic stem cell transplantation for patients with relapsed or poor responsive acute myeloid leukaemia (ASAP): a randomised, open-label, phase 3, non-inferiority trial.

BACKGROUND: Whether high-dose cytarabine-based salvage chemotherapy, administered to induce complete remission in patients with poor responsive or relapsed acute myeloid leukaemia scheduled for allogeneic haematopoietic stem-cell transplantation (HSCT) after intensive conditioning confers a survival advantage, is unclear. METHODS: To test salvage chemotherapy before allogeneic HSCT, patients aged between 18 and 75 years with non-favourable-risk acute myeloid leukaemia not in complete remission after first induction or untreated first relapse were randomly assigned 1:1 to remission induction with high-dose cytarabine (3 g/m2 intravenously, 1 g/m2 intravenously for patients >60 years or with a substantial comorbidity) twice daily on days 1-3 plus mitoxantrone (10 mg/m2 intravenously) on days 3-5 or immediate allogeneic HSCT for the disease control group. Block randomisation with variable block lengths was used and patients were stratified by age, acute myeloid leukaemia risk, and disease status. The study was open label. The primary endpoint was treatment success, defined as complete remission on day 56 after allogeneic HSCT, with the aim to show non-inferiority for disease control compared with remission induction with a non-inferiority-margin of 5% and one-sided type 1 error of 2·5%. The primary endpoint was analysed in both the intention-to-treat (ITT) population and in the per-protocol population. The trial is completed and was registered at ClinicalTrials.gov, NCT02461537. FINDINGS: 281 patients were enrolled between Sept 17, 2015, and Jan 12, 2022. Of 140 patients randomly assigned to disease control, 135 (96%) proceeded to allogeneic HSCT, 97 (69%) after watchful waiting only. Of 141 patients randomly assigned to remission induction, 134 (95%) received salvage chemotherapy and 128 (91%) patients subsequently proceeded to allogeneic HSCT. In the ITT population, treatment success was observed in 116 (83%) of 140 patients in the disease control group versus 112 (79%) of 141 patients with remission induction (test for non-inferiority, p=0·036). Among per-protocol treated patients, treatment success was observed in 116 (84%) of 138 patients with disease control versus 109 (81%) of 134 patients in the remission induction group (test for non-inferiority, p=0·047). The difference in treatment success between disease control and remission induction was estimated as 3·4% (95% CI -5·8 to 12·6) for the ITT population and 2·7% (-6·3 to 11·8) for the per-protocol population. Fewer patients with disease control compared with remission induction had non-haematological adverse events grade 3 or worse (30 [21%] of 140 patients vs 86 [61%] of 141 patients, χ2 test p<0·0001). Between randomisation and the start of conditioning, with disease control two patients died from progressive acute myeloid leukaemia and zero from treatment-related complications, and with remission induction two patients died from progressive acute myeloid leukaemia and two from treatment-related complications. Between randomisation and allogeneic HSCT, patients with disease control spent a median of 27 days less in hospital than those with remission induction, ie, the median time in hospital was 15 days (range 7-64) versus 42 days (27-121, U test p<0·0001), respectively. INTERPRETATION: Non-inferiority of disease control could not be shown at the 2·5% significance level. The rate of treatment success was also not statistically better for patients with remission induction. Watchful waiting and immediate transplantation could be an alternative for fit patients with poor response or relapsed acute myeloid leukaemia who have a stem cell donor available. More randomised controlled intention-to-transplant trials are needed to define the optimal treatment before transplantation for patients with active acute myeloid leukaemia. FUNDING: DKMS and the Gert and Susanna Mayer Stiftung Foundation.

Association of early life stress and cognitive performance in patients with schizophrenia and healthy controls.

As core symptoms of schizophrenia, cognitive deficits contribute substantially to poor outcomes. Early life stress (ELS) can negatively affect cognition in patients with schizophrenia and healthy controls, but the exact nature of the mediating factors is unclear. Therefore, we investigated how ELS, education, and symptom burden are related to cognitive performance. The sample comprised 215 patients with schizophrenia (age, 42.9 ± 12.0 years; 66.0 % male) and 197 healthy controls (age, 38.5 ± 16.4 years; 39.3 % male) from the PsyCourse Study. ELS was assessed with the Childhood Trauma Screener (CTS). We used analyses of covariance and correlation analyses to investigate the association of total ELS load and ELS subtypes with cognitive performance. ELS was reported by 52.1 % of patients and 24.9 % of controls. Independent of ELS, cognitive performance on neuropsychological tests was lower in patients than controls (p < 0.001). ELS load was more closely associated with neurocognitive deficits (cognitive composite score) in controls (r = -0.305, p < 0.001) than in patients (r = -0.163, p = 0.033). Moreover, the higher the ELS load, the more cognitive deficits were found in controls (r = -0.200, p = 0.006), while in patients, this correlation was not significant after adjusting for PANSS. ELS load was more strongly associated with cognitive deficits in healthy controls than in patients. In patients, disease-related positive and negative symptoms may mask the effects of ELS-related cognitive deficits. ELS subtypes were associated with impairments in various cognitive domains. Cognitive deficits appear to be mediated through higher symptom burden and lower educational level.

Treatment of adult ALL patients with third-generation CD19-directed CAR T cells: results of a pivotal trial.

BACKGROUND: Third-generation chimeric antigen receptor (CAR)-engineered T cells (CARTs) might improve clinical outcome of patients with B cell malignancies. This is the first report on a third-generation CART dose-escalating, phase-1/2 investigator-initiated trial treating adult patients with refractory and/or relapsed (r/r) acute lymphoblastic leukemia (ALL). METHODS: Thirteen patients were treated with escalating doses of CD19-directed CARTs between 1 × 106 and 50 × 106 CARTs/m2. Leukapheresis, manufacturing and administration of CARTs were performed in-house. RESULTS: For all patients, CART manufacturing was feasible. None of the patients developed any grade of Immune effector cell-associated neurotoxicity syndrome (ICANS) or a higher-grade (≥ grade III) catokine release syndrome (CRS). CART expansion and long-term CART persistence were evident in the peripheral blood (PB) of evaluable patients. At end of study on day 90 after CARTs, ten patients were evaluable for response: Eight patients (80%) achieved a complete remission (CR), including five patients (50%) with minimal residual disease (MRD)-negative CR. Response and outcome were associated with the administered CART dose. At 1-year follow-up, median overall survival was not reached and progression-free survival (PFS) was 38%. Median PFS was reached on day 120. Lack of CD39-expression on memory-like T cells was more frequent in CART products of responders when compared to CART products of non-responders. After CART administration, higher CD8 + and γδ-T cell frequencies, a physiological pattern of immune cells and lower monocyte counts in the PB were associated with response. CONCLUSION: In conclusion, third-generation CARTs were associated with promising clinical efficacy and remarkably low procedure-specific toxicity, thereby opening new therapeutic perspectives for patients with r/r ALL. Trial registration This trial was registered at www. CLINICALTRIALS: gov as NCT03676504.